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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). DHA has also been evaluated in combination with other ingredients. A moderate-sized clinical study in older adults with subjective cognitive impairment and objective mild cognitive impairment shows that taking a DHA-rich fish oil containing DHA 1.1 grams and EPA 0.4 grams 3 times daily with high-flavanol cocoa for 12 months does not improve most measures of cognitive function, and moderately worsens reaction time variability, executive function, and alertness when compared with placebo. Additionally, there is no evidence of benefit on brain volumes, and patients who took DHA-rich fish oil and cocoa had greater decreases in cortical volume at 12 months when compared with placebo (111453).
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). DHA has also been evaluated in combination with other ingredients. A moderate-sized clinical study in drug-naïve children ages 6 to 12 years with mild to moderate ADHD shows that taking DHA 87 mg in combination with eicosapentaenoic acid (EPA) and gamma linoleic acid (GLA) daily for 12 months does not improve inattentive symptoms, global functioning, or learning skills when compared with placebo. There also does not appear to be a correlation between plasma fatty acid levels and ADHD symptoms (111058).
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).

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 older adults. 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 older patients with mild cognitive impairment disagrees. Several clinical studies show that taking DHA 720-3300 mg plus EPA 351-1200 mg daily and other ingredients such as cocoa for 12 weeks to 12 months does not improve cognitive measures including memory and forgetfulness when compared with placebo (62847,90704,94665,109220,111453). One moderate-sized clinical study in older adults with subjective cognitive impairment and mild cognitive impairment shows that taking DHA 1.1 grams and EPA 0.4 grams 3 times daily with high-flavanol cocoa for 12 months moderately worsens reaction time variability, executive function, and alertness when compared with placebo. Additionally, there is no evidence of benefit on brain volumes, and those taking DHA-rich fish oil and cocoa had a greater decrease in cortical volume at 12 months when compared with placebo (111453).
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).
Glaucoma. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in older adults with glaucoma shows that taking DHA 1.5 grams 3 times daily with citicoline for 3 months reduces the amount and rate of visual field loss and improves visual field index but does not reduce intraocular pressure when compared to baseline (112236). It is unclear if these effects are due to DHA, citicoline, or the combination; however, since no effects were found in the groups administered DHA or citicoline alone, it is possible that the effects are due to the combination of ingredients. The validity of these effects is limited by a lack of a control group and the very small sample size.
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 in early 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). However, a cohort study in premature infants born before 29 weeks' gestation suggests that supplementation with enteral high-dose DHA emulsion 60 mg/kg daily to match in-utero requirements until 36 weeks' gestational age or discharge home is associated with an increased risk of bronchopulmonary dysplasia and a 3.45 point benefit in intelligence quotient (IQ) at 5 years' corrected age. Further analysis of this relationship suggests that the increased risk effect of bronchopulmonary dysplasia from neonatal high-dose DHA is not associated with a decrease in the beneficial effects of DHA on IQ (112238).
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).
Sickle cell disease. It is unclear if oral DHA is beneficial for treating sickle cell disease. Details: A very small clinical study in adults with sickle cell disease shows that eating mayonnaise enriched with DHA 1900 mg and eicosapentaenoic acid (EPA) daily for 28 days does not reduce vaso-occlusive crisis pain or biomarkers of systemic inflammation (112237). The validity of these effects is limited by a lack of a comparator group and a very small sample size.
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.

EICOSAPENTAENOIC ACID (EPA) (Eicosapentaenoic Acid)

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.

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).

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.

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.

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 large population study in patients with heart failure suggests that regular use of fish oil supplements is associated with a modest reduction in mortality when compared with non-use of fish oil supplements (114182). 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 periods 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. One 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 with 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 with 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, a secondary analysis of one of these clinical studies suggests that the risk may vary by maternal genotype (115737). 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). Recent research suggests that consuming fish oil increases the risk of atrial fibrillation, particularly at higher doses. In 2023, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency issued a public statement on the use of omega-3-acid ethyl esters, concluding that exposure to omega-3-acid ethyl esters for the treatment of hypertriglyceridemia is associated with a dose-dependent increased risk of atrial fibrillation in patients with established cardiovascular disease (CVD) or risk factors for CVD when compared with placebo. The highest risk of atrial fibrillation is associated with a dose of 4 grams daily (112467). Additionally, one large, high-quality clinical study (the STRENGTH trial) in patients at high risk for CVD shows that taking a prescription fish oil product (Epanova) 4 grams daily for up to 5 years is associated with an increased risk for atrial fibrillation, with a number needed to harm of 114 when compared with a corn oil control (103491). Meta-analyses and a large epidemiological study suggest that taking fish oil supplements at doses over 1 gram daily is associated with a 25% to 37% increased risk of atrial fibrillation in individuals with or without CVD, including those with risk factors for CVD, regardless of genetic predisposition (106075,107171,107181,109306). 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 (110332,103491). Fish oil also seems to increase the risk of atrial fibrillation after myocardial infarction. In a secondary analysis of the Omega-3 fatty acids in Elderly patients with Myocardial Infarction (OMEMI) trial, adults aged 70-82 years old with recent myocardial infarction supplementing with 1.8 grams daily of omega-3 fatty acid supplements for 24 months had a 90% increased risk of developing atrial fibrillation or micro-atrial fibrillation, which is characterized by short, atrial fibrillation-like activity lasting less than 30 seconds. Changes in serum EPA levels seem to mediate this risk, with higher serum EPA levels predictive of an increased risk of atrial fibrillation and intermediate serum EPA levels predictive of an increased risk of micro-atrial fibrillation (112469). 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: A meta-analysis of 16 moderate-quality, mostly randomized controlled studies in adults shows that taking fish oil 1-3 grams daily, starting in the 12^th to 20^th week of gestation, reduces the risk of pre-eclampsia when compared with placebo (115741). However, some individual clinical studies show that fish oil does not reduce the risk of pre-eclampsia (1042,89376,97174,110338). The reasons for these discrepant findings are unclear but may be related to the heterogeneous methods across clinical studies, including dose, duration, and timing of therapy initiation.
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 implantable defibrillator events for ventricular tachycardia or ventricular fibrillation in patients with an implantable defibrillator or all-cause mortality in patients with an implantable defibrillator or history of ventricular arrhythmias (16732,65923,89343,114186).

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: Clinical research shows that taking fish oil may reduce triglyceride levels in patients with diabetes (65577,65834,65878,66027,66436,66444,101538,101541,113215). However, although some individual studies disagree, most clinical research shows that taking fish oil has no clinically significant effect on fasting plasma glucose levels or glycated hemoglobin (HbA1c) in patients with type 2 diabetes (2299,2300,2302,7368,7369,12182,12925,13011,13147,13149)(65577,65834,65878,66316,66372,66426,66442,101504,101541,101542)(113212). A large, high-quality clinical study also shows that taking fish oil 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). However, observational research in adults over 60 years of age with diabetes suggests that habitual use of fish oil supplements is associated with a 24% lower risk of dementia over about 7 years when compared with not using fish oil. Consumption of oily or non-oily fish is not associated with dementia risk in individuals with diabetes (113213). Fish oil is also of interest for gestational diabetes. Taking fish oil does not seem to reduce the risk of gestational diabetes (89376,97174,110338). Also, taking fish oil does not seem to have beneficial effects on levels of fasting blood glucose during pregnancy in patients with or without any type of diabetes, including gestational diabetes (113211). One clinical trial shows that increased blood levels of omega-3 fatty acids following fish oil supplementation during pregnancy are associated with an increased odds of gestational diabetes. However, this association was no longer significant after taking dietary total and saturated fat into consideration (113222). However, a meta-analysis of 3 small clinical trials in patients with gestational diabetes shows that taking fish oil for 6 weeks during pregnancy modestly improves insulin resistance (113211).

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).
Atopic disease. Oral fish oil does not seem to reduce the odds of a child developing atopic disease when taken during pregnancy. Details: A moderate-sized clinical study in children of pregnant adults shows that taking fish oil capsules 2.4 grams, containing docosahexaenoic acid (DHA) 1.9 grams, eicosapentaenoic acid 0.22 grams, and other omega-3 fatty acids, starting in early pregnancy until 6 months postpartum does not lower the odds of the child developing atopic eczema, allergic rhinoconjunctivitis, recurrent wheezing, asthma, or food allergy at 12 or 24 months old when compared with placebo (112465). The study may have been inadequately powered to detect a difference between groups.
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. However, research is conflicting. A meta-analysis of 22 clinical studies that include some studies mentioned above in children aged 7-12 years old with ADHD shows that taking oral fish oil 51-2513 mg daily with or without stimulants for 4 weeks to 12 months does not improve parent-rated ADHD core symptoms when compared with control. However, subgroup analysis suggests that long-term supplementation with fish oil for 4 months or longer may improve parent-rated ADHD core symptoms when compared with control (112468). 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 prevention or treatment of 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). Oral fish oil has also been evaluated to determine its impact on the likelihood of autism in children. An observational study shows that self-reported prenatal DIETARY fish intake is associated with a 16% lower odds of autism diagnosis, while SUPPLEMENTAL fish oil is not associated with odds of autism diagnosis (115739). The validity of these findings is limited by the possibility of residual confounding and the lack of data on type of fish oil supplementation.
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 along with conventional therapies may improve symptoms of depression and increase length of remission when compared with placebo. The doses of fish oil used in these studies provided EPA 6.2 grams and DHA 3.4 grams daily for 4 months or EPA 1.7 grams and DHA 0.9 grams daily for 6 months (7202,113218). 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).
Burns. Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in hospitalized adults with 20-45% surface area 2^nd or 3^rd degree burns shows that consuming a beverage containing fish oil 3 grams and collagen peptides 40 grams daily for 4 weeks shortens the time to wound healing and improves scar scores but does not limit wound infections when compared with placebo (110667).
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). Some 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 cohort study from the United Kingdom has found that increased consumption of dietary fish oil is associated with an INCREASED risk of atrial fibrillation and stroke in people without CVD compared with non-use of fish oil (114182). Also, clinical research generally shows that taking fish oil has little benefit for the primary prevention of CVD. 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). Population research in patients with existing CVD suggests that intake of fish oil supplements is associated with a reduced risk of some cardiovascular events when compared with non-use of fish oil supplements (114182). One population study in patients with at least two cardiometabolic diseases suggests 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). Another large population study suggests that regular use of fish oil supplements is associated with a small reduction in transitions from atrial fibrillation to major adverse cardiovascular events or myocardial infarction, and from heart failure to death (114182). 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). In patients with a recent myocardial infarction, a smaller clinical trial shows that taking fish oil (Lovaza, formerly known as Omacor, GlaxoSmithKline) 4 grams daily for 6 months does not reduce the risk of a major adverse cardiovascular event over about 6 years, including death, heart failure hospitalization, recurrent acute coronary syndrome, or late coronary artery bypass graft, when compared with placebo. However, there was a statistically significant reduction in having at least one major adverse cardiovascular event in patients with at least a 5% increase in blood levels of omega-3 fatty acids (113220). 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. Fish oil has also been evaluated as part of combination therapy. A large clinical study in adults at least 55 years of age with cognitive impairment shows that taking fish oil, containing DHA 1.1 grams and EPA 0.4 grams, and dark chocolate containing 500 mg cocoa flavanols daily for 12 months does not improve cognitive function scores when compared with placebo (111453).
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 suggests that eating fish at least once weekly or the regular use of fish oil supplements is associated with a 7% to 57% reduced risk of developing dementia in older adults and elderly individuals (65595,108507,108724,109307,111452); 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 suggest 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 suggests that regular use of fish oil supplements is not associated with the risk of vascular dementia or frontotemporal dementia (108507). However, other studies suggest 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 suggests that associations between the regular use of fish oil supplements and the risks of all-cause or vascular dementia are stronger in males (109307). Some research suggests that the apolipoprotein E (APOE) genotype may alter the association between fish oil intake and dementia risk (65817,108507,108724), however, other research disagrees (111452). One large epidemiological study suggests that regular use of fish oil supplements is associated with a 15% lower risk of vascular dementia. However, this study suggests that the risk of vascular dementia is INCREASED by 86% in individuals with two APOE-e4 alleles, 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 (48282,66129,99356,102391,104551,107191,112032). However, populations included in these analyses have included older adults with or without clinical depression (99356,112032), 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). An analysis of a cohort of older adults with subthreshold depression or high-risk factors for depression from the VITAL-DEP trial shows that taking omega-3 fatty acids 1 gram daily for 2 years does not reduce the risk of major depressive disorder or improve mood scores when compared with placebo (112032). 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). Fish oil is also of interest for improving cognitive function in patients with depression. In patients newly diagnosed with depression, clinical research shows that taking fish oil 8 grams daily for 12 weeks in addition to venlafaxine modestly improves immediate memory, but not other measures of cognitive function, when compared with placebo and venlafaxine. Daily intakes of EPA and DHA were 1440 mg and 960 mg, respectively (113219).
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). Other clinical research in trained males shows that taking fish oil 5 grams, containing EPA 1882 mg and DHA 485 mg, orally daily for 4 weeks does not reduce muscle soreness after eccentric exercises when compared with placebo (111451). 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). Another small clinical trial in adults with overweight or obesity shows that taking fish oil (PronovaPure 500:200TG, Newtrition, BASF Pharma, Singapore) 4 grams daily for 4 weeks prior to and for 48 hours after a single high-intensity interval training cycling session modestly reduces calf pain, but not pain in the anterior or posterior thigh, compared with placebo (114188). These differing findings might be due to differences in patient populations due to their geographic location, but higher quality research is needed to confirm. Fish oil has also been evaluated as part of combination therapy. Preliminary clinical research in healthy untrained adults shows that taking a specific fish oil product (Nippon Suisan Kaisha Ltd) containing EPA 4.8 grams and DHA 2.08 grams, and branched-chain amino acid 9.6 grams orally daily for 8 weeks improves muscle soreness scores and range of motion after eccentric exercise when compared with placebo (111461). It is unclear if this effect is due to fish oil, branched-chain amino acid, or the combination.
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).
Frailty. It is unclear if oral fish oil is beneficial for preventing frailty. Details: Preliminary clinical research in community dwelling adults at least 70 years of age shows that taking fish oil 1 gram orally daily for 3 years does not reduce the odds of becoming pre-frail or frail over 36 months when compared with placebo (110829).
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 suggests 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 (15162,48105,97182,99364,113217). 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 stones (nephrolithiasis). It is unclear if oral fish oil is beneficial for preventing kidney stones. Details: A large observational study suggests that habitual use of fish oil by adults with low to moderate genetic risk is associated with a 16% reduced risk of developing kidney stones when compared with non-users of fish oil supplements. However, fish oil use was not associated with kidney stone prevention in adults with high genetic risk (113208).
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 suggests that there is a link 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). A meta-analysis of small randomized controlled trials in adult males with infertility shows that taking fish oil, containing DHA 400-720 mg and EPA 132-1,112 mg, orally daily for 10-32 weeks improves sperm concentration and sperm motility, but not pregnancy rates, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (111459).
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 (99363). However, a larger meta-analysis of low-quality clinical research in adults with menopausal symptoms shows that taking fish oil 300 mg-1800 with or without vitamin E 850 mg orally daily for 8-12 weeks modestly improves the intensity, but not frequency, of hot flashes when compared with control (111460). Evidence from one clinical trial also 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. It is unclear if supplemental fish oil is beneficial for reducing 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 providing EPA and DHA 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). Also, a clinical trial in patients with episodic migraines shows that taking fish oil 1 gram twice daily, providing EPA as ethyl ester 1.8 grams daily, for 12 weeks reduces the number of migraine days per month by 3.8 and the number of days requiring rescue analgesia per month by 1.2 when compared with placebo. Taking fish oil also improves headache severity, disability, anxiety, and depression. A sub-analysis shows that these beneficial effects are limited to females (114184). The reasons for these discrepancies are not clear but may be due to the dose, duration, and type of omega-3 fatty acids used. Also, some studies may have been inadequately powered to detect a difference between groups. 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 the treatment or prevention of Parkinson disease. Details: A large observational study suggests that habitual use of fish oil is associated with an 11% reduced risk of developing Parkinson disease when compared with non-users of fish oil supplements (113214). Also, preliminary observational research suggests that initiating supplemental fish oil is associated with a reduction in Parkinson symptoms (110343). However, 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 planing 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). Other clinical research in patients with periodontitis also receiving scaling and planing shows that taking high-dose fish oil, containing EPA 2.6 grams, 1.8 grams DHA, and other ingredients, orally once daily for 6 months improves bleeding and plaque scores, but not pocket depth, when compared with no intervention (111456). It is unclear if this effect is due to fish oil, other ingredients, or the combination. 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). Other subgroup analyses also suggest that fish oil may be more effective in patients with low baseline omega-3 levels and singleton pregnancy (111457). 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).
Pruritus. It is unclear if oral fish oil is beneficial in patients with pruritus. Details: A meta-analysis of low-quality clinical research in adults with pruritus while under palliative care shows that taking fish oil 2-6 grams for 20 days to 14 weeks significantly improves pruritus scores when compared with placebo (111455).
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). A network meta-analysis of clinical studies in adults with sarcopenia or at risk for sarcopenia shows that taking omega-3 polyunsaturated fatty acids at doses above 2.5 grams daily for 6-156 weeks improves upper-extremity muscle strength and lower-extremity physical function when compared with control or standard care. However, there was no improvement seen in skeletal muscle mass, fat mass, or overall body weight when compared with placebo or standard care. Subgroup analysis suggests that these effects endured even in the absence of concurrent resistance training programs (112470). 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 for the treatment or prevention of SLE. Details: A meta-analysis of 5 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). The relationship between fish oil use and the development of SLE has also been investigated. However, a large population study from the United Kingdom suggests no association between fish oil use and the risk of SLE (114183).
Tinnitus. It is unclear if oral fish oil is beneficial in the prevention of tinnitus. Details: An observational study in adults without tinnitus suggests that consuming DIETARY fish, including tuna fish, light-meat fish, or shellfish, once weekly is associated with a 13% reduced risk of persistent tinnitus, with more frequent consumption associated with a greater risk reduction. In contrast, taking SUPPLEMENTAL fish oil is associated with an increased risk of persistent tinnitus by approximately 12% (115738). The validity of these results is limited by the possibility of residual confounding, infrequent data collection on dietary intake, and the lack of data on the type of fish oil supplement used.
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.

