Omega-3 Fatty Acids

Common Name(s): Docosahexaenoic acid (DHA), Eicosapentaenoic acid (EPA), Fish Oils, LCPUFAs, Long-chain PUFAs, Lovaza, Marine oil fatty acids, Marine oils, N-3 fatty acids, Omega-3 polyunsaturated fatty acids, PUFAs

Medically reviewed by Drugs.com. Last updated on Nov 29, 2022.

Clinical Overview

Use

Meta-analyses of large data sets have reported that supplementation with omega-3 fatty acids increases serum concentrations of EPA and DHA and may decrease serum triglyceride levels. Guidelines recommend fish oil/omega-3 supplementation be considered as an adjunctive option in the management of severe hypertriglyceridemia; there is little or no effect on cardiovascular events or death, arrhythmias, or stroke.

Evidence supporting use of parenteral fish oil lipid emulsion in severely ill and surgical patients is mounting, while evidence remains equivocal but promising regarding use in rheumatoid arthritis. Data from meta-analyses suggest a small to modest benefit in depression and little to no effect in dementias. No consistent relationship between fish oil consumption and maintenance in inflammatory bowel disease has been established. Other areas of interest in the therapeutic use of fish oils requiring further study include asthma and allergy, dysmenorrhea, and the promotion of postnatal growth and development.

Dosing

The American Heart Association (AHA) recommends a minimum of 2 fatty fish servings per week. Clinical trials suggest fish oil supplementation of omega-3 fatty acids 1 g/day in coronary heart disease, and when triglycerides are elevated, a minimum of omega-3 fatty acids 2 g/day, up to a maximum of 4 g/day. Fish oil supplements generally contain 1,000 mg of fish oil, which approximates to 300 to 400 mg of EPA and DHA.

Contraindications

Contraindicated in individuals with active bleeding (eg, peptic ulcer, intracranial bleeding).

Pregnancy/Lactation

Potential for mercury ingestion. Eating fish lower in mercury and avoiding consumption of high-mercury–containing fish, such as tilefish from the Gulf of Mexico, swordfish, king mackerel, and shark is recommended.

Interactions

The anticoagulant effect of anticoagulant medications (including warfarin), may be increased by fish oil ingestion; case reports are limited.

Adverse Reactions

Fish oil at EPA/DHA dosages of 2 to 5.4 g/day is well accepted and tolerated. Mild GI discomfort was reported in clinical trials.

Toxicology

No data.

Source

Omega-3 fatty acids are found in a variety of plants and animals, with the highest concentration occurring in marine-based sources. EPA and DHA are found in trace amounts in beef. Grass-fed beef can have up to a 25% increase in the percentage of total polyunsaturated fatty acids (PUFAs) compared to grain-fed beef. Additionally, a higher ratio of omega-3 to omega-6 fatty acids, including EPA and DHA, is also found in grass-fed cattle compared to grain-fed comparators.Van Elswyk 2014 EPA and DHA can be synthesized, albeit inefficiently, from the essential omega-3 fatty acid alpha-linolenic acid (ALA). ALA cannot be synthesized by humans and must be obtained from the diet. ALA is found in flaxseed; canola, soybean, walnut, and wheat germ oils; nuts and seeds; and vegetables. Additionally, DHA can be synthesized from EPA.Krauss 2000, Wardlaw 1999, Whitney 1999

Fish oils are predominantly comprised of the omega-3 fatty acids EPA and DHA; "fish oil" is a term frequently used interchangeably with, and in reference to, EPA and DHA. Marine sources containing the highest content of omega-3 fatty acids are fatty fish (eg, mackerel, halibut, salmon, bluefish, mullet, sablefish, menhaden, anchovy, herring, lake trout, coho, sardines), which provide 1 g or more of omega fatty acids per 100 g (3.5 oz) of fish. Tuna, seal, and shellfish (eg, oysters) are additional marine-based sources.Krauss 2000, Mann 2010, Soyland 1993, Wardlaw 1999, Whitney 1999

Because marine fish stocks are limited and because many fish stocks are currently contaminated by pollutants (eg, methylmercury, organochlorine pesticides), it has been proposed that the algal genes responsible for EPA and DHA production be cloned into plants.Mozaffarian 2006, Racine 2007 Oils from transgenic plants would be rich in EPA and DHA, and although some success has been achieved, challenges in the biosynthetic pathways in higher plant species have not yet been surmounted.Graham 2007, Venegas-Caleron 2010

History

Most uses of fish oils have been based on the beneficial effects of EPA and DHA, specifically those related to cardiovascular, inflammatory, neural, and hormonal support. Interest in possible health benefits followed observations that populations with a high dietary intake of fish, such as Eskimo and Inuit populations, had low incidences of atherosclerotic and thrombotic disorders and inflammatory conditions.Farmer 2001, Woods 2002 In 1789, a publication described the beneficial effects of cod liver oil in rheumatism, and in 1824 the same oil was reported as effective in the prevention of rickets.Gadoth 2008 Historically, deficiencies were noted in infants fed non- or low-fat diets and in patients receiving long-term (eg, 2 to 3 weeks) parenteral nutritional formulations lacking PUFAs.Wardlaw 1999, Whitney 1999

Chemistry

EPA and DHA are omega-3, long-chain (20 carbons or more) PUFAs. EPA consists of a 20-carbon chain with 5 double bonds (20:5), while DHA is a 22-carbon chain with 6 double bonds (20:6). As represented by the omega-3 nomenclature, the first double bond is located at the third carbon from the methyl group (omega) end of the chain.Wardlaw 1999, Whitney 1999 C-13 nuclear magnetic resonance pattern recognition has been used to analyze the species of fish from which commercial fish oil products are derived.Aursand 2007 Homogenization of fish oils into milk has been explored.Let 2007 Challenges for the incorporation of fish oils into other foodstuffs include the propensity of EPA and DHA to oxidize, as well as their unpleasant tastes and smells. Thus, oil-filled capsules are the current preferred supplement form.

Uses and Pharmacology

Omega-3 fatty acids are metabolized into eicosanoids, which have important physiologic properties and include prostaglandins, prostacyclins, thromboxanes, and leukotrienes. Eicosanoids are potent regulators of blood pressure, blood clotting, childbirth, and gastric secretions, as well as immune and inflammatory responses. The actual location of the double bond in the fatty acid chain affects its metabolism such that the structure and function of omega-3–derived eicosanoids differ from those derived from omega-6 fatty acids (eg, arachidonic acid). For example, omega-3–derived eicosanoids tend to decrease blood clotting and inflammatory responses. This contrasts with the arachidonic acid (omega-6)–derived eicosanoids, which increase clotting and inflammatory responses.(Wardlaw 1999, Werbach 1996, Whitney 1999)

Whereas previous studies have been limited mostly to methyl ester fatty acid moieties, laboratory advances have recently allowed for a more detailed description of the postprandial incorporation of long-chain n-3 fatty acids across the full plasma lipidome. Acute changes were reported in the lipidome post consumption of krill oil or fish oil in which phospholipid species containing n-3 components were significantly increased in plasma. Fish oil phospholipids were increased equally or less so compared to krill oil. Plasma levels of several n-3 triacyl and diacyl glycerols were significantly higher after fish oil than krill oil.(Sung 2019) Compared to krill oil, short-term administration of fish oil produced lower plasma EPA levels (by 35.6%) after 30-day use but no differences were observed in the other long chain n-3 PUFA moieties (ie, DHA, DPA, arachidonic acid, linoleic acid, alpha-linolenic acid). Other significant differences included lower cholesterol-based lipids and higher phosphatidylserine with fish oil. Overall, 47% of lipid molecular species were altered following supplementation with krill oil or fish oil. Compared to krill oil, fish oil led to a significant decrease in 60% of both neutral and polar lipid species and a significant increase in 40%.(Sung 2020)

The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies largely redundant.

For further information on uses of omega-3 fatty acids from krill oil, see the Krill Oil monograph.

