Wild Alaskan Fish Oil Orange Burst by Wiley's Finest

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in healthy adults over 40 years of age with mild forgetfulness shows that taking a specific combination supplement (BGG Japan Co.) containing astaxanthin 9 mg and tocotrienols 50 mg daily for 12 weeks might improve composite and verbal memory when compared with placebo (105099). This study was funded by the supplement manufacturer.
• Age-related macular degeneration (AMD). Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with non-advanced AMD shows that a specific combination product (Azyr, Sifi S.p.A.) containing astaxanthin 4 mg, lutein, zeaxanthin, vitamin E, vitamin C, zinc, and copper, taken daily for 12 months, improves selective dysfunction in the central retina, but does not improve dysfunction in the peripheral retinal areas, when compared with baseline (19196). The validity of this finding is limited by the lack of a comparator group.
• Aging skin. Small studies suggest that oral and topical astaxanthin may be beneficial in aging skin; however, there is conflicting evidence regarding its effects on wrinkles. Details: Small studies in middle-aged adults show that taking astaxanthin (Astavita Astaxanthin, Astavita; AstaReal Oil 50F, Fuji Chemical Industry Co., Ltd.) 2-3 mg orally twice daily for 6-8 weeks improves elasticity, fine lines, wrinkles, and skin moisture when compared with placebo (19561,91734). However, a meta-analysis of small clinical studies in healthy adults shows that taking oral astaxanthin 2-12 mg daily for 4-16 weeks modestly improves moisture content and skin elasticity, but has no effect on wrinkle depth, when compared with placebo (107961). The validity of this meta-analysis is limited due to the population heterogeneity and variety of astaxanthin formulations utilized. In addition to oral astaxanthin, one study also used topical astaxanthin 0.094% (AstaTROL-Hp, Fuij Chemical Industry Co., Ltd.) 1 mL applied twice daily (91734). A systematic review of two very small, nonblinded studies in healthy adults suggests that topical application, either in combination with oral astaxanthin or alone, might have anti-aging skin effects when used for 2-3 weeks (107961).
• Alzheimer disease. Although there is interest in using oral astaxanthin for Alzheimer disease, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
• Athletic performance. Small studies suggest that oral astaxanthin may improve some aspects of athletic performance. Details: Two small studies in trained cyclists show that taking astaxanthin (Fuji Health Science, Inc. or AstaReal) 4-12 mg daily for 1 or 4 weeks decreases the time to complete a 20-40 km cycling trial by about 50-100 seconds when compared with placebo (91735,105096). However, a larger study in trained cyclists shows that taking astaxanthin (BioReal) 20 mg, vitamin C 300 mg, and vitamin E 50 mg daily for 4 weeks does not decrease time needed to complete a predetermined amount of cycling work (a timed trial) when compared with placebo (91738). Reasons for the discrepancies are not clear but may relate to the fitness level of the athletes in the studies or the differences in timed trial protocols used in the studies.
• Carpal tunnel syndrome. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of astaxanthin 4 mg, lutein, beta-carotene, and vitamin E (BioAstin, Cyanotech) orally 3 times daily for 8 weeks does not reduce the rate or duration of pain due to carpal tunnel syndrome when compared with placebo (19164).
• Diabetes. It is unclear if oral astaxanthin is beneficial for diabetes. Details: A small clinical trial in adults with diabetes shows that taking astaxanthin (Nature Vision) 8 mg daily for 8 weeks does not reduce levels of cholesterol or fasting blood glucose or reduce diastolic blood pressure when compared with placebo. However, there were some modest beneficial effects on visceral fat, triglyceride level, and systolic blood pressure (109778).
• Dry eye. It is unclear if oral astaxanthin is beneficial for dry eye syndrome. Details: A clinical study in adults and elderly patients with mild to moderate dry eye syndrome shows that taking oral astaxanthin 6 mg twice daily for 30 days improves symptom severity, tear break-up time, fluorescein break-up time, and meibomian gland dysfunction, but not visual acuity or intraocular pressure, when compared with baseline (107962). The validity of these findings is limited by the lack of a comparator group.
• Dyspepsia. It is unclear if oral astaxanthin improves symptoms of dyspepsia. Details: One clinical study in adults with functional dyspepsia with or without Helicobacter pylori infection shows that taking astaxanthin (AstaCarox, AstaReal AB) 16 mg or 40 mg daily for 4 weeks does not reduce indigestion, pain, or H. pylori counts when compared with placebo. However, astaxanthin 40 mg daily may reduce reflux in H. pylori-positive patients (19165).
• Exercise-induced muscle damage. Small clinical studies in trained athletes suggest that oral astaxanthin may not improve markers of muscle damage from exercise. Details: A small study in professional male soccer players shows that taking astaxanthin 4 mg daily for 90 days does not seem to reduce exercised-induced biomarkers of muscle damage, such as creatinine kinase, when compared with placebo (91739). Taking a combination of astaxanthin 4 mg and lutein 480 mg (BioAstin, Cyanotech) daily for 3 weeks also did not reduce creatinine kinase levels after exercise in trained athletes when compared with placebo (safflower oil) (19199).
• Exercise-induced muscle soreness. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in resistance trained athletes shows that taking a combination of astaxanthin 4 mg and lutein 480 mg (BioAstin, Cyanotech) daily for 3 weeks does not reduce muscle soreness or improve muscle performance 96 hours after exercise when compared with placebo (safflower oil) (19199).
• Fatigue. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy patients shows that taking a specific combination product (ASTOTS, Fujifilm Co.) containing astaxanthin 6 mg and sesamin 10 mg after breakfast daily for 4 weeks does not improve overall fatigue after completion of mental and physical tasks when compared with placebo (98769).
• Heart failure. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with heart failure with reduced left ventricular ejection fraction (LVEF) shows that taking a specific supplement containing astaxanthin 12 mg, tocotrienol 40 mg, and L-ascorbic acid 2-glucoside 30 mg (AstaReal ACT, AstaReal Co., Ltd.) daily for 3 months may increase LVEF from 34% to 38% and modestly increase exercise tolerance as measured by the six-minute walk test when compared with baseline (105097). The validity of these findings is limited by the lack of a comparator group. Furthermore, this study was funded by the supplement manufacturer.
• Hyperlipidemia. Small clinical studies suggest that oral astaxanthin is not beneficial for reducing cholesterol levels. Details: One small clinical study in adults with mild hyperlipidemia shows that taking astaxanthin (AstaReal Astaxanthin, Fuji Chemical Industry) 12 mg or 18 mg daily for 12 weeks reduces triglyceride levels, while taking 6 mg or 12 mg daily increases high-density lipoprotein (HDL) cholesterol levels, when compared with placebo. However, total cholesterol and low-density lipoprotein (LDL) cholesterol levels were not affected (19167). Meta-analyses of small clinical studies mostly in adults without hyperlipidemia have also been conducted. One shows that taking astaxanthin 4-18 mg daily for up to 12 weeks does not reduce total or LDL cholesterol levels, but may increase HDL cholesterol levels, when compared with control (105100). A more recent analysis shows that taking astaxanthin 4-20 mg daily for up to 6 months has no beneficial effects on blood lipid levels and might actually increase levels of LDL cholesterol (109776).
• Hypertension. It is unclear if oral astaxanthin reduces blood pressure. Details:A meta-analysis of four small clinical trials shows that taking astaxanthin does not have a clinically beneficial effect on systolic or diastolic blood pressure (109776). However, none of the trials were conducted in patients with hypertension.
• Impaired glucose tolerance (prediabetes). It is unclear if oral astaxanthin is beneficial in patients with prediabetes. Details: A small clinical study in healthy adults and adults with prediabetes shows that taking oral astaxanthin 12 mg daily for 12 weeks improves glycated hemoglobin (HbA1c) when compared with baseline, but not when compared with placebo. Insulin sensitivity and postprandial glucose levels were also improved when compared with baseline, but no statistical comparison to the placebo group was conducted (107965). The validity of this study is limited due to unclear reporting.
• Male infertility. It is unclear if oral astaxanthin improves male infertility. Details: A small low-quality clinical study in males with infertility who are participating in intra-uterine insemination shows that taking astaxanthin (AstaCarox, AstaReal AB) 16 mg daily for 3 months does not seem to increase sperm count and quality, but might result in a higher total pregnancy rate of 23% compared with a 3.6% rate in the placebo group (19197). The validity of this finding is limited by poor study methodology and differences between treatment groups. Another small clinical study in males with infertility and oligospermia shows that taking astaxanthin (Astasan, Sensilab) 16 mg daily does not increase sperm concentration or sperm motility when compared with placebo (105098).
• Menopausal symptoms. Although there is interest in using oral astaxanthin for menopausal symptoms, there is insufficient reliable information about the clinical effects of astaxanthin for this purpose.
• Metabolic syndrome. Although there is interest in using oral astaxanthin for metabolic syndrome, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
• Nonalcoholic fatty liver disease (NAFLD). Although there is interest in using oral astaxanthin for NAFLD, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
• Obesity. Although there is interest in using oral astaxanthin for weight loss, there is insufficient reliable information about the clinical effects of astaxanthin for this purpose.
• Parkinson disease. Although there is interest in using oral astaxanthin for Parkinson disease, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
• Physical performance. It is unclear if oral astaxanthin improves physical performance in older adults. Details: A small clinical trial in healthy nursing home residents shows that taking astaxanthin (AstaReal) 12 mg twice daily for 16 weeks, in combination with vitamin E 40 mg and vitamin C 30 mg daily, increases the 6-minute walking distance by about 38 meters, a significant increase when compared with placebo containing vitamin E and vitamin C. However, there was no effect on muscle strength (109777). Another small clinical trial in healthy, older adults (aged 65-85 years) undergoing exercise endurance testing shows that a specific combination product (AstaReal; Fuji Health Science, Inc) containing astaxanthin 12 mg, tocotrienol 10 mg, and zinc 6 mg, taken as 2 capsules daily for 12 weeks, reduces the respiratory exchange ratio, but does not improve leg muscle endurance or perceived exertion, when compared with placebo. In a subgroup analysis of males, but not females, those taking astaxanthin had a greater total exercise efficiency when compared with placebo (107963).
• Polycystic ovary syndrome (PCOS). It is unclear if oral astaxanthin is beneficial for PCOS. Details: A small clinical trial in patients with PCOS shows that taking astaxanthin (Algalife Pure astaxanthin) 8 mg daily for 40 days prior to egg retrieval modestly improves the high-quality embryo rate, but not the total number of embryos or the clinical pregnancy rate, when compared with placebo (109775).
• Rheumatoid arthritis (RA). Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with RA shows that taking a supplement containing astaxanthin 4 mg, lutein 40 mcg, vitamin A 65 IU, vitamin E 50 IU, and safflower oil 460 mg (BioAstin, Cyanotech) three times daily for 8 weeks reduces pain and improves satisfaction by approximately 40% when compared with placebo (94125).
• Stroke. Although there is interest in using oral astaxanthin for recovery from stroke, there is insufficient reliable information about the clinical effects of astaxanthin for this purpose.
• Sunburn. It is unclear if oral astaxanthin might help to prevent sunburn. Details: A very small clinical study in Japanese adults shows that taking astaxanthin (Astots, Fujifilm Corporation) 4 mg daily for 9 weeks might increase skin tolerance to ultraviolet (UV) light when compared with placebo (96884). It is unclear if this translates to a lower risk of sunburn. More evidence is needed to rate astaxanthin for these uses.

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POSSIBLY EFFECTIVE

• Hyperlipidemia. Most research shows that taking oral DHA alone or with eicosapentaenoic acid (EPA) seems to modestly reduce triglyceride levels. However, DHA does not decrease total cholesterol and may increase levels of low-density lipoprotein (LDL) cholesterol. Details: Clinical research shows that taking DHA 1.25-4 grams daily for up to 7 weeks can reduce triglyceride levels by 17% to 24% in adult patients with mild hyperlipidemia, dyslipidemia, or hypertriglyceridemia (6143,48013,48338). Also, taking DHA-enriched fish oil providing DHA 810 mg plus EPA 210 mg daily for 8 weeks reduces triglyceride levels by 23% in premenopausal adults with mild hypertriglyceridemia (99131). Most clinical research suggests that DHA does not decrease total cholesterol (6143,48013,99131). Although some conflicting research exists, most research suggests that DHA modestly increases HDL cholesterol (6143,48013,48338,99131,109216). Most clinical research shows that DHA increases LDL cholesterol by about 8% to 13.6% (6143,48174,48338,109216). However, it may actually decrease levels of small, dense LDL particles (48174). There are conflicting results regarding the effects of DHA on cholesterol levels in children. One preliminary clinical study in children with primary hyperlipidemia shows that taking DHA 500 mg alone or along with EPA does not improve cholesterol levels when compared with control. However, this study was probably too small to detect statistically significant changes (90712). Other research in children aged 9 years and up with familial hypercholesterolemia or familial combined hyperlipidemia shows that taking DHA (DHASCO oil, Martek Biosciences Corp.) 1.2 grams daily for 6 weeks along with the National Cholesterol Education Program Step II (NCEP-II) diet actually increases total cholesterol and LDL cholesterol when compared to following the diet alone (48078,48083). However, some clinical research shows that DHA increases the large buoyant type of LDL particles, but actually decreases the small, dense type (48083).
• Preterm labor. Most research shows that oral DHA seems to prevent preterm labor in those with low DHA status at baseline. Details: A large clinical trial shows that taking DHA 1000 mg daily during pregnancy, starting at 12-20 weeks' gestation and continuing until delivery, results in an early preterm birth rate of 1.7%, compared with 2.4% in those taking DHA 200 mg daily. Benefits were strongest in those with low DHA status at baseline, with no benefit in those with high DHA status at baseline and in those with high adherence to DHA 1000 mg daily (109204,110360). A secondary analysis of two studies shows that taking DHA 800 mg from algal oil or 1000 mg from fish oil modestly reduces the early preterm and preterm birth rates in those with a low DHA status at baseline compared with taking DHA 200 mg (110361). However, conflicting evidence exists. Some clinical research shows that taking DHA during pregnancy does not reduce the risk of preterm delivery. One study has used a specific fish oil supplement (Incromega DHA 500TG) 900 mg containing DHA 800 mg and eicosapentaenoic acid (EPA)100 mg daily, starting at 20 weeks' gestation and continuing to delivery or 34 weeks' gestation (101505). In another clinical trial, use of a high-DHA fish oil, providing EPA 100 mg and DHA 800 mg daily, from before 20 weeks' until 34 weeks' gestation, increases the risk of preterm birth prior to 34 weeks' gestation when compared with placebo in patients with baseline omega-3 status of greater than 4.9%. However, the risk is reduced from 3.2% to 0.7% in patients with baseline omega-3 status below 4.1%. In addition, taking this high-DHA fish oil had no effect on the risk of preterm birth prior to 37 weeks' gestation (103496). The reasons for any discrepancies may be due to the baseline omega-3 status, the use of algal or fish oil as the source of DHA, and/or the specific timing of preterm labor.

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Most research shows that taking oral DHA alone or with other ingredients does not slow or improve cognitive decline associated with age. Details: Most clinical research, from individual studies and a meta-analysis, shows that taking DHA orally, alone or with additional eicosapentaenoic acid (EPA) for up to 36 months, does not slow or improve age-related cognitive decline (97175,103313). In contrast, results from one large clinical study show that taking DHA 900 mg daily in the absence of EPA for 24 weeks improves episodic memory and visuospatial learning when compared with placebo in patients with age-related cognitive decline. However, DHA did not affect working memory or executive function (90717).
• Alzheimer disease. Taking oral DHA does not seem to slow Alzheimer disease progression. Details: Population research has found that a 0.1 gram per day increment of dietary DHA intake is associated with a 37% reduced risk of Alzheimer disease when taken for 2-21 years (15041,96527). However, a dose-response relationship was not seen, and a correlation between DHA blood concentration and dementia was not seen (96527). Furthermore, clinical research shows that taking DHA 2 grams daily for 18 months does not slow cognitive or functional decline in patients with mild to moderate Alzheimer disease (48290). DHA has also been examined in combination with other ingredients. Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking DHA 500 mg, as part of fish 1 gram with eicosapentaenoic acid (EPA) 150 mg, and along with lutein 10 mg, zeaxanthin 2 mg, meso-zeaxanthin 10 mg, and vitamin E 15 mg (Memory Health) daily for 12 months does not affect disease severity when compared with placebo. However, there were modest increases the number of patients experiencing either an improvement or an attenuated decline in memory and mood (109764). The effect of DHA alone is unclear from this study.
• Attention deficit-hyperactivity disorder (ADHD). Most research shows that taking oral DHA does not improve ADHD symptoms. Details: Low plasma levels of DHA are associated with ADHD in children (7599,15496). Although some preliminary clinical research shows that DHA might improve aggression, emotional problems, and social relationships in children with ADHD (15494,100940), taking DHA 345-500 mg daily or 3.6 grams weekly does not seem to improve objective or subjective measures of ADHD symptoms when compared with placebo (7599,15495,100940).
• Bronchopulmonary dysplasia. Most research shows that oral DHA does not prevent bronchopulmonary dysplasia (BPD) in preterm infants. Some research suggests that it might increase the risk of BPD in infants born before 29 weeks gestation. Details: One meta-analysis of clinical research in over 3,500 preterm infants shows that administration of EPA and DHA as part of formula or as a direct oral dose, starting within one month of birth, does not increase or decrease the risk for BPD, regardless of the dose of DHA administered (102390). A more recent meta-analysis of four clinical trials limited to infants born less than 29 weeks gestation also shows that administration of DHA at levels of at least 40 mg/kg, or at levels of at least 0.4% total fatty acids in breast milk or formula, does not increase or decrease the risk of bronchopulmonary dysplasia (110359). However, in this latter meta-analysis, when only clinical trials using a more stringent definition of bronchopulmonary dysplasia were included, there was a modest INCREASED risk (110359). Similar findings occurred in a study that was terminated early. This research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on mortality of breastfed infants or survival without BPD at 36 weeks postmenstrual age. However, the occurrence of BPD and severe BPD in surviving infants of mothers taking DHA were increased when compared to those whose mothers took placebo (104559). The conclusions of this study are limited by the early termination, the provision of intravenous DHA-rich lipids to some infants per standard of clinical care, and the increased number of infants born via cesarean delivery to the mothers randomized to DHA. A more recent clinical trial has investigated the inclusion of arachidonic acid in an enteral emulsion providing DHA. One clinical trial in preterm infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age does not increase the risk of bronchopulmonary dysplasia or other major morbidities compared to control (MCToil, Nutricia) emulsion. Also, infants given the arachidonic acid and DHA required 17 fewer days of respiratory support (110356).
• Cognitive function. Most research shows that oral DHA does not improve cognitive function in healthy adults. Details: Most clinical research shows that taking DHA 250-1000 mg daily for up to 6 months does not improve cognitive function in healthy children, healthy adults, or older females (48194,48216,48266,90668,90708,104560). Also, cognitive function does not seem to be improved when compared with placebo in trials in which omega-3 products containing higher ratios of DHA to eicosapentaenoic acid (EPA) were used. These trials have used a specific product (Efamol Ltd) containing DHA 1.16 grams and EPA 0.17 grams daily (90707), DHA 900 mg plus EPA 270 mg (Accelon DHA EE, BASF) daily (109215), or fish oil (Dasbrain, Max Biocare) providing DHA 520 mg or 270 mg daily (109310), for 3 or 6 months in children and adults. However, some clinical research shows that taking algal oil containing DHA 600 mg daily for 16 weeks improves reading scores when compared with placebo in a subgroup of children ages 6-10 years who are below the 20th percentile for reading (90699). However, these results could not be replicated in a later study that included only children below the 20th percentile for reading (98542). The reason for this discrepancy is not clear. Taking DHA does not appear to improve reading scores in children at or above the 20th percentile for reading, and there does not appear to be any benefit of DHA on working memory in any children (90699).
• Cystic fibrosis. Most research shows that oral DHA does not improve symptoms of cystic fibrosis. Details: Clinical research in infants, children, and young adults with cystic fibrosis shows that taking DHA (DHA-basic, CASEN Fleet SLU) 50 mg/kg daily for 48 weeks does not improve spirometry measures, reduce Pseudomonas aeruginosa primary infections, or reduce the number of, or time to, total or severe pulmonary exacerbations when compared with placebo (109217). Also, small clinical studies show that taking DHA 70 mg/kg daily for 6 weeks, or 100 mg/kg daily for one month and then 1 gram daily for 11 months, does not improve lung function or overall health in patients with cystic fibrosis (48119,90665).
• Depression. Most research shows that oral DHA does not improve depression, regardless of the type. Details: Taking DHA orally does not seem to relieve symptoms of major depression, peripartum depression, or postpartum depression in most patients (10869,48030,48238,90680,90691,90692,89353,102391). Also, taking DHA for two weeks prior to the start of interferon-alpha therapy does not appear to prevent depression during interferon-alpha treatment in patients with hepatitis C, although it may delay depression onset by about 6 weeks (90710).
• Macrosomia. Taking oral DHA during pregnancy does not seem to prevent fetal macrosomia. Details: Clinical research in overweight or obese individuals shows that taking DHA (S-oil, DSM Nutritional Products) 800 mg daily, starting before 15 weeks' gestation and continuing until delivery, with or without dietary counselling, does not reduce the incidence of macrosomia when compared with taking DHA 200 mg daily (109218).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Increased dietary consumption of DHA is associated with a decreased risk of AMD (10324). Preliminary clinical research shows that taking a combination of DHA 280 mg, lutein 12 mg, and zeaxanthin 0.6 mg daily for one year increases macular pigment optical density by 31% when compared with placebo in patients with AMD. Increased macular pigment optical density is associated with improve vision performance and a reduced risk of AMD (90678). However, other clinical research suggests that adding DHA plus EPA to an AREDS formula, with or without lutein and zeaxanthin, does not reduce the time to development of AMD or vision loss in patients at high risk of progression to advanced AMD when compared with the AREDS formula alone (60281).
• Allergic rhinitis (hay fever). Although there has been interest in using oral DHA for allergic rhinitis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Atopic dermatitis (eczema). It is unclear if adding DHA to infant formula prevents atopic dermatitis. Details: Evidence from an observational, open-label study shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months does not prevent the development of eczema when compared to control formulas without DHA and arachidonic acid (92505).
• Atopic disease. It is unclear if oral DHA during pregnancy prevents atopic disease in the infant. Details: Clinical research shows that supplementation with DHA during pregnancy may modestly protect against some respiratory symptoms in the infants of atopic mothers. Prenatal supplementation with DHA 400 mg, taken daily from 18-22 weeks gestation until delivery, reduces the incidence of phlegm with nasal discharge or nasal congestion in the infant by the age of 18 months by approximately 22% and the incidence of fever with phlegm and nasal discharge or nasal congestion in the infant by approximately 47% when compared with placebo (90676). However, it is unclear if these symptoms are due to atopy or infections.
• Atrial fibrillation. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research suggests that adipose tissue levels of DHA are not associated with a decreased risk of atrial fibrillation (90700). However, clinical research suggests that taking 2 grams per day of a combination of DHA plus EPA (2:1 ratio), starting 7 days before cardiac surgery and continuing until hospital discharge, reduces the relative risk of post-cardiac surgery atrial fibrillation by 72% when compared with placebo. These patients also received vitamin C 1 gram daily plus vitamin E 400 IU daily, starting 2 days prior to surgery and continuing until discharge (90701).
• Autism spectrum disorder. It is unclear if oral DHA is beneficial for autism. Details: One preliminary clinical study shows that taking DHA 200 mg daily for 6 months does not improve autism symptoms in children and may even worsen some behaviors (90713). Another preliminary clinical study in children and adults with autism shows that taking a specific product (SUNTGA40S, Aravita, Suntory Ltd) containing DHA, arachidonic acid, and astaxanthin daily for 16 weeks does not improve overall symptoms when compared with placebo, although the combination product may improve certain symptoms such as social withdrawal or social communication (90716).
• Behcet disease. Although there has been interest in using oral DHA for Behcet disease, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Bipolar disorder. It is unclear if oral DHA is beneficial for bipolar disorder in adults. Details: A small clinical trial shows that taking DHA 1250 mg daily for 12 weeks does not improve cognitive function when compared with placebo in patients with bipolar disorder (103312).
• Breast cancer. It is unclear if oral DHA is beneficial for breast cancer treatment or prevention. Details: Population research has found no association between dietary fatty acid intake, including DHA, and the risk of breast cancer (96528). The effect of DHA supplementation on breast cancer risk is unknown. Some early research has investigated the effects of DHA in patients with breast cancer. Preliminary clinical research shows that taking DHA (DHASCO, Martek Biosciences Corp.) 600 mg three times daily for 7-10 days prior to chemotherapy initiation, and then for 5 months during chemotherapy, induces complete or partial response in 44% of breast cancer patients. Patients with a greater increase in DHA levels (at least 2.5%) show a longer time to progression and longer survival when compared to those with a smaller increase in DHA levels (90671).
• Cancer. Taking oral DHA with oral eicosapentaenoic acid (EPA) does not seem to decrease the risk of cancer in patients with cardiovascular disease and may actually INCREASE the risk of cancer in females. The effect of DHA alone is unclear. Details: Clinical research suggests that taking a combination of EPA 400 mg plus DHA 200 mg, with or without B vitamins, for a median of 4.7 years does not reduce the risk of cancer in middle-aged and elderly patients with cardiovascular disease. Furthermore, this combination appears to increase the risk of cancer in females (90666).
• Child development. It is unclear if oral DHA is beneficial for child development. However, due to the lack of significant safety concerns and the possibility of some cognitive benefit, many experts recommend DHA 200 mg daily during pregnancy. Details: Clinical research shows that giving infants DHA-supplemented formula during infancy does not appear to improve language and school readiness by the age of 2-3.5 years, or improve neurodevelopment by the age of 6 years (90674,92503). In addition, most research suggests that DHA supplementation during pregnancy, occasionally continuing postpartum for 6 months, does not affect visual acuity, attention, working memory, behavior and most other measures of neurodevelopment by 1-7 years of age (48095,48285,48293,90679,90690,94600,96522,109219). There is some evidence to suggest that maternal supplementation with DHA 400 mg daily from 16 weeks gestation until delivery may reduce the risk of poor language development in the infant at age 14 and 18 months and the risk of lower visual acuity at 2 months when compared with placebo (90694); however, this benefit did not have lasting effects at 5-6 years of age (99133).
• Cognitive impairment. It is unclear if oral DHA is beneficial for cognitive impairment in the elderly. Details: Clinical research shows that taking DHA 800 mg daily, alone or with folic acid 800 mcg daily for 6 months, modestly improves some measures of cognitive function when compared with placebo in elderly patients with mild cognitive impairment (103978). Also, taking a specific product (Vayacog, Enzymotec Ltd.) providing phosphatidylserine 300 mg, DHA about 59 mg, and eicosapentaenoic acid (EPA) about 20 mg daily for 15 weeks improves verbal immediate recall when compared with placebo (94665). However, other research in elderly patients with mild cognitive impairment disagrees. One clinical trial shows that taking DHA 1491 mg plus EPA 351 mg daily for 12 months does not improve cognitive measures when compared with placebo (109220). In addition, taking DHA along with EPA and other ingredients for up to 24 weeks does not significantly improve memory, forgetfulness, or other measures of cognition in elderly patients with mild cognitive impairment (90704,94665). Also, a small clinical study shows that taking DHA 720 mg daily along with EPA and other ingredients for 12 weeks does not significantly improve memory, forgetfulness, or other measures of cognition (62847).
• Coronary heart disease (CHD). It is unclear if oral DHA is beneficial for CHD. Details: Increased dietary consumption of DHA may reduce the risk of death in patients with CHD (10322). However, the effect of DHA supplements is unclear.
• Crohn disease. It is unclear if oral DHA is beneficial for Crohn disease prevention. Details: Population research suggests that increased dietary intake of DHA is associated with a reduced risk of Crohn disease (90673).
• Dementia. It is unclear if oral DHA is beneficial for dementia prevention. Details: Population research has found that a 0.1 gram per day increment of dietary DHA intake is associated with a 14% reduced risk of dementia when taken for 2-21 years. However, a dose-response relationship was not seen, and a correlation between DHA blood concentration and dementia was not seen (96527).
• Developmental coordination disorder (DCD). Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in children with DCD shows that taking a tuna fish oil product providing DHA 480 mg daily for 4 months, in combination with evening primrose oil providing arachidonic acid 35 mg and gamma-linolenic acid 96 mg, thyme oil 24 mg, and vitamin E 80 mg (Efalex, Efamol Ltd.), modestly decreases movement disorders as determined by objective measures when compared with baseline (5708). It is unclear if these benefits are due to DHA, other ingredients, or the combination. Also, the validity of this finding is limited by the lack of a comparator group.
• Diabetes. It is unclear if oral DHA is beneficial for glycemic control or the prevention of type 1 or gestational diabetes. Details: A small clinical study in adults with type 2 diabetes shows that taking DHA orally does not improve levels of low-density lipoprotein (LDL) cholesterol or decrease blood sugar or glycated hemoglobin. However, triglyceride levels are reduced (10321). DHA has also been evaluated for the prevention of gestational or type 1 diabetes. Clinical research in overweight or obese individuals shows that taking DHA (S-oil, DSM Nutritional Products) 800 mg daily, starting before 15 weeks' gestation and continuing until delivery, with or without dietary counselling, does not reduce the incidence of gestational diabetes when compared with taking DHA 200 mg daily (109218). Additionally, population research suggests that maternal serum levels of DHA are not associated with the risk of childhood onset of type 1 diabetes (90705).
• Diabetic retinopathy. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diabetic macular edema related to diabetic retinopathy receiving ranibizumab shows that taking a combination supplement containing DHA 1050 mg daily along with other free fatty acids, minerals, and vitamins (Brudyretina, Brudy Lab S.L.) for 2 years reduces macular thickness, but not visual acuity, when compared with ranibizumab alone. The effect of DHA alone is unknown (96526).
• Diarrhea. It is unclear if infant formula containing DHA is beneficial for diarrhea prevention. Details: Preliminary clinical research suggests that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months reduces the incidence of diarrhea requiring medical attention when compared to control formulas (92505).
• Dyslexia. It is unclear if oral DHA is beneficial for improving night vision in children with this condition. Details: One small clinical study in children with dyslexia shows that taking fish oils rich in DHA, providing 480 mg daily for one month, seem to develop significantly better dark adaptation when compared with controls (5708).
• Dysmenorrhea. Although there has been interest in using oral DHA for dysmenorrhea, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Fractures. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not prevent fractures in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Hypertension. It is unclear if oral DHA is beneficial for reducing blood pressure in adults or if prenatal supplementation reduces blood pressure in children. Details: Clinical research shows that taking DHA-enriched canola oil containing 63% oleic acid and 6% DHA for 4 weeks reduces systolic blood pressure by 3% and diastolic blood pressure by 4% when compared to baseline in adults with at least one cardiovascular risk factor (26466). A meta-analysis of clinical research in adults with dyslipidemia shows that supplemental DHA reduces diastolic, but not systolic, blood pressure when compared with control (102389). A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not reduce blood pressure levels in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly. About 39% of the individuals included in this study were diagnosed with hypertension and about 50% were using antihypertensives (104619). The effect of DHA alone on blood pressure levels in a population of adults with diagnosed hypertension is unclear. Prenatal supplementation with DHA has also been evaluated for the prevention of hypertension in children. A secondary analysis of a large clinical trial shows that overweight children or children with obesity whose mothers took DHA 600 mg daily, starting at about 14.5 weeks' gestation and continuing until birth, have lower diastolic and systolic blood pressure at 5 years of age when compared with those whose mothers took placebo. Systolic and diastolic blood pressure were reduced by about 4 mm Hg and 5 mm Hg, respectively, in the children exposed to DHA during pregnancy when compared with those exposed to placebo. The blood pressure of the children exposed to DHA during pregnancy was similar to that of children with normal weight (98891). Results of this study are limited by the fact that confounding factors, such as shorter duration of breast-feeding and increased sodium intake for children with obesity in the placebo group, may have also contributed to differences in blood pressure. It is unclear if this reduction in elevated blood pressure during childhood reduces the risk of hypertension in adulthood.
• IgA nephropathy. Although there has been interest in using oral DHA for IgA nephropathy, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Infant development. Infant supplementation with DHA does not seem to improve development. Also, most evidence shows that maternal supplementation with DHA is not beneficial for infant cognitive development. However, due to the lack of significant safety concerns and the possibility of some cognitive benefit, many experts recommend DHA 200 mg daily during pregnancy. Details: Most clinical research shows that giving healthy, full-term infants formula supplemented with DHA 0.32% to 0.96% modestly improves measures of visual acuity at 2, 4, and 12 months of age when compared with standard infant formula (14403,15003,47980,48355,90670). However, formula supplemented with DHA 0.15% does not appear to improve visual acuity by about 12 months when given to preterm infants (48008). There is some evidence that giving healthy, full-term infants DHA-supplemented formula during infancy might improve language comprehension and development, as well as fine motor skills, by the age of 12-14 months when compared with standard formula (48247,48356). However, most clinical research, including meta-analyses of high-quality clinical trials, shows that giving infants formula supplemented with DHA during infancy does not improve overall cognition or motor skills at 12-14 months of age, regardless of DHA dosing or prematurity status (48247,48356,89363). Experts generally recommend breast-feeding as the preferred feeding method over DHA-supplemented formula; however, if formula is used, some experts suggest a formula providing at least 0.2% of lipids from DHA (14403). Some population research suggests that higher maternal DHA levels are associated with improved use of gestures and problem solving in infants (90709,99132). However, population research suggests that higher maternal DHA levels also appear to be associated with worsening mental development (90709), and most clinical research shows that maternal ingestion of DHA has little effect on fetal or infant development. Maternal ingestion of DHA 33-133 mg daily from an egg source or 400 mg daily from an algal-based source does not seem to significantly increase weight, length, or head circumference at birth (14395,48286). Also, maternal ingestion of DHA 200-400 mg daily from week 15-22 of pregnancy until term does not significantly improve visual or auditory development in term infants (14393,90706). A small clinical trial shows that taking DHA 1440 mg daily from fish oil also providing eicosapentaenoic acid (EPA) 260 mg, from 22-24 weeks gestation until delivery, does not improve most measures of developmental or behavioral milestones in the infant at 6 months, when compared with olive oil placebo (110354). In addition, most research suggests that DHA supplementation during pregnancy, occasionally continuing postpartum for 6 months, does not affect growth to age 18 months or visual acuity, attention, working memory, behavior and most other measures of neurodevelopment by 1-7 years of age (48095,48285,48293,90679,90690,94600,96522,109219). However, there is some evidence to suggest that maternal supplementation with DHA 214 mg daily may improve infant sleep patterning on the first day of life (90687). Also, maternal supplementation with DHA 400 mg daily from 16 weeks gestation until delivery may reduce the risk of poor language development in the infant at age 14 and 18 months and the risk of lower visual acuity at 2 months when compared with placebo (90694). However, this benefit did not have lasting effects at 5-6 years of age (99133).
• Intraventricular hemorrhage. It is unclear if oral DHA is beneficial for preventing intraventricular hemorrhage in premature infants. Details: Preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of intraventricular hemorrhage when compared with a control emulsion (110356).
• Keratoconus. It is unclear if oral DHA is beneficial for improving vision in people with keratoconus. Details: A small clinical trial in patients with early to advanced keratoconus shows that taking DHA 1000 mg daily for 3 months does not improve corneal thickness, measurements of corneal curve, or most other ophthalmological measures when compared with taking no DHA (110358).
• Lower respiratory tract infections. It is unclear if formula containing DHA is beneficial for preventing lower respiratory tract infections in infants. Details: Clinical research shows that giving preterm infants formula or breast milk containing high-dose DHA (1% of fatty acids) does not prevent hospitalizations due to bronchiolitis and other lower respiratory tract conditions when compared with giving breast milk or formula containing 0.35% DHA (90667). However, preliminary clinical research shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months reduces the risk of bronchiolitis and croup when compared with control formulas (92505).
• Male infertility. It is unclear if oral DHA is beneficial for improving fertility. Details: Clinical research shows that taking DHA (NuaDHA, Nua Biological Innovations SL) 0.5, 1, or 2 grams daily for 3 months increases progressive sperm motility by 24% to 30% when compared with placebo in men with a history of infertility. The greatest effects were seen in men with asthenozoospermia, with an overall effect of 35 (99134). It is unclear if the effects of DHA on sperm function correlate with increased fertility rates.
• Metabolic syndrome. Although there has been interest in using oral DHA for metabolic syndrome, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Migraine headache. Although there has been interest in using oral DHA for migraine headache, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Muscle strength. It is unclear if oral DHA is beneficial for increasing muscle strength. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not increase muscle strength in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Necrotizing enterocolitis (NEC). It is unclear if oral DHA is beneficial for preventing NEC in preterm infants. Details: Clinical research in preterm infants shows that providing DHA (Neuromins for Kids life's DHA; DSM Nutritional Products Inc.) 75 mg/kg for 14 days from the first enteral feed reduces the risk of confirmed NEC by 7% when compared with a control oil. Treatment of 15 infants with DHA would be needed to prevent one case of NEC (109213). However, preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks' gestation, has no effect on the incidence of NEC in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of NEC when compared with a control emulsion (110356).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral DHA is beneficial for NAFLD. Details: Preliminary clinical research shows that taking DHA (Martek Biosciences Corporation) 250-500 mg daily for 6-24 months reduces the risk of severe liver steatosis when compared with placebo in children with NAFLD (48295,90695,90696).
• Obesity. It is unclear if oral DHA is beneficial for improving weight loss in overweight or obese adults. Details: Preliminary clinical research shows that taking 2.8 grams daily of an oil emulsion containing approximately 46% DHA for 12 weeks decreases carbohydrate and fat intake, but does not reduce body weight or improve body composition, when compared with placebo in overweight or obese adults (90681).
• Otitis media. It is unclear if DHA in infant formula is beneficial for preventing otitis media in infants. Details: Preliminary clinical research shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) for 12 months does not prevent the development of ear infection when compared with control formulas (92505).
• Phenylketonuria (PKU). It is unclear if oral DHA is beneficial for PKU. Details: Children with PKU consume very low amounts of DHA. Clinical research shows that taking DHA up to approximately 7 mg/kg daily for 6 months improves DHA status, but not neurological function, in children aged 5-13 years with PKU (99631). The effect of higher doses of DHA, or the effect of DHA supplementation on neurological function in younger children with PKU, have not been determined.
• Physical performance. It is unclear if oral DHA is beneficial for increasing physical performance in older adults. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not improve physical performance in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Postoperative pain. It is unclear if oral DHA is beneficial for reducing postoperative analgesic use. Details: A post-hoc analysis shows that enteral DHA 75 mg/kg administered perioperatively to infants born at greater than 34 weeks gestation who are undergoing cardiac surgery reduces the cumulative analgesic dose and shortens the duration of buprenorphine during the postoperative period when compared with placebo. However, the use of fentanyl or ketorolac were not reduced (96524).
• Prematurity. It is unclear if oral DHA during lactation or early in infancy is beneficial for increasing growth or neurodevelopment of the premature infant. Details: Clinical research in lactating individuals who delivered prior to 29 weeks' gestation shows that taking DHA 1.2 grams daily, starting within 72 hours of delivery and continuing until the infant reached 36 weeks postmenstrual age, might have beneficial effects on the growth of female infants, but not male infants, when compared with placebo. Weight velocity and weight gain were significantly increased in the female infants, with a weight gain of 52.6 grams. However, weight gain and weight velocity were not improved in the male infants, and weight at 36 weeks postmenstrual age was 89 grams less than those whose mothers took placebo (109221). In addition, there was no improvement in neurodevelopmental outcomes at 18 to 22 months corrected age (110364). Other clinical research in infants born before 29 weeks' gestation shows that giving enteral DHA 60 mg/kg daily until 36 weeks corrected gestational age does not improve most measures of intelligence at 5 years when compared with placebo (110363).
• Prostate cancer. It is unclear if oral DHA is beneficial for prostate cancer prevention. Details: Observational research has found that higher consumption of DHA is associated with a reduced risk of total, advanced, and aggressive prostate cancer when compared to lower consumption of DHA (12961,25937). However, a meta-analysis of multiple population studies has found that higher DHA blood levels are associated with a 2.5-fold higher risk of aggressive prostate cancer, but not low-grade prostate cancer, when compared with lower blood percentages of DHA (25936). Another meta-analysis of population research has found that a higher blood level of DHA is associated with a slight increased risk of non-aggressive prostate cancer (90677).
• Psoriasis. Although there has been interest in using oral DHA for psoriasis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Raynaud syndrome. Although there has been interest in using oral DHA for Raynaud syndrome, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Restenosis. It is unclear if oral DHA is beneficial for preventing restenosis in people with stents. Details: Observational research has found that initiation of statin therapy in patients receiving stent placement after an acute coronary event is associated with a reduction in DHA levels. These reductions in DHA are associated with a greater prevalence of in-stent restenosis. From these results, researchers postulate that patients newly started on a statin after stent placement for acute coronary syndrome might benefit from DHA supplementation (100939). However, the effect of DHA supplementation is unknown.
• Retinitis pigmentosa. Evidence for the use of oral DHA for retinitis pigmentosa is inconsistent and contradictory. Details: Some clinical research shows that taking DHA 1200 mg daily for 4 years does not improve eye function in patients with retinitis pigmentosa who are also taking vitamin A when compared with placebo (48070). Also, taking DHA 600-3600 mg daily for 4 years does not maintain rod or cone function in boys or men with retinitis pigmentosa when compared with placebo (90683). However, a report of ancillary outcomes from this study shows that taking DHA might slow the rate of decline in final dark-adapted thresholds and visual field sensitivity in these patients (95738). Also, some research shows that taking DHA 400 mg daily for 4 years does maintain rod and cone function in some patients, although visual function is not improved when compared with placebo (48057,48115).
• Retinopathy of prematurity. It is unclear if maternal or infant supplementation with oral DHA is beneficial for preventing retinopathy of prematurity. Details: Preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on the incidence of retinopathy of prematurity in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of retinopathy of prematurity when compared with a control emulsion (110356).
• Rheumatoid arthritis (RA). Although there has been interest in using oral DHA for RA, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Schizophrenia. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking EPA 1000 mg, DHA 500 mg, and alpha-lipoic acid 150 mg twice daily for up to 2 years after discontinuing antipsychotic treatment does not prevent relapse in patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder (90675).
• Sepsis. It is unclear if oral DHA is beneficial for preventing sepsis in premature infants. Details: Preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on the incidence of sepsis in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of sepsis when compared with a control emulsion (110356).
• Spinocerebellar ataxia (SCA). It is unclear if oral DHA is beneficial for SCA. Details: Preliminary clinical research in patients with SCA shows that taking DHA 600 mg daily for 16 weeks reduces ataxia and improves cerebellar hypometabolism upon brain imaging when compared with placebo. These beneficial effects are sustained when DHA is taken for an additional 40 weeks (96525).
• Stroke. It is unclear if oral DHA is beneficial for stroke prevention. Details: Population research has found that serum DHA levels may be associated with a reduced risk of ischemic stroke, as well as any specific type of ischemic stroke, including cardioembolic stroke, atherothrombotic stroke, and lacunar stroke (90715).
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral DHA for SLE, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Systemic lupus erythematosus (SLE) nephritis. Although there has been interest in using oral DHA for SLE nephritis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Ulcerative colitis. Although there has been interest in using oral DHA for ulcerative colitis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Vascular dementia. It is unclear if DHA is beneficial for improving dementia severity. Details: Preliminary clinical research in patients with vascular dementia shows that taking DHA 0.72 grams daily for one year improves dementia severity based on the Hasegawa's Dementia Rating Scale and Mini-Mental State Examination Scale scores when compared to baseline (47940). More evidence is needed to rate DHA for these uses.

