Huma Chia Energy Gel (Apple and Cinnamon flavor) by Huma Products LLC

Alpha hydroxy acids represent a group of natural chemicals that are used alone or in combination. See specific monographs for effectiveness information.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if apple juice consumption is beneficial in patients with Alzheimer disease. Details: A small clinical study in adults with moderate to severe Alzheimer disease shows that drinking 4 ounces of apple juice twice daily for one month does not improve cognitive function when compared with baseline. However, according to caregiver assessment, it seems to improve aspects of mood and behavior, such as anxiety, depression, apathy, delusion, and agitation, when compared with baseline (94422). The validity of this finding is limited by the lack of a comparator group.
• Cancer. It is unclear if apple consumption is beneficial for preventing cancer. Details: Some population research has found that eating one or more apples daily may be associated with a decreased risk of esophageal, colorectal, larynx, or breast cancer when compared with eating less than 1 apple daily (31688). Also, a case-control study in adults with lung cancer has found that increased apple consumption may be associated with a reduced risk of lung cancer (3470).
• Dental plaque. It is unclear if apple consumption is beneficial for reducing dental plaque. Details: A small clinical study in healthy patients shows that eating an apple is less effective for reducing plaque than brushing teeth. Eating an apple actually increases plaque when compared with baseline, although it decreases the measure of bacterial vitality (99447).
• Diabetes. It is unclear if consumption of powdered, dehydrated apple is beneficial in patients with type 2 diabetes. Details: A small clinical study in patients with type 2 diabetes shows that substituting 26-52 grams of white wheat flour in bread with powdered, dehydrated apple and consuming the bread daily for up to 4 weeks does not improve fasting blood glucose or postprandial glucose levels when compared with a low-fiber white bread control (13141).
• Diarrhea. It is unclear if apple juice consumption is beneficial in infants with severe diarrhea. Details: A clinical study in infants with severe diarrhea shows that drinking apple juice 15 mL/kg twice daily during episodes of diarrhea results in more fecal loss when compared with drinking water (31687).
• Metabolic syndrome. Although there has been interest in using apple for metabolic syndrome, there is insufficient reliable information about the clinical effects of apple for this purpose.
• Muscle strength. Oral apple extract has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: Small clinical studies in resistance trained males show that taking a specific blend of ancient peat and apple extract (elevATP, VDF FutureCeuticals Inc.) 150 mg daily as a liquid with liposomes (QuSomes, BioZone Laboratories Inc.) for 12 weeks modestly increases lower body and total strength, improves lower body power output, and increases cross-sectional area of muscle when compared with placebo (94418,94419).
• Obesity. It is unclear if apple consumption is beneficial in patients with overweight or obesity. Details: A small clinical study in females with hypercholesterolemia and overweight or obesity shows that eating apples three times daily for 12 weeks is associated with weight loss of 1.2 kg, compared with weight loss of 0.9 kg in those consuming oat cookies (17997). More evidence is needed to rate apple for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dementia. It is unclear if consuming dewaxed brown rice improves cognitive function in adults with dementia. Details: A small clinical study in elderly nursing home residents with low cognitive function shows that eating dewaxed brown rice with 3 meals daily for 6 months improves scores on the Revised Hasegawa's Dementia Scale to a greater extent than eating white rice (103626).
• Diabetes. It is unclear if consuming brown rice as part of the diet is beneficial for improving glycemic control in adults with type 2 diabetes or for prevention of diabetes in healthy adults. Details: Meta-analyses of clinical trials evaluating adults with type 2 diabetes show that consuming a diet containing brown rice 50-450 grams daily for 4-104 weeks does not improve glycated hemoglobin (HbA1c) levels or fasting blood glucose levels when compared with a white rice diet (108661,108662). Clinical trials using non-glutinous brown rice for 24 hours or 16 weeks show similar results (96996,96998). However, not all research agrees. Preliminary clinical research in adults with type 2 diabetes shows that eating glutinous brown rice twice daily for 8 weeks modestly reduces HbA1c levels, compared with no change in those eating white rice (96995). Preliminary clinical research also shows that eating glutinous brown rice as the staple food over a 24-hour period helps with acute glycemic response when compared with white rice (96996). Other preliminary clinical research in females with type 2 diabetes shows that following a brown rice diet for 12 weeks reduces HbA1c and fasting blood glucose by 3% to 5% and reduces body weight and body fat by approximately 2% when compared with no intervention (18660). Clinical trials in adults with type 2 diabetes also report conflicting effects of brown rice on body weight, waist circumference, body fat, lipids, and blood pressure when compared with white rice (108661,108662). However, the limited studies showing positive benefits of brown rice report very minor effects with unclear clinical implications. The reasons for these discrepancies are unclear but may be related to the slight differences between the varieties of brown rice. Additionally, brown rice has been evaluated for prevention of diabetes. A meta-analysis of three cohort studies in healthy adults suggests that a higher consumption of brown rice is associated with a reduced risk of developing type 2 diabetes when compared with lower consumption (115486). The validity of this finding is limited by the inclusion of lower quality studies, reliance on self-reported outcomes, and a largely female population in the observational cohort studies.
• Impaired glucose tolerance (Prediabetes). It is unclear if consuming brown rice as part of the diet is beneficial for improving glycemic control; the available research is conflicting. Details: A meta-analysis of clinical trials evaluating adults with prediabetes shows that consuming a brown rice-based diet for 6-12 weeks does not improve glycated hemoglobin (HbA1c) levels, fasting blood glucose levels, body weight, or waist circumference when compared with a white rice-based diet (108662). However, some preliminary clinical research in middle-aged females with prediabetes shows that replacing staple white rice in the diet with pre-germinated brown rice for 4 months modestly reduces fasting blood glucose and HbA1c levels when compared with baseline. There were also small improvements in body fat, body mass, systolic and diastolic blood pressure, and total cholesterol levels when compared with baseline (96997). The validity of these findings is limited by the lack of a comparator group.
• Metabolic syndrome. It is unclear if consuming brown rice reduces the prevalence of metabolic syndrome or improves metabolic parameters in patients with this condition. Details: Preliminary clinical research in adults with metabolic syndrome shows that eating brown rice ad libitum for 16 weeks does not improve metabolic factors or reduce the number of patients still meeting the diagnosis of metabolic syndrome when compared with eating white rice ad libitum (96998). However, other clinical research shows that eating 200 grams daily of cooked, pre-germinated brown rice for 3 months reduces the number of patients meeting the diagnosis of metabolic syndrome by 30%, compared with a reduction of 10% in those eating 200 grams daily of cooked white rice (103627). This suggests that any benefit might be related to regular consumption of brown rice. A small clinical study in overweight adults with metabolic syndrome shows that eating brown rice with 2 meals per day, 6 days per week for 3 months, reduces glycated hemoglobin (HbA1c) when compared with eating the same amount of white rice (103623). Other preliminary clinical research shows that eating sticky or glutinous brown rice for 8 weeks modestly improves body weight, some measures of insulin resistance, and levels of low-density lipoprotein (LDL) cholesterol when compared with baseline (96999). The validity of these findings is limited by the lack of a comparator group.
• Obesity. Although there is interest in using oral brown rice for weight loss, there is insufficient reliable information about the clinical effects of brown rice for this purpose.
• Psoriasis. Although there is interest in using oral brown rice for psoriasis, there is insufficient reliable information about the clinical effects of brown rice for this condition. More evidence is needed to rate brown rice for these uses.