Anti-inflammatory effects

Clinical data

In a randomized, double-blind, placebo-controlled trial, 261 healthy adults received fish oil supplementation (EPA plus DHA 1,400 mg) or placebo for 18 weeks to determine the effects on biomarkers of chronic, systemic inflammation. This dose had no effect on serum C-reactive protein or interleukin-6 (IL-6) concentrations, with no evidence of heterogeneity found based on gender, body mass index (BMI), baseline IL-6, or postsupplementation red blood cell EPA plus DHA level. Adverse effects associated with the intervention included fishy belch or aftertaste, loose stool, and bloating or gas pains; no serious adverse events were reported.(Muldoon 2016)

Omega-3 fatty acids may be effective for managing pruritus in uremic patients according to a 2016 updated Cochrane systematic review of pharmacological interventions for pruritus in adult palliative care. An additional 10 studies with 627 participants were identified since the previous 2013 review, with 1 new study investigating omega-3 fatty acids. In this double-blind, randomized, placebo-controlled, crossover trial that enrolled 22 patients with end-stage renal disease, 3 g/day of omega-3s (1 g of omega-3s [as EPA 180 mg and DHA 120 mg] orally 3 times daily) was given over 20 days, with a 14-day washout prior to crossing over. Pruritus decreased from baseline by 65% with fish oil compared to 15% with placebo. Although the difference was statistically significant, the sample size was small and the study was of low methodological quality.(Siemens 2016)

Asthma/Allergy

Clinical data

Clinical benefit of fish oil use in asthma is controversial.(Nagakura 2000, Woods 2002) Omega-3 fatty acids do not have an effect on eosinophils and mast cells, which may explain a relative lack of efficacy in this inflammatory condition.(Woods 2002) The role of other constituents in fish oil is unknown. Limited evidence of an effect of fish oils on exercise-induced asthma exists.(Tecklenburg-Lund 2010) A potential for an enteral nutritional formula containing EPA plus gamma-linolenic acid as adjuvant therapy in the clinical management of acute respiratory distress syndrome has been suggested.(Gadek 1999) Use of fish oil supplementation during pregnancy and breastfeeding to reduce the incidence of food allergy in infants has also been evaluated; however, maternal fish oil supplementation during pregnancy did not reduce risk of allergic disease from birth up to 3 years in children with a hereditary risk.(Furuhjelm 2009, Palmer 2013) In contrast to these results, the risk of persistent wheeze or asthma was reduced by one-third in children (from birth to between 3 and 5 years of age) born of women who received 2.4 g/day of n-3 LCPUFA in a randomized, double-blind, placebo-controlled trial conducted in 736 pregnant women; 647 children were followed from birth to 5 years of age. This beneficial effect was found to be strongest in mothers with baseline EPA and DHA blood levels of 5% to 5.5%, whose pretrial dietary intake of EPA and DHA was in the lowest third (less than 321 mg/day), and in mothers who carried the G allele fatty acid desaturase gene variant at rs1535 (associated with low levels of EPA and DHA).(Bisgaard 2016) A systematic review and meta-analysis (N=99,093 individuals; 3,226 cases) found an inverse relationship between risk of asthma in childhood and fish consumption by infants and also n-3 LCPUFA levels in maternal expressed breast milk. However, no significant association was found between risk of childhood asthma and maternal fish consumption or fish oil supplementation by children. Additionally, no significant relationship was found between fish consumption and risk of asthma in adults.(Yang 2013)

The National British Clinical guidelines on the management of asthma (2019) state that in the absence of any evidence of benefit from use of fish oil supplementation in pregnancy, it is not possible to recommend it as a strategy for preventing childhood asthma. In addition, results from several controlled trials indicate there is insufficient evidence to recommend fish oil supplementation for the treatment of asthma.(SIGN 2019)

Cancer

Clinical data

An apparent link between inflammation and colon cancer has prompted studies of EPA and DHA in cancer prevention. EPA reduced crypt cell proliferation and increased apoptosis in subjects with a history of colorectal adenomas.(Courtney 2007) A molecular effect on lipid-modified protein trafficking was postulated as a mechanism by 1 review,(Chapkin 2008) while immunomodulatory effects on T-cell function and subsets were invoked by the same group.(Chapkin 2007) Other molecular targets of n-3 PUFAs in cancer have been reviewed.(Berquin 2008) In a 2-year randomized controlled trial in polypectomized patients (N=352), dietary increases in omega-3 fatty acids (ie, increased fish consumption, 456 mg/day of EPA:DHA fish oil supplementation, ALA-rich perilla oils) and reductions in omega-6 fatty acids (ie, vegetable oils, deep-fried foods) resulted in significantly increased plasma, red blood cell, and sigmoid colon membrane omega-3 fatty acids composition and reduced ratios of omega-6s:omega-3s at 12 and 24 months in the experimental group compared with controls. However, the crude number of participants with or without tumors at 24 months was not significantly different. No adverse events were observed.(Tokudome 2015)

The American Society of Clinical Oncology (ASCO) guideline update for prevention and management of chemotherapy-induced peripheral neuropathy (2020) recommends that clinicians not offer omega-3 fatty acids for the prevention of chemotherapy-induced peripheral neuropathy in adults with cancer undergoing treatment with neurotoxic agents (Intermediate; Moderate).(Loprinzi 2020)

Cardiovascular effects (eg, cardiovascular disease, arrhythmia, stroke, dyslipidemia)

A review of potential mechanisms of action has been published.(Goel 2018)

Clinical data

Arrhythmias

The 2018 Cochrane review of omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease included a meta-analysis of 28 clinical trials (n=53,796) evaluating outcomes of fatal or nonfatal new or recurrent arrhythmia, including atrial fibrillation, ventricular tachycardia, and ventricular fibrillation following omega-3 supplementation. Moderate-quality evidence demonstrates no effect of omega-3 supplementation for the prevention of arrhythmias overall (relative risk [RR], 0.97; 95% CI, 0.9 to 1.05).(Abdelhamid 2018) In adults 50 years and older (55 for women) without prior vascular disease, the effect of long-term supplementation of marine omega-3 fatty acids on primary prevention of atrial fibrillation was assessed as an ancillary study within the Vitamin D and Omega-3 (VITAL) trial (N=25,871). Omega-3 fatty acids (EPA 460 mg and DHA 380 mg) was administered daily with or without vitamin D₃ (2,000 units) for a median follow-up duration of 5.3 years. Of the 25,119 participants who met inclusion criteria for the ancillary study, 20% self-identified as Black or African American and the median age was approximately 67 years. No significant effect was found for the EPA-DHA group on incident atrial fibrillation compared to placebo; results remained nonsignificant in sensitivity and nonadherence analyses. Subgroup analyses also revealed no evidence of effect; only participants in the EPA-DHA group who had a baseline height above the median 67 inches exhibited a higher risk of incident atrial fibrillation compared to those taking placebo (P=0.02). Combining EPA-DHA with vitamin D₃ also resulted in no significant treatment effect.(Albert 2021)

Guidelines from the AHA (2017) do not support omega-3 PUFA supplementation to prevent recurrent atrial fibrillation (class III: no benefit recommendation); the guidelines also state that findings from randomized controlled trials do not support use for prevention of postoperative atrial fibrillation in patients undergoing cardiac surgery (class III: no benefit recommendation).(Siscovick 2017)

Cardiovascular events or death

Since 2004, the FDA has not objected to the qualified health claim regarding the consumption of EPA and DHA omega-3 fatty acids for reducing the risk of coronary heart disease (CHD) based on supportive but not conclusive evidence. In 2019 and based on some credible evidence, the FDA expanded these qualified health claims to include those reflecting that consumption of both EPA and DHA combined from food or supplements may help lower blood pressure and reduce the risk of hypertension and the risk of CHD. Noting, however, that the evidence is inconsistent and inconclusive.(FDA 2019)

A 2018 Cochrane review of omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease included 79 trials (published up to April 2017 and involving more than 112,000 participants) evaluating effects of omega-3 fatty acids on cardiovascular health. Overall, supplemental omega-3 fatty acids appear to have little or no effect on cardiovascular outcomes. A meta-regression of data found no dose-response or duration effects.(Abdelhamid 2018)