(Read more about DOCOSAHEXAENOIC ACID (DHA))

EFFECTIVE

• Hypertriglyceridemia. Oral prescription ethyl-EPA 4 grams daily reduces triglyceride levels in patients with hypertriglyceridemia, especially in severe cases. It is unclear if oral EPA supplements are beneficial in hypertriglyceridemia. Details: A specific ethyl-EPA product (Vascepa, formerly ARM101, Amarin) is approved by the US Food and Drug Administration (FDA) to be used at a dose of 4 grams daily with diet modification to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia. Clinical research shows that taking 4 grams daily in two divided doses for 12 weeks reduces triglyceride levels by 33%, total cholesterol by 16%, very low-density lipoprotein (VLDL) cholesterol by 29%, and apolipoprotein B by 9% when compared with placebo (91410). In patients taking statins with persistent elevated triglyceride levels (between 200 mg/dL and 500 mg/dL), this prescription product reduces triglyceride levels by about 22% and low-density lipoprotein (LDL) cholesterol by about 6% when compared with placebo (91409). In females with diabetes taking statins with persistent elevated triglyceride levels, this product reduces triglyceride levels by about 21.5% and total cholesterol levels by 12.5%, but does not reduce levels of LDL cholesterol when compared with placebo (99136). Furthermore, a large clinical trial (REDUCE-IT) in patients with LDL cholesterol levels controlled with statin therapy, but with persistent elevated triglyceride levels and other cardiovascular risk factors, shows that this product reduces the risk of major adverse cardiovascular events by 25% when compared with placebo after a median follow-up of 4.9 years. The number of these patients needed to be treated to prevent one major adverse cardiovascular event is 21 (95715). Preliminary clinical research in patients with hypertriglyceridemia also shows that taking a specific self-emulsifying ethyl-EPA (MND-2119, Mochida Pharmaceutical Co., Ltd., Tokyo, Japan) 2 grams or 4 grams once daily for 52 weeks reduces levels of triglycerides by 16.7% and 21.0%, respectively, compared with baseline (110365). This study is uncontrolled and open-label. There is no strong evidence that EPA SUPPLEMENTS reduce triglyceride levels in patients with hypertriglyceridemia.

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Oral prescription ethyl-EPA seems to reduce the risk of CVD events when used as an adjunct to statin therapy in patients with CVD risk. It is unclear if oral EPA supplements are beneficial in CVD. Details: A specific ethyl EPA product (Vascepa, Amarin) is approved by the US Food and Drug Administration (FDA) to be used as an adjunct to statin therapy to reduce the risk of cardiovascular events such as myocardial infarction and stroke in adult patients with elevated triglycerides (≥ 150 mg/dL) and CVD or diabetes mellitus and at least two additional risk factors for CVD (101286). This approval was mostly due to evidence from a large clinical trial (REDUCE-IT). For patients in the REDUCE-IT trial on statin therapy with persistent elevated triglyceride levels and other cardiovascular risk factors, taking Vascepa 4 grams daily reduced the risk of major adverse cardiovascular events by 25% when compared to placebo after a median follow-up of 4.9 years. To prevent one major cardiovascular event, 21 patients need to be treated (95715). There is no strong evidence that EPA SUPPLEMENTS reduce CVD risk in patients with hypertriglyceridemia.
• Depression. Oral EPA seems to reduce symptoms of depression, especially in patients already being treated with conventional antidepressants. Details: Meta-analyses of clinical research show that pure EPA or omega-3 fatty acid enriched in EPA (at least 60%) moderately reduces depressive symptoms in patients with major depressive disorder (MDD) and those with depressive symptomatology but no diagnosis of MDD (90680,66129,102391). The beneficial effect of EPA appears to be dose-dependent in patients with MDD but not in those with depressive symptomatology (90680). The duration of treatment and the age of the patients do not appear to influence the effects of EPA (66129). Patients already being treated with conventional antidepressant medications may benefit more from EPA than those not taking antidepressants. Preliminary clinical research shows that taking ethyl-EPA orally 500 mg to 1 gram twice daily with standard therapy improves symptoms of recurrent major depression, such as depressed mood, guilty feelings, worthlessness, and insomnia, after 2-4 weeks of treatment (10215,10872). A 1 gram per day dose of ethyl-EPA may be more effective for depression than 2 grams per day (10215). However, in patients not using standard therapy, taking EPA-enriched omega-3 fatty acid (ProEPA Xtra, NordicNaturals) standardized to contain EPA 1060 mg and docosahexaenoic acid (DHA) 274 mg daily for 8 weeks does not reduce symptoms of depression in patients with MDD (90691). Some research suggests that EPA may help prevent the development of major depression in patients treated with interferon-alpha. Clinical research shows that only 10% of patients taking EPA 3.5 grams daily for 2 weeks prior to the start of interferon-alpha therapy experience major depression during the 24 weeks of interferon-alpha treatment compared to 30% of patients taking placebo. Also, the onset of depression is delayed from approximately 5.3 weeks to 12 weeks (90710). Based on these and other findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids providing 1-2 grams EPA are recommended for adjunctive use in patients with major depressive disorder. However, omega-3 fatty acids are not recommended as monotherapy and products containing other doses of EPA are not recommended as adjunctive or monotherapy in these patients (110318).
• Myocardial infarction (MI). Oral prescription ethyl-EPA reduces the risk of MI when used as an adjunct to statin therapy in patients with cardiovascular disease (CVD) risk. Oral EPA supplements also seem to be beneficial for this purpose. Details: A specific ethyl-EPA product (Vascepa, Amarin) 4 grams daily is approved by the US Food and Drug Administration (FDA) to be used as an adjunct to statin therapy to reduce the risk of cardiovascular events such as myocardial infarction and stroke in adult patients with elevated triglycerides (≥ 150 mg/dL) and CVD or diabetes mellitus and at least two additional risk factors for CVD (101286). The effects of EPA SUPPLEMENTS for MI are less clear. Clinical research in patients with acute MI shows that taking EPA 1.8 grams daily along with pitavastatin 2 mg daily for one month starting within 24 hours of percutaneous coronary intervention (PCI) reduces the incidence of adverse cardiac events, including cardiac death, stroke, re-infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation, by 64% when compared with pitavastatin alone. In particular, the incidence of ventricular arrhythmias is reduced by about 66% for patients treated with EPA plus pitavastatin compared to pitavastatin alone (91411). Taking this same dose of EPA along with the same dose of pitavastatin for one year after PCI in patients with acute MI also reduces the absolute risk of cardiovascular death, MI, stroke, or coronary revascularization by 11% when compared to pitavastatin alone. The reduction in cardiovascular events after one year was largely due to a decrease in cardiovascular deaths by about 6% (96420). There is also evidence that taking EPA 1.8 grams daily along with pitavastatin 4 mg daily for 6-8 months following PCI for acute coronary syndrome reduces plaque lipid volume by 20% when compared to pitavastatin alone (96419). One clinical study also shows that taking EPA 0.9 grams twice daily along with statins for one month prior to undergoing PCI might reduce the incidence of periprocedural (type IV) MI by approximately 25% when compared to statins alone (91412).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). It is unclear if oral EPA is beneficial for AMD prevention. Details: Population research suggests that increased dietary consumption of EPA does not prevent AMD (10324).
• Allergic rhinitis (hay fever). Although there has been interest in using oral EPA for allergic rhinitis, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Alzheimer disease. It is unclear if oral EPA is beneficial for Alzheimer disease prevention. Details: Population research suggests that higher dietary intake of EPA is not associated with a decreased risk of developing Alzheimer disease (15041).
• Asthma. Although there has been interest in using oral EPA for asthma, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Atopic dermatitis (eczema). Although there has been interest in using oral EPA for atopic dermatitis, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral EPA is beneficial for ADHD treatment or prevention. Details: Some research shows that low plasma levels of EPA and other fatty acids are associated with ADHD in children (15496); however, it is not known if taking EPA supplements can treat or prevent ADHD.
• Behcet disease. Although there has been interest in using oral EPA for Behcet disease, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Bipolar disorder. Oral fish oil in doses providing 1-2 grams EPA may be beneficial for symptoms of depression in patients with bipolar disorder. It is unclear if EPA alone is beneficial. Details: Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids in doses standardized to 1-2 grams EPA are weakly recommended for adjunctive use in bipolar depression (110318). This recommendation is based mainly on an early meta-analysis of clinical research of various omega-3 sources (66126). Three clinical trials in this meta-analysis examined the effect of EPA alone in patients with bipolar disorder (110366,110367,110368), with only one study in patients also using stable routine treatment examining the effect of ethyl-EPA 1 gram or 2 grams daily for 12 weeks showing benefit on symptoms of depression, but not mania (110366). The largest clinical trial in patients with bipolar disorder shows that taking ethyl-EPA 6 grams daily for 4 months does not improve symptoms of depression or mania (110368). These findings suggest an unclear effect of ethyl-EPA on symptoms of depression, with no evidence of support for improving symptoms of mania. Also, theoretically, fish oil, a source of EPA in some clinical trials, might increase symptoms of mania in patients with bipolar disorder. Cases of hypomania have been reported in patients with bipolar disorder using fish oil (5713,7202).
• Borderline personality disorder. It is unclear if oral EPA is beneficial for improving symptoms of borderline personality disorder. Details: A small clinical trial shows that taking ethyl-EPA 1 gram orally daily for 8 weeks modestly improves aggressive behavior and depression in patients with moderately severe borderline personality disorder when compared with placebo (10348).
• Cachexia. It is unclear if oral EPA is beneficial for maintaining lean body mass in patients undergoing chemotherapy. Details: In patients with advanced non-small cell lung cancer, taking an oral nutritional supplement containing EPA (ProSure, Abbott Nutrition) 2 grams daily while undergoing chemotherapy modestly increases lean body mass by 1.6 kg, on average, compared with a 2 kg LOSS of lean body mass with an isocaloric nutritional supplement (91413). In patients with head and neck cancer, starting EPA 2 grams daily along with a polymeric diet prior to chemotherapy and continuing for 6 weeks results in weight and lean body mass maintenance when compared with baseline. However, this maintenance did not differ statistically from losses of 2.1 kg and 1.3 kg, respectively, in patients using the polymeric diet without EPA (99135). A meta-analysis of eight studies in cancer patients shows that taking EPA, usually alone in doses of 1.5-2.2 grams daily for 4-6 weeks, does not seem to prevent loss of lean body mass when compared with placebo. However, it is unclear how many of the included patients had malnutrition and/or weight loss (106070). Also, this analysis included two studies in which EPA was combined with docosahexaenoic acid (DHA) in fish oil.
• Chemotherapy-induced diarrhea. It is unclear if oral EPA is beneficial for preventing diarrhea during treatment with chemotherapy. Details: In patients with advanced non-small cell lung cancer, taking an oral nutritional supplement containing EPA (ProSure, Abbott Nutrition) 2 grams daily while undergoing chemotherapy with paclitaxel and cisplatin/carboplatin does not seem to prevent diarrhea when compared with taking an isocaloric control nutritional supplement (91413).
• Chemotherapy-induced nausea and vomiting (CINV). It is unclear if oral EPA is beneficial for preventing nausea and vomiting during treatment with chemotherapy. Details: In patients with advanced non-small cell lung cancer, taking an oral nutritional supplement containing EPA (ProSure, Abbott Nutrition) 2 grams daily while undergoing chemotherapy with paclitaxel and cisplatin/carboplatin does not seem to prevent nausea or vomiting when compared with taking an isocaloric control nutritional supplement (91413).
• Chemotherapy-induced peripheral neuropathy. It is unclear if oral EPA is beneficial for preventing peripheral neuropathy during treatment with chemotherapy. Details: In patients with advanced non-small cell lung cancer, taking an oral nutritional supplement containing EPA (ProSure, Abbott Nutrition) 2 grams daily while undergoing chemotherapy with paclitaxel and cisplatin/carboplatin moderately prevents the development of neuropathy symptoms when compared with taking an isocaloric control nutritional supplement (91413).
• Chemotherapy-related fatigue. It is unclear if oral EPA is beneficial for preventing fatigue during treatment with chemotherapy. Details: In patients with advanced non-small cell lung cancer, taking an oral nutritional supplement containing EPA (ProSure, Abbott Nutrition) 2 grams daily while undergoing chemotherapy with paclitaxel and cisplatin/carboplatin modestly reduces symptoms of fatigue when compared with taking an isocaloric control nutritional supplement (91413).
• Cognitive function. It is unclear if oral EPA alone is beneficial for improving cognitive function. Details: Clinical research in young and middle-aged adults shows that taking an omega-3 supplement providing EPA 900 mg plus docosahexaenoic acid (DHA) 360 mg (Accelon EPA EE, BASF) daily for 6 months improves some measures of cognitive function, including overall speed and overall memory-related accuracy, when compared with both placebo or an omega-3 supplement providing DHA 900 mg and EPA 270 mg daily (Accelon DHA EE, BASF). There were no benefits on other measures of cognitive performance (109215).
• Colorectal adenoma. Taking oral EPA with aspirin might reduce the development of new colorectal adenomas. However, it is unclear if oral EPA alone is beneficial. Details: Clinical research in adults determined to be at high risk for colorectal cancer shows that taking EPA 2 grams, with or without aspirin 300 mg, daily for one year does not reduce the rate of adenoma detection during colonoscopy when compared with placebo or aspirin alone. However, the combination of EPA with aspirin seems to reduce the total number of detected adenomas when compared with taking either EPA or aspirin alone (102501).
• Coronary heart disease (CHD). It is unclear if oral EPA alone is beneficial for CHD. Details: Population research suggests that increased dietary consumption of EPA is associated with a modest decrease in the risk of mortality in patients with CHD (10322). Also, preliminary clinical research shows that patients with hypercholesterolemia and a history of CHD who take ethyl-EPA 600 mg three times daily have a 19% reduction in the risk of major coronary events; however, ethyl-EPA doesn't appear to reduce sudden cardiac death (15497).
• Cystic fibrosis. Although there has been interest in using oral EPA for cystic fibrosis, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Diabetes. It is unclear if oral EPA is beneficial for glycemic control. Details: A small study shows that taking EPA 4 grams daily for 6 weeks does not seem to substantially improve cholesterol, blood sugar, or glycated hemoglobin in patients with type 2 diabetes when compared with placebo. However, triglyceride levels are reduced (10321).
• Dysmenorrhea. Although there has been interest in using oral EPA for dysmenorrhea, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Exercise-induced muscle damage. It is unclear if oral EPA alone is beneficial for preventing exercise-induced muscle damage. Details: Small clinical studies in untrained healthy males show that taking fish oil providing EPA 600 mg and docosahexaenoic acid (DHA) 260 mg daily for 4-8 weeks prior to exhaustive unaccustomed exercise has beneficial effects on immediate and/or delayed muscle soreness and range of motion when compared with placebo (98257,109222).
• Fractures. Oral EPA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing EPA 330 mg and docosahexaenoic acid (DHA) 660 mg, for 3 years does not prevent fractures in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Huntington disease. It is unclear if oral EPA is beneficial for this condition. Details: A meta-analysis of five clinical studies in adults with Huntington disease shows that taking EPA 1-2 grams daily for 6 months does not improve motor scores or symptoms when compared with placebo. In two clinical studies that continued for an additional 6 months, EPA supplementation improved total motor score at 12 months. However, the validity of this finding is confounded because the largest clinical trial included in this analysis converted to an open-label design after the first 6 months, eliminating the placebo control and introducing the risk for patient and investigator bias (102505).
• Hypercholesterolemia. It is unclear if oral EPA is beneficial for improving lipid levels. Details: Small clinical trials shows that taking EPA alone reduces serum triglyceride concentrations, but has no effect on total and low-density lipoprotein (LDL) cholesterol in mildly hypercholesterolemic males (6143,10322). The effect of EPA on cholesterol levels in other populations has also been evaluated. In patients with type 2 diabetes, EPA can increase high-density lipoprotein (HDL) cholesterol levels by approximately 12% (10321). In normolipidemic individuals, an algal oil enriched in EPA reduced levels of very low-density lipoprotein (VLDL) and total cholesterol but had no effect on triglyceride or LDL cholesterol levels (103314). Also, a meta-analysis of clinical research shows that taking EPA modestly decreases total and LDL cholesterol levels when compared with placebo (109216). However, not all patients in these studies had hyperlipidemia, and EPA was usually provided in oils that also include docosahexaenoic acid.
• Hypertension. Small clinical studies suggest that oral EPA, when used alone or in combination with docosahexaenoic acid (DHA), does not lower blood pressure. Details: A meta-analysis of clinical research in adults with dyslipidemia shows that supplemental EPA reduces systolic, but not diastolic, blood pressure when compared with control (102389). Other preliminary clinical research in adults with slightly elevated diastolic blood pressure (84-94 mmHg) also shows that taking a combination of EPA 0.48 grams plus gamma-linolenic acid 0.12 grams does not reduce diastolic blood pressure (13771). A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing EPA 330 mg and DHA 660 mg, for 3 years does not reduce blood pressure levels in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly. About 39% of the individuals included in this study were diagnosed with hypertension and about 50% were using antihypertensives (104619).
• IgA nephropathy. Although there has been interest in using oral EPA for IgA nephropathy, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Intrauterine growth restriction (IUGR). It is unclear if oral EPA during pregnancy reduces the risk of IUGR. Details: A small clinical study in patients with a history of IUGR during a previous pregnancy shows that taking EPA 3 grams daily, starting at 12-14 weeks gestation and continuing until delivery, does not seem to reduce the risk of IUGR when compared with placebo (1027).
• Lung cancer. It is unclear if oral EPA is beneficial for lung cancer treatment. Details: In patients with advanced non-small cell lung cancer, taking an oral nutritional supplement containing EPA (ProSure, Abbott Nutrition) 2 grams daily while undergoing chemotherapy with paclitaxel and cisplatin/carboplatin does not improve tumor response rate, survival, or physical functioning over a 12 month period when compared with taking an isocaloric control nutritional supplement (91413).
• Menopausal symptoms. It is unclear if oral EPA reduces hot flashes after menopause. Details: In post-menopausal adults with mild hot flash symptoms, clinical research shows that taking ethyl-EPA (ethyl-EPA) 500 mg three times daily, provides modest reduction in the frequency of hot flashes when compared with placebo. After 8 weeks of treatment, the mean number of hot flashes decreased by 1.58 per day in those taking ethyl-EPA. However, taking ethyl-EPA did not significantly decrease the severity of hot flashes or improve overall quality of life (16901). Research in patients with more severe hot flash symptoms is needed to confirm these results.
• Metabolic syndrome. Although there has been interest in using oral EPA for metabolic syndrome, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Migraine headache. Although there has been interest in using oral EPA for migraine headache, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Muscle strength. It is unclear if oral EPA is beneficial for increasing muscle strength. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing EPA 330 mg and docosahexaenoic acid (DHA) 660 mg, for 3 years does not increase muscle strength in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Physical performance. Taking EPA does not seem to improve physical performance in patients requiring mechanical ventilation. It is unclear if oral EPA is beneficial for increasing physical performance in older adults. Details: Clinical research in mechanically ventilated patients shows that taking EPA 2 grams daily for 10 days, alone or with beta-hydroxymethylbutyrate 3 grams daily, does not increase diaphragm or quadriceps strength or thickness when compared with placebo (109223). Also, a large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing EPA 330 mg and docosahexaenoic acid (DHA) 660 mg, for 3 years does not improve physical performance in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Postoperative infection. Oral EPA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that enteral nutrition supplemented with EPA in combination with RNA and L-arginine, given during the postoperative period, reduces the percentage of patients experiencing postoperative infectious/wound complications and shortens the duration of hospitalization by about 4 days when compared to standard enteral nutrition (5531). It is not clear if this effect is due to EPA, RNA, L-arginine, or the combination.
• Postoperative recovery. It is unclear if oral EPA helps to maintain postoperative lean body mass. Details: Weight loss and malnutrition are common after esophageal cancer resection. Preliminary clinical research shows that administering EPA-enhanced enteral nutrition does not attenuate loss of body weight or lean body mass by one month post-esophagectomy when compared with standard enteral nutrition (96504).
• Pregnancy-induced hypertension. It is unclear if oral EPA during pregnancy reduces the risk of hypertension. Details: A small study in patients with a history of intrauterine growth restriction during a previous pregnancy shows that taking EPA 3 grams daily, starting at 12-14 weeks gestation and continuing until delivery, does not seem to reduce the risk of pregnancy-induced hypertension when compared with placebo (1027).
• Prostate cancer. It is unclear if oral EPA is beneficial for prostate cancer treatment or prevention. Details: Preliminary clinical research shows that taking EPA 4.48 grams and docosahexaenoic acid 2.88 grams daily for 12 weeks reduces prostate specific antigen (PSA) levels in men with normal PSA levels at baseline. However, it is unclear if this effect was due to EPA alone. Additionally, it is unclear if this leads to a reduced risk for prostate cancer (89423). Observational research regarding the association between EPA and prostate cancer risk is conflicting. Although some early research suggests a possible association, a meta-analysis including this and other prospective observational research shows that increased dietary intake or serum levels of EPA are not associated with overall prostate cancer risk (90677,102503). One observational study in men with existing low-risk prostate cancer shows that the highest tertile of prostate tissue levels of EPA, as well as the highest tertile of dietary intake, is associated with 71% to 75% reduced odds for progression to high-grade prostate cancer when compared with the lowest tertile (102502). However, other prospective observational research suggests that increased dietary intake of EPA may be associated with an increased risk for fatal prostate cancer (102503). High-quality prospective research is needed to clarify these findings.
• Psoriasis. It is unclear if oral EPA is beneficial in psoriasis. Details: Preliminary clinical research shows that taking ethyl-EPA 1.8 grams daily in combination with low-dose (20 mg per day) etretinate (Tegison, no longer available in the US) for 12 weeks is more effective than etretinate alone for plaque psoriasis (66478).
• Quality of life. It is unclear if oral EPA is beneficial for improving quality of life in patients with cancer. Details: A meta-analysis of eight clinical trials in cancer patients shows that taking EPA, usually alone in doses of 2-2.2 grams daily for 6-12 weeks, does not seem to improve quality of life when compared with placebo (106070). This analysis included two studies in which EPA was combined with docosahexaenoic acid (DHA) in fish oil.
• Schizophrenia. Evidence for the use of oral EPA in schizophrenia is conflicting. Details: Some clinical research shows that EPA improves mental state and reduces dyskinesia when taken along with antipsychotic medications (8720). However, other clinical research shows that EPA does not improve mental state, cognitive function, or mood in patients with schizophrenia who are taking antipsychotics (10347). A meta-analysis of clinical research shows that EPA modestly improves the mental state of patients with schizophrenia who are not taking antipsychotic medications prior to treatment, but not those already being treating with antipsychotics at baseline. Some evidence suggests that ethyl-EPA might be more effective than EPA. Taking EPA does not appear to significantly decrease the need for conventional antipsychotics (15039). EPA or ethyl-EPA 1-3 grams daily in divided doses for 12-16 weeks has been used in these studies (8720,15039).
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral EPA for SLE, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Systemic lupus erythematosus (SLE) nephritis. Although there has been interest in using oral EPA for SLE nephritis, there is insufficient reliable information about the clinical effects of EPA for this condition.
• Ulcerative colitis. It is unclear if oral EPA is beneficial for ulcerative colitis prevention and treatment. Details: Population research derived from the Nurses' Health Study shows that a higher dietary intake of omega-3 fatty acids is associated with a reduced incidence of ulcerative colitis. One study shows that taking EPA 1 gram twice daily for 6 months reduces fecal calprotectin levels, a marker of intestinal mucosal inflammation, by 40% when compared with placebo. Additionally, a 27% reduction in disease relapse was seen in the EPA group (96503).
• Wound healing. Although there has been interest in using oral EPA for wound healing, there is insufficient reliable information about the clinical effects of EPA for this condition. More evidence is needed to rate eicosapentaenoic acid for these uses.

