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Age-related cognitive decline. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in healthy adults over 40 years of age with mild forgetfulness shows that taking a specific combination supplement (BGG Japan Co.) containing astaxanthin 9 mg and tocotrienols 50 mg daily for 12 weeks might improve composite and verbal memory when compared with placebo (105099). This study was funded by the supplement manufacturer.
Age-related macular degeneration (AMD). Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with non-advanced AMD shows that a specific combination product (Azyr, Sifi S.p.A.) containing astaxanthin 4 mg, lutein, zeaxanthin, vitamin E, vitamin C, zinc, and copper, taken daily for 12 months, improves selective dysfunction in the central retina, but does not improve dysfunction in the peripheral retinal areas, when compared with baseline (19196). The validity of this finding is limited by the lack of a comparator group.
Aging skin. Small studies suggest that oral and topical astaxanthin may be beneficial in aging skin; however, there is conflicting evidence regarding its effects on wrinkles. Details: Small studies in middle-aged adults show that taking astaxanthin (Astavita Astaxanthin, Astavita; AstaReal Oil 50F, Fuji Chemical Industry Co., Ltd.) 2-3 mg orally twice daily for 6-8 weeks improves elasticity, fine lines, wrinkles, and skin moisture when compared with placebo (19561,91734). However, a meta-analysis of small clinical studies in healthy adults shows that taking oral astaxanthin 2-12 mg daily for 4-16 weeks modestly improves moisture content and skin elasticity, but has no effect on wrinkle depth, when compared with placebo (107961). The validity of this meta-analysis is limited due to the population heterogeneity and variety of astaxanthin formulations utilized. In addition to oral astaxanthin, one study also used topical astaxanthin 0.094% (AstaTROL-Hp, Fuij Chemical Industry Co., Ltd.) 1 mL applied twice daily (91734). A systematic review of two very small, nonblinded studies in healthy adults suggests that topical application, either in combination with oral astaxanthin or alone, might have anti-aging skin effects when used for 2-3 weeks (107961).
Alzheimer disease. Although there is interest in using oral astaxanthin for Alzheimer disease, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
Athletic performance. Small studies suggest that oral astaxanthin may improve some aspects of athletic performance. Details: Two small studies in trained cyclists show that taking astaxanthin (Fuji Health Science, Inc. or AstaReal) 4-12 mg daily for 1 or 4 weeks decreases the time to complete a 20-40 km cycling trial by about 50-100 seconds when compared with placebo (91735,105096). However, a larger study in trained cyclists shows that taking astaxanthin (BioReal) 20 mg, vitamin C 300 mg, and vitamin E 50 mg daily for 4 weeks does not decrease time needed to complete a predetermined amount of cycling work (a timed trial) when compared with placebo (91738). Reasons for the discrepancies are not clear but may relate to the fitness level of the athletes in the studies or the differences in timed trial protocols used in the studies.
Carpal tunnel syndrome. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of astaxanthin 4 mg, lutein, beta-carotene, and vitamin E (BioAstin, Cyanotech) orally 3 times daily for 8 weeks does not reduce the rate or duration of pain due to carpal tunnel syndrome when compared with placebo (19164).
Diabetes. It is unclear if oral astaxanthin is beneficial for diabetes. Details: A small clinical trial in adults with diabetes shows that taking astaxanthin (Nature Vision) 8 mg daily for 8 weeks does not reduce levels of cholesterol or fasting blood glucose or reduce diastolic blood pressure when compared with placebo. However, there were some modest beneficial effects on visceral fat, triglyceride level, and systolic blood pressure (109778).
Dry eye. It is unclear if oral astaxanthin is beneficial for dry eye syndrome. Details: A clinical study in adults and elderly patients with mild to moderate dry eye syndrome shows that taking oral astaxanthin 6 mg twice daily for 30 days improves symptom severity, tear break-up time, fluorescein break-up time, and meibomian gland dysfunction, but not visual acuity or intraocular pressure, when compared with baseline (107962). The validity of these findings is limited by the lack of a comparator group.
