Re-Grow Double Chocolate by GNC Beyond Raw

POSSIBLY EFFECTIVE

• Hepatic encephalopathy. Oral and intravenous BCAAs improve symptoms and nutritional status in patients with hepatic encephalopathy, especially in those not tolerating protein supplementation. Details: Taking BCAAs 240 mg/kg (up to 25 grams) daily in 3 divided doses for up to 3 months can improve symptoms, liver function tests, and nitrogen balance in patients with chronic hepatic encephalopathy (68,69,82,690,92643,97531). Oral BCAAs are recommended for malnourished patients with chronic hepatic encephalopathy who cannot tolerate protein supplementation (69,4274). When the enteral route is unavailable and when patients cannot tolerate general purpose amino acid solutions, intravenous solutions with BCAAs can be used for nutritional support; however, most patients can tolerate standard amino acid mixtures (4274). Some clinical research also suggests that taking BCAAs orally improves psychomotor function, attention, intelligence, and driving ability in patients with latent hepatic encephalopathy (684,685,37131,97531). However, not all studies show a positive effect of BCAAs on psychometric outcomes (37135). There is also some preliminary evidence that intravenous BCAAs might be helpful for reversing coma in acute hepatic encephalopathy, although findings are conflicting (66,81,686,687,688,689,4274,37134). BCAAs do not appear to reduce the risk of mortality or improve quality of life in patients with hepatic encephalopathy (92643,97531).
• Tardive dyskinesia. Oral BCAAs might reduce symptoms of tardive dyskinesia precipitated by antipsychotic drugs. Details: Taking BCAAs orally seems to reduce symptoms of tardive dyskinesia (72,10146,13307). Clinical research in adult and pediatric patients who are taking antipsychotic drugs shows that taking a drink containing BCAAs 222 mg/kg three times daily for 3 weeks reduces tardive dyskinesia movements by 30% to 60% when compared with placebo (10146,13307).

POSSIBLY INEFFECTIVE

• Liver cancer. Oral BCAAs do not seem to improve outcomes or reduce the risk for recurrence in patients with liver cancer. Details: A meta-analysis of the available clinical research, as well as individual clinical studies, in patients with hepatocellular carcinoma show that consuming up to 50 grams of BCAAs twice daily for up to 4 years does not improve survival, reduce tumor recurrence, or reduce the risk of complications such as ascites following liver resection when compared with a control group receiving no intervention (37143,92646,97532,105578). However, one small clinical study suggests that BCAAs may be beneficial in patients recently diagnosed with hepatocellular carcinoma that does not require surgery. Taking two packets of a specific supplement (Aminoleban EN) daily containing a total of L-leucine 4 grams, L-isoleucine 3.8 grams, and L-valine 3.2 grams, starting two weeks before receiving transcatheter arterial chemoembolization and radiofrequency ablation and continuing for up to 5 years, reduces recurrence of liver cancer and increases event-free survival when compared with placebo (97533). However, the validity of these findings is limited by the high withdrawal rate in this study.

LIKELY INEFFECTIVE

• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Overall, oral BCAAs are not beneficial and might even lead to worsened outcomes in patients with ALS. Details: Although early studies have indicated that taking BCAAs might be beneficial in ALS, more recent studies show no benefit and a possible increased loss of pulmonary function and higher rate of mortality among patients using BCAAs (678,679,680,681,37154).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if dietary BCAAs prevent Alzheimer disease. Details: Observational research has found that higher blood levels of BCAAs are associated with an 11% to 13% lower risk of Alzheimer disease; however, when research was adjusted for mortality, body mass index, and concomitant cholesterol-lowering medications, the association was no longer significant (100469).
• Athletic performance. Small clinical trials suggest that although oral BCAAs may not enhance athletic performance, they may modestly reduce perceived exertion and fatigue with some forms of exercise. Details: In most studies, taking BCAAs orally does not enhance athletic performance (692,1135,37080,37094,37106,37123,37141,37142,37151,92641). For instance, BCAAs do not appear to improve strength or work power or to reduce completion times for long-distance running or cycling trials (692,37106,37112,37141,37142,92641). However, most research shows that BCAAs are beneficial for reducing exercise-induced fatigue and perceived exertion after prolonged or intense exercise, exercise in the heat, or exercise following glycogen depletion (692,37112,37124,37144,92642,92644,92645,92648,97529,97530)(97535,105582). In many cases, this improvement is observed when BCAAs are taken in combination with arginine, citrulline, or green tea powder (37124,92642,92645,92648,97529,100462). However, some conflicting evidence exists (1135,37080,37094). Overall, the validity of these findings is limited because most studies differ widely in the amount and type of product consumed. For example, studied doses included BCAAs 0.17-0.3 mg/kg daily; or valine 0.5-1.7 grams, leucine 1-3.5 grams, and isoleucine 0.48-2.1 grams given before and/or after exercise (37108,37123,92642,92644,92645). Other limitations include variability in the studied endpoints and control comparisons used.
• Bipolar disorder. It is unclear if oral BCAAs are beneficial in patients with bipolar disorder. Details: One small clinical study shows that consuming a tyrosine-free amino acid drink containing 60 grams of the BCAAs leucine, isoleucine, and valine in a ratio of 3:3:4, reduces acute manic symptoms within 6 hours when compared with placebo. When taken daily for 7 days, it seems to continue to improve symptoms over a 2-week period (10117).
• Cachexia. Small clinical studies suggest that oral BCAAs are beneficial in patients with cachexia from various causes. Details: Preliminary clinical research in elderly malnourished patients receiving hemodialysis shows that taking a combination of BCAAs 4 grams three times daily improves appetite and caloric intake and increases plasma albumin levels and anthropometric measurements when compared with placebo (10147). Also, small clinical studies in adults with cachexia due to cancer or cirrhosis show that taking oral BCAAs 2.4 grams twice daily for 1 year or 4.8 grams 3 times daily for 1 week might be helpful when compared to baseline (71,37090). This finding is limited by the lack of a comparator group. A small clinical study in adults with congestive heart failure who have lost at least 7.5% of dry weight over the past 6 months or have a body mass index below 20 kg/m² shows that taking BCAAs 10 grams every evening at bedtime for 8 weeks improves physical and emotional quality of life scores, appetite, and fatigue when compared with placebo. Patients taking melatonin 20 mg nightly in addition to BCAA supplementation observed greater improvements in appetite and fatigue when compared with placebo (108478). However, a statistical comparison of outcomes between the groups taking BCAA alone or BCAA with melatonin was not provided.
