So why is an excess of DHA detrimental and an excess of EPA useful? DHA has a larger structure with two extra carbons and two extra double bonds, so it literally takes up more space in cell membranes than EPA. On the one hand, this is important because DHA plays a structural role in maintaining the fluidity of cell membranes ( essential for the normal function of proteins, channels and receptors that are also embedded in the membrane), but if a cell membrane becomes too saturated with DHA it can become too fluid, which can have a negative effect on cell function. EPA, on the other hand, is constantly utilised and always in demand.

When taking fish oil, more is not always better. Remember that you want it to stay in a balanced ratio with omega-6 fats. For most people, I recommend a 1,000-milligram dose of fish oil daily as a good amount and the most scientifically studied dosage. I highly recommend not taking more than that unless directed to under the supervision of a doctor.
Depression. There is inconsistent evidence on the effect of taking fish oil for depression. Some research shows that taking fish oil along with an antidepressant might help improve symptoms in some people. Other research shows that taking fish oil does not improve depression symptoms. The conflicting results may be due to the amount of EPA and DHA in the supplement or the severity of depression before treatment.
The GISSI-Heart Failure trial was the first blinded, randomized trial to assess the efficacy of fish oil supplements in patients with heart failure.51 The trial enrolled 7046 subjects with heart failure; 60% with New York Heart Association class II symptoms and 40% with a history of MI. The majority of patients were on a standard heart failure regimen, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, and spironolactone, but only 22% were on a statin. At an average of 3.9 years, the coprimary end points of death and death or hospital admission for cardiovascular reasons were reduced by approximately 9% with fish oil supplementation. Sudden cardiac death, a secondary end-point, showed a statistically nonsignificant relative risk reduction of 7% with fish oil. There was also a reduction in 2 other arrhythmia-related secondary end-points: first hospitalization for ventricular arrhythmia and presumed arrhythmic death.
"Fish is still the mainstay of the diet in many parts of the world where there is very little heart disease," he says. "I think when you replace higher fat foods and highly processed foods with fish there is going to be some benefit.'' So it may be that by substituting fish for red meats, bacon and luncheon meats, and similar high-fat foods, you are making a change that will lead to improving your health outcomes, he says.
This article had several limitations and the findings need to be considered with caution. First, our participant population is too heterogeneous because of our broad inclusion criteria, which might be true if considering current Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases diagnostic systems. However, the novel Research Domain Criteria consider anxiety to be one of the major domains in Negative Valence Systems. Trials should be conducted in populations in which anxiety is the main symptom irrespective of the presence or absence of diagnosis of anxiety disorder. Second, because of the limited number of recruited studies and their modest sample sizes, the results should not be extrapolated without careful consideration. Third, the significant heterogeneity among the included studies (Cochran Q, 178.820; df, 18; I2, 89.934%; P < .001) with potential influence by some outlier studies, such as the studies by Sohrabi et al56 and Yehuda et al,61 would be another major concern. Therefore, clinicians should pay attention to this aspect when applying the results of the current meta-analysis to clinical practice, particularly when considering the subgroups of these 2 studies (ie, subgroups with specific clinical diagnoses, with <2000 mg/d, with EPA <60%, and with placebo-controlled trials).
EPA, which is eicosapentaenoic acid, and DHA, which is docosahexaenoic acid, are two types of omega-3 fatty acids that are most commonly found in seafood. These polyunsaturated fats are known to have preventative health benefits and have been studied for their role in treating certain chronic conditions. In addition to dietary sources, certain supplements such as fish oil, are also rich in EPA and DHA.
Matsumura  K, Noguchi  H, Nishi  D, Hamazaki  K, Hamazaki  T, Matsuoka  YJ.  Effects of omega-3 polyunsaturated fatty acids on psychophysiological symptoms of post-traumatic stress disorder in accident survivors: a randomized, double-blind, placebo-controlled trial.  J Affect Disord. 2017;224:27-31. doi:10.1016/j.jad.2016.05.054PubMedGoogle ScholarCrossref