(Read more about EICOSAPENTAENOIC ACID (EPA))

EFFECTIVE

• Hypertriglyceridemia. Oral prescription fish oil products reduce triglyceride levels in patients with hypertriglyceridemia, especially in severe cases. Oral fish oil supplements may reduce triglyceride levels when used in very high doses of up to 12 capsules per dose. Details: Fish oil can reduce triglyceride levels by 20% to 50% (1024,2299,2300,2301,2302,2315,2317,5702,5705,5706)(6394,6399,7368,7369,7380,12921,12922,13011,13766,65846)(66154,65504,66370,66156,66338,65589,66221,66257,66278,98004,100253). The effect is dose-dependent and greatest in individuals with severe hypertriglyceridemia (triglyceride levels of 500 mg/dL and above) (5706,7380,65846,66278,100253). However, fish oil might be less effective than fibrates. One clinical study shows that fish oil in doses of 4 grams daily is not as effective as gemfibrozil (Lopid) 1200 mg daily (7377). For patients with hypertriglyceridemia associated with the atherogenic lipoprotein phenotype (ALP), which is thought to be a marker for cardiovascular disease, taking fish oil 6 grams daily might reduce triglyceride levels by 35% (8683). Preliminary clinical research shows that taking the omega-3 fatty acids found in fish oil might also reduce fatty liver disease and serum transaminase levels associated with hypertriglyceridemia (13755). Three specific fish oil preparations (Lovaza, formerly known as Omacor, GlaxoSmithKline; Omtryg, Trygg Pharma, Inc.; Epanova, AstraZeneca Pharmaceuticals), are approved by the US Food and Drug Administration (FDA) for use as an adjunct to diet to lower triglyceride levels in adults with severe hypertriglyceridemia (12982,96117). These prescription-only products are typically used at dosages of 4 grams providing 3.4-3.6 grams of omega-3 fatty acids daily (98004). When a 4-gram daily dose is used, triglycerides are lowered by about 20% to 30%. When a 2-gram daily dose is used, the triglyceride-lowering effect is reduced by about half (100253). In 2019, the American Heart Association (AHA) stated that prescription fish oil products, taken in doses of 4 grams daily, are clinically useful for lowering triglyceride levels in patients with hypertriglyceridemia or severe hypertriglyceridemia (100253). Fish oil supplements have also shown benefit in clinical research when used in doses ranging from 1-15 grams daily for up to 6 months, or when providing EPA 1.45 to 2.7 grams and DHA 1.05 to 1.8 grams daily for 2 to 12 weeks (1024,2301,2315,2317,5705,5707,6394,6399,7368,7369)(8683,13766,65589,66156,66257,66370). However, some experts view these forms of fish oil as inadequate, as the omega-3 fatty acid content of fish oil supplements is usually lower and often variable compared to prescription fish oil. Often, up to 12 capsules of fish oil supplements daily may be needed to produce the same triglyceride-lowering effect as prescription fish oil (98004). In 2019, the AHA did not recommend for or against the use of fish oil supplements for hypertriglyceridemia (100253). There is limited evidence regarding the effects of fish oil in younger patients with hypertriglyceridemia (100253). Two small clinical studies in adolescents with hypertriglyceridemia show that fish oil supplements 4 grams daily for 2-6 months do not reduce triglyceride levels when compared with placebo (89339,100253). However, the lack of benefit in this patient population might be due to the small study sizes or due to potential underlying genetic resistance to treatment.

POSSIBLY EFFECTIVE

• Angioplasty. Oral fish oil seems to prevent restenosis when started at least 3 weeks before percutaneous transluminal coronary angioplasty (PTCA). Details: Meta-analyses of clinical research show that taking fish oil orally prevents restenosis after PTCA (13750,66376,65569). Also, clinical research shows that fish oil decreases restenosis rate by up to 45% when given for at least three weeks before PTCA and continued for one month thereafter (8680,65614). In these clinical trials, two different dosing regimens were used; fish oil 6 grams daily starting at least one month before PTCA and continuing one month after PTCA, followed by 3 grams of fish oil daily for 6 months thereafter (8680); and fifteen 1 gram capsules of fish oil (containing 2.7 grams of EPA 1.8 grams of DHA daily) daily starting 3 weeks before PTCA and continuing for 6 months thereafter (65614). When given for two weeks or less before PTCA, fish oil doesn't seem to have any effect on restenosis (1028,1038,2320,65462,66390,65626,66203,66212), although some conflicting evidence exists (66202).
• Cachexia. Oral fish oil in doses of 7.5-8.1 grams daily seems to slow weight loss in patients with cachexia. Lower doses might not be effective. Details: Taking a high-dose fish oil supplement seems to slow weight loss in some patients with cancer-related cachexia (11979,62390). Lower doses (3 grams daily) do not seem to have any effect (10008). Higher doses (7.5-8.1 grams daily) have come from a specific fish oil preparation (ACO Omega-3, Pharmacia) 30 mL providing EPA 4.9 grams and DHA 3.2 grams daily for 4 weeks (62390), or fish oil 7.5 grams daily providing EPA 4.7 grams and DHA 2.8 grams for a median of 5 weeks (11979). There is also preliminary evidence that a product providing protein 32 grams, EPA 2.18 grams, and DHA 1.92 grams daily for up to 7 weeks might help to improve appetite and increase lean body mass in patients with advanced pancreatic cancer (5701). In contrast, a meta-analysis of three studies in cancer patients shows that taking fish oil for 4-25 weeks does not seem to prevent loss of fat-free mass or body weight, or prevent a decrease in upper arm circumference, when compared with placebo. However, it is unclear how many of the included patients had malnutrition and/or weight loss (106070).
• Cyclosporine-induced nephrotoxicity. Oral fish oil seems to prevent cyclosporine-induced nephrotoxicity. Details: Some clinical research shows that taking fish oil orally seems to significantly improve glomerular filtration rate (GFR) and renal blood flow in individuals taking cyclosporine after kidney or liver transplant (1021,66187). Taking fish oil orally also seems to improve kidney function during the recovery phase following a rejection episode in kidney transplant recipients taking cyclosporine when compared with coconut oil (65590). In addition, another clinical study shows that taking fish oil modestly improves kidney function in patients following a recent kidney transplant (66472). Doses used in these studies include fish oil 12 grams, containing 18% EPA and 12% DHA, daily for 2 months following liver transplant or fish oil 3-6 grams, usually containing 30% EPA and 20% DHA, daily for up to 12 months following kidney transplant (1021,66187,65590,66472).
• Dysmenorrhea. Oral fish oil seems to reduce symptoms of dysmenorrhea. Details: Clinical research in adolescents and adults with dysmenorrhea shows that taking fish oil, alone or in combination with vitamin B1 100 mg, vitamin B12 11 mcg, or vitamin E 1.5 mg or 200 IU, seems to decrease pain, nonsteroidal anti-inflammatory drug (NSAID) consumption, and interference with daily activities (7574,7575,15738,89341,99367,107174). Doses of fish oil used in these studies provided EPA 1080 mg and DHA 720 mg daily for up to 2 months or EPA 180 mg and DHA 120 mg daily for 5 days (7574,99367). Alternatively, fish oil 2.5 grams daily for 3-4 months or 500 mg daily for 2 months has been used (7575,89341).
• Gastroenteritis-associated nausea and vomiting. Oral fish oil during pregnancy seems to be beneficial for preventing gastroenteritis in early childhood. It is unclear if oral fish oil is beneficial for gastroenteritis prevention or treatment in children or adults. Details: Clinical research shows that taking fish oil 2.4 grams daily (Incromega TG33/22, Croda Health Care), containing 55% eicosapentaenoic acid (EPA) and 37% docosahexaenoic acid (DHA), from week 24 of pregnancy until one week postpartum reduces the number of days of gastroenteritis in the first 3 years of the child's life by 2.5 days or 14% when compared with an olive oil control. There was also a 16% reduction in the number of gastroenteritis episodes and a 20% reduced risk of having a gastroenteritis episode. A sub-analysis suggests that benefits are limited to the winter months and to the children of mothers with the lowest blood levels of EPA and DHA (107182). More research is needed to determine the effect of fish oil in children or adults.
• Heart failure. Dietary fish oil seems to prevent heart failure. Also, oral fish oil seems to prevent further hospitalization, and possibly mortality, in patients with heart failure. Details: Dietary fish oil might be beneficial for primary prevention of heart failure. Population research found that higher intake of DIETARY fish oil is associated with a 15% reduced risk of incident heart failure (17994). Based on this data and other population research, the American Heart Association (AHA) recommends that patients consume 1-2 weekly servings of non-fried fish in place of less healthy protein options to reduce the risk of congestive heart failure (97185). There is not enough available information to know if fish oil SUPPLEMENTS are beneficial for primary prevention of heart failure (93568). However, taking fish oil supplements seems to be beneficial for secondary prevention of outcomes in patients with heart failure. A meta-analysis of clinical research shows that taking omega-3 fatty acids 600-4300 mg orally daily for up to 12 months can improve left ventricular ejection fraction and cardiac function in patients with non-ischemic chronic heart failure (89373). Another meta-analysis shows that although taking omega-3 fatty acids 961-6000 mg orally daily for up to 6.2 years does not reduce cardiovascular mortality or first hospitalization due to heart failure, recurrent hospitalizations due to heart failure were reduced by approximately 9% when compared with placebo (106061). A large-scale clinical trial (GISSI-HF) also shows that taking fish oil 1 gram daily, providing 850-882 mg of EPA and DHA as ethyl esters in a ratio of 1:1.2, for an average of 3.9 years significantly reduces the risk of all-cause mortality, cardiovascular mortality, and hospitalization in patients with New York Heart Association class II-IV heart failure. Based on these findings, approximately 56 patients would need to be treated for 3.9 years to prevent one death. Approximately 44 patients would need to be treated for 3.9 years to prevent one cardiovascular-related death or hospitalization (16733). Based on these findings, an AHA science advisory states that it is reasonable to consider supplementation with fish oil 1 gram daily in patients with heart failure (93568).
• HIV/AIDS-related dyslipidemia. Oral fish oil seems to reduce triglyceride levels in patients with this condition. It is unclear if oral fish oil reduces levels of low-density lipoprotein (LDL) cholesterol in these patients. Details: A meta-analysis of clinical research shows that supplementation with fish oil reduces triglycerides by 12-99 mg/dL in patients with HIV treatment-related dyslipidemia when compared to control (66177,66144,65993). Two capsules of a specific fish oil supplement (Omacor, Pronova BioPharma) containing EPA 460 mg plus DHA 380 mg twice daily for 12 weeks has been used in one study (65993). The effect of fish oil on total cholesterol levels is mixed, with some evidence showing a decrease in total cholesterol of 14 mg/dL (66177), while other evidence suggests that fish oil does not affect total cholesterol levels in these patients (65993,89359). An observational cohort study has found that taking fish oil is associated with reduced triglyceride levels in patients with HIV and hypertriglyceridemia, with overall effects similar to statins but less than fibrates (89354).
• Hypertension. Oral fish oil seems to reduce systolic and diastolic blood pressure in adults with moderate or severe hypertension. It is unclear if oral fish oil reduces blood pressure in patients with mild hypertension or in those using antihypertensive drugs. Details: Most clinical research shows that taking fish oil produces modest but significant reductions in systolic and diastolic blood pressure in adults with moderate or severe hypertension (1020,2301,66215,66095). In patients with mild hypertension, however, the evidence is mixed (1001,66385,66180). The discrepancy regarding the hypotensive effect of fish oil in individuals with mild hypertension may result from the type of fish oil used for treatment (66180). Meta-analyses of clinical research suggest that, in general, fish oil reduces systolic blood pressure by 2.5-5.5 mmHg and diastolic blood pressure by 1.5-3.5 mmHg in individuals with hypertension (66358,66379,89324,89350). In 2019, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that consuming EPA and DHA in combination may be beneficial for moderating blood pressure and reducing the risk of hypertension in the general population. However, the FDA noted that this claim is based on inconsistent and inconclusive evidence (102372). It is unclear whether fish oil is beneficial in people who are already using antihypertensive drugs. Some clinical research suggests that taking fish oil 5 grams daily for 6 weeks does not further improve the hypertensive effects of ACE inhibitors in individuals being treated for hypertension (66359), while other research suggests that fish oil decreases systolic and diastolic blood pressure in hypertensive individuals currently taking beta-blockers or diuretics (66331,66100). However, taking fish oil does not seem to significantly improve blood pressure in individuals with hypertension that remains uncontrolled despite the use of antihypertensive drugs (66418). Clinical trials showing blood pressure-lowering effects have used fish oil 4-15 grams daily, in single or divided doses, for up to 36 weeks, or fish oil providing EPA 2.04 grams and DHA 1.4 grams daily (1001,1020,2301,66100,66180,66331,66385). Omega-3 fatty acids 3-15 grams daily for 4 weeks have also been used (66215). There is conflicting evidence regarding whether the hypotensive effect of fish oil is dose-dependent (66358,66379,89350). Other research has assessed whether fish oil affects the risk of developing additional cardiometabolic disorders in adults with hypertension. In a cohort of over 81,500 patients followed for 9 years, those who consumed fish oil as supplements or in the diet at baseline had a 9%, 11%, and 14% reduction, respectively, in the risk for diabetes, coronary heart disease, and cardiac death, when compared with those with hypertension who did not consume fish oil (108508).
• IgA nephropathy. When used for 2-4 years, oral fish oil seems to slow the rate of renal function loss in high-risk patients. It is unclear if oral fish oil slows renal function loss when used for shorter time points or in low-risk patients. Details: Some clinical research shows that long-term use (2-4 years) of fish oil 1-12 grams daily can slow the rate of renal function loss in high-risk patients with IgA nephropathy (8686,8711,66343,65615). However, short-term use may not be as effective. Some research shows that fish oil 4-6 grams daily for 6 months does not attenuate the loss of renal function (66351,65593), although a combination of fish oil 3 grams containing 85% EPA plus DHA daily plus renin-angiotensin system blockers (RASB) for 6 months seems to reduce proteinuria in patients with IgA nephropathy when compared with RASB alone (65887). The conflicting data regarding the effect of fish oil on IgA nephropathy has been attributed to different factors. Some analysis of clinical evidence suggests that the effects of fish oil on proteinuria in patients with IgA nephropathy is dose-dependent (65792). Another analysis suggests that the effect of fish oil may be beneficial in only IgA nephropathy patients with more proteinuria (66455).
• Nonalcoholic fatty liver disease (NAFLD). Oral fish oil seems to reduce liver steatosis in adults and children with NAFLD. Details: Meta-analyses of mainly small clinical studies show that taking omega-3 fatty acids from fish oil or seal oil reduces serum liver enzymes and liver fat when compared to control treatment in patients with NAFLD (98258,103498). However, these analyses are limited by the heterogeneity and small size of the available studies. In one small clinical trial not included in these analyses, taking fish oil providing eicosapentaenoic acid (EPA) 735 mg and docosahexaenoic acid (DHA) 1605 mg daily for 3 months modestly reduces triglyceride levels and waist circumference when compared to control. However, insulin and alanine transaminase (ALT) levels were only reduced when fish oil was used in combination with vitamin D 1680 IU daily. There was no effect of fish oil on other liver, glycemic, or lipid parameters (107186). In one meta-analysis, omega-3 fatty acids such as fish oil were used in a median dose of 2.7 grams daily for an average of 6 months (98258). Omega-3 fatty acids such as fish oil might also benefit children with NAFLD. A meta-analysis of three small clinical trials shows that taking omega-3 fatty acids modestly improves steatosis grade in children with NAFLD when compared with placebo (98241). Larger studies are needed to confirm these results.
• Rheumatoid arthritis (RA). Oral fish oil seems to reduce pain and stiffness in patients with RA; however, oral fish oil does not seem to be beneficial for RA prevention when used alone. Details: Taking fish oil orally, alone or in combination with the nonsteroidal anti-inflammatory drug (NSAID) naproxen, seems to significantly decrease the duration of morning stiffness and the number of tender joints in patients with RA (1017,1039,1041,12924,12925,15738,65629,66313,66352,66191) (66248). Use of fish oil might also reduce NSAID requirements when used concomitantly (1031,15738,65610). Also, taking omega-3 fatty acids 5.5 grams daily for 12 months upon initiating treatment with methotrexate, hydroxychloroquine, and sulfasalazine may slow time to conventional therapy failure and decrease time to first remission in patients with early onset RA (89362). In this clinical research, fish oil 10 grams daily for 6 months or fish oil preparations containing EPA 0.5-4.6 grams and DHA 0.2-3 grams, sometimes along with vitamin E 15 IU, have been used daily for up to 15 months (1017,1031,1039,1041,12924,12925,15738,65610,66352,66191,66248). The effect of oral fish oil on RA prevention has also been investigated in a large clinical trial of approximately 25,000 older adults. Taking fish oil 1 gram daily for 5 years providing EPA 0.46 grams and DHA 0.38 grams does not reduce the risk of developing definite or probable RA when compared with placebo. However, the risk of RA is reduced by 77% when fish oil is taken in combination with vitamin D3 2000 IU daily (107184). Although this study was large, the primary endpoint was the effect of taking fish oil and/or vitamin D on the development of autoimmune diseases as a group. The number of patients with a specific autoimmune disease such as RA was relatively small.

POSSIBLY INEFFECTIVE

• Age-related macular degeneration (AMD). Oral fish oil does not seem to prevent the incidence or progression of AMD. However, eating fish regularly might help to reduce the risk of AMD. Details: The best available clinical research shows that fish oil supplements (Omacor) are not beneficial for preventing AMD or its progression. A large, high-quality clinical study in over 25,800 adults at least 50 years of age shows that taking fish oil providing DHA 450 mg and EPA 550 mg daily for 3.8 to 6.1 years, with or without vitamin D, does not prevent AMD or its progression (105214). Other clinical research shows that taking fish oil containing DHA 350 mg and EPA 650 mg daily for up to 6.1 years does not prevent the development of advanced AMD (60281). Also, clinical research shows that taking fish oil containing DHA 840 mg and EPA 270 mg by mouth daily for 3 years does not prevent choroidal neovascularization in patients with AMD (89369). However, regular consumption of fish might be beneficial for preventing the incidence or progression of AMD. Observational research has found that consuming dietary fish more than once weekly is associated with a reduced risk of developing age-related maculopathy or AMD (6260,65724,65725,65889). Also, a meta-analysis of observational research has found a 6% and 22% decreased risk of early or late AMD, respectively, for every gram increase in dietary omega-3 fatty acid intake, and a 13% and 14% decreased risk, respectively, for every 15-gram daily increase in fish intake. Sub-analyses found 9% to 15% decreased risks for early or late AMD per 0.15 grams daily of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), but not alpha-linolenic acid. Although research examining the relationship between omega-3 intake and AMD progression is limited, the highest consumption of dietary fish is associated with a 36% lower risk of AMD progression when compared with the lowest consumption (107176).
• Angina. Oral fish oil does not seem to improve cardiovascular outcomes in patients with angina. Details: Clinical research shows that taking fish oil supplements does not improve mortality or cardiovascular outcomes in patients with angina (66255). In fact, some evidence suggests that fish oil supplements or increasing oily fish intake might increase the risk of cardiac death by 26% and sudden cardiac death by 54% in males with angina (17988). More evidence is needed before this potential risk can be confirmed.
• Atherosclerosis. Oral fish oil does not seem to attenuate atherosclerosis progression. Details: Most research shows that fish oil supplementation does not attenuate atherosclerosis progression when compared with placebo (1022,8681). Also, fish oil doesn't seem to improve luminal diameter (1022,2311) or decrease intima-media thickness of the carotid arteries in people with coronary artery disease (CAD) (8681). However, some research disagrees. One clinical study in adults with CAD shows that taking fish oil supplements 6 grams daily for 3 months and then 3 grams daily for 21 months modestly slows the progression, or causes mild to moderate regression, of atherosclerosis as measured by angiography (2311).
• Atopic dermatitis (eczema). Oral fish oil does not seem to treat or prevent atopic dermatitis. Details: A meta-analysis of clinical research shows that fish oil is not effective for TREATING established atopic dermatitis (13758,66151,13758). Also, despite conflicting results from preliminary clinical research (12971,17409), higher quality clinical studies show that fish oil does not PREVENT eczema development. A meta-analysis of clinical research, as well as results from more recent clinical trials, show that maternal supplementation or infant supplementation with fish oil does not reduce the risk of eczema development in infants or young children (66112,89338,89360,89361,96120). However, some population research suggests that eating fish in early childhood is associated with a reduced risk of developing childhood eczema (65992).
• Atrial fibrillation. Oral fish oil does not seem to reduce the risk of new or recurrent atrial fibrillation. Some clinical research suggests that high-dose fish oil may actually increase the risk for new atrial fibrillation. Details: Although some population research has found that consuming fish as part of the diet is associated with a reduced risk of atrial fibrillation (12055), most evidence from epidemiological and clinical research suggests that eating fatty fish or taking fish oil supplements does not reduce the risk of new onset or recurrent atrial fibrillation (12919,17995,66101,89357,105209,106075,107171,107181,109306,110332). One large epidemiological study has actually found that taking fish oil supplements is associated with a modest increase in the risk of atrial fibrillation in individuals without cardiovascular disease. This association seems to be independent of genetic predisposition or oily fish consumption and is not present in individuals with cardiovascular disease (109306). Additionally, in one large, high-quality clinical study (the STRENGTH trial), taking a prescription fish oil product (Epanova) 4 grams daily for up to 5 years was associated with an increased risk for atrial fibrillation, with a number needed to harm of 114 when compared with a corn oil control. The patients in this study were considered to be at high risk for future cardiovascular disease (CVD) (103491). Also, meta-analyses of randomized controlled trials show that taking omega-3 fatty acid supplements increases the incidence rate ratio for atrial fibrillation by 25% to 37% when compared with placebo, with an increased incidence rate associated with doses of more than 1 gram daily. Patients in the included studies were at risk for CVD or had established CVD. Also, some studies included in the analyses used eicosapentaenoic acid (EPA) alone as purified icosapent ethyl (106075,107171,107181). The available meta-analyses are limited by the small number of studies in which atrial fibrillation is the primary endpoint, possibly over-estimating the effects of omega-3 fatty acid supplements on atrial fibrillation (110332). There is conflicting evidence regarding the effects of fish oil on recurrent atrial fibrillation following cardioversion. Some clinical research shows that taking fish oil 6 grams daily by mouth for one month prior to cardioversion and continuing for up to one year thereafter reduces the absolute risk of atrial fibrillation recurrence by about 39% when compared with placebo (89344). However, a meta-analysis of clinical research shows that fish oil does not reduce the risk of atrial fibrillation following cardioversion (89325). A reason for this discrepancy may be the duration of fish oil supplementation prior to cardioversion. Taking fish oil for at least 4 weeks before cardioversion appears to decrease the absolute risk of recurrent atrial fibrillation by about 18% when compared with placebo, whereas taking fish oil for less than 4 weeks before cardioversion appears to increase the absolute risk of atrial fibrillation by about 6% (89325). Most clinical research shows that fish oil does not decrease the risk of atrial fibrillation following cardiac surgery (17996,89352,89374). However, it is possible that fish oil formulations containing at least 1 gram of DHA may be beneficial. Evidence from clinical research and analysis of clinical data shows that taking fish oil containing DHA 1 gram or more reduces the risk of atrial fibrillation following cardiac surgery by about 37% to 72% (89374,96113). Fish oil containing lower doses of DHA does not appear to be beneficial (89374). A science advisory statement published by the American Heart Association (AHA) in 2017 states that fish oil is not indicated for secondary prevention of atrial fibrillation in patients with prior atrial fibrillation or those with atrial fibrillation after cardiac surgery. The cumulative evidence showed no benefit of fish oil in these populations (93568).
• Bronchopulmonary dysplasia. Oral fish oil does not seem to prevent bronchopulmonary dysplasia in preterm infants. Details: A meta-analysis of the available clinical research in over 3,500 preterm infants shows that receiving fish oil daily as part of formula or as a direct oral dose, starting within one month of birth, does not reduce the risk for bronchopulmonary dysplasia when compared with control (102390).
• Cerebrovascular disease. Oral fish oil does not seem to prevent cerebrovascular disease. Details: Although a meta-analysis of population studies has found that increased fish consumption lowers the risk of cerebrovascular disease, results from a pooled analysis of clinical trials show that fish oil supplementation does not reduce the risk of primary or secondary cerebrovascular disease (89334).
• Cognitive function. Oral fish oil does not seem to improve cognitive function in most people. Details: Most clinical research shows that fish oil supplementation does NOT improve cognitive function in healthy elderly individuals, elderly patients with self-reported cognitive decline, or adults and children (65880,66030,66492,97175,98248,103501,109310). However, fish oil supplementation may modestly help older patients with self-reported cognitive decline to perform daily activities (97181). Also, clinical research in young and middle-aged adults shows that taking a fish oil supplement providing eicosapentaenoic acid (EPA) 900 mg plus docosahexaenoic acid (DHA) 360 mg (Accelon EPA EE, BASF) daily for 6 months improves some measures of cognitive function, including overall speed and overall and memory-related accuracy, when compared with both placebo or a fish oil supplement providing DHA 900 mg and EPA 270 mg daily (Accelon DHA EE, BASF). There were no benefits on other measures of cognitive performance (109215). This suggests that any beneficial effects associated with fish oil might be related to the levels or ratio of EPA to DHA or the specific endpoints measured. Observational research has also found conflicting associations between dietary fish and fish oil intake and cognitive function (13747,15740,15741,15742).
• Helicobacter pylori. Oral fish oil does not seem to aid in the Helicobacter pylori eradication. Details: Clinical research shows that taking fish oil (Eicosapen) orally, in combination with pantoprazole and clarithromycin, is inferior for eradicating Helicobacter pylori infection when compared with a combination of pantoprazole, clarithromycin, and metronidazole (8710).
• Kidney transplant. Oral fish oil does not seem to improve survival or rejection rate following a kidney transplant. Details: A meta-analysis of a small number of clinical studies shows that taking fish oil does not improve patient survival, graft survival, or acute rejection rates when compared with placebo following kidney transplant (96121).
• Mastalgia. Oral fish oil does not seem to reduce chronic breast pain. Details: Clinical research shows that taking fish oil orally 3 grams daily for 6 months does not improve severe chronic breast pain when compared with placebo (9156).
• Multiple sclerosis (MS). Oral fish oil does not seem to improve symptoms in patients with MS. Details: Clinical research shows that taking fish oil (MaxEPA) 10 grams containing EPA 1.71 grams and DHA 1.14 grams daily for 2 years does not improve the duration, frequency, or severity of relapses when compared with placebo in patients with MS (66205). Also, in patients with relapsing remitting MS who are taking the medication fingolimod, taking fish oil 1 gram, providing EPA 180 mg and DHA 120 mg, daily for 12 months does not improve levels of inflammatory markers or symptoms of disability when compared with placebo (103502).
• Osteoarthritis. Oral fish oil does not seem to improve pain or function in patients with osteoarthritis. However, oral fish oil might be beneficial for osteoarthritis-related joint pain in overweight patients. Details: Clinical research shows that patients with osteoarthritis or knee pain taking low-dose fish oil 0.45 grams daily for 2 years have better pain and function scores when compared with those taking high-dose fish oil 4.5 grams daily (97179). The unexpected improvement in pain and function score in the low-dose fish oil group might be due to a placebo effect. Other clinical research shows that adding fish oil 444 mg to a glucosamine sulfate supplement does not further decrease osteoarthritis symptoms, such as morning stiffness or pain in the hips and knees, when compared with glucosamine alone (65998). In addition, one large study shows that taking fish oil (Omacor) 1 gram daily for an average of 5.3 years has no effect on knee pain due to osteoarthritis when compared with placebo (101548). In contrast to these findings, a meta-analysis of clinical research shows that taking fish oil seems to reduce joint pain (106066). However, only two studies were included in this analysis and both used fish oil in combination with other ingredients, including stinging nettle (76415) and lemon verbena (17748). In addition, one of these studies did not limit to patients with osteoarthritis (17748). Due to the overall negative findings, the American College of Rheumatology (ACR) conditionally recommends AGAINST the use of fish oil in patients with knee, hip, or hand osteoarthritis (102114). Taking fish oil might be beneficial for joint pain reduction in a population of older overweight or obese patients with osteoarthritis-specific pain in the knees, lower back, or shoulders. Clinical research shows that taking fish oil (Blackmores Omega Brain) providing EPA 400 mg and DHA 2000 mg daily for 16 weeks reduces pain by approximately 42%. This is significantly greater than placebo. The overall osteoarthritis burden was reduced by about 40% (103499).
• Pregnancy-induced hypertension. Oral fish oil does not seem to reduce the risk for hypertension during pregnancy. Details: Clinical research shows that fish oil does not reduce the risk of pregnancy-induced hypertension (1026,1027,12972,97174,110338).
• Pre-eclampsia. Oral fish oil does not seem to reduce the risk of pre-eclampsia. Details: Clinical research shows that fish oil does not reduce the risk of pre-eclampsia (1042,89376,97174,110338).
• Psychosis. Most research shows that oral fish oil is not beneficial for the treatment or prevention of psychosis. Details: Although some individual research shows that taking fish oil modestly reduces symptoms of psychosis and the absolute conversion rate to psychotic disorders (17084), most research disagrees (105217,105554,109308). A meta-analysis of randomized controlled trials in patients with psychosis shows that taking fish oil does not reduce psychotic symptoms when compared with placebo. However, it might modestly improve function (109308). Doses of fish oil used in the available research have ranged from 570 mg to 3000 mg daily for up to 1 year (17084,105554,109308).
• Unstable angina. Oral fish oil does not seem to prevent unstable angina. Details: In patients at high cardiovascular risk, taking a fish oil-based preparation (Epanova, AstraZeneca Pharmaceuticals) 4 grams daily for up to 5 years does not prevent unstable angina requiring hospitalization (103491).
• Ventricular arrhythmias. Oral fish oil does not seem to prevent ventricular arrhythmias or prevent mortality in patients with a history of ventricular arrhythmias. Details: Epidemiological research suggests that eating a diet high in fish has no effect on risk for premature ventricular complexes (12920). Clinical research is inconsistent. In one clinical trial, taking fish oil 2.6 grams daily did not prolong the time to the first event, such as ventricular tachycardia, ventricular fibrillation, or death, in patients with implantable defibrillators. However, in the subgroup of patients who adhered to therapy for a full 11 months, fish oil treatment did seem to significantly prolong time to first event (14436). Other clinical evidence suggests that taking fish oil 2 grams daily for 1-2 years does not reduce cardiac events such as cardiac defibrillation, ventricular tachyarrhythmia, ventricular fibrillation, or death from any cause in patients with implantable defibrillators (12986,14382). Also, other research suggests that taking fish oil supplements might actually increase the risk of ventricular tachycardia and fibrillation in some patients with implantable defibrillators (12986). Overall, meta-analyses of clinical studies show that taking fish oil does not reduce all-cause mortality in patients with an implantable defibrillator or history of ventricular arrhythmias (16732,65923,89343).