Dyspepsia. It is unclear if oral astaxanthin improves symptoms of dyspepsia. Details: One clinical study in adults with functional dyspepsia with or without Helicobacter pylori infection shows that taking astaxanthin (AstaCarox, AstaReal AB) 16 mg or 40 mg daily for 4 weeks does not reduce indigestion, pain, or H. pylori counts when compared with placebo. However, astaxanthin 40 mg daily may reduce reflux in H. pylori-positive patients (19165).
Exercise-induced muscle damage. Small clinical studies in trained athletes suggest that oral astaxanthin may not improve markers of muscle damage from exercise. Details: A small study in professional male soccer players shows that taking astaxanthin 4 mg daily for 90 days does not seem to reduce exercised-induced biomarkers of muscle damage, such as creatinine kinase, when compared with placebo (91739). Taking a combination of astaxanthin 4 mg and lutein 480 mg (BioAstin, Cyanotech) daily for 3 weeks also did not reduce creatinine kinase levels after exercise in trained athletes when compared with placebo (safflower oil) (19199).
Exercise-induced muscle soreness. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in resistance trained athletes shows that taking a combination of astaxanthin 4 mg and lutein 480 mg (BioAstin, Cyanotech) daily for 3 weeks does not reduce muscle soreness or improve muscle performance 96 hours after exercise when compared with placebo (safflower oil) (19199).
Fatigue. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy patients shows that taking a specific combination product (ASTOTS, Fujifilm Co.) containing astaxanthin 6 mg and sesamin 10 mg after breakfast daily for 4 weeks does not improve overall fatigue after completion of mental and physical tasks when compared with placebo (98769).
Heart failure. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with heart failure with reduced left ventricular ejection fraction (LVEF) shows that taking a specific supplement containing astaxanthin 12 mg, tocotrienol 40 mg, and L-ascorbic acid 2-glucoside 30 mg (AstaReal ACT, AstaReal Co., Ltd.) daily for 3 months may increase LVEF from 34% to 38% and modestly increase exercise tolerance as measured by the six-minute walk test when compared with baseline (105097). The validity of these findings is limited by the lack of a comparator group. Furthermore, this study was funded by the supplement manufacturer.
Hyperlipidemia. Small clinical studies suggest that oral astaxanthin is not beneficial for reducing cholesterol levels. Details: One small clinical study in adults with mild hyperlipidemia shows that taking astaxanthin (AstaReal Astaxanthin, Fuji Chemical Industry) 12 mg or 18 mg daily for 12 weeks reduces triglyceride levels, while taking 6 mg or 12 mg daily increases high-density lipoprotein (HDL) cholesterol levels, when compared with placebo. However, total cholesterol and low-density lipoprotein (LDL) cholesterol levels were not affected (19167). Meta-analyses of small clinical studies mostly in adults without hyperlipidemia have also been conducted. One shows that taking astaxanthin 4-18 mg daily for up to 12 weeks does not reduce total or LDL cholesterol levels, but may increase HDL cholesterol levels, when compared with control (105100). A more recent analysis shows that taking astaxanthin 4-20 mg daily for up to 6 months has no beneficial effects on blood lipid levels and might actually increase levels of LDL cholesterol (109776).
Hypertension. It is unclear if oral astaxanthin reduces blood pressure. Details:A meta-analysis of four small clinical trials shows that taking astaxanthin does not have a clinically beneficial effect on systolic or diastolic blood pressure (109776). However, none of the trials were conducted in patients with hypertension.
Impaired glucose tolerance (prediabetes). It is unclear if oral astaxanthin is beneficial in patients with prediabetes. Details: A small clinical study in healthy adults and adults with prediabetes shows that taking oral astaxanthin 12 mg daily for 12 weeks improves glycated hemoglobin (HbA1c) when compared with baseline, but not when compared with placebo. Insulin sensitivity and postprandial glucose levels were also improved when compared with baseline, but no statistical comparison to the placebo group was conducted (107965). The validity of this study is limited due to unclear reporting.
Infertility. It is unclear if oral astaxanthin improves reproductive outcomes in patients with infertility due to endometriosis or polycystic ovary syndrome (PCOS). Details: A small clinical study in adults with infertility secondary to moderate or severe endometriosis undergoing assisted reproductive therapy in Iran shows that taking astaxanthin (AstaReal, AstaReal Co.) 6 mg daily for 12 weeks improves the numbers of oocytes retrieved, mature oocytes, and high-quality embryos but not the quantity of immature oocytes, fertilization rate, number of transferred embryos, or clinical pregnancy rate when compared with placebo (112434). Similarly, a small clinical study also conducted in Iran in patients with infertility due to PCOS undergoing assisted reproductive therapy shows that taking astaxanthin (Algalife Pure astaxanthin) 8 mg daily for 40 days prior to egg retrieval modestly improves the high-quality embryo rate, but not the total number of embryos or the clinical pregnancy rate, when compared with placebo (109775).
