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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 Oct 23, 2018.

Clinical Overview

Use

Clinical benefit is strongest for lowering the risk of coronary artery disease and decreasing serum triglycerides. Reductions in the risk for all-cause mortality, cardiac death, and sudden death have been established for omega-3 fatty acid supplementation for at least 1 year's duration. The United States Food and Drug Administration (FDA) has approved the use of fish oil for reducing very high triglyceridemia (at least 500 mg/dL [5.65 mmol/L]) in adults as an adjunct to diet. Evidence for use of parenteral fish oil lipid emulsion is mounting in severely ill and surgical patients. Evidence for a role in rheumatoid arthritis remains equivocal but promising. No consistent relationship between fish oil consumption and reduction in the risk of stroke or 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, mental health, and the promotion of postnatal growth and development.

Dosing

The American Heart Association (AHA) recommends a minimum of 2 fatty fish meals 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 1,000 mg approximates to omega-3 fatty acids (eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA]) 300 to 400 mg.

Contraindications

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

Pregnancy/Lactation

Potential for mercury ingestion. Eat fish lower in mercury and avoid consumption of high-mercury containing fish, such as tilefish from the Gulf of Mexico, swordfish, king mackerel, and shark.

Interactions

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

Adverse Reactions

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

Toxicology

Research reveals little or no information.

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 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 than grain-fed comparators.199 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.1, 2, 3

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.1, 2, 3, 4, 5

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.6, 7 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 plants have not yet been surmounted.8, 9

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.10, 11 In 1789, a publication described the beneficial effects of cod liver oil in rheumatism, and in 1824 the same oil was reported effective in the prevention of rickets.12 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 polyunsaturated fatty acids.2, 3

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.2, 3 C-13 nuclear magnetic resonance pattern recognition has been used to analyze the species of fish from which commercial fish oil products are derived.13 Homogenization of fish oils into milk has been explored.14 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 product.

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.2, 3, 15

Antiinflammatory

In a randomized, double-blind, placebo-controlled trial, 261 healthy adults received fish oil supplementation (EPA + DHA 1,400 mg) or placebo for 18 weeks to determine the effects on biomarkers of chronic, systemic inflammation. This dose of fish oil had no effect on serum c-reactive protein or IL-6 concentrations with no evidence of heterogeneity found based on gender, body mass index, baseline IL-6, or post-supplementation red blood cell EPA+DHA. Side effects associated with the intervention included fishy belch or aftertaste, loose stool, and bloating or gas pains; no serious adverse events were reported.175

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 that investigated 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 given 3 times daily) was given orally 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.189

Arrhythmias

Animal data

Studies in animals have demonstrated pro- and anti-arrhythmic properties of fish oil.24, 25 In experimental arrhythmias, fish oil prevented arrhythmias related to ischemia, but not to reperfusion injury.24

Clinical data

Reviews have examined the utility of fish oils in treating arrhythmias. The mechanism of protection is not well understood, and some classes of patients may not benefit.26, 27, 28 A meta-analysis of all studies up to the year 2008 for ventricular arrhythmias found only a trend of a protective effect of fish oil on time to first ventricular fibrillation. Dosages used in the included trials ranged from fish oil 900 to 2,600 mg.29, 30 A further meta-analysis found a nonsignificant reduction in the primary outcome of arrhythmias or death from all causes. For the secondary outcome of death from cardiac causes, a reduction was found.31 Results from the 2003 Diet and Angina Randomized Trial (DART-2) found an increase in death in patients with angina pectoris, and in patients with implanted cardioverter defibrillators, no overall effect on the risk of discharge has been found, possibly because of the potential for fish oil to exhibit pro-arrhythmic properties.25, 32

Two meta-analysis evaluating fish oil’s impact on atrial fibrillation (AF) have been published. One pooled data from studies of perioperative fish oil administration on the incidence of postoperative AF. The sum of the evidence from 8 studies (n = 2687) was that fish oil did not significantly reduce the incidence of postoperative AF, length of hospital stay or intensive care unit (ICU) days, postoperative mortality, or major bleeding. Additional analysis found that studies using fish oil with DHA doses more than 1 g/day did have a significantly lower incidence of postoperative AF, and length of hospital stay.147 The other meta-analysis looked at the incidence of AF recurrence (8 studies, n = 1990) in adult patients undergoing cardioversion or with symptomatic persistent/paroxysmal AF in sinus rhythm. There was no significant reduction in incidence of AF recurrence with fish oil compared with placebo with data from all 8 studies. Subsequent analysis showed that when data from the 3 studies that initiated fish oil at least 4 weeks prior to cardioversion was pooled, a significant reduction in AF recurrence was seen with fish oil versus control. And pooling of data from the 5 studies that did not initiate fish oil at least 4 weeks prior to cardioversion found that fish oil significantly increased the incidence of AF recrurrence.148