EFFECTIVE

Familial hypophosphatemia. Oral vitamin D in combination with phosphate is effective for bone disorders in patients with familial hypophosphatemia. Details: Taking calcitriol or dihydrotachysterol orally in combination with phosphate supplements is effective for treating bone disorders in people with familial hypophosphatemia (11818).
Hypoparathyroidism. Oral vitamin D increases serum calcium concentrations in people with hypoparathyroidism or pseudohypoparathyroidism. Details: Vitamin D2 (ergocalciferol) is effective in high doses for increasing serum calcium concentrations in people with hypoparathyroidism or pseudohypoparathyroidism (11820). Also, taking vitamin D (form unspecified) or calcitriol postoperatively is effective for preventing hypocalcemia in people with hypoparathyroidism due to thyroidectomy (39045).
Osteomalacia. Oral vitamin D is effective for osteomalacia. Details: Oral calcifediol is effective for treating osteomalacia secondary to liver disease (hepatic osteodystrophy) and anticonvulsant-induced osteomalacia. Vitamin D2 (ergocalciferol) is effective for osteomalacia due to malabsorption syndromes, Fanconi syndrome, and corticosteroid-induced osteomalacia (11819,11821).
Renal osteodystrophy. Oral calcitriol prevents renal osteodystrophy in patients with chronic renal failure. Details: Taking calcitriol orally manages hypocalcemia and prevents renal osteodystrophy in patients with chronic renal failure undergoing dialysis (11823).
Rickets. Oral vitamin D prevents and treats rickets. Details: Vitamin D is effective for preventing and treating rickets, a consequence of vitamin D deficiency. Calcitriol should be used in patients with renal failure (11824). Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from vitamin D fortified foods, vitamin D supplements, or vitamin formulations that contain vitamin D to prevent nutritional rickets in children and adolescents aged 1 to 18 years. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502). A large clinical study in pregnant adults shows that taking vitamin D 28,000 IU weekly from the second trimester up to 6 months post-partum decreases the risk of biochemical rickets by about 84% in the offspring at 6-12 months of age when compared with placebo. However, taking vitamin D 4200, 16,800, or 28,000 IU weekly from the second trimester to delivery does not decrease the risk of rickets in the offspring when compared with placebo (114503).
Vitamin D deficiency. Oral vitamin D prevents and treats vitamin D deficiency. Details: Vitamin D is effective for preventing and treating vitamin D deficiency using a wide range of doses and dosing frequencies (7555,16888,16891,17476,115590). Optimal blood levels of 25-hydroxyvitamin D for maintaining bone density is controversial; however, it is typically estimated that blood levels of 20-100 ng/mL are needed. Toxicity usually does not occur until levels exceed 150 ng/mL (17476,93945). Vitamin D also alleviates symptoms and syndromes associated with vitamin D deficiency. Administering vitamin D2 (ergocalciferol) intramuscularly or orally seems to help treat severe proximal myopathy associated with severe vitamin D deficiency. Several case reports suggest vitamin D therapy can provide prompt relief of muscle weakness and restore mobility (11923,84348,84687).

LIKELY EFFECTIVE

Corticosteroid-induced osteoporosis. Oral vitamin D prevents corticosteroid-induced osteopenia and osteoporosis. Details: Taking calcifediol, cholecalciferol, calcitriol, or alfacalcidol orally prevents corticosteroid-induced osteopenia and osteoporosis (7555,83933). Vitamin D3 metabolites, including calcitriol and alfacalcidol, seem to be more effective at preventing bone loss compared to cholecalciferol in these patients, although the vitamin D3 metabolites seem to be inferior to bisphosphonates (83955). Furthermore, taking activated vitamin D or other forms of vitamin D alone or along with calcium improves bone mineral density in people with corticosteroid-induced osteoporosis (38493,38581).
Osteoporosis. Adequate intake of vitamin D in conjunction with adequate calcium intake helps to prevent the progression of osteoporosis. It might also reduce the risk of a first fracture in some patients. However, its place in the prevention of secondary fracture is unclear. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate vitamin D intake of 800-1000 IU daily along with adequate calcium intake for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake, with a target serum vitamin D level of 30 ng/mL (109425). In the US, foods that contain at least 120 IU vitamin D can be labelled with a health claim regarding the relationship between adequate vitamin D intake and a reduced risk for osteoporosis (97001). However, vitamin D supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Clinical research shows that vitamin D3 (cholecalciferol) and calcium can decrease postmenopausal bone loss, improve bone density, help prevent osteoporosis, and decrease the risk of fractures (10932,12926,12930,12934,12952) (38973,39015,39026,84003,113584). According to one analysis, taking oral vitamin D3 700-800 IU daily with or without calcium reduces fracture risk in ambulatory and institutionalized elderly people (12933). Other analyses suggest that taking vitamin D as cholecalciferol, ergocalciferol, calcifediol, calcitriol, or alfacalcidol with or without calcium can reduce the risk of all fractures by up to 17%, nonvertebral fractures by up to 49%, and hip fractures by up to 30% in older adults. However, the incidence of vertebral fractures does not appear to be reduced with vitamin D supplementation (38942,38970,38973,39015,39026,84660,109053). Despite the majority of research showing benefit, some studies have not found a positive effect of vitamin D on fracture risk. Some analyses of clinical evidence, including patients with and without osteoporosis, show that taking vitamin D3 or vitamin D2 (ergocalciferol) alone does not reduce fracture risk, suggesting that adequate calcium intake is needed for any benefit to be realized (39015,84471). Also, some evidence suggests that vitamin D3 400 IU daily is not effective for the prevention of osteoporotic fractures in elderly nursing home residents (109053). Another clinical trial found that taking vitamin D3 800 IU daily with calcium 1200-1500 mg daily for 2 years does not increase bone mineral density (BMD) in Black postmenopausal adults. This may be due to the fact that Black females have a lower rate of bone remodeling, an increased calcium absorption efficiency, and reduced calcium excretion when compared with other ethnic groups; therefore, supplementation with vitamin D3 and calcium might not be as beneficial in these patients (16878). There is concern that vitamin D might not be effective for secondary prevention of fractures in elderly patients. A meta-analysis of clinical studies, including many studies cited above, and a large clinical study in elderly adults with a previous osteoporotic fracture show that taking vitamin D3 400-4000 IU daily or as a single dose up to 500,000 IU orally or injected annually with or without calcium 480-1200 mg daily for up to 5 years does not reduce the risk of hip, vertebral, or other fractures when compared with placebo or no treatment (13073,112486). Another study also shows that taking vitamin D3 800 IU and calcium 1000 mg daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (under 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). However, these studies have been criticized for failing to measure vitamin D levels and low adherence to study protocol (12931). Also, one of these studies did not use a placebo control (12929). Taking alfacalcidol orally seems to maintain BMD in prostatic carcinoma patients at risk for osteoporosis when treated with luteinizing hormone-releasing hormone analogue (LHRH-a). Alfacalcidol maintains, but does not increase, BMD in these patients (6360).
Psoriasis. Topical vitamin D or vitamin D analogues improve symptoms of psoriasis. This benefit is not seen with oral vitamin D. Details: Topical application of vitamin D in the form of calcitriol or other vitamin D analogues, such as calcipotriene, maxacalcitol, and paricalcitol, effectively treats plaque psoriasis in some patients, including those with chronic plaque psoriasis (11822,84325). Applying topical vitamin D or its analogues in combination with topical corticosteroids such as betamethasone seems to be more effective for treating plaque psoriasis than either agent used alone (22283,82572,84325,84536,84647). Despite evidence that patients with psoriasis have low baseline serum levels of vitamin D, taking oral vitamin D does not seem to prevent psoriasis, improve symptoms, or reduce the severity of psoriasis in general (11822,22283,82572,84325,84536,84647,98193,108426,112481,112482). An analysis of a large clinical study in older adults with mild psoriasis shows that taking a vitamin D3 (cholecalciferol) loading dose of 200,000 IU followed by vitamin D3 100,000 IU monthly for 1 year does not affect the severity or spread of psoriasis when compared with placebo (98193).

Allergic rhinitis (hay fever). Some research suggests that oral vitamin D reduces symptoms of allergic rhinitis in children and adults. It is unclear if oral vitamin D during pregnancy is beneficial for the prevention of allergic rhinitis in the child. Details: Preliminary clinical research in adults with allergic rhinitis and vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 8 weeks along with cetirizine improves overall symptom severity when compared with placebo and cetirizine. This improvement was not significant at 4 weeks, suggesting that symptom improvement might not occur until vitamin D has been adequately replenished (102120). Another moderate-sized clinical study conducted in China in adults with moderate to severe allergic rhinitis and vitamin D levels at the low end of the normal range shows that taking vitamin D 800 IU daily for 4 weeks along with mometasone nasal spray improves runny nose, itchy nose, and nasal congestion but does not reduce sneezing when compared with placebo and mometasone (112483). In children aged 5-15 years, 4 small- or moderate-sized clinical trials show that taking vitamin D 800 IU or 1000 IU daily for 1-6 months modestly reduces symptoms such as nasal congestion and rhinorrhea when compared with placebo or no supplementation (109728). It is unclear whether these children had vitamin D deficiency at baseline. Vitamin D supplementation during pregnancy has also been evaluated. A meta-analysis of three large clinical studies shows that prenatal vitamin D supplementation does not reduce the risk of the child developing allergic rhinitis when compared with low-dose vitamin D, placebo, or no intervention (108438).
Coronavirus disease 2019 (COVID-19). Clinical research suggests that vitamin D deficiency is associated with greater risk for and severity of COVID-19 infection. Research of varying quality has evaluated the use of vitamin D supplementation in adults with COVID-19 infection, suggesting that it does not reduce overall mortality, but may reduce the risk of intubation and admission to the intensive care unit (ICU). It is unclear whether any benefits are correlated to baseline vitamin D status. Details: Clinical and observational research suggests that prophylactic vitamin D supplementation may reduce the risk for and severity of COVID-19 infection in people with vitamin D deficiency or insufficiency at baseline. An umbrella review of meta-analyses summarizing data from 9 observational studies suggests that vitamin D deficiency is associated with an increased risk for COVID-19 infection and a greater severity of illness when compared with control (114583). Additionally, a separate meta-analysis of 12 observational studies conducted early in the COVID-19 pandemic suggests that low baseline vitamin D status (25-hydroxyvitamin D levels below 30 ng/mL) is associated with a greater risk of severe COVID-19 pneumonia and mortality when compared with higher levels. However, patients with lower vitamin D levels were also more likely to have baseline hypertension and cardiovascular disease (107206). While earlier meta-analyses suggested that vitamin D supplementation did not prevent COVID-19 (109040,112488), a larger and more recent meta-analysis of 5 clinical studies conducted in healthcare workers, of whom 85-94% had vitamin D insufficiency or deficiency, shows that taking vitamin D reduces the odds of developing a COVID-19 infection by about 80% when compared with control. A separate meta-analysis of 2 clinical studies in the general population found no correlation between vitamin D supplementation and risk of COVID-19 infection; however, the people in these studies had adequate vitamin D levels at baseline (113590). The benefits of vitamin D prophylaxis in people with sufficient vitamin D levels is unclear. Clinical studies have evaluated the use of vitamin D supplementation in hospitalized adults with COVID-19, assessing hospital length of stay (LOS), the risk of ICU admission, and rate of intubation. Although meta-analyses conducted in the first year of the COVID-19 pandemic did not identify an association between vitamin D supplementation and any of these outcomes (107206,109733,112490), more recent meta-analyses suggest benefit in certain populations. Meta-analyses of clinical studies in adults with COVID-19 show that vitamin D supplementation may be correlated with a modest reduction in hospital LOS in certain patients when compared with placebo or a lower dose of vitamin D. Subgroup analyses suggest that this reduction may be limited to patients with non-severe disease and those aged 60-65 years and older (115575,115578). Additionally, more recent meta-analyses of clinical studies show that vitamin D supplementation reduces the risk of admission to the ICU when compared with control, although the odds ratio varies depending on the analysis conducted (112488,112490,115578). Similarly, meta-analyses of observational studies suggest that vitamin D supplementation is associated with a reduced odds of ICU admission when compared with control (113590,115578). Also, meta-analyses of clinical studies show that vitamin D supplementation modestly reduces the risk of intubation when compared with control (112488,115578). Meta-analyses of observational studies, as well as studies conducted early in the COVID-19 pandemic, originally suggested a potential reduction in mortality with the use of vitamin D supplementation during hospitalization (109040,114583,115578). However, more recent meta-analyses of prospective clinical studies do not support this finding. A meta-analysis of 19 clinical studies in adults with moderate to severe COVID-19 shows that vitamin D supplementation does not reduce mortality when compared with placebo or standard care, when controlling for heterogeneity. Additionally, a subgroup analysis of 13 clinical studies administering high-dose vitamin D does not show a reduction in mortality (115576). Other meta-analyses of clinical studies also show that vitamin D supplementation does not reduce mortality when compared with control, regardless of baseline vitamin D status (114488,115578). In most studies that provided vitamin D to hospitalized patients, oral doses ranged from 1000-25,000 IU daily for 1-3 weeks, 10,000-25,000 weekly for up to 6 weeks or until hospital discharge, or as a single 140,000-600,000 IU dose. In some studies, vitamin D 200,000-500,000 IU was administered intramuscularly as a single dose. Cholecalciferol was the most common form administered. However, some studies used calcitriol or calcifediol (107206,107208,109040,109733,112488,112490,113590,114583,115575,115578). Overall, the validity of the findings from meta-analyses is limited by the significant heterogeneity of the included studies, which enrolled patients of varying age, disease severity, and baseline vitamin D status, and implemented highly variable vitamin D supplementation protocols. The relationship between vitamin D levels and COVID-19 has also been evaluated in pregnant adults. A meta-analysis of observational research suggests that, while lower vitamin D levels are not associated with an increased risk of COVID-19, the presence of severe COVID-19 symptoms during pregnancy may be correlated to lower vitamin D levels when compared with non-severe COVID-19 symptoms (112025). Vitamin D has also been evaluated for post-COVID-19 symptoms. A clinical study in adults with vitamin D deficiency, as well as fatigue and neuropsychiatric symptoms for at least one month post-COVID-19, shows that taking vitamin D 60,000 IU weekly for 8 weeks modestly improves fatigue, anxiety, and some aspects of cognitive function, but not symptoms of depression, when compared with placebo (115580). It is unclear if the improvements in anxiety and cognitive function were clinically significant. Additionally, it is unclear if vitamin D supplementation is beneficial in adults with adequate baseline vitamin D levels.
Dental caries. Some research suggests that oral vitamin D reduces the risk of dental caries in children. Details: A meta-analysis of clinical research suggests that vitamin D3 (cholecalciferol) reduces the risk of cavities by 49%, and vitamin D2 (ergocalciferol) reduces the risk by 36% when compared with placebo in infants, children, and adolescents (84690). The validity of this finding is limited by the heterogeneity of the included trials. Also, clinical research shows an inverse correlation between cord blood vitamin D status and the number of decayed primary teeth in the infant at 12 months of age (104620). However, this same research shows that taking two oral prenatal doses of vitamin D2 50,000 IU during pregnancy does not prevent dental caries in the infant at 12 months of age or increase vitamin D levels in the cord blood (104620).
Heart failure. Limited research suggests that oral vitamin D reduces the risk of developing heart failure in some patients. However, vitamin D does not seem to improve outcomes in patients that have already developed heart failure. Details: Population research has found that vitamin D levels below 15 ng/mL are associated with increased risk of developing heart failure (16615). A meta-analysis of 17 trials, including the landmark Randomized Evaluation of Calcium Or vitamin D (RECORD) trial, shows that vitamin D reduces the risk of heart failure by 21% compared to not taking vitamin D in patients 60 years or older (91343). This finding is limited because none of the included trials were designed to determine effects on cardiovascular outcomes. In contrast, a secondary analysis of data from the Women's Health Initiative trial shows that taking vitamin D 400 IU with calcium 1000 mg daily is not associated with a reduced risk of heart failure in postmenopausal adults. However, a subgroup analysis of that trial shows that taking vitamin D plus calcium is associated with a 37% lower risk of developing heart failure in postmenopausal adults classified as low-risk for heart failure at baseline. It is speculated that high-risk patients might not benefit from vitamin D plus calcium due to negative interactions with medications used to manage cardiovascular risk factors in this group (97307). While vitamin D might be associated with a reduced risk of developing heart failure, most evidence suggests that vitamin D is not beneficial in patients already diagnosed with heart failure. In one small clinical trial, taking vitamin D3 50,000 IU weekly along with calcium citrate 800 mg daily for 6 months was not associated with an improvement in 6-minute walk test, timed get up and go test (TGUG), electrocardiographic variables, or health status when compared with placebo in adults with heart failure; mortality was not evaluated (97299,97300). In another clinical trial, taking vitamin D3 2000 IU daily did not decrease the risk of mortality when compared with placebo in New York Heart Association (NYHA) class 2 heart failure patients (16620).
Hyperparathyroidism-related bone loss. Limited evidence suggests that oral vitamin D is beneficial in patients with this condition. Details: Taking vitamin D3 (cholecalciferol) orally seems to help decrease secondary hyperparathyroidism and bone turnover in females. In one study, supplementation with vitamin D3 increased serum levels of 25-hydroxyvitamin D, reduced levels of parathyroid hormone, and decreased production of markers of bone turnover (3463).
Respiratory tract infections. Clinical research shows that oral vitamin D supplementation reduces the risk for respiratory tract infections (RTIs) in children but not in adults or older adults. Some clinical practice guidelines recommend vitamin D supplements or fortified foods for children to potentially lower the risk of RTIs. It is unclear if oral vitamin D is beneficial for the treatment of RTIs. Details: Prenatally, increased levels of vitamin D during pregnancy have been associated with a lower incidence of childhood RTIs (98197). However, two meta-analyses of small clinical studies and one meta-analysis of large clinical studies show no effect of prenatal vitamin D supplementation on the incidence of infant or childhood RTIs, including lower RTIs, when compared with control. Results related to risk of wheeze are conflicting (95910,95912,108438). In children, most research shows that vitamin D supplementation reduces the risk of RTIs. A meta-analysis of clinical trials in children aged 1-16 years shows that taking vitamin D decreases the odds of having an RTI by about 29% when compared with control, although this study also identified a high likelihood of publication bias (105721). Daily or weekly vitamin D doses seem to be more beneficial than single bolus doses, although the largest meta-analysis failed to confirm this result (84689,93766,105721). One clinical study in preterm Black infants shows that taking vitamin D3 (cholecalciferol) 200 IU daily and then 400 IU daily until 6 months of age does not affect the rate of RTIs, but does reduce wheeze by 11%, when compared with a normal diet without vitamin D supplementation (98191). This study may not have been powered to detect a difference in RTIs between groups. Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from vitamin D fortified foods, vitamin D supplements, or vitamin formulations that contain vitamin D to potentially lower the risk of RTIs in children and adolescents aged 1 to 18 years. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502). In adults, vitamin D supplementation does not seem to reduce the risk of RTIs. Observational research in adults has found that low levels of vitamin D are associated with worsened RTI complications, and even increased mortality in older adults ages 50-75 years (103659). However, meta-analyses of prospective clinical trials in adults show that taking vitamin D supplements 300-4000 IU daily for 7 weeks to 5 years or taking vitamin D 30,000-100,000 IU monthly or 96,000-120,000 IU every 2 months for 1-5 years does not reduce the odds of developing an RTI or severe respiratory complications, such as emergency department utilization, hospitalization, and death, when compared with placebo. These results were similar in subgroup analyses evaluating overall vitamin D dose and baseline vitamin D status (84689,105721,114506). The largest single clinical trial, conducted in adults at least 60 years of age, shows that taking vitamin D3 (cholecalciferol) 60,000 IU once monthly for up to 5 years reduces the duration of total and severe respiratory symptoms by approximately 0.5 days, but does not reduce the incidence of respiratory illness or hospitalization, when compared with placebo (105726,110825). When adults and children are evaluated together, vitamin D supplementation does not seem to reduce the risk of respiratory infections. Two large meta-analyses of 40 clinical studies in both children and adults shows that taking vitamin D does not reduce the risk of acute RTIs. While subgroup analyses suggest a potential modest reduction in risk of acute RTIs in studies not exceeding 4 months' duration and with daily supplementation of 400-1200 IU during winter, spring, and autumn, these findings are limited by the low quality of the evidence and publication bias (108435,115582). Vitamin D has also been evaluated for the treatment of RTIs. A large meta-analysis of clinical studies in both children and adults shows that taking vitamin D improves outcomes (e.g., sputum conversion, survival rate, therapeutic success, need for intensive care admission) by a small, but not clinically relevant, amount. In subgroup analyses, these beneficial effects only persisted in studies considered to be of low quality (108436). The validity of these findings is limited by publication bias.
Tooth retention. Oral vitamin D with calcium seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking vitamin D3 (cholecalciferol) 700 IU daily along with calcium citrate malate 500 mg daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