For all-cause mortality, high-quality evidence from a meta-analysis of 39 clinical studies (n=92,653) found little to no effect (RR, 0.98; 95% CI, 0.9 to 1.03). Similarly, no or little effect was reported for cardiovascular mortality (25 trials [n=67,772]; RR, 0.95; 95% CI, 0.87 to 1.03) or coronary heart disease mortality (21 trials [n=73,491]; RR, 0.93; 95% CI, 0.79 to 1.09).(Abdelhamid 2018)

For the risk of combined cardiovascular events, high-quality evidence from 38 trials (n=90,378) found little or no effect (RR, 0.99; 95% CI, 0.94 to 1.04). For risk of coronary heart disease (CHD) events (ie, CHD, coronary events, myocardial infarction [MI], acute coronary syndrome, angina), moderate-quality evidence from 28 clinical trials (n=84,301) found a less than 7% reduction in CHD events with higher intake of omega-3 fatty acids (RR, 0.93; 95% CI, 0.88 to 0.97). For MI (fatal and nonfatal), a meta-analysis of 23 trials found a small reduction in total MI (RR, 0.95; 95% CI, 0.88 to 1.03).(Abdelhamid 2018)

Guidelines from the AHA published in 2017 state that omega-3 PUFA supplements are not indicated in patients at high cardiovascular disease risk (class III: no benefit recommendation), but there is a lack of consensus, with a minority of reviewers concluding that treatment of such patients is reasonable (class IIb recommendation). For the secondary prevention of CHD and sudden cardiac death among patients with prevalent CHD, the AHA review concluded that treatment with omega-3 PUFA supplements is reasonable for the secondary prevention of CHD death.(Siscovick 2017)

In the 7-year ASCEND study, patients with diabetes without evidence of atherosclerotic cardiovascular disease (N=15,480) were randomized to receive supplemental omega-3 fatty acids (1 g/day) or placebo (olive oil) over 7 years. No difference in the risk of serious vascular events was observed (rate ratio, 1; 95% CI, 0.91 to 1.09).(Bowman 2018)

Guidelines from the AHA (2017) further reiterate a lack of benefit in preventing cardiovascular disease with use of supplemental marine omega-3 fatty acids.(Siscovick 2017) However, the American Diabetes Association's updated guidelines on the standards of medical care in diabetes (2021) recommends an individualized medical nutrition therapy program as needed to achieve treatment goals for all people with types 1 or 2 diabetes, prediabetes, and gestational diabetes (level A) with dietary fats supplied by eating foods rich in long-chain omega-3 fatty acids, including fatty fish containing EPA and DHA, to prevent or treat cardiovascular disease (level B).(ADA 2021)

Lipid-lowering effects

The 2018 Cochrane review of omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease included meta-analyses of clinical trials evaluating lipid-lowering effects of omega-3 fatty acids. High-quality evidence from 23 trials (n=more than 35,000) showed that omega-3 fatty acid supplementation reduces serum triglycerides (mean difference, −0.24 mmol/L; 95% CI, −0.31 to −0.16). A systematic review and meta-analysis of krill oil also revealed significant improvements in low-density lipoprotein (LDL; −15.52 mg/dL, P=0.008) and high-density lipoprotein (HDL; +6.65 mg/dL, P=0.003) cholesterol as well as triglycerides (−14.03 mg/dL, P<0.001) following supplementation with doses ranging from 500 mg/day to 4 g/day given for a duration of 4 weeks to 3 months. A total of 662 participants were enrolled in the 7 studies included in the meta-analysis. In the subgroup of studies with a duration of at least 12 weeks, significant improvement in lipid parameters was extended to also include total cholesterol. No adverse events were reported and common side effects usually experienced with fish oil supplementation (ie, reflux, fishy aftertaste) were not reported with the krill oil supplementation.(Ursoniu 2017) Other meta-analyses included in the review reported moderate- to high-quality evidence that omega-3 fatty acid supplementation has little or no effect on serum cholesterol, high-density lipoprotein (HDL) cholesterol, or LDL cholesterol.(Abdelhamid 2018)

Guidelines recommend fish oil/omega-3 supplementation be considered as adjunctive options in the management of severe hypertriglyceridemia. An American Association of Clinical Endocrinologists/American College of Endocrinology guideline for the management of dyslipidemia and prevention of cardiovascular disease recommends prescription-grade omega-3 oil 2 to 4 g daily to treat severe hypertriglyceridemia (triglycerides greater than 500 mg/dL),(Jellinger 2017) as does the 2018 American College of Cardiology/AHA Task Force guideline for persistently elevated severe hypertriglyceridemia.(Grundy 2018)

Stroke

The 2018 Cochrane review of omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease included a meta-analysis of 28 clinical trials (n=89,358) evaluating the outcome of at least one fatal or nonfatal ischemic or hemorrhagic stroke following omega-3 supplementation. Moderate-quality evidence demonstrates no effect of omega-3 supplementation for the prevention of stroke (RR, 1.06; 95% CI, 0.96 to 1.16).(Abdelhamid 2018)

Guidelines from the AHA (2017) state that evidence does not support omega-3 PUFA supplementation to reduce the risk of stroke among patients without a history of stroke (class III: no benefit recommendation); the guidelines further state there is no evidence of benefit of omega-3 PUFA supplementation in reducing the risk of recurrent stroke or other cardiovascular diseases among patients with a prior stroke (no recommendation).(Siscovick 2017)

CNS effects (eg, depression, dementia)

Animal data

Studies using rodents to elucidate possible mechanisms of action for fish oils in depression, and to identify the role of key compounds, such as resolvin generated from DHA, are ongoing.(Deyama 2017, Hashimoto 2017, Robertson 2017)

A systematic review of the effects of omega-3 fatty acid supplementation on animal models of Alzheimer disease has been published. Fifteen studies (published up to 2011) were included in the review, 9 of which were included in a meta-analysis evaluating effects on cognition. Findings suggest supplementation decreases the omega-6:omega-3 ratio and reduces amyloid-beta pathology in models of Alzheimer disease; supplementation also improved cognitive function, an effect more pronounced in rats compared to mice and in males compared to females.(Hooijmans 2012)

Clinical data

Alzheimer disease/dementia

Meta-analyses and systematic reviews evaluating effects of omega-3 fatty acid intake on dementia and Alzheimer disease have been published.(de Souza Fernandes 2015, Sydenham 2012, Wu 2015, Zhang 2016)

While there is evidence of an association between dementia and low levels of n-3 fatty acids in diet and plasma, and some evidence of improved cognitive outcomes with higher dietary intake of omega-3 fatty acids, supplementation with fish oil or omega-3 fatty acids has not been consistently shown to prevent or reverse dementia or Alzheimer disease.(Rabins 2014, Sydenham 2012, Wu 2015)

Published clinical studies aside from those used in the previously mentioned reviews and meta-analyses are available. Findings from smaller clinical studies evaluating effects of omega-3 in elderly subjects with cognitive impairment tend to report positive outcomes,(Hashimoto 2017, Kulzow 2016, McNamara 2018, Zhang 2017) while the larger Multidomain Alzheimer Preventive Trial (MAPT), a 3-year, multicenter clinical study of elderly subjects (70 years of age or older) with memory complaints (N=1,525) reported no effects of omega-3 PUFA supplementation (total daily dose of DHA 800 mg and EPA 225 mg) on cognitive decline.(Andrieu 2017)

In a study in healthy older individuals 50 to 75 years of age (N=44), memory, but not learning, function was improved in those who received long-chain omega-3 PUFAs (2,200 mg/day [EPA 1,320 mg plus DHA 880 mg]) for 26 weeks compared to those who received placebo. No linear relationship was found between changes in Omega-3 Index values and recall or learning scores.(Kulzow 2016)