Asthma/Allergy

Clinical data

To date, clinical benefit of fish oil in asthma is controversial.10, 16 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.10 The role of other constituents in fish oil is unknown. Limited evidence exists of an effect of fish oils on exercise-induced asthma.17 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.18 Use of fish oil supplementation during pregnancy and breast-feeding 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 of life in children with a hereditary risk. 19, 159 In contrast to these results, the risk of persistent wheeze or asthma was reduced by a third in children (from birth to between 3 and 5 years of age) born of women who received 2.4 g/day of n3-LCPUFA. In this 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 pre-trial dietary intake of EPA and DHA was in the lowest third (<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).186 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 n3-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.158

Older trials are inconclusive regarding clinical benefit of n-3 fatty acid supplementation in patients with psoriasis or atopic dermatitis.4, 20, 21, 22, 23 A Cochrane review notes some positive outcomes on effect on daily living, area affected, and itch in a couple of studies, although these were of poor quality; a larger trial showed no benefit over placebo.145 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.198

The National British Clinical guidelines on the management of asthma (2012) states that in the absence of any evidence of benefit from the 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 management of asthma.134

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.89 A molecular effect on lipid-modified protein trafficking was postulated as a mechanism by 1 review,90 while immunomodulatory effects on T-cell function and subsets were invoked by the same group.91 Other molecular targets of n-3 PUFAs in cancer have been reviewed.92 A 2-year randomized controlled trial in polypectomized patients (N = 352) found that dietary advice to increase omega-3 fatty acids (ie, increased fish consumption, 456 mg/day EPA:DHA fish oil supplementation, ALA-rich perilla oils) and reduce 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 while reducing ratios of omega-6s:omega-3s in the experimental group at 12 and 24 months 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.174

The American Society of Clinical Oncology clinical practice guidelines for prevention and management of chemotherapy-induced peripheral neuropathy (CIPN) in survivors of adult cancers (2014) made no recommendations on the use of omega-3-fatty acids for the prevention of CIPN due to inconclusive evidence (low-quality evidence, inconclusive).161

Cardiovascular disease

Clinical data

A potential role for fish oils in cardiovascular disease risk reduction first came from observations of Inuit populations in Greenland. Despite ingesting up to 40% of calories as fat (mostly from marine sources), this group exhibited a lower incidence of coronary artery disease compared with individuals on a more conventional diet.33

Systematic reviews and meta-analyses have been published on trials evaluating the effect of fish oil supplementation on coronary heart disease. Reductions in the risk for all-cause mortality, cardiac death, and sudden death have been established for omega-3 fatty acid supplementation for at least 1 year's duration. Although, a 2013 meta-analysis of 9 randomized controlled trials (n = 32,919) showed a statistically nonsignificant reduction in risk of ventricular arrhythmias or sudden death compared with placebo; heterogeneity was moderate.141 A sub-analysis with significantly less heterogeneity revealed a strong trend towards benefit in patients with recent myocardial ischemic events.141 Evidence for secondary prevention of coronary heart disease (CHD) is greater than that for primary prevention and is informed mainly by 3 large trials; the GISSI trials (Italy) and the JELIS (Japan) trial and an older study with ALA. Evidence from these meta-analyses is inconclusive for prevention of stroke and nonfatal myocardial infarction (MI).28, 30, 34, 35, 36 At daily doses less than 2 g EPA (range, 226 to 1,800 mg) and less than 2 g DHA (range, 0 to 1,700 mg), a meta-analysis of 10 randomized controlled trials (N=77,917; range, 563 to 18,645) at high-risk of CHD who had a history of prior CHD, stroke, and/or diabetes found no significant association of these doses with any CHD event, major vascular events, or all-cause mortality. The mean age at study entry was 64 years, and the duration of treatment ranged from 1 to 6.2 years (mean, 4.4 years).195

The GISSI-Prevenzione trial enrolled 11,324 patients with CHD (post-MI) and evaluated omega-3 fatty acid supplementation compared with vitamin E. A reduction was found for the primary end point of a combined outcome of death, nonfatal MI, and stroke for omega-3 fatty acids.34, 37 Data from the GISSI heart failure trial (n = 7,046) allows for a calculation of 56 patients with preexisting heart to be treated with omega-3 fatty acid supplementation for 3.9 years to avoid 1 death, or 44 patients to be treated for the same length of time to avoid 1 death or hospital admission for cardiac causes. No benefit for the prevention of stroke was found. For the primary prevention of CHD, the GISSI heart failure trial found a nonsignificant effect for omega-3 fatty acids. The JELIS trial enrolled 18,645 persons with hypercholesterolemia and found a reduction in the risk from a major coronary event, including sudden death and MI, and found evidence of secondary protection against the risk of stroke.30, 34 A randomized, double-blind, controlled study (n = 12,505) using olive oil for the control group evaluated the effect of fish oil 1 g/day for 5 years in patients with no prior MI, but with atherosclerotic disease or multiple cardiovascular risk factors. No significant difference between fish oil and olive oil was seen for incidence of cardiovascular death or hospital admission for cardiovascular causes.149 Some questioned the selection of olive oil as the “placebo” in letters to the editor, but the chief investigators defended their choice, in part, by stating that the dose of 1 g/day of olive oil was lower than the dose found to be beneficial in other studies.150