Added inactive ingredients also contribute to product safety. Eight supplements in this study contained ‘natural’ flavors such as citrus-derived additives. One product, Coromega Omega-3, also contained benzoic acid, a popular antibacterial agent linked to carcinogenic risks when combined with vitamin C. Other controversial excipients included the artificial coloring agents FD&C Blue 1 and FD&C Red 40 as well as the whitening agent titanium dioxide.
Human diet has changed rapidly in recent centuries resulting in a reported increased diet of omega−6 in comparison to omega−3.[83] The rapid evolution of human diet away from a 1:1 omega−3 and omega−6 ratio, such as during the Neolithic Agricultural Revolution, has presumably been too fast for humans to have adapted to biological profiles adept at balancing omega−3 and omega−6 ratios of 1:1.[84] This is commonly believed to be the reason why modern diets are correlated with many inflammatory disorders.[83] While omega−3 polyunsaturated fatty acids may be beneficial in preventing heart disease in humans, the level of omega−6 polyunsaturated fatty acids (and, therefore, the ratio) does not matter.[78][85]
Evidence linking fish oil and cancer has been all over the map. Some research suggests diets high in fatty fish or fish oil supplements might reduce the risk of certain cancers, including prostate cancer. Other research shows just the opposite, a  link between eating a lot of oily fish or taking potent fish oil supplements and a 43% increased risk for prostate cancer overall, and a 71% increased risk for aggressive prostate cancer.
So why is an excess of DHA detrimental and an excess of EPA useful? DHA has a larger structure with two extra carbons and two extra double bonds, so it literally takes up more space in cell membranes than EPA. On the one hand, this is important because DHA plays a structural role in maintaining the fluidity of cell membranes ( essential for the normal function of proteins, channels and receptors that are also embedded in the membrane), but if a cell membrane becomes too saturated with DHA it can become too fluid, which can have a negative effect on cell function. EPA, on the other hand, is constantly utilised and always in demand.
Dry eye disease occurs when tears don’t provide enough moisture, causing eye discomfort and vision problems. Some studies show that getting more omega-3s from foods or supplements—mainly EPA and DHA—helps relieve symptoms of dry eye disease. But a large, recent study found that the symptoms of people with dry eye disease who took fish oil supplements of 2,000 mg EPA plus 1,000 mg DHA daily for 1 year did not improve any more than those who took a placebo (a dummy pill). More research on the effects of omega-3s on dry eye disease is needed.
Rogers, P. J., Appleton, K. M., Kessler, D., Peters, T. J., Gunnell, D., Hayward, R. C., Heatherley, S. V., Christian, L. M., McNaughton, S. A., and Ness, A. R. No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial. Br J Nutr 2008;99(2):421-431. View abstract.
Since EPA and DHA are both essential for health and appear together in nature, many studies have attempted to treat clinical conditions with combined EPA and DHA oils, but the outcomes have been varied, contradictory and disappointing. Consequently, researchers have started to investigate the individual actions of EPA and DHA in isolation, in numerous health conditions where an omega-3 deficiency is related to symptoms or known to play a causative role. The emerging evidence shows marked differences between how these two fatty acids affect us – not just at the cellular level but also the body as a whole.
In comparison, the omega-3s found in krill appear to be more rapidly incorporated into red blood cell phospholipids.7 This is important, because not only do scientists view the uptake of essential fatty acids in red blood cells as a biomarker for uptake into the brain,8 but additional research suggests that when omega-3 fatty acids such as DHA are bound to phospholipids as they are with krill, it increases their uptake to the brain.9 This is further supported by human clinical research, which suggests ingestion of phospholipid-bound EPA and DHA increase cognitive function scores to a greater degree compared with scores obtained when the fatty acids in the ingested oil were provided in the triglycerides storage form.10
In short, there is no single optimal EPA:DHA ratio. If we are really healthy, with an optimal omega-6 to omega-3 ratio (from a diet rich in omega-3 fatty acids and low in grains and vegetable oils) and have an active, stress-free lifestyle, relying on standard fish oil in the natural 1.5:1 EPA:DHA ratio or simply consuming oily fish is completely adequate.