• Cancer. It is unclear if dietary BCAA consumption improves cancer-related mortality. Details: Observational research in adults has found that consuming BCAAs 19 grams or more daily as part of the diet is not associated with a reduced risk of cancer-related mortality when compared with a lower dietary BCAA intake of less than 7.8 grams daily (108467). The validity of this finding is limited due to unclear reporting; additionally, dietary intake was recorded from a single survey.
• Cardiovascular disease (CVD). It is unclear if dietary BCAA consumption reduces the risk of CVD-related mortality. Details: Observational research in adults has found that CVD-related mortality is not associated with dietary BCAA intake or with individual leucine, isoleucine, or valine intake (108467). The validity of this meta-analysis is limited due to unclear reporting; additionally dietary intake was recorded from a single survey.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral BCAAs can improve physical performance in adults with COPD. Details: A clinical study in adults with stable, stage 2 or 3 COPD undergoing a pulmonary rehabilitation program shows that taking a BCAA powder 4.3 grams, diluted in water and consumed once daily for 4 weeks, may improve recovery after exercise, but does not impact maximal exercise capacity, functional and muscular performance, or quality of life when compared with placebo (108464). The validity of these findings is limited due to the short duration of treatment.
• Cirrhosis. Most small studies suggest that BCAAs may modestly improve certain measures in some patients with liver cirrhosis. Details: One small clinical study shows that although taking BCAAs 14.4 grams daily for 12 months does not improve survival or liver function in patients with advanced liver cirrhosis, the number of hospitalizations and prevalence of cachexia are reduced and quality of life is improved when compared with control or whey protein (37090). A clinical study in patients with sarcopenia and liver cirrhosis shows that taking BCAAs 7.2 grams for 6 months decreases bilirubin levels and improves Child-Turcotte-Pugh and model for end-stage liver disease (MELD) scores when compared with baseline (108468). Although the study enrolled a control group (whey protein), the investigators did not provide a statistical comparison of outcomes between groups. In addition, a small study in Japanese patients with cirrhosis shows that taking BCAAs 12.45 grams daily for at least 12 months improves liver function and reduces liver complications by 50% to 60% over 3-5 years when compared with control (37120). Also, taking a specific product (Livact, Samil Pharmaceutical) providing the same dose for 11-22 months improves liver function by a small to moderate amount over a 24-month period when compared with not taking BCAAs. There was also a moderate reduction in the rate of developing or worsening major complications such as ascites or hepatic encephalopathy (103351). However, some research providing BCAAs as part of a late evening snack has found no benefit. In one small study, consuming BCAAs as part of a late evening snack in an undefined dose for 3 months does not seem to improve quality of life when compared with a late evening snack without BCAAs (37101). Also, a very small clinical study in patients with abnormal glucose metabolism related to cirrhosis shows that consuming BCAAs in an undefined dose as part of a late evening snack for 1 week does not improve glycemic control when compared with baseline. Instead, glucose levels increased in some patients (103348). It is possible that the doses provided in these latter studies were lower than those used in the studies showing benefit. Additionally, these very small studies may not have been adequately powered to detect a difference between groups.
• Colorectal cancer. It is unclear if dietary BCAAs are beneficial or harmful in patients with colorectal cancer. Details: An observational study in Italy has found that increased dietary intake of BCAAs is associated with a lower risk of developing sigmoid colon cancer, but not overall colorectal cancer risk, when compared with lower intake (105584). However, there's some concern that increased dietary BCAAs may have negative effects in patients who have been diagnosed with colorectal cancer. Observational research in patients living in the US has found that higher dietary intake of BCAAs is associated with a slightly higher risk of all-cause mortality when compared with lower intake (105581).
• Dementia. It is unclear if dietary BCAAs help to prevent dementia. Details: Observational research has found that higher blood levels of BCAAs are associated with a 13% to 17% lower risk of dementia. The lowered risk was maintained when research was adjusted for mortality, body mass index, and concomitant cholesterol-lowering medications (100469).
• Diabetes. It is unclear if dietary BCAAs reduce the risk for developing diabetes. Details: Some population research in Japanese females has found a decreased risk of diabetes associated with higher intake of BCAAs (97543). However, other observational research in people from the US has found that increased dietary intake of BCAAs is associated with an increased risk of diabetes (97536). Reasons for the conflicting finding are not entirely clear. Some evidence suggests that the dietary pattern of BCAA intake, rather than the total intake, may influence the risk of diabetes. Also, there is some speculation that differences in gut microbiota may attribute to the observed differences in diabetes risk associated with BCAA intake (100465). Prospective clinical research is needed to determine whether this association is causal or correlative.
• Exercise-induced muscle damage. Small studies suggest that BCAAs might reduce some, but not all, markers of muscle damage caused by exercise. Details: A meta-analysis of small clinical studies shows that supplementation with BCAAs reduces creatine kinase (CK) levels 24 hours post-exercise, but not 48 hours post-exercise. Additionally, this analysis shows that lactate dehydrogenase (LDH) levels are not affected by BCAA supplementation (97534). The validity of this analysis was limited because baseline dietary protein consumption was not taken into consideration as a potential confounder. A separate meta-analysis of clinical research in trained male athletes performing various resistance exercises shows that taking BCAAs 0.2-1.76 grams/kg for 1-28 days improves CK levels immediately following exercise, and at 24 and 48 hours post-exercise, but does not reduce LDH levels at any timepoint, when compared with placebo or control (108469). Most doses of BCAAs studied consisted of a 2:1:1 ratio of leucine, isoleucine, and valine, respectively. The validity of these findings is limited due to the short duration of treatment and various doses studied. Small individual clinical trials show that taking BCAAs does not affect urinary myoglobin after a marathon nor plasma myoglobin or CK levels after isotonic muscular exercise (37123,92641,100471). The benefits of BCAAs might depend on baseline protein consumption. A small clinical study in resistance trained males shows that adding BCAAs 0.22 grams/kg (MusclePharm BCAA) daily for 8 days to a high daily protein consumption of 1.2 grams/kg does not attenuate muscle damage or improve muscle recovery when compared with placebo (100471). Conversely, a meta-analysis of clinical research in adults completing various exercises shows that taking BCAAs consisting of any combination of valine, leucine, and isoleucine ratios modestly reduces CK, LDH, and myoglobin 24 and 48 hours post-exercise, but does not improve muscle recovery or muscle force after exercise, when compared with placebo (108471). The validity of these findings is limited due to unclear reporting.