An ancillary Cardiovascular Outcomes Study of the Age-Related Eye Disease Study 2 evaluated the effect of omega-3 fatty acids (DHA 350 mg/day + EPA 650 mg/day) versus macular xanthophylls (lutein 10 mg/day + zeaxanthin 2 mg/day) versus a combination of the 2 versus placebo on cardiovascular outcomes in 4,203 AREDS patients (median age, 74 years) over a median of 4.8 years. Only patients with a negative baseline history for hypertension, cardiovascular disease (CVD), or hypercholesterolemia showed significant protective effects from either group of supplements. A significant interaction was found with the omega-3 fatty acid treatment and history of CVD and with history of hypertension. Serious hyponatremia requiring hospitalization that was considered possibly related to the supplements occurred in one 76-year-old patient who was randomized to the combination supplement group.151

A large (n = 13,578), older study found no effect of ALA supplementation on cardiovascular outcomes.30 Similarly, in a longitudinal study within the PREDIMED trial (a randomized nutrition intervention trial for the primary prevention of CVD conducted in Spain), consumption of ALA was associated with a significant reduction by 28% in overall mortality (P=0.013) but not cardiovascular mortality. A total of 7,202 participants 60 to 80 years of age, at high risk of CVD (but with no CVD), and who have a diet high in marine n-3 fatty acids (ie, seafood) were randomized to a Mediterranean diet plus extra virgin olive oil (1 L/week) or plus mixed nuts (30 g/day), or a control diet. Significant reductions in fatal CVD (by 39%) and CHD (by 46%) were evident in those who consumed ≥500 mg/day of EPA plus DHA (P=0.032 and P=0.046, respectively). Additionally, those allocated to the MedDiet plus extra virgin olive oil experienced a significant 42% reduction in total mortality. The highest reduction in all-cause mortality was documented in participants who met both the ALA requirement (0.7% of their total energy) and the long-chain n-3 fatty acid requirement (≥500 mg/day of EPA plus DHA; P=0.005).185 In healthy young adults (n = 328), vascular function and some risk factors for cardiovascular disease (ie, triglycerides, very low density lipoprotein concentrations) were improved by supplementation of 1.6 g/day of DHA for 4 months; however, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, as well as blood pressure, fasting insulin, glucose, and c-reactive protein were unchanged.146 Evidence is inconclusive for the effect of fish oils on hypertension and is based on older studies.38, 39, 40, 41, 42 Reductions in heart rate, especially where the resting rate is higher than 69 bpm, have been demonstrated in some, but not all, studies of 12 weeks of fish oil supplementation.43, 44, 45 Effects of fish oil supplementation on C-reactive protein (a marker for coronary heart disease) are equivocal.46, 47

A meta-analysis of 10 randomized controlled trials (N = 550) using long-chain n-3 fatty acids (ie, DHA or EPA) monotherapy at a specific dosage for more than 1 month that evaluated effects on arterial stiffness found statistically significant improvements in pulse wave velocity (P < 0.01) and arterial compliance (P < 0.001) compared to controls. Participants received daily doses of 640 to 3,000 mg of combined EPA and DHA capsules for 6 to 105 weeks. No evidence of heterogeneity or publication bias was found.184

CNS effects

Clinical data

Polyunsaturated fatty acids, including DHA, are essential for normal brain development and any deviation from normal levels is associated with cognitive impairment.12 Data from adequately controlled clinical trials are insufficient to make definitive statements about omega-3 fatty acid supplemental in specific mental health disease. Limited trials have evaluated fish oil supplementation in schizophrenia and in attention deficit hyperactivity disorder with equivocal results.12, 48, 157 The OFFER trial, a randomized controlled trial of omega-3 fatty acids in first-episode schizophrenia, will compare 26 weeks of EPA plus DHA as add-on therapy to olive oil placebo for effects on symptoms and relapse rates.173

