Tanaka, K., Ishikawa, Y., Yokoyama, M., Origasa, H., Matsuzaki, M., Saito, Y., Matsuzawa, Y., Sasaki, J., Oikawa, S., Hishida, H., Itakura, H., Kita, T., Kitabatake, A., Nakaya, N., Sakata, T., Shimada, K., and Shirato, K. Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke 2008;39(7):2052-2058. View abstract.
We included 79 RCTs (112,059 participants) in this review update and found that 25 were at low summary risk of bias. Trials were of 12 to 72 months’ duration and included adults at varying cardiovascular risk, mainly in high‐income countries. Most studies assessed LCn3 supplementation with capsules, but some used LCn3‐ or ALA‐rich or enriched foods or dietary advice compared to placebo or usual diet.
In fact, fish oil is even dipping its way into mainstream medicine. In September 2018, Amarin Corporation, the biopharmaceutical developer of pharmaceutical-grade fish oil Vascepa, released preliminary findings of its double-blind clinical trial. In the study, researchers tracked more than 8,000 adults for a median 4.9 years. The mix of study participants had either established cardiovascular disease or type 2 diabetes and another cardiovascular disease risk factor, along with persistently elevated triglycerides.

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
Capanni, M., Calella, F., Biagini, M. R., Genise, S., Raimondi, L., Bedogni, G., Svegliati-Baroni, G., Sofi, F., Milani, S., Abbate, R., Surrenti, C., and Casini, A. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment.Pharmacol.Ther. 4-15-2006;23(8):1143-1151. View abstract.
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
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)
I now suspect that those thousands of gel-covered capsules I’ve swallowed over the years may have done little more than enrich the pockets of supplement producers and sellers. A number of extensive analyses have been conducted, some supporting and others refuting the value of fish oils to the cardiovascular system, along with studies of other purported health benefits that also have had mixed results.

Boucher, O., Burden, M. J., Muckle, G., Saint-Amour, D., Ayotte, P., Dewailly, E. ... Jacobson, J. L.. (2011, May). Neurophysiologic and neurobehavioral evidence of beneficial effects of prenatal omega-3 fatty acid intake on memory function at school age. American Journal of Clinical Nutrition 93(5), 1025-1037. Retrieved from http://ajcn.nutrition.org/content/93/5/1025.full
For those who do not eat seafood, another way exists for you to get a healthy dose of EPA and DHA each day. Fish oil supplements, which are rich in EPA and DHA, can be made from a variety of fish, with the most common ones being halibut, tuna, salmon, cod liver, mackerel and herring. On average, one 3.5 ounce serving of fatty fish contains about 1 gram of omega-3s, which can be obtained through fish oil supplements, according to MedlinePlus.
There is some evidence that omega−3 fatty acids are related to mental health,[47] including that they may tentatively be useful as an add-on for the treatment of depression associated with bipolar disorder.[48] Significant benefits due to EPA supplementation were only seen, however, when treating depressive symptoms and not manic symptoms suggesting a link between omega−3 and depressive mood.[48] There is also preliminary evidence that EPA supplementation is helpful in cases of depression.[49] The link between omega−3 and depression has been attributed to the fact that many of the products of the omega−3 synthesis pathway play key roles in regulating inflammation (such as prostaglandin E3) which have been linked to depression.[50] This link to inflammation regulation has been supported in both in vitro[51] and in vivo studies as well as in meta-analysis studies.[33] The exact mechanism in which omega−3 acts upon the inflammatory system is still controversial as it was commonly believed to have anti-inflammatory effects.[52]

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
Schilling, J., Vranjes, N., Fierz, W., Joller, H., Gyurech, D., Ludwig, E., Marathias, K., and Geroulanos, S. Clinical outcome and immunology of postoperative arginine, omega-3 fatty acids, and nucleotide-enriched enteral feeding: a randomized prospective comparison with standard enteral and low calorie/low fat i.v. solutions. Nutrition 1996;12(6):423-429. View abstract.

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In fact, fish oil is even dipping its way into mainstream medicine. In September 2018, Amarin Corporation, the biopharmaceutical developer of pharmaceutical-grade fish oil Vascepa, released preliminary findings of its double-blind clinical trial. In the study, researchers tracked more than 8,000 adults for a median 4.9 years. The mix of study participants had either established cardiovascular disease or type 2 diabetes and another cardiovascular disease risk factor, along with persistently elevated triglycerides.
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.