• Exercise-induced muscle soreness. Limited evidence suggests that oral BCAAs may modestly attenuate exercise-induced muscle soreness. Details: One meta-analysis shows that taking BCAAs does not reduce delayed-onset muscle soreness after exercise when assessed at the individual time points of 24, 48, or 72 hours (97534). However, when results of all time points are pooled together in two separate meta-analyses, supplementation modestly reduces soreness after exercise (97534,103353). Most, but not all, individual trials also show that taking BCAAs in various doses, such as 0.087 grams/kg or 5-10 grams before and/or after exercise, modestly reduces muscle soreness after exercise (37108,37123,37124,92648,97530,97535,100467,100471,103346,108471). The validity of these individual trials is limited by their small sample sizes, variable dosing regimens, and enrolled populations, which were mainly limited to young untrained adult males (97534,103353). A separate meta-analysis of clinical research in trained male athletes performing various resistance exercises shows that taking BCAAs 0.2-1.76 grams/kg for 1-28 days may improve muscle soreness during the first 24 hours after exercise, but not at 24 or 48 hours post-exercise, when compared with placebo or control (108469). The validity of these findings is limited due to the short duration of treatment and various doses studied. Also, it is not clear whether taking BCAAs before or after a workout may be more beneficial. Some research found a nonsignificant trend toward reduced muscle soreness when consuming a specific product (Aminofeel, Seikatsu Bunkasya Co. Ltd.) containing BCAAs 3.2 grams three times daily starting 3 days before working out and continuing 3 days after, when compared to control (100467). More research is needed to determine the best dosing regimen and which populations, if any, may benefit.
• Heart failure. It is unclear if oral BCAAs are beneficial in patients with heart failure. Details: A small clinical study in patients with heart failure and hypoalbuminemia shows that taking a specific packet of BCAA granules (LIVACT, Ajinomoto Co) containing L-valine 1144 mg, L-leucine 1904 mg, and L-isoleucine 952 mg, three times daily for at least 7 days and stopping after discharge from the hospital, does not affect serum albumin or cardiothoracic ratio (CTR) when compared with placebo (100470). It is possible that this study was underpowered to detect differences between groups. Another small clinical study in adults with chronic heart failure participating in a cardiac rehabilitation program shows that taking a specific oral supplement (Meiji Mei Balance Rehasupport Mini; Meiji Group) containing BCAAs 2.5 grams and various vitamins, minerals, and whey protein, twice daily for 12 weeks increases fat mass, but has no effect on peak oxygen uptake, 6-minute walking distance, or strength parameters, when compared with no supplementation (108470). It is unclear if these effects are due to BCAAs, the other ingredients, or the combination.
• Hepatitis. It is unclear if oral BCAAs are beneficial in patients with hepatitis. Details: Preliminary clinical research in patients with alcoholic hepatitis shows that taking BCAAs 20 grams daily orally or enterally for 3 weeks or until discharge, in combination with a controlled diet, does not reduce the risk of mortality when compared with conventional protein or a controlled diet alone (37133).
• Inflammatory myopathies. It is unclear if oral BCAAs are beneficial in patients with polymyositis and dermatomyositis. Details: A small clinical study in adults with suspected or confirmed polymyositis or dermatomyositis who are receiving standard corticosteroid therapy shows that a BCAA-specific product containing L-isoleucine 952 mg, L-leucine 1904 mg, and L-valine 1144 mg for 12-28 weeks, taken as two packages three times daily for a total daily dose of 24 grams, does not improve manual muscle test scores or clinical response at 12 and 28 weeks when compared with placebo (108477).
• Obesity. It is unclear of oral BCAAs can reduce the likelihood of developing obesity or improve weight loss in adults with overweight or obesity. Details: Some observational research has found that higher dietary intake of BCAAs is associated with lower odds of obesity when compared with a lower intake (100466). Conversely, a large observational study in adults in Iran, including those who are overweight or obese, has found that the highest dietary intake of BCAAs is associated with a 24% higher likelihood of general obesity in males, but not in females, when compared with the lowest dietary BCAA intake (108465). This study did not report ranges for highest and lowest BCAA intake, limiting the validity of this study. BCAAs have also been evaluated in adults with overweight or obesity. A small clinical study in obese females that underwent a 4-week calorie-restricted diet shows that taking 6 caplets daily containing a total of L-leucine 3 grams, L-isoleucine 1.5 grams, and L-valine 1.5 grams in addition to vitamin B6 40 mg daily for 4 weeks does not further reduce weight, but may slightly preserve lean body mass, when compared with placebo (100464). Another small clinical study in overweight and obese adults shows that taking BCAAs 0.1 gram/kg daily in addition to starting a low-calorie diet for 16 weeks does not improve weight loss, but may preserve lean muscle mass, when compared with taking placebo while following the low-calorie diet (105583).
• Overall mortality. It is unclear if dietary BCAA consumption reduces the risk of all-cause mortality. Details: Observational research in adults has found that total BCAA intake, as well as isoleucine intake, is associated with a reduced risk of all-cause mortality, particularly in those with higher serum triglyceride concentrations (108467). However, this association was not present for leucine or valine intake. The validity of this meta-analysis is limited due to unclear reporting; additionally dietary intake was recorded from a single survey.
• Pancreatic cancer. The association between dietary BCAA intake and pancreatic cancer risk is unclear. Details: Observational research in adults in Italy has found that consuming BCAAs as part of the diet in quantities greater than 18 grams daily is associated with a 2-fold increased risk of pancreatic cancer when compared with less than 12 grams daily. This relationship was stronger in younger males, those with higher body mass indexes, and in those who smoke or have high alcohol intake (108476). Dietary information was recorded from a single, weekly consumption questionnaire.
• Phenylketonuria (PKU). It is unclear if oral BCAAs are beneficial in patients with PKU. Details: A small clinical trial in adolescents and young adults with PKU shows that taking BCAAs, consisting of valine 150 mg/kg, isoleucine 150 mg/kg, and leucine 200 mg/kg, with meals and at bedtime for up to 6 months seems to improve attention and processing when compared with a control group (37127).
• Physical performance. It is unclear if oral BCAAs are beneficial for improving physical function and muscle strength in older adults. Details: In malnourished elderly individuals, preliminary clinical research shows that taking a supplement providing BCAAs 5000 mg daily, in addition to other amino acids, vitamin B6, and vitamin B1 (Aminotrofic) for 2 months, does not improve muscle mass, muscle strength, or physical function to a greater extent than dietary advice intended to maximize nutritional intake from food and drink (103349). Similarly, a clinical study in middle aged and elderly adults shows that a specific product (Sarcojoint; Orient Euro Pharma, Inc) containing leucine 1 gram, arginine, vitamin D3, glucosamine, chondroitin, and calcium, taken twice daily in addition to regular resistance exercise for 12 weeks, does not improve muscle strength, muscle mass, or physical performance when compared with taking an unspecified vitamin B supplement twice daily with regular exercise (108472). Conversely, one small clinical study in older adults who have had a hip replacement shows that taking BCAAs 1.2 grams and lysine 1.8 grams (Amino-aile, Ajinomoto Co., Inc.) daily for one month after undergoing exercise therapy sessions modestly increases the strength of both legs and arms when compared with taking starch. However, there was no effect on hip abductor strength of the operated leg or on grip strength or measures of independence (103347).