Children (N = 200) 8 to 16 years of age with antisocial and aggressive behavior problems were randomized to either a daily supplement drink containing omega-3 1,000 mg (DHA 300 mg, EPA 200 mg, DPA 100 mg, and alpha-linolenic acid 400 mg) or placebo for 6 months in a double-blind fashion. Omega-3 supplementation led to significant group x 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.163 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, 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, almost 40% (38.5%) of children in the study exhibited fatty acid insufficiency at baseline.167

Clinical trials are more supportive of a place in therapy of depression for fish oils, although specific sub-populations are considered more likely to benefit, including perinatal depression, childhood/adolescent depression, and depression associated with bipolar disorder.49, 50, 51 Guidelines have been published discussing the relationship between fish oils and major depressive disorder (MDD). The American Psychiatrist Association Practice Guideline for the Treatment of Patients With MDD discusses evidence for omega-3 fatty acids and states that most of the data have been adjunctive studies and are limited by heterogeneity in study design, dose, duration, and outcomes. Further data are needed. No recommendation is provided.136 The Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of MDD in adults (2016) recommends omega-3 fatty acids as second line monotherapy or adjunctive therapy in mild to moderate MDD (Level 1) and second-line adjunctive therapy for moderate to severe disease (Level 2).137 A 2015 Cochrane review assessing omega-3 fish oils for MDD in adults concluded that combined EPA:DHA doses less than 6.6 g/day, sole EPA doses not greater than 4 g/day, sole DHA doses not greater than 2 g/day, or EPA:DHA and other n-3 PUFAs not greater than 3.13 g/day provided a small to modest benefit in depressive symptoms compared to placebo that was of statistical, but not likely clinical, significance. This was based on 25 very low quality studies (N = 1,373). The one study comparing EPA to antidepressant therapy found a comparable effect between EPA 1 g/day and fluoxetine 20 mg/day (n = 40).172 Similar results were reported from a 12-week, double-blind, randomized, placebo-controlled trial in 35 Koreans with documented MDD. Supplementation with 1,740 mg/day of n-3 PUFAs significantly improved 1 of the 4 depression rating scales; however, the difference was not clinically significant.178 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 Beck Depression Inventory scores in this patient population without significant heterogeneity among studies.177 To explain heterogeneity experienced in previous meta-analyses, a meta-regression analysis tested the effects of EPA and DHA dose, EPA:DHA ratio, percentage of antidepressant users, baseline MDD symptom severity, study duration, patient age, publication year, and study quality on the effectiveness of n-3 PUFAs for the treatment of MDD. The meta-analysis of 13 randomized clinical trials (N = 1,233) found an overall beneficial effect of n-3 PUFAs on depressive symptoms in MDD (P = 0.006, random effects model). Meta-regression tests showed that statistically significantly better outcomes were associated with higher EPA dose, higher percentage of antidepressant users, and earlier publication year (P = 0.009, P = 0.044, P = 0.04, respectively). No significant publication bias was identified.181

While there is evidence of an association of dementia with low levels of n-3 fatty acids in diet and plasma, supplementation with fish oil has not been shown to reverse or prevent dementia52 or to improve quality of life indices in elderly patients.53

A 12-month randomized, double-blind, placebo-controlled comparator trial (n = 39) in patients with probable mild Alzheimer disease (Mini-Mental State Examination [MMSE] 15-26; Clinical Dementia Rating Scale 0.5-1) found no difference in oxidative stress marker (F2-isoprostane) levels in patients receiving either combination therapy of ALA (600 mg/day) plus omega-3 fatty acids (DHA 675 mg/day, EPA 975 mg/day), monotherapy with omega-3 fatty acids, or placebo (that contained 5% fish oil). However, over 12 months the combination therapy significantly decreased cognitive and functional decline (MMSE and Instrumental Activities of Daily Living, respectively).152 In contrast, a 16-week, randomized, double-blind, placebo-controlled trial randomly assigned 160 healthy adults to fish oil 3 g (EPA 240 mg/DHA 240 mg) plus a multivitamin, fish oil 6 g (EPA 480 mg/DHA 480 mg) with and without a multivitamin, or placebo to determine effects of fish oil on cognitive and cardiovascular function. Each fish oil capsule contained fish oil 1 g (80 mg each of EPA and DHA) plus 50 units of vitamin E; it should be noted that the multivitamin also contained 21 herbal and other natural products plus probiotics. The arachidonic acid (AA)/EPA ratio improved in all treatment groups compared to placebo confirming compliance. EPA increased significantly only in the fish oil 6 g groups: by 57% without the multivitamin and by 96% with the multivitamin. No effects on any of the cognitive function scores such as information processing speed, attention, and memory were observed at 16 weeks; however, a significant time by treatment effect was observed for short-term memory at 6 weeks, with the placebo group performing better on average than the fish oil 6 g group (P < 0.05). Additionally, the fish oil 6 g group experienced significantly lower aortic pulse pressure compared to the fish oil 3 g + multivitamin group (P < 0.05) and to baseline (P = 0.01); aortic augmentation pressure was also improved in this group compared to baseline (P = 0.01). Higher aortic pressures are associated with cerebrovascular damage and cognitive impairment. No serious adverse events were reported.176 Memory, but not learning, function was improved significantly in healthy older individuals (50 to 75 years of age) who received LC-n3-FA (2,200 mg/day; EPA 1,320 mg + DHA 880 mg) for 26 weeks compared to those receiving placebo in a small randomized, double-blind, controlled trial (n=44). Both object-location-memory (OLM) as well as recall and recognition performance was tested. Mean improvement in OLM was 13.2% with treatment vs 3.5% with placebo (P=0.049); significance held true after correcting for the covariates of "change in dietary habits" and the "ApoE-epsilon4 allele" (P=0.004 and P=0.007, respectively). Erythrocyte omega-3 levels (both EPA and DHA) increased significantly in the treatment group (P=0.013) and decreased significantly with placebo (P=0.032); the difference between groups was also significant (P=0.001). No significant linear relationship was found between changes in omega-3-index values and recall or learning scores. Adverse events included GI symptoms, headache, and skin irritations; no severe events were reported.187 The American Psychiatric Association (APA) guideline watch for the treatment of patients with Alzheimer disease and other dementias (2014) did not find enough definitive new evidence to change the 2007 guideline recommendations for alternative agents, including fish oils.191