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POSSIBLY INEFFECTIVE

• Hyperlipidemia. A meta-analysis of small clinical studies suggests that consuming chia seeds, flour, powder, or oil for 7-24 weeks does not improve lipid levels in patients with conditions associated with hyperlipidemia. Details: A meta-analysis of 10 small clinical trials in patients with various metabolic conditions, including diabetes, metabolic syndrome, nonalcoholic fatty liver disease, and obesity, shows that consuming chia seeds, flour, or powder 15-60 grams daily for 7-24 weeks, or taking chia oil 6 grams daily for 8 weeks, does not reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglyceride levels or increase high-density lipoprotein (HDL) cholesterol levels when compared with control groups consuming wheat bran, oat bran, dietary fiber, poppy seeds, or soybean oil (106657). While the patient populations in the studies analyzed are more likely to develop hyperlipidemia, it is unclear if these findings can be generalized to patients diagnosed with hyperlipidemia.
• Obesity. Small clinical studies suggest that consuming chia seeds for up to 12 weeks does not reduce body weight in overweight or obese adults. Details: One small clinical study in overweight or obese individuals shows that ingesting chia seeds 25 grams mixed in 0.25 liters of water twice daily before meals for 12 weeks does not improve body composition or reduce blood pressure when compared with placebo (25533). Another small clinical study in overweight, postmenopausal females shows that ingesting milled or whole chia seeds 25 grams daily for 10 weeks does not improve body composition or blood pressure when compared to baseline (25532).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. It is unclear if oral chia is beneficial for improving athletic performance. Details: A small clinical study in trained athletes shows that drinking a beverage containing 50% of calories from chia seeds (Greens Plus Omega 3 Chia seeds) and 50% of calories from a carbohydrate-containing beverage (Gatorade) for 2 days prior to participating in an endurance exercise lasting more than 90 minutes leads to similar performance when compared with Gatorade alone (25531).
• Cardiovascular disease (CVD). Although there has been interest in using oral chia for CVD, there is insufficient reliable information about the clinical effects of chia for this purpose.
• Diabetes. Small clinical studies suggest that consuming chia for 4-6 months might reduce systolic blood pressure (SBP) in patients with type 2 diabetes, although it does not appear to improve glycemic control or lipid levels and has shown mixed effects on body weight and inflammatory markers. Details: One small clinical trial in patients with type 2 diabetes shows that consuming bread containing a specific, selectively bred type of chia (Salba, Salba Smart Natural Products LLC), providing 37 grams of chia daily for 12 weeks reduces SBP, C-reactive protein, and vonWillebrand factor, but not lipid levels, when compared with consuming bread containing wheat bran. This form of chia also significantly reduced glycated hemoglobin (HbA1c) when compared to baseline, but not when compared with a wheat bran control (16124). Another small clinical study in adults with type 2 diabetes and obesity shows that consuming Salba chia 40 grams daily, either baked into bread or as a powder, in conjunction with a restricted calorie diet for 6 months reduces weight by 1.6 kg and waist circumference by 2.8 cm when compared with an oat bran control. However, consuming chia had no effect on body fat percentage, HbA1c, or fasting glucose levels (97940). Also, a small clinical study in adults with type 2 diabetes shows that consuming chia seeds 40 grams daily for 12 weeks reduces SBP, but does not improve body weight, HbA1c, or levels of fasting glucose, lipids, or C-reactive protein, when compared with those not consuming chia (106658).
• Hypertension. It is unclear if oral chia is beneficial in patients with hypertension. Details: A very small clinical study in patients with mild hypertension shows that consuming chia flour 35 grams daily for 12 weeks reduces systolic blood pressure (SBP) by around 10 mm Hg and diastolic blood pressure (DBP) by almost 9 mm Hg when compared to baseline. In patients already taking antihypertensive drugs, chia seems to have an even greater impact on SBP and DBP. However, in patients not being treated with antihypertensive drugs, chia flour modestly reduces SBP by 6.5%, but does not significantly reduce DBP. No improvements in blood pressure were reported in patients consuming a wheat bran control (91516).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral chia is beneficial in patients with NAFLD. Details: Small, uncontrolled clinical studies in patients with NAFLD show that consuming milled chia seeds 25 grams daily for 8 weeks may reduce hepatic steatosis, as measured by the liver: spleen attenuation ratio, in up to 43% of subjects with prediabetes and 100% of subjects with diabetes when compared to baseline. Chia seed supplementation may also modestly reduce visceral fat, body mass index, and waist circumference in patients with prediabetes when compared to baseline, but does not seem to improve lipid levels (104530,110438). The validity of these findings is limited by the lack of a comparator group in both studies.
• Metabolic syndrome. Oral chia has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with metabolic syndrome shows that reducing daily caloric intake by 500 kcal and drinking a beverage containing chia seed 4 grams, soy protein 32 grams, dehydrated nopal 7 grams, and oat 22 grams daily for 2 months reduces body weight, body mass index, and waist circumference when compared to baseline, but not when compared with following a reduced calorie diet alone. However, following the reduced calorie diet and drinking this beverage appears to lower serum triglycerides and C-reactive protein and improve glucose tolerance when compared with a reduced calorie diet alone (25534). It is unclear if these findings are due to chia, other ingredients, or the combination.
• Muscle strength. It is unclear if oral chia is beneficial for increasing muscle strength and muscle mass during resistance training. Details: A very small clinical trial in healthy, non-resistance trained males shows that drinking a supplemental beverage containing chia flour 50 grams, providing 20 grams of protein and 3 grams of omega-3 fatty acids, is no more effective than whey protein 20 grams or placebo for augmenting the increases in muscle strength and fat-free mass that occur with an 8-week whole body resistance training program (112385). The habitual baseline diet of the study participants already contained dietary protein intakes recommended for strength training, and the beverage was only consumed three times per week immediately after training sessions.
• Pruritus. It is unclear if topical chia seed oil is beneficial in patients with pruritus. Details: One very small, uncontrolled clinical study in patients with xerotic pruritus or pruritus caused by kidney failure or diabetes shows that applying lotion containing chia seed oil 4% for 8 weeks improves skin hydration and reduces the severity of lichen simplex chronicus and prurigo nodularis when compared to baseline (25537). The validity of these findings is limited by the small study size and lack of a comparator group. More evidence is needed to rate chia for these uses.