• Postoperative infection. There is limited evidence on the intravenous and oral use of BCAAs for reducing infection after oncologic surgery. Details: A meta-analysis of 6 small heterogeneous clinical trials in patients after oncologic surgery, mostly for liver cancer, suggests that receiving oral or intravenous BCAAs reduces the risk of postoperative infection by 38% when compared with control (105577).
• Postoperative recovery. There is limited evidence on the intravenous and oral use of BCAAs for improving postoperative recovery after oncologic surgery. Details: A meta-analysis of small heterogeneous clinical trials in patients after oncologic surgery, mostly for liver cancer, suggests that receiving oral or intravenous BCAAs reduces hospital stay by about 2 days, but does not reduce mortality or post-operative complications, when compared with control (105577).
• Psychological well-being. It is unclear if oral BCAAs are beneficial for psychological well-being. Details: A cross-sectional observational study has found that higher dietary consumption of BCAAs is associated with a lower risk of anxiety and depression when compared with lower consumption (105579).
• Sarcopenia. It is unclear if oral BCAAs are beneficial in patients with primary sarcopenia or in those with sarcopenia related to liver cirrhosis. Details: A small clinical study in postmenopausal adults at risk for sarcopenia shows that consuming BCAAs 9 grams daily for 8 weeks in addition to resistance training increases strength and muscle mass when compared with baseline, but is no different than resistance training plus a placebo (105576). Another small clinical study in adults 65 years or older with sarcopenia shows that taking a supplement containing BCAAs 2500 mg, vitamin D 500 IU, protein, and other vitamins daily for 8 weeks in addition to resistance training does not improve physical function when compared with resistance training alone. The supplement did seem to slightly improve handgrip strength and body mass when compared with no supplementation (100468). However, overall the study was inadequately powered to detect smaller effects on physical function and muscle mass. There is also interest in using BCCAs in patients with sarcopenia and liver cirrhosis. A clinical study in this population shows that taking BCAAs 7.2 grams (containing 1.2 grams of L-leucine, 600 mg of L-isoleucine, and 600 mg of L-valine) daily for 6 months improves handgrip strength, gait speed, and muscle mass when compared with baseline (108468). Although the study enrolled a control group (whey protein), the investigators did not provide a statistical comparison of outcomes between groups. A separate meta-analysis of low-quality clinical research in this population shows that taking BCAAs has no effect on handgrip strength when compared with no supplementation (108473). Although other outcomes were evaluated, results are inconclusive due to the limited number of studies available for each outcome.
• Spinocerebellar ataxia (SCA). It is unclear if oral BCAAs are beneficial in patients with SCA. Details: Although there is some preliminary clinical evidence that oral BCAAs might have a beneficial effect on symptoms of SCA (73), a small clinical crossover study shows that taking a particular BCAA compound (Livact) 4.5-18 grams daily for 4 weeks does not improve ataxia in patients with SCA when compared with placebo (37088).
• Stroke. It is unclear if oral BCAAs are beneficial in patients recovering from stroke. Details:A small nonblinded, clinical study in elderly patients with subacute stroke and sarcopenia currently undergoing intensive inpatient rehabilitation therapy shows that administering a specific product (Seniup; Enterogenomics Co) containing BCAAs 6 grams, given twice daily orally or by feeding tube for 1 month, modestly improves skeletal muscle index, dysphagia, gait, balance, and handgrip strength, and may attenuate muscle loss in affected upper and lower extremities, when compared with rehabilitation alone (108474). The validity of these findings is limited by the short duration of treatment. Other research has compared BCAA dosing regimens. A small study in stroke patients taking part in exercise sessions shows that taking BCAAs 3.5 grams (Hepas, Clinico Co. Ltd) daily for 2 months with breakfast is more effective for improving leg strength and balance than when taken post-exercise in the mid-afternoon. However, there were no differences in most measures of strength or in skeletal muscle mass (103352). More evidence is needed to rate BCAAs for these uses.

(Read more about BRANCHED-CHAIN AMINO ACIDS (BCAA))

EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount in adults with or without hypertension. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies, including a meta-analysis of 18 high-quality clinical trials, show that intake of calcium supplements or dietary calcium modestly reduces systolic blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as those who are salt-sensitive or have low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221,113920,113925). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplemental sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367). Research evaluating the effect of calcium supplementation during pregnancy on the child's blood pressure has yielded conflicting findings. A systematic review of 2 clinical studies and 3 observational studies found that calcium intake during pregnancy is associated with a 1-2 mmHg reduction in the systolic blood pressure of the offspring between the ages of 1-7 years (38852). However, a separate meta-analysis of 3 clinical studies shows that calcium intake during pregnancy does not reduce systolic or diastolic blood pressure in the offspring (113923).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia, especially in high-risk individuals and those with low baseline dietary calcium intake. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces the risk of pre-eclampsia (973,1833,8828,39043,39319,39426,97348,113919). A large clinical trial of 11,000 pregnant individuals in India and Tanzania shows that supplementation with 500 mg daily is similarly effective to 1500 mg daily (113908). Multiple meta-analyses which include 16-30 clinical studies have found that varying doses of calcium supplementation reduce the relative risk of pre-eclampsia by 46% to 51% when compared with placebo (97348,113909,113919). One of these meta-analyses found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (97348). Additionally, one of these meta-analyses found that calcium reduces the relative risk of pre-eclampsia by 51%, regardless of whether it is taken at a dose above or below 1000 mg daily (113919). Some research suggests that calcium supplementation may have a greater effect in individuals at high risk of pre-eclampsia or with low baseline dietary calcium intake, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,97348,99714,113919). However, another meta-analysis of 30 clinical studies found a similar benefit of calcium in both high- and low-risk individuals (113919). A separate meta-analysis of 6 clinical studies conducted in China evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy. This combination was associated with an 80% lower relative risk of pre-eclampsia and an 83% lower relative risk of pre-eclampsia with gestational hypertension when compared with routine care (113913). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely (102366). Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low (97347).