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).162

Critical illness and surgical patients

Clinical data

Randomized, controlled trials have been conducted in severely ill patients in intensive care units (ICUs) and among elective surgical patients comparing 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)54 and the difficulty in recruiting patients into trials.54, 55, 56, 57

Findings from these meta-analyses are in favor of supplemental fish oil in terms of reduced length of stay in hospital and in ICU, decreased ventilator time, decreased new organ failure, and decreased postoperative infections.54, 55, 56, 57, 58 Twenty-eight–day mortality was decreased in 1 meta-analysis of ICU patients54 but not in an analysis of major abdominal surgery. No serious adverse events were recorded in the included trials.56 Further clinical trials in patients with GI surgery, not included in the meta-analyses, have been conducted with similar positive results.59, 60, 61, 62

Cystic fibrosis

A pilot trial of intravenous fish oil emulsion in cystic fibrosis found no benefits and some potential deleterious effects.92 A systematic review and meta-analysis identified 4 randomized controlled trials that included 91 subjects that compared omega-3 fatty acid supplementation with placebo for effects on morbidity and mortality of 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 recommendations that would impact clinical practice.154 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.183

Diabetes

Clinical data

A Cochrane systematic review of patients with type 2 diabetes mellitus revealed that fish oil 3 to 18 g/day supplementation lowered triglycerides and had no statistically significant effect on glycemic control, total cholesterol, or HDL cholesterol. However, it did raise LDL cholesterol by 0.21 mmol/L (8.12 mg/kL), especially in patients with hypertriglyceridemia on doses higher than EPA 2 g.9 Further randomized controlled trials in overweight patients and in patients with type 2 diabetes do not demonstrate an effect of fish oils on insulin sensitivity or fasting blood glucose.63, 64 These findings are consistent with an Agency for Healthcare Research and Quality evidence report.65

As a component of medical nutrition therapy for patients with type 1 or type 2 diabetes, the American Diabetes Association (ADA) Standards of Care (2014) recommends an increase in foods containing n-3 fatty acids (EPA and DHA; from fatty fish), viscous fiber (eg, oats, legumes, citrus), and plant-based stanols/sterols based on beneficial effects observed on lipoprotein profiles, heart disease prevention, and overall positive health in patients with diabetes (moderate quality evidence). However, data do not support the use of n-3 fatty acids (EPA and DHA) for preventing or treating cardiovascular events (high-quality evidence). It was noted that in order to reduce risk of acute pancreatitis, patients with severe hypertriglyceridemia may benefit from immediate therapy with fish oil.160 Likewise, the ADA statement from 2015 recommends at least 2 servings per week of foods containing EPA and DHA, such as fatty fish (moderate-quality evidence). However, use of omega-3 supplements is still not supported in people with diabetes for prevention or treatment of cardiovascular events (high-quality evidence).168

Drug-resistant epilepsy

Clinical data

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 (1,080 mg/day), high-dose (2,160 mg/day), and placebo in a randomized, 3-period crossover trial. A borderline significant 31% reduction was observed for low-dose fish oil compared with high-dose (P = 0.05).165