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POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Most research shows that taking oral DHA alone or with other ingredients does not slow or improve cognitive decline associated with age. Details: Most clinical research, from individual studies and a meta-analysis, shows that taking DHA orally, alone or with additional eicosapentaenoic acid (EPA) for up to 36 months, does not slow or improve age-related cognitive decline (97175,103313). In contrast, results from one large clinical study show that taking DHA 900 mg daily in the absence of EPA for 24 weeks improves episodic memory and visuospatial learning when compared with placebo in patients with age-related cognitive decline. However, DHA did not affect working memory or executive function (90717). DHA has also been evaluated in combination with other ingredients. A moderate-sized clinical study in older adults with subjective cognitive impairment and objective mild cognitive impairment shows that taking a DHA-rich fish oil containing DHA 1.1 grams and EPA 0.4 grams 3 times daily with high-flavanol cocoa for 12 months does not improve most measures of cognitive function, and moderately worsens reaction time variability, executive function, and alertness when compared with placebo. Additionally, there is no evidence of benefit on brain volumes, and patients who took DHA-rich fish oil and cocoa had greater decreases in cortical volume at 12 months when compared with placebo (111453).
• Alzheimer disease. Taking oral DHA does not seem to slow Alzheimer disease progression. Details: Population research has found that a 0.1 gram per day increment of dietary DHA intake is associated with a 37% reduced risk of Alzheimer disease when taken for 2-21 years (15041,96527). However, a dose-response relationship was not seen, and a correlation between DHA blood concentration and dementia was not seen (96527). Furthermore, clinical research shows that taking DHA 2 grams daily for 18 months does not slow cognitive or functional decline in patients with mild to moderate Alzheimer disease (48290). DHA has also been examined in combination with other ingredients. Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking DHA 500 mg, as part of fish 1 gram with eicosapentaenoic acid (EPA) 150 mg, and along with lutein 10 mg, zeaxanthin 2 mg, meso-zeaxanthin 10 mg, and vitamin E 15 mg (Memory Health) daily for 12 months does not affect disease severity when compared with placebo. However, there were modest increases the number of patients experiencing either an improvement or an attenuated decline in memory and mood (109764). The effect of DHA alone is unclear from this study.
• Attention deficit-hyperactivity disorder (ADHD). Most research shows that taking oral DHA does not improve ADHD symptoms. Details: Low plasma levels of DHA are associated with ADHD in children (7599,15496). Although some preliminary clinical research shows that DHA might improve aggression, emotional problems, and social relationships in children with ADHD (15494,100940), taking DHA 345-500 mg daily or 3.6 grams weekly does not seem to improve objective or subjective measures of ADHD symptoms when compared with placebo (7599,15495,100940). DHA has also been evaluated in combination with other ingredients. A moderate-sized clinical study in drug-naïve children ages 6 to 12 years with mild to moderate ADHD shows that taking DHA 87 mg in combination with eicosapentaenoic acid (EPA) and gamma linoleic acid (GLA) daily for 12 months does not improve inattentive symptoms, global functioning, or learning skills when compared with placebo. There also does not appear to be a correlation between plasma fatty acid levels and ADHD symptoms (111058).
• Bronchopulmonary dysplasia. Most research shows that oral DHA does not prevent bronchopulmonary dysplasia (BPD) in preterm infants. Some research suggests that it might increase the risk of BPD in infants born before 29 weeks gestation. Details: One meta-analysis of clinical research in over 3,500 preterm infants shows that administration of EPA and DHA as part of formula or as a direct oral dose, starting within one month of birth, does not increase or decrease the risk for BPD, regardless of the dose of DHA administered (102390). A more recent meta-analysis of four clinical trials limited to infants born less than 29 weeks gestation also shows that administration of DHA at levels of at least 40 mg/kg, or at levels of at least 0.4% total fatty acids in breast milk or formula, does not increase or decrease the risk of bronchopulmonary dysplasia (110359). However, in this latter meta-analysis, when only clinical trials using a more stringent definition of bronchopulmonary dysplasia were included, there was a modest INCREASED risk (110359). Similar findings occurred in a study that was terminated early. This research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on mortality of breastfed infants or survival without BPD at 36 weeks postmenstrual age. However, the occurrence of BPD and severe BPD in surviving infants of mothers taking DHA were increased when compared to those whose mothers took placebo (104559). The conclusions of this study are limited by the early termination, the provision of intravenous DHA-rich lipids to some infants per standard of clinical care, and the increased number of infants born via cesarean delivery to the mothers randomized to DHA. A more recent clinical trial has investigated the inclusion of arachidonic acid in an enteral emulsion providing DHA. One clinical trial in preterm infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age does not increase the risk of bronchopulmonary dysplasia or other major morbidities compared to control (MCToil, Nutricia) emulsion. Also, infants given the arachidonic acid and DHA required 17 fewer days of respiratory support (110356).
• Cognitive function. Most research shows that oral DHA does not improve cognitive function in healthy adults. Details: Most clinical research shows that taking DHA 250-1000 mg daily for up to 6 months does not improve cognitive function in healthy children, healthy adults, or older females (48194,48216,48266,90668,90708,104560). Also, cognitive function does not seem to be improved when compared with placebo in trials in which omega-3 products containing higher ratios of DHA to eicosapentaenoic acid (EPA) were used. These trials have used a specific product (Efamol Ltd) containing DHA 1.16 grams and EPA 0.17 grams daily (90707), DHA 900 mg plus EPA 270 mg (Accelon DHA EE, BASF) daily (109215), or fish oil (Dasbrain, Max Biocare) providing DHA 520 mg or 270 mg daily (109310), for 3 or 6 months in children and adults. However, some clinical research shows that taking algal oil containing DHA 600 mg daily for 16 weeks improves reading scores when compared with placebo in a subgroup of children ages 6-10 years who are below the 20th percentile for reading (90699). However, these results could not be replicated in a later study that included only children below the 20th percentile for reading (98542). The reason for this discrepancy is not clear. Taking DHA does not appear to improve reading scores in children at or above the 20th percentile for reading, and there does not appear to be any benefit of DHA on working memory in any children (90699).
• Cystic fibrosis. Most research shows that oral DHA does not improve symptoms of cystic fibrosis. Details: Clinical research in infants, children, and young adults with cystic fibrosis shows that taking DHA (DHA-basic, CASEN Fleet SLU) 50 mg/kg daily for 48 weeks does not improve spirometry measures, reduce Pseudomonas aeruginosa primary infections, or reduce the number of, or time to, total or severe pulmonary exacerbations when compared with placebo (109217). Also, small clinical studies show that taking DHA 70 mg/kg daily for 6 weeks, or 100 mg/kg daily for one month and then 1 gram daily for 11 months, does not improve lung function or overall health in patients with cystic fibrosis (48119,90665).
• Depression. Most research shows that oral DHA does not improve depression, regardless of the type. Details: Taking DHA orally does not seem to relieve symptoms of major depression, peripartum depression, or postpartum depression in most patients (10869,48030,48238,90680,90691,90692,89353,102391). Also, taking DHA for two weeks prior to the start of interferon-alpha therapy does not appear to prevent depression during interferon-alpha treatment in patients with hepatitis C, although it may delay depression onset by about 6 weeks (90710).
• Macrosomia. Taking oral DHA during pregnancy does not seem to prevent fetal macrosomia. Details: Clinical research in overweight or obese individuals shows that taking DHA (S-oil, DSM Nutritional Products) 800 mg daily, starting before 15 weeks' gestation and continuing until delivery, with or without dietary counselling, does not reduce the incidence of macrosomia when compared with taking DHA 200 mg daily (109218).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Increased dietary consumption of DHA is associated with a decreased risk of AMD (10324). Preliminary clinical research shows that taking a combination of DHA 280 mg, lutein 12 mg, and zeaxanthin 0.6 mg daily for one year increases macular pigment optical density by 31% when compared with placebo in patients with AMD. Increased macular pigment optical density is associated with improve vision performance and a reduced risk of AMD (90678). However, other clinical research suggests that adding DHA plus EPA to an AREDS formula, with or without lutein and zeaxanthin, does not reduce the time to development of AMD or vision loss in patients at high risk of progression to advanced AMD when compared with the AREDS formula alone (60281).
• Allergic rhinitis (hay fever). Although there has been interest in using oral DHA for allergic rhinitis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Atopic dermatitis (eczema). It is unclear if adding DHA to infant formula prevents atopic dermatitis. Details: Evidence from an observational, open-label study shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months does not prevent the development of eczema when compared to control formulas without DHA and arachidonic acid (92505).
• Atopic disease. It is unclear if oral DHA during pregnancy prevents atopic disease in the infant. Details: Clinical research shows that supplementation with DHA during pregnancy may modestly protect against some respiratory symptoms in the infants of atopic mothers. Prenatal supplementation with DHA 400 mg, taken daily from 18-22 weeks gestation until delivery, reduces the incidence of phlegm with nasal discharge or nasal congestion in the infant by the age of 18 months by approximately 22% and the incidence of fever with phlegm and nasal discharge or nasal congestion in the infant by approximately 47% when compared with placebo (90676). However, it is unclear if these symptoms are due to atopy or infections.
• Atrial fibrillation. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research suggests that adipose tissue levels of DHA are not associated with a decreased risk of atrial fibrillation (90700). However, clinical research suggests that taking 2 grams per day of a combination of DHA plus EPA (2:1 ratio), starting 7 days before cardiac surgery and continuing until hospital discharge, reduces the relative risk of post-cardiac surgery atrial fibrillation by 72% when compared with placebo. These patients also received vitamin C 1 gram daily plus vitamin E 400 IU daily, starting 2 days prior to surgery and continuing until discharge (90701).
• Autism spectrum disorder. It is unclear if oral DHA is beneficial for autism. Details: One preliminary clinical study shows that taking DHA 200 mg daily for 6 months does not improve autism symptoms in children and may even worsen some behaviors (90713). Another preliminary clinical study in children and adults with autism shows that taking a specific product (SUNTGA40S, Aravita, Suntory Ltd) containing DHA, arachidonic acid, and astaxanthin daily for 16 weeks does not improve overall symptoms when compared with placebo, although the combination product may improve certain symptoms such as social withdrawal or social communication (90716).
• Behcet disease. Although there has been interest in using oral DHA for Behcet disease, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Bipolar disorder. It is unclear if oral DHA is beneficial for bipolar disorder in adults. Details: A small clinical trial shows that taking DHA 1250 mg daily for 12 weeks does not improve cognitive function when compared with placebo in patients with bipolar disorder (103312).
• Breast cancer. It is unclear if oral DHA is beneficial for breast cancer treatment or prevention. Details: Population research has found no association between dietary fatty acid intake, including DHA, and the risk of breast cancer (96528). The effect of DHA supplementation on breast cancer risk is unknown. Some early research has investigated the effects of DHA in patients with breast cancer. Preliminary clinical research shows that taking DHA (DHASCO, Martek Biosciences Corp.) 600 mg three times daily for 7-10 days prior to chemotherapy initiation, and then for 5 months during chemotherapy, induces complete or partial response in 44% of breast cancer patients. Patients with a greater increase in DHA levels (at least 2.5%) show a longer time to progression and longer survival when compared to those with a smaller increase in DHA levels (90671).