The National Institutes of Health (NIH) has created a website, NIH Clinical Research Trials and You, to help people learn about clinical trials, why they matter, and how to participate. The site includes questions and answers about clinical trials, guidance on how to find clinical trials through ClinicalTrials.gov and other resources, and stories about the personal experiences of clinical trial participants. Clinical trials are necessary to find better ways to prevent, diagnose, and treat diseases.
Nakamura, N., Hamazaki, T., Ohta, M., Okuda, K., Urakaze, M., Sawazaki, S., Yamazaki, K., Satoh, A., Temaru, R., Ishikura, Y., Takata, M., Kishida, M., and Kobayashi, M. Joint effects of HMG-CoA reductase inhibitors and eicosapentaenoic acids on serum lipid profile and plasma fatty acid concentrations in patients with hyperlipidemia. Int J Clin Lab Res 1999;29(1):22-25. View abstract.
Birch, E. E., Carlson, S. E., Hoffman, D. R., Fitzgerald-Gustafson, K. M., Fu, V. L., Drover, J. R., Castaneda, Y. S., Minns, L., Wheaton, D. K., Mundy, D., Marunycz, J., and Diersen-Schade, D. A. The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid. Am J Clin Nutr 2010;91(4):848-859. View abstract.
Several studies suggest that people suffering symptoms of depression and/or anxiety see improvement after adding an omega-3 supplement to their routine, even in double-blinded, randomized, controlled trials. (29, 30, 31, 32, 33) At least one study comparing a common depression medication found omega-3 supplements to be just as effective in combating depression symptoms. (34)
In 2016, AHRQ reviewed 143 studies that evaluated the effects of giving omega-3 supplements to pregnant or breastfeeding women or giving formulas with added DHA to infants. They found that when women took omega-3 supplements during pregnancy, their babies’ birth weight was slightly higher, but the risk of an undesirably low birth weight did not change. Also, when women took omega-3 supplements during pregnancy, their pregnancies lasted a little longer, but there was no effect on the risk of premature birth. Omega-3s were not found to have effects on any other aspects of the mothers’ or infants’ health or the infants’ long-term development. Aspects of the infants’ health that were not shown to be affected by omega-3s include growth after birth, visual acuity, long-term neurological and cognitive development, and the risks of autism, ADHD, learning disorders, and allergies.

Bemelmans, W. J., Broer, J., Feskens, E. J., Smit, A. J., Muskiet, F. A., Lefrandt, J. D., Bom, V. J., May, J. F., and Meyboom-de Jong, B. Effect of an increased intake of alpha-linolenic acid and group nutritional education on cardiovascular risk factors: the Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) study. Am J Clin Nutr 2002;75(2):221-227. View abstract.
The bottom line of all that is that there was no clear health benefit from consuming omega-3 fatty acids in food or supplements. There was a suggestion of a possible benefit from LCn3 on cardiac events, but this did not hold up when they took into consideration the quality of the evidence. The better trials, with less risk of bias, tended to be negative.
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.
Fish oil supplement studies have failed to support claims of preventing heart attacks or strokes.[3][4][5][6] Earlier, in 2007, the American Heart Association had recommended the consumption of 1 gram of fish oil daily, preferably by eating fish, for patients with coronary artery disease, but cautioned pregnant and nursing women to avoid eating fish with high potential for mercury contaminants including mackerel, shark, and swordfish.[32] (Optimal dosage was related to body weight.)
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).
Bell, J. G., Miller, D., MacDonald, D. J., MacKinlay, E. E., Dick, J. R., Cheseldine, S., Boyle, R. M., Graham, C., and O'Hare, A. E. The fatty acid compositions of erythrocyte and plasma polar lipids in children with autism, developmental delay or typically developing controls and the effect of fish oil intake. Br J Nutr 2010;103(8):1160-1167. View abstract.
The National Institutes of Health (NIH) has created a website, NIH Clinical Research Trials and You, to help people learn about clinical trials, why they matter, and how to participate. The site includes questions and answers about clinical trials, guidance on how to find clinical trials through ClinicalTrials.gov and other resources, and stories about the personal experiences of clinical trial participants. Clinical trials are necessary to find better ways to prevent, diagnose, and treat diseases.
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

A tremendous body of research has been conducted on these important nutrients since it was first discovered in the 1950s that fish oil offered many health benefits and that these benefits were attributable to a type of polyunsaturated fat called omega-3. Despite the volumes of research on omega-3s, it is only in recent years (within the last 15 years or so) that the actions of EPA and DHA have come to be understood individually. Researchers now often investigate the actions of EPA and DHA individually rather than together, no longer simply under the generic label omega-3 as they are widely referred to.


