To evaluate the potential placebo effect, we made further subgrouping analyses. In the subgroups of studies using placebo controls, the omega-3 PUFAs still revealed a consistent positive anxiolytic association with anxiety symptoms. These phenomena meant that the anxiolytic effect of omega-3 PUFAs is probably not entirely owing to the placebo effect.
Participants treated with a daily dose of 2000 mg or more of omega-3 PUFAs showed a significantly greater association of treatment with reduced anxiety symptoms. In addition, participants receiving supplements containing less than 60% EPA showed a significant association, but not those receiving supplements containing 60% or more EPA. The depression literature supports the clinical benefits of EPA-enriched formulations (≥60% or ≥50%) compared with placebo for the treatment of clinical depression.9,13,73-75 This opposite effect of EPA-enriched formations on anxiety and depression is intriguing and possibly linked to a distinct underlying mechanism of omega-3 PUFAs. Exploration of the effects of omega-3 PUFAs on anxiety symptoms is just beginning and studies assessing the dose response anxiolytic effects of omega-3 PUFAs have not yet been performed. Further phase 2 trials of anxiety symptoms among participants with neuropsychiatric illness or physical illness should aim to determine the optimal dose.

Despite this one study, you should still consider eating fish and other seafood as a healthy strategy. If we could absolutely, positively say that the benefits of eating seafood comes entirely from omega-3 fats, then downing fish oil pills would be an alternative to eating fish. But it’s more than likely that you need the entire orchestra of fish fats, vitamins, minerals, and supporting molecules, rather than the lone notes of EPA and DHA.
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)

Not surprising, there are some areas in which both EPA and DHA appear to be equally beneficial. As an example, both are equally effective in reducing triglyceride levels (10). This is probably due to the relatively equivalent activation of the gene transcription factor (PPAR alpha) that causes the enhanced synthesis of the enzymes that oxidize fats in lipoprotein particles. There is also apparently equal activation of the anti-inflammatory gene transcription factor PPAR-gamma (11). Both seem to be equally effective in making powerful anti-inflammatory eicosanoids known as resolvins (12). Finally, although both have no effect on total cholesterol levels, DHA can increase the size of LDL particle to a greater extent than can EPA (10).
The omega-3 PUFA EPA and DHA are important throughout life and are a dietary necessity found predominantly in fish and fish-oil supplements. The omega-3 fatty acids EPA and DHA are essential for proper fetal development, and supplementation during pregnancy has also been linked to decreased immune responses in infants including decreased incidence of allergies in infants. Omega-3 fatty acid consumption has been associated with improved cardiovascular function in terms of antiinflammatory properties, PAD, reduced major coronary events, and improved antiplatelet effects in the face of aspirin resistance or clopidogrel hyporesponsiveness. Patients with AD have been shown to be deficient in DHA, and supplementing them with EPA+DHA not only reverses this deficiency, but may also improve cognitive functioning in patients with very mild AD. With increasing rates of pediatric allergies, cardiovascular disease, and AD in the United States, EPA and DHA may be a safe and inexpensive link to a healthier life. Further research should be conducted in humans to assess a variety of clinical outcomes including quality of life and mental status. In addition, because potent lipid mediator metabolites of EPA and DHA are of great interest currently, their influence on these important outcomes should be assessed because current evidence suggests that their antiinflammatory and tissue-protective effects are nearly 1000 times greater than those of EPA and DHA (7).
A 2008 meta-study by the Canadian Medical Association Journal found fish oil supplementation did not demonstrate any preventative benefit to cardiac patients with ventricular arrhythmias.[36] A 2012 meta-analysis published in the Journal of the American Medical Association, covering 20 studies and 68,680 patients, found that Omega-3 Fatty Acid supplementation did not reduce the chance of death, cardiac death, heart attack or stroke.[37]
The way that fish oil does that is to interfere with carbohydrate metabolism, and in insulin-resistant people or in people with specific genetic differences that might predispose them to having very high triglycerides, you do benefit from interfering that pathway with the fish oil, but I would actually try a low-carbohydrate diet in a lot of those situations to see if that helps with lowering triglycerides, or in the case of insulin resistance, I would try to address the insulin resistance at its root cause.
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.
Three omega−3 fatty acids are important in human physiology, α-linolenic acid (18:3, n-3; ALA), eicosapentaenoic acid (20:5, n-3; EPA), and docosahexaenoic acid (22:6, n-3; DHA).[67] These three polyunsaturates have either 3, 5, or 6 double bonds in a carbon chain of 18, 20, or 22 carbon atoms, respectively. As with most naturally-produced fatty acids, all double bonds are in the cis-configuration, in other words, the two hydrogen atoms are on the same side of the double bond; and the double bonds are interrupted by methylene bridges (-CH