• Cancer. Taking oral DHA with oral eicosapentaenoic acid (EPA) does not seem to decrease the risk of cancer in patients with cardiovascular disease and may actually INCREASE the risk of cancer in females. The effect of DHA alone is unclear. Details: Clinical research suggests that taking a combination of EPA 400 mg plus DHA 200 mg, with or without B vitamins, for a median of 4.7 years does not reduce the risk of cancer in middle-aged and elderly patients with cardiovascular disease. Furthermore, this combination appears to increase the risk of cancer in females (90666).
• Child development. It is unclear if oral DHA is beneficial for child development. However, due to the lack of significant safety concerns and the possibility of some cognitive benefit, many experts recommend DHA 200 mg daily during pregnancy. Details: Clinical research shows that giving infants DHA-supplemented formula during infancy does not appear to improve language and school readiness by the age of 2-3.5 years, or improve neurodevelopment by the age of 6 years (90674,92503). In addition, most research suggests that DHA supplementation during pregnancy, occasionally continuing postpartum for 6 months, does not affect visual acuity, attention, working memory, behavior and most other measures of neurodevelopment by 1-7 years of age (48095,48285,48293,90679,90690,94600,96522,109219). There is some evidence to suggest that maternal supplementation with DHA 400 mg daily from 16 weeks gestation until delivery may reduce the risk of poor language development in the infant at age 14 and 18 months and the risk of lower visual acuity at 2 months when compared with placebo (90694); however, this benefit did not have lasting effects at 5-6 years of age (99133).
• Cognitive impairment. It is unclear if oral DHA is beneficial for cognitive impairment in older adults. Details: Clinical research shows that taking DHA 800 mg daily, alone or with folic acid 800 mcg daily for 6 months, modestly improves some measures of cognitive function when compared with placebo in elderly patients with mild cognitive impairment (103978). Also, taking a specific product (Vayacog, Enzymotec Ltd.) providing phosphatidylserine 300 mg, DHA about 59 mg, and eicosapentaenoic acid (EPA) about 20 mg daily for 15 weeks improves verbal immediate recall when compared with placebo (94665). However, other research in older patients with mild cognitive impairment disagrees. Several clinical studies show that taking DHA 720-3300 mg plus EPA 351-1200 mg daily and other ingredients such as cocoa for 12 weeks to 12 months does not improve cognitive measures including memory and forgetfulness when compared with placebo (62847,90704,94665,109220,111453). One moderate-sized clinical study in older adults with subjective cognitive impairment and mild cognitive impairment shows that taking DHA 1.1 grams and EPA 0.4 grams 3 times daily with high-flavanol cocoa for 12 months moderately worsens reaction time variability, executive function, and alertness when compared with placebo. Additionally, there is no evidence of benefit on brain volumes, and those taking DHA-rich fish oil and cocoa had a greater decrease in cortical volume at 12 months when compared with placebo (111453).
• Coronary heart disease (CHD). It is unclear if oral DHA is beneficial for CHD. Details: Increased dietary consumption of DHA may reduce the risk of death in patients with CHD (10322). However, the effect of DHA supplements is unclear.
• Crohn disease. It is unclear if oral DHA is beneficial for Crohn disease prevention. Details: Population research suggests that increased dietary intake of DHA is associated with a reduced risk of Crohn disease (90673).
• Dementia. It is unclear if oral DHA is beneficial for dementia prevention. Details: Population research has found that a 0.1 gram per day increment of dietary DHA intake is associated with a 14% reduced risk of dementia when taken for 2-21 years. However, a dose-response relationship was not seen, and a correlation between DHA blood concentration and dementia was not seen (96527).
• Developmental coordination disorder (DCD). Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in children with DCD shows that taking a tuna fish oil product providing DHA 480 mg daily for 4 months, in combination with evening primrose oil providing arachidonic acid 35 mg and gamma-linolenic acid 96 mg, thyme oil 24 mg, and vitamin E 80 mg (Efalex, Efamol Ltd.), modestly decreases movement disorders as determined by objective measures when compared with baseline (5708). It is unclear if these benefits are due to DHA, other ingredients, or the combination. Also, the validity of this finding is limited by the lack of a comparator group.
• Diabetes. It is unclear if oral DHA is beneficial for glycemic control or the prevention of type 1 or gestational diabetes. Details: A small clinical study in adults with type 2 diabetes shows that taking DHA orally does not improve levels of low-density lipoprotein (LDL) cholesterol or decrease blood sugar or glycated hemoglobin. However, triglyceride levels are reduced (10321). DHA has also been evaluated for the prevention of gestational or type 1 diabetes. Clinical research in overweight or obese individuals shows that taking DHA (S-oil, DSM Nutritional Products) 800 mg daily, starting before 15 weeks' gestation and continuing until delivery, with or without dietary counselling, does not reduce the incidence of gestational diabetes when compared with taking DHA 200 mg daily (109218). Additionally, population research suggests that maternal serum levels of DHA are not associated with the risk of childhood onset of type 1 diabetes (90705).
• Diabetic retinopathy. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diabetic macular edema related to diabetic retinopathy receiving ranibizumab shows that taking a combination supplement containing DHA 1050 mg daily along with other free fatty acids, minerals, and vitamins (Brudyretina, Brudy Lab S.L.) for 2 years reduces macular thickness, but not visual acuity, when compared with ranibizumab alone. The effect of DHA alone is unknown (96526).
• Diarrhea. It is unclear if infant formula containing DHA is beneficial for diarrhea prevention. Details: Preliminary clinical research suggests that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months reduces the incidence of diarrhea requiring medical attention when compared to control formulas (92505).
• Dyslexia. It is unclear if oral DHA is beneficial for improving night vision in children with this condition. Details: One small clinical study in children with dyslexia shows that taking fish oils rich in DHA, providing 480 mg daily for one month, seem to develop significantly better dark adaptation when compared with controls (5708).
• Dysmenorrhea. Although there has been interest in using oral DHA for dysmenorrhea, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Fractures. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not prevent fractures in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Glaucoma. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in older adults with glaucoma shows that taking DHA 1.5 grams 3 times daily with citicoline for 3 months reduces the amount and rate of visual field loss and improves visual field index but does not reduce intraocular pressure when compared to baseline (112236). It is unclear if these effects are due to DHA, citicoline, or the combination; however, since no effects were found in the groups administered DHA or citicoline alone, it is possible that the effects are due to the combination of ingredients. The validity of these effects is limited by a lack of a control group and the very small sample size.
• Hypertension. It is unclear if oral DHA is beneficial for reducing blood pressure in adults or if prenatal supplementation reduces blood pressure in children. Details: Clinical research shows that taking DHA-enriched canola oil containing 63% oleic acid and 6% DHA for 4 weeks reduces systolic blood pressure by 3% and diastolic blood pressure by 4% when compared to baseline in adults with at least one cardiovascular risk factor (26466). A meta-analysis of clinical research in adults with dyslipidemia shows that supplemental DHA reduces diastolic, but not systolic, blood pressure when compared with control (102389). A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not reduce blood pressure levels in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly. About 39% of the individuals included in this study were diagnosed with hypertension and about 50% were using antihypertensives (104619). The effect of DHA alone on blood pressure levels in a population of adults with diagnosed hypertension is unclear. Prenatal supplementation with DHA has also been evaluated for the prevention of hypertension in children. A secondary analysis of a large clinical trial shows that overweight children or children with obesity whose mothers took DHA 600 mg daily, starting at about 14.5 weeks' gestation and continuing until birth, have lower diastolic and systolic blood pressure at 5 years of age when compared with those whose mothers took placebo. Systolic and diastolic blood pressure were reduced by about 4 mm Hg and 5 mm Hg, respectively, in the children exposed to DHA during pregnancy when compared with those exposed to placebo. The blood pressure of the children exposed to DHA during pregnancy was similar to that of children with normal weight (98891). Results of this study are limited by the fact that confounding factors, such as shorter duration of breast-feeding and increased sodium intake for children with obesity in the placebo group, may have also contributed to differences in blood pressure. It is unclear if this reduction in elevated blood pressure during childhood reduces the risk of hypertension in adulthood.
• IgA nephropathy. Although there has been interest in using oral DHA for IgA nephropathy, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Infant development. Infant supplementation with DHA does not seem to improve development. Also, most evidence shows that maternal supplementation with DHA is not beneficial for infant cognitive development. However, due to the lack of significant safety concerns and the possibility of some cognitive benefit, many experts recommend DHA 200 mg daily during pregnancy. Details: Most clinical research shows that giving healthy, full-term infants formula supplemented with DHA 0.32% to 0.96% modestly improves measures of visual acuity at 2, 4, and 12 months of age when compared with standard infant formula (14403,15003,47980,48355,90670). However, formula supplemented with DHA 0.15% does not appear to improve visual acuity by about 12 months when given to preterm infants (48008). There is some evidence that giving healthy, full-term infants DHA-supplemented formula during infancy might improve language comprehension and development, as well as fine motor skills, by the age of 12-14 months when compared with standard formula (48247,48356). However, most clinical research, including meta-analyses of high-quality clinical trials, shows that giving infants formula supplemented with DHA during infancy does not improve overall cognition or motor skills at 12-14 months of age, regardless of DHA dosing or prematurity status (48247,48356,89363). Experts generally recommend breast-feeding as the preferred feeding method over DHA-supplemented formula; however, if formula is used, some experts suggest a formula providing at least 0.2% of lipids from DHA (14403). Some population research suggests that higher maternal DHA levels are associated with improved use of gestures and problem solving in infants (90709,99132). However, population research suggests that higher maternal DHA levels also appear to be associated with worsening mental development (90709), and most clinical research shows that maternal ingestion of DHA has little effect on fetal or infant development. Maternal ingestion of DHA 33-133 mg daily from an egg source or 400 mg daily from an algal-based source does not seem to significantly increase weight, length, or head circumference at birth (14395,48286). Also, maternal ingestion of DHA 200-400 mg daily from week 15-22 of pregnancy until term does not significantly improve visual or auditory development in term infants (14393,90706). A small clinical trial shows that taking DHA 1440 mg daily from fish oil also providing eicosapentaenoic acid (EPA) 260 mg, from 22-24 weeks gestation until delivery, does not improve most measures of developmental or behavioral milestones in the infant at 6 months, when compared with olive oil placebo (110354). In addition, most research suggests that DHA supplementation during pregnancy, occasionally continuing postpartum for 6 months, does not affect growth to age 18 months or visual acuity, attention, working memory, behavior and most other measures of neurodevelopment by 1-7 years of age (48095,48285,48293,90679,90690,94600,96522,109219). However, there is some evidence to suggest that maternal supplementation with DHA 214 mg daily may improve infant sleep patterning on the first day of life (90687). Also, maternal supplementation with DHA 400 mg daily from 16 weeks gestation until delivery may reduce the risk of poor language development in the infant at age 14 and 18 months and the risk of lower visual acuity at 2 months when compared with placebo (90694). However, this benefit did not have lasting effects at 5-6 years of age (99133).