Cardiovascular disease (CVD). Most research shows that taking vitamin D with or without calcium does not reduce the risk of CVD or CVD complications. There is some speculation that there might be modest benefit in the elderly, but more research is needed to confirm. Details: Population research has found that low vitamin D levels, especially those below 15 ng/mL, are associated with an increased risk of developing CVD (15630,16618,93944,113588). However, taking vitamin D supplements does not seem to prevent CVD. The majority of evidence from clinical research, population research, and meta-analyses shows that vitamin D supplementation, with or without calcium, does not reduce the risk of mortality, myocardial infarction, cardiac-related hospitalizations, or stroke when compared with placebo in patients with or without CVD risk factors (91343,97296,97305,97308,98902,98916,99762,109729,110811,110827)(112021,112022,113588). The most reliable evidence comes from two meta-analyses of mainly high-quality clinical research investigating the effect of supplementation with vitamin D alone or with calcium for at least 1 year. These analyses show that vitamin D does not reduce major adverse cardiovascular events, stroke, CVD mortality, or all-cause mortality, regardless of baseline vitamin D level, vitamin D dosage, sex, formulation, or concomitant calcium supplementation (99762,109729). One large clinical trial in individuals at increased CVD risk shows that taking vitamin D as cholecalciferol 60,000 IU monthly modestly INCREASES the risk of CVD- and presumed CVD-related mortality (110827). The effect of vitamin D supplementation in elderly adults on CVD outcomes has also been evaluated. In some research, taking vitamin D 700-1000 IU daily shows a trend towards lower CVD events and reduced risk of major adverse cardiovascular events in elderly patients (11931,98916,99762). However, another study in adults aged 70 years or older without a history of cardiovascular events and who are vitamin D replete at baseline shows that taking vitamin D 2000 IU daily for 3 years does not decrease the risk of coronary heart disease, heart failure, stroke, or hypertension when compared with placebo (113581). Larger, high-quality trials with prespecified primary outcomes are needed to determine whether or not vitamin D supplementation reduces CVD risk in elderly populations.
Critical illness (trauma). Taking vitamin D 540,000 IU as a single oral dose does not reduce death or hospital stay in critically ill patients. However, limited research suggests that taking a smaller dose of vitamin D long-term might have a modest benefit. Details: The most robust evidence to date shows that correcting vitamin D levels in critically ill patients with vitamin D deficiency does not reduce mortality rate or duration of hospital stay. A large, multicenter clinical study in critically ill patients with vitamin D deficiency shows that administering a single, enteral dose of vitamin D 540,000 IU does not reduce 90-day all-cause mortality, duration of hospital stay, ventilator-free days, or other clinical outcomes when compared with placebo (103656). A previous meta-analysis of clinical research showed that vitamin D supplementation administered for a duration of 7 days or up to 6 months reduces the risk of death by 30% in critically ill hospitalized patients (95913). However, included studies were of low methodological quality, had high heterogeneity, assessed patients with and without vitamin D deficiency, and used variable vitamin D dose regimens and administrations methods (95913,95914).
Fractures. Most evidence shows that oral vitamin D alone does NOT prevent factures in people who do not have osteoporosis. Some research shows that taking vitamin D with calcium prevents fractures; however, more research is needed to determine who is most likely to benefit. Details: Clinical research shows that taking vitamin D alone does not seem to prevent fractures in older adults. Most adults in these studies did not have osteoporosis, although osteoporosis status was unclear in some research (10140,12933,14282,38970,39015,84660,95822,97296,102145,104619)(109059,110827). However, several meta-analyses suggest that taking higher doses of vitamin D (about 800 IU daily) in combination with calcium might reduce overall fracture risk in older patients (38942,38970,39015,84660,102145,110809). One meta-analysis of clinical research in community- or long-term care-living males and females at least 65 years of age shows that taking vitamin D 800 IU daily in combination with calcium reduces the risk of hip and non-vertebral fractures by 25% and 20%, respectively, compared with placebo (110809). However, discrepancies exist which are possibly related to the dose and form of calcium used in combination with vitamin D and/or the patient population. Some research shows that taking vitamin D 800 IU daily in combination with calcium 1200 mg daily as tricalcium phosphate reduces fracture risk by up to 31% while taking vitamin D with calcium carbonate does not reduce fracture risk (12929,14282,16878,110809). Some individual clinical studies in postmenopausal females aged 50-79 years show that taking vitamin D plus calcium daily for 2-7 years does not prevent fractures when compared with placebo (14282,16878). Other confounding variables include the possible additional effects of hormonal therapy when given with calcium to postmenopausal adults and/or the inclusion of institutionalized patients with unclear osteoporotic status (95822,97296). Most research shows that taking vitamin D in combination with omega-3 fatty acids does not prevent fractures. A large clinical study shows that taking vitamin D 2000 IU daily alone or with omega-3 fatty acids 1 gram daily and/or strength training three times weekly does not prevent fractures in adults over 70 years of age when compared with placebo (104619). Another large clinical trial shows that taking vitamin D 2000 IU daily, alone or with omega-3 fatty acids 1 gram daily, over approximately 5 years does not prevent overall fractures, nonvertebral fractures, or hip fractures in adults over 50 (males) or 55 (females) years old when compared with placebo. Although the osteoporosis status of the population was unclear, findings were consistent in adults at high fracture risk based on use of osteoporosis medications and/or a history of fragility fractures (109059). As of April 2018, the US Preventative Services Task Force (USPSTF) recommends against supplementing with vitamin D 400 IU daily or less along with calcium 1000 mg daily or less for preventing primary fractures in community-dwelling postmenopausal adults. The USPSTF also concludes that there is insufficient evidence to determine whether supplementing with doses of vitamin D greater than 400 IU daily along with calcium doses greater than 1000 mg daily is safe or effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture (95695). For information on patients WITH osteoporosis, refer to the Osteoporosis discussion. There is limited research available regarding the effects of vitamin D supplementation for fracture prevention in children. Preliminary research in children aged 2 to 17 years with vitamin D insufficiency and one or more previous fractures shows that taking vitamin D 2000 IU daily with calcium 600 mg daily for 6 months modestly reduces the risk of forearm fractures over 12 months compared with children not given vitamin D or calcium (110820).
Hypertension. Overall, vitamin D does not seem to prevent or lower high blood pressure in most patients; however, it may lower blood pressure in hypertensive patients with vitamin D deficiency. Details: Although population research has found that lower vitamin D levels are associated with a higher risk of developing hypertension, clinical research shows vitamin D supplementation does not prevent hypertension (15630). A large clinical trial in postmenopausal adults shows that taking vitamin D3 400 IU with calcium 1000 mg daily does not reduce the risk of developing hypertension (16714). Most meta-analyses and clinical trials in patients with existing hypertension show that vitamin D supplementation does not lower blood pressure when compared with placebo, regardless of vitamin D formulation, dose, or duration of supplementation (16714,91340,96405,103657,104619,113583,113668). However, a meta-analysis of 5 clinical studies in patients with hypertension and vitamin D deficiency shows that supplementation with vitamin D reduces systolic and diastolic blood pressure by about 7 mmHg and 3 mmHg, respectively, when compared with placebo (100895). Another meta-analysis of 11 clinical trials in patients over 60 years of age with hypertension and vitamin D deficiency shows that taking vitamin D supplements significantly reduces systolic, but not diastolic, blood pressure when compared with placebo, especially in trials lasting more than 8 weeks where the total dose of vitamin D is above 400,000 IU (113592). An individual clinical study in patients with hypertension and vitamin D deficiency or insufficiency shows that taking vitamin D 50,000 IU weekly or 1000 IU daily reduces systolic blood pressure by about 6 mmHg and mean arterial pressure by about 4 mmHg, but does not affect diastolic blood pressure, when compared to baseline (108440).
Prostate cancer. Oral vitamin D does not appear to affect prostate cancer progression or cancer-related mortality. Details: A meta-analysis of three clinical trials shows that vitamin D supplementation does not affect prostate cancer progression as measured by prostate-specific antigen (PSA), or mortality in patients with prostate cancer (99770).
Psychosis. Oral vitamin D does not seem to improve symptoms in patients with a functional psychotic disorder. Details: A clinical study in adults with a functional psychotic disorder shows that taking oral vitamin D3 (cholecalciferol) 20,000 IU monthly for 6 months has no effect on total positive and negative syndrome scale score (PANSS) when compared with placebo. The majority of patients included in this study were deficient in vitamin D at baseline (107226).
Tuberculosis. Oral vitamin D seems to be ineffective for reducing the severity of tuberculosis or mortality from tuberculosis. Limited research suggests that vitamin D may have small benefits in newly diagnosed patients receiving tuberculosis treatment for the first time. Details: Although population research has found that tuberculosis is associated with vitamin D deficiency, most clinical research shows that taking vitamin D does not improve clinical outcomes in people with tuberculosis infection. Meta-analyses and individual clinical studies show that taking vitamin D as a single 100,000 IU dose, or as 400 IU daily for 2 months, along with standard care does not improve tuberculosis severity or reduce the risk of mortality in children or adults with tuberculosis, regardless of their baseline vitamin D levels (82570,82475,98913,103655,103668,104022). However, some research has identified modest benefits in newly diagnosed patients receiving anti-tuberculosis treatment for the first time. A meta-analysis of clinical research in this population shows that taking vitamin D at a dose of 1000 IU daily or 600,000 IU monthly modestly increases the odds of sputum smear conversions by 1.2-fold, but does not improve the time to sputum smear conversions, when compared with placebo (98235). A small clinical study in treatment-naïve adults with low levels of serum vitamin D shows that taking calcitriol 0.25 mcg twice daily for up to 6 months, starting with anti-tuberculosis treatment initiation, decreases the time to sputum smear conversion and 50% lesion absorption by about 3 days when compared with not taking vitamin D (109045). Additionally, a small clinical study in children aged 6-18 years with vitamin D insufficiency receiving standard treatment for newly diagnosed pulmonary tuberculosis shows that taking vitamin D 1000 IU daily reduces the duration of fever and cough by 1 and 2 weeks, respectively, when compared with placebo (108437).