The effect of fish oil on incident atrial fibrillation has not been studied in large randomized trials, and observational population-based trials show mixed results. The Danish Diet, Cancer and Health Study, and the Rotterdam Study followed 47,000 and 5100 middle-aged adults, respectively.45,46 Neither study found that the consumption of fish oil affected the incidence of atrial fibrillation. Similar findings were seen in the Women’s Health Initiative where there was no association between fish and omega-3 FA intake regarding incident atrial fibrillation.47 However, in a 12-year prospective, observational study of 4815 adults over the age of 65, daily fish consumption was associated with a 31% risk reduction in incident atrial fibrillation.48
Omega-3 [(n-3)] long-chain PUFA, including EPA and DHA, are dietary fats with an array of health benefits (1). They are incorporated in many parts of the body including cell membranes (2) and play a role in antiinflammatory processes and in the viscosity of cell membranes (3, 4). EPA and DHA are essential for proper fetal development and healthy aging (5). DHA is a key component of all cell membranes and is found in abundance in the brain and retina (6). EPA and DHA are also the precursors of several metabolites that are potent lipid mediators, considered by many investigators to be beneficial in the prevention or treatment of several diseases (7).
The competition between EPA and DHA during digestion and absorption and the fact that DHA appears to ‘block’ the therapeutic actions of EPA can therefore be an issue if we are looking to optimise the benefits associated with EPA (Martins 2009; Bloch & Qawasmi et al, 2011; Sublette et al, 2011). High dose, high concentration and high ratio EPA supplements increase the effectiveness in depression studies, and pure EPA-only is optimal. Depression is also a condition with an inflammatory basis, so this is likely another significant reason for EPA being the key player – its antagonistic relationship with the inflammatory omega-3 AA (arachidonic acid) is very effective at reducing inflammation.

A 2014 meta-analysis of eleven trials conducted respectively on patients with a DSM-defined diagnosis of major depressive disorder (MDD) and of eight trials with patients with depressive symptomatology but no diagnosis of MDD demonstrated significant clinical benefit of omega-3 PUFA treatment compared to placebo. The study concluded that: "The use of omega-3 PUFA is effective in patients with diagnosis of MDD and on depressive patients without diagnosis of MDD."[42]
Additional side effects of fish oil supplements which have been reported include headache, short-term memory loss, depression, somatic disorders, and increased risk of colon cancer, nasopharyngitis, worsening of asthma symptoms, hemolytic anemia, decreased physical activity, increased appetite, a general uncomfortable feeling or increased blood pressure. The percentage of users that develop these side effects is not known. If these side effects become severe it is recommended that you stop using fish oil supplements.
Scaly, itchy skin (eczema). Fish oil might help PREVENT eczema, but research is not consistent. Some early research suggests that mothers who take fish oil supplements during pregnancy reduce the risk of severe eczema in their infants. Also, population research suggests that children who eat fish at least once weekly from 1 to 2 years of age have a lower risk of developing eczema. But other research, including recent studies, suggests that neither supplementation during pregnancy nor supplementation during infancy reduces the risk of eczema. Overall, research suggests that fish oil does not help TREAT eczema once it has developed.
Fish or seafood allergy: Some people who are allergic to seafood such as fish might also be allergic to fish oil supplements. There is no reliable information showing how likely people with seafood allergy are to have an allergic reaction to fish oil. Until more is known, advise patients allergic to seafood to avoid or use fish oil supplements cautiously.
Most Americans take in far more of another essential fat—omega-6 fats—than they do omega-3 fats. Some experts have raised the hypothesis that this higher intake of omega-6 fats could pose problems, cardiovascular and otherwise, but this has not been supported by evidence in humans. (4) In the Health Professionals Follow-up Study, for example, the ratio of omega-6 to omega-3 fats wasn’t linked with risk of heart disease because both of these were beneficial. (5) Many other studies and trials in humans also support cardiovascular benefits of omega-6 fats. Although there is no question that many Americans could benefit from increasing their intake of omega-3 fats, there is evidence that omega-6 fats also positively influence cardiovascular risk factors and reduce heart disease.