• Intraventricular hemorrhage. It is unclear if oral DHA is beneficial for preventing intraventricular hemorrhage in premature infants. Details: Preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of intraventricular hemorrhage when compared with a control emulsion (110356).
• Keratoconus. It is unclear if oral DHA is beneficial for improving vision in people with keratoconus. Details: A small clinical trial in patients with early to advanced keratoconus shows that taking DHA 1000 mg daily for 3 months does not improve corneal thickness, measurements of corneal curve, or most other ophthalmological measures when compared with taking no DHA (110358).
• Lower respiratory tract infections. It is unclear if formula containing DHA is beneficial for preventing lower respiratory tract infections in infants. Details: Clinical research shows that giving preterm infants formula or breast milk containing high-dose DHA (1% of fatty acids) does not prevent hospitalizations due to bronchiolitis and other lower respiratory tract conditions when compared with giving breast milk or formula containing 0.35% DHA (90667). However, preliminary clinical research shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months reduces the risk of bronchiolitis and croup when compared with control formulas (92505).
• Male infertility. It is unclear if oral DHA is beneficial for improving fertility. Details: Clinical research shows that taking DHA (NuaDHA, Nua Biological Innovations SL) 0.5, 1, or 2 grams daily for 3 months increases progressive sperm motility by 24% to 30% when compared with placebo in men with a history of infertility. The greatest effects were seen in men with asthenozoospermia, with an overall effect of 35 (99134). It is unclear if the effects of DHA on sperm function correlate with increased fertility rates.
• Metabolic syndrome. Although there has been interest in using oral DHA for metabolic syndrome, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Migraine headache. Although there has been interest in using oral DHA for migraine headache, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Muscle strength. It is unclear if oral DHA is beneficial for increasing muscle strength. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not increase muscle strength in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Necrotizing enterocolitis (NEC). It is unclear if oral DHA is beneficial for preventing NEC in preterm infants. Details: Clinical research in preterm infants shows that providing DHA (Neuromins for Kids life's DHA; DSM Nutritional Products Inc.) 75 mg/kg for 14 days from the first enteral feed reduces the risk of confirmed NEC by 7% when compared with a control oil. Treatment of 15 infants with DHA would be needed to prevent one case of NEC (109213). However, preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks' gestation, has no effect on the incidence of NEC in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of NEC when compared with a control emulsion (110356).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral DHA is beneficial for NAFLD. Details: Preliminary clinical research shows that taking DHA (Martek Biosciences Corporation) 250-500 mg daily for 6-24 months reduces the risk of severe liver steatosis when compared with placebo in children with NAFLD (48295,90695,90696).
• Obesity. It is unclear if oral DHA is beneficial for improving weight loss in overweight or obese adults. Details: Preliminary clinical research shows that taking 2.8 grams daily of an oil emulsion containing approximately 46% DHA for 12 weeks decreases carbohydrate and fat intake, but does not reduce body weight or improve body composition, when compared with placebo in overweight or obese adults (90681).
• Otitis media. It is unclear if DHA in infant formula is beneficial for preventing otitis media in infants. Details: Preliminary clinical research shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) for 12 months does not prevent the development of ear infection when compared with control formulas (92505).
• Phenylketonuria (PKU). It is unclear if oral DHA is beneficial for PKU. Details: Children with PKU consume very low amounts of DHA. Clinical research shows that taking DHA up to approximately 7 mg/kg daily for 6 months improves DHA status, but not neurological function, in children aged 5-13 years with PKU (99631). The effect of higher doses of DHA, or the effect of DHA supplementation on neurological function in younger children with PKU, have not been determined.
• Physical performance. It is unclear if oral DHA is beneficial for increasing physical performance in older adults. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not improve physical performance in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Postoperative pain. It is unclear if oral DHA is beneficial for reducing postoperative analgesic use. Details: A post-hoc analysis shows that enteral DHA 75 mg/kg administered perioperatively to infants born at greater than 34 weeks gestation who are undergoing cardiac surgery reduces the cumulative analgesic dose and shortens the duration of buprenorphine during the postoperative period when compared with placebo. However, the use of fentanyl or ketorolac were not reduced (96524).
• Prematurity. It is unclear if oral DHA during lactation or in early infancy is beneficial for increasing growth or neurodevelopment of the premature infant. Details: Clinical research in lactating individuals who delivered prior to 29 weeks' gestation shows that taking DHA 1.2 grams daily, starting within 72 hours of delivery and continuing until the infant reached 36 weeks postmenstrual age, might have beneficial effects on the growth of female infants, but not male infants, when compared with placebo. Weight velocity and weight gain were significantly increased in the female infants, with a weight gain of 52.6 grams. However, weight gain and weight velocity were not improved in the male infants, and weight at 36 weeks postmenstrual age was 89 grams less than those whose mothers took placebo (109221). In addition, there was no improvement in neurodevelopmental outcomes at 18 to 22 months corrected age (110364). Other clinical research in infants born before 29 weeks' gestation shows that giving enteral DHA 60 mg/kg daily until 36 weeks corrected gestational age does not improve most measures of intelligence at 5 years when compared with placebo (110363). However, a cohort study in premature infants born before 29 weeks' gestation suggests that supplementation with enteral high-dose DHA emulsion 60 mg/kg daily to match in-utero requirements until 36 weeks' gestational age or discharge home is associated with an increased risk of bronchopulmonary dysplasia and a 3.45 point benefit in intelligence quotient (IQ) at 5 years' corrected age. Further analysis of this relationship suggests that the increased risk effect of bronchopulmonary dysplasia from neonatal high-dose DHA is not associated with a decrease in the beneficial effects of DHA on IQ (112238).
• Prostate cancer. It is unclear if oral DHA is beneficial for prostate cancer prevention. Details: Observational research has found that higher consumption of DHA is associated with a reduced risk of total, advanced, and aggressive prostate cancer when compared to lower consumption of DHA (12961,25937). However, a meta-analysis of multiple population studies has found that higher DHA blood levels are associated with a 2.5-fold higher risk of aggressive prostate cancer, but not low-grade prostate cancer, when compared with lower blood percentages of DHA (25936). Another meta-analysis of population research has found that a higher blood level of DHA is associated with a slight increased risk of non-aggressive prostate cancer (90677).
• Psoriasis. Although there has been interest in using oral DHA for psoriasis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Raynaud syndrome. Although there has been interest in using oral DHA for Raynaud syndrome, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Restenosis. It is unclear if oral DHA is beneficial for preventing restenosis in people with stents. Details: Observational research has found that initiation of statin therapy in patients receiving stent placement after an acute coronary event is associated with a reduction in DHA levels. These reductions in DHA are associated with a greater prevalence of in-stent restenosis. From these results, researchers postulate that patients newly started on a statin after stent placement for acute coronary syndrome might benefit from DHA supplementation (100939). However, the effect of DHA supplementation is unknown.
• Retinitis pigmentosa. Evidence for the use of oral DHA for retinitis pigmentosa is inconsistent and contradictory. Details: Some clinical research shows that taking DHA 1200 mg daily for 4 years does not improve eye function in patients with retinitis pigmentosa who are also taking vitamin A when compared with placebo (48070). Also, taking DHA 600-3600 mg daily for 4 years does not maintain rod or cone function in boys or men with retinitis pigmentosa when compared with placebo (90683). However, a report of ancillary outcomes from this study shows that taking DHA might slow the rate of decline in final dark-adapted thresholds and visual field sensitivity in these patients (95738). Also, some research shows that taking DHA 400 mg daily for 4 years does maintain rod and cone function in some patients, although visual function is not improved when compared with placebo (48057,48115).
• Retinopathy of prematurity. It is unclear if maternal or infant supplementation with oral DHA is beneficial for preventing retinopathy of prematurity. Details: Preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on the incidence of retinopathy of prematurity in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of retinopathy of prematurity when compared with a control emulsion (110356).
• Rheumatoid arthritis (RA). Although there has been interest in using oral DHA for RA, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Schizophrenia. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking EPA 1000 mg, DHA 500 mg, and alpha-lipoic acid 150 mg twice daily for up to 2 years after discontinuing antipsychotic treatment does not prevent relapse in patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder (90675).
• Sepsis. It is unclear if oral DHA is beneficial for preventing sepsis in premature infants. Details: Preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on the incidence of sepsis in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of sepsis when compared with a control emulsion (110356).
• Sickle cell disease. It is unclear if oral DHA is beneficial for treating sickle cell disease. Details: A very small clinical study in adults with sickle cell disease shows that eating mayonnaise enriched with DHA 1900 mg and eicosapentaenoic acid (EPA) daily for 28 days does not reduce vaso-occlusive crisis pain or biomarkers of systemic inflammation (112237). The validity of these effects is limited by a lack of a comparator group and a very small sample size.
• Spinocerebellar ataxia (SCA). It is unclear if oral DHA is beneficial for SCA. Details: Preliminary clinical research in patients with SCA shows that taking DHA 600 mg daily for 16 weeks reduces ataxia and improves cerebellar hypometabolism upon brain imaging when compared with placebo. These beneficial effects are sustained when DHA is taken for an additional 40 weeks (96525).
• Stroke. It is unclear if oral DHA is beneficial for stroke prevention. Details: Population research has found that serum DHA levels may be associated with a reduced risk of ischemic stroke, as well as any specific type of ischemic stroke, including cardioembolic stroke, atherothrombotic stroke, and lacunar stroke (90715).
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral DHA for SLE, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Systemic lupus erythematosus (SLE) nephritis. Although there has been interest in using oral DHA for SLE nephritis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Ulcerative colitis. Although there has been interest in using oral DHA for ulcerative colitis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Vascular dementia. It is unclear if DHA is beneficial for improving dementia severity. Details: Preliminary clinical research in patients with vascular dementia shows that taking DHA 0.72 grams daily for one year improves dementia severity based on the Hasegawa's Dementia Rating Scale and Mini-Mental State Examination Scale scores when compared to baseline (47940). More evidence is needed to rate DHA for these uses.