The ultimate goal of using omega-3 fatty acids is the reduction of cellular inflammation. Since eicosanoids derived from arachidonic acid (AA), an omega-6 fatty acid, are the primary mediators of cellular inflammation, EPA becomes the most important of the omega-3 fatty acids to reduce cellular inflammation for a number of reasons. First, EPA is an inhibitor of the enzyme delta-5-desaturase (D5D) that produces AA (1). The more EPA you have in the diet, the less AA you produce. This essentially chokes off the supply of AA necessary for the production of pro-inflammatory eicosanoids (prostaglandins, thromboxanes, leukotrienes, etc.). DHA is not an inhibitor of this enzyme because it can’t fit into the active catalytic site of the enzyme due to its larger spatial size. As an additional insurance policy, EPA also competes with AA for the enzyme phospholipase A2 necessary to release AA from the membrane phospholipids (where it is stored). Inhibition of this enzyme is the mechanism of action used by corticosteroids. If you have adequate levels of EPA to compete with AA (i.e. a low AA/EPA ratio), you can realize many of the benefits of corticosteroids but without their side effects. That’s because if you don’t release AA from the cell membrane then you can’t make inflammatory eicosanoids. Because of its increased spatial dimensions, DHA is not a good competitor of phospholipase A2 relative to EPA. On the other hand, EPA and AA are very similar spatially so they are in constant competition for the phospholipase A2 enzyme just as both fatty acids are in constant competition for the delta-5 desaturase enzyme. This is why measuring the AA/EPA ratio is such a powerful predictor of the state of cellular inflammation in your body.
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.
CHAMPAIGN, Ill. — Chemical compounds called cannabinoids are found in marijuana and also are produced naturally in the body from omega-3 fatty acids. A well-known cannabinoid in marijuana, tetrahydrocannabinol, is responsible for some of its euphoric effects, but it also has anti-inflammatory benefits. A new study in animal tissue reveals the cascade of chemical reactions that convert omega-3 fatty acids into cannabinoids that have anti-inflammatory benefits – but without the psychotropic high.

Dry eye disease occurs when tears don’t provide enough moisture, causing eye discomfort and vision problems. Some studies show that getting more omega-3s from foods or supplements—mainly EPA and DHA—helps relieve symptoms of dry eye disease. But a large, recent study found that the symptoms of people with dry eye disease who took fish oil supplements of 2,000 mg EPA plus 1,000 mg DHA daily for 1 year did not improve any more than those who took a placebo (a dummy pill). More research on the effects of omega-3s on dry eye disease is needed.

“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.
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.
LCn3s are long chain fatty acids from fish, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA is plant-based omega 3-alpha‐linolenic acid. Fatty acids are essentially chains of carbon atoms with an OOH group at one end. The available binding sites on the carbon atoms are filled with hydrogen atoms. If every binding site is occupied with a hydrogen, that is a saturated fatty acid. If instead of hydrogen atoms there is a double bond between two adjacent carbon atoms, that is an unsaturated fatty acid. If there are multiple double bonds, that is polyunsaturated. Omega 3 fatty acids are unsaturated, with a double bond between the third and fourth carbon atoms from the end opposite the OOH group.

The short answer is no. There are many websites which advise people to stop eating vegetable oils and switch to fish oil in order to increase their intake of omega-3 fatty acids. Fish oil is a good source of omega-3 essential fatty acids and should be consumed, but that doesn’t necessarily mean that one should completely replace vegetable oils with fish oil.
Children require DHA for growth and development, and the brain, CNS and retina rely heavily on the adequate supply of DHA during growth in the womb. Thus women should emphasise DHA in their diets when they become pregnant and continue to take this until they cease breastfeeding. Children continue to need DHA up until the age they start school, so if children under the age of five are taking an omega-3 supplement, it should contain DHA. The exception is for children with developmental problems – where pure EPA or high EPA omega-3 has been shown to be most effective for supporting cognitive function. We would still recommend, where possible, naturally derived sources of omega-3 such as oily fish to support a balanced EPA and DHA intake.