As mentioned above, the omega-3 index has been suggested as a predictor of the risk of coronary heart disease and other cardiovascular events. One study on a population in Seattle found that people with low omega-3 index levels were 10 times as likely to die from sudden cardiac death compared to people with higher omega-3 index levels (13). The NIH-funded Framingham study referenced above showed that the people with the highest omega-3 index levels had a 33% reduction in risk of death from any cause compared to the people with the lowest levels (2). In addition, a new study focused on individuals age 25 to 41 found that higher omega-3 index levels were associated with lower blood pressure in healthy adults (14).


Heterogeneity was examined using the Q statistic and the corresponding P values,41 and the I2 statistic was used to evaluate the proportion of variation resulting from among-study differences. Any possible publication bias was detected with both funnel plots and Egger regression in the main part of the meta-analysis.42 By using Duval and Tweedie’s trim-and-fill test, we adjusted the effect sizes for potential publication bias if there was evidence of publication bias detected by this test in the Comprehensive Meta-analysis statistical software, version 3.43 To investigate the potential confounding effects of any outliers within the recruited studies, sensitivity testing was conducted with the 1-study removal method to detect the potential outliers.44
The American Heart Association (AHA) recommends that everyone eats fish (particularly fatty, coldwater fish) at least twice a week. Salmon, mackerel, herring, sardines, lake trout, and tuna are especially high in omega-3 fatty acids. While foods are your best bet for getting omega-3s in your diet, fish oil supplements are also available for those who do not like fish. The heart-healthy benefits of regular doses of fish oil supplements are unclear, so talk to your doctor to see if they're right for you. If you have heart disease or high triglyceride levels, you may need even more omega-3 fatty acids. Ask your doctor if you should take higher doses of fish oil supplements to get the omega-3s you need.
Studies have also shown that omega-3 fats are anti-arrhythmic (preventing or counteracting cardiac arrhythmia), anti-thrombotic (prevents thrombosis or a blood clot within a blood vessel), anti-atherosclerotic (preventing fatty deposits and fibrosis of the inner layer of your arteries), and anti-inflammatory (counteracting inflammation – the heat, pain, swelling, etc).
Special attention should also be given to the fact that most women have major deficiencies of omega-3. A 1991 study at the Mayo Clinic focused on 19 "normal" pregnant women consuming "normal diets," and it showed that all were deficient in omega-3 fats. Another study compared Inuit (Eskimo) women to Canadian women, and it revealed omega-3 deficiency in the milk of the Canadian nursing moms.
In addition to depression, chronic stress leads to loss of volume of the hippocampus—and also causes enlargement of the amygdala, the portion of the brain that regulates anxiety and anger.24 When rats were supplemented with omega-3s during exposure to stress, they showed lower corticosterone levels (a marker of stress), and improved learning on a maze—indicating that the omega-3s helped preserve memory and reduce anxiety.24
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.
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