Male infertility. It is unclear if oral astaxanthin improves male infertility. Details: A small low-quality clinical study in males with infertility who are participating in intra-uterine insemination shows that taking astaxanthin (AstaCarox, AstaReal AB) 16 mg daily for 3 months does not seem to increase sperm count and quality, but might result in a higher total pregnancy rate of 23% compared with a 3.6% rate in the placebo group (19197). The validity of this finding is limited by poor study methodology and differences between treatment groups. Another small clinical study in males with infertility and oligospermia shows that taking astaxanthin (Astasan, Sensilab) 16 mg daily does not increase sperm concentration or sperm motility when compared with placebo (105098).
Menopausal symptoms. Although there is interest in using oral astaxanthin for menopausal symptoms, there is insufficient reliable information about the clinical effects of astaxanthin for this purpose.
Metabolic syndrome. Although there is interest in using oral astaxanthin for metabolic syndrome, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
Nonalcoholic fatty liver disease (NAFLD). Although there is interest in using oral astaxanthin for NAFLD, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
Osteoarthritis. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with mild knee or hip osteoarthritis shows that taking a combination product containing astaxanthin 2 mg, krill oil, and hyaluronic acid daily for 12 weeks (FlexPro MD, Valensa) reduces joint pain and stiffness and improves objective and subjective measures of joint function but does not improve overall physical function when compared with placebo (112432). It is unclear if these effects are due to astaxanthin, other ingredients, or the combination.
Obesity. Although there is interest in using oral astaxanthin for weight loss, there is insufficient reliable information about the clinical effects of astaxanthin for this purpose.
Parkinson disease. Although there is interest in using oral astaxanthin for Parkinson disease, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
Physical performance. It is unclear if oral astaxanthin improves physical performance in older adults. Details: A small clinical trial in healthy nursing home residents shows that taking astaxanthin (AstaReal) 12 mg twice daily for 16 weeks, in combination with vitamin E 40 mg and vitamin C 30 mg daily, increases the 6-minute walking distance by about 38 meters, a significant increase when compared with placebo containing vitamin E and vitamin C. However, there was no effect on muscle strength (109777). Another small clinical trial in healthy, older adults (aged 65-85 years) undergoing exercise endurance testing shows that a specific combination product (AstaReal; Fuji Health Science, Inc) containing astaxanthin 12 mg, tocotrienol 10 mg, and zinc 6 mg, taken as 2 capsules daily for 12 weeks, reduces the respiratory exchange ratio, but does not improve leg muscle endurance or perceived exertion, when compared with placebo. In a subgroup analysis of males, but not females, those taking astaxanthin had a greater total exercise efficiency when compared with placebo (107963).
Rheumatoid arthritis (RA). Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with RA shows that taking a supplement containing astaxanthin 4 mg, lutein 40 mcg, vitamin A 65 IU, vitamin E 50 IU, and safflower oil 460 mg (BioAstin, Cyanotech) three times daily for 8 weeks reduces pain and improves satisfaction by approximately 40% when compared with placebo (94125).
Stroke. Although there is interest in using oral astaxanthin for recovery from stroke, there is insufficient reliable information about the clinical effects of astaxanthin for this purpose.
Sunburn. It is unclear if oral astaxanthin might help to prevent sunburn. Details: A very small clinical study in Japanese adults shows that taking astaxanthin (Astots, Fujifilm Corporation) 4 mg daily for 9 weeks might increase skin tolerance to ultraviolet (UV) light when compared with placebo (96884). It is unclear if this translates to a lower risk of sunburn. More evidence is needed to rate astaxanthin for these uses.