In a study conducted in elderly individuals (88.5±0.6 years of age) in Japanese care facilities and nursing homes (N=75), supplemental DHA 1,720 mg/day for 12 months resulted in a nonsignificant tendency towards improved dementia- and depression-related outcomes compared to placebo.(Hashimoto 2017)

In another study in older adults with subjective cognitive impairment (N=76), fish oil (total daily doses of EPA 1.6 g and DHA 0.8 g) over 6 months reportedly reduced everyday cognitive inefficiency, as did supplementation with blueberry; the effect was also reported to extend to 48 weeks. However, an additive effect was not demonstrated with fish oil plus blueberry combination treatment.(McNamara 2018)

Older adults (65 years of age and older) with mild cognitive impairment (N=240) given 12-month DHA supplementation (2 g/day) showed improvements over placebo (corn oil), as measured by the Chinese version of the Wechsler Adult Intelligence Scale-Revised.(Zhang 2017)

Depression

Meta-analyses of available clinical data have been published. The 2015 American Psychiatric Association practice guideline for treatment of patients with major depressive disorder (MDD) suggests the use of supplemental omega-3 fatty acids in MDD may be recommended on the basis of individual circumstances (clinical confidence level III). The guideline notes that most data are derived from adjunctive studies and limited by heterogeneity in study design, dose, duration, and outcomes.(Gelenberg 2010)

A Cochrane review of clinical trials (published up to May 2015) evaluating effects of omega-3 PUFA on MDD in adults reported a small to modest benefit in depressive symptoms with supplemental omega-3 fish oils compared with placebo, based on 25 low-quality studies (N=1,373); though this effect was statistically significant, it is unlikely to be clinically meaningful. Dosages included combined EPA/DHA doses up to 6.6 g/day, EPA alone at doses up to 4 g/day, and DHA alone at a dose of 2 g/day; 4 studies used an intervention consisting of EPA, DHA, and other n-3 PUFAs at total doses up to 3.13 g/day. The one study comparing EPA with antidepressant therapy (n=40) found a comparable effect between EPA 1 g/day and fluoxetine 20 mg/day, and reported wide confidence intervals in the findings (odds ratio [OR], 1.23; 95% CI, 0.35 to 4.31).(Appleton 2015) Similarly, a meta-analysis of 13 clinical studies (12 of which were included in the Cochrane review) found an overall beneficial effect of omega-3 fatty acids on depressive symptoms in MDD. Meta-regression tests showed that statistically significantly better outcomes were associated with studies using a higher EPA dose and studies with a higher percentage of antidepressant users. Earlier publications were also noted to report better outcomes.(Mocking 2016)

A meta-analysis of data from 31 observational studies reported evidence in support of dietary n-3 PUFA intake to reduce depression. A dose-response effect was noted, with a peak decreased risk of depression observed with intake of n-3 PUFA 1.8 g/day.(Grosso 2016)

Meta-analyses and systematic reviews on the effects of fish oils on depressive symptoms in specific populations have also been published. In a review of studies evaluating effects of omega-3 fatty acids on menopausal depressive symptoms, equivocal findings were noted among the few heterogeneous and likely underpowered included trials.(Ciappolino 2018) A meta-analysis of 3 clinical studies (N=172) conducted between 2004 and 2016 found no evidence of a difference between fish oils and placebo on reducing the severity of antenatal depression.(Smith 2019) Among 60 women at risk of postpartum depression, daily supplementation of 1.8 g of n-3 PUFAs for 16 weeks did not prevent maternal depressive symptoms versus placebo, despite achieving higher serum concentrations.(Vaz 2017) A systematic review of 13 randomized clinical trials (N=916) assessed the efficacy of fish oil supplementation on depression among patients undergoing maintenance hemodialysis; compared with placebo, supplementation with fish oil improved Beck Depression Inventory scores in this patient population, without significant heterogeneity among studies.(He 2016)

Studies have addressed the link between deficiency of PUFAs and depressive symptoms, with equivocal findings. In 2020, a meta-analysis of 18 randomized, controlled trials (N=4,052) in women who had experienced perinatal depression reported an overall small improvement with n-3 PUFA supplementation compared to controls (P=0.042). Heterogeneity was significant. Initiation of n-3 PUFAs ranged from during pregnancy to postpartum with daily doses of EPA 0 to 2,200 mg and DHA 120 to 1,638 mg. Benefit was associated with postpartum supplement initiation, women exhibiting depressive symptoms, and those who had presented with a major depressive episode. Overall, the quality of the studies was low.(Mocking 2020) A meta-analysis of 12 clinical studies (published up to December 2016) compared PUFA indices among women with perinatal depression and controls. The study reports an association between perinatal depression and lower levels of n-3 PUFAs in red blood cells and plasma tissue, as well as increased n-6/n-3 ratios.(Lin 2017) Based on a systematic review of 18 clinical studies (published up to September 2016), an association between deficiency of n-3 PUFAs and mental illness or suicidal behavior could not be established.(Pompili 2017) In a study of 91 recruited participants with heart disease and depressive symptoms, no association between the Omega-3 Index (erythrocyte membrane EPA and DHA) and symptoms of depression could be established.(Cai 2017) In another study, supplementation with omega-3 fatty acids in 7- to 14-year-old patients with depression (n=72) or bipolar disorder (n=23) improved fatty acid profiles and symptoms of depression at 12 weeks.(Arnold 2017)

Further clinical studies published after available meta-analyses provide additional evidence regarding use of omega-3 use for depression. Results from a multicenter clinical study (the NEURAPRO study) in 304 adults at ultrahigh risk for psychotic disorders showed that 1.4 g/day of omega-3 PUFAs added to high-quality psychosocial intervention (ie, cognitive behavioral case management) lacked efficacy for depression compared to good-quality cognitive behavioral case management alone.(McGorry 2017) Results from other ongoing clinical studies, such as a double-blind, placebo-controlled trial evaluating omega-3 fatty acid supplementation versus placebo among veterans and nonveterans at risk of suicide (the Bravo study)(Marriott 2016) and a randomized controlled trial evaluating omega-3 fatty acid supplementation versus sertraline in an older age cohort at risk for depression (the Beyond Ageing Project) are pending.(Cockayne 2015)

The Veteran’s Affairs and Department of Defense (VA/DoD) clinical practice guideline for the management of major depressive disorder (2022) recommends against the use of omega-3 fatty acids for treatment of MDD (Weak).(VA/DoD 2022)

Other CNS conditions

Limited trials have evaluated fish oil supplementation in schizophrenia and in attention deficit–hyperactivity disorder, with equivocal results.(Gadoth 2008, Joy 2000, Sarris 2011) The OFFER trial, a randomized controlled trial of omega-3 fatty acids in first-episode schizophrenia, will compare effects of 26 weeks of EPA plus DHA as add-on therapy with olive oil placebo on symptoms and relapse rates.(Pawelczyk 2015) A meta-analysis of 20 double-blind, randomized, controlled trials conducted in patients with schizophrenia and other psychotic conditions within the spectrum (N=1,494) describes the effects of omega-3 fatty acids on psychopathology and metabolic parameters. The studies were published between 2001 and 2020 with outcomes considered to be of moderate to high quality; 15 included patients with schizophrenia, 3 first-episode psychosis, and 2 ultra-high-risk populations. Total Positive and Negative Symptom Scores (PANSS) (12 studies; n=918; P<0.001), positive symptoms (9 studies; n=741; P=0.004), and general psychopathology (5 studies; n=316; P<0.001) improved significantly with omega-3 supplementation, but heterogeneity was high. No significant effect of supplementation was observed on overall negative symptoms. Subgroup analysis revealed significant benefit of supplementation in all 4 outcomes (total PANSS, positive, negative, general) for patients with first-episode psychosis, those with severe illness, and schizophrenia patients who received EPA of more than 1 g/day (P<0.01 for all). Benefit in at least 1 outcome measure was observed for patients with schizophrenia, ultra-high-risk group, and schizophrenic patients who received no more than 1 g/day EPA (P≤0.01 for each). Significantly lower risks of muscle rigidity (P=0.04) and diarrhea (P=0.004) were noted with omega-3 supplementation as well as an increased risk of bleeding (P=0.01).(Goh 2021)