Acne. It is unclear if oral vitamin D is beneficial for acne. Details: A small clinical trial in patients with acne and vitamin D deficiency shows that taking cholecalciferol 1,000 IU daily for 2 months reduces the number of inflammatory lesions by about 35%, compared with 6% in those taking placebo. There was no effect on the total or non-inflammatory lesion count (106127). Other preliminary clinical research shows that taking alfacalcidol (One Alpha, LEO Company, Denmark) 0.25 mcg daily for 3 months modestly improves acne severity when compared with taking placebo (106128). In addition, population research has found that individuals with acne have modestly lower vitamin D levels than healthy controls. The odds of vitamin D deficiency were approximately three times higher in patients with acne when compared with healthy controls (106105).
Age-related cognitive decline. It is unclear if oral cholecalciferol is beneficial for preventing age-related cognitive decline. Details: Pooled results of two large clinical sub-studies in community-dwelling adults aged 60 years or older show that taking cholecalciferol 2000 IU daily for 2-3 years has no effect on cognitive decline when compared with placebo. A subgroup analysis in Black patients suggests a modest effect of vitamin D when compared with placebo (108428).
Alzheimer disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Some population research has found that lower serum concentrations of vitamin D are associated with higher risk of Alzheimer disease, and also with decreased cognition. People with Alzheimer disease seem to have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without Alzheimer disease (84672,103666). However, other population research has found that vitamin D deficiency (<25 nmol/L) or insufficiency (25-50 nmol/L) is not associated with increased risk of Alzheimer disease (100899).
Asthma. Oral vitamin D might reduce asthma exacerbations in adults and children with mild, but not severe or persistent, asthma. Vitamin D supplementation during pregnancy or the first 6 months of an infant's life does not seem to prevent the development of asthma later in infancy or childhood. Details: Population research in patients with asthma suggests that low vitamin D levels are associated with an increased risk of exacerbations and increased need for medication therapy (94693). However, findings from clinical research are mixed. Some meta-analyses of clinical trials in adults and children with asthma show that taking vitamin D for 3 months to 1 year reduces the rate of asthma exacerbations by 31% to 38% when compared with control (92690,94686,115584). However, other meta-analyses show that vitamin D supplementation does not reduce the risk of asthma exacerbations when compared with placebo (109728,109732,110833). The reasons for this discrepancy are not clear. However, some clinical research suggests that vitamin D supplements might only prevent asthma in people with non-persistent asthma (92690,94685,94686,94688,104020). Also, many studies are small and do not represent patients with severe asthma exacerbations (92690,94687). Baseline levels of vitamin D may play a role. A clinical study in children aged 6-16 years with persistent asthma and low vitamin D levels shows that taking vitamin D 4000 IU daily for 48 weeks does not reduce severe asthma exacerbations when compared with placebo (104020). However, a meta-analysis including this study shows that taking vitamin D does reduce risk of asthma exacerbations in children with low baseline vitamin D levels (109728). Additionally, two meta-analyses show that taking vitamin D seems to modestly improve pulmonary function when compared with placebo (109732,115584). Vitamin D doses have varied, with oral doses of 200-4000 IU daily, 1000-14,000 IU once weekly, 60,000 IU once monthly, 120,000 IU every 2 months, 100,000 IU 14 days apart, or 100,000 to 600,000 IU as a bolus dose followed by 400-4000 IU daily (92690,94686,104020,109728,110833,115584). Vitamin D supplementation for the prevention of asthma in infants has also been evaluated. A meta-analysis of 4 large clinical studies shows that taking vitamin D 400-1200 IU daily for the first 6 months of life does not reduce the risk of asthma or wheezing at 6-30 months of age when compared with control (112031). Vitamin D supplementation during pregnancy has also been evaluated (97306,99763,102146,112031). A meta-analysis of 3 large clinical studies shows that taking vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy reduces the risk of recurrent wheezing by 23% but does not reduce the risk of asthma diagnosis within the first 3-6 years of life when compared with vitamin D 400 IU daily (112031). Some research suggests that the dose of vitamin D plays a role. A meta-analysis shows that prenatal vitamin D 800 IU daily reduces the odds of wheeze or asthma by 32%, while lower or higher vitamin D doses were not beneficial (103661).
Athletic performance. It is unclear if oral vitamin D is beneficial for athletic performance. Details: One small clinical trial in athletes shows that taking vitamin D 20,000 or 40,000 IU once weekly for 2 doses does not affect performance on vertical jumps, sprints, or leg and bench presses when compared with placebo (98188). Another small clinical trial in professional rugby players shows that taking vitamin D3 (cholecalciferol) 50,000 IU once every two weeks over 12 weeks does not improve sprinting speed or the ability to perform bench presses, bench pulls, and chin-ups when compared with placebo (98189). Also, most research shows that taking vitamin D does not improve measures of cardiorespiratory fitness. One small study in young males undergoing resistance training shows that taking vitamin D 8000 IU daily for 12 weeks does not improve cardiorespiratory fitness compared with taking placebo (110812).
Atopic dermatitis (eczema). Most research shows that oral vitamin D reduces eczema severity in children. However, most research shows that oral vitamin D, taken during pregnancy or infancy, does not prevent eczema in the child. Details: A meta-analysis of eight moderate-quality clinical trials in children shows that taking vitamin D, most commonly 1000-2000 IU daily for 4-12 weeks, modestly reduces severity of eczema when compared with placebo (109728). Most of the children in these studies were also given conventional medications. Oral vitamin D has also been evaluated for eczema prevention. A meta-analysis of two clinical studies shows that consuming vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy is not associated with a reduced risk for eczema in children during the first 3 years of life when compared with vitamin D 400 IU daily (97306). Another meta-analysis of five large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing eczema when compared with low-dose vitamin D, placebo, or no intervention (108438).
Atrial fibrillation. It is unclear if oral vitamin D is beneficial for preventing atrial fibrillation. Details: A large clinical trial in adults without cardiovascular disease shows that taking vitamin D 2000 IU daily for an average of 5 years does not reduce the incidence of atrial fibrillation when compared with placebo or fish oil 840 mg daily (105209). However, observational research in postmenopausal adults with osteoporosis found that vitamin D supplementation is associated with a lower occurrence of atrial fibrillation when compared with not taking vitamin D (98922). Also, one large observational study in vitamin D-deficient patients with no history of atrial fibrillation has found that vitamin D supplementation for at least 6 months is associated with up to a 16% decreased risk of atrial fibrillation when compared with not taking vitamin D. There were also modest improvements in atrial fibrillation-free survival. In males 65 years and older with hypertension or diabetes at baseline, blood levels of at least 30 ng/mL following vitamin D supplementation were associated with decreased risk of atrial fibrillation; a post-supplementation blood level of 21-29 ng/mL was not associated with decreased risk (109043).
Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin D is beneficial for ADHD. Details: A small clinical trial in children 5-12 years of age with ADHD and vitamin D insufficiency shows that taking vitamin D 2000 IU daily along with methylphenidate for 8 weeks seems to improve parental ratings of evening, but not morning or overall, symptoms of inattentiveness and impulsivity when compared with methylphenidate alone. Vitamin D insufficiency was defined as levels less than 30 ng/mL (98196). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive use in children with ADHD, especially those with insufficient intake or skin exposure to sunlight (110318).
Autism spectrum disorder. It is unclear if oral vitamin D is beneficial for autism spectrum disorder. Details: A small clinical study in children aged 2.5-8 years with autism spectrum disorder shows that taking vitamin D 2000 IU daily for 12 months modestly reduces irritability and hyperactivity when compared with placebo (99767).
Autoimmune thyroiditis. It is unclear of oral vitamin D improves outcomes in patients with Hashimoto's thyroiditis. Details: A meta-analysis of 12 clinical trials in patients with Hashimoto's thyroiditis shows that taking vitamin D for at least 12 weeks increases free triiodothyronine (T3) and thyroxine (T4) levels, and reduces levels of thyroid stimulating hormone, thyroglobulin antibody, and anti-thyroid peroxidase antibody, when compared with placebo or no treatment (113593).
Back pain. It is unclear if oral vitamin D is beneficial for reducing chronic low back pain. Details: A meta-analysis of 10 clinical studies in adults with chronic low back pain shows that taking vitamin D does not reduce pain scores when compared with placebo, regardless of baseline vitamin D status or duration of supplementation. Oral vitamin D dosages used in these studies included 400-4000 IU daily for 1-6 months, 50,000 IU once weekly for 8 weeks, or 150,000-300,000 IU as a single dose. Intramuscular dosages ranged from 150,000-300,00 IU as a single dose (115588).
Bacterial vaginosis. It is unclear if oral vitamin D is beneficial for bacterial vaginosis. Details: Preliminary clinical research in females at high risk for sexually transmitted disease shows that taking vitamin D along with standard therapy for bacterial vaginosis does not reduce the prevalence of bacterial vaginosis when compared with placebo. Patients in this study had been treated with metronidazole 500 mg orally twice daily for 7 days along with vitamin D3 (cholecalciferol) 50,000 IU each week for 4 weeks and then every 4 weeks for the remaining 20 weeks (91348).
Bariatric surgery complications. It is unclear if vitamin D supplementation after bariatric surgery attenuates any bone health-related complications. Details: Clinical research in adults who had undergone bariatric surgery shows that vitamin D supplementation in doses of 800-7900 IU daily improves vitamin D status when compared with placebo. It is unclear if vitamin D supplementation in these doses for 1 year improves parathyroid hormone levels or bone mineral density or reduces fracture risk (115589).
Breast cancer. It is unclear if oral vitamin D is beneficial for the prevention of breast cancer. Details: Some population research evaluating intake of calcium plus vitamin D suggests that higher vitamin D intake is not associated with a reduced risk of breast cancer in premenopausal or postmenopausal adults (15631). Similarly, a large observational study in females with a biological sibling with breast cancer has found that taking vitamin D recently or prior to enrollment is not associated with a reduced risk of breast cancer when compared with nonrecent vitamin D use or never taking vitamin D, respectively (107215). However, other research found that higher vitamin D intake is associated with a 17% reduced risk of breast cancer in premenopausal and perimenopausal, but not postmenopausal, adults (39001). Observational research has also examined the association between blood levels of vitamin D and risk of developing breast cancer. A meta-analysis found that those with serum levels of about 52 ng/mL had a 50% lower risk of developing breast cancer when compared with those with serum levels of less than 13 ng/mL. This high serum level of vitamin D corresponds to a high dose of about 4000 IU daily (16049). Other observational research has found that baseline vitamin D levels of more than 20 ng/mL are associated with a 48% reduced risk of developing breast cancer over approximately 9 years in Latina females in the US when compared with levels below 20 ng/mL; however, this association was not present in Black females (109058). Despite the contradictory findings from observational research, results from clinical research are generally negative. Evidence from one large-scale clinical trial (Women's Health Initiative) shows that postmenopausal adults who take vitamin D3 (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years do not have a significantly reduced risk of developing breast cancer (16715,98895). Also, a meta-analysis of two large-scale clinical trials, which did not include the Women's Health Initiative trial, shows that taking vitamin D 800-1000 IU daily, alone or with calcium, for 3-4 years does not reduce the incidence of breast cancer in postmenopausal adults, although there was a trend towards reduced risk with higher doses of vitamin D supplementation (97301). While vitamin D and calcium supplementation during the intervention period of the Women's Health Initiative trial was not associated with a reduced risk of developing breast cancer or ductal carcinoma in situ (DCIS), a precursor to breast cancer, a secondary post-hoc analysis of the data shows that supplementation reduces the risk of developing DCIS by 18% over a median follow-up of 19 years (107216). Additional research is needed regarding an optimal dose of vitamin D, timing of initiation, and whether any benefit is affected by menopausal status.
Bronchopulmonary dysplasia. Limited research suggests that vitamin D deficiency is linked with bronchopulmonary dysplasia in the infant. Details: Observational research has found that vitamin D deficiency at birth is associated with about a 2-fold increased odds of developing bronchopulmonary dysplasia (104021). However, it is unclear if vitamin D supplementation is beneficial.
Cancer. Vitamin D does not seem to reduce overall cancer risk. However, some research shows that vitamin D might slightly reduce the risk of metastatic cancer and cancer-related mortality. Details: There is interest in vitamin D for cancer PREVENTION, as observational research suggests that higher vitamin D intake and higher 25-hydroxyvitamin D levels are associated with a lower risk of cancer (111150). While individual clinical trials evaluating vitamin D for cancer have produced inconsistent findings, most meta-analyses and clinical trials show that taking vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol) alone or with calcium does not significantly reduce the risk of developing cancer (15629,91344,93943,97296,98916,104024,104618,110811). However, vitamin D supplementation might reduce the risk of metastatic cancer and cancer-related mortality. A large clinical trial shows that taking vitamin D3 2000 IU daily for a median of 5.3 years slightly reduces the risk of advanced metastatic or fatal cancers when compared with placebo (104618). Additionally, meta-analyses of several large clinical trials show that taking vitamin D 400-4000 IU daily, with or without calcium, for 1-7 years reduces the risk of cancer-related mortality by 12-13% when compared with control, while intermittent bolus dosing of vitamin D at high doses for 1-5 years does not appear to reduce the risk of cancer-related mortality (104024,111149). The role of vitamin D in cancer TREATMENT is unclear. A meta-analysis of clinical and observational research suggests that supplementation of vitamin D after a cancer diagnosis is associated with a modest improvement in overall survival, but not progression-free or cancer-specific survival (109726). Doses used in clinical research ranged between 1200 IU and 8000 IU daily or 100,000 IU every 50 days, after surgery and/or during treatment (99195,99196,109726). Other clinical research in patients with luminal gastrointestinal cancers shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse when compared with placebo (99195). It is unclear which, if any, types or stages of cancer respond best to vitamin D, and what dose of vitamin D is optimal.
Child growth. It is unclear if oral vitamin D is beneficial for improving infant growth or bone structure. Details: Meta-analyses and individual clinical trials show that vitamin D supplementation during pregnancy modestly increases length at birth and bone mineral density at up to 7 years of age when compared with control, usually placebo or vitamin D 400 IU daily. However, there was no effect on length in the infant up to one year of age, weight at birth or up to one year of age, head circumference at birth or up to 6 years of age, bone mineral content at up to 6 years of age, or neonatal bone mineral density, bone mineral content, bone area, or femur or humoral length (98198,109737,112028,115585). In the available research, vitamin D was taken in doses of 200 IU to 4400 IU daily, 4200 IU to 50,000 IU weekly, 50,000 IU every 2 weeks, or 60,000 IU every 4-8 weeks, starting from the early to late stages of pregnancy and usually continued until birth (98198,109737,115585).
Chronic kidney disease (CKD). It is unclear if oral vitamin D is beneficial in patients with CKD. Most research suggests that it does not reduce the risk for adverse cardiovascular events. Details: Population research in patients on dialysis has found that vitamin D levels less than 17.8 ng/mL are associated with a higher risk of all-cause mortality compared with higher levels (16619). A meta-analysis and individual clinical studies show that vitamin D and vitamin D analogues decrease parathyroid hormone (PTH) levels and urine protein levels in people with CKD (84376,84377,84628,98233,98236). However, taking vitamin D does not appear to decrease the risk of death or parathyroidectomy in CKD patients (84376,84377). Also, taking vitamin D increases the risk for hypercalcemia and hyperphosphatemia in this patient population (84376,84377,98236). Vitamin D has also been evaluated for the prevention of cardiovascular events in adults with CKD. Observational research has found that vitamin D deficiency in patients with CKD is associated with adverse cardiovascular events. However, vitamin D supplementation does not seem to be beneficial. One clinical study shows that taking paricalcitol, an active form of vitamin D, titrated to maintain adequate serum calcium levels, for 48 weeks does not affect the size of the left ventricle or heart function when compared with placebo (98233). Other clinical research in Japanese patients on hemodialysis for CKD shows that adding alfacalcidol, another active form of vitamin D, 0.5 mcg daily to standard treatment for 4 years does not affect mortality or cardiovascular events such as myocardial infarctions, stroke, aortic dissection, and others compared to standard treatment only (98920). Also, a large clinical trial in patients with CKD shows that taking vitamin D as cholecalciferol 2000 IU daily, alone or with omega-3 fatty acids 1 gram daily, does not affect major cardiovascular events or invasive cancer when compared with placebo (110811). Vitamin D has also been evaluated for musculoskeletal health in adults with CKD. A small clinical study shows that taking cholecalciferol 4000 IU daily, with or without physical activity, for 3 months improves bicep strength, but not back flexibility or aerobic fitness capacity, when compared with baseline. In patients taking cholecalciferol in combination with physical activity, musculoskeletal health was similar when compared with cholecalciferol alone (108431). However, this study was inadequately powered to detect a difference between groups, and it is unclear if the improvement from baseline differed between groups. Vitamin D has also been evaluated for the improvement of iron status in adults with CKD and secondary hyperparathyroidism. Clinical research shows that taking Vitamin D as cholecalciferol (Vitamin D3 Forte Renapharma) 8000 IU daily for 12 weeks does not improve iron status compared with taking placebo. However, a sub-analysis shows that hemoglobin levels are modestly improved in patients with a low Vitamin D status at baseline suggesting that Vitamin D might improve iron availability in these patients (110819).
Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin D is beneficial for COPD; benefits may be limited to patients with severe vitamin D deficiency. Details: Population research has found an association between low vitamin D levels and reduced lung function, increased risk of developing COPD, and worsening COPD severity (17685,96401). However, 3 meta-analyses of clinical research in adults with COPD show that, overall, oral vitamin D does not have beneficial effects on mortality, rate of COPD exacerbations, pulmonary function, or most measures of symptom severity when compared with placebo (109732,112485,115586). A subgroup analysis suggests that any benefits of vitamin D supplementation may be limited to patients with severe vitamin D deficiency (25-hydroxyvitamin D levels below 25 nmol/L) at baseline (115586).
Cognitive function. It is unclear if oral vitamin D is beneficial for cognitive function. Details: Population research has found that low vitamin D levels are associated with worse cognitive performance and cognitive decline when compared to high vitamin D levels in healthy adults (84672,95916). However, the effect of vitamin D supplementation on cognitive function is unclear. One small meta-analysis of clinical research shows that vitamin D supplementation does not improve cognitive function (95916). However, the included trials evaluated a widely heterogeneous study population and utilized variable measures of cognitive function.
Cognitive impairment. It is unclear if oral vitamin D is beneficial for older adults with mild cognitive impairment. Details: A small clinical study in older adults with mild cognitive impairment shows that taking vitamin D3 10,000 IU three times weekly for 20 weeks in addition to exercise and cognitive training does not improve cognitive function when compared with placebo and exercise with or without cognitive training. However, most participants had sufficient serum vitamin D levels at baseline (112489).
Colorectal cancer. It is unclear if oral vitamin D is beneficial for the treatment or prevention of colorectal cancer. Details: Epidemiological research has found that a higher serum vitamin D level is associated with decreased risk of mortality and increased survival in patients with colorectal cancer (16101,99196). However, it is unclear whether vitamin D supplementation improves survival in patients with colorectal cancer, as research has generally involved small populations and results are somewhat conflicting. A subgroup analysis of one clinical study shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse or death, death due to any cause, or relapse over 5 years when compared with placebo in patients with colorectal cancer (99195). However, this subgroup may have been underpowered to detect between-group differences. Another small clinical trial in patients with advanced or metastatic colorectal cancer shows that taking high-dose vitamin D 8000 IU daily during the first cycle of chemotherapy, and then 4000 IU daily for subsequent cycles, does not increase median progression-free survival when compared with taking vitamin D 400 IU daily. However, patients taking high-dose vitamin D were 36% less likely to experience disease progression or death during follow-up when compared with patients taking the lower dose of vitamin D (99196). This latter result suggests that high-dose vitamin D supplementation might be beneficial for patients with advanced or metastatic colorectal cancer, but larger, multicenter studies are needed to confirm. The role of vitamin D in colorectal cancer prevention has also been investigated. A meta-analysis of epidemiological research has found that a higher serum vitamin D level is associated with a decreased colorectal cancer risk; however, sub-analyses suggest that this association only occurs in females, not males (109740). Most studies have evaluated vitamin D supplements in combination with calcium; the effects of vitamin D supplementation alone are unclear. One meta-analysis of clinical research suggests that taking vitamin D plus calcium is not associated with a decreased incidence of colorectal cancer in people with a low baseline risk of colorectal cancer (39042). Another meta-analysis of clinical research shows that vitamin D supplementation, with or without calcium, does not reduce the incidence of colorectal cancer or colorectal adenomas (109730). Additionally, a large clinical trial suggests that postmenopausal adults who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290,98895). One clinical study shows that taking calcium supplements reduces the risk of colorectal adenomas, but not in people with lower than average vitamin D levels (12118).
Crohn disease. Limited evidence suggests that vitamin D reduces relapses in patients with Crohn disease. Details: A meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). The validity of these findings is limited by the heterogeneity of the included studies.
Dementia. It is unclear if oral vitamin D is beneficial for dementia. Details: Population research has found that patients with any type of dementia have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without dementia (84672). However, it is unclear if vitamin D supplementation is beneficial.