• Pregnancy-induced hypertension. Oral calcium may reduce the risk of pregnancy-induced hypertension. Details: A meta-analysis of 17 clinical studies shows that calcium supplementation during pregnancy may reduce the relative risk of pregnancy-induced hypertension by 30% when compared with control (113909). A separate meta-analysis of 6 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of pregnancy-induced hypertension by 85% when compared with routine care (113913).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium, via supplementation or as part of the diet, does not seem to be beneficial for breast cancer prevention. Details: Although some studies disagree (15631,39041,95811,107237,113917), most population research suggests that increased calcium intake is not associated with overall breast cancer risk (15631,16715,98895,107236,107237,113917). However, one meta-analysis of observational studies shows that although higher total calcium intake is not associated with breast cancer risk, higher dietary calcium intake, specifically, may be associated with a slightly reduced risk (113917). Also, some analyses suggest that calcium intake may be associated with the risk for certain breast cancer sub-types. Some subgroup analyses suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237) and that dietary calcium intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: Robust meta-analyses of mostly large, high-quality clinical studies show that calcium supplementation 500-1600 mg daily for 0.5-7 years with or without vitamin D does not reduce total fractures, hip fractures, vertebral fractures, or non-vertebral fractures in older adults without osteoporosis (95822,112486). A large-scale study in postmenopausal females aged 50-79 years who were enrolled in the Women's Health Initiative (WHI) suggests that calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the WHI study found that, in older females with the lowest genetic susceptibility to low BMD, taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss in adults or children with overweight or obesity. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905,113918), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). A meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308,113584).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Brain tumor. It is unclear if dietary calcium intake is associated with risk of brain tumor. Details: A meta-analysis of 4 case-control studies has found that higher dietary calcium intake is associated with a lower odds of brain tumor when compared with lower dietary intake (113922). The validity of this finding is limited by the exploratory nature of the included studies, which analyzed all dietary ingredients for any potential associations.
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if dietary calcium intake is associated with type 2 diabetes risk. Details: Some population research has found that a higher intake of calcium from the diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473,113929). One meta-analysis of cohort and cross-sectional studies found that the highest level of dietary calcium intake is associated with an 18% relative reduction in risk of type 2 diabetes when compared with the lowest level of intake. A dose-response analysis suggests that each 300, 600, and 1000 mg per day increase in dietary calcium intake is associated with a 7%, 14%, and 23% reduced risk of type 2 diabetes, respectively (113929). However, population research is often limited by confounding variables. For example, one analysis suggests that any beneficial effect might be influenced by concomitant magnesium intake (96473,113929), while another suggests that any benefit from increased intake may be more pronounced in females, adults aged 50 years or older, and Asian populations (113929). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis (95815).
• Dyslipidemia. It is unclear if oral calcium is beneficial for dyslipidemia. Details: One clinical study in adults with mild to moderate hypercholesterolemia shows that adding calcium carbonate 400 mg three times daily to a low-fat diet (American Heart Association Step 1) for 6 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% when compared with the low-fat diet and placebo (2557). In contrast, a clinical study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years INCREASES total cholesterol levels and carotid intima-media thickness in postmenopausal, but not premenopausal, females when compared with placebo (97350). Calcium supplementation has also been evaluated in combination with vitamin D. A meta-analysis of randomized controlled trials including adults with normolipidemia and dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is most beneficial in patients with dyslipidemia at baseline (107227). The relationship between dietary calcium intake and serum lipid levels has also been evaluated in observational research. A meta-analysis of 7-11 observational studies found that dietary calcium intake is not associated with total cholesterol levels, although small differences in individual lipid parameters were identified. Additionally, a meta-analysis of 4-9 observational studies suggests that calcium intake is not associated with the risk of developing hypertriglyceridemia, hypercholesterolemia, or low HDL. A subgroup analysis found that higher calcium intake may be associated with lower triglyceride levels in Asian populations (113927). Overall, these findings are limited by significant heterogeneity and the cross-sectional nature of the included studies.
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Exercise-induced muscle damage. It is unclear if oral calcium is beneficial for reducing exercise-induced muscle damage. Details: A very small clinical study in resistance-trained adults shows that taking calcium carbonate 500 mg 4 times daily for 3 weeks does not attenuate exercise-induced muscle damage from bench presses when compared with placebo (113933). This study may have been inadequately powered to detect a difference between groups.
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prematurity. It is unclear if supplemental calcium is beneficial for the growth and development of preterm infants. Details: A small clinical study in preterm infants consuming human milk shows that supplementation with calcium 45 mg/kg daily and phosphorus 25 mg/kg daily does not affect infant weight, length, head circumference, or risk of osteopenia after 6 weeks when compared with human milk alone (113924). However, the duration and size of this study may have been too limited to detect any difference between groups.
• Preterm labor. It is unclear if oral calcium reduces the risk of preterm labor. Details: A meta-analysis of 10 clinical studies shows that taking calcium supplements during pregnancy does not reduce the risk of preterm labor when compared with placebo (113909). A separate meta-analysis of 7 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of preterm labor by 74% when compared with routine care (113913).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

(Read more about CALCIUM)

EFFECTIVE

• Sickle cell disease. A specific oral glutamine powder (Endari, Emmaus Medical, Inc) is approved by the US Food and Drug Administration (FDA) to reduce acute complications of sickle cell disease. Details: Clinical research in adults and children 5 years of age and older shows that taking glutamine 5-15 grams (0.3 grams/kg body weight) orally twice daily for 48 weeks, either with or without hydroxyurea, delays the median time to first crisis by 30 days, and reduces the incidence of acute chest syndrome by 15%, number of hospitalizations by 33%, and the number of hospitalized days by 40%, when compared with placebo (96519,99414).

POSSIBLY EFFECTIVE

• Burns. Oral glutamine seems to improve healing in patients with severe burns and may also reduce the risk for burn wound infections; however, it is unclear if glutamine improves hospitalization length or mortality. Details: Some clinical research shows that administering enteral nutrition supplemented with glutamine 0.35-0.5 grams/kg daily for 12-14 days, beginning within 24-48 hours of hospitalization for severe burn injury (excluding inhalation injury), decreases the length of hospital stay by 6-9 days and may shorten wound healing when compared to control enteral nutrition (52307,52337). A clinical study in adults with moderate to severe burns (including inhalation injury) shows that administering enteral nutrition supplemented with intravenous alanyl glutamine 0.5 grams/kg daily, beginning within 24 hours of burn injury and continued for 14 days, may improve burn-induced organ damage, particularly intestinal mucosal injury, but does not improve mortality or length of hospitalization, when compared with standard nutritional support (108027). Another study in the same population shows that administering enteral nutrition supplemented with glutamine 4.3 grams every 4 hours, beginning within 24 hours of burn injury, decreases the risk of mortality by 83% and the risk of Pseudomonas wound infections; however, it does not decrease the duration of hospitalization (52311). A meta-analysis of these trials and one additional trial shows that administering glutamine enterally reduces the risk of Gram-negative bacterial wound infections by 73% and reduces the risk of mortality by 87% when compared to a control group. However, there was no difference in length of stay or overall wound infection rate (97363). Results were based on a small number of patients within each outcome evaluation. Intravenous glutamine has also been evaluated. One small clinical study shows that intravenous glutamine 0.57 grams/kg daily decreases the incidence of Gram-negative bacteremia by 35% when compared with control in patients with severe burns. However, it does not appear to decrease the incidence of Gram-positive bacteremia, the need to use antibiotics, or risk of mortality (52272).