You “beat me to the punch.” despite labels, cured meats , aged fats, as well as those heated to a high enough temperature all have trans bonds. Fish that offer high amounts of Omega-3 also often are high in mercury. I was fortunate to have a very good teacher for experimental design. One should be careful to assume that a study actually measures what it claims to and without “confounders” Confounders are parts of the study that complicate the the “logic” of the design. Also, were other fat contents measured or controlled? It would be reasonable to suspect that those with higher levels of Omega-3 could have higher levels of Omega-6, fats in general , High levels of protein, higher levels of testosterone, or lower levels of certain hormones. In addition, statistical studies do not and have never indicated a causal relationship. I have a fear of how much we have begun to rely on statistical correlational studies which are at the end of the day”soft” science.
The short answer is no. There are many websites which advise people to stop eating vegetable oils and switch to fish oil in order to increase their intake of omega-3 fatty acids. Fish oil is a good source of omega-3 essential fatty acids and should be consumed, but that doesn’t necessarily mean that one should completely replace vegetable oils with fish oil.
Fortier, M., Tremblay-Mercier, J., Plourde, M., Chouinard-Watkins, R., Vandal, M., Pifferi, F., Freemantle, E., and Cunnane, S. C. Higher plasma n-3 fatty acid status in the moderately healthy elderly in southern Quebec: higher fish intake or aging-related change in n-3 fatty acid metabolism? Prostaglandins Leukot.Essent.Fatty Acids 2010;82(4-6):277-280. View abstract.
DHA is vital for early brain development and maintenance, while EPA seems to be closely related to behavior and mood. Together, both molecules provide critical neuroprotective benefits.11 These neuroprotective effects are important for the prevention of age-related brain shrinkage (cortical atrophy). Aging adults with brain shrinkage often experience memory loss, cognitive decline, and an increase in depression.12-14

Research conducted at the Louisiana State University has shown that fatty acids are effective in treating Alzheimer’s disease. Since fish oil is one of the best sources of essential fatty acids, including EPA and DHA, it helps in the treatment of Alzheimer’s disease. More research conducted at the University of California in Los Angeles (UCLA) validates the usefulness of fish oil as a possible remedy for the disease. The Alzheimer’s Association recommends fish containing a higher content of omega-3 fatty acids to patients since it acts as a defense against Alzheimer’s disease and dementia.
Three randomized trials assessing more than 600 patients with known malignant ventricular arrhythmia were carried out under the protection of implanted cardioverter defibrillator (ICD) therapy.41–43 In all 3 of the trials, 75% of the patients had ischemic heart disease, survived ventricular tachycardia or ventricular fibrillation and were randomized to 1 to 3 g/d of fish oil. In the first trial of its kind, 402 patients with ICDs were randomized to either a fish oil or an olive oil supplement.41 Although statistical significance was not reached, after approximately 1 year the primary end-point of time to first ICD cardioversion for ventricular tachycardia or fibrillation or death from any cause was longer in the fish oil group. This finding was not replicated in a trial of 200 patients who were randomized to either fish oil or a placebo and followed for a median of approximately 2 years.42 In fact, time to first ICD cardioversion was not changed and the incidence of recurrent ventricular tachycardia and fibrillation was more common in the group assigned to fish oil. In the largest trial, 546 patients were randomized to supplemental fish oil or a placebo and were followed for a mean period of 1 year.43 The primary outcome of the rate of ICD cardioversion or all-cause mortality was not reduced. It was concluded in a recent meta-analysis of these trials that fish oil did not have a protective effect.44
Fish oil combined with fenofibrate has not been studied extensively in randomized controlled trials. Data to date, however, suggest that the combination is safe and effective.63,64 A recent randomized controlled trial of 100 patients with severe hypertriglyceridemia and HIV on highly active antiretroviral therapy showed that a regimen of fenofibrate and 3 g/d of fish oil for 8 weeks was well tolerated. The median baseline triglyceride level of 650 mg/dL was reduced by 65%.63 Another recent randomized, 2 month, double-blind, placebo-controlled trial, which was set up to assess the safety and efficacy of fenofibrate with 4 g of fish oil, showed that in the 81 patients assigned to combination therapy, triglyceride levels were reduced by 61%. Therapy was well-tolerated without significant adverse reactions at 8 weeks or at the end of a 2-year open label extension.64 The combination of fish oil and niacin requires further study.
Jump up ^ Naliwaiko, K.; Araújo, R.L.F.; Da Fonseca, R.V.; Castilho, J.C.; Andreatini, R.; Bellissimo, M.I.; Oliveira, B.H.; Martins, E.F.; Curi, R.; Fernandes, L.C.; Ferraz, A.C. (2004). "Effects of Fish Oil on the Central Nervous System: A New Potential Antidepressant?". Nutritional Neuroscience. 7 (2): 91–99. doi:10.1080/10284150410001704525. PMID 15279495.
The U.S. Food and Drug Administration recommends consuming no more than 3 g/day of EPA and DHA combined, including up to 2 g/day from dietary supplements. Higher doses are sometimes used to lower triglycerides, but anyone taking omega-3s for this purpose should be under the care of a healthcare provider because these doses could cause bleeding problems and possibly affect immune function. Any side effects from taking omega-3 supplements in smaller amounts are usually mild. They include an unpleasant taste in the mouth, bad breath, heartburn, nausea, stomach discomfort, diarrhea, headache, and smelly sweat.