In a double-blind trial, children 8 to 16 years of age with antisocial and aggressive behavior problems (N=200) were randomized to either a daily supplement drink containing omega-3 1,000 mg (DHA 300 mg, EPA 200 mg, DPA 100 mg, and ALA 400 mg) or placebo for 6 months. Omega-3 supplementation led to significant group times time interactions for all but one internalizing (P=0.002) and externalizing (P=0.001) subscale, and interactions for callous-unemotional traits (P<0.05) and narcissism (P=0.048) were noted. Effects were observed at the end of the 6-month treatment period and were maintained for a subsequent 6 months.(Raine 2015) A small randomized, controlled, crossover trial in 21 children (6 to 17 years of age) presenting with impulsive aggression found no effect on primary ratings of aggression after 6 weeks of fish oil capsules (4 g daily [EPA 400 mg plus DHA 2,000 mg]) compared with placebo (polyphenol olive oil with 10 mg standard fish oil), although one rating of hyperactivity significantly improved (P<0.05). A trend suggested that fish oil worsened the conduct subscore (P=0.056). Notably, 38.5% of children in the study exhibited fatty acid insufficiency at baseline.(Dean 2014)

The American Academy of Neurology guideline on complementary and alternative medicine in multiple sclerosis (2014) advises that a low-fat diet supplemented with fish oil is probably ineffective for improving multiple sclerosis–related relapse, disability, magnetic resonance imaging lesions, or quality of life (moderate-quality evidence).(Yadav 2014)

Critical illness and surgical patients

Clinical data

Randomized, controlled trials conducted in severely ill patients in intensive care units (ICUs) and in elective surgical patients have compared fish oil–enriched lipid emulsions with standard enteral formulations. Meta-analyses have been conducted that recognize the heterogenous nature of the study populations (including medical, surgical, and trauma related) and formulations used (ranging from EPA/DHA 1 to 6.6 g/L)(Stapleton 2010) and the difficulty in recruiting patients into trials.(Chen 2010, Mayer 2008, Stapleton 2010, Wei 2010)

Findings from these meta-analyses are in favor of supplemental fish oil in terms of reduced length of stay in the hospital and ICU, decreased ventilator time, decreased new organ failure, and decreased postoperative infections.(Chen 2010, Mayer 2008, Stapleton 2010, Waitzberg 2009, Wei 2010) Twenty-eight-day mortality was decreased in 1 meta-analysis of ICU patients(Stapleton 2010) but not in an analysis of major abdominal surgery. No serious adverse events were recorded in the included trials.(Chen 2010) Further clinical trials in patients with GI surgery not included in the meta-analyses have been conducted with similar positive results.(Badía-Tahull 2010, Barbosa 2010, Calder 2006, Jiang 2010)

Cystic fibrosis

A pilot trial of intravenous fish oil emulsion in cystic fibrosis found no benefits and some potential deleterious effects.(Berquin 2008) A systematic review and meta-analysis identified 4 randomized controlled trials (N=91) comparing omega-3 fatty acid oral supplementation with placebo for effects on morbidity and mortality in patients with cystic fibrosis. EPA doses ranged from 200 mg to 3.2 g, and study durations ranged from 6 weeks to 6 months. Only 1 small short-term study demonstrated clinical benefit (ie, lung function improvement, sputum volume reduction), and 2 longer-term studies reported increases in essential fatty acid content of white blood cell membranes and serum phospholipids; few adverse effects were reported. Evidence was lacking to draw any conclusions or provide recommendations that would impact clinical practice.(Oliver 2013) A 2016 updated review included 4 randomized controlled trials (N=91) published since 2013 that studied the effect of fish oil in children and adults with cystic fibrosis. Similar to the earlier review, sufficient data were not available to recommend routine use or draw firm conclusions for use in this patient population.(Oliver 2016)

Diabetes

Clinical data

A Cochrane review of 23 randomized trials (maximum duration, 8 months) among patients with type 2 diabetes (N=1,075) found no statistically significant effect on glycemic control or fasting insulin with omega-3 fatty acid supplementation compared to controls (mean differences for hemoglobin A_1c, −0.01% [95% CI, −0.03% to 0.01%], and for fasting plasma glucose, 0.16 mmol/L [95% CI, −0.13 to 0.46]).(Hartweg 2018)

A further meta-analysis of 17 studies with 672 participants (with some overlap of studies included in the Cochrane review) found no effect on insulin sensitivity with fish oil supplementation compared with placebo (standardized mean difference, 0.17; 95% CI, –0.15 to 0.48; P=0.292).(Gao 2017)

Guidelines from the American Diabetes Association (2018) note that dietary supplementation with n-3 fatty acids has not been shown to improve glycemic control in individuals with type 2 diabetes, according to a systematic review.(ADA 2018)

Drug-resistant epilepsy

Clinical data

In a randomized, 3-period crossover trial, low-dose fish oil was associated with a significant 33.6% decrease in seizure frequency in 24 adults (average age, 33 years) with drug-resistant partial-onset or generalized tonic-clonic seizures compared with placebo (P=0.02). Participants received 10 weeks of supplementation with low-dose fish oil (1,080 mg/day), high-dose fish oil (2,160 mg/day), and placebo. A borderline significant 31% reduction was observed for low-dose fish oil compared with high-dose (P=0.05).(DeGiorgio 2015)

Dry eye disease

Clinical data

The benefit of oral omega-3 fatty acid supplementation for signs and symptoms of dry eye syndrome has been demonstrated in several double-blind, randomized, placebo-controlled trials.(Bhargava 2016, Bhargava 2015, Chinnery 2017, Deinema 2017, Risk 2013) Omega-3 fatty acid supplementation provided as EPA 720 mg plus DHA 480 mg daily for 3 months to 456 adults with symptomatic computer vision syndrome(Bhargava 2015) and for 6 months to 130 adults with rosacea and dry eye syndrome(Bhargava 2016) significantly improved outcome measures (ie, dry eye score, tear production, tear film stability, cellular morphology, Meibomian gland score, goblet cell density, wetting outcomes); improvements that were not seen with placebo. Gastric intolerance was the most common adverse effect reported. Similar results were reported by a smaller study (N=27) in which fish oil supplementation (EPA 1,245 mg/day and DHA 540 mg/day) given for 12 weeks in combination with usual dry eye treatment (eye drops) significantly improved subjective eye pain, break-up time of tear film, and rose bengal staining score compared with placebo.(Risk 2013) Effects of omega-3 fatty acids on the neural architecture and immune response of the cornea were investigated in a small follow-up pilot study conducted in 12 adults with moderate dry eye disease who had been part of a larger, double-blind, randomized, placebo-controlled trial. After 3 months of 1.5 g/day of omega-3 (1,000 mg EPA plus 500 mg DHA) or olive oil (as placebo), the total corneal nerve branch and main fiber densities improved significantly (P=0.004 and P=0.03, respectively) compared to placebo. Ocular symptom scores, absolute level of tear osmolarity, and tear osmolarity also improved significantly with treatment (P=0.04, P=0.02, and P=0.04, respectively) compared to placebo.(Chinnery 2017)

A double-blind, randomized, placebo-controlled comparator trial in 60 adults with dry eye syndrome reported some differences in 60- and 90-day outcomes depending upon whether omega-3 fatty acid supplementation was given as either fish oil or krill oil. Both fish and krill oil significantly improved tear osmolarity, tear film stability, and ocular redness at day 90 compared to placebo, as well as a transient significant improvement in ocular surface staining at day 60 but not day 90. Krill oil, but not fish oil, significantly improved the ocular surface disease index at day 90 compared to placebo (P=0.02). Unlike krill oil, fish oil supplementation did not reduce the proinflammatory cytokine IL-17A. Oral daily EPA and DHA doses for each omega-3 fatty acid group were 1,000 mg plus 500 mg for fish oil and 945 mg plus 510 mg from krill oil; olive oil was used as a placebo. Overall, adverse events were similar among all 3 arms. No serious adverse events were reported and no significant changes in intraocular pressure or best-corrected visual acuity occurred.(Deinema 2017)