Dry eye disease

Clinical data

In a double-blind, randomized, placebo-controlled trial (n = 27), fish oil supplementation (EPA 1,245 mg/day and DHA 540 mg/day) given for 12 weeks in combination with usual eye-drop dry eye treatment significantly improved subjective eye pain, break-up time of tear film, and rose bengal staining score compared with placebo.149 Similar results were documented in another double-blind, randomized, placebo-controlled trial in 456 adults with symptomatic computer vision syndrome in the northern part of the India subcontinent where a predominantly vegetarian diet provides unacceptable levels of omega-3 fatty acids. After 3 month’s supplementation with omega-3 fatty acids (EPA 720 mg and DHA 480 mg) or placebo (olive oil), all primary and secondary outcome measures (dry eye score, tear production, tear film stability, and cellular morphology and goblet cell density) were significantly improved with omega-3 supplementation but not placebo. Six participants in the intervention group dropped out because of gastric intolerance to the fish oil supplements.180 The effect of omega-3 fatty acids on the neural architecture and immune response of the cornea was 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 + 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.192 Similarly, dry eye symptoms, Meibomian gland score, tear film breakup time, and wetting outcomes were improved significantly with 6-month omega-3 fatty acid supplementation. In this particular double-blind, randomized, placebo-controlled trial (n=130), adults with dry eye symptoms who were also diagnosed with rosacea were eligible to participate. Omega-3 fatty acid supplementation was provided as EPA 720 mg plus DHA 480 mg daily for 6 months. A significant change in the slope of the regression plots indicated a direct treatment-related response to the omega-3 fatty acid dietary supplement. Gastric intolerance was the most common side effect reported in the treatment group that led to 8 patients (12%) dropping out in the omega-3 group.193

Gynecological

Clinical data

Trials are limited, but suggest a role for fish oil in the management of dysmenorrhea. Reduced requirement for analgesia and reported reduction in pain have been found after 2 to 3 months of supplementation.93, 94, 95 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 suggested fish oil may not be as effective as vitamin B1 (1 randomized clinical trial, n = 120).182

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 (n=95). Incongruencies throughout this paper between reference numbers in the table of studies vs reference numbers in the text led to conflicting data, specifically for fish oil and study doses of EPA and DHA. Although the author declares 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, P<0.001) compared to placebo. Mixed findings were reported for several of the secondary outcomes, such as triglycerides, HDL, LDL, body mass index, fasting glucose, and insulin resistance.194

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.96, 97, 98, 99

Clinical trials

A randomized controlled trial (n = 66) evaluated the hepatoprotective effect of omega-3 fish oil lipid emulsion versus standard parenteral nutrition (PN) in adult liver transplant patients diagnosed with end-stage liver disease or hepatic cellular carcinoma.142 Patients were randomized to either PN 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, alanine aminotransferase 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, post-transplant hospital stay was significantly shorter in the PUFA group versus PN (P = 0.041). Potential mechanisms for these effects include immunomodulation and down-regulation of inflammatory responses.142

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.66, 67 Accretion occurs primarily during the last trimester of pregnancy via the placenta and the infant's first year of life from breast milk and dietary sources.68, 69

Clinical data

Evidence from systematic reviews provides little support for benefit of supplementation with long-chain PUFAs (LCPUFAs), such as DHA, to either term or preterm infants.68, 69, 153 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 breast-fed. A review of LCPUFA supplementation studies demonstrated no benefit to visual or cognitive development in infants born at term receiving LCPUFA-supplemented formula.68 However, some evidence did show that omega-3 fatty acid supplementation of formula increases the early rate of visual maturation in preterm infants.69 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 (odds ratio: 0.76; 95% confidence interval 0.06 to 0.911; P = 0.04).156

Malnourished infants, who may have poor fat absorption, appear to also absorb fish oil supplements well and use this source of fatty acid for more than an energy source.70

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 breast-fed infant.66, 67, 71

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.72

Clinical data

Cochrane meta-analyses and systematic reviews of randomized controlled trials have been undertaken for the effect of omega-3 fatty acids in induction of remission in ulcerative colitis and for maintenance of remission of ulcerative colitis and Crohn disease.73, 74, 75 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 can be made regarding the effect of fish oil supplementation.73 For maintenance of remission in ulcerative colitis74 and Crohn disease75 relapse rates were similar for omega-3 fatty acids and the control intervention. For Crohn disease, the meta-analysis included data from both of the large EPIC trials. The conclusion that omega-3 fatty acids have no effect on maintenance of remission is an update on previous meta-analyses.75 The 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 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).164

Lipid-lowering effects

Animal data

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 in hyperlipidemia redundant.