DOCOSAHEXAENOIC ACID (DHA) (Omega-3 Fatty Acids, Docosahexaenoic Acid)

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

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

EICOSAPENTAENOIC ACID (EPA) (Omega-3 Fatty Acids, 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.

POSSIBLY EFFECTIVE

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

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.

VITAMIN A

EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

LIKELY INEFFECTIVE

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

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

Safety view details

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

ASTAXANTHIN

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

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

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

DOCOSAHEXAENOIC ACID (DHA) (Omega-3 Fatty Acids, 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) (Omega-3 Fatty Acids, 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.

VITAMIN A

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

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

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

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

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

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

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

Interactions with Drugs view details

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

ASTAXANTHIN

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, astaxanthin may decrease levels of drugs metabolized by CYP2B6.

Details

In vitro research shows that astaxanthin induces cytochrome CYP2B6 enzyme activity in human hepatocytes (32613). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, astaxanthin may decrease levels of drugs metabolized by CYP3A4.

Details

In vitro research shows that astaxanthin induces CYP3A4 enzyme activity in human hepatocytes (32613). This effect has not been reported in humans.

DOCOSAHEXAENOIC ACID (DHA) (Omega-3 Fatty Acids, 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) (Omega-3 Fatty Acids, 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.

VITAMIN A

HEPATOTOXIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, taking high doses of vitamin A in combination with other potentially hepatotoxic drugs might increase the risk of liver disease.

Details

The tolerable upper intake level (UL) is the highest level of intake that is likely to pose no risk of adverse effects. Doses of vitamin A above the UL can cause hepatotoxicity, ranging from elevated liver enzymes to liver failure (7135,82554).

RETINOIDS

Interaction Rating = Major Do not take this combination.

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

Concomitant use of retinoids with vitamin A supplements might produce supratherapeutic vitamin A levels.

Details

Retinoids, which are vitamin A derivatives, could have additive toxic effects when taken with vitamin A supplements (3046).

TETRACYCLINE ANTIBIOTICS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, taking tetracycline antibiotics with high doses of vitamin A can increase the risk of pseudotumor cerebri.

Details

Benign intracranial hypertension (pseudotumor cerebri) can occur with tetracyclines and with acute or chronic vitamin A toxicity. Case reports suggest that taking tetracyclines and vitamin A concurrently can increase the risk of this condition (10545,10546,10547). Avoid high doses of vitamin A in people taking tetracyclines chronically.

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, high doses of vitamin A could increase the risk of bleeding with warfarin.

Details

Vitamin A toxicity is associated with hemorrhage and hypoprothrombinemia, possibly due to vitamin K antagonism (505). Advise patients taking warfarin to avoid doses of vitamin A above the tolerable upper intake level of 10,000 IU/day for adults.

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Adverse Effects view details

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

ASTAXANTHIN

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

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

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

DOCOSAHEXAENOIC ACID (DHA) (Omega-3 Fatty Acids, 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) (Omega-3 Fatty Acids, 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.

VITAMIN A

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

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

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

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

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

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

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

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

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

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

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

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

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

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