Gynecological effects

Clinical data

Trials are limited, but suggest a role for fish oil in the management of dysmenorrhea. Reduced requirements for analgesia and reductions in pain have been reported after 2 to 3 months of supplementation.(Durieu 2007, Moghadamnia 2010, Proctor 2001) A Cochrane systematic review and meta-analysis of dietary supplements for dysmenorrhea identified only low- or very low–quality studies with very small sample sizes. Very limited evidence of effectiveness was found for the treatment of primary dysmenorrhea with a fish oil 500 mg/day pearl capsule with or without vitamin B₁ 100 mg/day compared to placebo or no treatment; these data suggest fish oil may not be as effective as vitamin B₁ (1 randomized clinical trial, N=120).(Pattanittum 2016)

A 2017 systematic review and meta-analysis of nutritional supplements and herbal medicines for polycystic ovary syndrome identified 3 studies that investigated omega-3 fish oils; however, data were summarized for only 2 studies (n=95). Incongruences throughout the published paper between reference numbers in the table of studies versus reference numbers in the text led to conflicting data, specifically for fish oil and study doses of EPA and DHA. Although the author states that neither study reported on menstrual regulation, a meta-analysis of the data reported a significant treatment effect for omega-3s associated with reduced total cholesterol (−0.49 mmol) compared to placebo (P<0.001). Mixed findings were reported for several of the secondary outcomes, such as triglycerides, HDL, LDL, BMI, fasting glucose, and insulin resistance.(Arentz 2017)

Hepatoprotective effects

A fish oil–based lipid emulsion is gaining popularity over conventional soybean oil–based parenteral nutrition because of its apparent ability to reduce the incidence of parenteral nutrition–associated liver disease or hepatobiliary dysfunction.(de Meijer 2009, de Meijer 2010, Fallon 2010, Koletzko 2010)

Clinical trials

A randomized controlled trial (N=66) evaluated the hepatoprotective effect of omega-3 fish oil lipid emulsion versus standard parenteral nutrition in adult liver transplant patients diagnosed with end-stage liver disease or hepatic cellular carcinoma. Patients were randomized to either parenteral nutrition with standard 20% lipid emulsion or PUFA, in which omega-3 fish oil emulsion (2 mL/kg/day) replaced part of the standard lipid emulsion. At 2 and 9 days after transplant, ALT and prothrombin time were significantly decreased (P=0.024 and P=0.035, respectively) and on day 9, pathology revealed hepatocyte injury and inflammatory cell aggregation were markedly ameliorated in the PUFA group. Additionally, posttransplant hospital stay was significantly shorter in the PUFA group versus the standard parenteral nutrition group (P=0.041). Potential mechanisms for these effects include immunomodulation and down-regulation of inflammatory responses.(Zhu 2012)

Infant development

Dietary fat is fundamental for the growth and development of infants. DHA is an important component of structural lipids of cell membranes, and its perinatal availability has been related to visual acuity development, neurological development, behavior, and brain growth.(Jensen 2000, Smit 2000) Accretion occurs primarily during the last trimester of pregnancy via the placenta and in the infant's first year of life from breast milk and dietary sources.(Simmer 2001, Simmer 2004)

Clinical data

Evidence from systematic reviews provides little support for supplementation with LCPUFAs, such as DHA, to either term or preterm infants.(Makrides 2014, Simmer 2001, Simmer 2004) Formula-fed infants have been shown to have less DHA than infants fed breast milk. Reduced neural function and visual acuity have been documented in preterm infants fed formula relative to those who were breastfed. A review of LCPUFA supplementation studies demonstrated no benefit to visual or cognitive development in infants born at term receiving LCPUFA-supplemented formula.(Simmer 2001) However, some evidence did show that omega-3 fatty acid–supplemented formula increases the early rate of visual maturation in preterm infants.(Simmer 2004) Additionally, multivariate analysis revealed that risk of "retinopathy of prematurity" was significantly decreased in very low–birth-weight (less than 1,500 g) preterm infants who received fish oil lipid emulsion in their total parenteral nutrition compared with those who did not (5% vs 32.5%, respectively; OR, 0.76; 95% CI, 0.06 to 0.911; P=0.04).(Beken 2014)

Malnourished infants, who may have poor fat absorption, appear to absorb fish oil supplements well and use this source of fatty acid for more than an energy source.(Smit 2000)

Although formula supplemented with omega-3 fatty acids increases DHA and EPA levels in healthy and malnourished infants, this may be at the expense of omega-6–derived fatty acids (eg, arachidonic acid). Because high levels of DHA and EPA appear to successfully compete for cyclooxygenase and other eicosanoid enzymes, formula-fed infants should be supplemented with omega-3 as well as omega-6 LCPUFAs if their fatty acid status is to be comparable with that of the breastfed infant.(Jensen 2000, Lapillonne 2000, Smit 2000)

Inflammatory bowel disease

Animal data

In animal models of inflammatory bowel disease, fish oil has been shown to exert a protective effect, which is considered to be via anti-inflammatory mechanisms.(Turner 2011)

Clinical data

Cochrane meta-analyses and systematic reviews of randomized controlled trials have evaluated the effects of omega-3 fatty acids on induction of remission in ulcerative colitis and for maintenance of remission of ulcerative colitis and Crohn disease.(De Ley 2007, Turner 2007, Turner 2007) For induction of remission in ulcerative colitis, trials were of crossover and parallel design, and because of heterogeneity of outcomes and methodology, the data were not pooled. Of the 6 included studies, 1 small study showed benefit for induction within 3 months. The other trials showed benefit only for secondary outcome measures, and no recommendation could be made regarding the effect of fish oil supplementation.(De Ley 2007) For maintenance of remission in ulcerative colitis(Turner 2007) and Crohn disease,(Turner 2007) relapse rates were similar for omega-3 fatty acids and the control intervention. The Crohn disease meta-analysis included data from both of the large EPIC trials; its conclusion that omega-3 fatty acids have no effect on maintenance of remission is an update on previous meta-analyses.(Turner 2007) A Cochrane 2014 updated systematic review for Crohn disease concluded that omega-3s were probably ineffective for maintenance of remission based on the pooled analysis that had no significant heterogeneity. Interventions included both enteric-coated and gelatin capsules, with EPA and DHA doses ranging from 1.2 to 3.3 g/day and 0.6 to 1.8 g/day, respectively, while placebo capsules contained corn oil, olive oil, or medium-chain triglyceride oil (ie, caprylic and capric acid).(Lev-Tzion 2014)

Menopause

Clinical data

A double-blind, randomized, placebo-controlled trial conducted in 180 postmenopausal (natural) women investigated the effect of omega-3 fatty acid or soybean supplementation on menopausal symptoms. Daily supplementation with omega-3 fatty acids 1,000 mg (EPA 180 mg, DHA 120 mg), soybean extract 500 mg, or placebo for 3 months resulted in significant improvements with both active interventions compared to placebo for the overall Menopause Rating Scale score (P<0.001) with no difference between the omega-3 and soybean groups. Likewise, significant differences were observed for both active interventions compared to placebo in subscale scores related to hot flushes/sweating, sleep problems, somato-vegetative symptoms, depression, and psychological scores with no significant differences between omega-3 fatty acid and the soybean extract groups. All treatments were well tolerated.(Purzand 2020)

The Endocrine Society clinical practice guidelines for the treatment of symptoms of the menopause (2015) recommend counseling patients on the lack of consistent evidence for benefit of complementary medicine therapies, including fish oils, as an alternative nonhormonal therapy for vasomotor symptoms (weak recommendation; low-quality evidence).(Stuenkel 2015) The North American Menopause Society position statement for nonhormonal management of menopause-associated vasomotor symptoms (2015) states that data from 2 trials are equivocal with regards to the effect of omega-3 fatty acids on menopausal vasomotor symptoms (Level II).(NAMS 2015)