• Critical illness (trauma). Oral and intravenous glutamine seem to reduce infectious complications in critically ill adults. However, glutamine does not seem to reduce mortality in this population. Details: Some studies show that glutamine reduces the risk of infectious complications in critically ill, multiple-trauma, or postoperative adult patients (5449,5450,7309,7731,8184,52288,52359). However, other studies show no benefit (52308,52360,97362). Meta-analyses of these and other clinical trials suggest that glutamine supplementation reduces the risk of nosocomial infections in critically ill patients by 15% to 18% and the risk of nosocomial infections in surgical patients by 30% to 41%. This benefit was seen only with parenteral glutamine; enteral glutamine does not appear to reduce the risk for nosocomial infection (91355,91358). The role of glutamine for reducing mortality in critically ill adults is conflicting. Some clinical trials suggest that glutamine-enriched enteral and parenteral nutrition reduces mortality in critically ill patients (52283,52289,52408). However, other studies show no benefit (52288,52308,52354,52359,97362). Meta-analyses of results from these and other clinical trials show that, overall, taking glutamine does not reduce the risk of mortality in critically ill patients (91355,91358). However, the dose and dosage form may affect outcomes. One meta-analysis shows that glutamine does not affect the risk of mortality when administered at doses up to 0.5 grams/kg daily, although doses greater than 0.5 grams/kg daily may INCREASE mortality by 18% (91355). Another meta-analysis shows that glutamine decreases short-term mortality in critically ill patients by 25% when administered parenterally, but not enterally (91358). Neither parenteral nor enteral glutamine appears to decrease the risk of long-term mortality in critically ill patients (91358). Research evaluating glutamine in critically ill children is limited. One clinical study in children ages 1-17 admitted to an intensive care unit (ICU) shows that enteral administration of glutamine along with zinc, selenium, and intravenous metoclopramide does not reduce nosocomial infections when compared with whey supplementation (86095).
• HIV/AIDS-related wasting. Oral glutamine seems to attenuate weight loss related to HIV/AIDS. Details: Very small clinical studies show that taking glutamine orally seems to enhance intestinal absorption of nutrients, decrease intestinal permeability, and increase weight gain in adults with HIV/AIDS when compared with placebo. Doses of 40 grams daily seem to produce the greatest effect (2337,2702). Lower doses of 14 grams daily might also be effective when used in combination with arginine and hydroxymethylbutyrate (a leucine metabolite) (7310).
• Postoperative recovery. Oral or intravenous glutamine seems to reduce the duration of hospitalization and improve postoperative nutritional status in adults. However, it does not seem to reduce postoperative mortality. Details: Although some conflicting evidence exists (52316), most clinical research shows that receiving free glutamine or glutamine-containing dipeptide intravenously decreases the duration of hospitalization after surgery, particularly after major abdominal surgery (2363,5448,7300,7732,52275,52341). A meta-analysis of this research and other studies shows that IV supplementation with glutamine-containing dipeptides reduces the length of hospital stay by 3 days when compared with no supplementation (96507). Other meta-analyses of clinical research also show that glutamine supplementation, as free glutamine or glutamine-containing dipeptides, reduces the risk of hospital-acquired infections by 30% in surgical intensive care unit (ICU) patients and by 41% in elective surgical patients (91355,91358). In cancer patients undergoing abdominal surgery, glutamine-supplemented parenteral nutrition seems to improve nutritional status and gastrointestinal function (100943). Glutamine-containing dipeptides also appear to help to preserve intestinal integrity (7299,7300,7732,52306). One small study has evaluated oral glutamine 10 grams, in combination with arginine 4.5 grams, in patients undergoing surgery for enterocutaneous fistulas. This study shows that taking this combination daily for 7 days prior to surgery reduces recurrence of fistulas by 35%, and also reduces postoperative infections (103837). Although glutamine seems to decrease length of stay and reduce infection rate, it does not appear to reduce the risk of mortality in either surgical ICU or elective surgical patients (91355,91358,96509,103834), including those receiving major abdominal surgery (5448,52316,91355,96507). Additionally, most research shows that glutamine supplementation does not reduce the incidence of infectious complications following abdominal surgery (52306,52316,52341,5448,7300,96507). The effects of glutamine on reducing infection rate might be related to patient population, modes of nutrition, or dose of glutamine. Taking a combination of glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.2 grams (Abound, Abbott) orally daily for 3 days before and 7 days after abdominal surgery does not reduce the incidence of wound infections or other complications (99413). Most of the research evaluating glutamine in surgical patients has been conducted in adults. Information in children is limited. Existing clinical research shows that glutamine-fortified parenteral nutrition does not improve intestinal permeability, nitrogen balance, duration of hospitalization, incidence of infectious complications, or risk of mortality in newborns and infants undergoing digestive-tract surgery (52338,96508).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral glutamine does not seem to improve athletic performance. Details: Small studies in trained athletes or healthy adults show that taking glutamine orally does not seem to enhance performance or immune response during intense acute or prolonged exercise when compared with placebo (2341,2342,5455,5456).
• Crohn disease. Oral glutamine does not seem to improve symptoms of this condition. Details: Small clinical studies in adults and children with Crohn disease show that taking glutamine 7 grams three times daily or following a glutamine-enriched diet for 4 weeks does not seem to improve intestinal permeability or disease activity, and might even worsen disease activity, when compared with placebo or a low-glutamine diet (2338,6256).
• Cystinuria. Oral glutamine does not seem to improve cystinuria. Details: According to case reports, taking glutamine orally does not seem to reduce the excretion of cysteine in the urine in patients with homozygous cystinuria (2339).
• Low birth weight. Oral glutamine does not seem to reduce adverse consequences of low birth weight in infants. Details: Most clinical studies show that glutamine supplementation does not improve the time to full enteral feeding, infant growth rate, or length of hospital stay in low birth weight infants (52305,52312,52325,52342,52362,52410). One follow-up study also shows that neonatal glutamine supplementation is not associated with improvements in cognitive function, motor skills, or behavior outcomes by school age when corrected for neonatal infection rate (52342,97365).
• Muscular dystrophy. Oral glutamine does not seem to improve symptoms of Duchenne muscular dystrophy. Details: Clinical studies show that taking glutamine 0.5-0.6 grams/kg orally does not significantly improve muscle strength or whole body protein degradation in children with Duchenne muscular dystrophy when compared with placebo or a nonspecific amino acid mixture (46657,52363).