(Read more about DOCOSAHEXAENOIC ACID (DHA))

EFFECTIVE

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

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about EICOSAPENTAENOIC ACID (EPA))

LIKELY EFFECTIVE

• Cystic fibrosis. Long-term nebulized hypertonic sodium chloride improves lung function and reduces pulmonary exacerbations in patients with cystic fibrosis. Details: Meta-analyses of clinical research in adults with cystic fibrosis show that, when taken along with a bronchodilator and other standard therapies, nebulized hypertonic sodium chloride in concentrations of 3% to 7%, up to 10 mL twice daily for 4 weeks, increases forced expiratory volume at one second (FEV1) when compared with isotonic saline (sodium chloride 0.9%) (26230,26230). This benefit was not seen at 48 weeks. Other clinical research in adults with cystic fibrosis shows that inhaling sodium chloride 7%, 4 mL twice daily for 48 weeks, does not improve FEV1 when compared with isotonic saline. However, chronic treatment with hypertonic saline does reduce the number of pulmonary exacerbations and increase the number of patients without pulmonary exacerbations when compared with isotonic saline (29402). It is not clear if this benefit occurs in children with cystic fibrosis. The Pulmonary Clinical Practice Guidelines Committee of the Cystic Fibrosis Foundation recommends that individuals with cystic fibrosis aged 6 years or older use nebulized hypertonic saline long-term to improve lung function, reduce the number of exacerbations, and improve quality of life (29403).

POSSIBLY EFFECTIVE

• Amphotericin B nephrotoxicity. Oral sodium chloride seems to prevent nephrotoxicity associated with use of amphotericin B. Details: Clinical research shows that administering oral or intravenous sodium chloride 150 mEq daily during treatment with amphotericin B can attenuate the rise in serum creatinine levels and preserve renal function when compared to treatment with amphotericin B alone (26226).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bipolar disorder. It is unclear if oral sodium is beneficial in preventing lithium level fluctuations in patients with bipolar disorder. Details: A moderate-sized open-label clinical study in adults with type I bipolar disorder receiving lithium carbonate shows that taking sodium chloride 1 gram daily for 12 weeks along with dietary salt restriction of 1 gram daily reduces the percentage of patients with lithium level fluctuations above 0.8 mEq/L, but does not significantly affect serum sodium, potassium, aldosterone, or creatinine levels when compared with controls who were not salt restricted, but were advised not to consume additional salt at the table (112909). However, the interpretation of these findings is limited by missing data in both groups.
• Canker sores. Although there is interest in using topical sodium chloride for canker sores, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Congestive heart failure. It is unclear if oral sodium is beneficial in patients with acute decompensated heart failure requiring decongestive therapy with diuretics. Details: A moderate-sized clinical study in adults hospitalized with acute decompensated heart failure requiring high-dose intravenous furosemide shows that taking sodium chloride 2 grams three times daily for up to 96 hours does not affect patient weight or serum creatinine levels when compared with placebo (112911). However, the clinical relevance of this study is unclear and it may have been inadequately powered to detect a difference between groups.
• Conjunctivitis. Although there is interest in using ophthalmic sodium chloride for conjunctivitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Hyponatremia. Although there is interest in using oral sodium chloride for hyponatremia, there is insufficient reliable information about the clinical effects of oral sodium chloride for this condition.
• Pharyngitis. Although there is interest in using topical sodium chloride for pharyngitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Prematurity. It is unclear if oral sodium is beneficial for premature infants. Details: Preliminary clinical research in infants born at less than 32 weeks' gestation shows that adding sodium 4 mEq/kg daily to enteral feedings, starting from the 7th day after birth and continuing through the 35th day, reduces the risk of developing hyponatremia and improves weight gain when compared with adding water (98180). A small, open-label clinical study in newborns less than 35 weeks gestation shows that high sodium intake, defined as an average of 0.25% sodium in maintenance fluids, for 48 hours on day 2 and 3 after birth results in less weight loss within the first 72 hours of life when compared with control, but does not improve mortality, length of hospital stay, or complications from prematurity (112908). However, interpretation of these findings is limited by varied concentrations of sodium as an intervention. More evidence is needed to rate sodium for these uses.