Obesity

Clinical data

A double-blind, randomized controlled trial found no significant difference in weight reduction, fat mass reduction, or inflammatory biomarkers with fish oil or placebo in parallel groups that followed a low-energy diet for 12 weeks. However, significant correlations were identified in the fish oil group between leptin and weight change, fat mass, EPA, and DHA.(Munro 2013) Similar results were also found in another randomized, double-blind, placebo-controlled, parallel trial (N=97) conducted in otherwise generally healthy overweight and obese women (BMI, 27.5 to 40) on a 30% calorie-restricted diet for 10 weeks. Significant changes in waist-to-hip ratio were observed in the EPA 1,300 mg/day group (EPA plus DHA 1,341 mg/day) but not in the alpha-lipoic acid (300 mg/day), alpha-lipoic plus EPA, or placebo groups; whereas a significant increase in weight loss was noted only in the alpha-lipoic group. Total cholesterol was reduced significantly in all 4 groups; however, the EPA groups also experienced significant changes in LDL cholesterol (P<0.05), beta-hydroxybutyrate (P<0.05), triglycerides (P<0.01), and diastolic blood pressure (P<0.05). The decline in leptin levels that accompanied the fat loss was significant in all groups except for the EPA group, in which the nonsignificant reduction in leptin was associated with a positive significant effect on resting metabolic rate (r=0.42; P<0.001).(Huerta 2015)

Omega-3 fatty acid deficiency

The 2016 Academy of Nutrition and Dietetics' (AND) updated position statement on vegetarian diets states that omega-3 fatty acid intake, specifically EPA and DHA, is lower in vegetarians and typically absent in vegans compared with non-vegetarians. A good source of omega-3 fatty acids, including alpha-linolenic acid (ALA) such as flaxseed, chia seeds, hemp seeds, walnuts, and their oils, should be included in the diet of vegetarians, whereas those with increased requirements, such as pregnant and lactating individuals or patients with hypertension or diabetes who have reduced ALA conversion, would benefit from DHA-rich microalgae supplementation.(Melina 2016)

Osteoarthritis

Clinical data

The American College of Rheumatology/Arthritis Foundation (ACR/AF) guideline for the management of osteoarthritis of the hand, hip, and knee (2019) conditionally recommends against the use of fish oil in patients with knee, hip, and/or hand osteoarthritis (Low-Very Low). Risk versus benefit is fairly well balanced and necessitates a shared decision between the patient and clinician.(Kolasinski 2020)

Psoriasis

Clinical data

Older trials are inconclusive regarding clinical benefit of n-3 fatty acid supplementation in patients with psoriasis or atopic dermatitis.(Berth-Jones 1993, Bjørneboe 1989, Søyland 1994, Søyland 1993, Veale 1994) A Cochrane review notes some positive outcomes on effects on daily living, area affected, and itch in a couple studies, although these were of poor quality; a larger trial showed no benefit over placebo.(Bath-Hextall 2012) A systematic review of alternative therapies for psoriasis found equivocal data for the use of fish oil in patients with mild to moderate psoriasis. Effectiveness at various doses and durations was not supported.(Gamret 2018)

The joint American Academy of Dermatology and National Psoriasis Foundation (AAD-NPF) guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures (2020) states that the use of topical omega-3 fatty acids (fish oils) may be useful as an adjunct to other topical and oral systemic therapies, and phototherapy for chronic plaque psoriasis, but not as monotherapy. No evidence-based recommendations were made.(Elmets 2020)

Renal effects

Clinical data

The ability of n-3 fatty acids to reduce eicosanoid production or action has led to the testing of dietary fish oil in patients with immunoglobulin A (IgA) nephropathy. In these patients, the initial immunological renal injury evokes cytokine and eicosanoid activity. Dietary fish oil has been tested in patients with several types of renal disease with varying results. Results in patients with IgA nephropathy are conflicting.(Lorenz 1989) The use of fish oil on lipoprotein A in end-stage renal disease and among kidney transplant recipients has also been evaluated.(Beavers 2009, Lim 2007)

A systematic review and meta-analysis of 13 randomized clinical trials (N=916) assessed the efficacy of fish oil supplementation on maintenance hemodialysis. Compared with placebo, supplementation with fish oil significantly improved arteriovenous graft thrombosis, cardiovascular events, depression scores, secondary hyperparathyroidism, C-reactive protein, and triglycerides, without significant heterogeneity. No significant difference was found for lipids, some inflammatory biomarkers, or mortality. Dose subanalysis for less than 2 g/day and 2 g/day or more found no significant difference in these effects. Based on the studies reviewed, the authors suggested a dose of 1 to 2 g/day would be effective and well tolerated in this high-risk group; specific EPA or DHA was not noted. This suggestion was considered in line with the AHA recommendation for patients at high cardiovascular risk (1 g/day with an omega-6 to omega-3 dietary ratio of 4).(He 2016)

Respiratory infections

Clinical data

A 200 mL drink containing fish oil (DHA 550 mg plus EPA 550 mg), vitamin D₃ 10 mcg, and whey protein 8 g twice daily for 16 weeks in young athletes did not provide a significant difference in the incidence, severity, or duration of upper respiratory tract infections; number of practitioner visits; or number of times medication was taken compared with placebo. However the total number of symptom days reported was significantly shorter with the intervention than placebo (1.72±1.67 vs 2.79±1.76; P<0.05).(Da Boit 2015)

In a large, quadruple-blind, randomized, placebo-(corn oil) controlled study conducted in Norway (N=37,741), no significant difference was found in positive SARS-CoV-2 PCR test results (1.31% vs 1.32%), serious covid-19 infections (0.70% vs 0.58%), admissions to hospital for COVID-19 (n=8 vs n=9), admissions to ICU for COVID-19 (n=4 each), more than 1 negative SARS-CoV-2 test (49.5% vs 49.4%), or at least 1 acute respiratory tract infection (22.9% vs 22.1%) among generally healthy participants who consumed cod liver oil versus those on placebo. Overall, the majority of patients had no chronic disease (73.4%), had more than 30 hours of sun exposure from July to October 2020 (58.4%), did not take vitamin D supplements (75.5%) but consumed fatty fish at least 1 to 2 days/week (61.5%), and had never smoked (51.4%). Their mean BMI at baseline was 26.1, 64.6% were female, 2.1% had a positive antibody test, and 35.6% reported having at least 1 SARS-CoV-2 vaccine during the study period, which ran from December 21, 2020 through June 2, 2021. These effects were not modified by covariates of sex, age, BMI, skin type, sun exposure, use of vitamin D supplements, vaccination status, consumption of fatty fish, or strict compliance. The intervention was 5 mL/day cod liver oil that provided vitamin D 10 mcg, EPA 0.4 g, DHA 0.5 g, vitamin A 250 mcg, and vitamin E 3 mg, whereas the corn oil placebo provided vitamin A 15.8 mcg and vitamin E 38 mg. Although, no statistically significant difference was found in blood levels of 25(OH)D₃ between groups, the significant reduction in 25(OH)D₃ observed in the placebo group in winter (−12.5 nmol/L; P<0.001) was prevented in the cod liver oil group (+15 nmol/L; P<0.001). Additionally, cod liver oil led to a significant increase in omega-3 index by 1.9% (P<0.001) while placebo led to a significant decrease (−0.5%; P<0.001). The incidence and types of side effects were similar between groups.(Brunvoll 2022)

Rheumatoid arthritis

EPA is a substrate that competes with arachidonic acid for the generation of less active eicosanoid metabolites (eg, leukotrienes) and acts to reduce inflammation.(Woods 2002) The most profound anti-inflammatory effects of n-3 fatty acids are on neutrophil function and mediator generation, providing a more likely benefit in neutrophilic inflammatory diseases, including arthritis.(Mori 1992)