• Prematurity. Oral glutamine does not seem to reduce morbidity or mortality associated with prematurity. Details: A meta-analysis of clinical trials in preterm infants, including infants with low to very low birth weight, shows that use of enteral or parenteral glutamine does not reduce the risk of mortality or morbidities, such as necrotizing enterocolitis, when compared with control. However, limited evidence from a sub-group analysis suggests that enteral glutamine might modestly reduce the risk of invasive infection when compared with control (105015). These findings are limited by the selection bias and heterogeneity of the included trials.
• Radiation-induced diarrhea. Oral glutamine does not seem to improve diarrhea due to radiation therapy. Details: One meta-analysis of five randomized, controlled trials shows that taking oral glutamine during radiotherapy for pelvic cancers does not prevent or reduce the severity of diarrhea when compared with placebo (97367).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antiretroviral-associated diarrhea. It is unclear if oral glutamine improves diarrhea caused by antiretroviral agents. Details: A small crossover clinical study in HIV patients shows that oral glutamine 30 grams daily for 10 days seems to reduce the severity of nelfinavir-associated diarrhea when compared with placebo (52313).
• Alcohol use disorder. Although there is interest in using oral glutamine for alcohol use disorder, there is insufficient reliable information about the clinical effects of glutamine for this condition.
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral glutamine for ADHD, there is insufficient reliable information about the clinical effects of glutamine for this condition.
• Chemotherapy-induced diarrhea. It is unclear if oral glutamine improves diarrhea caused by chemotherapy. Details: Although preliminary clinical studies show that glutamine might reduce the occurrence of chemotherapy-induced diarrhea (7235,7285), a meta-analysis of this research and others shows no difference in the severity of diarrhea (7233,7295,96516). Despite results showing a significant 1-day reduction in the duration of diarrhea, this might not be considered clinically significant (96516).
• Chemotherapy-induced lymphocytopenia. It is unclear if oral glutamine reduces lymphocytopenia caused by chemotherapy. Details: One small clinical study in patients with esophageal cancer receiving chemo-radiotherapy shows that taking glutamine 30 grams daily for 28 days seems to prevent a reduction in lymphocytes when compared with placebo (2705). However, another small clinical trial in patients with leukemia or lymphoma receiving intensive chemotherapy shows that adding glutamine 26 grams to total parenteral nutrition (TPN), in place of other amino acids, does not affect duration of neutropenia when compared with receiving an isonitrogenous standard TPN (7295).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral glutamine is beneficial in patients hospitalized with COVID-19 pneumonia. Details: A very small, nonblinded, non-randomized evaluation of otherwise healthy patients over 50 years of age who were hospitalized with mild COVID-19 pneumonia shows that taking glutamine 10 grams three times daily orally with meals is associated with a 1-day decrease in hospital stay (from 10 days to 9) when compared with patients not taking glutamine. In the latter group, 4 patients required transfer to the ICU, compared with no patients in the glutamine group (103839). A similar, non-randomized evaluation of adults hospitalized with COVID-19 pneumonia shows that adding the same dose of glutamine to other therapies for 5 days is associated with a 3-day decrease in hospital stay (from 14 days to 11) when compared with patients not taking glutamine. At the end of treatment, 0% of patients in the glutamine group required ICU services, compared with 54% of patients who did not receive glutamine. This study also shows that taking glutamine may increase appetite (108035). The validity of these findings is limited by short duration of treatment and use of non-standardized treatments.
• Cystic fibrosis. It is unclear if oral glutamine improves growth and development in children with cystic fibrosis. Details: A small clinical study in undernourished or stunted children with cystic fibrosis shows that taking glutamine 0.7 grams/kg daily orally for 4 weeks with or without recombinant human growth hormone (rhGH) does not promote protein gain when compared with rhGH alone (52321).
• Diabetic foot ulcers. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific nutritional supplement drink containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams (Abound, Abbott) twice daily for 16 weeks does not improve total wound closure or reduce the time to complete healing when compared with a control drink in patients with diabetic foot ulcers (96637). It is unclear if this effect is due to glutamine, other ingredients, or the combination.
• Diarrhea. It is unclear if oral glutamine improves diarrhea in children and infants. Details: One preliminary clinical study in 6-24 month-old otherwise healthy children with acute diarrhea shows that taking capsules prepared with a specific glutamine powder (Power Glutamine, Champion Nutrition) 0.3 grams/kg daily for 7 days reduces the duration of diarrhea by about one day when compared with placebo (52323). However, other clinical research in male infants 1-12 months old with acute diarrhea and dehydration shows that adding glutamine 90 mmol/L along with the standard World Health Organization oral rehydration salts (ORS) does not decrease the duration of diarrhea, stool output, or the volume of oral rehydration solution required to achieve and maintain hydration when compared with standard ORS alone (7298).
• Hematopoietic stem cell transplant (HSCT). It is unclear whether oral glutamine or glutamine added to parenteral nutrition improves morbidity and mortality in patients undergoing HSCT. Some research has suggested that intravenous glutamine may actually worsen outcomes. Details: Some research suggests that patients receiving glutamine-supplemented parenteral nutrition (PN) after HSCT primarily to treat hematologic malignancies have a diminished incidence of clinical infections, lower rates of microbial colonization, and decreased length of hospital stay when compared to control (2366,52381). However, not all patients seem to benefit. Some research shows that oral glutamine or PN with glutamine does not reduce the risk of mortality or infections in patients with hematologic malignancies and/or solid tumors (5451,52385). Also, a small clinical study in patients undergoing HSCT shows that PN with glutamine dipeptide may increase the duration of hospital stay (52292). Furthermore, one small study has found that receiving PN with glutamine was associated with lower disease-free survival and event-free survival over 3 years when compared with standard PN in patients receiving HSCT for hematologic malignancies (52355).
• Irritable bowel syndrome (IBS). There is limited evidence on the oral use of glutamine in patients with IBS. Details: A clinical trial in adults with IBS (diarrhea-predominant, constipation-predominant, mixed, or alternating bowel habits) shows that following a low FODMAP diet supplemented with oral glutamine 15 grams three times daily for 6 weeks improves IBS-Severity Scoring System (IBS-SSS) scores, with 88% of patients in the glutamine group reporting a 45% improvement in severity scores, compared with 60% of patients following the low FODMAP diet alone (108037). The validity of this finding is limited by short duration of treatment and lack of follow-up. Preliminary clinical research in patients with postinfectious, diarrhea-predominant IBS shows that taking glutamine 5 grams three times daily for 8 weeks leads to a nearly 14-fold greater likelihood of symptom improvement, defined as a reduction of 50 points or more on the IBS-SSS, and decreases stool frequency by 2.45 stools daily when compared with placebo. Taking glutamine also seems to reduce abdominal pain ratings by 55% and improve quality of life scores by 53% when compared to baseline in these patients (100944). The validity of these findings is limited by the lack of a comparator group.