(Read more about SODIUM)

Some alpha hydroxy acids are used topically, while others are used orally, intravaginally, or by inhalation. See specific monographs for safety information.

PREGNANCY AND LACTATION:
See specific monographs for safety information.

(Read more about ALPHA HYDROXY ACIDS (AHAs))

LIKELY SAFE ...when used orally in food amounts. Eating apples and consuming apple juice is safe for most people. Apples are a common food source (3470,3472). However, eating apple seeds should be avoided because they can be toxic (6).

CHILDREN: LIKELY SAFE
when used orally in food amounts. Eating apples and consuming apple juice is safe for most people. Apples are a common food source (3470,3472).

CHILDREN: POSSIBLY SAFE
when apple pectin is used orally and appropriately, short-term. Preliminary clinical research suggests that combination products containing apple pectin and German chamomile (Diarrhoesan) are safe when used in infants for up to one week (19705,19706).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of apple in amounts greater than those found in foods during pregnancy and lactation; avoid using.

(Read more about APPLE)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Brown rice has Generally Recognized as Safe (GRAS) status in the US (7705). There is insufficient reliable information available about the safety of brown rice when used orally in medicinal amounts.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in food. Brown rice has Generally Recognized as Safe (GRAS) status in the US (7705). There is insufficient reliable information available about the safety of brown rice when used in medicinal amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (7705). There is insufficient reliable information available about the safety of brown rice when used in medicinal amounts during pregnancy or lactation.

(Read more about BROWN RICE)

LIKELY SAFE ...when used orally in amounts commonly found in foods (104531,104532).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Chia has been used safely at doses up to 40 grams daily for up to 6 months (16124,97940). ...when used topically, short-term. A product containing chia seed oil 4% has been applied to the skin safely for up to 8 weeks (25537).

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

(Read more about CHIA)

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

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

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

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

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

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

(Read more about DOCOSAHEXAENOIC ACID (DHA))

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

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

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

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

(Read more about EICOSAPENTAENOIC ACID (EPA))

LIKELY SAFE ...when used orally and appropriately. Sodium is safe in amounts that do not exceed the Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams daily (100310). Higher doses can be safely used therapeutically with appropriate medical monitoring (26226,26227).

POSSIBLY UNSAFE ...when used orally in high doses. Tell patients to avoid exceeding the CDRR intake level of 2.3 grams daily (100310). Higher intake can cause hypertension and increase the risk of cardiovascular disease (26229,98176,98177,98178,98181,98183,98184,100310,109395,109396,109398,109399). There is insufficient reliable information available about the safety of sodium when used topically.

CHILDREN: LIKELY SAFE
when used orally and appropriately (26229,100310). Sodium is safe in amounts that do not exceed the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Tell patients to avoid prolonged use of doses exceeding the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310). Higher intake can cause hypertension (26229).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Sodium is safe in amounts that do not exceed the CDRR intake level of 2.3 grams daily (100310).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in higher doses. Higher intake can cause hypertension (100310). Also, both the highest and the lowest pre-pregnancy sodium quintile intakes are associated with an increased risk of hypertensive disorders of pregnancy, including gestational hypertension and pre-eclampsia, and the delivery of small for gestational age (SGA) infants when compared to the middle intake quintile (106264).

(Read more about SODIUM)

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ALISKIREN (Tekturna, Rasilez) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Concomitant consumption of apple juice can significantly decrease oral absorption and blood levels of aliskiren.  Details Pharmacokinetic research shows that coadministration of apple juice 200 mL along with aliskiren 150 mg decreases the bioavailability of aliskiren by 63% (17670). Apple juice seems to inhibit organic anion transporting polypeptide (OATP), which is involved in drug uptake in the gut, liver, and kidney (7046,94413). It is thought that apple juice might affect OATP for only a short time. Therefore, separating drug administration and consumption of apple juice by at least 4 hours might avoid this interaction (17603,17604).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, consuming apple juice with antidiabetes drugs might interfere with blood glucose control.  Details Clinical research suggests that consuming apples or drinking apple juice can raise blood glucose levels, with the effects of drinking apple juice being more significant than consuming apples (31699).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Consuming apple juice with antihypertensive drugs might interfere with blood pressure control.  Details Some clinical evidence suggests that consuming apple and cherry juice can increase blood pressure in elderly patients (31680).

ATENOLOL (Tenormin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Concomitant consumption of apple juice can significantly decrease oral absorption and blood levels of atenolol.  Details Pharmacokinetic research shows that coadministration of apple juice 600-1200 mL decreases levels of atenolol by 58% to 82% in a dose-dependent manner (17999). Apple juice seems to inhibit organic anion transporting polypeptide (OATP), which is involved in drug uptake in the gut, liver, and kidney (7046). It is thought that apple juice might affect OATP for only a short time. Therefore, separating drug administration and consumption of apple juice by at least 4 hours might avoid this interaction (17603,17604).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Concomitant consumption of apple juice can significantly decrease oral absorption and blood levels of fexofenadine.  Details Pharmacokinetic research shows that coadministration of apple juice 400-1200 mL along with fexofenadine 60-120 mg decreases bioavailability of fexofenadine by up to 78% (7046,94413). Coadministration with smaller quantities of apple juice (150 mL or less) does not appear to affect the bioavailability of fexofenadine (94421). Apple juice seems to inhibit organic anion transporting polypeptide (OATP), which is involved in drug uptake in the gut, liver, and kidney (7046,94413). It is thought that apple juice might affect OATP for only a short time. Therefore, separating drug administration and consumption of apple juice by at least 4 hours might avoid this interaction (17603,17604).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D There is some concern that concomitant consumption of apple juice might decrease oral absorption and blood levels of lithium.  Details In one case report, a patient had an undetectable serum lithium level when lithium citrate was administered with apple juice. When lithium was administered with an alternative beverage, the lithium level became detectable and the patient demonstrated clinical improvement (105342).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Concomitant consumption of apple juice can significantly decrease oral absorption and blood levels of OATP substrates.  Details Research shows that consuming apple juice inhibits OATP, which reduces bioavailability of oral drugs that are substrates of OATP (7046,17605). Fexofenadine, atenolol, and aliskiren are substrates of OATP. Clinical research shows that coadministration of apple juice decreases bioavailability of fexofenadine by up to 78% (7046,94413), aliskiren by 63% (17670), and atenolol by up to 82% (17999). These effects appear to increase with larger quantities of apple juice. It is thought that apple juice might affect OATP for only a short time. Therefore, separating drug administration and consumption of apple juice by at least 4 hours might avoid this interaction (17603,17604).

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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.

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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.

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, a high intake of dietary sodium might reduce the effectiveness of antihypertensive drugs.  Details High intake of dietary sodium can increase systolic and diastolic blood pressure (26222). Also, high intake of sodium may necessitate increased use of antihypertensive medications to achieve blood pressure control in some patients, such as those with chronic kidney disease (26223).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of mineralocorticoids and some glucocorticoids with sodium supplements might increase the risk of hypernatremia.  Details Mineralocorticoids and some glucocorticoids (corticosteroids) cause sodium retention. This effect is dose-related and depends on mineralocorticoid potency. It is most common with hydrocortisone, cortisone, and fludrocortisone, followed by prednisone and prednisolone (4425).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Altering dietary intake of sodium might alter the levels and clinical effects of lithium.  Details High sodium intake can reduce plasma concentrations of lithium by increasing lithium excretion (26225). Reducing sodium intake can significantly increase plasma concentrations of lithium and cause lithium toxicity in patients being treated with lithium carbonate (26224,26225). Stabilizing sodium intake is shown to reduce the percentage of patients with lithium level fluctuations above 0.8 mEq/L (112909). Patients taking lithium should avoid significant alterations in their dietary intake of sodium.

SODIUM-CONTAINING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of sodium-containing drugs with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia and long-term sodium-related complications.  Details The Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams of sodium daily indicates the intake at which it is believed that chronic disease risk increases for the apparently healthy population (100310). Some medications contain high quantities of sodium. When used in conjunction with sodium supplements or high-sodium diets, the CDRR may be exceeded. Additionally, concomitant use may increase the risk for hypernatremia; this risk is highest in the elderly and people with other risk factors for electrolyte disturbances.