LIKELY INEFFECTIVE

• Diabetes. Oral fish oil does not improve glycemic control or prevent cardiovascular outcomes in patients with type 2 diabetes. However, oral fish oil may lower triglyceride levels in patients with type 2 diabetes. Details: Although fish oil may reduce triglyceride levels in patients with diabetes (65577,65834,65878,66027,66436,66444,101538,101541), taking fish oil orally has no clinically significant effect on fasting plasma glucose levels or glycated hemoglobin (HbA1c) in patients with type 2 diabetes in most studies (2299,2300,2302,7368,7369,12182,12925,13011,13147,13149)(65577,65834,65878,66316,66372,66426,66442,101504,101541,101542). A large, high-quality clinical study also shows that taking fish oil supplements 840 mg daily with or without aspirin for an average of 7.4 years does not decrease the risk for serious vascular complications, including myocardial infarction, stroke, or transient ischemic attack (TIA), when compared with placebo (102401). Additionally, fish oil does not seem to reduce the risk of gestational diabetes (89376,97174,110338).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). It is unclear if enteral fish oil is beneficial in patients with ARDS. Details: The effect of enteral fish oil, with or without borage oil and antioxidants, has been evaluated for improving outcomes in patients with ARDS. A meta-analysis of randomized controlled trials evaluating these ingredients, provided as a specific enteral formula (Oxepa, Abbott Nutrition) or a combination supplement given as a bolus, shows that there is no effect on overall all-cause mortality or ventilator- or ICU-free days when compared with generally isonitrogenous and isocaloric control formulas. A sub-group analysis of lower quality research shows that there may be a modest benefit for patients with a higher risk of mortality (105250). Two more recent meta-analyses have yielded similar results (105248,105249). Most studies included in these analyses investigated the use of Oxepa and found there was no effect on mortality when compared with control enteral formulas. Studies investigating other sources of enteral or intravenous fish oil were also included in these analyses (105248,105249). In one of these analyses, some overall low- to very low-quality evidence suggests that use of Oxepa modestly reduces mortality at 28 days, as well as ICU length of stay and duration of mechanical ventilation (105248). However, these benefits were not found in the second meta-analysis (105249). Most studies included in these analyses used fish oil in combination with other ingredients. Therefore, the effect of fish oil alone is unclear.
• Age-related cognitive decline. It is unclear if oral fish oil prevents age-related cognitive decline. Details: A meta-analysis of clinical research shows that there is no effect of increased dietary or supplemental omega-3 intake on global cognition in older adults (103501). The effect of fish oil supplements, specifically, is unclear.
• Allergic rhinitis (hay fever). It is unclear if taking oral fish oil during pregnancy prevents allergic rhinitis in the child. Details: Preliminary clinical research shows that maternal ingestion of fish oil 4 grams daily, providing 32% EPA and 23% DHA with tocopherol, during late pregnancy might reduce the occurrence of allergic rhinitis in the offspring at 16 years of age when compared with placebo (17409). However, higher-quality clinical research shows that maternal intake of fish oil supplements containing DHA 800 mg and EPA 100 mg by mouth daily starting at 21 weeks gestation and continuing until delivery, does not affect the development of allergic rhinitis in offspring by the age of 3 or 6 years (89361,97172).
• Alzheimer disease. It is unclear if oral fish oil is beneficial for preventing Alzheimer disease or for improving cognition in those with this condition. Details: Higher fish and fish oil intake has been linked to a decreased risk of developing Alzheimer disease in population studies (15040,15041,65817). However, in patients with existing mild-to-moderate Alzheimer disease, taking a specific fish oil supplement (EPAX1050TG, Pronova Biocare A/S) providing the omega-3 fatty acids DHA 1.7 grams and EPA 0.6 grams daily for 6 months does not significantly delay cognitive decline, although this fish oil supplement might slow cognitive decline in a subgroup of patients with very mild cognitive dysfunction (15024). Also, preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking fish oil 1 gram (providing docosahexaenoic acid 500 mg and eicosapentaenoic acid 150 mg), lutein 10 mg, zeaxanthin 2 mg, meso-zeaxanthin 10 mg, and vitamin E 15 mg (Memory Health) daily for 12 months does not affect disease severity when compared with placebo. However, there were modest increases the number of patients experiencing either an improvement or an attenuated decline in memory and mood (109764). The effect of fish oil alone is unclear from this study.
• Antiphospholipid syndrome-associated miscarriage. It is unclear if oral fish oil prevents miscarriage in patients with antiphospholipid syndrome. Details: Preliminary clinical research shows that taking fish oil 5.1 grams standardized to a 1.5 ratio of EPA:DHA, daily for 3 years seems to prevent recurrent miscarriage and increase live birth rate in pregnant patients with antiphospholipid syndrome (1032).
• Antipsychotic-induced metabolic side effects. It is unclear if oral fish oil is beneficial for metabolic side effects related to the use of olanzapine. Details: In patients with both schizophrenia and metabolic syndrome using olanzapine, clinical research shows that taking fish oil (Nature Made) providing EPA 720 mg and DHA 480 mg daily for 12 weeks reduces triglyceride levels by about 27% when compared with placebo. However, there was no effect on blood pressure or levels of fasting glucose or high-density lipoprotein (HDL) cholesterol (105225). In patients taking olanzapine with sodium valproate or lithium, a small clinical trial shows that taking fish oil (Zahravi Pharmaceutical Company), starting at a dose of 300 mg EPA plus DHA to 600 mg daily in two divided doses and titrating up to 900 mg daily in three divided doses for a total of 6 weeks, does not improve anthropometric measures or lipid parameters when compared with placebo (105226). These differing findings may be due to differences in fish oil dose and duration.
• Asthma. It is unclear if oral fish oil prevents or treats asthma. Details: Some research suggests that fish oil supplements may help TREAT asthma symptoms in some patients, but results are conflicting. Some clinical research shows that taking a fish oil supplement improves peak flow and reduces medication use and cough in children with asthma (12954,12963). Fish oil providing EPA 17-26.8 mg/kg and DHA 7.3-11.5 mg/kg has been used in one study (12954). However, other clinical research shows that taking fish oil does not improve asthma severity in children with bronchial asthma when compared to control, although asthma severity seems to be reduced when compared to baseline (65497). In adults, fish oil does not seem to improve measures of asthma such as forced expiratory volume in one second (FEV1), peak flow rate, asthma symptoms, asthma medication use, or bronchial hyper-reactivity (12954,17411,66266,1036,20546,66206). However, in asthmatic patients experiencing exercise-induced bronchoconstriction, fish oil (EPAX 3000 TG; Pronova Biocare), 20 capsules totaling 3.2 grams of EPA and 2 grams of DHA daily for 3 weeks seems to improve pulmonary function and reduce bronchodilator use when compared with placebo (65680). There is also conflicting evidence for the use of fish oil in asthma PREVENTION. For example, clinical research shows that maternal ingestion of fish oil supplements 4 grams daily or omega-3 fatty acids 0.65-3.7 grams daily during late-phase pregnancy reduces the occurrence of asthma in infants and children by 31% to 63% when compared with control (17409,66112,96120). The benefit seems to be greater for children of mothers with the lowest blood levels of EPA and DHA at baseline (96120). Conversely, other research found no benefit for asthma prevention with fish oil supplementation during lactation (66112). Also, giving fish oil containing DHA 280 mg plus EPA 110 mg daily to children during the first 6 months of life does not appear to prevent asthma development by the age of 6-12 months (89338). However, in a meta-analysis of 10 trials with follow-up of 6 months to 24 years, maternal intake of fish oil supplements at a dose of at least 1200 mg daily during pregnancy, lactation, or both, reduces the risk of asthma in the infant, but does not affect the rate of wheezing (108506).
• Athletic performance. It is unclear if oral fish oil improves athletic performance. Details: Evidence on the effect of fish oil in athletic performance is mixed. Some clinical research in athletes participating in intensive wrestling training shows that taking fish oil 1 gram daily for 12 weeks improves pulmonary function when compared with placebo (65971). In another small clinical study in professional rugby players, taking fish oil containing EPA 551 mg and DHA 551 mg twice daily for 5 weeks during training attenuates the decline in counter movement jump when compared with placebo (99357). However, taking fish oil 1 gram daily for 5 weeks does not seem to improve endurance or recovery in professional Australian Football League athletes when compared with baseline or placebo (65876).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral fish oil is beneficial in children or adults with ADHD. Details: Some, but not all, preliminary clinical research shows that taking fish oil or other sources of long chain omega-3 fatty acids orally improves attention, cognitive function, and behavior in children aged 8-13 years with or without an official diagnosis of ADHD (8800,65868). Omega-3 fatty acids 250 mg esterified to phosphatidylserine 300 mg daily for 3 months has been used (65868). Additional clinical research shows that taking a specific supplement containing fish oil 400 mg and evening primrose oil 100 mg (Eye Q, Novasel), six capsules daily for 15 weeks, improves cognitive function, hyperactivity, inattentiveness, and behavior in children aged 7-12 years with ADHD (15739). It is unclear if these effects are due to fish oil, evening primrose oil, or the combination. Fish oil has also been evaluated in adults with ADHD and autism spectrum disorder. One clinical study in this population shows that taking fish oil 5.2 grams daily for 4 weeks modestly improves inattention when compared with control (108725). Despite some positive findings from mainly preliminary clinical research, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids in doses of 120 mg to 1200 mg are not currently recommended for adjunctive or monotherapy use in children with ADHD. Furthermore, there is not enough research in adults to make a recommendation (110318).
• Autism spectrum disorder. It is unclear if oral fish oil is beneficial in children or adults with autism spectrum disorder. Details: Clinical research in children with autism shows that taking omega-3 fatty acids (Zahravi Company) 1000 mg daily for 8 weeks, providing EPA 180 mg and DHA 120 mg, modestly reduces overall autism severity and modestly improves stereotyped behavior and social communication when compared with a control group taking medium chain triglycerides. However, there was no benefit on social interaction (105218). The evidence related to hyperactivity in children with autism is mixed. One small clinical study in children aged 5-17 years shows that taking 1.5 grams of fish oil providing EPA 0.84 grams and DHA 0.7 grams daily for 6 weeks reduces hyperactivity when compared with placebo. However, there was a large between-group difference in baseline hyperactivity ratings, which may have exaggerated the effect size (65732). Other clinical research in children aged 3-8 years shows that taking fish oil 1.3 grams daily for 12 weeks does not improve hyperactivity when compared with placebo (66070). Fish oil has also been evaluated in adults with autism. One small clinical study shows that taking fish oil 5.2 grams daily for 4 weeks improves neurocognition, including attention and working memory, when compared with placebo. However, it does not affect social interaction (108725). Other clinical research in adults with autism spectrum disorder and attention deficit hyperactivity disorder (ADHD) shows that taking fish oil 5.2 grams daily for 4 weeks modestly improves inattention when compared with control (108725).
• Autoimmune thyroiditis. It is unclear if oral fish oil is beneficial for autoimmune thyroiditis prevention. Details: The effect of oral fish oil on autoimmune thyroiditis prevention has been investigated in a large clinical trial of approximately 25,000 older adults. Taking fish oil 1 gram daily for 5 years providing EPA 0.46 grams and DHA 0.38 grams, alone or in combination with vitamin D3 2000 IU daily, does not reduce the risk of developing definite or probable autoimmune thyroiditis when compared with placebo (107184). Although this study was large, the primary endpoint was the effect of taking fish oil and/or vitamin D on the development of autoimmune diseases as a group. The number of patients with a specific autoimmune disease such as autoimmune thyroiditis was relatively small.
• Bipolar disorder. Oral fish oil may be beneficial for symptoms of depression in patients with bipolar disorder. However, taking fish oil does not seem to prevent mood relapses or improve symptoms of mania in these patients. Details: Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids in doses standardized to 1-2 grams eicosapentaenoic acid (EPA) are weakly recommended for adjunctive use in bipolar depression (110318). This recommendation is based mainly on an early meta-analysis of clinical research of flaxseed oil, EPA alone, or oil containing EPA and DHA (66126). Also, some preliminary clinical research shows that taking fish oil providing EPA 6.2 grams and DHA 3.4 grams daily for 4 months, along with conventional therapies, may improve symptoms of depression and increase length of remission when compared with placebo (7202). However, a more recent small clinical trial shows that taking omega-3 fatty acids, including EPA 1 gram plus DHA 1 gram daily for 52 weeks, in a 200 mL smoothie (Nutrifriend, Smartfish) also providing vitamin D 35 micrograms and vitamin E 1.89 mg does not reduce the number of mood episode relapses, increase the time to first mood episode relapse, or improve measures of depression when compared with placebo (105216). Omega-3 fatty acids have not been shown to be effective in attenuating mania or hypomania. Most research shows that fish oil doesn't seem to have beneficial effects on manic symptoms in patients with bipolar disorder (5713,7202,66126,105216,110318). Also, theoretically, fish oil might increase symptoms of mania in patients with bipolar disorder. Cases of hypomania have been reported in patients with bipolar disorder using fish oil (5713,7202).
• Borderline personality disorder. It is unclear if oral fish oil is beneficial for borderline personality disorder. Details: A meta-analysis of clinical research in patients with borderline personality disorder shows that taking omega-3 fatty acids modestly reduces overall symptom severity, especially impulsive behavior, when compared with control. However, one of the studies included in the analysis used eicosapentaenoic acid (EPA) alone and another was limited by the lack of a placebo group (106065).
• Cancer. It is unclear if dietary or supplemental fish oil can reduce the risk for cancer; the available research is conflicting. Details: There is conflicting evidence about the role of fish oil in cancer prevention. Many epidemiological studies have found that increased intake of supplemental or dietary fish oil, as well as higher blood levels or dietary intakes of omega-3 fatty acids, are associated with a decreased risk of several cancers including oral, pharyngeal, esophageal, pancreatic, colon, rectal, lung, breast, ovarian, and prostate cancers (6395,7378,9773,9774,10153,12958,12959,12960,12961,12962,15736,17412)(25937,101536,103494,107175). Also, a meta-analysis of epidemiological research has found that the highest fish or fish oil intake is associated with a 13% or 19% reduced incidence of mortality in patients with cancer when compared to the lowest intake (107183). However, most meta-analyses of epidemiological research have identified no benefit (14264,66078,66092,103494) and a large clinical trial shows that fish oil does not reduce the risk of invasive cancers (99362). Also, one large epidemiological study has found that dietary intake of fish oil from fatty fish twice a week or more was associated with a 16% increased risk of breast cancer when compared with eating fatty fish less than twice weekly (107175). In addition, a meta-analysis of results from the Prostate Cancer Prevention Trial suggests that higher blood percentages of docosahexaenoic acid (DHA) are associated with a 2.5-fold higher risk of aggressive prostate cancer, but not low-grade prostate cancer, when compared with lower blood percentages of DHA (25936).
• Canker sores. It is unclear if oral fish oil is beneficial for preventing or treating canker sores. Details: In patients with chronic canker sores presenting with 1-3 ulcers at baseline, preliminary clinical research shows that taking omega-3 fatty acids (Zahravi Company) 1000 mg daily, providing EPA 180 mg and DHA 120 mg, for 6 months reduces the size, number, duration, pain, and overall severity of ulcers by 32% to 63%. These changes were significant when compared with placebo. In addition, the ulcer-free period was increased by approximately 45% (105219).
• Cardiovascular disease (CVD). The effect of fish oil on cardiovascular health is controversial. Oral fish oil in doses of up to 4 grams daily does not seem to be beneficial for primary or secondary prevention of CVD. It is unclear whether dietary fish oil or a higher daily dose is beneficial for prevention of CVD. Details: In 2018, the American Heart Association (AHA) recommended that healthy individuals consume 1-2 servings of non-fried fish weekly in place of less healthy sources of protein and fat for primary prevention of CVD. This recommendation was based mainly on evidence from prospective cohort studies showing a modestly lower risk of coronary heart disease (CHD) with higher seafood intake or dietary intake of fish oil (97185). Population research has also found that increased consumption of dietary fish oil is associated with a reduced risk of all-cause mortality, cardiovascular death, sudden death, and myocardial infarction in people without CVD (2309,8676,10006,12915,12917,12977,65723,94231). However, a large meta-analysis of moderate to high quality clinical research published in 2018 shows that higher intake of fish oil as part of the diet or from supplements has little to no benefit for primary prevention of CVD, including all-cause mortality, CVD or CHD mortality, CVD or CHD events, stroke, or arrhythmias (98231). An additional meta-analysis published in 2020 shows that although fish oil supplementation had a very small protective effect overall against CVD death, there was no benefit on all-cause mortality or on primary prevention of CVD death (104547). Reasons for these conflicting results may relate to the fact that most of the primary prevention studies included in these meta-analyses evaluated fish oil supplements rather than dietary fish oil. Only two studies included in one of the meta-analyses assessed the effects of dietary fish oil, while up to 33 studies assessed the effects of fish oil supplements (98231,104547). Some newer, large, high-quality clinical studies have also found no benefit with fish oil supplements for this purpose. One high-quality study shows that taking fish oil 1 gram daily for about 5.3 years is not beneficial for primary prevention of CVD (99362). Another large study including 15,480 patients with diabetes and no evidence of CVD at baseline shows that taking fish oil supplements 1 gram daily does not reduce the risk of serious vascular events, such as nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, when compared with placebo over a 7.4-year follow-up period (98232). Also, in patients at high cardiovascular risk, taking a prescription-only fish oil product (Epanova, AstraZeneca Pharmaceuticals) 4 grams daily for up to 5 years does not prevent major adverse cardiovascular events, such as cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization, or hospitalization for unstable angina, when compared with a corn oil placebo (103491). Based on the cumulative evidence, fish oil SUPPLEMENTS do not appear to be beneficial for primary prevention of CVD. DIETARY fish oil may reduce the risk of CVD, but results are conflicting and any benefit is probably modest at best. Research has also evaluated fish oil for prevention of cardiovascular events in people with existing CVD (secondary prevention). An analysis of two secondary prevention trials shows that consuming fatty fish 2-3 times weekly reduces the risk of overall mortality by 30%, but does not reduce the risk of nonfatal myocardial infarction (7359,8673). Also, population research in patients with at least two cardiometabolic diseases has found that use of fish oil supplements is associated with a 19% lower risk of CVD-related mortality over 12 years, and a 17% lower risk of overall mortality, when compared with not using fish oil supplements. The additional life expectancy range of 1.4 to 2.3 years was dependent on age and the severity of cardiometabolic morbidity (110333). However, in clinical research, the effect of fish oil supplements for secondary prevention of CVD is controversial and contradictory. Most older research shows that taking fish oil supplements provides benefit; however, these studies are at high risk for bias (1007,2307,8673,12916,12917,13750,65723,66495). Additionally, newer research shows that supplemental fish oil does not help with secondary prevention of CVD. A large meta-analysis of moderate to high quality clinical research published in 2018 also shows that higher intake of fish oil, mainly as supplements, has little to no benefit for secondary prevention of CVD, including all-cause mortality, CVD or CHD mortality, CVD or CHD events, stroke, or arrhythmias (98231). In addition, a meta-analysis published in 2020 shows that although fish oil supplementation had a very small protective effect overall against CVD death, there was no benefit on all-cause mortality or on the secondary prevention of CVD death (104547). A large clinical trial shows that taking fish oil 1 gram daily for 5 years does not significantly reduce cardiovascular events when compared with an olive oil control in patients with multiple cardiovascular risk factors or atherosclerosis (93576). Multiple other meta-analyses published from 2012 to 2018 also show no benefit of fish oil supplements for cardiovascular risk in patients with existing CVD (17990,94231,96116). Some meta-analyses have combined all studies related to both primary and secondary prevention. A meta-analysis published in 2021 shows that fish oil supplementation reduces the risk of CVD death by 7%, non-fatal myocardial infarction by 13%, CHD events by 9%, and major adverse cardiovascular events by 5%, with no benefit on all-cause mortality or stroke. This analysis also showed that use of eicosapentaenoic acid (EPA) alone, as investigated in only four of the 38 trials, offered the largest protective effect (107181). Another meta-analysis of a small group of randomized trials analyzing the effectiveness of fish oil for protection against CHD in patients with and without CHD at baseline shows that taking fish oil reduces CHD by 16%. However, there was no effect on angina, sepsis, or death (107185). This analysis is limited by the small number and suboptimal quality of studies, as well as the age of the publications. Since these analyses combine patients with and without CVD at baseline, it is difficult to draw any conclusions related to primary CVD outcomes. There has been speculation that patients in more recent studies were more likely to be receiving protective effects from treatment with statins and other drugs, which could reduce the potential benefit of fish oil (17990,17991). However, two meta-analyses of clinical data shows that fish oil does not reduce the risk of major vascular events, regardless of prior or concomitant statin use (96116,98231). Interestingly, in 2017 the AHA published a science advisory stating that it is reasonable to supplement with fish oil 1 gram daily for secondary prevention in patients with cardiovascular disease. The AHA concluded that the cumulative evidence generally supports that fish oil supplementation reduces cardiovascular death, though not nonfatal recurrent myocardial infarction, and the benefit of using fish oil for secondary prevention outweighs the treatment risk. However, the AHA noted that most evidence of benefit is based on research published before 2002 (93568). Furthermore, the AHA recommendation was released prior to the publication of the most recent clinical trials and meta-analyses showing no benefit of fish oil for secondary prevention of CVD. Many other guidelines including that of the Canadian Cardiovascular Society, the European Society of Cardiology, and European Atherosclerosis Society state that fish oil supplements are not significantly beneficial for secondary prevention of cardiovascular events (96116,97477). Overall, best evidence to date show that fish oil SUPPLEMENTS, typically taken in doses of 1 gram daily, are not beneficial for primary or secondary prevention of CVD. Additionally, prescription fish oil products in higher doses of 4 grams daily do not seem to be beneficial for primary prevention of CVD. DIETARY fish oil might be beneficial for primary or secondary prevention, but benefits are probably modest at best. Still, people should continue to eat fish and other foods that provide omega-3 fatty acids, as these foods make up part of a healthy diet. In fact, in 2019, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that foods containing EPA and DHA may reduce the risk of CHD. However, the FDA has determined that this claim is based on supportive, rather than conclusive, evidence (102370).
• Cataracts. It is unclear if oral fish oil prevents the development of cataracts. Details: Epidemiological research has found that eating fish three times weekly is associated with a modestly reduced risk of developing cataracts in females. Eating fish three times weekly rather than once monthly is associated with an 11% reduction in developing cataracts (12955).
• Chemotherapy-induced peripheral neuropathy. It is unclear if oral fish oil is beneficial for the prevention of peripheral neuropathy in patients receiving chemotherapy. Details: A meta-analysis of three clinical trials with unclear or high risk of bias in patients with breast, colon, lung, or ovarian cancer shows that taking omega-3 fatty acids for 3-6 months reduces the odds of developing chemotherapy-induced peripheral neuropathy by approximately 80% when compared with placebo (106070).
• Chronic kidney disease (CKD). It is unclear if oral or dietary fish oil is beneficial in patients with CKD or for CKD prevention. Details: A meta-analysis of the available clinical research in adults with CKD who are receiving hemodialysis shows that taking fish oil supplements might reduce the risk of cardiovascular mortality. However, this finding is based on low to very-low quality evidence, and there was no difference identified for risk of all-cause mortality. Additionally, adults with CKD who are not receiving hemodialysis do not seem to benefit from fish oil supplementation (102395). Observational research in adults with CKD has found that dietary omega-3 fatty acid intake of 1.93-9.65 grams daily is associated with a 33% reduced risk of mortality when compared with intakes of less than 0.86 gram daily. However, the amount of omega-3 intake from fish oil, specifically, is unknown (107173). Observational research has also been conducted to examine the association between habitual fish oil supplementation and developing CKD. A large observational study in individuals without prior CKD has found that taking fish oil supplements is associated with a 10% reduced incidence of CKD over the next 10 years when compared with not taking fish oil supplements (110330).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral fish oil is beneficial in patients with COPD or for COPD prevention. Details: A small clinical trial shows that taking fish oil (Omax3, Cenestra Health) 3 grams daily for 6 months does not improve pulmonary function, respiratory symptoms, or endothelial function when compared with placebo in patients with COPD. However, it increased the number of people experiencing improvements in health-related quality of life (104546). Another small clinical trial in patients with COPD shows that taking a specific medical nutrition product (Nutrifriend Cachexia; Smartfish) providing omega-3 fatty acids 2 grams, 25-hydroxyvitamin D3 10 mcg, and whey protein 10 grams twice daily for 12 weeks does not improve lung function when compared with an isocaloric placebo based on milk protein and sunflower oil. However, there was a modest increase in fat mass, as well as modest reductions in triglyceride levels, systolic blood pressure, and exercise-induced fatigue and dyspnea in those taking the omega-3 fatty acid combination product (107189). Observational research has also been conducted to examine the association between habitual fish oil supplementation and developing COPD. A large observational study in individuals without prior COPD has found that taking fish oil supplements is associated with a 12% reduced incidence of COPD over the next 9 years when compared with not taking fish oil supplements (110331).
• Cirrhosis. It is unclear if oral fish oil is beneficial in patients with cirrhosis. Details: Preliminary clinical research in adults with advanced cirrhosis shows that taking fish oil orally does not seem to improve the severity of renal impairment associated with cirrhosis (1013).
• Cognitive impairment. It is unclear if oral fish oil prevents or treats cognitive impairment. Details: Some clinical research suggests that taking 3 fish oil capsules (EPAX 1050TG; EPAX AS) by mouth daily for 12 months may improve memory in patients with mild cognitive impairment. Each capsule contained 1 gram of fish oil, comprised of DHA 430 mg and EPA 150 mg (89346). However, a meta-analysis of clinical research shows that increased dietary or supplemental omega-3 intake has no preventive effect on cognitive impairment in older adults (103501). The effect of fish oil is unclear.
• Colorectal cancer. It is unclear if oral fish oil prevents or treats colorectal cancer. Details: Fish oil has been evaluated for the PREVENTION of colorectal cancer. A large, high-quality clinical study shows that taking fish oil 1 gram daily for a median of 5.3 years does not reduce the risk for colorectal cancer precursors, including colorectal adenomas and serrated polyps, when compared with placebo. Subgroup analyses suggest that patients with low omega-3 fatty acid levels at baseline or those with African American heritage might have a reduced risk for colorectal cancer precursors; however, further research is needed to confirm these findings (102400). Fish oil has also been evaluated for the TREATMENT of colorectal cancer. One small clinical trial shows that taking a specific fish oil supplement (Omega-3, Phytomare) 2 grams daily containing 360 mg of EPA and 240 mg of DHA for 9 weeks along with chemotherapy prolongs the time to tumor progression when compared with not receiving a fish oil supplement. However, it does not reduce the number of patients with tumor progression, hospitalizations, deaths, or chemotherapy requirements (91249). Observational research has found that increased dietary or supplemental fish oil intake is not associated with increased survival in stage three colon cancer patients overall. However, it is associated with increased survival in patients with wild-type KRAS tumors (101274). Further research is needed to confirm whether specific patient populations might benefit from fish oil supplementation.
• Contrast induced nephropathy. It is unclear if oral fish oil is beneficial for preventing contrast induced nephropathy. Details: Preliminary clinical research in patients with chronic kidney disease undergoing coronary angiography shows that taking omega-3 fatty acids (Omacor, Abbott Laboratories) 4 grams twice daily on the day before and the day of angiography does not reduce the number of patients with an increase in serum creatinine levels of at least 0.5 mg/dL within 48 hours, or the need for renal replacement therapy, when compared with taking N-acetyl cysteine 1200 mg (107193).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral fish oil is beneficial for reducing symptoms in patients hospitalized with COVID-19. Details: A small preliminary clinical trial in patients hospitalized with COVID-19 shows that taking omega-3 fatty acids 2 grams daily for 2 weeks modestly reduces body pain and fatigue and improves appetite when compared with patients not taking omega-3 fatty acids. However, there were no significant differences in olfactory symptoms between groups. All patients were also taking hydroxychloroquine 800 mg daily (107188).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral fish oil is beneficial following CABG surgery. Details: Preliminary clinical research shows that taking supplemental fish oil 4 grams orally, containing EPA 2.04 grams and DHA 1.3 grams, beginning on the first postoperative day and continuing for one year thereafter, seems to decrease the incidence of CABG occlusion following surgery when compared with control (2314).
• Crohn disease. It is unclear if oral fish oil is beneficial for reducing the risk of Crohn disease or the risk for relapse in patients with Crohn disease who are in remission; the available evidence is conflicting.
• Crohn disease. Some preliminary clinical research shows that taking a specific enteric coated fish oil supplement (Purepa, Tillotts Pharma) providing 2.7 grams omega-3 fatty acids daily for 12 months can reduce the relapse rate for patients who are in remission (6257). However, other clinical trials show that taking fish oil 4-5 grams daily does not significantly reduce relapse when compared with placebo (6259,16734). A meta-analysis of clinical research shows that treatment with enteric-coated, time-released omega-3 fatty acid or fish oil capsules containing EPA 1.2-3.3 grams and DHA 0.6-1.8 grams daily for up to one year reduces the relapse rate by 13% when compared to control (66061,89347). However, this risk reduction was not observed when only high-quality studies were considered. Also, a meta-analysis of clinical research shows that taking omega-3 fatty acids for 12-24 months does not reduce relapse rate when compared with control (105224).
• Cyclosporine-induced hypertension. Small clinical studies suggest that oral fish oil may prevent or modestly improve symptoms in patients with cyclosporine-induced hypertension. Details: Taking fish oil 3 grams daily for 3 months orally seems to prevent cyclosporine-induced hypertension following cardiac transplant (66367). There is also some evidence that fish oil 4 grams daily for 6 months can maintain pre-cyclosporine blood pressure in patients taking cyclosporine (1012). A meta-analysis of two small clinical studies shows that fish oil 2-18 grams containing 0.6-5.4 grams of EPA and DHA daily for 1-12 months reduces diastolic blood pressure by 4.5 mmHg in kidney transplant recipients using calcineurin inhibitors, including cyclosporine, when compared with placebo (65770).
• Cystic fibrosis. It is unclear if oral fish oil is beneficial in patients with cystic fibrosis. Details: Preliminary clinical research shows that taking omega-3 fatty acids (EPA plus DHA) as 1.3% of total caloric intake for up to 8 months improves pulmonary function based on forced expiratory volume and reduces the number of days during which antibiotics are needed when compared to baseline (65553).
• Dementia. It is unclear if oral fish oil, as supplements or in the diet, reduces the risk of dementia; the available research is conflicting. Details: Some epidemiological research has found that eating fish at least once weekly or the regular use of fish oil supplements is associated with a reduced risk of developing dementia in elderly individuals (65595,108507,108724,109307); however, other research has found no correlation between overall dementia risk and the consumption of fish or fish oil (65962,103501). Some epidemiological research has examined the association between the regular use of fish oil supplements and the risk of individual types of dementia in large prospective studies. These studies have found that regular use of fish oil supplements is not associated with the risk of Alzheimer disease (108507,108724,109307). Also, a study in over 215,000 older adults shows that regular use of fish oil supplements is not associated with the risk of vascular dementia or frontotemporal dementia (108507). However, other studies have found that regular use of fish oil supplements may be associated with 15% and 57% lower risks of vascular dementia or frontotemporal dementia, respectively (108724,109307). The reasons for these discrepancies are unclear. One large epidemiological study has found that associations between the regular use of fish oil supplements and the risks of all-cause or vascular dementia are stronger in males (109307). Also, some research has found that the apolipoprotein E (APOE) genotype may alter the association between fish oil intake and dementia risk (65817,108507,108724). One large epidemiological study has found that regular use of fish oil supplements is associated with a 15% lower risk of vascular dementia. However, the presence of the APOE-e4 genotype alters this affect. In individuals with two APOE-e4 alleles, the risk of vascular dementia is INCREASED by 86%, whereas the risk is reduced by 19% in those with one APOE-e4 allele and by 22% in those with no APOE-e4 alleles (108724). Further research is needed to confirm the clinical relevance of this potential interaction.
• Depression. It is unclear if oral or dietary fish oil is beneficial for the prevention of depression or in patients with depressive symptoms. There is some evidence that benefits vary depending on the form of fish oil used and the patient population studied. Details: Observational research has found that higher dietary intake of fish has been associated with a lower risk of depression and suicide (10867,10868,99368). Also, low omega-3 fatty acid levels in plasma and red blood cells have been associated with depression (10859,10860). However, clinical research does not show that taking fish oil is beneficial for the prevention of depression. A large clinical trial in adults 50 years or older without depression shows that taking fish oil 1 gram daily, providing eicosapentaenoic acid (EPA) 465 mg and docosahexaenoic acid (DHA) 375 mg, for a median of 5.3 years results in a small increased risk of depression or symptoms of depression when compared with placebo (107196). Also, one small clinical study in healthy female nurses shows that taking omega-3 fatty acids containing EPA 1200 mg and DHA 600 mg daily for 90 days does not affect measures or depression or prevent a major depressive episode when compared with placebo (105220). It is also unclear whether oral fish oil is beneficial for reducing symptoms of depression. Results from meta-analyses have been mixed (48282,66129,99356,102391,104551,107191). However, populations included in these analyses have included older adults with or without clinical depression (99356), mixed populations (48282,66129,102391), patients with perinatal depression (104551), patients with mild depression (48282), or patients with major or unipolar depression (107191). Despite the mixed findings overall, most research suggests that taking fish oil may have a small beneficial effect in patients with clinical depression. A meta-analysis of clinical studies in patients with clinical depression shows that fish oil supplementation has a small to modest beneficial effect on symptoms when compared with placebo (107191). However, it is unknown if these benefits are clinically meaningful since most studies are small and generally low-quality. Also, this analysis combined studies investigating fish oil with studies investigating EPA or DHA alone (107191). Small clinical studies in children and adults with clinical depression support the potential for beneficial effects of fish oil (10871,65712,65869). Also, clinical research in postmenopausal females with moderate to severe psychiatric distress shows that fish oil reduces depressive symptoms when compared with placebo (65925). However, a small clinical study in Japanese workers with mild to moderate depression shows that taking fish oil containing DHA 500 mg and EPA 1000 mg daily for 12 weeks in addition to a psychological intervention is no different than the psychological intervention alone (100251). Also, a large clinical trial in patients with depression and coronary heart disease shows that adding fish oil 2 grams daily for 10 weeks, providing 930 mg of EPA and 750 mg of DHA, to sertraline 50 mg daily does not improve depression when compared with sertraline and placebo (17408). Additionally, clinical research in patients with a history of ischemic stroke shows that taking fish oil 3 grams daily for 12 weeks does not improve depression or other mood-related parameters when compared with placebo (65996). Most research in patients with perinatal depression has found no benefit. One small study using fish oil capsules 6 grams daily in divided doses for 6 weeks showed positive outcomes (48198). However, a meta-analysis and individual clinical studies show that taking EPA plus DHA does not help to prevent or improve depression in these patients, and, when used along with supportive psychotherapy, is no more effective than therapy alone (65830,89353,104551). Taking fish oil 1.9 grams daily or omega-3 fatty acids containing EPA 900-1060 mg and DHA 180-274 mg daily for 6-8 weeks does not improve depression when compared with control (65830,89353). The best dose of fish oil for reduction of depression symptoms is unknown. Doses of omega-3 fatty acids used in clinical trials in adults have included fish oil supplements providing EPA, usually 0.6-4 grams daily, alone or with DHA 0.15-2.4 grams daily for 4-16 weeks. In one study, a specific fish oil product (Isodisnatura) 1.5 grams, containing 1.05 grams ethyl-EPA and 0.15 grams ethyl-DHA, daily for 8 weeks was used. In children 6-12 years of age, fish oil 1 gram daily for 16 weeks has been used (10871,65712,65869,65925,107191). However, meta-analyses of research related to symptoms of depression in mixed populations suggest that fish oil supplements containing only EPA or at least 60% EPA are effective, whereas other fish oil supplements are not (48282,66129,102391). Also, although one subgroup analysis of 9 clinical trials found that taking at least 1.5 grams of fish oil daily reduces depressive symptoms (99356), another meta-analysis found that only fish oil formulations containing no more than 1 gram of EPA demonstrated benefit (102391). Based on these and other findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids providing 1-2 grams EPA are recommended for adjunctive use in patients with major depressive disorder. However, omega-3 fatty acids are not recommended as monotherapy and products containing other doses of EPA are not recommended as adjunctive or monotherapy in these patients (110318).
• Developmental coordination disorder (DCD). Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking a combination of fish oil (80%) and evening primrose oil (20%) for 3 months seems to improve reading, spelling, and behavior when given to children aged 5-12 years with DCD. The combination contains EPA 558 mg, DHA 174 mg, gamma-linolenic acid 60 mg, and vitamin E 9.6 mg daily (13748). One study shows that taking fish oil with evening primrose oil does not improve motor skills in children with DCD (13748). However, another very small study shows that taking fish oil in combination with evening primrose oil, thyme oil, and vitamin E (Efalex, Efamol Ltd), for 4 months improves motor skills including manual dexterity, ball skills, and balance in children with dyslexia and DCD (5708). The effect of fish oil when used alone is unclear.
• Diabetic nephropathy. It is unclear if oral fish oil is beneficial in patients with diabetic nephropathy. Details: Fish oil has been evaluated for the management of diabetic nephropathy in patients with both type 1 and type 2 diabetes. One small clinical study in patients with diabetic nephropathy related to type 1 diabetes shows that taking fish oil 4.6 grams daily for one year does not improve albuminuria or glomerular filtration rate (GFR) when compared with placebo (66427). In patients with type 2 diabetes, the evidence is mixed. In one study of patients taking angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs), clinical research shows that taking fish oil (Lovaza) providing EPA 1.86 grams and DHA 1.5 grams daily for one year attenuates the progression of albuminuria, but has no effect on the estimated GFR. In patients not taking ACE-inhibitors or ARBs, there was no effect on albuminuria. The patients in this study had not all been diagnosed with nephropathy (101537). In another study of patients with diabetic nephropathy taking ACE-inhibitors or ARBs, taking fish oil (Omacor) 3 grams daily for 12 weeks had no effect on proteinuria when compared with control (101538).
• Diabetic neuropathy. It is unclear if oral fish oil is beneficial for the treatment or prevention of neuropathy in patients with type 1 diabetes. Details: Preliminary clinical research in patients with type 1 diabetes shows that taking fish oil 1800 mg daily for 6 months does not prevent the development of new onset diabetic neuropathy or reduce the severity of neuropathy in patients with existing signs of disease when compared with placebo (106072). However, 86% of patients did not have neuropathy at baseline.
• Diabetic retinopathy. It is unclear if oral fish oil is beneficial in patients with diabetic retinopathy. Details: Population research in adults with type 2 diabetes has found that consuming at least 500 mg of long-chain omega-3 fatty acids from fish and seafood daily as part of a Mediterranean diet is associated with a 48% reduced risk of developing sight-threatening diabetic retinopathy when compared with consuming lower amounts (96115). In contrast, preliminary clinical research in patients with type 1 diabetes shows that taking fish oil 1800 mg daily for 6 months does not affect the severity of retinopathy when compared with placebo (106072). However, most patients did not have retinopathy at baseline and the study was designed to examine diabetic retinopathy severity as a safety assessment, not as a primary or secondary efficacy endpoint.
• Dry eye. Oral fish oil does not seem to reduce the risk of developing dry eye. It is unclear if oral fish oil is beneficial in patients with existing dry eye. Details: While some preliminary observational research has found that higher dietary intake of omega-3 fatty acids, primarily from seafood sources, is associated with a reduced risk of dry eye syndrome in females (13770), a large ancillary analysis of the VITAL study, which included over 23,500 adults aged 50 years and older, shows that taking fish oil 1 gram daily is not associated with reduced incidence of dry eye disease over a median follow-up of 5.3 years when compared with placebo (108510). There is also interest in the use of fish oil supplements for the treatment of dry eye. The American Academy of Ophthalmology Preferred Practice Pattern guidelines published in 2013 state that omega-3 fatty acids such as fish oil have been reported to be beneficial for dry eye, but the evidence is insufficient to establish effectiveness (95702). Several studies in patients with mild to moderate dry eye suggest that taking fish oil supplements providing EPA 360-1680 mg plus DHA 240-560 mg orally daily for 30 days to 12 weeks reduces tear osmolarity, increases tear film stability, and improves some symptoms of dry eye such as pain, blurred vision, and sensitivity, when compared with placebo (89342,91861,93251,96114,101544). Specific commercial fish oil products (Nippon Suisan Kaisha, Ltd; Caruso's Natural Health UltraMAX fish oil; PRN Dry Eye Omega Benefits softgels, PRN Physician Recommended Nutraceuticals) have been used (89342,91861,96114). However, many of these studies are small, and some used highly restrictive eligibility criteria, which may limit the generalizability of the results. Furthermore, some of these studies show that taking fish oil does not improve volume of tears produced, damage to the eye, or Meibomian gland dysfunction, which is a leading cause of dry eye (91861,93251). A larger study in over 500 patients shows that taking fish oil providing EPA 2000 mg plus DHA 1000 mg orally daily for 12 months does not improve symptoms of dry eye when compared with placebo in patients with moderate to severe dry eye (95701). However, the validity of these results is reduced by the use of other medications during the course of the study. Preliminary research investigating fish oil in combination with other ingredients also shows conflicting results (17523,91860). One of these studies used a specific combination product (TheraTears Nutrition, Advanced Nutrition Research) providing EPA 450 mg, DHA 300 mg, and flaxseed oil 1000 mg daily for 90 days (17523).
• Dyslexia. It is unclear if oral fish oil is beneficial in patients with dyslexia. Details: In a small clinical trial, taking fish oil containing DHA acid 480 mg daily for one month orally seems to improve night vision in children aged 5 to 12 years with dyslexia. Dyslexic children who take fish oil seem to develop significantly better darkness adaptation (5708).
• Dyslipidemia. It is unclear if oral fish oil is beneficial in patients with dyslipidemia. Details: There is contradictory evidence about the effects of fish oil on lipid levels. Consuming about 250 grams of fish in the DIET twice weekly for 8 weeks has been shown to lower total cholesterol, triglyceride, and low-density lipoprotein (LDL) cholesterol levels, as well as increase high-density lipoprotein (HDL) cholesterol levels, in patients with hyperlipidemia (97186). However, most research shows that taking fish oil SUPPLEMENTS does not improve cholesterol levels and might even increase LDL cholesterol levels in patients with hypercholesterolemia or dyslipidemia (2318,8714,12182,66196,97186,99358). Oftentimes, increases in LDL cholesterol levels occur when fish oil supplements are taken in higher doses such as 5-20 grams daily; however, doses of fish oil supplements containing as little as 2 grams of omega-3 fatty acids daily have been shown to increase LDL cholesterol levels in patients with hyperlipidemia (2318,12182,65729,66224,66267,66257,97186). Despite its unfavorable effects on LDL cholesterol, fish oil supplements might still be beneficial for patients with dyslipidemia and diabetes. Some clinical research shows that taking fish oil supplements can decrease elevated triglyceride levels, decrease secretion of very low-density lipoproteins (VLDLs), increase VLDL apolipoprotein B secretion, and increase levels of HDL cholesterol in people with type 2 diabetes and dyslipidemia (8714,8807,12182). Fish oil 4 grams daily for up to 8 weeks has been used (8714,8807). Also, preliminary clinical research shows that fish oil, 6 grams daily for 3 months taken alone, or fish oil 1 gram daily combined with pravastatin 20 mg, can correct the dyslipidemia associated with renal transplantation (8805,66454). Some research has shown that taking fish oil in combination with garlic and plant sterols reduces lipid levels in patients with hypercholesterolemia or dyslipidemia. However, it is possible that these favorable effects are due to the other ingredients, since garlic and plants sterols have been shown to independently reduce lipid levels (2318,2319,97173).