Clinical data

Several meta-analyses and systematic reviews of clinical trials in hyperlipidemia have been conducted.76, 77, 78, 79 Clinical reductions in triglycerides of −0.34 mmol/L (−30.12 mg/dL) (95% CI, −0.41 to −0.27 mmol/L [−36.32 to −23.91 mg/dL]) were found in a meta-analysis of 47 randomized, controlled trials (N = 16,511).76 In 2004, the FDA approved the use of a fish oil for reducing very high triglyceride levels (at least 500 mg/dL [5.65 mmol/L]) in adults as an adjunct to diet.78 The investigators of the effect of fish oil in maintenance of remission in Crohn disease (the EPIC trials) reported decreases in serum triglycerides in the study populations.75 A place in therapy is also suggested for fish oil in hypertriglyceridemia consequent to type 2 diabetes and chronic kidney disease and as add-on therapy with statins in cardiovascular disease.11, 76, 78, 79 Increases in LDL cholesterol as well as HDL have been observed, and may be clinically important.76, 78, 80 Other studies have noted changes in concentration and particle size of very low-density lipoproteins.79, 81

Comparative effectiveness of fish oil, gemfibrozil, fenofibrate, and atorvastatin on reducing triglyceride (TG) levels in routine clinical care of HIV-infected adults was evaluated via a large retrospective cohort (n = 493).143 Although new use of fish oil resulted in a 0.51 mmol/L reduction, fibrates were more effective producing a change of −0.75 mmol/L. Dosage information was only available for 14% of patients (61% received ≤2 g/day of fish oil, 2% ≥4 g/day). These results are smaller than those reported in previous trials and likely reflect doses used in clinical care per se versus controlled trials.143

There have been several guidelines published discussing the relationship between fish oils and hypertriglyceridemia. The American Association of Clinical Endocrinologists' Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis (2012) recommend that omega-3 fish oil is very effective in treating hypertriglyceridemia and may also be used as adjunctive therapy in lower doses.135 The 2013 American College of Cardiology (ACC)/ American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease (ASCVD) Risk in Adults states that if omega-3 fatty acids (eg, EPA and/or DHA) are used for the management of severe hypertriglyceridemia (500 mg/dL or more), it is reasonable to evaluate the patient for GI disturbances, skin changes, and bleeding.138 The Endocrine Society’s clinical practice guideline on the management of hypertriglyceridemia (2012) states that the use of omega-3 fatty acids may be considered for treatment of triglyceride levels higher than 1,000 mg/dL. Due to variability in content amounts in over-the-counter preparations of omega-3, they suggest that nutritional labels should be studied to calculate the number of capsules required to obtain a dose of 3 to 5 g of n-3 fatty acids.139

Menopause

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).188

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.144 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 (body mass index, 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 + DHA 1,341 mg/day) but not in the alpha-lipoic acid (300 mg/day), ALA + EPA, or placebo groups; whereas a significant increase in weight lost was noted only in the ALA 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). Interestingly, the decline in leptin levels that accompanied the fat loss was significant in all groups except for the EPA group, in which the non-significant reduction in leptin was associated with a positive significant effect on resting metabolic rate (r = 0.42, P < 0.001).171

Renal effects

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.100 The use of fish oil on lipoprotein-a in end-stage renal disease and among kidney transplant recipients has also been evaluated.101, 102

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 American Heart Association recommendation for patients at high cardiovascular risk (1 g/day with a dietary ratio of omega-6 to omega-3 of 4).177

Respiratory infections

Clinical data

A 200 mL drink containing supplementation with fish oil (DHA 550 mg, 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 were significantly shorter with the intervention than placebo (1.72 ± 1.67 vs 2.79 ± 1.76; P < 0.05).179

Rheumatoid arthritis

EPA is a competitive substrate with arachidonic acid for the generation of less active eicosanoid metabolites (eg, leukotrienes) and acts to reduce inflammation.10 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.82

Animal data

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 irrelevant.

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.83 Meta-analyses of controlled trials have been conducted with equivocal findings.65, 83, 84 Issues raised by the analyses include confounding of results with the use of potentially active placebo oils (eg, corn and olive oil) and management of dropouts in the individual trials.83, 85 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.83

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 interleukin-1 from monocytes, while dosages of more than 6 g/day do not appear to confer any additional benefit.48

In disease-modifying antirheumatic drug (DMARD)-naive adults with rheumatoid arthritis of less than 12-months onset, high-dose fish oil (5.5 g/day) significantly reduced failure of triple DMARD (methotrexate, sulfasalazine, hydroxychloroquine) therapy compared with control (0.4 g/day of fish oil) at 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).166

Stroke

Animal data

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 in stroke largely irrelevant.