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use of tolvaptan with sodium might increase the risk of hypernatremia.  Details Tolvaptan is a vasopressin receptor 2 antagonist that is used to increase sodium levels in patients with hyponatremia (29406). Patients taking tolvaptan should use caution with the use of sodium salts such as sodium chloride.

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General ...Alpha hydroxy acids represent a group of natural chemicals, some of which can cause adverse effects. See specific monographs for safety information.

(Read more about ALPHA HYDROXY ACIDS (AHAs))

General ...Orally, apple fruit is well tolerated. Apple seeds, which contain cyanide, may cause serious adverse effects when consumed in large amounts.
Most Common Adverse Effects:
Orally: Bloating, flatulence.
Serious Adverse Effects (Rare):
Orally: Allergic reactions, including anaphylaxis. Ingestion of large amounts of apple seeds may cause cyanide poisoning, leading to death.

Gastrointestinal ...Orally, apple products, including whole apples, apple puree, and apple juice, may cause bloating and flatulence in some people (104184).

Immunologic ...Patients allergic to other fruits in the Rosaceae family, including apricot, almond, plum, peach, pear, and strawberry, can also be allergic to apples (7129). Rarely, the allergy has resulted in anaphylaxis (94425).

Other ...Orally, ingestion of large amounts of apple seeds, which contain hydrogen cyanide (HCN), may cause cyanide poisoning, leading to death. One death is attributed to ingestion of a cupful of apple seeds. To release cyanide, seeds must be hydrolyzed in the stomach, and several hours may elapse before poisoning symptoms occur (6).

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General ...Orally, brown rice is well tolerated when consumed as a food. No adverse effects have been reported when used in medicinal amounts; however, a thorough evaluation of safety outcomes has not been conducted.

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General ...Orally and topically, chia seems to be well tolerated.
Most Common Adverse Effects:
Orally: Flatulence and soft stools.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis in sensitive individuals.

Cardiovascular ...Chia contains a high concentration of alpha-linolenic acid (ALA). There is some concern that ALA might increase triglyceride levels more than other omega-3 fatty acids (12918); however, clinical research with a specific variety of chia called Salba shows that it does not significantly increase triglyceride levels (16124).

Gastrointestinal ...Orally, chia might cause mild gastrointestinal adverse effects. Some patients consuming chia 40 grams daily for up to 6 months reported mild and transient gastrointestinal adverse effects such as flatulence and soft stools; however, the frequency of these adverse effects was similar to patients consuming an oat bran control (97940). Bloating and flatulence have been reported with a chia flour-based sports beverage (112385).

Immunologic ...Orally, chia might cause anaphylaxis in sensitive individuals. A single case of IgE-mediated anaphylactic reaction has been reported for a patient who consumed chia seeds. Symptoms, including pruritus in the mouth, urticaria, facial angioedema, shortness of breath, and dizziness, developed a few days after consuming chia seeds. The reaction was attributed to sensitivity to proteins in chia seeds (91517).

Oncologic ...Chia seeds contain a high concentration of alpha-linolenic acid (ALA). Epidemiologic research suggests that high dietary intake of ALA might increase risk for prostate cancer (1337,2558,7823,7147,12978). Other research suggests high intake or serum levels of ALA does not increase the overall risk of prostate cancer (12961,15736); however, it might increase the risk of advanced prostate cancer (12961). Association with prostate cancer appears to depend on the sources of ALA. Dairy and meat sources have been positively associated with prostate cancer, whereas plant sources, such as chia seed, don't seem to affect prostate cancer risk (12909). According to a clinical trial, intake of ALA does not appear to increase levels of prostate specific antigen (PSA) (91402).

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

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

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

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

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

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

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

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

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

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

(Read more about DOCOSAHEXAENOIC ACID (DHA))

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

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

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

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

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

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

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

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

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General ...Orally, sodium is well tolerated when used in moderation at intakes up to the Chronic Disease Risk Reduction (CDRR) intake level. Topically, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Worsened cardiovascular disease, hypertension, kidney disease.

Cardiovascular ...Orally, intake of sodium above the CDRR intake level can exacerbate hypertension and hypertension-related cardiovascular disease (CVD) (26229,98176,100310,106263). A meta-analysis of observational research has found a linear association between increased sodium intake and increased hypertension risk (109398). Observational research has also found an association between increased sodium salt intake and increased risk of CVD, mortality, and cardiovascular mortality (98177,98178,98181,98183,98184,109395,109396,109399). However, the existing research is unable to confirm a causal relationship between sodium intake and increased cardiovascular morbidity and mortality; high-quality, prospective research is needed to clarify this relationship (100312). As there is no known benefit with increased salt intake that would outweigh the potential increased risk of CVD, advise patients to limit salt intake to no more than the CDRR intake level (100310).
A reduction in sodium intake can lower systolic blood pressure by a small amount in most individuals, and diastolic blood pressure in patients with hypertension (100310,100311,106261). However, post hoc analysis of a small crossover clinical study in White patients suggests that 24-hour blood pressure variability is not affected by high-salt intake compared with low-salt intake (112910). Additionally, the available research is insufficient to confirm that a further reduction in sodium intake below the CDRR intake level will lower the risk for chronic disease (100310,100311). A meta-analysis of clinical research shows that reducing sodium intake increases levels of total cholesterol and triglycerides, but not low-density lipoprotein (LDL) cholesterol, by a small amount (106261).
It is unclear whether there are safety concerns when sodium is consumed in amounts lower than the adequate intake (AI) levels. Some observational research has found that the lowest levels of sodium intake might be associated with increased risk of death and cardiovascular events (98181,98183). However, this finding has been criticized because some of the studies used inaccurate measures of sodium intake, such as the Kawasaki formula (98177,98178,101259). Some observational research has found that sodium intake based on a single 24-hour urinary measurement is inversely correlated with all-cause mortality (106260). The National Academies Consensus Study Report states that there is insufficient evidence from observational studies to conclude that there are harmful effects from low sodium intake (100310).

Endocrine ...Orally, a meta-analysis of observational research has found that higher sodium intake is associated with an average increase in body mass index (BMI) of 1. 24 kg/m2 and an approximate 5 cm increase in waist circumference (98182). It has been hypothesized that the increase in BMI is related to an increased thirst, resulting in an increased intake of sugary beverages and/or consumption of foods that are high in salt and also high in fat and energy (98182). One large observational study has found that the highest sodium intake is not associated with overweight or obesity when compared to the lowest intake in adolescents aged 12-19 years when intake of energy and sugar-sweetened beverages are considered (106265). However, in children aged 6-11 years, usual sodium intake is positively associated with increased weight and central obesity independently of the intake of energy and/or sugar-sweetened beverages (106265).

Gastrointestinal ...In one case report, severe gastritis and a deep antral ulcer occurred in a patient who consumed 16 grams of sodium chloride in one sitting (25759). Chronic use of high to moderately high amounts of sodium chloride has been associated with an increased risk of gastric cancer (29405).

Musculoskeletal ...Observational research has found that low sodium levels can increase the risk for osteoporosis. One study has found that low plasma sodium levels are associated with an increased risk for osteoporosis. Low levels, which are typically caused by certain disease states or chronic medications, are associated with a more than 2-fold increased odds for osteoporosis and bone fractures (101260).
Conversely, in healthy males on forced bed rest, a high intake of sodium chloride (7.7 mEq/kg daily) seems to exacerbate disuse-induced bone and muscle loss (25760,25761).

Oncologic ...Population research has found that high or moderately high intake of sodium chloride is associated with an increased risk of gastric cancer when compared with low sodium chloride intake (29405). Other population research in patients with gastric cancer has found that a high intake of sodium is associated with an approximate 65% increased risk of gastric cancer mortality when compared with a low intake. When zinc intake is taken into consideration, the increased risk of mortality only occurred in those with low zinc intake, but the risk was increased to approximately 2-fold in this sub-population (109400).

Pulmonary/Respiratory ...In patients with hypertension, population research has found that sodium excretion is modestly and positively associated with having moderate or severe obstructive sleep apnea. This association was not found in normotensive patients (106262).

Renal ...Increased sodium intake has been associated with impaired kidney function in healthy adults. This effect seems to be independent of blood pressure. Observational research has found that a high salt intake over approximately 5 years is associated with a 29% increased risk of developing impaired kidney function when compared with a lower salt intake. In this study, high salt intake was about 2-fold higher than low salt intake (101261).

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