• Endometrial cancer. It is unclear if oral fish oil reduces the risk for endometrial cancer. Details: Some epidemiological research has found that consuming approximately two servings of fatty fish weekly is associated with a reduced risk for endometrial cancer. However, other epidemiological research has not found an association between fish consumption and risk of endometrial cancer (8690,9774). It is unclear if taking fish oil supplements reduces the risk of endometrial cancer.
• Endometriosis. It is unclear if oral fish oil is beneficial in patients with endometriosis. Details: Clinical research in females aged 12-25 years who had surgery for endometriosis at least 6 weeks prior shows that taking fish oil (NatureMade) 1 gram daily for 6 months has no clinical effect on pain or analgesic use when compared with placebo (101546). It is not known whether taking fish oil helps to reduce pain related to endometriosis prior to surgery.
• Epilepsy. Some clinical research suggests that oral omega-3 fatty acids may modestly reduce seizure frequency in patients with epilepsy. However, it is unclear if oral fish oil itself is beneficial in patients with epilepsy. Details: A meta-analysis of seven clinical trials in adults and children with epilepsy shows that taking omega-3 fatty acids, usually as fish oil, for 10-42 weeks modestly reduces seizure frequency when compared with placebo. The most frequent doses were 1000-2800 mg daily (106067). Although most studies included in the analysis investigated the combined effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), some studies used purified or semi-purified EPA or DHA. Also, some studies included in the analysis were very small in size (89337,106067). More recent clinical research in children with attention deficit-hyperactivity disorder (ADHD) and intractable epilepsy who are also taking risperidone 0.5 mg daily shows that taking fish oil 1 gram daily, providing EPA 180 mg and DHA 120 mg daily for 6 months, decreases monthly seizure frequency to a median of zero, compared with no change in children taking placebo. However, there was no change in seizure severity (107172).
• Exercise-induced muscle soreness. It is unclear if oral fish oil reduces the severity of exercise-induced muscle soreness. Details: Small clinical studies in untrained healthy adults in the United Kingdom show that taking fish oil orally 1.8-3 grams daily for 4-6 weeks prior to and during physical exercise does not prevent muscle soreness following elbow flexion or knee contractions (8524,89340). Also, a small clinical study in healthy young females shows that taking fish oil (Vital Atman) 3.2 grams at dinner after a resistance exercise protocol and at lunch over the next three days does not prevent muscle soreness when compared with placebo (106071). However, other small clinical studies in untrained healthy adults in Japan show that taking fish oil 1.8-2.4 grams (containing about 300-600 mg EPA and 200-260 mg DHA) daily for 1-2 months ameliorates muscle soreness and improves range of motion following knee extensor exercises or eccentric contraction exercises (65958,98257,100252,109222). Also, a small clinical study in professional rugby players shows that taking fish oil containing EPA 551 mg and DHA 551 mg twice daily for 5 weeks reduces subjective ratings of whole body muscle soreness when compared with placebo (99357).These differing findings might be due to differences in patient populations due to their geographic location, but higher quality research is needed to confirm.
• Food allergies. It is unclear if oral fish oil is beneficial in patients with food allergies. Details: A pooled analysis of clinical research shows that maternal fish oil supplementation during pregnancy reduces the risk of allergic sensitization to egg by 31%, but not to milk or peanuts (97177).
• Gingivitis. It is unclear if oral fish oil is beneficial in patients with gingivitis. Details: Preliminary clinical research shows that taking fish oil 1.8 grams three times daily for 8 days does not improve severity of gingivitis on days 14, 28, or 35 when compared with placebo (1005).
• Glaucoma. Although there has been interest in using oral fish oil for glaucoma, there is insufficient reliable information about the clinical effects of fish oil for this condition.
• Hemodialysis graft dysfunction. It is unclear if oral fish oil is beneficial in patients with hemodialysis graft dysfunction. Details: The evidence on the effects of fish oil for preventing thrombosis or maintaining hemodialysis graft patency is conflicting (8684,65762,89348,96119). However, a meta-analyses of the available clinical research provides moderate evidence that taking fish oil containing omega-3 fatty acids 1.6-3.4 grams daily for 3-12 months reduces thrombosis or the need for intervention to restore arteriovenous access by about 19% to 29% when compared with placebo in patients with fistula or grafts due to kidney failure (96123,98247). Fish oil 4 grams daily for one year has been used to prevent thrombosis after graft placement (8684).
• Heart transplant. It is unclear if oral fish oil is beneficial in patients after a heart transplant. Details: A small clinical trial shows that taking fish oil orally seems to preserve renal function and reduce the long-term continuous rise in blood pressure after heart transplantation. There is evidence that a dose of 4 grams of fish oil composed of 46.5% EPA and 37.8% DHA, taken daily for one year after heart transplantation, prevents changes in systolic and diastolic blood pressures, glomerular filtration rate, and serum creatinine when compared with placebo (8687).
• HIV/AIDS. It is unclear if oral fish oil is beneficial for HIV. Details: Some clinical evidence shows that taking fish oil-containing food bars does not improve CD4 counts in patients with HIV (66414). Other clinical research shows that enteral supplementation with a fish oil-enriched peptide-based formula improves CD4 count, but not viral load, in patients with HIV when compared with standard formula (65525).
• Impaired glucose tolerance (prediabetes). It is unclear if oral fish oil is beneficial for impaired glucose tolerance. Details: Preliminary clinical research shows that fish oil supplements might reduce the risk of conversion from prediabetes to type 2 diabetes. In patients with hypertriglyceridemia and prediabetes, taking a specific fish oil product (ESAPENTR, Pharmacia and Upjohn) 1 capsule by mouth three times daily (for a total of EPA 1530 mg and DHA 1050 mg) for 6 months lowers triglycerides with no deterioration in glucose tolerance over one year (7368). Although fish oil may prevent worsening of glycemic parameters, it does not seem to improve them. A small clinical trial shows that taking a specific fish oil supplement (EPAX AS) 6 grams containing 3.9 grams of omega-3 fatty acids does not improve glycemic outcomes when compared with placebo in patients with impaired glucose regulation (98242).
• Infant development. It is unclear if oral fish oil, taken during pregnancy or by the infant, is beneficial for improving vision or cognitive development in infants. Details: Population research has found that increased consumption of seafood during pregnancy is associated with improved measures of infant and child development such as verbal intelligence, communication, and social development (15743). In contrast, supplementation with fish oil during pregnancy and/or lactation does not seem to be beneficial, or may only be beneficial in male offspring. A meta-analysis of clinical research shows that intake of long-chain omega-3 fatty acids during pregnancy and/or lactation, mainly from fish oil, does not improve cognitive outcomes in the infant up to approximately 2 years of age when compared with control (103495,105213). This is supported from the findings of most individual clinical trials providing fish oil supplements 1-4 grams daily from 20-21 weeks gestation until delivery or until 30 days after childbirth, or providing fish oil supplements or dietary fish during lactation (15162,48105,97182,99364). An additional small clinical trial shows that taking fish oil 2000 mg daily, providing eicosapentaenoic acid (EPA) 260 mg and docosahexaenoic acid (DHA) 1440 mg, from 22-24 weeks gestation until delivery, does not improve most measures of developmental or behavioral milestones in the infant at 6 months, when compared with olive oil placebo (110354). A large clinical trial shows that ingestion of fish oil (Incromega TG3322, Croda) 4 grams daily during late-phase pregnancy, providing 1.3 grams EPA and 0.9 grams DHA, results in a 17- to 21-day earlier achievement of some, but not all, late motor milestones in male infants. However, there was no improvement in earlier motor milestones. This study also identified modest improvements in male infants for early, but not late, word production, cognitive development at 2.5 years, and behavior and emotion at 6 years (105213). Providing fish oil supplementation directly to infants may improve the development of vision, but not cognition. Clinical research shows that infants supplemented with fish oil-containing formula beginning within 3-10 days of birth have improved visual acuity at 2 months and improved oscillatory potentials, which are thought to reflect retinal function, at 1 year when compared to infants supplemented with linolenic acid-containing formula (66399,66569). However, supplementing infants with omega-3 fatty acids such as fish oil does not affect cognition and neurodevelopment (89349,89363).
• Insomnia. It is unclear if oral fish oil is beneficial for insomnia. Details: In a group of healthy female nurses also undergoing a mindfulness-based stress management program or given a psychoeducation leaflet, preliminary clinical research shows that taking omega-3 fatty acids containing EPA 1200 mg and DHA 600 mg daily for 90 days modestly reduces insomnia severity when compared with placebo. However, benefits were no longer present after 6 or 12 months (105220).
• Intrauterine growth restriction (IUGR). Although there has been interest in using oral fish oil for prevention of IUGR, there is insufficient reliable information about the clinical effects of fish oil for this condition.
• Joint pain. Oral fish oil has only been evaluated in combination with other ingredients; its effects when used alone are unclear. Details: Preliminary clinical research shows that taking fish oil powder 375 mg in combination with lemon verbena extract (Monteloeder, Ltd) 230 mg six times daily for 5 weeks, followed by three capsules daily for 3 weeks, reduces symptoms of joint pain and stiffness when compared with placebo (17748). It is unclear if these effects are due to fish oil, lemon verbena, or the combination.
• Kidney failure. Small clinical studies in patients with kidney failure suggest that oral fish oil may modestly improve some blood lipid and inflammatory marker levels. Details: Some clinical research shows that taking fish oil reduces levels of inflammatory markers. A meta-analysis of clinical research and individual preliminary clinical trials in patients on hemodialysis show that taking omega-3 fatty acids, usually as fish oil, reduces C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels when compared with a control oil. Studies have used doses of up to 9 grams daily for 2-12 months (8685,65959,107190). Additional preliminary clinical research in adults on chronic hemodialysis shows that taking three packets of a specific product (Coromega) containing emulsified fish oil (EPA 350 mg and DHA 230 mg) 650 mg per packet daily for 8 weeks modestly increases hemoglobin, albumin levels, and urine output (8685). However, a meta-analysis of clinical research shows that any benefit on hemoglobin levels is small, that albumin levels are not improved, and that mortality is not reduced (107190). Oral fish oil may also improve some, but not all, blood lipid levels in patients on hemodialysis. A meta-analysis of clinical research in adults undergoing dialysis shows that taking fish oil modestly reduces triglyceride and low-density lipoprotein (LDL) cholesterol levels, but not total cholesterol levels (107190). Also, in children aged 8-17 years on chronic hemodialysis, preliminary clinical research shows that taking fish oil 2 grams daily for 3 months reduces total cholesterol, triglyceride, and LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels when compared to baseline. It also seems to improve some inflammatory markers and quality of life (102396,103596). The validity of these findings is limited by the lack of a comparator group. A small clinical trial shows that taking fish oil 2 grams, containing EPA 160 mg, DHA 100 mg, and d-alpha-tocopherol 0.9 IU, three times daily for 6 months does not reduce lipoprotein(a) levels, when compared with placebo (65997).
• Kidney transplant-related bone loss. Clinical research suggests that oral fish oil does not improve bone mineral density following a kidney transplant. Details: : Clinical research in adults shows that taking omega-3 fatty acids 2.6 grams daily, starting 8 weeks post-kidney transplant and continuing for 44 weeks, does not affect the change in bone mineral density at the hip, spine, or forearm or alter mineral metabolism when compared with olive oil as placebo. The omega-3 supplement used in the study (Omacor, Pronova Biopharma) provided eicosapentaenoic acid (EPA) 460 mg/gram capsule and docosahexaenoic acid (DHA) 380 mg/gram capsule for a total of three capsules daily (107179). A larger study population and duration are needed to confirm these findings.
• Lung cancer. It is unclear if oral fish oil can improve nutritional status in patients with lung cancer. Details: Clinical research in patients with lung cancer shows that taking fish oil providing eicosapentaenoic acid (EPA) 1.6 grams and docosahexaenoic acid (DHA) 0.8 grams daily for 12 weeks modestly increases body weight, serum albumin, and triglyceride levels, and decreases the inflammatory markers C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha), when compared with sunflower oil as placebo. However, there was no effect on body mass index or arm circumference (107194).
• Lyme disease. Although there has been interest in using oral fish oil for Lyme disease, there is insufficient reliable information about the clinical effects of fish oil for this condition.
• Male infertility. It is unclear if oral fish oil is beneficial for male infertility. Details: Observational research has found an association between fish oil supplement intake and semen quantity and quality. In men who took fish oil supplements on less than 60 of the last 90 days, semen volume was 0.38 mL higher and testicular size was 0.8 mL larger than those who had taken no fish oil supplements. In men who took fish oil supplements on at least 60 of the past 90 days, semen volume was 0.64 mL higher and testicular size was 1.5 mL larger than those who had taken no fish oil supplements. These findings suggest a dose-dependent effect of fish oil. However, the validity of these findings is limited by the observational nature of the study, the unclear health status of the participants, and the lack of information on clinical fertility outcomes (102394).
• Melanoma. It is unclear if there is a link between fish oil intake and the incidence of melanoma. Details: An analysis of the NIH-AARP Diet and Health Study, a prospective cohort study in over 491,000 older adults, has found that total intake of fish is associated with increased melanoma risk over a median follow-up of 15.5 years. When the lowest and highest quintiles of intake are compared, there is a 22% increase in the risk for malignant melanoma and a 28% increase in the risk for melanoma in situ. In sub-group analyses, all melanoma incidence is positively associated with tuna intake or non-fried fish intake, but malignant melanoma incidence is inversely associated with fried fish intake (108509). It was suggested that the positive associations could be due to contaminants in fish such as polychlorinated biphenyls, dioxins, arsenic, and mercury.
• Menopausal symptoms. It is unclear if oral fish oil is beneficial for menopausal symptoms. Details: A meta-analysis of three clinical trials shows that fish oil supplements do not affect hot flashes, insomnia, or quality of life during menopause when compared with placebo. However, evidence from one clinical trial suggests that fish oil supplements might reduce night sweats (99363). In addition, clinical research shows that taking fish oil (Omega-rex, Daana Pharmaceutical Co.) 1 gram, providing EPA 180 mg and DHA 120 mg, daily for 12 weeks improves overall symptoms of menopause, including hot flashes, sleep problems, and anxiety, when compared with placebo. However, there was no effect on blood lipid levels, urogenital symptoms, joint problems, or feelings of exhaustion (103492).
• Migraine headache. Supplemental fish oil does not seem to reduce the frequency or severity of migraine headaches. However, dietary fish oil may reduce the frequency and duration of migraine headaches. Details: Most research shows that taking fish oil supplements orally does not decrease the frequency or severity of migraine headaches in adolescents and adults (8712,8713,99361). However, one meta-analysis of two very small clinical trials shows that fish oil supplements might decrease the duration of migraines by an average of 3.4 hours (99361). One clinical study suggests that increasing dietary intake of fish oil may be beneficial. Increasing dietary intake of EPA plus DHA in the form of fish oil to 1.5 grams daily for 16 weeks, while maintaining dietary intake of linoleic acid at levels no greater than 7% of energy, decreases the frequency and duration of migraines, but does not improve migraine-related quality of life, when compared with intakes of EPA plus DHA of less than 150 mg daily, as is commonly found in the North American diet. Some patients also further reduced dietary linoleic acid intake. In those increasing fish oil intake and maintaining linoleic acid intake, headache duration was reduced by 1.3 hours per day; in the patients who also reduced linoleic acid intake to no more than 1.8% of energy, it was reduced by 1.7 hours per day. The duration of moderate to severe headaches was also reduced and patients had 2-4 fewer headaches each month depending on linoleic acid intake. There was no clear effect on the use of acute pain medication (105289).
• Muscle strength. It is unclear if oral fish oil is beneficial for improving muscle strength in young adults. Details: A small preliminary clinical trial in young resistance trained adults undergoing training three times weekly shows that taking fish oil (Nordic Naturals, ProOmega) 4.5 grams daily, providing eicosapentaenoic acid (EPA) 2.275 grams and docosahexaenoic acid (DHA) 1.575 grams, for 10 weeks modestly improves upper and lower body strength when compared with taking placebo. There were no differences between groups in lean body mass or fat mass changes (110341).
• Obesity. Most clinical research shows that fish oil supplements do not improve weight loss; however, dietary fish intake might be beneficial for obesity. Clinical research also shows that taking fish oil during pregnancy does not seem to prevent overweight or obesity in the infant. It is unclear if fish oil is beneficial for improving cardiometabolic risk factors in overweight or obese children. Details: Most research shows that fish oil supplementation does not improve weight loss in obese adults or children (15737,66004,89355,89356,100247,100250,106073). A meta-analysis of clinical research shows that fish oil supplementation alone or with lifestyle modification does not reduce body weight or body mass index. However, fish oil supplementation seems to modestly reduce waist to hip ratio and waist circumference (97176). The reduction in waist circumference might be due to a decrease in body fat when fish oil is combined with exercise (15737,89355). A meta-analysis of clinical research in overweight or obese children and adolescents also shows that taking omega-3 fatty acids 250 mg to 3360 mg, usually as fish oil, for 3-52 weeks does not reduce body weight or waist circumference when compared with placebo. However, there was a modest reduction in body mass index (BMI) of approximately 1 kg/m2. Taking fish oil does not seem to improve most cardiometabolic risk factors in this population, although there were modest improvements in serum triglyceride levels and systolic blood pressure (106073). This analysis is limited by the inclusion of at least one study that investigated the use of an algae-derived docosahexaenoic acid (DHA) product. Research has also investigated the effect of fish oil supplementation on the prevention of overweight or obesity in the infant or young child when taken during pregnancy by females with overweight or obesity. Clinical research shows that taking fish oil 6 grams daily from mid-pregnancy until 3 months postpartum or when breastfeeding stopped, providing a total of 3.55 grams daily omega-3 fatty acids, does not affect infant body fat percentage or most measures of body anthropometry at 2 weeks or 3 months of age when compared with olive oil placebo. However, there was a slight increase in body mass index for age at 3 months, possibly related to increased fat mass (110338). Another clinical trial shows that taking two capsules daily of fish oil (Croda Europe Ltd.) during pregnancy and for 6 months postpartum, providing eicosapentaenoic acid (EPA) 0.22 grams and DHA 1.9 grams daily, does not prevent overweight in the child at 24 months when compared with taking placebo. The odds of overweight at 24 months were reduced by approximately 78% in children of those taking fish oil along with 10 billion colony forming units each of Lacticaseibacillus rhamnosus HN001 and Bifidobacterium animalis subsp. lactis 420; however, this reduction was similar to findings related to taking the probiotics alone in the absence of fish oil (110336). In contrast to fish oil supplements, dietary fish might enhance weight loss. Some evidence shows that dietary fish intake improves weight loss and decreases blood glucose and insulin concentrations in overweight and hypertensive patients when combined with a calorie-restricted diet (2049).
• Oral mucositis. It is unclear if oral fish oil is beneficial for oral mucositis. Details: A small clinical trial in patients with chemotherapy-induced mucositis shows that taking fish oil 2000 mg containing 360 mg EPA and 240 mg of DHA daily for 21 days reduces mucositis severity and pain when compared with placebo (98246).
• Osteoporosis. Oral fish oil has predominantly been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Epidemiological research has found that increasing intake of foods including fish that are high in omega-3 fatty acids while decreasing intake of omega-6 fatty acids is associated with higher bone mineral density (BMD) at the hip in both males and females (12956,65895). Clinical research shows that taking fish oil orally, in combination with evening primrose oil and calcium, for 18 months seems to decrease bone turnover and increase spinal and femoral BMD in elderly people with osteoporosis (7611,12925). 2000 mg of a mixture of evening primrose and fish oil (containing 60% Iinoleic acid, 8% gamma-Iinolenic acid, 4% EPA and 3% DHA), taken three times daily with meals along with calcium carbonate 600 mg has been used (7611). However, taking fish oil containing 0.45 or 4.5 grams EPA plus DHA daily for 2 years does not improve BMD in middle-aged to elderly patients with knee osteoarthritis who do not have osteoporosis (96122).
• Parkinson disease. It is unclear if oral fish oil is beneficial for Parkinson disease. Details: Preliminary observational research has found that initiating supplemental fish oil is associated with a reduction in Parkinson symptoms (110343). This study is limited by its retrospective design and the lack of symptom specific information.
• Peripheral arterial disease (PAD). It is unclear if oral fish oil is beneficial for PAD. Details: A small clinical trial shows that taking fish oil orally appears to have no effect on walking distance in patients with stable claudication (1002).
• Periodontitis. It is unclear if oral fish oil is beneficial for periodontitis. Details: Preliminary clinical research in individuals with chronic mild or moderate periodontitis treated with scaling and planning shows that taking fish oil providing 180 mg EPA and 120 mg DHA daily for one or three months modestly reduces pocket depth and improves clinical attachment, when compared with taking a placebo or no fish oil (101545,110347). One study shows that pocket depth is reduced by 21%, compared with 5% in those taking no fish oil; however there were no benefits on gingivitis or plaque (101545). Benefits seem to be maintained up to 3 months post-treatment (101545).
• Phenylketonuria (PKU). Small clinical studies suggest that oral fish oil may modestly improve symptoms in patients with PKU. Details: Some small clinical trials show that taking fish oil supplements (Ameu, Omega Pharma) containing DHA 15 mg/kg daily for 3 months improves motor skills, coordination, and visual function in children with PKU when compared to control. However, it does not affect plasma levels of phenylalanine (65771,65981).
• Pneumonia. It is unclear if oral fish oil is beneficial for pneumonia. Details: Epidemiological research found no relationship between fish consumption and the risk of developing community-acquired pneumonia (13760).
• Polycystic ovary syndrome (PCOS). Most small clinical studies suggest that oral fish oil is not beneficial for weight loss or glucose homeostasis in patients with PCOS. Details: Small clinical trials in patients with PCOS show that taking fish oil alone or with vitamin D3 does not affect body weight or body mass index (BMI) when compared with placebo or control oils (21906,107187,107197). Also, taking fish oil does not seem to affect most measures of glucose homeostasis or blood lipids when compared to control oils (21906,107197). However, when used in combination with vitamin D3, taking fish oil modestly reduces levels of testosterone and results in some overall improvement in feelings of depression and anxiety (107187). Doses used in clinical trials have included fish oil (Nordic Naturals) providing eicosapentaenoic acid (EPA) 2148 mg and docosahexaenoic acid (DHA) 1452 mg daily for 6 weeks, or fish oil 2 grams daily plus vitamin D3 50,000 IU biweekly for 12 weeks (21906,107187,107197).
• Polymyalgia rheumatica. It is unclear if oral fish oil is beneficial for polymyalgia rheumatica prevention. Details: Oral fish oil for the prevention of polymyalgia rheumatica has been investigated in a large clinical trial of approximately 25,000 older adults. Taking fish oil 1 gram daily for 5 years providing eicosapentaenoic acid (EPA) 0.46 grams and docosahexaenoic acid (DHA) 0.38 grams alone or in combination with vitamin D3 2000 IU daily does not reduce the risk of developing definite or probable polymyalgia rheumatica when compared with placebo (107184). Although this study was large, the primary endpoint was the effect of taking fish oil and/or vitamin D on the development of autoimmune diseases as a group. The number of patients with a specific autoimmune disease such as polymyalgia rheumatica was relatively small.
• Post-traumatic stress disorder (PTSD). It is unclear if oral fish oil is beneficial for PTSD. Details: Some preliminary clinical research shows that adding omega-3 polyunsaturated fatty acid supplementation to psychoeducation does not further improve symptoms of PTSD in subjects that were part of the Disaster Medical Assistance Team after the Great East Japan Earthquake (89358). Additional preliminary clinical research in patients in intensive care shows that use of fish oil 18.8 grams per liter of enteral feed is no more effective than enteral feeding without fish oil in preventing symptoms of PTSD from developing up to 6 months later (104549).
• Postmenopausal conditions. Most research shows that oral fish oil is beneficial for improving triglyceride levels after menopause. More research is needed to determine the optimal dose and duration. Details: Lipid metabolism is often altered after menopause. A meta-analysis of mainly small clinical trials in postmenopausal females shows that taking fish oil supplements for a period of 2 weeks to 24 months decreases triglyceride levels by an average of 17.8 mg/dL when compared to placebo. The greatest evidence of benefit occurred in individuals with a body mass index (BMI) of at least 30 kg/m2 or with baseline hypertriglyceridemia. Levels of high-density lipoprotein (HDL) cholesterol, as well as low-density lipoprotein (LDL) cholesterol, were modestly increased. The dose of fish oil used in the individual clinical trials ranged between 285 mg and 14 grams daily, with the most evidence of benefit associated with doses of at least one gram daily (110351).
• Postoperative fistula. Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients undergoing head and neck cancer surgery shows that use of a specific liquid diet (Neo-Mune, Thai Otsuka Pharmaceutical Co., Ltd.), providing supplementary arginine 12.3 grams/L, glutamine 6.15 grams/L, and fish oil 5.42 grams/L, starting 7 days before surgery and continuing for 21 days, reduces the risk of a mucocutaneous fistula diagnosis to 8%, compared with 23% of those given a hospital-prepared blended diet (107178).
• Postoperative infection. Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients undergoing head and neck cancer surgery shows that use of a specific liquid diet (Neo-Mune, Thai Otsuka Pharmaceutical Co., Ltd.), providing supplementary arginine 12.3 grams/L, glutamine 6.15 grams/L, and fish oil 5.42 grams/L, starting 7 days before surgery and continuing for 21 days, does not reduce the risk of a wound infection or general infection when compared with a hospital-prepared blended diet (107178).
• Postoperative recovery. Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients undergoing head and neck cancer surgery shows that use of a specific liquid diet (Neo-Mune, Thai Otsuka Pharmaceutical Co., Ltd.), providing supplementary arginine 12.3 grams/L, glutamine 6.15 grams/L, and fish oil 5.42 grams/L, starting 7 days before surgery and continuing for 21 days, reduces hospital length of stay by 5 days when compared with a hospital-prepared blended diet. Also, body weight was modestly higher at treatment completion in those taking the fish oil product (107178).
• Postpartum depression. It is unclear if oral fish oil is beneficial for postpartum depression. Details: Meta-analyses of available research show that taking fish oil, usually during pregnancy, has no effect on the prevention or treatment of perinatal depression when compared with placebo. In addition, when used along with supportive psychotherapy, fish oil is no more effective than therapy alone for perinatal depression (103493,104551). However, a meta-analysis of a small number of studies shows that taking omega-3 fatty acids might have a moderate effect on the prevention of postpartum depression (103493). The studies included in this analysis were heterogeneous. Most studies used fish oil providing EPA up to 2200 mg daily and DHA up to 1638 mg daily, but some studies in the analysis used DHA alone from algal sources (103493).
• Preterm labor. Research on the use of oral fish oil for the prevention of preterm labor is conflicting; however, there may be benefit of oral fish oil in patients with low baseline omega-3 status. Details: Population research has found that eating seafood during pregnancy is associated with a reduced risk of preterm delivery when compared with never eating fish (65528). Clinical research also shows that taking a specific omega-3 fatty acids supplement (Pikasol) 2.7 to 6.1 grams, containing DHA 0.9 to 2.1 grams and EPA 1.3 to 2.9 grams, daily beginning at 20-33 weeks' gestation reduces the risk of premature delivery (8706,12972,66105). Meta-analyses of these and other studies show that taking omega-3 fatty acids, including fish oil and supplements or foods enriched in docosahexaenoic acid (DHA), during pregnancy reduces the risk of early preterm delivery (gestational age less than 34 weeks) by 22% to 27% and may reduce the risk of preterm delivery (gestational age less than 37 weeks) by 10% to 11% when compared to control (98240,106069). However, conflicting evidence exists. The most recent meta-analysis shows that taking omega-3 fatty acids during pregnancy does not reduce the risk of early preterm or preterm delivery when compared to control when only studies with low risk of bias were analyzed (106069). Numerous individual studies support this finding (66020,98255,101505,101540,102397,103496,110338). Some individual studies included in the meta-analysis have used a specific fish oil supplement (Incromega DHA 500TG) 900 mg containing DHA 800 mg and EPA 100 mg daily, starting at 20 weeks' gestation and continuing to delivery or 34 weeks' gestation (101505) or fish oil 2 grams daily, containing EPA 660 mg and DHA 440 mg, starting mid-gestation and continuing until the last day of the 37th week of gestation (102397). Other clinical trials not included in the meta-analysis also show that perinatal fish oil does not prevent preterm labor when compared with placebo. These studies have used fish oil 1000 mg containing EPA 180 mg and DHA 120 mg daily, starting at week 20 of gestation and continuing until birth (98255) or fish oil (Incromega TG33/22) 4 grams daily, providing 2.4 grams long chain omega-3 fatty acids, starting at about 24 weeks' gestation (101540). However, in this study, birth weight was increased by about 97 grams and gestation was increased by approximately 2 days when compared with olive oil placebo (101540). In one clinical trial, use of a high-DHA fish oil, providing EPA 100 mg and DHA 800 mg daily, from before 20 weeks' until 34 weeks' gestation, increases the risk of preterm birth prior to 34 weeks' gestation when compared with placebo in patients with baseline omega-3 status of greater than 4.9%. However, the risk is reduced from 3.2% to 0.7% in patients with baseline omega-3 status below 4.1%. In addition, taking fish oil had no effect on the risk of preterm birth prior to 37 weeks' gestation (103496). The reasons for these discrepancies are not clear but may be due to the dose, duration, and type of omega-3 fatty acids used, or the baseline omega-3 status (102397,103496).
• Prematurity. It is unclear if oral fish oil is beneficial for improving the development of premature infants. Details: Formula supplemented with long-chain polyunsaturated fatty acids from fish oil and borage oil daily for up to 18 months seems to improve growth and neurodevelopment in preterm infants, especially boys (13745).
• Pressure ulcers. It is unclear if enteral or topical fish oil is beneficial in patients with pressure ulcers. Details: Preliminary clinical research in critically ill, hospitalized adults shows that giving enteral or parenteral formula supplemented with fish oil containing EPA 0.125-0.282 grams and DHA 0.144-0.309 grams per 100 mL for 28 days may slow the progression of grade II or higher pressure ulcers when compared with standard formula (89370). In patients with acute lung injury, other preliminary clinical research shows that giving a specific enteral emulsion (Oxepa, Ross Laboratories) providing fish oil, borage oil, and vitamins A, C and E for 7 days does not improve the healing of existing pressure ulcers when compared with a control enteral formula. Although the number of pressure ulcers in the group given the GLA-containing formula was lower when compared with the control formula, these patients also seemed to have fewer pressure ulcers at baseline and no statistical comparison was conducted. The clinical significance of this finding is unknown (105252). Topical fish oil has also been evaluated. One small clinical study shows that applying fish oil dressing once daily to the heels of immobile intensive care unit patients for 7 days does not reduce the risk for heel pressure ulcers when compared with olive oil dressing (102392). However, other clinical research in patients in the ICU shows that applying fish oil by hand to the sacrum for 30 seconds daily for up to 6 days modestly reduces the incidence of pressure ulcers when compared with soybean oil or routine care only. However, applying fish oil reduces the risk of pressure ulcers when compared with routine care, not when compared with soybean oil (110344).
• Prostate cancer. It is unclear if oral fish oil is beneficial for improving quality of life in patients with prostate cancer undergoing a prostatectomy. Details: Clinical research in patients with prostate cancer shows that taking fish oil 3.75 grams (75% EPA and 10% DHA) daily, for approximately 14 months starting 7 weeks prior to radical prostatectomy, does not improve most prostate cancer-specific quality of life measures when compared with placebo. However, urinary function was improved 12 months after surgery (110353).
• Psoriasis. It is unclear if oral or topical fish oil is beneficial for the treatment or prevention of psoriasis. Intravenous fish oil seems to reduce symptoms in patients with acute, extended guttate psoriasis or chronic plaque psoriasis. Details: Despite some promising, low-quality studies, taking fish oil orally doesn't seem to have a significant effect on psoriasis severity (1035,8708,66585,66157,66233,102393). However, when administered in combination with sub-erythemal ultraviolet B (UVB) therapy, oral fish oil therapy providing EPA 3.6 grams and DHA 2.4 grams daily for 15 weeks seems to decrease the total body surface area of psoriasis when compared with placebo (66220). Topical fish oil has also been evaluated. Applying fish oil under an occlusive dressing for 6 hours daily for 4 weeks seems to improve scaling, but not erythema, in patients with psoriasis when compared with liquid paraffin (65575). The effect of oral fish oil on psoriasis prevention has been investigated in a large clinical trial of approximately 25,000 older adults. Taking fish oil 1 gram daily for 5 years providing EPA 0.46 grams and DHA 0.38 grams alone or in combination with vitamin D3 2000 IU daily does not reduce the risk of developing definite or probable psoriasis when compared with placebo (107184). Although this study was large, the primary endpoint was the effect of taking fish oil and/or vitamin D on the development of autoimmune diseases as a group. The number of patients with a specific autoimmune disease such as psoriasis was relatively small.
• Raynaud syndrome. It is unclear if oral fish oil is beneficial in patients with this condition. Details: A small clinical trial shows that taking fish oil orally containing EPA 3.96 grams and DHA 2.64 grams daily for 12 weeks can improve tolerance to cold and delay the onset of vasospasm in people with primary Raynaud syndrome; however, people with Raynaud syndrome caused by progressive systemic sclerosis don't seem to respond to fish oil supplements (7573).
• Salicylate intolerance. It is unclear if oral fish oil is beneficial in patients with salicylate intolerance. Details: A case series including three patients suggests that taking fish oil 10 grams daily in divided doses for 6-8 weeks might improve symptoms of salicylate intolerance (17410). High-quality, prospective research is needed to confirm this finding.
• Sarcopenia. There is conflicting evidence as to whether oral fish oil improves muscle strength in adults with sarcopenia. Details: A meta-analysis of clinical trials shows that taking omega-3 fatty acids improves lean body mass, skeletal muscle mass, and quadriceps function in older adults. Although most studies used eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), a few studies used EPA alone and others used alpha-linolenic acid (107195). Also, small clinical trials in older adults involving fish oil and increased dietary omega-3 intake show that fish oil, when used alone or in combination with a resistance exercise program, may have a small effect on some measures of muscle strength and the timed up-and-go test (89368,105222,109309,110335). However, one large study included in the most recent meta-analysis (107195) shows that fish oil is not beneficial for improving muscle strength in older adults. This large, high-quality clinical study in over 1,600 elderly adults shows that taking fish oil, providing DHA 800 mg and EPA 225 mg daily for 3 years, with or without physical activity and counselling, does not improve chair stand test performance or handgrip strength when compared with placebo and lifestyle interventions (102398). Also, an additional small clinical trial in older healthy adults shows that taking fish oil 3 grams daily for 18 weeks in addition to resistance training does not affect strength or functional ability when compared with resistance training plus placebo (98244).
• Schizophrenia. It is unclear if oral fish oil is beneficial in patients with schizophrenia. Details: There is contradictory evidence about the effects of fish oil in patients following a single episode of psychosis. A preliminary clinical study shows that taking fish oil containing 2.2 grams of EPA and DHA daily for 26 weeks modestly reduces negative and positive symptoms and improves functioning when compared with olive oil placebo. All patients were stabilized on antipsychotic medications (97183). However, conflicting evidence exists. One small clinical study shows that taking alpha-lipoic acid 150 mg, EPA 1000 mg, and DHA 500 mg twice daily does not prevent 2-year cumulative relapse or delay relapse when compared with placebo in patients who responded well to antipsychotic treatment after a single episode of psychosis (90675). A meta-analysis of these two studies shows that taking fish oil modestly reduces negative and positive symptoms and improves functioning when compared with placebo (105217). A small clinical trial shows that taking fish oil containing DHA 360 mg and EPA 540 mg daily for 12 weeks does not improve most symptoms of schizophrenia, although it may modestly reduce aggression when compared with placebo (98256). Due to the general lack of supporting evidence related to the use of omega-3 fatty acids for schizophrenia, the Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids in doses of 1-2 grams are not recommended for adjunctive or monotherapy use in these patients (110318).
• Sepsis. It is unclear if oral fish oil is beneficial in patients with sepsis. Details: Meta-analyses of generally low-quality clinical trials show that parenteral or enteral supplementation with lipid emulsions containing refined fish oil or other omega-3 fatty acids reduces the duration of stay in the intensive care unit (ICU) and the hospital by about 4 and 10 days, respectively, and reduces the need for mechanical ventilation by about 2 days when compared with placebo or no supplementation in patients with sepsis (98253,105221,109305). Also, although an earlier meta-analysis disagrees (98253), most meta-analyses show that use of fish oil-containing nutrition supplementation reduces mortality by up to 26% (105221,109305). This discrepancy may be related to the form of the lipid emulsion. One sub-analysis shows no beneficial effect from enteral supplementation with lipid emulsions containing fish oil. Only parenteral supplementation reduces mortality by 32% (109305). However, clinical research in patients with sepsis shows that supplementing with lipid emulsions containing refined fish oil does not prevent brain injury or delirium when compared with control (89323).
• Sickle cell disease. It is unclear if oral fish oil is beneficial in patients with sickle cell disease. Details: Preliminary clinical research shows that taking menhaden fish oil 0.25 grams/kg containing 12% EPA and 18% DHA daily for one year reduces the frequency of severe pain episodes when compared with olive oil in patients with sickle cell disease (65510).
• Stroke. It is unclear if oral fish oil is beneficial in the secondary prevention of stroke or for improving recovery from a stroke. Oral supplemental fish oil does not seem to be beneficial in the primary prevention of stroke. Details: Taking a fish oil SUPPLEMENT does not seem to be beneficial for primary prevention of stroke. Clinical research shows that taking a fish oil supplement 1 gram or 4 grams daily does not reduce the risk of stroke (2307,66185,103491). In 2017, the American Heart Association (AHA) published a science advisory stating that fish oil supplements should not be used for primary prevention of stroke in patients at high risk for CVD, as the cumulative evidence shows no benefit (93568). Furthermore, a 2018 meta-analysis including 24 studies and over 79,000 patients with or without CVD confirms that taking fish oil SUPPLEMENTS does not reduce the risk of ischemic or hemorrhagic stroke (98231). The effect of DIETARY fish oil for the primary prevention of stroke is controversial. Higher serum levels of fish oil have been associated with a decreased risk of stroke (7372). Early research found that consuming fish oil from dietary sources at least once weekly is associated with a 27% reduced risk of ischemic stroke (7373). However, the method of preparing fish may be important. Eating tuna or other broiled or baked fish has been associated with lower risk of ischemic stroke, while fried fish or fish sandwiches has been associated with higher risk of ischemic stroke in elderly people (12923). There has also been some concern that consumption of very high amounts of fish oil from dietary sources might increase the risk of stroke. People who eat more than 46 grams daily of fish appear to be nearly twice as likely to have an ischemic or hemorrhagic stroke (7603,7610,8699); however, these findings are questionable due to poor study design. In 2018, the American Heart Association (AHA) issued a science advisory recommending that patients consume 1-2 weekly servings of non-fried fish in place of less healthy protein options for the primary prevention of ischemic stroke (97185). However, dietary intake of fish oil may not be beneficial for stroke prevention in all patients. A 2018 meta-analysis including 4 studies and over 10,000 patients shows that increased dietary fish oil intake does not reduce the risk of stroke (98231). The majority of the studies included in this meta-analysis evaluated only patients with existing CVD. Therefore, it is possible that increased dietary intake of fish oil may not be beneficial in patients with a history of CVD. There is currently not enough reliable information available to know if increased intake of fish oil, either as part of the diet or as a supplement, has any benefit for stroke prevention in people who have already had a stroke (secondary prevention). Fish oil has also been evaluated for the improvement of symptoms in patients who are post-stroke. A meta-analysis of the available clinical research shows that due to the heterogeneity and low quality of the available clinical research, it is unclear if fish oil supplements are beneficial for stroke recovery, including mood, mobility, and performance on the Glasgow Outcome Scale, or for the prevention of vascular-related death when compared with placebo or control (102399). One clinical study shows that taking fish oil 1 gram daily, starting before the stroke and continuing for a total median duration of 5.3 years, does not improve functional limitations or physical disabilities over a median 1.4 years after the first stroke (104550). However, the data was heterogeneous in this study and it is unclear what effects, if any, post-stroke supplementation of fish oil might have on these outcomes.
• Systemic lupus erythematosus (SLE). It is unclear if oral fish oil is beneficial in patients with SLE. Details: A meta-analysis of five low-quality randomized controlled trials shows that taking fish oil for 12-26 weeks modestly reduces SLE symptoms (104548). However, results from individual studies are mixed (7571,7572,12925,12953,104548). A specific fish oil supplement (MaxEPA) 3-20 grams daily, alone or along with copper 3 mg daily, has been used in some studies for 24-34 weeks (7572,12953).
• Ulcerative colitis. It is unclear if oral fish oil is beneficial in patients with ulcerative colitis. Details: Some clinical research shows that taking fish oil (HiEPA) providing 4.5 grams of EPA daily for 12 months can reduce corticosteroid requirements in adults with ulcerative colitis. However, fish oil does not seem to reduce relapse rates in these patients (1040). Other clinical research shows that taking fish oil 4.2 grams daily for 8 months reduces the symptoms of ulcerative colitis when compared with placebo (65620). However, another clinical study shows that a specific commercial fish oil supplement (MaxEPA, Seven Seas Ltd) does not reduce symptoms such as disease relapse, stool frequency, rectal bleeding, or rectal histology when compared with placebo (1037). Overall, a meta-analysis of clinical research shows that fish oil does not reduce the relapse rate of ulcerative colitis when compared with control (65786,105224). Although population research has found that habitual intake of fish oil supplements is associated with a modestly reduced risk of ulcerative colitis (109303), a meta-analysis of two clinical trials shows that taking omega-3 fatty acids for about 1 year does not reduce the likelihood of an ulcerative colitis diagnosis when compared with a control group receiving monounsaturated fats (105224). Fish oil has also been evaluated in combination with other ingredients. One clinical trial shows that taking a supplement containing fish oil in combination with fructo-oligosaccharides, gum arabic, vitamin E, and vitamin C might reduce corticosteroid requirements in patients with ulcerative colitis; however, it doesn't seem to reduce disease activity or improve histology when compared with placebo (13757).
• Upper respiratory tract infection (URTI). It is unclear if oral fish oil is beneficial for URTI prevention or treatment. Details: One small clinical trial in healthy athletes shows that consuming a drink fortified with docosahexaenoic acid (DHA) 550 mg, eicosapentaenoic acid (EPA) 550 mg, vitamin D3 10 mcg, and whey protein 8 grams twice daily for 16 weeks does not reduce the incidence or duration of URTIs when compared with placebo (98243). However, a large clinical trial shows that taking fish oil (Incromega) 2.4 grams daily, providing 55% EPA and 37% DHA, starting at gestational week 24 and continuing until one week after birth, reduces the risk of developing croup by 38% in the offspring aged up to 3 years when compared with olive oil as placebo. This risk reduction remained after adjusting for the use of vitamin D 2800 IU daily, as well as for concomitant persistent wheeze and/or lower respiratory tract infections (109304).
• Venous thromboembolism (VTE). It is unclear if dietary fish or omega-3 fatty acids are beneficial in VTE prevention. Details: A meta-analysis of population research has found that the highest fish consumption is not associated with risk of VTE when compared with the lowest. However, overall intake of omega-3 fatty acids was associated with a small reduction in risk of VTE, as well as a modest reduction in risk of recurrent VTE (105223).
• Vitamin D deficiency. It is unclear if fish oil is beneficial for vitamin D deficiency. Details: A meta-analysis of clinical research shows that taking omega-3 fatty acid supplements for at least 8 weeks modestly increases 25-hydroxyvitamin D levels by an average of 3.8 ng/mL. A sub-group analysis shows that this benefit is limited to patients with vitamin D deficiency (105215). More evidence is needed to rate fish oil for these uses.