Depression. It is unclear if oral vitamin D is beneficial for treating depression. Vitamin D does not seem to prevent the development of depression. Details: The role of vitamin D in the treatment of depression is unclear. Earlier meta-analyses of clinical research show that vitamin D supplementation does not improve overall symptoms of depression. However, some subgroup analyses suggest that vitamin D may be beneficial for improving the symptoms of depression in people with clinically significant symptoms, as well as those with baseline vitamin D deficiency (97295,97298). More recent meta-analyses of several clinical trials, that include some of the same studies, show that vitamin D modestly improves symptoms of depression in adults; however, subgroup analysis suggests that vitamin D does not improve depressive symptoms in older adults (110832,112786). These analyses are mixed over whether baseline vitamin D status affects results (110832,112786) and one of these analyses shows no evidence that the type of depression affects findings (110832). Another meta-analysis of generally small clinical trials in patients with type 2 diabetes and depression shows that taking vitamin D modestly improves depressive symptoms when compared with placebo or no intervention (110814). Although, results of an individual clinical trial in patients with type 2 diabetes are in contrast (108423). The evaluated research implemented one-time doses of 150,000-500,000 IU, as well as daily and weekly doses ranging between 400-5000 IU daily or 5000-100,000 IU weekly for 6 weeks to 2 years, with the most evidence of benefit related to one-time high doses. Cholecalciferol was the most common form of vitamin D used (97295,97298,108423,110814,110832,112786). Significant heterogeneity between studies and the wide variability in dosing strategies limit the validity of these findings, as well as identification of an effective dose or target population. Vitamin D has also been evaluated for the prevention of depression. One large clinical study (VITAL-DEP) in healthy patients 50 years and older shows that taking vitamin D 2000 IU daily for about 5.3 years does not prevent depression or depressive symptoms, or improve mood, when compared with placebo (103670). An analysis of a cohort of patients from the VITAL-DEP trial also shows that taking vitamin D 2000 IU daily for 2 years does not reduce the risk of major depressive disorder or improve mood scores in patients with subthreshold depression or risk factors for late-life depression when compared with placebo (112032). In addition, a meta-analysis of several clinical studies suggests that vitamin D supplementation does not prevent depression based on subgroup analysis of patients without depression at baseline (112786). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive or monotherapy use in patients with depression, especially those with insufficient intake or skin exposure to sunlight (110318).
Diabetes. Oral vitamin D might improve glycemic indices in some patients with type 2 diabetes and gestational diabetes. It is unclear if oral or intramuscular vitamin D is beneficial for the prevention of type 1 or gestational diabetes. Details: Most meta-analyses of mainly small clinical trials show that vitamin D supplementation is beneficial for measures of glycemic control in adults with diabetes. However, the best evidence of benefit is in people with baseline vitamin D deficiency. Five meta-analyses of clinical studies in patients with type 2 diabetes show that vitamin D supplementation reduces glycated hemoglobin (HbA1c) by 0.2% to 0.3%, and improves serum insulin, fasting blood glucose, and measures of insulin resistance when compared with control (96403,110822,112487,115581,115583). Supplemental vitamin D seems to be most beneficial in patients with baseline vitamin D deficiency or insufficiency (96403,107210,110822,112487,115581). Furthermore, correlation analysis suggests an inverse relationship between serum vitamin D levels and serum insulin, fasting blood glucose, and measures of insulin resistance (112487). In most clinical studies vitamin D supplementation ranged from 1000-6000 IU daily, 20,000-60,000 IU weekly, or 100,000-400,000 IU once over 8-48 weeks (96403,107210,110822,115581,115583). Most analyses exhibited significant heterogeneity related to vitamin D dosing regimen, geographic location, and patient population. However, one meta-analysis of clinical research in patients with diabetes shows that vitamin D improves HbA1c, insulin resistance, and insulin measures in studies lasting less than 6 months, but not in studies lasting longer than 6 months (99764). An additional meta-analysis suggests that most evidence of benefit is associated with doses of more than 2000 IU daily for 4-12 weeks (110822). Another meta-analysis suggests that benefits may be greater in adults with less severe obesity and a shorter duration of type 2 diabetes (115583). Vitamin D has been evaluated for the prevention of type 1 diabetes. There is preliminary evidence that daily vitamin D supplementation (form not specified) in infants during the first year of life is associated with a reduced incidence of type 1 diabetes development later in life (10139). Also, a meta-analysis of population studies has found that vitamin D supplementation in early childhood is associated with a 29% reduced risk of developing type 1 diabetes later in life (84225). Vitamin D has been evaluated in adults with gestational diabetes, yielding conflicting findings. One clinical trial shows that oral vitamin D 50,000 IU every 4 weeks modestly reduces levels of insulin, as well as measures of insulin resistance, with no effect on fasting blood glucose (106125), whereas other clinical research shows that this same dosing regimen modestly reduces levels of fasting blood glucose and HbA1c, with no effect on insulin measures (106126). A separate clinical study shows that taking oral vitamin D 500 IU twice daily in yogurt modestly improves all measures of glycemic indices (101775). Additionally, a large clinical trial shows that taking oral vitamin D 1600 IU daily modestly reduces fasting blood glucose when compared with vitamin D 400 IU daily (112020). Some clinical research also shows that oral vitamin D modestly improves levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides when compared with control (106125,110823), although not all research agrees (106126). Also, a meta-analysis of clinical research shows that taking oral vitamin D reduces the risk of premature birth and neonatal hospitalization by approximately 63% and 62%, respectively (110823). A meta-analysis of 5 small clinical studies shows that taking oral vitamin D 400-1000 IU daily for 6 weeks or 50,000 IU twice over 6 weeks along with calcium decreases fasting plasma glucose and serum insulin when compared with placebo (115579). One small clinical study shows that giving vitamin D 300,000 IU as a single intramuscular injection at 24-28 weeks' gestation does not affect HbA1c (106124). Vitamin D has also been evaluated for the prevention of gestational diabetes. A Cochrane analysis of one large clinical study shows that taking vitamin D during pregnancy does not lower the risk of gestational diabetes when compared with no supplementation (114587). In addition, a meta-analysis of population studies suggests that there is a U-shaped association between serum vitamin D levels and the risk of developing gestational diabetes, with 25-hydroxyvitamin D levels of 40-90 nmol/L associated with the lowest risk (106109). A meta-analysis of clinical research in adults with insulin resistance during pregnancy, but not gestational diabetes, shows that taking vitamin D at varying doses for 6-26 weeks modestly decreases measures of insulin resistance when compared with placebo (110821). However, this study did not evaluate whether vitamin D prevented the development of gestational diabetes in these patients. Vitamin D has also been evaluated in combination with other ingredients. One study evaluated vitamin D in combination with eicosapentaenoic acid (EPA) 360 mg plus docosahexaenoic acid (DHA) 240 mg twice daily, suggesting that this combination improves glycemic markers when compared with taking vitamin D alone (106122). Other clinical research in patients with gestational diabetes shows that taking vitamin D with omega-3 fatty acids 8,000 mg twice daily for 6 weeks modestly improves glycemic indices when compared with placebo (106114). However, it is unclear if these effects are due to vitamin D, other ingredients, or the combination.
Diabetic foot ulcers. It is unclear if oral vitamin D is beneficial for diabetic foot ulcers. Details: A meta-analysis of clinical research in patients with diabetic foot ulcers shows that taking vitamin D modestly reduces ulcer size and improves glycemic and lipid indices when compared with placebo (110835). This meta-analysis is limited by the availability of three small clinical trials, as well as the heterogeneous doses of vitamin D in the included studies.
Diabetic nephropathy. Limited evidence suggests that vitamin D improves some markers of kidney function in patients with diabetic nephropathy. Details: A meta-analysis of small clinical studies in patients with diabetic nephropathy shows that taking vitamin D or its analogs reduces inflammatory markers and protein in the urine, but does not affect measures of kidney function such as serum creatinine or glomerular filtration rate, when compared to control (99771).
Diabetic retinopathy. It is unclear if oral vitamin D is beneficial in diabetic retinopathy. Details: There is weak evidence from observational research suggesting a link between vitamin D deficiency and diabetic retinopathy (112095). However, clinical research addressing the effectiveness of vitamin D supplementation for treatment or prevention of diabetic retinopathy is lacking.
Dysmenorrhea. Limited evidence suggests that oral vitamin D reduces pain in patients with dysmenorrhea. Details: A meta-analysis of 9 small clinical studies in patients with dysmenorrhea shows that taking vitamin D in doses ranging from 5000 IU daily to 300,000 IU monthly modestly reduces pain when compared with control (112029). However, the validity of these findings is limited by a high degree of heterogeneity across the studies, including differences in blinding and control interventions, vitamin D doses and frequency of supplementation, and baseline vitamin D levels. Another small clinical study in adolescent patients with dysmenorrhea shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces pain when compared to baseline (98912). The validity of this finding is limited by the lack of a control group.
Erectile dysfunction (ED). It is unclear if oral vitamin D is beneficial for ED. Details: Although some data suggest ED is associated with low serum 25-hydroxy-vitamin D levels, preliminary research in males aged 60-84 years shows that taking vitamin D 60,000 IU once monthly for up to 5 years does not prevent or improve ED when compared with placebo (113580).
Exercise-induced muscle damage. Small studies suggest that vitamin D does not improve exercise-induced muscle damage. Details: A meta-analysis of 6 small studies shows that taking vitamin D before and/or during exercise does not improve circulating levels of creatine kinase, lactate dehydrogenase, or myoglobin when compared with placebo (107218).
Fall prevention. The role of vitamin D in fall prevention is confusing and controversial. Most clinical research shows that taking vitamin D 800-1000 IU daily decreases the risk of falls, with effects most apparent with daily over intermittent dosing and in those with vitamin D deficiency or insufficiency. Taking vitamin D at doses higher or lower than this may be associated with increased risk of falls. Details: Higher serum levels of vitamin D have been associated with improved lower-extremity function in elderly adults (15636). Clinical research in older adults shows that taking vitamin D or vitamin D analogues, with or without calcium, reduces the number of people who have a fall by up to 19% (39038,84215,84374,84539,94130,104023,113595,114504). Other research shows that vitamin D, with or without calcium, reduces number of falls by 19% to 50% (11939,16275,84404,93941,109053). The beneficial effect does not appear to depend on the form of vitamin D used (ergocalciferol, cholecalciferol, calcitriol, or alfacalcidol) (39038,84374,113595). Multiple meta-analyses of clinical research show that taking vitamin D leads to a decreased rate of falls in patients with low baseline levels of vitamin D, but not in those with adequate vitamin D levels (84670,84684,109053,114504). One meta-analysis also suggests that taking vitamin D as cholecalciferol up to 1000 IU daily reduces fall risk by up to 19%, whereas higher doses do not reduce fall risk (109053). Also, daily dosing, but not intermittent dosing, seems to be associated with a reduced risk of falling (109053,114504). Similarly, another meta-analysis of clinical research shows that taking vitamin D 800-1000 IU daily, with or without calcium, lowers the risk of falls by about 15-26% when compared with placebo, no treatment, or calcium alone. However, taking vitamin D 500 IU or less daily and vitamin D 1100 IU or more daily, with or without calcium, is not associated with a lower risk of falls and may even increase the risk of falls by 22-44% (114504). Despite the above meta-analyses, other clinical research shows that vitamin D does not reduce the risk of falling (84404,84670), the rate of falls overall (84670,93942), or the rate of injurious falls (93942) in elderly patients (93942). One study in adults over 70 years of age with a history of falling found that taking high-dose vitamin D, either as 60,000 IU monthly or 24,000 IU plus calcifediol 300 mcg monthly, increased both the risk of falling and the mean number of falls compared to a lower dose of 24,000 IU monthly (93940). One meta-analysis of 20 trials including nearly 30,000 patients shows that taking vitamin D, with or without calcium, does not reduce the risk of falling in elderly patients, regardless of baseline 25-hydroxyvitamin D levels, level of 25-hydroxyvitamin D achieved with treatment, duration of treatment, or residential status of the patients (91342). While a meta-analysis of 10 trials in nearly 6,000 patients shows that taking vitamin D 700-1000 IU daily with calcium 1000-2000 mg daily reduces the risk of falling in the elderly by 12% when compared with placebo or no treatment, a meta-analysis of 21 trials in nearly 52,000 patients shows that vitamin D alone is only associated with a reduced risk of falls in patients with baseline vitamin D levels of less than 50 nmol/L when compared with placebo or no treatment (107224). The 2018 US Preventative Services Task Force (USPSTF) guidelines for fall prevention acknowledges this research by recommending AGAINST vitamin D supplementation for fall prevention in community dwelling adults 65 years of age and older who do not have osteoporosis or vitamin D deficiency (95703). The reasons for the disparate study results may have to do with the way in which clinical trials have reported outcomes. Clinical trials assessing the effect of vitamin D on fall risk may report results as the number of patients who experience one or more falls, the total number of falls, or the rate of falls per individual. This can affect ultimate conclusions and, in some cases, can be misleading. For example, when studies report on only the total number of falls, it is unclear if vitamin D reduces the rate of falls across the study population, or if it only reduces falls in a small subset of patients. Also, analyses of research suggest that the size of the clinical study appears to affect the trial results. Most trials showing significant reductions in fall risk have been small and of short duration (91342,94132); whereas larger and longer-term studies tend to show no benefit (13073,84399).
Fetal and premature infant mortality. Taking vitamin D during pregnancy might reduce the risk of fetal or early infant death. Details: A meta-analysis of clinical research shows that vitamin D supplementation during pregnancy reduces the risk of intrauterine or neonatal death by 31% when compared with not supplementing with vitamin D. A sub-analysis shows that this benefit was limited to doses of up to 4000 IU daily (109055). However, a Cochrane review suggests that the evidence linking vitamin D supplementation to a lower risk of fetal or neonatal death is very uncertain (114587). Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of intra-uterine and neonatal mortality, preeclampsia, preterm birth, and small for gestational age (SGA) birth. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
Fibromyalgia. A small clinical study suggests that vitamin D might improve pain in patients with fibromyalgia. Details: A small clinical study in fibromyalgia patients with low vitamin D levels shows that taking vitamin D3 (cholecalciferol) 1200-2400 IU daily seems to reduce pain, but not mood or quality of life, when compared with placebo (91349).
Food allergies. It is unclear if prenatal or infant oral vitamin D supplementation reduces the risk of developing food allergies. Details: A meta-analysis of two large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing food allergies when compared with low-dose vitamin D or no intervention (108438).
Frailty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of frailty in older adults. Details: Frailty involves a combination of muscle loss and weakness, with exhaustion and reduced ability for physical activity. Some observational research has found that low vitamin D status is associated with frailty occurrence. However, clinical research in community dwelling older adults shows that taking vitamin D as 1000 IU, 2000 IU, or 4000 IU daily for 24 months does not prevent frailty or attenuate the worsening of frailty when compared with low-dose vitamin D 200 IU daily. Baseline vitamin D status did not affect these findings. Also, a sub-analysis suggests that vitamin D 2000 IU might increase frailty; however, only a small number of participants were randomized to this dose (109046). Other clinical research in community dwelling adults at least 70 years of age shows that taking cholecalciferol 2000 IU daily for 3 years does not reduce the odds of becoming pre-frail or frail over 36 months when compared with placebo. However, when taken in combination with omega-3 fatty acids 1 gram daily and a home exercise program, the odds of becoming pre-frail is reduced by 39% (110829).
Generalized anxiety disorder (GAD). A small clinical study suggests that vitamin D may modestly improve anxiety in patients with GAD. Details: A small clinical study in patients with GAD shows that taking vitamin D 50,000 IU once weekly for 3 months, in addition to taking an antidepressant and an anxiolytic, moderately reduces anxiety scores when compared with taking these medications alone (103654).
Hematopoietic stem cell transplant (HSCT). It is unclear if oral vitamin D is beneficial for improving outcomes in patients receiving HSCT. Details: A small clinical study in patients who have undergone an autologous HSCT shows that taking calcitriol 0.25 mcg three times daily for 30 days can reduce the time to absolute lymphocyte count recovery, but does not affect time to recovery of absolute neutrophil and platelet counts, when compared with placebo (103665).
Hepatitis C. Low levels of vitamin D have been associated with an inadequate response to hepatitis C therapy. Adding vitamin D to standard therapy for hepatitis C may improve viral response, especially in specific genotypes. Details: A small clinical trial in patients with hepatitis C genotypes 2-3 receiving standard therapy with PEG-interferon and ribavirin shows that adding vitamin D 2000 IU daily for 24 weeks results in 95% of patients achieving undetectable levels of hepatitis C RNA, compared to only 77% of patients treated with standard therapy alone (98917). Another small clinical study in patients with hepatitis C genotype 1b receiving the same standard therapy shows that adding vitamin D 1000 IU daily for 16 weeks results in about 79% of patients achieving undetectable levels of hepatitis C RNA, compared to about 55% of patients treated with standard therapy alone. The TT genotype seems to be especially susceptible to vitamin D supplementation, while TG/GG genotype does not seem to be susceptible (98923).
HIV/AIDS. It is unclear if oral vitamin D is beneficial for improving bone mineral density (BMD) in children and young adults with HIV. Details: Vitamin D deficiency and hyperparathyroidism are common in children and young adults with HIV. A meta-analysis of two clinical trials in this population shows that taking cholecalciferol for 12 months does not improve spine BMD when compared with placebo. Also, an analysis of two clinical trials shows that taking doses of 1600 IU to 4000 IU daily does not improve spine BMD when compared with taking doses of 400-800 IU daily. However, taking higher dose vitamin D has a small beneficial effect on total BMD when compared with taking lower doses. There was no improvement on parathyroid hormone levels (110824). This meta-analysis is limited by the availability of small clinical trials, as well as the heterogeneous doses of vitamin D used in the included studies.
Hyperlipidemia. Although population research has found that higher vitamin D levels are associated with improved lipid levels, it is unclear if vitamin D supplementation is beneficial. Clinical research results are conflicting. Details: Population research has found that higher vitamin D levels are associated with lower low-density lipoprotein (LDL) cholesterol and triglyceride levels and higher high-density lipoprotein (HDL) cholesterol levels when compared with lower vitamin D levels (15630,98919). However, supplementation might not be beneficial. A meta-analysis of small clinical studies suggests that taking vitamin D as cholecalciferol, ergocalciferol, alfacalcidol, or calcitriol slightly increases LDL cholesterol, but does not affect total cholesterol, triglycerides, or HDL cholesterol, when compared with placebo (84642). The validity of these findings is limited by the variability in patient populations, vitamin D dose and formulation, and study duration. Also, none of the included studies were prospectively designed to test the effect of vitamin D on lipid levels. Another meta-analysis of clinical studies in a mixed population of healthy adults and adults with metabolic disease shows that taking vitamin D 1400-50,000 IU weekly with calcium 500-2000 mg daily results in very modest improvements in total cholesterol, triglyceride, and HDL cholesterol levels, but not LDL or very low-density lipoprotein (VLDL) cholesterol levels, when compared with placebo. Subgroup analyses suggest that effects are more pronounced in people with metabolic disease (107227). The validity of these findings is limited by the heterogeneity of the included studies, which persisted throughout subgroup analyses.
Hyperthyroidism. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research suggests that serum vitamin D levels are decreased in patients with newly diagnosed Graves' disease. A small preliminary clinical trial in patients with newly diagnosed Graves' disease taking methimazole and low levels of selenium and vitamin D shows that taking vitamin D as cholecalciferol for 270 days, in combination with selenium for the first 180 days, modestly reduces levels of serum free thyroxine and improves quality of life when compared with no vitamin D or selenium. However, taking vitamin D and selenium did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
Hypothyroidism. It is unclear if oral vitamin D is beneficial in the treatment of subclinical hypothyroidism. Details: Preliminary clinical research in patients with vitamin D deficiency and subclinical hypothyroidism shows that taking vitamin D 50,000 IU weekly for 2-12 weeks decreases mean thyroid stimulating hormone levels by about 20% when compared with placebo, or by 3.55 mIU/L when compared to baseline (107213,113589).
Ichthyosis. It is unclear if oral vitamin D is beneficial in patients with inherited ichthyosis. Details: A small clinical study in patients with congenital non-syndromic ichthyosis shows that taking vitamin D 2000 IU daily for 24 weeks reduces the clinical severity of disease at 12 weeks, but not 24 weeks, when compared with baseline. When compared with patients taking acitretin 0.5 mg/kg daily, results were similar at both 12 and 24 weeks, but it is unclear if the improvement from baseline differed between groups (108441).
IgA vasculitis. It is unclear if oral alfacalcidol is beneficial in children with IgA vasculitis. Details: A clinical study in children with IgA vasculitis shows that taking alfacalcidol 0.25 mcg daily along with vitamin C, rutin, dipyridamole, cimetidine, calcium, and glucocorticoids for 4 weeks improves rates of recurrence and incidence of kidney damage when compared with those receiving the same regimen without alfacalcidol. Alfacalcidol also improves cellular immune function and reduces levels of inflammatory biomarkers (107212).
Irritable bowel syndrome (IBS). It is unclear if oral vitamin D is beneficial for IBS; the available research is conflicting. Details: Although some meta-analyses show that taking vitamin D is moderately more effective than placebo for improving IBS symptom severity and quality of life, other analyses disagree. Doses of vitamin D have included 50,000 IU weekly or every 2 weeks or 2000-4000 IU daily for up to 6 months (109041,109054,109057). The reasons for these discrepancies might be attributed to the inclusion criteria related to the individual trials, the small sample sizes, and varied dosing strategies used in the available research.
Kidney transplant. It is unclear if oral cholecalciferol is beneficial for improving allograft function or preventing non-skeletal complications in kidney transplant recipients. Details: Following a kidney transplant, patients are at increased risk of vitamin D insufficiency and related outcomes. A large clinical trial shows that taking a high dose of cholecalciferol for 2 years does not reduce the composite risk of developing type 2 diabetes, major cardiovascular events, or cancer, or death when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). The effect of a high dose of vitamin D on these outcomes individually is not clear. However, taking vitamin D does not seem to improve allograft function. A clinical study in kidney transplant recipients shows that taking cholecalciferol 4000 IU daily, beginning 1-month posttransplant and continuing for 11 months, has no effect on allograft function when compared with placebo (108425).
Kidney transplant-related bone loss. Oral vitamin D might be beneficial for preventing bone loss associated with kidney transplantation. Details: A large clinical trial shows that taking a high dose of cholecalciferol for 2 years modestly reduces the odds of a fracture by 76% when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). A prespecified secondary analysis of a clinical study in patients at 1-month post-kidney transplant from a living donor in Japan shows that taking vitamin D (cholecalciferol) 4000 IU daily for months 1-12 posttransplant reduces whole blood parathyroid hormone levels by 15%, but does not alter levels of tartrate-resistant acid phosphatase 5-b or bone-specific alkaline phosphatase, when compared with placebo. The greatest effects on parathyroid hormone levels are observed in those with more severe vitamin D deficiency, hypocalcemia, and more preserved kidney function. Vitamin D supplementation also attenuates changes in bone mineral density (BMD) at the lumbar spine, but not the distal radius, from prior to transplant. Patients taking vitamin D had a loss of only 0.2%, compared with a loss of 2% in those receiving placebo. The greatest effects are observed in those with osteoporosis or osteopenia (107220). Conversely, a small clinical trial shows that taking calcitriol (1,25-dihydroxyvitamin D3) 0.25 mcg daily in combination with calcium carbonate 500 mg daily does not decrease bone loss associated with kidney transplantation. However, calcitriol might reduce osteoclast suppression, help maintain trabecular bone volume and wall thickness, and improve axial BMD (4823).