Clinical data

Inuit populations with a diet high in LCPUFAs (especially EPA and DHA from seal and fish oils) report a low incidence of rheumatoid arthritis.(James 2010) Meta-analyses of controlled trials have been conducted with equivocal findings.(Goldberg 2007, James 2010, MacLean 2004) Issues raised by the analyses include confounding results with the use of potentially active placebo oils (eg, corn and olive oil) and management of dropouts in the individual trials.(James 2010, Kremer 2000) Reductions in patient-reported joint pain and morning stiffness and a reduced need for nonsteroidal anti-inflammatory drugs are potential benefits of fish oil therapy, while reduction in cardiovascular risk may also be a valuable attribute.(James 2010)

A minimum daily dose of EPA/DHA 3 g appears to be necessary to reduce the release of leukotriene B₄ from stimulated neutrophils and of IL-1 from monocytes, while dosages of more than 6 g/day do not appear to confer any additional benefit.(Joy 2000)

In disease-modifying antirheumatic drug (DMARD)–naive adults with rheumatoid arthritis onset of less than 12 months, high-dose fish oil (5.5 g/day) significantly reduced failure of triple DMARD therapy (methotrexate, sulfasalazine, hydroxychloroquine) compared with control (0.4 g/day of fish oil) at the 1 year follow-up (P=0.002 unadjusted; P=0.0006 adjusted). Time to first remission was also significantly less in the high-dose fish oil group (P=0.03 unadjusted; P=0.04 adjusted).(Proudman 2015)

Vegetarian diet

Clinical data

The Academy of Nutrition and Dietetics' updated position paper on vegetarian diets (2016) states that adequate nutrition can be provided by a well-planned vegetarian diet that includes legumes. Therapeutic vegetarian diets are useful in maintaining a healthy weight and BMI and are associated with a reduction in cardiovascular disease risk and type 2 diabetes. Walnuts, seeds (ie, chia, flax) and their oils are some of the most concentrated plant sources of omega-3 fatty acids. Special consideration for omega-3 fatty acids is required for pregnant and lactating vegetarians or those with reduced ability to convert alpha-linolenic acid to EPA and DHA (ie, vegetarians with hypertension or diabetes).(Melina 2016)

Dosing

The AHA recommends a minimum of 2 fatty fish servings per week.Krauss 2000, Roth 2010 Clinical trials suggest fish oil supplementation of omega-3 fatty acid 1 g/day in coronary heart disease, and when triglycerides are elevated, a minimum of omega-3 fatty acid 2 g/day, up to a maximum of 4 g/day. Fish oil supplements generally contain 1,000 mg of fish oil, which approximates to 300 to 400 mg of EPA and DHA.Roth 2010 Krill oil has been used in doses ranging from 500 mg/day to 4 g/day given for a duration of 4 weeks to 3 months.Ursoniu 2017

Emulsified oral preparations have been developed to improve the taste over encapsulated fish oils and may increase digestion and absorption of the fatty acids via modifications in solubility.Raatz 2009 Encapsulated oils have been found to oxidize and become rancid over time and with processing method, which may have an effect on total EPA/DHA delivered.Farooqui 2007, Poppitt 2009

Pregnancy / Lactation

Documented adverse effects have occurred in pregnancy and lactation. In 2004, the FDA recommended that pregnant women avoid certain fish due to the potential for mercury contamination; however, June 2014 draft revisions encourage pregnant women, those of child-bearing age, breastfeeding mothers, and young children to eat 2 or 3 servings (approximately 4 oz per serving) of low-mercury varieties of fish each week.FDA 2014 The Food and Agriculture Organization of the United Nations and the World Health Organization recommend daily intake of omega-3 supplementation during pregnancy.Saccone 2015 Farmed salmon may have a greater potential for contamination than wild sources.de Leiris 2009, Farooqui 2007, He 2009

Omega-3 fatty acids may prevent preterm birth via delayed induction of labor and cervical ripening through the inhibition of prostaglandin F₂-alpha and E₂ production, and by relaxation of the myometrium. A 2007 Cochrane meta-analysis found that mean gestation was 2.6 days longer (95% CI, 1.03 to 4.07) in women who took fish oil supplementation. No significant difference was found for the relative risk of birth before 37 weeks, while a significant decrease in the risk of birth before 34 weeks gestation was found (RR, 0.69; 95% CI, 0.5 to 0.99).Secher 2007 A 2015 meta-analysis of randomized clinical trials (N=3,854) in women carrying singleton gestations without prior preterm birth found no significant effect of omega-3 supplementation on rate of preterm birth before 37 weeks compared with controls. However, in a subgroup analysis in women who received EPA plus DHA, mean birth weight was significantly higher (mean difference, 51.18 g). Additionally, perinatal death rate was lower in women receiving omega-3s before 21 weeks of gestation compared with controls.Saccone 2015

A study in which fish oil supplementation was taken starting at pregnancy week 22 suggested an increase in oxidative stress in the plasma at week 30.Franke 2010 Effects of fish oil on lipids and blood pressure do not appear to be sustained during pregnancy.Barden 2006

While evidence indicates that the DHA and EPA composition of breast milk is affected by fish oil supplementation, there is little evidence supporting benefit to the infant.Jensen 2000, Simmer 2001, Simmer 2004, Smit 2000 Use of fish oil supplementation during pregnancy and breastfeeding to reduce the incidence of food allergy in infants has also been evaluated.Furuhjelm 2009

Interactions

Agents with antiplatelet properties: Omega-3 fatty acids may enhance the antiplatelet effect of agents with antiplatelet properties. Monitor therapy.(Goodnight 1981, Hay 1982, Juan 1989, Larson 2008, Mayer 2002, Serebruany 2011, Thorngren 1981)

Anticoagulants: Omega-3 fatty acids may enhance the anticoagulant effect of anticoagulants. Monitor therapy.(Buckley 2004, Englyst 2007, Freese 1997, Goodnight 1981, Heller 2002, Juan 1989, Lovaza September 2012, McClaskey 2007, Møller 1992, Nelson 1997, Nilsen 1993, Radack 1990, Sakamoto 2000, Sanders 1981, Serebruany 2011, Shahar 1993, Shimizu 1995, Thorngren 1981, Tomer 2001, Vanschoonbeek 2004, Vascepa July 2012, Yoshimura 1987)

Ibrutinib: Omega-3 fatty acids may enhance the antiplatelet effect of ibrutinib. Monitor therapy. The Canadian ibrutinib product monograph recommends avoiding this combination.(Imbruvica November 2014, Imbruvica July 2014)

Adverse Reactions

EPA/DHA at dosages ranging from 2 to 5.4 g/day has been well tolerated. In clinical trials, only mild GI-related adverse effects such as dyspepsia, diarrhea, and nausea were reported.Chen 2010, León 2008, Turner 2007, Turner 2007, Wang 2006 An increased risk of diarrhea was noted in a meta-analysis of trials conducted among patients with inflammatory bowel disease who were given enteric-coated, timed-release capsules.Turner 2011

Prolonged bleeding time was noted during and after cardiac surgery in a 55-year-old man despite cessation of oral antiplatelet medications a week prior to surgery. Dramatic clinical improvement was noted immediately following transfusion of donor platelets. Follow-up detailed inquiry revealed a 3-month history of supplementation with garlic-thyme (20 mg to 100 mg/day) and fish oils (EPA 675 mg plus DHA 450 mg daily), both reported to potentially inhibit platelet aggregation.Bedi 2016

A safety study in subjects with schizophrenia found similar adverse events for intervention (EPA 2 g/day for 12 weeks) and placebo groups. Increased BMI and increased bleeding time were reported. In an open-label extension, there was again a modest increase in BMI.Emsley 2008

Although an increase in LDL cholesterol has been occasionally reported, evidence does not suggest that the risk is greater than the benefit related to increased fish oil consumption.Eslick 2009, He 2009

Fish oil supplementation should be used with caution in individuals allergic to seafood.

Toxicology

Research reveals limited information regarding toxicity with the use of fish oil supplementation. Omega-3 acid ethyl esters have shown an embryocidal effect in pregnant rats when given in doses 7 times the recommended human dose of 4 g/day based on a body surface area comparison.Lovaza September 2012

Index Terms

• Krill oil

References

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