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POSSIBLY EFFECTIVE

• Coronary heart disease (CHD). Supporting, but not conclusive, evidence suggests that consuming fats and oils rich in oleic acid might reduce the risk of CHD (26466,95745,98563,101821). However, the relationship between blood levels of oleic acid and risk of CHD or CVD is unclear (101832,101834,101838). In 2018, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that replacing dietary fats and oils higher in saturated fat with oils containing at least 70% oleic acid may reduce the risk of CHD. To achieve this benefit, high-oleic acid containing oils should not increase total daily energy intake. The suggested daily dietary intake is about 20 grams (1.5 tablespoons) of high oleic acid oils in place of other fats and oils. These oils include olive oil, high-oleic acid sunflower oil, and high-oleic acid canola oil (98563). A meta-analysis of clinical studies shows that replacing 7.5% of energy from partially hydrogenated vegetable oils with high oleic acid sunflower oil can reduce coronary heart disease risk by about 9% to 19%. Furthermore, analysis of results from observational studies found that replacing partially hydrogenated oil with high oleic acid sunflower oil is associated with a 16% to 35% reduction in the risk of coronary heart disease events (95745). Clinical research in patients with cardiovascular disease (CVD) risk shows that taking high-oleic acid canola oil 60 grams per 3000 kcal of energy daily as part of a fixed composition diet for 4-6 weeks reduces the Framingham 10-year coronary heart disease risk scores by 6.8% compared to baseline (26466,101821). However, taking the high-oleic acid canola oil is no more effective than regular canola oil, which contains approximately 62% oleic acid (26466,101821). The relationship between blood levels of oleic acid and risk of CHD or CVD is unclear. While some population research has found that having the highest blood levels of oleic acid is associated with an increased risk of CVD when compared to having the lowest blood levels of oleic acid, other research suggests an inverse association or no association at all (101832,101834,101838). One study has found that having the highest blood levels of oleic acid is associated with a 1.4- to 2-fold increased risk of heart failure, other cardiovascular events, and all-cause mortality (101832). In contrast, another found that the highest blood levels of oleic acid is associated with a 73% reduced risk of having a stroke (101838). A third study found no association at all between plasma levels of oleic acid and risk of heart failure (101834). The clinical significance of these findings is unclear, and results should not necessarily be extrapolated to dietary oleic acid (101832). While plasma oleic acid levels seem to be a weak indirect marker of moderate to high olive oil use, it is also a weak marker of intake of butter and avian fats (101838). Furthermore, there is no clear evidence that plasma levels of oleic acid directly correlate with dietary oleic acid, especially where dietary oleic acid intake is relatively low (101832). As a non-essential fatty acid, oleic acid is endogenously synthesized in the liver from saturated fats (101832,101834,101838).
• Hypercholesterolemia. Evidence from small studies shows that consuming oils rich in oleic acid as part of the diet in place of other dietary fats may improve cholesterol levels (21698,26466,67569,101821). Preliminary clinical research in patients with hypercholesterolemia shows that consuming oleic acid as part of a high oleic sunflower oil- or high oleic canola oil-rich diet for 3-4 weeks decreases total and low-density lipoprotein (LDL) cholesterol levels by a moderate amount when compared with diets rich in palm oil, medium-chain triglycerides, or a blend of fats found in a regular Western diet (21698,67569). Other clinical research in patients with at least one cardiovascular risk factor shows that consuming oleic acid as part of high oleic acid canola oil for up to 4 weeks reduces total cholesterol by up to 9.4% and LDL cholesterol by up to 12.5% compared to baseline or a diet higher in saturated fats. However, taking the high oleic acid canola oil is no more effective than regular canola oil, also a source of oleic acid (26466,101821).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bladder cancer. Population research has found that the highest blood levels of oleic acid are associated with a 46% decreased risk of having bladder cancer when compared to the lowest blood levels (101844). However, plasma oleic acid levels are only a weak indirect marker of dietary intake of oleic acid. As a non-essential fatty acid, oleic acid is endogenously synthesized in the liver from saturated fats (101832,101834,101838). The effect of oleic acid supplementation on bladder cancer risk is unknown.
• Breast cancer. Population research has found no association between dietary fatty acid intake, including oleic acid, and the risk of breast cancer (96528). The effect of oleic acid supplementation on breast cancer risk is unknown.
• Depression. An observational study in perimenopausal patients aged 42-52 years has found that increasing dietary intake of oleic acid is associated with an increase in depression symptom scores. The odds ratio for depressive symptoms was approximately 2-fold higher for the highest quartile of oleic acid intake when compared with the lowest quartile (108924).
• Diabetes. A small clinical trial in patients with type 2 diabetes shows that taking oleic acid as part of a low-fat diet containing 15% monounsaturated fatty acids for 3 weeks does not alter levels of total or low-density lipoprotein (LDL) cholesterol or the change in LDL oxidation when compared with taking linoleic acid as part of a low-fat diet containing 15% polyunsaturated fatty acids (101847).
• Diarrhea. Preliminary clinical research in patients with chronic diarrhea shows that taking oleic acid 1.6 or 3.2 mL before a meal reduces bowel movements over the next 24 hours by approximately 22% compared with taking no oleic acid. Intestinal transit time was also increased by 28 and 54 minutes, respectively (101848). Since the specific cause of chronic diarrhea differed among the patients included in this study, it is unclear if oleic acid is beneficial for most or only certain forms of chronic diarrhea.
• Hypertension. Preliminary clinical research in patients with central obesity and at least one other cardiovascular disease risk factor shows that taking oleic acid as high oleic acid canola oil for 4 weeks does not reduce systolic or diastolic blood pressure compared to baseline (26466).
• Obesity. Preliminary clinical research in patients with central obesity shows that taking oleic acid as high oleic acid canola oil for 4 weeks reduces abdominal fat mass by approximately 0.1 kg compared to baseline (98564). Other preliminary clinical research in patients with central adiposity and at least one other risk factor of cardiovascular disease shows that taking high oleic acid canola oil for 6 weeks reduces total and low-density lipoprotein (LDL) cholesterol by 3.4% and 5.6%, respectively, compared with a control oil lower in monounsaturated fats and higher in saturated fats (101821). However, in these studies, taking the high oleic acid canola oil is no more effective than regular canola oil, also a source of oleic acid (98564,101821). Any effect of oleic acid itself is unclear.
• Pancreatic cancer. The association between dietary oleic acid and pancreatic cancer risk is unclear. Most population research shows no association between dietary oleic acid and pancreatic cancer risk. However, one large population study has found that the highest intake of oleic acid, at least 23.7 grams daily, is associated with a 71% decreased risk of pancreatic cancer when compared with the lowest intake. The benefit is only observed in overweight or obese individuals. (101833). The effect of oleic acid supplementation on pancreatic cancer risk is unknown.
• Short bowel syndrome. A small preliminary clinical trial in patients with surgical short bowel syndrome of at least 2 years shows that taking oleic acid 3.2 mL in 50 mL of a beverage daily for 3 months does not reduce intestinal transit time or diarrhea, or improve body weight, when compared with placebo. In addition, energy absorption was reduced by 14% (101843).
• Stroke. Population research has found that highest blood levels of oleic acid are associated with a 73% reduced risk of stroke when compared with lowest blood levels of oleic acid (101838). However, plasma oleic acid levels are only a weak indirect marker of dietary oleic acid. As a non-essential fatty acid, oleic acid is endogenously synthesized in the liver from saturated fats (101832,101834,101838). The effect of oleic acid supplementation on stroke risk is unknown.
• Ulcerative colitis. Although some contradictory evidence exists, a large population study has found that, after adjusting for dietary intake of omega-3 fatty acids, highest dietary intake of oleic acid is associated with a 97% reduced odds of developing ulcerative colitis when compared with the lowest intake (101846). The effect of oleic acid supplementation on ulcerative colitis risk is unknown.

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EFFECTIVE

• Vitamin A deficiency. Oral vitamin A is effective for treatment and prevention of vitamin A deficiency. Details: Clinical and observational research in children shows that taking vitamin A orally is effective for preventing and improving symptoms of vitamin A deficiency, including xerophthalmia, night blindness, and Bitot's spots (82329,82689,82710,90773). Vitamin A deficiency can occur due to abnormal storage and transport of vitamin A in people with abetalipoproteinemia, protein deficiency, diabetes mellitus, hyperthyroidism, fever, liver disease, and cystic fibrosis (7135). However, research suggests that supplementation with vitamin A may not be necessary for most newborns with vitamin A deficiency. An observational study in newborns with vitamin A levels of 0.43-0.59 mcmol/L or >0.59 mcmol/L found that vitamin A levels increased naturally over the first six months of life, regardless of oral vitamin A supplementation. However, in infants with very low vitamin A levels (<0.43 mcmol/L), vitamin A supplementation was associated with significant increases in vitamin A levels at 6 months of age when compared with no supplementation, suggesting that only newborns with very low vitamin A levels should receive oral vitamin A (107298).

POSSIBLY EFFECTIVE

• Aging skin. Topical vitamin A (retinol) formulations seem to improve symptoms of aging skin, such as wrinkles and mottled pigmentation. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of aging facial skin (103711). However, this drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Although research evaluating non-prescription topical vitamin A shows benefit for reducing wrinkles, most studies have been small and used different formulations. One small study in adults over 40 years of age shows that applying a pea size amount of 0.075% retinol cream to the face daily for 26 weeks seems to reduce deep and fine wrinkling when compared with placebo. Applying a lower dose of 0.04% retinol cream for 13 weeks seems to reduce fine wrinkling to a lesser degree, with no effect on deep wrinkles, when compared with placebo cream (104458). Another small clinical study in adults over 80 years of age shows that applying 2 mL of retinol 0.4% lotion to the upper arm up to 3 times weekly for 24 weeks reduces visible wrinkles when compared with placebo (94683). Two small studies in females ages 33 to 65 show that applying retinol 0.15%, 0.3% and 0.5% in liquid crystal formulation once daily to the face for 2-3 months improves skin pigmentation, elasticity, and wrinkles when compared with baseline (103680,104464). The validity of these two studies is limited by the lack of a comparator treatment. Topical vitamin A is frequently combined with other ingredients in commercial formulations; however these combinations have rarely been studied. A small clinical study in adults over 35 years with skin aging shows that applying a cream containing retinol 0.5%, niacinamide, resveratrol, and hexylresorcinol seems to improve wrinkling and skin tone when compared with baseline (104455). Another small preliminary clinical trial in adults ages 35-65 years with periorbital lines and wrinkles shows that applying a cream containing retinol modestly improves dryness, puffiness, redness, and darkness when compared with baseline. The retinol was conjugated with lactic acid, and the cream contained other nutrient and herbal ingredients It was applied around the eyes each evening, sometimes used in combination with another product each morning (109747).
• Bronchopulmonary dysplasia. Intramuscular vitamin A may reduce the risk of bronchopulmonary dysplasia (BPD) in very low birth weight infants when given at a dose of 5000 IU three times weekly for 28 days. Lower doses do not seem to be effective. It is unclear if enteral vitamin A is beneficial for BPD. Details: A meta-analysis of 6 clinical trials in premature infants shows that intramuscular administration of vitamin A every other day or three times weekly for 28 days reduces the risk of BPD by around 33% when compared with control (107297). The results from this meta-analysis are primarily driven by a modestly sized clinical trial in very low birth weight infants which shows that intramuscular administration of vitamin A 5000 IU three times weekly for 28 days reduces the risk of BPD by 15% when compared with a sham control (82195). A subgroup analysis of this trial suggests that infants with the lowest BPD risk estimate based on gestational age, birth weight, sex, ethnicity, and oxygen levels 24 hours after birth appear to benefit more from vitamin A therapy than those with higher BPD risk estimates (107296). Previous research in this area utilized a lower dose of only 2000 IU every other day for 28 days, and showed no significant improvement in the rate of BPD (82331,82613). The evaluation of a higher dose was prompted by research noting that the lower doses evaluated in these earlier studies were unable to achieve serum retinol concentrations above 25 mcg/dL, while doses at or above 5000 IU three times weekly could reach this level (82731). Enteral vitamin A has also been investigated. Meta-analyses of two clinical trials show that supplementation with vitamin A at an average of 5,000 IU daily, staring within four days of birth, does not reduce the incidence of BPD when compared with placebo (109750,109753).
• Diarrhea. Vitamin A seems to reduce the incidence of diarrhea in young children. However, it is unclear if oral vitamin A while breastfeeding is beneficial for preventing diarrhea in nursing infants. Details: A meta-analysis of clinical research in children up to age 5 shows that vitamin A supplementation reduces the incidence of diarrhea by 15% and mortality related to diarrhea by 12% when compared with control, usually placebo or no supplementation (109755). However, one small clinical trial in breastfeeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of diarrhea in the nursing infants when compared with placebo (107293).
• Measles. High-dose oral vitamin A seems to reduce mortality from measles in children under 2 years of age and may also reduce the incidence of measles in children up to 5 years of age. Details: Meta-analyses of clinical research show that taking vitamin A does not reduce mortality in children with measles when all ages and/or doses are considered (82373,82502,95055,109755). However, in children with measles who are less than 2 years of age, taking vitamin A 200,000 IU orally for at least two doses seems to reduce mortality by up to 83% when compared with placebo (82373,82502). Also, taking vitamin A seems to reduce the incidence of measles in children ages 6 months to 5 years (95055,109755).
• Night vision. Oral vitamin A as retinyl palmitate seems to reduce night blindness during pregnancy in malnourished patients. Details: Clinical research shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related night blindness by 37% in malnourished patients (6154). Some evidence suggests that zinc supplements might potentiate the effects of vitamin A in restoring sight in zinc-deficient pregnant patients affected by night blindness (8630).
• Oral leukoplakia. High-dose oral vitamin A seems to reduce oral leukoplakia lesions in patients that chew tobacco and/or betel nut. Details: Clinical research in patients with tobacco and/or betel nut chewing habits shows that taking oral vitamin A 200,000-300,000 IU weekly for 6-12 months seems to result in remission of leukoplakia lesions in over 50% of participants when compared with placebo (34674,82617). However, it is unknown if vitamin A prevents the development of oral cancer from oral leukoplakia lesions.
• Overall mortality. In children at risk for vitamin A deficiency, oral vitamin A seems to reduce mortality. However, it does not seem to reduce mortality in healthy adults. Details: Despite previous debate on whether the programs supplying high-dose vitamin A in low- and middle-income countries with prevalent vitamin A deficiency are safe and effective for reducing child mortality, most experts, including World Health Organization, recommend high-dose vitamin A supplementation for those children (95055,95724,97170,109755). In 2010, a meta-analysis of 17 trials involving over 194,000 patients, showed that vitamin A supplementation reduces all-cause mortality by about 24% in children 6 months to 5 years of age (82559). However, some research published after this meta-analysis shows conflicting results (90773,90777). In fact, the largest clinical trial conducted to date (Deworming and Enhanced Vitamin A; DEVTA), which was published after the analysis and involved one million preschool children, suggests that high-dose vitamin A supplementation does not reduce mortality (90773). However, this trial was limited due to under-resourcing and undetermined patient consent and treatment compliance (90773). Furthermore, in 2017, a meta-analysis including the DEVTA trial along with 46 additional studies involving over 1.2 million preschool children, shows that vitamin A supplementation does reduce all-cause mortality by 12% when compared with control (95055). This meta-analysis was updated in 2022 with no additional studies or changes in conclusions (109755). Adult mortality is not reduced by vitamin A supplementation. In fact, some evidence even shows that vitamin A supplementation increases mortality when administered to healthy adult patients or those with a stabilized disease (15305,34622,90775).
• Postpartum complications. Oral vitamin A seems to reduce postpartum diarrhea and mortality in malnourished patients. Details: A large clinical study in malnourished pregnant patients in Nepal shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before, during, and after pregnancy reduces the occurrence of blood and mucus in the stool by 93% and the occurrence of diarrhea by up to 90% during the first 6 months postpartum when compared with placebo (2581). Another clinical study in the same population shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related mortality by 40% when compared with placebo (6153).
• Retinitis pigmentosa. Oral vitamin A supplementation in children with retinitis pigmentosa seems to slow retinal function decline. Details: Observational and clinical research in children with retinitis pigmentosa shows that taking an age-adjusted dose of vitamin A, up to a maximum dose of 15,000 IU daily, modestly attenuates the decline in retinal function when compared with control (83,97167,103677).
• Ulcerative colitis. Oral vitamin A supplementation in patients with ulcerative colitis seems to improve clinical response and mucosal healing. Details: A clinical study in adults with symptomatic ulcerative colitis despite treatment with 5-aminosalicylic acid shows that taking vitamin A 25,000 IU daily for 2 months reduces disease severity and increases the rate of clinical response and mucosal healing when compared with placebo. The number needed to treat (NNT) for clinical response is 3; the NNT for mucosal healing is 5 (100329).
• Wrinkled skin. Topical vitamin A (retinol) formulations seem to improve photodamage and wrinkles. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of facial skin (103711). This drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Still, some research in females ages 35-65 with moderately wrinkled and photoaged skin suggests that commercially available retinol formulations might reduce wrinkles and skin roughness similarly to tretinoin. One study used retinol serum starting at a concentration of 0.25% and increased to 1% over 3 months, compared with tretinoin cream 0.025% gradually increased to 0.1% (103671), while another study compared a gradual release tri-retinol 1.1% cream applied daily for 3 months to tretinoin 0.025% cream (104456). Commercial retinol also seems to be beneficial when compared with placebo. A small study in adults over 40 years old with photodamaged skin shows that applying stabilized retinol 0.1% to the face daily for one year improves wrinkles and mottled pigmentation in over 50% of the participants when compared with a placebo treatment (104463).