Impaired glucose tolerance (prediabetes). Taking vitamin D might slow prediabetes progression to diabetes in people with low baseline levels of vitamin D or in people achieving high levels of vitamin D following supplementation. It is unclear if vitamin D supplementation is beneficial in people with prediabetes and sufficient vitamin D levels. Details: Observational research has found that low vitamin D levels are linked with a higher risk of prediabetes and higher dietary vitamin D is linked with a lower chance of developing diabetes (84594,103669). Meta-analyses and individual clinical studies in patients with prediabetes and unclear or sufficient vitamin D levels show that vitamin D supplementation might improve some glycemic indices, but does not seem to prevent progression of prediabetes to diabetes (84594,91347,99769,108421). However, a more recent meta-analysis of 3 clinical studies designed to evaluate the preventative effects of oral vitamin D shows that taking it in the form of cholecalciferol 4000 IU daily or 20,000 IU weekly or eldecalcitol 0.75 mcg daily reduces the risk of developing diabetes with an absolute risk reduction of 3.3% over 3 years when compared with placebo. However, the actual risk reduction is highly dependent on vitamin D status. Patients achieving the highest serum vitamin D levels have absolute 3-year risk reductions of 11.4% to 18.1% (110810). In patients with vitamin D deficiency and prediabetes, vitamin D might improve beta-cell function, suggesting reduced disease progression (99768,107210). One clinical study in adults with vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 3 months, and then monthly for 3 months, modestly improves insulin resistance and beta-cell function as measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), but does not affect fasting or postprandial glucose levels when compared with placebo (99768). Further, a meta-analysis of randomized controlled trials in patients with vitamin D deficiency and prediabetes shows that oral vitamin D at a median dose of 50,000 IU weekly for 26 weeks modestly improves fasting blood glucose and some markers of islet function, but not postprandial blood glucose or glycated hemoglobin (HbA1c) levels, when compared with control. Additionally, a significantly greater proportion of patients receiving vitamin D supplementation regressed from prediabetes to normal glucose status (107210). A meta-analysis of clinical studies in overweight or obese children and adolescents shows that high doses of vitamin D, 4000 IU daily or higher for 12-52 weeks, reduce HOMA-IR and C-reactive protein levels, but do not affect body weight, cholesterol, or parathyroid hormone (113596). A study in females with vitamin D deficiency and prediabetes shows that taking vitamin D 60,000 IU weekly for 8 weeks, followed by a maintenance dose of 200 IU daily, has no effect on the incidence of type 2 diabetes at 2 years (107211). Clinical practice guidelines from the Endocrine Society conditionally recommend, with moderate certainty of evidence, empiric vitamin D supplementation in addition to lifestyle modification for adults with high-risk prediabetes to reduce the risk of progression to diabetes. Empiric vitamin D supplementation is defined as vitamin D from supplements or fortified food above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
Infant development. It is unclear if giving oral vitamin D in doses above the recommended dietary allowance during infancy is beneficial for improving neurodevelopment. It is also unclear if oral vitamin D during pregnancy is beneficial for improving cognitive development in the offspring. Details: Clinical research shows that giving vitamin D 1200 IU daily to healthy term infants of Northern European ethnicity starting at 2 weeks of age does not improve measures of neurodevelopment at 2 years of age when compared with giving the standard dose of vitamin D 400 IU (106121). Overall, the evidence from population research is mixed as to whether vitamin D status during gestation is associated with infant developmental outcomes. However, some population research has found that increased vitamin D status during pregnancy is associated with improved anthropomorphic and neurodevelopmental outcomes (104621,105724). Two meta-analyses of observational research show that low vitamin D status during pregnancy is associated with reduced head circumference and cognitive development scores, and higher odds of the offspring developing autism and attention deficit hyperactivity disorder (105724,105725). However, one meta-analysis suggests these risks may be limited to those with very low vitamin D status (serum level < 12 ng/mL) (105724). Multiple meta-analyses show that vitamin D status during pregnancy does not appear to affect motor development (105724,105725). In one observational study, plasma vitamin D concentrations in the second trimester of pregnancy was associated with increased IQ scores in the offspring at age 4-6 years. Each 10 ng/mL increase in vitamin D levels was associated with a 1.17-point increase in IQ (104621). In contrast, clinical research shows that taking vitamin D3 2800 IU daily during the third trimester does not improve neurodevelopmental outcomes in the first 6 years of life when compared to taking lower doses of 400 IU daily (104623).
Infertility. It is unclear if oral or intramuscular vitamin D is beneficial in females with infertility. Details: Observational research in females undergoing in vitro fertilization suggests no association between dietary vitamin D intake and oocyte quality, successful embryo transfer, clinical pregnancy rate, or term pregnancy rate (112097). Additionally, a meta-analysis of clinical research in females with infertility shows that, although there was no effect of taking vitamin D on implantation rate or miscarriage, taking vitamin D increases the odds of clinical pregnancy by 49% when compared with placebo. However, sub-analyses of clinical and observational research found that benefits on clinical pregnancy rates were limited to populations with vitamin D insufficiency, but not vitamin D deficiency, and for doses between 1000 to 10,000 IU daily for 30-90 days (110818). Most studies included in the analysis used oral vitamin D; however, intramuscular vitamin D was used in one cohort study. A smaller meta-analysis of clinical studies in females with infertility and vitamin D insufficiency undergoing IVF shows that taking vitamin D increases the rate of chemical pregnancy by 50%, but has no effect on the clinical pregnancy rate (108432).
Lichen planus. It is unclear if oral vitamin D is beneficial for lichen planus. Details: A small clinical study in patients with oral lichen planus and vitamin D deficiency or insufficiency shows that taking vitamin D 60,000 IU weekly in combination with systemic steroids for 1 month reduces pain severity and improves healing of lesions when compared with systemic steroids alone (114586). The validity of the study is limited by the lack of a placebo.
Low birth weight. It is unclear if oral vitamin D can reduce the risk for low birth weight; the available evidence is conflicting. Details: A meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with lower birth weight and increased odds of SGA births. However, these risks have not been demonstrated in those with less severe vitamin D deficiency (serum level <20 ng/mL) (105724). Most research also shows that vitamin D supplementation during pregnancy reduces the risk of low birth weight. A meta-analysis of three clinical trials shows that supplementation with vitamin D 800-1000 IU daily starting between 27 and 32 weeks' gestation, or 200,000 IU administered as a single dose or in two divided doses during the seventh and eighth month of pregnancy, reduces the risk of delivering a low birth weight infant by 60% (84659). Other meta-analyses of clinical research show that supplementation with vitamin D during pregnancy results in a 31% to 60% reduced risk of low birth weight and a 103 gram greater average birth weight when compared with placebo or no intervention (99766,114587). However, some meta-analyses show that vitamin D supplementation during pregnancy does not reduce the risk of low birth weight when compared with no supplementation (95910,109055). One meta-analysis that included studies that did not directly measure birth weight shows no effect of vitamin D supplementation during pregnancy on the rate of low birth weight, despite showing an increase in overall birth weight of about 58 grams (95910).
Lung cancer. It is unclear if oral vitamin D prevents lung cancer or improves lung cancer prognosis. Details: A small meta-analysis of randomized controlled trials and observational research has found that high intake of vitamin D is associated with a 10% reduction in the risk of developing lung cancer when compared with low vitamin D intake. In terms of prognosis, high vitamin D intake is associated with improvements in both overall survival and relapse-free survival (107217).
Male infertility. It is unclear if oral cholecalciferol is beneficial in males with infertility. Details: A small clinical study in males with infertility shows that taking cholecalciferol 2500 IU daily for 6 months modestly improves progressive sperm motility, sperm concentration, and sperm morphology when compared with baseline (108427). The validity of these findings is limited by the lack of a comparator group.
Melanoma. It is unclear if oral vitamin D is beneficial in patients with melanoma. Details: A meta-analysis of 14 observational studies suggests that vitamin D deficiency is associated with a 45% greater risk of melanoma when compared with normal vitamin D levels (112027). However, a small clinical study in patients with newly resected stage II melanoma shows that taking vitamin D3 100,000 IU every 50 days for 3 years does not improve disease-free survival when compared with placebo. Most patients in this study had vitamin D deficiency or insufficiency at baseline (106113).
Metabolic syndrome. It is unclear if oral vitamin D is beneficial for preventing or treating metabolic syndrome. Details: In patients with metabolic syndrome, clinical research shows that taking vitamin D 50,000 IU weekly for 16 weeks does not affect most metabolic or anthropometric factors when compared with placebo, although there was a modest decrease in triglyceride levels (106123). However, almost all of the individuals in this study were vitamin D deficient or insufficient, and many remained in that category even after supplementation. It is unclear if vitamin D supplementation is beneficial in vitamin D sufficient patients with metabolic syndrome. There is conflicting evidence about the association between vitamin D and metabolic syndrome (14265,16713,98234). Some population research has found that higher vitamin D levels are associated with a lower risk of metabolic syndrome, while other research found no association (14265,16713). Furthermore, a small clinical trial in patients with metabolic syndrome shows that taking vitamin D 20,000 IU or 40,000 IU weekly for 8 weeks does not affect metabolic risk factors when compared with placebo (98234).
Migraine headache. It is unclear if oral vitamin D reduces the frequency of migraine. Details: A meta-analysis of three small high-quality clinical studies in patients with migraine shows that taking vitamin D 2000 or 4000 IU daily for 12-24 weeks or 500,000 IU weekly for 2 months reduces the frequency of migraines by 2-3 attacks monthly when compared with usual care or placebo (108439).
Miscarriage. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in pregnant adults with threatened miscarriage between the 6th and 13th week of gestation shows that taking a specific combination product (DAV HA, Lo.Li pharma s.r.l) containing vitamin D 50 mcg, alpha-lipoic acid, hyaluronic acid, magnesium, and vitamin B6 daily in combination with conventional treatment of vaginal progesterone over 2 weeks of observation results in a faster resorption of the subchorionic hematoma and faster decrease of patient-reported vaginal bleeding, abdominal pain, and uterine contractions when compared with vaginal progesterone alone (113893). It is unclear if these effects are due to vitamin D, other ingredients, or the combination. Additionally, the validity of these findings is limited by the lack of a placebo for the control group.
Multiple sclerosis (MS). Although vitamin D supplementation has been linked with a lower risk of developing MS, taking oral vitamin D supplements does not seem to reduce MS relapses. Details: Vitamin D deficiency appears to be linked to the risk of MS development and progression. Population research suggests that long-term supplementation with vitamin D 400 IU is associated with a 40% lower risk of MS in females. The effect seems to be dose-dependent. Consumption of at least 400 IU daily, mainly in the form of a multivitamin supplement, appears to have the greatest protective effect (11356). Additional population research in over 7 million people suggests that higher levels of calcifediol are associated with a lower risk of developing MS. In white adults, for every 20 ng/mL increase in vitamin D levels, there appears to be a 41% decrease in MS risk. However, this was not found in black and Hispanic adults (15159). Vitamin D supplementation has also been examined in patients with MS. Population research suggests that taking vitamin D supplements and the maintenance of optimal blood levels of vitamin D are associated with a reduction in the development of new areas of demyelination detected by magnetic resonance imaging (MRI) over 24 months. However, there are no correlations between vitamin D consumption or vitamin D blood levels and clinical outcomes (110816). Also, vitamin D supplementation does not seem to impact MS relapses or most symptoms in patients with MS. Meta-analyses of preliminary clinical research show that vitamin D supplementation does not affect the rate of MS relapses, overall symptoms, disability scores, or the number of MS nerve lesions detected by MRI, regardless whether the vitamin D was low-dose or high-dose (98192,98914,106119,113586). However, one meta-analysis of 6 small clinical studies shows that taking vitamin D for 8-96 weeks slightly improves fatigue scores when compared with placebo (112024). These analyses are limited by the small size and heterogeneity of most of the included studies and variability in dosing and duration of vitamin D regimens.
Muscle strength. It is unclear if oral vitamin D improves muscle strength in middle aged or older adults with low or sufficient levels of vitamin D. The available research is conflicting. Details: Clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not increase muscle strength when compared with placebo (11814,104619,108429). In patients 40-80 years of age with low vitamin D levels, taking vitamin D3 100,000 IU (2500 mcg) once, followed by 20,000 IU (500 mcg) weekly for 4 months, does not improve muscle strength when compared with placebo (103658). Similarly, meta-analyses of clinical research show that vitamin D does not increase grip strength, muscle mass, global muscle strength, or back extensor strength when compared with control (91341,113595). However, some research has found some benefit with the use of vitamin D supplements. One meta-analysis shows that taking vitamin D increases grip strength after menopause when compared with placebo or low-dose vitamin D, although a sub-analysis shows that beneficial effects are limited to individuals aged 60-69 years, when vitamin D is taken without calcium, when baseline vitamin D levels are at least 30 ng/mL, or when the treatment consists of the vitamin D analog alfacalcidol. This suggests heterogeneity between studies (109048). Another meta-analysis in elderly adults shows that taking vitamin D as calcifediol 10-30 mcg daily for a median of 24 weeks modestly improves hand grip strength and leg extension, but not leg flexion, when compared with baseline (109042). Also, some individual clinical research in older adults with low levels of vitamin D at baseline shows that taking vitamin D3 800 IU daily or vitamin D2 (ergocalciferol) 1000 IU daily for 12 months in combination with calcium 1000 mg daily modestly improves lower extremity or hip strength by 8% to 23% when compared with calcium alone (38915,84530).
Myalgia. It is unclear if oral vitamin D is beneficial for reducing myalgia associated with obesity. Details: Preliminary clinical research in obese individuals with vitamin D deficiency who are on a low-calorie diet shows that taking vitamin D 50,000 IU weekly, alone or in combination with an aerobic exercise program three times weekly for 12 weeks, modestly reduces muscle pain when compared with only aerobic exercise three times weekly (106118).
Myelodysplastic syndromes. It is unclear if oral vitamin D is beneficial for patients with myelodysplastic syndromes. Details: A small observational study in patients with myelodysplastic syndromes has found that taking calcitriol or calcifediol orally is associated with slowed disease progression (11825).
Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral or intramuscular vitamin D is beneficial in children or adults with NAFLD. Details: Although findings from individual research are mixed, one meta-analysis of mainly small clinical trials in patients with NAFLD shows that vitamin D modestly improves insulin resistance and serum alanine aminotransferase (ALT) levels, with no effect on serum aspartate aminotransferase (AST) levels. Most studies included in the analysis used oral vitamin D 1000 IU daily or 50,000 IU weekly or biweekly for 3-6 months and compared with placebo; however, one study used a single intramuscular injection of vitamin D 600,000 IU compared with lifestyle modifications (109056). Vitamin D has also been evaluated in combination with fish oil. A clinical study in adults with NAFLD shows that taking oral vitamin D3 1680 IU daily in combination with fish oil or fish oil alone for 3 months improves serum ALT levels similarly to a control group (107186). Vitamin D has also been evaluated for use in children with NAFLD. One clinical study in children with obesity and biopsy-proven NAFLD shows that taking oral vitamin D3 2000 IU daily for 6 months with a hypocaloric diet improves liver histopathology in terms of steatosis, lobular inflammation, and NAFLD activity score at 6 months, but not hepatocyte ballooning or fibrosis, when compared with baseline. These improvements were not seen in the group receiving placebo with a hypocaloric diet, but it is unclear if the improvement from baseline differed between groups (107222).
Nonmelanoma skin cancer. It is unclear if oral vitamin D is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking vitamin D3 1000 IU daily for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking vitamin D3 with calcium 1200 mg daily as calcium carbonate reduces the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but has no effect on the risk of basal cell carcinoma. Vitamin D taken alone has no effect on the risk for either type of cancer (104622).
Obesity. The evidence for the use of oral vitamin D in obesity is conflicting and unclear. Details: Population research has found that people with lower vitamin D levels are significantly more likely to be obese when compared to people with higher vitamin D levels (15630). Also, a large-scale, high-quality clinical trial in postmenopausal adults taking calcium 1000 mg plus vitamin D3 (cholecalciferol) 400 IU daily for 3 years shows that these patients are more likely to lose weight and maintain their weight when compared with those taking placebo. This beneficial effect is mainly seen in females who have inadequate intake of calcium, less than 1200 mg/day, before starting a calcium supplement (15604). However, other evidence suggests that vitamin D alone does not improve weight loss. One clinical trial shows that taking vitamin D3 2000 IU/day without calcium for 12 months does not increase weight loss when compared with placebo in overweight and obese postmenopausal adults who are deficient in vitamin D at baseline (91345).
Orthostatic hypotension. It is unclear if oral vitamin D is beneficial for prevention of orthostatic hypotension. Details: A secondary analysis of a clinical study in older patients with vitamin D insufficiency who are at an increased risk for falls shows that taking vitamin D 1000-4000 IU daily for up to 2 years has no effect on the risk of orthostatic hypotension or orthostatic symptoms when compared with those receiving vitamin D 200 IU daily (107223).
Osteoarthritis. It is unclear if oral vitamin D is beneficial for osteoarthritis. Details: The evidence for the use of vitamin D in osteoarthritis is conflicting. Some clinical research shows that taking vitamin D3 (cholecalciferol) 2000 IU daily, or at a higher dose to reach serum vitamin D levels over 36 ng/mL, for 2 years does not reduce knee pain or loss of cartilage when compared with placebo in patients with symptomatic osteoarthritis (84688). However, another clinical study shows that taking vitamin D3 daily for 10 days and then vitamin D3 60,000 IU monthly for 12 months modestly reduces pain and improves function when compared with placebo in patients with osteoarthritis and vitamin D insufficiency (98199). It is possible that higher doses of vitamin D have an effect on osteoarthritis, while lower doses do not. Due to this conflicting and low-quality evidence, the American College of Rheumatology (ACR) recommends against the use of vitamin D for any form of osteoarthritis (102114).
Otitis media. It is unclear if oral vitamin D is beneficial in patients with otitis media. Details: The relationship between vitamin D status and otitis media is unclear. Population research has found that having otitis media is associated with lower blood levels of vitamin D; however, lower vitamin D levels were not associated with greater risk of otitis media (98194).
Overactive bladder. It is unclear if oral vitamin D is beneficial for overactive bladder in children or adults. Details: A large clinical trial in older males shows that taking vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the odds of weekly overactive bladder when compared with placebo. In males with low baseline serum vitamin D, taking vitamin D reduces the odds of overactive bladder at 5 years by 49%, including 34% reduced odds of overactive bladder with urinary incontinence and 81% reduced odds of overactive bladder without incontinence. However, urinary incontinence while sleeping or napping was increased (109738). Vitamin D has also been evaluated for overactive bladder in children with low vitamin D levels. A large, single-blind clinical study in children with overactive bladder without urinary incontinence, and with vitamin D insufficiency or deficiency, shows that taking vitamin D 2400 IU daily for 8 weeks with standard urotherapy reduces voiding frequency by about 3 or 4 voids daily when compared with standard urotherapy, with or without solifenacin 5 mg daily (115574,115591). Standard urotherapy was defined in this study as medical education, timed voiding, and pelvic floor muscle training.
Overall mortality. Taking oral vitamin D alone does not seem to reduce mortality; however, there is some evidence that taking certain forms of vitamin D with calcium might have a modest benefit. Details: While higher vitamin D levels have been associated with a small reduction in mortality when compared with lower vitamin D levels (98187), clinical research shows that taking vitamin D does not reduce the risk of mortality. A comprehensive meta-analysis shows that vitamin D supplementation alone does not reduce all-cause mortality when compared to control (100900). However, giving vitamin D with calcium may modestly reduce the risk of mortality. Meta-analyses show a 4% to 9% reduced risk of mortality when trials of vitamin D alone and vitamin D with calcium are pooled together (16102,97296,98186,112022). Finally, some research suggests that the type of vitamin D supplementation might influence the results. A meta-analysis of clinical research found that vitamin D3 (cholecalciferol) with or without calcium reduces mortality risk by 6%, while alfacalcidol, calcitriol, and vitamin D2 (ergocalciferol) do not have benefit (84595,98186). Other clinical research suggests that vitamin D supplementation in older adults may reduce the risk of all-cause mortality by about 4%, with an estimated effect size of 6 fewer deaths per 1000 individuals. This finding informed the 2024 Endocrine Society Clinical Practice Guidelines on vitamin D for the prevention of disease in the general population. The Endocrine Society conditionally recommends, with moderate certainty of evidence, empiric vitamin D supplementation from fortified foods or vitamin D-containing supplements in the general population aged 75 years and older to potentially lower the risk of mortality. Empiric vitamin D is defined as vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status. For empiric supplementation and for those who have indications for vitamin D treatment or supplementation, daily lower-dose versus intermittent higher doses was suggested (114502).
Pain (chronic). It is unclear if oral vitamin D is beneficial for chronic pain. Details: A meta-analysis of clinical research in patients with chronic pain shows that taking vitamin D for 1-24 months produces a 43% greater decrease in pain score when compared with placebo. However, the final follow-up pain score is similar for both groups (96402). The effect of vitamin D on pain based on pain-related diagnosis, vitamin D status, or dose is unknown.
Parkinson disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Population research found that higher levels of vitamin D are associated with milder Parkinson disease symptoms, while deficiency is associated with increased risk of Parkinson disease (97000,99772). One small study shows that taking vitamin D3 (cholecalciferol) 1200 IU daily for one year might modestly slow the progression of Parkinson disease based on the Hoehn and Yars staging criteria. However, there was no improvement in disease severity according to the more widely used Unified Parkinson Disease Rating Stage (UPDRS). The UPDRS includes measures of activities of daily living and non-motor symptoms. Vitamin D had no effect on most quality of life measures (95915).