“This systematic review did find moderate evidence that ALA, found in plant oils (such as rapeseed or canola oil) and nuts (particularly walnuts) may be slightly protective of some diseases of the heart and circulation. However, the effect is very small, 143 people would need to increase their ALA intake to prevent one person developing arrhythmia. One thousand people would need to increase their ALA intake to prevent one person dying of coronary heart disease or experiencing a cardiovascular event.  ALA is an essential fatty acid, an important part of a balanced diet, and increasing intakes may be slightly beneficial for prevention or treatment of cardiovascular disease."


Respected health care organizations proposed intake recommendations for oily fish of two servings per week for healthy adults, which equates to approximately a daily total of 500 milligrams (mg) EPA and DHA.‡ The recommendation encourages adults already with or at-risk of developing cardiovascular disease to talk to their primary healthcare professional about supplementing with amounts greater than 500 mg of EPA and DHA per day. Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.

Chemical structure of alpha-linolenic acid (ALA), an essential omega−3 fatty acid, (18:3Δ9c,12c,15c, which means a chain of 18 carbons with 3 double bonds on carbons numbered 9, 12, and 15). Although chemists count from the carbonyl carbon (blue numbering), biologists count from the n (ω) carbon (red numbering). Note that, from the n end (diagram right), the first double bond appears as the third carbon-carbon bond (line segment), hence the name "n-3". This is explained by the fact that the n end is almost never changed during physiological transformations in the human body, as it is more energy-stable, and other compounds can be synthesized from the other carbonyl end, for example in glycerides, or from double bonds in the middle of the chain.
Omega-3 fatty acids have been found to play a role in atherosclerosis and peripheral arterial disease (PAD). It is thought that both EPA and DHA improve plaque stability, decrease endothelial activation, and improve vascular permeability, thereby decreasing the chance of experiencing a cardiovascular event (41). It was found that EPA supplementation is associated with significantly higher amounts of EPA in the carotid plaque than placebo (P < 0.0001), which may lead to decreased plaque inflammation and increased stability (42). PAD, a manifestation of atherosclerosis, is characterized by buildup of plaque in the arteries of the leg and can eventually lead to complete blockage of the arteries. EPA+DHA supplementation has been shown to improve endothelial function in patients with PAD by decreasing plasma levels of soluble thrombomodulin from a median value of 33.0 μg/L to 17.0 μg/L (P = 0.04) and improve brachial artery flow–mediated dilation from 6.7% to 10.0% (P = 0.02) (43). Patients who had PAD and were supplemented with EPA experienced a significantly lower major coronary event HR than those who did not take EPA (HR: 0.44; 95% CI: 0.19–0.97; P = 0.041) (44).
Thusgaard, M., Christensen, J. H., Morn, B., Andersen, T. S., Vige, R., Arildsen, H., Schmidt, E. B., and Nielsen, H. Effect of fish oil (n-3 polyunsaturated fatty acids) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy: a randomized, double-blind, placebo-controlled study. Scand.J.Infect.Dis. 2009;41(10):760-766. View abstract.
ODS seeks to strengthen knowledge and understanding of dietary supplements by evaluating scientific information, supporting research, sharing research results, and educating the public. Its resources include publications (such as Dietary Supplements: What You Need to Know), fact sheets on a variety of specific supplement ingredients and products (such as vitamin D and multivitamin/mineral supplements), and the PubMed Dietary Supplement Subset
Rondanelli, M., Giacosa, A., Opizzi, A., Pelucchi, C., La, Vecchia C., Montorfano, G., Negroni, M., Berra, B., Politi, P., and Rizzo, A. M. Effect of omega-3 fatty acids supplementation on depressive symptoms and on health-related quality of life in the treatment of elderly women with depression: a double-blind, placebo-controlled, randomized clinical trial. J.Am.Coll.Nutr. 2010;29(1):55-64. View abstract.
×