POSSIBLY INEFFECTIVE

• Atopic disease. Supplementation with oral vitamin A does not seem to reduce the risk of atopy. Details: Clinical research in infants born in Guinea-Bissau shows that a single dose of vitamin A does not reduce the incidence of atopy when compared with placebo (90779,90780). Furthermore, giving a single dose of vitamin A to some infants, such as low birth weight infants and infants given Bacille Calmette-Guerin (BCG) vaccination, was associated with increased atopy and wheeze (90779).
• Fetal and premature infant mortality. Giving oral vitamin A to malnourished adults during pregnancy and postpartum does not seem to reduce fetal, early infant, or first year mortality. Giving oral or intramuscular vitamin A to the infant also does not seem to reduce mortality in most patients. Details: Most meta-analyses of clinical research in malnourished patients suggest that vitamin A supplementation during pregnancy or postpartum does not reduce fetal, early infant, or first year mortality (6152,34601,34602,34627,82479,82566,82567,90774,90776,90782,90784,95057,109750,109753). Also, giving vitamin A supplements or intramuscular vitamin A to low birth weight infants does not appear to reduce mortality in these patients (82195,82431,82498,90778,90781,95053,107296,107297). Furthermore, vitamin A supplementation in term infants from low or middle income countries also does not appear to reduce the risk of mortality at 6 or 12 months of age when compared with placebo (95054,103674). Some evidence from a meta-analysis of clinical research shows that vitamin A supplementation may reduce the risk of mortality at 6 months in Asian infants, although it appears to increase the risk of mortality at 6 months in studies conducted in Africa. It also appears to increase the risk of mortality in female term infants by 12 months (95054).
• Intestinal parasite infection. Oral high-dose vitamin A does not seem to prevent reinfection with intestinal parasites. Details: Clinical research in children living in Malaysia that were given albendazole 400 mg daily for 3-4 days for parasitic worms, shows that adding a single dose of vitamin A 200,000 IU does not help to prevent reinfection when compared with placebo (90772).
• Melanoma. Oral vitamin A in patients with resected melanoma does not seem to improve survival and disease recurrence. Details: A clinical study in patients with completely resected melanoma shows that taking vitamin A 100,000 IU daily for 18 months does not increase disease-free survival when compared with no supplementation (82670).
• Miscarriage. Oral vitamin A given to the mother does not prevent miscarriage or stillbirth. Details: A meta-analysis of clinical research shows that maternal supplementation with oral vitamin A, either alone or in combination with other vitamins, prior to or during early pregnancy does not reduce the risk of miscarriage or stillbirth when compared with control (104462).
• Sepsis. Most research shows that oral vitamin A does not reduce the risk of sepsis in premature infants. Details: A meta-analysis of three clinical trials in premature infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the incidence of sepsis when compared with placebo (109753).
• Tuberculosis. Oral vitamin A does not seem to improve tuberculosis disease duration or mortality. Details: Low levels of vitamin A are common in patients with tuberculosis. However, taking vitamin A 2000 IU to 200,000 IU by mouth for 2-24 months does not improve symptoms, decrease disease duration, or reduce mortality when compared with placebo in these patients (82570,103668,109754). This may be due to the fact that vitamin A levels may normalize following the initiation of tuberculosis treatment, even without additional vitamin A supplementation.

LIKELY INEFFECTIVE

• Head and neck cancer. Oral vitamin A taken for 2 years does not seem to improve survival or prevent head and neck cancer recurrence. Details: A large clinical study n patients with a history of head and neck cancer shows that taking vitamin A as retinyl palmitate 300,000 IU daily for 1 year, and followed by 150,000 IU daily for another year, does not reduce the risk of second primary tumors or tumor recurrence when compared with placebo. Also, vitamin A does not seem to improve survival or event-free survival (1710).
• HIV transmission. Oral vitamin A does not reduce vertical HIV transmission risk. There is some concern that vitamin A might increase HIV transmission through breast milk. Details: Observational and intervention research shows that taking vitamin A orally does not decrease the risk of HIV transmission to the fetus during pregnancy, to newborns during delivery, or to infants during early breast-feeding (6376,82470,95059). Preliminary clinical research also shows that vitamin A supplementation of pregnant adults with HIV infection might increase the risk of HIV transmission to their babies through breast milk (9801).
• Lower respiratory tract infections. Oral vitamin A does not reduce the risk for lower respiratory tract infections in children. It is unclear if supplementation of oral vitamin A while breast-feeding reduces the risk of lower respiratory tract infections in nursing infants. Details: Taking vitamin A by mouth does not prevent or reduce symptoms of lower respiratory tract infections, such as cough and fever, in children (82288,82443). Furthermore, some research shows that vitamin A is associated with a slight increase in the risk of respiratory tract infections when administered to children with adequate nutritional status (82288). Additionally, one small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of febrile illness or respiratory tract infections in the nursing infants when compared with placebo (107293).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although prescription vitamin A analogs are approved to treat acne, it is unclear if non-prescription topical vitamin A products help with acne symptoms. Details: The high-dose vitamin A analogs adapalene (Differin) and tazarotene (Tazorac) are prescription drugs approved by the US Food and Drug Administration for the treatment of acne (103712,103713). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol, which have not been extensively evaluated in clinical research. A small preliminary clinical trial in adolescents and young adults with mild to moderate acne shows that applying topical benzoyl peroxide 2.5% each morning and a topical retinol plus salicylic acid product each evening for 12 weeks modestly improves acne severity and other measures of complexion when compared with baseline. All patients also used the same cleanser twice daily (109748). The validity of this finding is limited by the lack of a comparator group.
• Alcohol-related liver disease. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with acute alcoholic hepatitis shows that taking vitamin A in combination with coenzyme Q10 and other vitamins and minerals daily for 6 months does not improve survival when compared with placebo (61392).
• Asthma. It is unclear if oral vitamin A is beneficial for preventing asthma in children. Details: An observational study in children has found that higher dietary intake of vitamin A is associated with a lower risk of asthma. Children in the highest quartile of vitamin A intake (median of 2267 IU daily) at 7 years of age had improved lung function and 32% lower odds of asthma at 11-14 years of age when compared with children in the lowest quartile of vitamin A intake (median of 870 IU daily) (107291).
• Atopic dermatitis (eczema). It is unclear if supplementation of oral vitamin A while breast-feeding is beneficial for preventing eczema in nursing infants. Details: One small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of eczema in the nursing infants when compared with placebo (107293).
• Autism spectrum disorder. It is unclear if oral vitamin A is beneficial for improving symptoms of autism. Details: Children with autism spectrum disorder are at increased risk for vitamin A deficiency, and vitamin A levels have been inversely associated with autism symptoms. Preliminary clinical research shows that taking a single dose of vitamin A 200,000 IU slightly improves emotional response, communication, and other symptoms when compared to baseline (97168). The lack of a control group limits the validity of these findings. Another preliminary clinical study in children with autism and vitamin A deficiency shows that taking vitamin A 50,000 IU weekly for 6 months, but not as a single dose of 200,000 IU, seems to improve social impairment scores when compared with control. Controls were children with autism without vitamin A deficiency that did not take a supplement (104459).
• Breast cancer. Although vitamin A intake has been associated with a reduced risk for breast cancer, it is unclear if vitamin A supplements are beneficial. Details: Epidemiological evidence has found an association between high intake of vitamin A and a reduced risk of breast cancer. A meta-analysis of epidemiological research has found that the adults with the highest intake of vitamin A, either from diet alone or also from supplements, reduces the odds of developing breast cancer by 16% when compared with the lowest intake (1444,34610,109752). However, the effects of supplemental vitamin A, specifically, are unclear.
• Cataracts. It is unclear if oral vitamin A is beneficial for cataract prevention. Details: A large-scale population-based study has found that high dietary intake of vitamin A is associated with a reduced risk of nuclear cataracts (6378). Also, other population research has found that the highest dietary intake of vitamin A is associated with a 17% lower risk of cataracts when compared with the lowest intakes (90786). However, there is conflicting evidence regarding the association between blood levels of vitamin A and the risk of cataracts (90786,90944). It is not known if supplemental vitamin A is beneficial.
• Cervical cancer. It is unclear if oral vitamin A is beneficial for cervical cancer prevention. Details: A meta-analysis of clinical research shows that increased vitamin A levels in the blood or higher vitamin A intakes are associated with a reduced risk of cervical cancer. However, this effect is observed when both forms of vitamin A, either retinol or carotenoids, are considered. When only the retinol form is considered, vitamin A supplementation does not seem to reduce the risk of cervical cancer (34613,109752). Also, a meta-analysis of epidemiological research has found that vitamin A intake, either from diet alone or supplements, does not affect the risk of cervical cancer (109752).
• Chemotherapy-induced diarrhea. It is unclear if oral vitamin A helps to prevent diarrhea caused by chemotherapy. Details: A very small clinical study in children receiving chemotherapy shows that taking vitamin A orally does not seem to prevent GI adverse effects, including diarrhea and mouth pain, when compared with control (9802).
• Child development. Oral vitamin A might improve growth and development in children with vitamin A deficiency, but not in those with good nutritional status. Details: Supplementing with vitamin A 60 mg for up to 9 years does not promote or improve child growth in children with appropriate nutritional status (20132). However, in children with vitamin A deficiency, supplementation with vitamin A may improve growth (82246).
• Chronic obstructive pulmonary disease (COPD). There is limited evidence on the oral use of vitamin A in patients with emphysema. Details: Observational research has found that consuming recommended amounts of vitamin A in the diet is associated with 33% lower odds of developing emphysema (103678).
• Colorectal adenoma. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination supplement containing selenium, zinc, vitamin A, vitamin C, and vitamin E orally daily for 5 years or until the recurrence of an adenoma reduces the risk of recurrent large-bowel adenomas by about 40% when compared with placebo in patients with large-bowel adenomas (92903). It is not clear if this benefit is due to vitamin A or other constituents.
• Colorectal cancer. It is unclear if oral vitamin A is beneficial for colorectal cancer prevention. Details: Taking vitamin A alone or in combination with beta-carotene does not seem to reduce the risk of colorectal cancer (12185).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral vitamin A improves recovery after CABG surgery. Details: Preliminary clinical research shows that taking vitamin A 5000 IU daily (as retinol palmitate) for 21 days starting on the day of CABG surgery reduces time in intensive care after surgery by 46% to 69% compared to a control group not given vitamin A (90783). Supplementation with vitamin A also improves total hospitalization time for those patients with adequate zinc status (90783).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin A is beneficial for the treatment of mild to moderate COVID-19. Details: Clinical research in COVID-19 outpatients treated with hydroxychloroquine shows that taking vitamin A 25,000 IU daily for 10 days modestly reduces the number of patients with symptoms of fever, body ache, and fatigue when compared with placebo. However, there was no effect on the number of patients with cough, shortness of breath, lack of appetite, chest pain, diarrhea, loss of smell, or headache (109745).
• Depression. It is unclear if oral vitamin A is beneficial for depression. Details: A meta-analysis of observational research has found that dietary intake of vitamin A is inversely associated with depression. The highest intake of vitamin A was associated with a 17% reduced risk of depression when compared with the lowest intake. Also, vitamin A intake was lower in individuals with depression (109743). The effect of vitamin A supplementation is unclear.
• Esophageal cancer. It is unclear if oral vitamin A is beneficial for esophageal cancer prevention. Details: Observational research has found that higher beta-carotene and vitamin A intake is associated with a reduced risk of esophageal cancer (34551,103675). However, evidence from higher-quality clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of esophageal cancer (12185).
• Gastric cancer. It is unclear if oral vitamin A is beneficial for gastric cancer prevention. Details: Taking vitamin A alone and in combination with beta-carotene does not seem to reduce the risk of gastric cancer (12185).
• Glaucoma. It is unclear if oral vitamin A is beneficial for glaucoma prevention. Details: A meta-analysis of observational research has found that a high dietary intake of vitamin A is associated with a 37% reduced risk of glaucoma when compared with a low intake (109742).
• HIV/AIDS. It is unclear if oral vitamin A is beneficial for improving HIV/AIDs outcomes. Details: A meta-analysis of clinical trials and population research shows that maternal vitamin A supplementation of mothers with poor vitamin A status at baseline does not influence child or maternal mortality, hospitalization rate, or HIV/AIDS progression. However, pediatric vitamin A supplementation seems to decrease mortality rates in children with HIV/AIDS when compared with placebo (34529,95059).
• HIV/AIDS-related diarrhea. It is unclear if oral vitamin A is beneficial for preventing diarrhea associated with HIV. Details: A large clinical trial shows that taking vitamin A can decrease the rate of diarrhea-specific mortality by up to 92% in vitamin A-deficient children with or without HIV/AIDS (1465). However, a meta-analysis of clinical research shows that taking vitamin A does not significantly reduce diarrhea-specific mortality when only children with HIV/AIDS are considered (82511). But vitamin A does appear to reduce overall mortality in these children by 50% to 63% (1465,82511).
• Human papillomavirus (HPV). It is unclear if topical or oral vitamin A is beneficial for the resolution of genital warts caused by HPV. Details: A meta-analysis of small clinical trials in patients with genital warts suggests that the oral prescription drugs isotretinoin and etretinate might promote resolution of warts when compared with baseline. However, the topical prescription drug tretinoin 0.05% cream does not seem to help (104460). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
• Infant development. It is unclear if intramuscular vitamin A improves the development of low birth weight infants. Details: A meta-analysis of clinical research shows that giving intramuscular vitamin A to very low birth weight infants reduces the risk of chronic lung disease at 36 weeks postmenstrual age by about 13% compared to control (95053). Preliminary clinical research also shows that giving intramuscular vitamin A along with inhaled nitric oxide gas for 3 weeks to low birth weight infants on mechanical ventilation might improve mental development at one year in some of these patients when compared with inhaled nitric oxide gas alone (90778). However, a meta-analysis of clinical research shows that intramuscular vitamin A does not improve neurodevelopment in very low birth weight infants (95053).
• Iron deficiency anemia. It is unclear if oral vitamin A is beneficial for the prevention or treatment of anemia due to iron deficiency. Details: Some research in children and pregnant adults without anemia shows that taking vitamin A increases plasma levels of hemoglobin and ferritin, and may reduce the risk of developing anemia (9518,34627). However, another study in pregnant patients, half of whom had anemia at baseline and half of whom did not have anemia, shows that taking 3000 mcg retinol orally in combination with iron and folate does not improve hemoglobin or erythropoietin concentrations when compared with taking iron and folate (9188). In preterm infants with existing anemia, taking vitamin A 5000 IU and vitamin B complex 40 mg daily improves serum ferritin, hemoglobin, and reticulocyte levels and reduces the need for blood transfusions when compared with taking either vitamin alone. Taking vitamin A alone, however, does not improve these outcomes (100330).
• Leukemia. It is unclear if oral vitamin A is beneficial for leukemia prevention. Details: Preliminary clinical research in adults with chronic myelogenous leukemia shows that taking a specific vitamin A product (Aquasol, Armour Pharmaceuticals) 50,000 IU orally daily in combination with busulfan therapy does not significantly increase progression-free survival or overall survival when compared with busulfan alone. Furthermore, supplementation with vitamin A plus busulfan seems to increase the percentage of patients who experience grade 2 toxicity by about 5-fold when compared with busulfan alone (82652).
• Liver cancer. It is unclear if oral vitamin A is beneficial for liver cancer prevention. Details: Population research has found that vitamin A supplementation or serum levels of vitamin A are not associated with the risk of liver cancer (97169).
• Lung cancer. It is unclear if oral vitamin A is beneficial for lung cancer treatment or prevention. Details: Population research has found that increased dietary intake of vitamin A is not associated with a reduced risk of lung cancer (35628). Furthermore, supplementation with vitamin A and beta-carotene seems to increase the risk of lung cancer in smokers or those exposed to asbestos (2642,34675). A large clinical trial in patients with existing lung cancer shows that vitamin A 300,000 IU daily for one year followed by 150,000 IU daily for a second year does not increase survival (1710). However, some clinical research shows that high-dose vitamin A 300,000 IU daily following curative lung cancer resection reduces the risk of new primary tumors in patients heavily exposed to tobacco (7875).
• Malaria. It is unclear if oral vitamin A is beneficial for reducing symptoms of malaria in young children. Details: Taking vitamin A orally seems to help decrease symptoms of malaria in children less than 3 years of age living in endemic areas (1464). However, other clinical research shows that single doses of vitamin A 100,000 to 200,000 IU do not improve coma resolution, convulsions, fever, parasite clearance, or mortality in infants and children less than 5 years of age with cerebral malaria (90785).
• Multiple sclerosis-related fatigue. It is unclear if oral vitamin A is beneficial for reducing fatigue in patients with multiple sclerosis. Details: Preliminary clinical research in patients with relapsing-remitting multiple sclerosis receiving interferon beta-1a shows that taking vitamin A 25,000 IU (as retinyl palmitate) (Zahravi Pharmaceutical) daily for 6 months followed by 10,000 IU daily for 6 months, improves physical, cognitive, and psychosocial fatigue when compared with placebo (95052).
• Necrotizing enterocolitis (NEC). A meta-analysis of several small clinical trials suggests that intramuscular vitamin A does not seem to prevent NEC. Details: A meta-analysis of 3 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 1500-5000 IU every other day or three times weekly for 28 days does not reduce the risk of NEC when compared with a control (107297).
• Non-Hodgkin lymphoma. It is unclear if oral vitamin A is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that intake of vitamin A at levels above 2330 mcg daily is associated with a 17% lower risk of non-Hodgkin lymphoma when compared with those whose daily intake of vitamin A is less than 642 mcg per day (90945).
• Nonmelanoma skin cancer. It is unclear if oral vitamin A is beneficial for nonmelanoma skin cancer prevention. Details: Observational research over 26 years found that higher dietary vitamin A intake is associated with a 12% reduced risk for cutaneous squamous cell carcinoma in healthy patients when compared with lower vitamin A intake (101673).
• Oral clefts. It is unclear if oral vitamin A is beneficial for oral cleft prevention. Details: A meta-analysis of observational research has found that periconceptional use of vitamin A, from diet and/or supplements, is associated with a 13% reduced incidence of cleft lip alone or with a cleft palate, but is not associated with the risk of cleft palate alone, in the child (109751).
• Osteoarthritis. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with osteoarthritis shows that taking a specific product containing vitamin A in combination with selenium, vitamin C, and vitamin E (Selenium ACE, Carls-Berghs Farmaceutiska AB) does not appear to alleviate symptoms when compared with placebo (74449).
• Ovarian cancer. It is unclear if oral vitamin A is beneficial for ovarian cancer prevention. Details: Most observational research has found that increased dietary intake of vitamin A is associated with a reduced risk of developing ovarian cancer (9193,103679,109752). The most recent meta-analysis of epidemiological research has found that adults with the highest intake of vitamin A, either from diet alone or supplements, reduces the odds of developing ovarian cancer by 19% when compared with the lowest intake (109752).
• Pancreatic cancer. It is unclear if oral vitamin A is beneficial for pancreatic cancer prevention. Details: A meta-analysis of observational research has found that higher intake of vitamin A is associated with a reduced risk of pancreatic cancer; however, this benefit appears to be limited to only hospital-based cases and studies conducted in Europe (95060). In contrast, a meta-analysis of clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of pancreatic cancer (12185).
• Parkinson disease. It is unclear if oral vitamin A prevents Parkinson disease development. Details: Population research has found that blood levels or dietary intake of vitamin A are not associated with the risk of Parkinson disease (91164).
• Photoreactive keratectomy. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking a specific product (Evitex capsules, Alcon) containing vitamin A along with vitamin E seems to improve healing after photoreactive keratectomy. High dose (50,000 to 75,000 IU) vitamin A in the form of retinol palmitate taken daily with vitamin E (alpha-tocopheryl nicotinate) 460-590 mg daily seems to accelerate re-epithelialization, reduce haze formation, and improve visual acuity in patients undergoing laser surgery for myopia (348).
• Pneumonia. Oral vitamin A does not seem to prevent mortality related to pneumonia in children. However, it is unclear if vitamin A reduces symptom severity and hospitalization in children. Details: Clinical research in children living in developing countries shows that taking vitamin A orally does not prevent mortality related to pneumonia (1466,82362,82504,82717,109749). However, the evidence related to symptom duration and severity is mixed. A large study and early meta-analyses show that vitamin A does not prevent pneumonia or decrease the severity or length of hospitalization in children with pneumonia (1466,82362,82504,82717). A more recent meta-analysis also shows that giving vitamin A to children at or below 5 years of age does not affect the duration of hospitalization (109755). The best evidence to date comes from a recent meta-analysis of randomized clinical trials. This meta-analysis shows that, when given in combination with conventional therapy to children up to 10 years of age, vitamin A reduces the duration of symptoms including fever, cough, lung rale, and shortness of breath, as well as the duration of hospitalization and time to a negative X-ray, when compared with conventional therapy alone (109749). However, the number of trials evaluating each endpoint is small and more research is needed to confirm these findings.
• Prematurity. It is unclear if vitamin A reduces the duration of hospitalization for premature infants. Details: A meta-analysis of four randomized controlled trials in preterm infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the duration of hospitalization when compared with placebo (109750).
• Prostate cancer. It is unclear if oral vitamin A is beneficial for prostate cancer prevention. Details: Observational studies suggest that dietary intake of vitamin A is not associated with a reduced risk of prostate cancer (14134).
• Psoriasis. It is unclear if topical vitamin A is beneficial for psoriasis symptoms. Details: The vitamin A analog tazarotene (Tazorac) is a prescription drug that is approved by the U.S. Food and Drug Administration to treat stable plaque psoriasis covering up to 20% body surface area (103713). This drug is not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
• Radiation proctopathy. It is unclear if oral vitamin A is beneficial for reducing chronic radiation proctopathy symptoms. Details: A small clinical study in patients experiencing chronic radiation proctopathy caused by pelvic radiotherapy shows that taking retinol palmitate 10,000 IU daily for 90 days might reduce rectal symptoms when compared with placebo (82350).
• Retinopathy of prematurity. Most small studies show that oral or intramuscular vitamin A does not reduce the risk of retinopathy of prematurity (ROP). Details: A meta-analysis of 4 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 2000-10,000 IU every other day or three times weekly, or oral vitamin A 2000 IU daily, for 28 days does not reduce the risk of ROP when compared with a control (107297). Another meta-analysis of clinical research shows that providing supplemental enteral vitamin A 1500 IU or an average of 5000 IU daily, starting within four days of birth, does not reduce the incidence of severe ROP (109750,109753). However, a very small clinical study in preterm infants, which was not included in the meta-analysis, shows that receiving retinol palmitate drops 3000 IU/kg daily for 28 days reduces the risk of ROP by 88% when compared with no treatment (103672).
• Urinary tract infections (UTIs). It is unclear if adding oral vitamin A to antibiotic therapy is beneficial for symptoms of acute pyelonephritis in young females. Details: A small clinical study in females 2-12 years of age with a first occurrence of acute pyelonephritis shows that taking vitamin A 1500 units/kg daily for 10 days in conjunction with antibiotics decreases the duration of fever by about 1.3 days and reduces urinary frequency by about 1.5 episodes per day when compared to taking placebo with antibiotics. Taking vitamin A might also reduce the occurrence of moderate or severe renal scarring after 6 months when compared with placebo (100327). The validity of these findings is limited by small study size and a high dropout rate.
• Warts. It is unclear if topical or oral vitamin A improves the resolution of viral warts. Details: A meta-analysis of observational and clinical research in patients with viral warts suggests that receiving prescription oral retinoids (isotretinoin, acitretin, etretinate) seems to produce a 61% rate of wart resolution. Prescription topical retinoids seems to produce a 64% rate of wart resolution (104461). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol. More evidence is needed to rate vitamin A for these uses.

(Read more about VITAMIN A)

LIKELY SAFE ...when used in amounts found in foods. Astaxanthin has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when taken orally and appropriately. Astaxanthin 4-18 mg daily has been used with apparent safely for up to 12 weeks. Doses of 40 mg daily have been used with apparent safety for up to 4 weeks (19165,19167,19197,32621,96884,105100).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using in amounts greater than those typically found in foods.

(Read more about ASTAXANTHIN)

LIKELY SAFE ...when used orally and appropriately. DHA has been used safely in studies lasting up to 4 years (1016,1043,6413,10321,10869,11333,90684). Fish oil supplements containing DHA have also been safely used in studies lasting up to 7 years (1016). While doses of DHA up to 4 grams orally daily have been used safely in some clinical research (6143), there is some concern that high intake of omega-3 fatty acids such as DHA might increase the risk of bleeding. For this reason, the US Food and Drug Administration (FDA) recommends that consumers limit intake of DHA plus eicosapentaenoic acid (EPA), another omega-3 fatty acid also found in fish oil, to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

POSSIBLY SAFE ...when used intravenously and appropriately, in combination with eicosapentaenoic acid (EPA), short-term. Daily infusions with an omega-3 fatty acid-based lipid emulsion (Omegavenous 10%, Fresenius Aktiengesellschaft) providing 4.2 grams/day of DHA and EPA has been used safely for 14 days (1004).

POSSIBLY UNSAFE ...when used orally in high doses. Doses greater than 3 grams daily might decrease platelet aggregation and increase the risk of bleeding (1313). The US Food and Drug Administration (FDA) recommends that consumers limit intake of DHA plus eicosapentaenoic acid (EPA), another omega-3 fatty acid, to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

CHILDREN: LIKELY SAFE
when used orally and appropriately. DHA is a component of some infant formula (424,1045,5708,5941,7599,14403,15003,15495,17735,48088)(48194,48266,48343,90665,90713,90716,110357). In children 7 years and older, DHA 30 mg/kg daily has been used safely for up to 4 years (90684). Also, DHA 0.4-1 grams daily has been safely used in children ages 4 years and older for up to 1 year (11333,90665,100940,104560).

CHILDREN: POSSIBLY UNSAFE
when used orally in preterm infants born less than 29 weeks gestation. Although not all findings agree (110356,110359), supplementation with an enteral emulsion containing DHA 40 mg/kg to 60 mg/kg daily might increase the risk of developing or worsening bronchopulmonary dysplasia compared to control emulsion (96523,110359).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. An intake of DHA 650 mg daily from food and/or supplements during pregnancy seems to be required to prevent a reduction in DHA status before delivery (110329). DHA is commonly used during pregnancy and lactation and is a component of some prenatal supplements. DHA is a normal component of breast milk, with higher levels in breast milk following term vs. preterm pregnancies (14393,14394,14396,14400,14403,14397,20000,47977,47994,48095)(90672,90718,110355). When taken as a prenatal supplement, DHA increases DHA levels in breast milk (90685). Doses of DHA ranging from 300-600 mg daily beginning during the first trimester of pregnancy have been used safely in clinical research (90672,90676,90687,90694). When taken during lactation, DHA increases DHA levels in breast milk (109214,110362). When initiated within 72 hours of delivery of a very preterm infant, taking DHA 1.2 grams daily increases DHA levels in breast milk within 14 days (109214). One study found that DHA supplementation during lactation increased the risk of bronchopulmonary dysplasia in breast-feeding infants born less than 29 weeks gestational age (104559); however, it is unclear if this was due to DHA or various confounding factors. The tolerable upper intake level of DHA during pregnancy or lactation has not been established; most experts recommend DHA 200-300 mg daily. While it is typically advised that this need is met by consuming 8-12 ounces of seafood weekly during pregnancy and 4-8 ounces weekly during lactation, those with nutrient deficiency or those following a vegan diet may meet this need with supplementation (95740,95741).

(Read more about DOCOSAHEXAENOIC ACID (DHA))

LIKELY SAFE ...when fish oil or prescription EPA is used orally and appropriately as a source of EPA. Fish oil containing EPA has been used safely for up to 7 years (1016,7819,15497). While doses of prescription EPA (Vascepa, formerly ARM101, Amarin) have been used safely at doses up to 4 grams daily (91409,91410,95715,99136), there is some concern that high intake of omega-3 fatty acids such as EPA might increase the risk of bleeding. For this reason, the US Food and Drug Administration (FDA) recommends that consumers limit intake of EPA plus docosahexaenoic acid (DHA), another omega-3 fatty acid also found in fish oil, to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

POSSIBLY SAFE ...when algal oil is used orally and appropriately as a source of EPA. A specific algal oil supplement (Almega PL) providing EPA 250 mg daily has been used with apparent safety for up to 12 weeks (103314). ...when used intravenously under the guidance of a healthcare professional. Fish oil or omega-3 fatty acid lipid emulsions containing EPA, administered intravenously for 1-4 weeks, have been safely used (1004,66042,66421,89323).

POSSIBLY UNSAFE ...when used orally in high doses. Doses greater than 3 grams daily might decrease blood coagulation and increase the risk of bleeding (1313). The US Food and Drug Administration (FDA) recommends that consumers limit intake of EPA plus DHA, another omega-3 fatty acid, to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about EICOSAPENTAENOIC ACID (EPA))

LIKELY SAFE ...when used orally and appropriately. Doses of 3 grams per day and less can be safely used by most people. Fish oil has Generally Recognized As Safe (GRAS) status in the US (1313,1024,2299,2300,2301,2302,2315,2317,4912,5702)(5705,5706,6394,6399,7368,7369,7380,12921,12922,13011)(13766,14382,16733,17408,17991,17992,66454,89325,89336,89346)(89351,89352,89373,89374,101543,103492,103499,103502,104546,105220)(107180,107181). Although higher doses of fish oil, such as 6 grams daily for up to 1 year, have been used safely (89344), there are some safety concerns about using high doses of fish oil. Some older research suggests that doses greater than 3 grams per day can inhibit blood coagulation and potentially increase bleeding risk (8671,8679,8696,66258,21223,21224). However, the most rigorous research to date shows that short-term doses of fish oil 10 grams daily and long-term doses of 1.5 grams daily for up to 52 weeks do not increase the risk of bleeding or affect coagulation parameters in chronically ill and vulnerable patients (97180). Still, doses greater than 3 grams per day might suppress immune response (1313,7384). Patients should only take high-dose fish oil while under medical supervision.

POSSIBLY SAFE ...when parenteral nutrition supplemented with a lipid emulsion enriched in fish oil is used, short-term. Fish oil or omega-3 fatty acid lipid emulsions, administered intravenously for 1-4 weeks, have been safely used (1004,66042,66421,89323,103497).

POSSIBLY UNSAFE ...when fish oil from dietary sources is consumed in large amounts. Fatty fish can contain significant amounts of toxins such as mercury, polychlorinated biphenyls (PCBs), dioxin, and dioxin-related compounds. Very frequent consumption of contaminated fish can cause adverse effects such as tremor, numbness and tingling, difficulty concentrating, and vision problems. Avoid frequent consumption of swordfish, king mackerel, tilefish (also called golden bass or golden snapper), and farm-raised salmon (12964,12965,12966). There is insufficient reliable information available about the safety of fish oil when used topically.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately (5708,5711,65732,66070). In adolescents 9 years of age and older, fish oil providing doses of up to 2250 mg omega-3 fatty acids daily have been used with apparent safety for up to 12 weeks (101543). Fish oil used in enteral feeds for up to 9 months has been shown to be safe in infants (13745). Young children should limit dietary consumption to no more than two ounces of fish per week (12967,12968). ...when given as part of parenteral nutrition in infants receiving long-term parenteral nutrition (96118,110340,110346,110352).