Periodontitis. It is unclear if oral vitamin D is beneficial for periodontal disease. Details: A meta-analysis of mostly observational research suggests that vitamin D levels are not associated with an increased or decreased risk of periodontitis (112026). Other population research suggests that higher blood levels of vitamin D may be associated with a reduced risk of periodontal disease in adults 50 years of age or older. However, this association was not found for adults younger than 50 years (15634).
Physical performance. It is unclear if oral vitamin D improves muscle strength in elderly adults. Details: Some clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not improve physical performance when compared with placebo (11814,104619,108429). Also, results from one meta-analysis of clinical research in postmenopausal females with low levels of vitamin D shows that taking vitamin D does not improve the timed up and go test when compared with placebo or low-dose vitamin D (109048). One meta-analysis that included studies specifically evaluating the use of calcifediol in older adults shows a large benefit on gait speed; however, only one study included in the analysis used this endpoint and other measures of physical performance were not affected (109042).
Pneumonia. High-dose oral vitamin D does not reduce pneumonia severity in children. Details: Although vitamin D supplementation might prevent respiratory tract infections in children, it might not prevent recurrent pneumonia. A small clinical study in children under 5 years of age with recurrent pneumonia and variable vitamin D blood levels shows that taking vitamin D 300,000 IU quarterly for 1 year does not reduce respiratory infections, severity of pneumonia, hospital admissions, or disease complications when compared with placebo (103667). However, it's unknown if vitamin D supplementation using lower and more frequent doses, or supplementation in patients with vitamin D deficiency, might be beneficial. Some observational research has found that having vitamin D deficiency is linked to a higher risk for developing community-acquired pneumonia (CAP) (102118). For information on other respiratory infections, refer to the Respiratory Tract Infection discussion.
Polycystic ovary syndrome (PCOS). It is unclear if vitamin D improves pregnancy rates and outcomes, clinical symptoms, metabolic parameters, or hormone levels in patients with PCOS. Details: Observational research in adults with infertility, PCOS, and insulin resistance suggests that normal vitamin D levels are associated with better embryo quality and increased pregnancy rate when compared with vitamin D deficiency or insufficiency (100834). It is unclear if supplementation with vitamin D improves pregnancy rates in patients with PCOS. A meta-analysis of several mostly low-quality clinical studies in patients with PCOS and vitamin D deficiency at baseline shows that intramuscular or oral vitamin D 200-10,000 IU daily for up to 24 weeks in addition to fertility treatment improves pregnancy rates and reduces premature miscarriage and premature delivery, but does not impact the incidence of pregnancy complications including gestational hypertension or gestational diabetes, when compared with control. This analysis also suggests vitamin D supplementation improves certain IVF-related outcomes including ovulation rate, fertilization rate, and number of mature oocytes (112787). An earlier meta-analysis of clinical research shows that taking vitamin D 400-12,000 IU daily for 2-6 months improves follicular development when compared with placebo. Taking vitamin D in combination with metformin 1500 mg daily also appears to increase the number of regular menstrual cycles by 85% when compared with metformin alone, but without an effect on follicular development (96404). However, a meta-analysis of 3 clinical studies shows that combining vitamin D with metformin probably does not improve menstrual cycle regulation when compared with metformin alone (113594). The effect of vitamin D on the hormonal and metabolic profiles of patients with PCOS has also been evaluated. An umbrella review of up to 15 meta-analyses of clinical studies in patients with PCOS shows that taking vitamin D 2000-8500 IU daily for 6.5-13.5 weeks reduces levels of serum triglycerides, total and low-density lipoprotein (LDL) cholesterol, and total testosterone, but not body mass index (BMI) or insulin levels, when compared with placebo (115577). A separate meta-analysis of 9 clinical studies, not included in the umbrella review, shows that combining vitamin D with metformin reduces insulin resistance, BMI, and testosterone levels when compared with metformin alone (113594). Additionally, a small clinical study in adults with PCOS and vitamin D deficiency or insufficiency shows that taking vitamin D 2000 IU daily in combination with diet and exercise for 12 weeks reduces insulin resistance, BMI, waist to hip ratio, serum triglyceride levels, and total and LDL cholesterol levels when compared with diet and exercise alone (114580). The interpretation of the results in this clinical study is limited by the lack of a placebo control.
Post-stroke fatigue. It is unclear if oral vitamin D is beneficial for post-stroke fatigue. Details: A retrospective study in patients with post-stroke fatigue and vitamin D deficiency suggests that vitamin D (cholecalciferol) 600 IU daily is associated with improvements in fatigue severity at months 1 and 3 when compared with control. Neurologic disability also showed improvement at 3 months, but not at 1 month, when compared with control. It is unclear if improvements from baseline differed between groups (107225).
Pre-eclampsia. It is unclear if oral vitamin D during pregnancy is beneficial for the prevention or treatment of pre-eclampsia. Details: While some clinical research suggests that taking vitamin D during pregnancy does not reduce the risk of pre-eclampsia (113585,114587), clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small for gestational age (SGA) birth, and neonatal mortality. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
Precocious puberty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of precocious puberty. Details: A meta-analysis of 43 mostly observational studies from China suggests that vitamin D deficiency or insufficiency is associated with 2.25-fold greater odds of precocious puberty when compared with normal vitamin D levels. Taking vitamin D 200-1000 IU daily for 3-12 months along with a gonadotropic-releasing hormone analog (GnRHa) is associated with lower luteinizing hormone, follicle-stimulating hormone, and estradiol levels and reduced bone age when compared with GnRHa therapy alone (112019). Another meta-analysis of 15 studies, mainly from China and with high heterogeneity and publication bias, suggests that there is a negative correlation between serum 25-hydroxy-vitamin D concentrations and precocious puberty, and that vitamin D deficiency increases the risk of precocious puberty by about 53% (113578).
Pregnancy-induced hypertension. It is unclear if oral vitamin D is beneficial for patients with gestational hypertension. Details: Meta-analyses of two low-quality clinical trials show that vitamin D supplementation during pregnancy does not reduce the risk for gestational hypertension when compared with control (95910,114587).
Prematurity. It is unclear if taking vitamin D during pregnancy prevents respiratory complications in preterm neonates. Details: A large clinical study in pregnant patients with gestational age less than 34 weeks and at risk of preterm delivery shows that a single intramuscular injection of vitamin D 50,000 IU within 72 hours before delivery decreases the risk of respiratory distress syndrome treated by surfactant in the neonate by about 2.25-fold and increases the 5th minute APGAR scores, but not 1st minute APGAR scores, gestational age, neonatal intensive care unit admission, length of hospital stay, or delivery method, when compared with no treatment (114581).
Premenstrual syndrome (PMS). It is unclear if oral vitamin D is beneficial in patients with PMS. Details: Observational research has found that increasing dietary intake of vitamin D above 706 IU daily is linked to a reduced risk of developing PMS when compared with consuming 112 IU daily (13094). Furthermore, a clinical study shows that taking vitamin D 400 IU daily in combination with calcium 1000 mg daily can decrease the severity of PMS symptoms (16869). Another clinical study in adolescent females with PMS shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces PMS symptoms when compared to baseline (98912). A small clinical study in young adults with PMS and vitamin D deficiency shows that taking vitamin D 50,000 IU every 2 weeks for 16 weeks reduces psychological symptom scores by 54% and physical symptom scores by 39% when compared with placebo (113582).
Preterm labor. It is unclear if oral vitamin D is beneficial for preterm labor. Details: Vitamin D deficiency, defined as serum levels less than 20 ng/mL, during pregnancy has been associated with a 25% greater risk of preterm birth (95911). The risk seems to be especially prominent in those with darker colored skin (103662). However, meta-analyses of clinical research show that vitamin D supplementation during pregnancy does not reduce the risk of a preterm birth when compared with no supplementation with vitamin D (84659,95910,109055,114587). The effect vitamin D specifically in vitamin D-deficient patients is still unclear. Some small, heterogeneous, and low-quality studies show that vitamin D supplementation might reduce the rate of preterm birth in vitamin D-deficient patients (84659,95910). Additional studies are needed to determine the effect of vitamin D supplementation on the risk of preterm birth. Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of preterm birth, small for gestational age (SGA) birth, preeclampsia, intra-uterine mortality, and neonatal mortality. Empiric vitamin D supplementation iss defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
Rheumatoid arthritis (RA). Small clinical studies suggest that oral vitamin D may not improve symptoms in patients with RA. Details: Population research has found that higher intake of vitamin D from foods or supplements is associated with a lower risk of developing RA (12206,98200). However, a meta-analysis of two small clinical trials shows that vitamin D supplementation does not reduce pain or recurrence of RA when compared with placebo (98190).
Rhinosinusitis. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients over 12 years of age with chronic sinusitis shows that taking 1 or 2 sachets of a specific combination product (Flogostop Forte, Humana Italia) containing vitamin D 600 IU, black currant, Boswellia serrata, and bromelain along with a nasal corticosteroid daily for 15-30 days reduces symptoms of nasal hyperemia and rhinorrhea when compared with corticosteroid nasal spray alone (111501). It is unclear if these findings are due to vitamin D, other ingredients, or the combination.
Sarcopenia. It is unclear if oral vitamin D is beneficial in older adults with sarcopenia. Details: A meta-analysis of randomized trials in older adults with sarcopenia shows that taking vitamin D3 (cholecalciferol) 100-800 IU daily, with protein 10-44 grams daily or amino acids 2.5-6 grams daily, for 2-6 months moderately improves muscle strength, but not muscle mass or walking speed, when compared with placebo (105727). The validity of this study is limited by high heterogeneity and an unreported baseline vitamin D status. Similarly, a small network meta-analysis of randomized trials shows that taking vitamin D 500-1600 IU daily or 2500-5000 IU weekly with protein 20-80 grams daily or amino acids 3-32 grams daily with and without exercise for 3-18 months increases hand grip strength and shortens time to chair-stand, respectively, but not gait speed or lower-limb mass when compared with usual care (107221). It is unclear if these effects are due to vitamin D, protein/amino acid supplementation, exercise, or the combinations.
Schizophrenia. It is unclear if oral vitamin D is beneficial for schizophrenia. Details: Based on preliminary clinical evidence, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is not recommended for adjunctive use in patients with schizophrenia (110318). A moderate-sized clinical study in patients with schizophrenia shows that taking a specific combination product (BioZenD, Tak Gen Zist Pharmaceutical Company) containing vitamin D 400 IU in combination with a blend of probiotics (Lactobacillus acidophilus, Lacticaseibacillus rhamnosus, Limosilactobacillus reuteri, Lacticaseibacillus paracasei, Bifidobacterium longum, Bacillus coagulans) 2 x 10⁹ CFU daily for 12 weeks improves cognitive function scores but does not improve the severity of positive and negative schizophrenia symptoms when compared with placebo (114582). It is unclear if this effect is due to vitamin D, the probiotics, or the combination.
Sciatica. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary research in adults up to 45 years of age with discogenic sciatica shows that taking cholecalciferol 800 IU with alpha-lipoic acid, acetyl-L-carnitine, and resveratrol daily for 30 days, in combination with a 20-session rehabilitation protocol, improves pain, disability, and quality of life when compared with the supplements alone or the rehabilitation protocol alone (112933).
Seasonal affective disorder (SAD). One small study suggests that a large dose of oral vitamin D can improve symptoms of SAD. Details: A small clinical study in patients with SAD suggests that a single dose of vitamin D2 (ergocalciferol) 100,000 IU improves symptoms after one month when compared to baseline (83791). The validity of this finding is limited by the lack of a control group.
Seborrheic keratosis. It is unclear if topical vitamin D analogues improve symptoms of seborrheic keratosis. Details: Preliminary clinical research suggests that topical ointments containing activated vitamin D in the form of tacalcitol, calcipotriol or maxacalcitol, applied for 3-12 months, can reduce tumor volume by at least 40% in 75% of patients with seborrheic keratosis. Additionally, over 30% of patients seem to experience complete tumor resolution or a reduction in tumor volume of at least 80% (84033). The validity of this finding is limited by the lack of a control group.
Sexual dysfunction. One small study suggests that injecting a large dose of vitamin D might improve sexual function. Details: A small clinical study in females with vitamin D deficiency and sexual dysfunction shows that receiving an intramuscular injection of vitamin D as cholecalciferol 300,000 IU once at baseline and a second time 4 weeks later improves sexual function at 4 and 8 weeks when compared with placebo (100896).
Sickle cell disease. One small study suggests that oral vitamin D reduces pain and improves quality of life in children with sickle cell disease with vitamin D insufficiency or deficiency. Details: A small clinical study in children with sickle cell disease shows that taking vitamin D3 (cholecalciferol) 40,000-100,000 IU weekly for 6 weeks reduces days with pain and improves physical activity and quality of life for up to 6 months when compared with placebo. Of the children included in the study, 82.5% had vitamin D insufficiency, while 52.5% were deficient in vitamin D (98918). It is unclear if vitamin D is effective for patients with sickle cell disease who have adequate levels of vitamin D.
Small for gestational age (SGA). It is unclear if oral vitamin D can reduce the risk for SGA births; the available evidence is conflicting. Details: Two meta-analyses of clinical research show no effect of vitamin D on the risk of SGA birth (84659,109055). However, one meta-analysis shows a 40% reduction in the risk of SGA births with vitamin D supplementation (95910). Also, one meta-analysis shows that when vitamin D supplementation is initiated before the 20^th week of gestation, the risk of SGA is reduced by 54% (109055). Most individual clinical trials are small and heterogeneous. Also, the formulation of vitamin D and/or vitamin D status at baseline may explain part of the discrepant findings. For example, a meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with increased odds of SGA births. This association does not seem to be present with less severe vitamin D deficiency (serum level <20 ng/mL) (105724). Clinical practice guidelines from the Endocrine Society conditionally recommend, with low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of SGA births, as well as preeclampsia, intra-uterine mortality, preterm birth, and neonatal mortality. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
Statin-induced myalgia. It is unclear if oral vitamin D is beneficial for patients with statin-induced myalgia. Details: Observational research has found that taking oral vitamin D supplements is associated with decreased symptoms of myalgia in patients taking statin drugs. In a small case series, patients who discontinued statins due to myalgia were able to resume statin therapy after starting vitamin D supplements. The majority of patients with myalgia were found to be vitamin D deficient, with vitamin D levels less than 12 ng/mL at baseline (16829). An observational study has also found that administering 50,000 units of vitamin D2 (ergocalciferol) once a week for 12 weeks reversed symptoms of myalgia in 92% of statin treated patients with low serum vitamin D levels of less than 32 ng/mL (16831).
Stroke. Although low vitamin D levels are associated with higher risk of stroke, taking vitamin D supplements does not seem to reduce stroke risk. Details: Population research has found that low vitamin D levels are associated with an increased risk of stroke. Furthermore, increased dietary intake of vitamin D is associated with a reduced risk of stroke (15630,16618,93944,97303,106106). However, clinical research shows that vitamin D supplementation does not reduce stroke risk. Several meta-analyses and randomized controlled trials show that taking vitamin D alone or with calcium does not reduce the risk of stroke in patients with or without cardiovascular disease risk factors (16616,91343,97296,97308,106106,112022). It is difficult to draw firm conclusions from these studies, as they did not assess whether patients had adequate vitamin D levels at baseline. It is unclear if vitamin D supplementation might prevent strokes in patients with vitamin D deficiency.
Sunburn. Although there is interest in using oral vitamin D for the treatment of sunburns, there is insufficient reliable information about the clinical effects of vitamin D for this purpose.
Systemic lupus erythematosus (SLE). It is unclear if oral vitamin D is beneficial in patients with SLE. Details: While some observational research has found that adults with SLE are more likely to have vitamin D deficiency than healthy controls (102119), a small cross-sectional study in females has found no association between serum levels of 25-hydroxyvitamin D, SLE disease activity, and the presence or absence of lupus nephritis (107214). A meta-analysis of three small clinical studies shows that taking vitamin D3 (cholecalciferol) 2000 IU daily or 50,000 IU weekly seems to reduce anti-dsDNA positive, a marker of disease activity, when compared with placebo in patients with SLE (98190). However, the clinical significance of this finding is unclear. A small clinical trial in females with SLE shows that taking vitamin D3 5000 IU daily for 12 weeks modestly improves overall disease activity, but not quality of life, when compared with placebo (109735).
Thyroid cancer. It is unclear if oral vitamin D is beneficial in patients with thyroid cancer. Details: Observational research in patients undergoing thyroidectomy for differentiated thyroid cancer suggests that taking vitamin D daily for at least 6 months after surgery is associated with a 38% lower risk of all-cause mortality and a 33% lower risk of total cancer-related mortality when compared with no vitamin D supplementation at around 10 years' follow-up. However, vitamin D does not appear to be linked to a lower risk of thyroid cancer-related mortality in these patients (112018).
Ulcerative colitis. Limited evidence suggests that vitamin D may be beneficial in patients with ulcerative colitis. Details: A meta-analysis of mainly small clinical trials in patients treated with mesalazine shows that taking vitamin D for up to 24 weeks modestly increases clinical efficacy and reduces disease score when compared with mesalazine alone (109044). Also, a meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). These findings are limited because of the heterogeneity of the included studies.
Upper respiratory tract infection (URTI). It is unclear if oral vitamin D is beneficial for dementia. Details: A large clinical trial shows that taking vitamin D 2800 IU daily, starting at gestational week 24 and continuing until one week after birth, reduces the risk of the child developing croup by 3 years of age by 40% when compared with olive oil as placebo. This risk reduction did not change after adjusting for the use of omega-3 fatty acids 2.4 grams daily, as well as for concomitant persistent wheeze and/or lower respiratory tract infections (109304).
Urinary incontinence. Limited evidence suggests that vitamin D may be beneficial in middle-aged, but not older, adults with urinary incontinence. Details: Clinical research in middle-aged premenopausal females with stress urinary incontinence and low vitamin D status shows that taking vitamin D 5000 IU once weekly for 12 weeks has a moderate to large beneficial effect on the severity of incontinence and quality of life when compared with placebo. Kegel exercises were performed by all participants (109736). However, vitamin D supplementation does not seem to be beneficial for reducing urinary incontinence in older adults. In older females and males, a large clinical trial shows that vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the incidence or progression of urinary incontinence when compared with placebo (109738,109741). In older males with low vitamin D status, vitamin D supplementation may actually increase some types of incontinence (109738).
Urinary tract infections (UTIs). It is unclear if oral vitamin D is beneficial for the prevention of UTIs in children. Details: A meta-analysis of 13 small observational studies in children suggests that lower levels of vitamin D are associated with 2.8-fold greater odds of UTI when compared with higher vitamin D levels. Further, this analysis shows that vitamin D deficiency in children is linked to 5.5-fold greater odds of UTI when compared with normal vitamin D levels (112030).
Urticaria. It is unclear if oral vitamin D is beneficial for the prevention or treatment of urticaria. Details: A meta-analysis of population research has found that having urticaria is associated with a slightly lower vitamin D blood level and a greater likelihood of vitamin D deficiency when compared with individuals without urticaria. In addition, a meta-analysis of 6 clinical trials shows that taking vitamin D at an average daily dose of at least 4100 IU has a modest effect on the severity of urticaria symptoms (106115). Pooled data from 2 clinical studies in adults with chronic urticaria shows that taking vitamin D for 12 weeks, either as cholecalciferol 60,000 IU every 2 weeks or as alfacalcidol, 0.25 mcg once daily, reduces pruritus severity when compared with placebo (115587).
Uterine fibroids. Low vitamin D status is associated with uterine fibroids and some clinical research suggests that taking vitamin D may modestly decrease the size of uterine fibroids. Details: Two meta-analyses of 5 clinical studies in premenopausal adults with uterine fibroids shows that taking vitamin D, either 50,000 IU weekly or biweekly for 8-12 weeks or 1000 IU daily for 1 year, decreases fibroid size when compared with placebo or no treatment (113577,115573). One of the meta-analyses found a 5.7% difference in fibroid size between vitamin D and control (115573). Observational research also suggests that vitamin D status is associated with uterine fibroids. Specifically, meta-analyses of a total 23 observational studies suggest that individuals with uterine fibroids have lower serum vitamin D levels and a 3.7-times higher odds of vitamin D deficiency (115573).
Vaginal atrophy. It is unclear if oral vitamin D is beneficial for vaginal atrophy. There is limited evidence on the topical use of vitamin D in vaginal atrophy in postmenopausal adults or patients taking tamoxifen. Details: A small cross-sectional study in postmenopausal adults has found that taking a vitamin D supplement for at least one year improves the maturation index of superficial vaginal wall cells when compared with those who do not take vitamin D. However, symptoms of vaginal atrophy were not different between groups (16879). Vitamin D has also been evaluated for vaginal atrophy due to tamoxifen. A small clinical trial in females with breast cancer using tamoxifen shows that receiving vitamin D 1000 IU vaginal suppositories daily for 8 weeks improves maturation index of vaginal walls and self-reported symptoms when compared with placebo (99773).
Vertigo. It is unclear if oral vitamin D is beneficial in patients with vertigo. Details: An analysis of observational research suggests that lower serum levels of vitamin D are associated with a higher risk of benign paroxysmal positional vertigo (BPPV) when compared with higher vitamin D levels (114579). However, it is unclear if vitamin D supplementation can reduce the risk of BPPV in individuals with low vitamin D levels. Vitamin D has been evaluated in combination with other ingredients for the treatment of BPPV. A large clinical study in adults with recurrent BPPV shows that taking vitamin D 400 IU and calcium 500 mg twice daily for one year reduces the risk of recurrence by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 4 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination.
Vitiligo. Although there is interest in using oral vitamin D for vitiligo, there is insufficient reliable information about the clinical effects of vitamin D for this condition.
Warts. Although there is interest in using topical vitamin D derivatives for warts, there is insufficient reliable information about the clinical effects of vitamin D for this condition. More evidence is needed to rate vitamin D for these uses.