Children: Fish oil is POSSIBLY SAFE when taken by mouth appropriately. Fish oil has been used safely through feeding tubes in infants for up to 9 months. But young children should not eat more than two ounces of fish per week. Fish oil is POSSIBLY UNSAFE when consumed from dietary sources in large amounts. Fatty fish contain toxins such as mercury. Eating contaminated fish frequently can cause brain damage, mental retardation, blindness and seizures in children.


An animal study involving the omega-3 ETA discovered that subjects experienced a drop in overall inflammation similar to that caused by NSAIDs (non-steroidal anti-inflammatory drugs), but without the dangerous gastrointestinal side effects. The study authors also pointed out that eicosapentaenoic acid seems to be even more potent than the conventional omega-3s found in fish oil supplements (EPA/DHA). (56)
According to research conducted at Harvard University, omega-3 fatty acid deficiency is officially one of the top 10 causes of death in America, claiming the lives of up to 96,000 people each year. Out of the 12 dietary, lifestyle and metabolic risk factors examined in the study, omega-3 fatty acid deficiency ranked as the sixth highest killer of Americans. (1) These deaths are considered preventable since getting enough omega 3-fatty acids in your diet can ward off this now common cause of death, and fish oil benefits omega-3 intake as a potent omega-3 source.
Due to the anticipated heterogeneity, a random-effects meta-analysis was chosen rather than a fixed-effects meta-analysis because random-effects modeling is more stringent and incorporates an among-study variance in the calculations. The entire meta-analysis procedure was performed on the platform of Comprehensive Meta-analysis statistical software, version 3 (Biostat). Under the preliminary assumption that the scales for anxiety symptoms are heterogeneous among the recruited studies, we chose Hedges g and 95% confidence intervals to combine the effect sizes, in accordance with the manual of the Comprehensive Meta-analysis statistical software, version 3. Regarding the interpretation of effect sizes, we defined Hedges g values 0 or higher as a better association of treatment with reduced anxiety symptoms of omega-3 PUFAs than in controls. For each analysis, a 2-tailed P value less than .05 was considered to indicate statistical significance. When more than 1 anxiety scale was used in a study, we chose the one with the most informative data (ie, mean and standard deviation [SD] before and after treatment). We entered the primary outcome provided in the included articles or obtained from the original authors. As for the variance imputation, we mainly chose the mean and SD before and after treatment. Later, we entered the mean and SD and calculated the effect sizes based on the software option, standardized by post score SD. In the case of studies with 2 active treatment arms, we merged the 2 active treatment arms into 1 group. If these 2 active treatment arms belonged to different subgroups (ie, different PUFA dosage subgroups), we kept them separate. Regarding the numbers of participants counted, we chose intention-to-treat as our priority. If there were insufficient data in the intention to treat group (ie, some studies only provided the changes in anxiety severity in those participants completing trials), we chose instead the per-protocol numbers of participants.
Fish oil supplement studies have failed to support claims of preventing heart attacks or strokes.[3][4][5][6] Earlier, in 2007, the American Heart Association had recommended the consumption of 1 gram of fish oil daily, preferably by eating fish, for patients with coronary artery disease, but cautioned pregnant and nursing women to avoid eating fish with high potential for mercury contaminants including mackerel, shark, and swordfish.[32] (Optimal dosage was related to body weight.)
Docosahexaenoic acid (DHA) found primarily in fish oil, this is the ultimate form of fatty acid in humans. Most people get far too little of this all-important fatty acid, especially since the conversion of ALA to DHA is slow and minimally yielding. Getting a daily dose of of DHA (600 to 1000 mg) from supplements is preferable to reap the health benefits. You have a choice of taking a fish oil supplement or one derived from algae or krill, a shrimp-like crustacean.
High triglycerides. Most research shows that fish oil from supplements and food sources can reduce triglyceride levels. The effects of fish oil appear to be the greatest in people who have very high triglyceride levels. Also the amount of fish oil consumed seems to directly affect how much triglyceride levels are reduced. Some fish oil supplements including Lovaza, Omtryg, and Epanova have been approved by the FDA to lower triglycerides.
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