Clinical data

Despite data from large trials being available (including the GISSI, JELIS, and EPIC-Norfolk trials), no consistent relationship between fish oil consumption and reduction in the risk of stroke has been established.34, 78, 86, 87 The etiology of the stroke may be of relevance, with omega-3 fatty acids considered to be more likely to demonstrate positive effects on stroke related to ischemic causes than hemorrhagic stroke because of platelet anti-aggregating properties.78, 86 A 2004 meta-analysis of prospective cohort studies found a higher incidence of stroke in people who never consumed fish or only consumed fish less than once per month versus a higher fish intake. A reduced risk for total stroke was found for intakes of fish at least once per week. Whole fish also contain the proteins taurine, arginine, and glutamine, which may be involved in cardiovascular function.78

A randomized, controlled trial evaluated the effect of daily fish oil supplementation 3 g for 12 weeks on quality of life outcomes in CT-confirmed ischemic stroke. No effect was found for all outcome measures, including serum triglycerides, total cholesterol, blood pressure, mood, and quality of life indicators.88

A 16-week randomized, double-blind, placebo-controlled trial randomly assigned 160 healthy adults to fish oil 3 g (EPA 240 mg/DHA 240 mg) plus a multivitamin, fish oil 6 g (EPA 480 mg/DHA 480 mg) with and without a multivitamin, or placebo to determine effects of fish oil on cognitive and cardiovascular function. Each fish oil capsule contained fish oil 1 g (80 mg each of EPA and DHA) plus 50 units of vitamin E; it should be noted that the multivitamin also contained 21 herbal and other natural products plus probiotics. The AA/EPA ratio improved in all treatment groups compared to placebo confirming compliance. EPA increased significantly only in the fish oil 6 g groups; by 57% without the multivitamin and by 96% with the multivitamin. The fish oil 6 g group experienced significantly lower aortic pulse pressure compared to the fish oil 3 g + multivitamin group (P < 0.05) and to baseline (P = 0.01); aortic augmentation pressure was also improved in this group compared to baseline (P = 0.01). Higher aortic pressures are associated with cerebrovascular damage and cognitive impairment. No serious adverse events were reported.176

Dosing

The AHA recommends a minimum of 2 fatty fish meals per week.1, 34 Clinical trials suggest fish oil supplementation of omega-3 fatty acid 1 g/day in coronary heart disease, and where triglycerides are elevated, a minimum of omega-3 fatty acid 2 g/day up to a maximum of 4 g/day. Fish oil 1,000 mg approximates to omega-3 fatty acid 300 to 400 mg (EPA/DHA).34

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.103 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.88, 104

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/serving) of low-mercury varieties of fish each week.169 The Food and Agriculture Organization of the United Nations and the World Health Organization recommend daily intake of omega-3 supplementation during pregnancy.170 Farmed salmon may have a greater potential for contamination than wild sources.78, 86, 104

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% confidence interval [CI], 1.03 to 4.07) in women who took fish oil supplementation. No significant difference was found for the relative risk (RR) 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).105 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 (total daily dose range, 650 to 3,000+ mg EPA + DHA; 200 to 500 mg DHA monotherapy) on rate of preterm birth before 37 weeks compared with controls. However, in a subgroup analysis in women who received EPA + 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.170

A study in which fish oil supplementation was taken after 22 weeks suggested an increase in oxidative stress in the plasma at week 30.106 Effects of fish oil on lipids and blood pressure do not appear to be sustained during pregnancy.107

While evidence indicates that the DHA and EPA composition of breast milk is affected by fish oil supplementation, there is little evidence in support of benefit to the infant.66, 67, 68, 69 Use of fish oil supplementation during pregnancy and breast-feeding to reduce the incidence of food allergy in infants has also been evaluated.19

Briggs Book Link

Interactions

Agents with antiplatelet properties: Omega-3 fatty acids may enhance the antiplatelet effect of agents with antiplatelet properties. Monitor therapy.108, 109, 110, 111, 112, 113, 114

Anticoagulants: Omega-3 fatty acids may enhance the anticoagulant effect of anticoagulants. Monitor therapy.108, 111, 112, 113, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132

Ibrutinib: Omega-3 fatty acids may enhance the antiplatelet effect of Ibrutinib. Monitor therapy. International labeling: The ibrutinib Canadian product monograph recommends avoiding this combination.196, 197

Adverse Reactions

Fish oil at dosages of EPA/DHA 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.30, 31, 56, 75 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.72

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 + DHA 450 mg daily); both reported to potentially inhibit platelet aggregation.190

A safety study found similar adverse events for intervention (EPA 2 g/day for 12 weeks) and placebo groups. Increased body mass index and increased (but modest) bleeding time were reported.133

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.76, 78

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

Toxicology

Research reveals limited information regarding toxicology 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.133

Index Terms

  • Krill oil

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