Safety view details

Below is general information about the safety of the known ingredients contained in the product Biomega. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

DOCOSAHEXAENOIC ACID (DHA) (Docosahexaenoic Acid)

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).

EICOSAPENTAENOIC ACID (EPA) (Eicosapentaenoic Acid)

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.

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)(107180,107181,113220). 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)(15015,15162,101540,110338,113217,114181). One large clinical trial shows that intake of fish oil from the 24th week of gestation increases the odds of the child having overweight and having metabolic syndrome measurements at age 10 when compared with placebo (114181). More research is needed to confirm these findings. 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).

LIKELY SAFE ...when used orally or intramuscularly and appropriately. Vitamin D has been safely used in a wide range of doses (7555,16888,16891,17476,95913,98186,104619,105209,109040,109059)(115580,115590). When used orally long-term, doses should not exceed the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for adults (17506,99773); however, much higher doses such as 50,000 IU (1250 mcg) weekly orally for 6-12 weeks are often needed for the short-term treatment of vitamin D deficiency (16891,17476,115590). Monthly oral doses of up to 60,000 IU (1500 mcg) have also been safely used for up to 5 years (105726). Toxicity usually does not occur until plasma levels exceed 150 ng/mL (17476).

POSSIBLY UNSAFE ...when used orally in excessive doses, long-term. Taking doses greater than the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for adults for long periods can increase the risk of hypercalcemia (17506); however, much higher doses are often needed for short-term treatment of vitamin D deficiency. Toxicity typically occurs when levels exceed 150 ng/mL (17476).

CHILDREN: LIKELY SAFE
when used orally and appropriately. When used long-term, doses should not exceed the tolerable upper intake level (UL) of 1000 IU (25 mcg) daily for those 0-6 months of age, 1500 IU (37.5 mcg) daily for those 6-12 months of age, 2500 IU (62.5 mcg) daily for those 1-3 years of age, 3000 IU (75 mcg) daily for those 4-8 years of age, and 4000 IU (100 mcg) daily for those 9 years and older (17506); however, much higher doses are often needed for the short-term treatment of vitamin D deficiency. Some research shows that giving vitamin D 14,000 IU (350 mcg) weekly for a year in children aged 10-17 years is safe (16875). A meta-analysis of clinical studies shows that 1000 IU (25 mcg) daily in those up to a year of age and greater than 2000 IU (50 mcg) daily in those aged 1-6 years does not increase the risk of serious adverse events (108424).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses for longer than one year. Taking doses greater than the tolerable upper intake level (UL) long-term can increase the risk of hypercalcemia (17506).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506,95910).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily. Hypercalcemia during pregnancy due to excessive vitamin D intake can lead to several fetal adverse effects, including suppression of parathyroid hormone, hypocalcemia, tetany, seizures, aortic valve stenosis, retinopathy, and mental and/or physical developmental delay (17506).

LACTATION: LIKELY SAFE
when used orally and appropriately. Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).

LACTATION: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).

Interactions with Drugs view details

Below is general information about the interactions of the known ingredients contained in the product Biomega. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

DOCOSAHEXAENOIC ACID (DHA) (Docosahexaenoic Acid)

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.

EICOSAPENTAENOIC ACID (EPA) (Eicosapentaenoic Acid)

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.

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).

ALUMINUM

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Vitamin D might increase aluminum absorption and toxicity, but this has only been reported in people with renal failure.

Details

The protein that transports calcium across the intestinal wall can also bind and transport aluminum. This protein is stimulated by vitamin D, which may therefore increase aluminum absorption (11595,11597,22916). This mechanism may contribute to increased aluminum levels and toxicity in people with renal failure, when they take vitamin D and aluminum-containing phosphate binders chronically (11529,11596,11597).

ATORVASTATIN (Lipitor)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Vitamin D might reduce absorption of atorvastatin.

Details

A small, low-quality clinical study shows that taking vitamin D reduces levels of atorvastatin and its active metabolites by up to 55%. However, while atorvastatin levels decreased, total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels did not substantially change (16828). Atorvastatin is metabolized in the gut by CYP3A4 enzymes, and researchers theorized that vitamin D might induce CYP3A4, causing reduced levels of atorvastatin. However, this proposed mechanism was not specifically studied.

CALCIPOTRIENE (Dovonex)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Taking calcipotriene with vitamin D increases the risk for hypercalcemia.

Details

Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (15). Theoretically, combining calcipotriene with vitamin D supplements might increase the risk of hypercalcemia.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Vitamin D might induce CYP3A4 enzymes and reduce the bioavailability of CYP3A4 substrates.

Details

There is some concern that vitamin D might induce CYP3A4. In vitro research suggests that vitamin D induces CYP3A4 transcription. Additionally, observational research has found that increased UV light exposure and serum vitamin D levels are associated with decreased serum levels of CYP3A4 substrates such as tacrolimus and sirolimus, while no association between UV light exposure or vitamin D levels and levels of mycophenolic acid, a non-CYP3A4 substrate, was found (110539). A small, low-quality clinical study shows that taking vitamin D reduces levels of the CYP3A4 substrate atorvastatin and its active metabolites by up to 55%; however, the clinical effects of atorvastatin were not reduced (16828). While researchers theorized that vitamin D might induce CYP3A4, this proposed mechanism was not specifically studied.

DIGOXIN (Lanoxin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, hypercalcemia induced by high-dose vitamin D can increase the risk of arrhythmia from digoxin.

Details

High doses of vitamin D can cause hypercalcemia. Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (15). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and digoxin concurrently.

DILTIAZEM (Cardizem, others)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Theoretically, hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of diltiazem for arrhythmia.

Details

High doses of vitamin D can cause hypercalcemia. Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically this could also occur with diltiazem. Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and diltiazem concurrently.

THIAZIDE DIURETICS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, taking thiazide diuretics and high-dose vitamin D can increase the risk of hypercalcemia.

Details

Thiazide diuretics decrease urinary calcium excretion, which could lead to hypercalcemia if vitamin D supplements are taken concurrently (3072,11541,69580). This has been reported in people being treated with vitamin D for hypoparathyroidism, and also in elderly people with normal parathyroid function who were taking a thiazide, vitamin D, and calcium-containing antacids daily (11539,11540).

VERAPAMIL (Calan, others)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of verapamil for arrhythmia.

Details

Hypercalcemia due to high doses of vitamin D can reduce the effectiveness of verapamil in atrial fibrillation (10574). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and verapamil concurrently.

Report an Adverse Reaction to Biomega

Adverse Effects view details

Below is general information about the adverse effects of the known ingredients contained in the product Biomega. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

DOCOSAHEXAENOIC ACID (DHA) (Docosahexaenoic Acid)

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).

EICOSAPENTAENOIC ACID (EPA) (Eicosapentaenoic Acid)

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.

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 (AF). 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 AF, 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, one large population study in adults without CVD suggests that regular use of fish oil supplements is associated with a modestly higher risk of both atrial fibrillation and stroke when compared with non-use of fish oil supplements (114182).
In a secondary analysis of the Omega-3 fatty acids in Elderly patients with Myocardial Infarction (OMEMI) trial, adults aged 70-82 years with recent myocardial infarction supplementing with 1.8 grams daily of n-3 PUFA (EPA/DHA) for 24 months had a 90% increased risk of developing AF or micro-AF, which is characterized by short, AF-like activity lasting less than 30 seconds. Changes in serum EPA levels seem to mediate this risk, with higher serum EPA levels predictive of an increased risk of AF and intermediate serum EPA levels predictive of an increased risk of micro-AF (112469).
Meta-analyses of randomized controlled trials show that taking omega-3 fatty acid supplements increases the incidence rate ratio for AF 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).
In 2023, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency issued a public statement on the use of omega-3-acid ethyl esters, concluding that exposure to omega-3-acid ethyl esters for the treatment of hypertriglyceridemia is associated with a dose-dependent increased risk of AF in patients with established cardiovascular disease or risk factors for cardiovascular disease when compared with placebo. The highest risk of AF is associated with a dose of 4 grams daily. If AF occurs, treatment should be permanently discontinued (112467).

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)(89347,89357,103491,103551,107172,114184). 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)(66494,66498,89347,103491,104551,110353,114184). 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)(66492,66494,104551,114184), acid reflux, heartburn (104551,110338), indigestion (65566,65830,66061,66104,66173,89359,114184), 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, such as alanine aminotransferase and aspartate aminotransferase, have been reported rarely (66353,113218).

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).

General ...Orally or intramuscularly, vitamin D is well tolerated.
Serious Adverse Effects (Rare):
Orally or intramuscularly: Excessive doses can lead to vitamin D toxicity with symptoms of hypercalcemia, and also sometimes azotemia and anemia.

Cardiovascular ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Rarely, people develop hypertension (10142). An analysis of clinical research suggests that, when taken orally, vitamin D might modestly increase levels of low-density lipoprotein (LDL)-cholesterol. However, it is not clear if this increase is clinically significant (84642).

Gastrointestinal ...Orally, vitamin D may cause dry mouth. In clinical research, intake of vitamin D 50,000 IU weekly for 4 weeks followed by 50,000 IU monthly for 5 months thereafter was associated with a 3.7-fold increase in reports of dry mouth compared with placebo (91348).Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Symptoms of vitamin D toxicity include pancreatitis (10142,84433). Vomiting occurred in one patient given a single dose of 200,000 IU (104624).

Genitourinary ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Advanced symptoms may include decreased libido (10142). Vaginal discharge and itching have been reported in a clinical trial following oral use (91348).

Hematologic ...Lab values of urinary and blood calcium, phosphate, albumin, blood urea nitrogen, serum cholesterol, aspartate aminotransferase, and alanine aminotransferase concentrations might increase with vitamin D use, especially with high doses (10142,91349,93943).
A case of elevated international normalized ration (INR) has been reported for an 84 year-old patient who took vitamin D 50,000 IU daily for 2 months. The patient's serum levels of vitamin D increased from <7 ng/mL to 100 ng/mL over 6 months. To resolve symptoms, vitamin D supplementation was discontinued (84433).

Musculoskeletal ...Vitamin D intoxication can occur when vitamin D supplements are taken in excessive doses (10142,17506). Symptoms of vitamin D toxicity include osteoporosis in adults and decreased growth in children (10142).

Ocular/Otic ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses (10142,17506). Symptoms of vitamin D toxicity include calcific conjunctivitis and photophobia (10142).

Psychiatric ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses (10142,17506). In rare cases, symptoms of vitamin D toxicity include psychosis (10142,93002).

Pulmonary/Respiratory ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Advanced symptoms of vitamin D toxicity may include runny nose (10142,17506,93002).

Renal ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Symptoms of vitamin D toxicity include azotemia. Vitamin D may also cause hypercalcemia, with advanced symptoms including kidney stones or kidney insufficiency due to precipitation of calcium phosphate in the tubules. Symptoms of renal impairment include frequency, nighttime awakening to urinate, thirst, inability to concentrate urine, and proteinuria. Renal impairment is usually reversible with discontinuation of vitamin D supplements (10142,93002,93943,110831,110833).

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