CHILDREN: POSSIBLY UNSAFE
when fish oil from dietary sources are consumed in large amounts. Fatty fish can contain significant amounts of toxins such as mercury, polychlorinated biphenyls (PCBs), dioxin, and dioxin-related compounds. Frequent consumption of contaminated fish can cause brain damage, mental retardation, blindness and seizures in children. Lower levels can cause more subtle problems such as learning disabilities (12964). Young children should limit consumption to no more than 2 ounces per week of fish (12967,12968).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Intake of fish oil during pregnancy does not appear to adversely affect the fetus or nursing infant (1026,1027,1042,8706,12969,12970,12971,12972,12973,14397)(15015,15162,101540,110338). The adequate intake level of omega-3 fatty acids during pregnancy is 1.4 grams daily; the adequate intake level during lactation is 1.3 grams daily (89377). If possible, people who are trying to become pregnant, as well as those who are pregnant or lactating, should avoid swordfish, king mackerel, and tilefish (also called golden bass or golden snapper), as these may contain high levels of methylmercury. Pregnant individuals should also limit consumption of other fatty fish to 12 ounces, or about 3-4 servings, per week.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when fish oil from dietary sources are consumed in large amounts. Fatty fish can contain significant amounts of toxins such as mercury, polychlorinated biphenyls (PCBs), dioxin, and dioxin-related compounds. If possible, people who are trying to become pregnant, as well as those who are pregnant or lactating, should avoid swordfish, king mackerel, and tilefish (also called golden bass or golden snapper), as these may contain high levels of methylmercury. Pregnant individuals should also limit consumption of other fatty fish to 12 ounces, or about 3-4 servings, per week (12967,12968).

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LIKELY SAFE ...when used orally in food amounts. Edible oils containing high amounts of oleic acid are commonly used in foods (26466,90681,94452,101821,101824,101828,101830,101838). There is insufficient reliable information available about the safety of oleic acid when used as medicine.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using in amounts greater than those commonly found in foods.

(Read more about OLEIC ACID)

LIKELY SAFE ...when used orally or intramuscularly and appropriately. Vitamin A, as pre-formed vitamin A (retinol or retinyl ester), is safe in adults when taken in doses below the tolerable upper intake level (UL) of 10,000 IU (3000 mcg) per day (7135). Higher doses increase the risk of side effects. There is also growing concern that taking high doses of antioxidants such as vitamin A might do more harm than good. In an analysis of studies, taking vitamin A supplements alone or in combination with other antioxidants is associated with an increased risk of mortality from all causes (15305,90775). Keep in mind that vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used to determine if the amount of vitamin A is safe.

POSSIBLY SAFE ...when used topically and appropriately, short-term. Retinol 0.5% has been used on the skin daily for up to 12 weeks with apparent safety. No serious adverse effects have been reported in clinical trials (103671,103680).

POSSIBLY UNSAFE ...when used orally in high doses. Doses higher than the UL of 10,000 IU (3000 mcg) per day of pre-formed vitamin A (retinol or retinyl ester) might increase the risk of side effects (7135). While vitamin A 25,000 IU (as retinyl palmitate) daily for 6 months followed by 10,000 IU daily for 6 months has been used with apparent safety in one clinical trial (95052), prolonged use of excessive doses of vitamin A can cause significant side effects such as hypervitaminosis A. The risk for developing hypervitaminosis A is related to total cumulative dose of vitamin A rather than a specific daily dose (1467,1469). There is also concern that taking high doses of antioxidants such as vitamin A might do more harm than good. In an analysis of studies, taking vitamin A supplements alone or in combination with other antioxidants is associated with an increased risk of mortality from all causes (15305,90775). There is insufficient reliable information available about the safety of using sublingual formulations of vitamin A.

CHILDREN: LIKELY SAFE
when used orally or intramuscularly and appropriately. The amount of pre-formed vitamin A (retinol or retinyl ester) that is safe depends on age. For children up to 3 years of age, doses less than 2000 IU (600 mcg) per day seem to be safe. For children ages 4 to 8, doses less than 3000 IU (900 mcg) per day seem to be safe. For children ages 9 to 13, doses less than 5667 IU (1700 mcg) per day seem to be safe. For children 14 to 18, doses less than 9333 IU (2800 mcg) per day seem to be safe (7135). Keep in mind that vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used to determine if the amount of vitamin A is safe.

CHILDREN: POSSIBLY UNSAFE
when pre-formed vitamin A (retinol or retinyl ester) is used orally in excessive doses. For children up to 3 years of age, avoid doses greater than 2000 IU (600 mcg) per day. For children ages 4 to 8, avoid doses greater than 3000 IU (900 mcg) per day. For children ages 9 to 13, avoid doses greater than 5667 IU (1700 mcg) per day. For children ages 14 to 18, avoid doses greater than 9333 IU (2800 mcg) per day (7135). Higher doses of vitamin A supplementation have been associated with increased risk of side effects such as pneumonia, bone pain, and diarrhea (319,95051). Long-term supplementation with low to moderate doses on a regular basis can cause severe, but usually reversible, liver damage (11978).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally or intramuscularly and appropriately. Vitamin A, as pre-formed vitamin A (retinol or retinyl ester), is safe during pregnancy and lactation when used in doses less than 10,000 IU (3000 mcg) per day (7135,16823,107293). Keep in mind that vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used to determine if the amount of vitamin A is safe.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally or intramuscularly in excessive doses. Daily intake of greater than 10,000 IU (3000 mcg) can cause fetal malformations (3066,7135). Excessive dietary intake of vitamin A has also been associated with teratogenicity (11978). The first trimester of pregnancy seems to be the critical period for susceptibility to vitamin A-associated birth defects such as craniofacial abnormalities and abnormalities of the central nervous system (7135). Pregnant patients should monitor their intake of pre-formed vitamin A (retinol or retinyl ester). This form of vitamin A is found in several foods including animal products, some fortified breakfast cereals, and dietary supplements (3066).

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CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, astaxanthin may decrease levels of drugs metabolized by CYP2B6.  Details In vitro research shows that astaxanthin induces cytochrome CYP2B6 enzyme activity in human hepatocytes (32613). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, astaxanthin may decrease levels of drugs metabolized by CYP3A4.  Details In vitro research shows that astaxanthin induces CYP3A4 enzyme activity in human hepatocytes (32613). This effect has not been reported in humans.

(Read more about ASTAXANTHIN)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, DHA may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Although some clinical evidence suggests that DHA might reduce collagen-stimulated platelet aggregation and thromboxane release, most clinical evidence suggests that DHA alone does not affect blood clotting (11112,11113,48020). However, theoretically, when given in combination with EPA as fish oil, concomitant use with anticoagulant or antiplatelet drugs (including aspirin) might increase risk of bleeding.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking DHA with antidiabetes drugs might reduce the effects of these medications.  Details In people with type 2 diabetes, including those taking oral hypoglycemic medications, DHA seems to increase fasting blood glucose levels (10321).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking DHA with antihypertensive drugs might increase the risk of hypotension.  Details Fish oils containing DHA can lower blood pressure and might have additive effects in patients treated with antihypertensives (1001,1020,1030,1033,47944,48013,48020,48163); use with caution.

(Read more about DOCOSAHEXAENOIC ACID (DHA))

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, EPA may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In human research, taking EPA has been shown to inhibit platelet aggregation (9930).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking EPA with antihypertensive drugs might increase the risk of hypotension.  Details Fish oils containing EPA can lower blood pressure and might have additive effects in patients treated with antihypertensives (1001,1020,1030,1033); use with caution.

(Read more about EICOSAPENTAENOIC ACID (EPA))

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Fish oil may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs. However, evidence is conflicting.  Details While fish oil may not be a potent inhibitor of platelet function, high doses of fish oil might have antiplatelet effects. Theoretically, concomitant use of fish oil with anticoagulant or antiplatelet drugs may increase the risk of bleeding (8671,8679,8696,13769,21223,21224,66258). However, the most rigorous research shows that short-term doses of fish oil 10 grams daily or long-term doses of 1.5 grams daily for up to 52 weeks does not increase the risk of bleeding or affect coagulation parameters in chronically ill and vulnerable patients (97180). Other controlled research shows that fish oil does not affect platelet function or increase the risk of bleeding (17990,17996,66105,66267,89374,107180). Some research even suggests that perioperative fish oil use decreases bleeding risk (89352). Some research suggests fish oil does not have additive antiplatelet effects when combined with aspirin (13769), but other clinical evidence suggests that adding fish oil to low-dose aspirin treatment increases antiplatelet effects in patients who are aspirin-resistant (21226). Also, some clinical research seems to show that fish oil has additive antiplatelet effects when used with aspirin and clopidogrel compared to aspirin and clopidogrel alone (21225).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking fish oil with antihypertensive drugs might increase the risk of hypotension.  Details Clinical evidence indicates that fish oils can modestly lower blood pressure and might have additive effects in patients treated with antihypertensives (1001,1020,1030,1033,66095,66100,66215,66331,66358,66379,66385).

CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking fish oil with contraceptive drugs might decrease the triglyceride-lowering effects of fish oil.  Details There is some evidence that contraceptive drugs might interfere with the triglyceride lowering effects of fish oils (8694).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Taking fish oil with cyclosporine might increase levels and adverse effects of cyclosporine.  Details In kidney transplant recipients on a general immunosuppressive regimen, taking omega-3 fatty acids daily seems to increase peak blood levels of cyclosporine when compared with placebo. This increase was as much as 20% after one month. However, the area under the curve was not significantly affected (66472).

ORLISTAT (Xenical, Alli) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking fish oil with orlistat might decrease the absorption of fish oil fatty acids.  Details Orlistat binds lipase in the gastrointestinal tract and reduces fat absorption. Theoretically, taking fish oil with orlistat might decrease absorption of fish oil fatty acids. To avoid this potential interaction, recommend separating administration of orlistat and fish oil by at least 2 hours.

PLATINUM AGENTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, taking fish oil with platinum agents can cause resistance to platinum agents, potentially decreasing their effectiveness.  Details Platinum-induced fatty acids (PIFAs) are fatty acids secreted from human and mouse stem cells when exposed to platinum-based chemotherapy. Animal research suggests that PIFAs cause resistance to chemotherapy by stimulating lysophospholipid production in the spleen, which interferes with the DNA damage caused by certain chemotherapy drugs (92076). One PIFA, known as 16:4(n-3), has been found in both raw fish and some commercially available fish oil products. Mackerel and herring have high PIFA concentrations, while salmon and tuna have low PIFA concentrations. Levels of PIFA in commercial fish oil products ranged from 0.2- 5.7 microMol. Animal research shows that PIFA-containing fish oil products cause resistance to cisplatin, fluorouracil, irinotecan, and oxaliplatin (91250,92075). It is unclear if all commercially available fish oil products contain PIFAs. Additionally, it is argued that levels of PIFA found in some fish oil products are too low to be of clinical concern. Furthermore, a lack of chemotherapy resistance in countries with high fish intake, such as Greenland, Japan, and Norway, suggest that this interaction may not be clinically significant (91288,91289).

SIROLIMUS (Rapamune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Taking fish oil with sirolimus might increase levels and adverse effects of sirolimus.  Details Pharmacokinetic research shows that omega-3 fatty acids increase exposure to sirolimus in kidney transplant patients on a calcineurin inhibitor-free immunosuppressive regimen. A 25% dose reduction in sirolimus was required to keep patients within the expected trough-concentration window (105232). Researchers hypothesize that this may be due to inhibition of cytochrome P450 3A4 (CYP3A4) by fish oil, although this has not been confirmed in clinical research.

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Taking fish oil with tacrolimus might increase levels and adverse effects of tacrolimus.  Details In a small group of patients, taking fish oil 2.6 grams (Omacor) daily for 4 weeks increased the 8-hour area under the curve of tacrolimus by 25% when compared with baseline. Peak levels were increased by approximately 22% (105212). Researchers hypothesize that this may be due either to an increase in bioavailability or to inhibition of cytochrome P450 3A4 (CYP3A4) by fish oil, although this has not been confirmed in clinical research.

WARFARIN (Coumadin) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Fish oil may have antiplatelet effects and might increase the risk of bleeding if used with warfarin.  Details Fish oil has antiplatelet effects at high doses. Case reports show elevated INR in patients taking warfarin and fish oil 1-2 grams daily (21222,21223). However, some clinical research shows that taking fish oil 3-6 grams daily does not significantly increase INR in patients taking warfarin (8801).

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(Read more about OLEIC ACID)

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = C Theoretically, taking high doses of vitamin A in combination with other potentially hepatotoxic drugs might increase the risk of liver disease.  Details The tolerable upper intake level (UL) is the highest level of intake that is likely to pose no risk of adverse effects. Doses of vitamin A above the UL can cause hepatotoxicity, ranging from elevated liver enzymes to liver failure (7135,82554).

RETINOIDS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Concomitant use of retinoids with vitamin A supplements might produce supratherapeutic vitamin A levels.  Details Retinoids, which are vitamin A derivatives, could have additive toxic effects when taken with vitamin A supplements (3046).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking tetracycline antibiotics with high doses of vitamin A can increase the risk of pseudotumor cerebri.  Details Benign intracranial hypertension (pseudotumor cerebri) can occur with tetracyclines and with acute or chronic vitamin A toxicity. Case reports suggest that taking tetracyclines and vitamin A concurrently can increase the risk of this condition (10545,10546,10547). Avoid high doses of vitamin A in people taking tetracyclines chronically.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, high doses of vitamin A could increase the risk of bleeding with warfarin.  Details Vitamin A toxicity is associated with hemorrhage and hypoprothrombinemia, possibly due to vitamin K antagonism (505). Advise patients taking warfarin to avoid doses of vitamin A above the tolerable upper intake level of 10,000 IU/day for adults.

(Read more about VITAMIN A)

General ...Orally, astaxanthin seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, red fecal color.

Gastrointestinal ...Orally, astaxanthin 6 mg daily has caused two cases of increased bowel movements and two cases of red fecal color (91736). A higher dose of astaxanthin (AstaCarox, AstaReal AB) 40 mg daily has caused severe stomach/abdominal pain in two patients (19165).

Ocular/Otic ...Canthaxanthin, another carotenoid substance that is chemically related to astaxanthin, has caused crystals in the retina and loss of visual acuity in one patient (8455). This effect has not been observed with astaxanthin, but patients who have visual changes while taking astaxanthin should stop taking it immediately.

(Read more about ASTAXANTHIN)

General ...Orally, DHA is generally well-tolerated when used in doses up to 3 grams daily. Intravenously, DHA seems to be well tolerated.
Most Common Adverse Effects:
Orally: Belching, fishy aftertaste, loose stools, and nausea.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about increased risk of bleeding with high doses of fish oil containing DHA.

Cardiovascular ...Orally, DHA might increase low-density lipoprotein (LDL) cholesterol levels. However, this appears to be primarily due to increases in the large buoyant type of LDL particles. The small, dense type of LDL particles are reduced (6143,48013,48078,48083,48174,48338).

Dermatologic ...Orally, DHA has been associated with one report of rash and one report of warmth on hands in one clinical study (48217). In another clinical study, two patients taking DHA 400 mg daily reported acne (11333). In another clinical study, one parent of a pediatric patient treated with DHA 600 mg daily reported increased hair loss beginning 6 weeks after completion of supplementation (90699). It is unclear if this adverse effect is specifically related to DHA intake.

Gastrointestinal ...Orally, DHA may cause gastrointestinal upset, fishy aftertaste, belching, flatulence, heartburn, loose stools, anorexia, and dry mouth (10869,11333,48217,109218). There is also some evidence that increased serum levels of DHA might be associated with an increased risk for atrophic gastritis associated with Helicobacter pylori infection, but further research is needed to clarify this finding (8709).
For fish oils containing EPA and DHA, side effects can include fishy taste, belching, nausea, and loose stools (1009,1313,8699,10007). Three people with pre-existing familial adenomatous polyposis were diagnosed with malignant lesions during the course of long-term fish oil use (999).

Genitourinary ...Orally, one patient in one clinical study who was taking DHA 1, 2, or 4 grams daily (specific dose unclear) reported decreased libido (48217).

Hematologic ...Orally, DHA might cause nose bleeds, but this is uncommon. Onset of severe nose bleeds has been reported in one clinical study in one child who took DHA 600 mg daily (98542). Although most clinical research shows that DHA does not affect blood clotting when taken alone (11112,11113,48020), there is some concern that taking high doses of oils providing DHA along with eicosapentaenoic acid (EPA) might decrease blood coagulation and increase the risk of bleeding (1313). The US Food and Drug Administration (FDA) recommends that consumers limit intake of EPA plus DHA to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

Neurologic/CNS ...Orally, DHA may cause dizziness, headache, insomnia, fatigue, and anxiety (10869,11333,48217). In one clinical study, one parent of a pediatric patient treated with DHA 600 mg daily reported increased disruptive behavior in the child (90699).

Ocular/Otic ...Orally, DHA may cause watery eyes but results are inconsistent. In one clinical study, five of 167 infants fed formula containing 0.32% or 0.64% DHA experienced watery eyes. However, none of the infants fed formula containing 0.96% DHA experienced watery eyes (90670). In one clinical study, one patient taking DHA 400 mg daily experienced an ear infection. It is unclear if this event was related to DHA supplementation.

Oncologic ...Orally, DHA may increase the risk of prostate cancer, but additional research is needed to clarify this finding. A meta-analysis of data from observational studies found that higher dietary intake of DHA is associated with a non-linear increased risk of prostate cancer (90677). It is unclear if supplemental DHA intake is associated with increased risk of prostate cancer.

Pulmonary/Respiratory ...Orally, worsened asthma symptoms were reported by one parent of one patient with asthma taking DHA 600 mg daily (90699).

(Read more about DOCOSAHEXAENOIC ACID (DHA))

General ...Orally, prescription EPA or EPA derived from fish oil is generally well tolerated in doses of up to 3 grams daily. Agal oil providing EPA seems to be well tolerated. Doses of EPA greater than 3 grams daily are possibly unsafe.
Intravenously, fish oil or omega-3 fatty acid lipid emulsions containing EPA seem to be well tolerated.
Most Common Adverse Effects:
Orally: Belching, diarrhea, epigastric discomfort, fishy aftertaste, and nausea.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about increased risk of bleeding with high doses.

Cardiovascular ...Orally, taking the prescription ethyl-EPA product (Vascepa, Amarin) 4 grams daily has been linked to a 1% greater risk of atrial fibrillation or atrial flutter that required hospitalization when compared with placebo (101286).

Dermatologic ...Orally, reported side effects of EPA have included skin rash and itching (15497).

Gastrointestinal ...Orally, reported side effects of EPA have included nausea, diarrhea, and epigastric discomfort (15497,103314,110365,110366). For fish oils containing EPA and docosahexaenoic acid, side effects can include fishy taste, belching, nausea, and loose stools (10007).

Hematologic ...Orally, reported side effects of EPA, as well as fish oils containing EPA and docosahexaenoic acid (DHA), have included nosebleed (10007,15497). There is some concern that taking high doses of oils providing EPA along with DHA might decrease blood coagulation and increase the risk of bleeding (1313). To reduce this risk, the US Food and Drug Administration (FDA) recommends that consumers limit intake of EPA plus DHA to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739). The prescription ethyl-EPA product (Vascepa, Amarin) 4 grams daily has been linked to bleeding in 12% of patients, compared with 10% in the placebo group. Serious bleeding occurred in 3% of the Vascepa group compared to 2% in the placebo group (101286).

Immunologic ...There is preliminary evidence that the EPA in fish oil decreases natural killer (NK) cell activity. Due to this effect, there is concern that increased intake of EPA might have some adverse immunologic effects and possibly increase the risk for viral infections and some cancers (8718).

Musculoskeletal ...Orally, EPA may cause musculoskeletal pain in some patients, although results from clinical research are conflicting. In one clinical study, a higher percentage of patients treated with ethyl-EPA 2 or 4 grams daily experienced joint pain compared to placebo (3.4% and 1.7% vs 0.4%, respectively) (91409). However, in another study, slightly fewer patients taking ethyl-EPA 1.8 grams daily experienced joint, lumbar, or muscle pain compared to placebo (1.6% vs 2.0%, respectively) (15497).

Oncologic ...Three people with pre-existing familial adenomatous polyposis have been diagnosed with malignant lesions during the course of long-term high-docosahexaenoic acid fish oil use (999); however, it is unclear if fish oil, or more specifically EPA, was the cause.

(Read more about EICOSAPENTAENOIC ACID (EPA))

General ...Orally and parenterally, fish oil is generally well-tolerated. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Abdominal pain, bad breath, fishy aftertaste, heartburn, increased low-density lipoprotein (LDL) cholesterol levels, loose stools, nausea, and rash.
Serious Adverse Effects (Rare):
Orally: Atrial fibrillation. When taken in doses of 3 grams or more daily, there are rare reports of increased risk of bleeding and stroke, as well as immune suppression.

Cardiovascular ...Orally, fish oil supplements in doses of 3-10 grams daily can cause a dose-dependent increase in low-density lipoprotein (LDL) cholesterol levels in some people (2299,2318,8678,8698,15734,15735,48120,65729) by increasing the size of LDL particles (9771). Therefore, LDL levels should be monitored in people who take fish oil supplements (15734). But fish oil doesn't seem to cause development of atherosclerosis, despite earlier concerns that polyunsaturated fatty acids, such as omega-3 fatty acids, might increase the oxidation of LDL (1011,2323,7165,7366,8695,8700,9771).
There is concern that fish oil supplements may be associated with an increased risk for atrial fibrillation, particularly in patients with or at risk for cardiovascular disease (CVD). In one large clinical study (the STRENGTH trial), taking a prescription fish oil product (Epanova) 4 grams daily for up to 5 years was associated with an increased risk for atrial fibrillation, with a number needed to harm of 114 when compared with a corn oil control. The patients in this study were considered to be at high risk for future CVD (103491). Also, meta-analyses of randomized controlled trials show that taking omega-3 fatty acid supplements increases the incidence rate ratio for atrial fibrillation by up to 37% when compared with placebo, with an increased incidence rate associated with doses of more than 1 gram daily. One study in these analyses used eicosapentaenoic acid (EPA) alone as purified icosapent ethyl (106075,107171,107181).

Dermatologic ...Orally, skin rashes, itching, and skin irritation have been reported (66498,66492,66488,89369,104551).
A case of severe tissue inflammation and breast tissue necrosis has been reported for a female who injected fish oil from capsules subcutaneously for breast augmentation (89371).

Gastrointestinal ...Orally, most adverse effects of omega-3 fatty acids are gastrointestinal in nature (12915,65599,65728,65770,65780,65904,66061,66104,66164,66488)(89347,89357,103491,103551,107172). Gastrointestinal upset is common with the use of fish oil supplements, occurring in up to 5% of patients in clinical trials, with nausea in up to 1.5% of patients (2307,16733,65599,65732,65762,65830,65886,65925,65974)(66020,66042,66083,66104,66130,66164,66169,66358,66370,66488)(66494,66498,89347,103491,104551,110353). Diarrhea and loose stools may also occur (6257,10871,65599,65648,65830,65935,66042,66061,66104,66119)(66130,66173,66492,89347,89359,103491,104551,107172,110353), with potentially severe diarrhea at very high doses (12986,16901,66093,66356). There have also been reports of increased burping (17963,65648,65729,65770,65830,66020,66042,66077,66164,66169)(66492,66494,104551), acid reflux, heartburn (104551,110338), indigestion (65566,65830,66061,66104,66173,89359), abdominal bloating (66083,66104), abdominal or gastrointestinal pain or discomfort (8680,17996,66119,66492,103491), anorexia (62390,89359), flatulence (66492), constipation (16901), nausea and vomiting (65728,65830,66104,66130,66488,103491,104551), steatorrhea (66119,66354,66356), fishy hiccups (66488), metallic taste (66488), and a fishy breath odor and aftertaste (16901,65648,65729,65762,66020,66042,66061,66077,66083,66104)(66130,66164,66172,66173,66424,66488,66494,89369,104551,107172). Also, some preliminary evidence suggests that increased serum levels of omega-3 fatty acids, especially DHA, might increase the risk for atrophic gastritis (8709).
Gastrointestinal side effects may be minimized if fish oils are taken with meals and if doses are started low and gradually increased. Taking supplements with meals or freezing them seems to help decrease these side effects for some patients (12975). Enteric coated fish products might also help reduce side effects (6258).

Hematologic ...Orally, 3 grams or greater of omega-3 fatty acids daily may inhibit platelet aggregation and increase the risk of bleeding; however, there is little evidence of statistically significant bleeding risk at lower doses (1313,8699,66500,66501,66334,101543). Very large intakes of fish oil or omega-3 fatty acids (more than 46 grams per day) may increase the risk of ischemic or hemorrhagic (bleeding) stroke (7603,66502).
A case of hemolytic anemia has been reported for an infant with short bowel syndrome who developed liver disease from total parenteral nutrition (TPN) and was switched to a specific TPN with fish oil (Omegaven, Fresenius-Kabi, Graz, Austria) instead. After stopping the fish oil-TPN, the anemia was reversed suggesting that parenteral fish oil might cause hemolytic anemia (66022).

Hepatic ...Orally, mild elevations in liver function tests (alanine aminotransferase) have been reported, although these events are rare (66353).

Immunologic ...A case of anaphylaxis following ingestion of a fish oil capsule has been reported for a female patient with a history of allergy to crab. The patient was treated successfully with epinephrine, but had several recurrences of stridor over the next 2 days (89378).
There is also some evidence that fish oil in doses greater than 3 grams per day might adversely affect immune function. Fish oil appears to suppress T- and B-cell function and to reduce the production of cytokines, which might be detrimental to elderly people and people with suppressed immune function such as patients with human immunodeficiency virus (HIV) infection (1313,7383,7384).

Neurologic/CNS ...Orally, fish oil may cause headache, dizziness, and inability to sleep (65599,65648,89359,103491,104551). Also, restlessness and formication have been reported in less than 1% of studied cases of patients taking fish oil (66498).

Oncologic ...There is some concern that high fish intake may increase the risk for certain types of cancer. One large epidemiological study has found that dietary intake of fish oil from fatty fish twice a week or more is associated with a 16% increased risk of breast cancer when compared with eating fatty fish less than twice weekly (107175). Additionally, an analysis of the NIH-AARP Diet and Health Study, a prospective cohort study in over 491,000 older adults, has found that total intake of fish is associated with increased melanoma risk over a median follow-up of 15.5 years. When the lowest and highest quintiles of intake are compared, there is a 22% increase in the risk for malignant melanoma and a 28% increase in the risk for melanoma in situ. In sub-group analyses, all melanoma incidence is positively associated with tuna intake or non-fried fish intake, but malignant melanoma incidence is inversely associated with fried fish intake (108509). It was suggested that the positive associations could be due to contaminants in fish such as polychlorinated biphenyls, dioxins, arsenic, and mercury.

Pulmonary/Respiratory ...Orally, fish oil has been reported to cause nasopharyngitis and upper respiratory tract infections in 3. 3% of patients in one clinical trial (65798). Exacerbation of asthma and apnea have been reported for patients using fish oil (1040,66061,66119,66354).

Other ...Fish oil can contribute to caloric intake and may cause weight gain if used long-term. One gram of fat or oil provides 9 kcal (6871). Fish oil capsules containing 500 mg omega-3 fatty acids in 1 gram of oil would supply about 13.5 kcal per capsule (6871,6874). Fish oil supplements also contain cholesterol in amounts from 1-6 mg per gram of fish oil (3022,6871).

(Read more about FISH OIL)

General ...Orally, oleic acid generally well tolerated when used as part of oils and fats in the diet (26466,90681,94452,101821,101824,101828,101830,101838). Temporary burning in the mouth or throat has occurred in some patients (101848).

Gastrointestinal ...Orally, oleic acid has caused temporary burning in the mouth or throat in some patients in one clinical study (101848).

(Read more about OLEIC ACID)

General ...Orally, vitamin A is generally well-tolerated at doses below the tolerable upper intake level (UL).
Serious Adverse Effects (Rare):
Orally: In very high doses, vitamin A can cause pseudotumor cerebri, pain, liver toxicity, coma, and even death.

Dermatologic ...Chronic oral use of large amounts of vitamin A causes symptoms of vitamin A toxicity including dry skin and lips; cracking, scaling, and itchy skin; skin redness and rash; hyperpigmentation; shiny skin, and massive skin peeling (7135,95051). Hypervitaminosis A can cause brittle nails, cheilitis, gingivitis, and hair loss (15,95051). Adverse effects from a single ingestion of a large dose of vitamin A is more common in young children than adults (15). In children, approximately 25,000 IU/kg can cause skin redness and generalized peeling of the skin a few days later and may last for several weeks (15).

Gastrointestinal ...There is some evidence that oral vitamin A supplementation might increase the risk of diarrhea in children. Although vitamin A can prevent diarrhea and reduce mortality in malnourished children, doses as low as 10,000 IU weekly for 40 weeks have been associated with diarrhea in well-nourished children (319). Diarrhea (82326,82389), nausea (7135,100329), abdominal pain (95051), abdominal fullness (100329), and vomiting (7135,82559,95051,95055,109755) have been reported following use of large doses of oral vitamin A. Adverse effects from a single ingestion of a large dose of vitamin A is more common in young children than adults (15). In children, approximately 25,000 IU/kg can cause vomiting and diarrhea (15). Chronic use of large amounts of vitamin A causes symptoms of vitamin A toxicity including anorexia, abdominal discomfort, and nausea and vomiting (7135).

Genitourinary ...Hypervitaminosis A can cause reduced menstrual flow (15). Intravaginally, all-trans retinoic acid can cause vaginal discharge, itching, irritation, and burning (9199).

Hematologic ...Hypervitaminosis A can cause spider angiomas, anemia, leukopenia, leukocytosis, and thrombocytopenia (15,95051).

Hepatic ...Since the liver is the main storage site for vitamin A, hypervitaminosis A can cause hepatotoxicity, with elevated liver enzymes such as alanine aminotransferase (ALT, formerly SGPT) and aspartate aminotransferase (AST, formerly SGOT), as well as fibrosis, cirrhosis, hepatomegaly, portal hypertension, and death (6377,7135,95051).

Musculoskeletal ...Vitamin A can increase the risk for osteoporosis and fractures. Observational research has found that chronic, high intake of vitamin A 10,000 IU or more per day is associated with an increased risk of osteoporosis and hip fracture in postmenopausal adults, as well as overall risk of fracture in middle-aged males (7712,7713,9190). A meta-analysis of these and other large observational studies shows that high dietary intake of vitamin A or retinol is associated with a 23% to 29% greater risk of hip fracture when compared with low dietary intake (107294). High serum levels of vitamin A as retinol also increase the risk of fracture in males. Males with high serum retinol levels are seven times more likely to fracture a hip than those with lower serum retinol levels (9190). Vitamin A damage to bone can occur subclinically, without signs or symptoms of hypervitaminosis A. Some researchers are concerned that consumption of vitamin A fortified foods such as margarine and low-fat dairy products in addition to vitamin A or multivitamin supplements might cause excessive serum retinol levels. Older people have higher levels of vitamin A and might be at increased risk for vitamin A-induced osteoporosis.
Vitamin A's effects on bone resorption could lead to hypercalcemia (95051).
Hypervitaminosis can cause slow growth, premature epiphyseal closure, painful hyperostosis of the long bones, general joint pain, osteosclerosis, muscle pain, and calcium loss from the bones (15,95051). One child experienced severe bone pain after taking vitamin A 600,000 IU daily for more than 3 months (95051). Vitamin A was discontinued and symptoms lessened over a period of 2 weeks. The patient made a full recovery 2 months later.

Neurologic/CNS ...Orally, adverse effects from a single large dose of vitamin A are more common in young children than adults (15). Headache, increased cerebrospinal fluid pressure, vertigo, and blurred vision have been reported following an acute oral dose of vitamin A 500,000 IU (7135). In children, approximately 25,000 IU/kg can cause headache, irritability, drowsiness, dizziness, delirium, and coma (15). Chronic use of large amounts of vitamin A causes symptoms of vitamin A toxicity including fatigue, malaise, lethargy, and irritability (7135).
There are reports of bulging of the anterior fontanelle associated with an acute high oral dose of vitamin A in infants (7135,90784,95053,95054). In children, approximately 25,000 IU/kg can cause increased intracranial pressure with bulging fontanelles in infants (15). Also, muscular incoordination has been reported following short-term high doses of vitamin A (7135).
A case of intracranial hypertension involving diffuse headaches and brief loss of vision has been reported secondary to topical use of vitamin A. The patient was using over-the-counter vitamin A preparations twice daily including Avotin 0.05% cream, Retin-A gel 0.01%, and Isotrexin gel containing isotretinoin 0.05% and erythromycin 2%, for treatment of facial acne. Upon exam, the patient was noted to have bilateral optic disc edema. The patient discontinued use of topical vitamin A products. Two months later, the patient reported decreased headaches and an improvement in bilateral optic disc edema was seen (95056).

Ocular/Otic ...In children, oral vitamin A approximately 25,000 IU/kg can cause swelling of the optic disk, bulging eyeballs, and visual disturbances (15). Adverse effects from a single ingestion of a large dose of vitamin A are more common in young children than adults (15).

Oncologic ...There is concern that high intake of vitamin A might increase some forms of cancer. Population research suggests high vitamin A intake might increase the risk of gastric carcinoma (9194).

Psychiatric ...Chronic oral use of large amounts of vitamin A causes symptoms of vitamin A toxicity, which can include symptoms that mimic severe depression or schizophrenic disorder (7135).

Pulmonary/Respiratory ...There is some evidence that oral vitamin A supplementation might increase the risk of pneumonia and diarrhea in children. Although vitamin A can prevent diarrhea and reduce mortality in malnourished children, doses as low as 10,000 IU weekly for 40 weeks have been associated with pneumonia and diarrhea in well-nourished children (319). In preschool children, high-dose vitamin A also increases the risk of respiratory infection (82288).

Other ...Chronic use of large amounts of vitamin A (>25,000 IU daily for more than 6 years or 100,000 IU daily for more than 6 months) can cause symptoms of vitamin A toxicity including mild fever and excessive sweating (7135). High intakes of vitamin A may result in a failure to gain weight normally in children and weight loss in adults (15).

(Read more about VITAMIN A)