• Lung cancer. It is unclear if oral glutamine improves survival in patients with advanced lung cancer. Details: One small clinical study in patients with advanced non-small cell lung cancer shows that taking glutamine 10 grams three times daily for 12 months along with palliative chemoradiotherapy prevents weight loss, which is an important predictor of survival, but does not increase the likelihood of progression-free survival when compared with palliative chemoradiotherapy alone (100942). It is unclear if this study was adequately powered to detect a difference in survival between groups.
• Malnutrition. It is unclear if oral alanyl-glutamine improves height and weight in children at risk for malnutrition. Details: Preliminary clinical research in children aged 2 months to 5 years from a low-income area of Brazil and at risk for malnutrition, shows that taking 3-12 grams of alanyl-glutamine orally daily for 10 days improves gut integrity and is associated with a modest, short-term increase in weight when compared with a glycine placebo (103838).
• Exercise-induced muscle damage. It is unclear if oral glutamine is beneficial for exercise-induced muscle damage. Details: A very small clinical crossover trial in professional athletes undergoing rigorous training shows that taking oral glutamine 6 grams daily for 20 days reduces serum levels of creatine kinase and myoglobin when compared with placebo (108031). The validity of these findings is limited due to the small size and short duration of treatment.
• Obesity. It is unclear if oral glutamine is beneficial for weight loss. Details: A preliminary clinical study in 36 overweight or obese adults shows that taking glutamine 30 grams daily for 2 weeks reduces waist circumference by 1.8 cm, but does not improve body weight, body mass index, or glycemic indices, when compared to baseline. None of these outcomes were improved over baseline in an alanine control group (100941). Given the small study size and short duration of therapy, the long-term effects of glutamine on anthropometric measures is unclear.
• Opioid withdrawal. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in Chinese patients undergoing detoxification from heroin shows that taking a combination of tyrosine, lecithin, 5-HTP, and glutamine 50 mg/kg orally daily for 6 days might reduce mood-related withdrawal symptoms when compared with placebo (88178). It is unclear if this effect is due to glutamine, other ingredients, or the combination.
• Oral mucositis. There is contradictory evidence about the effects of glutamine in patients with, or at risk of developing, oral mucositis from chemotherapy or radiotherapy. Details: Small clinical studies suggest that taking glutamine orally or swishing and swallowing a glutamine solution can decrease the incidence, severity, and duration of oral mucositis in some patients undergoing chemotherapy and/or radiation therapy for cancer or hematopoietic stem cell transplant (HSCT) (2336,2368,2704,5029). Additionally, three meta-analyses of highly heterogeneous clinical trials in patients with cancer receiving chemotherapy and/or radiation therapy suggests that glutamine reduces the incidence of severe (grade ≥3) oral mucositis when compared with control (105014,108028,108036). These analyses are limited for several reasons, including reporting bias, lack of sensitivity analysis, and population heterogeneity. Some small clinical studies included in these meta-analyses suggest that supplementation with glutamine may reduce the need for feeding tubes and opioid analgesics (108028,108036). However, not all research has been positive. Some small clinical studies in patients receiving chemotherapy with 5-fluorouracil for cancer or HSCT suggest that oral or intravenous glutamine does not reduce the incidence of oral mucositis when compared with control (2365,5451,5462,7296,52349,52350). Furthermore, a meta-analysis of 5 clinical trials in patients with head or neck cancers shows that oral glutamine does not reduce the overall incidence or the incidence of moderate to severe radiation-induced oral mucositis when compared with control (103836). The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology (MASCC/ISOO) cautiously recommends the use of oral glutamine to prevent oral mucositis in patients with head and neck cancer receiving chemoradiotherapy. However, due to some evidence suggesting that intravenous glutamine may actually worsen outcomes in HSCT patients, the MASCC/ISOO recommends against its use for the prevention of oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (105004).
• Paclitaxel-induced myalgia and arthralgia. It is unclear if oral glutamine reduces the risk for myalgias and arthralgias due to paclitaxel. Details: One small clinical study shows that taking glutamine 10 grams three times daily for 5 days, starting on the day of chemotherapy and repeated over 2 cycles of chemotherapy, does not reduce the rate or severity of paclitaxel-induced myalgias or arthralgias when compared with placebo (52331).
• Pancreatitis. It is unclear if oral glutamine improves outcomes in patients with acute pancreatitis. Details: Two meta-analyses of the available clinical research in patients with pancreatitis show that enteral or parenteral supplementation with glutamine increases albumin, decreases C-reactive protein, and might reduce mortality, multiple organ dysfunction syndrome, hospital length of stay, and infections. Results are difficult to interpret due to the significant heterogeneity of the included trials and limited generalizability of the results (96513,103835).
• Peptic ulcers. Although there is interest in using oral glutamine for peptic ulcers, there is insufficient reliable information about the clinical effects of glutamine for this condition.
• Postoperative infection. It is unclear if oral or intravenous glutamine is beneficial for the prevention of postoperative infection in patients with colorectal cancer who are recovering from surgery. Details: A meta-analysis of nonblinded clinical research in adults with colorectal or colon cancer who recently underwent radical surgery shows that daily supplementation with glutamine 0.3-1 grams/kg, administered either orally or parenterally, improves the rate of surgical site infections and anastomotic leakage when compared with control (108033). These findings are limited by the high heterogeneity of the included studies and unclear reporting.
• Postoperative recovery. It is unclear if oral or intravenous glutamine is beneficial in patients with colorectal cancer who are recovering from surgery. Details: A meta-analysis of nonblinded clinical research in adults with colorectal or colon cancer who recently underwent radical surgery shows that taking either oral or parenteral glutamine 0.3-1 grams/kg daily may reduce the length of hospital stay when compared with control (108033). These findings are limited by the high heterogeneity of the included studies and unclear reporting.
• Pressure ulcers. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with stages II-IV pressure ulcers shows that taking a specific nutritional supplement drink containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams per packet (Abound, Abbott Nutrition) as two packets twice daily by mouth for 2 weeks has no effect on wound area or healing scores by the Pressure Ulcer Scale for Healing (PUSH) measurement when compared with standard nutritional care (96506).
• Radiation dermatitis. It is unclear if oral glutamine reduces the risk of developing dermatitis from radiation therapy. Details: One small clinical study in patients with head and neck cancers receiving cisplatin shows that taking a specific supplement containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams (Abound, Abbott) orally twice daily, starting on day 1 of radiation and continuing until 1 week after radiation therapy, does not reduce the incidence of severe radiation-induced dermatitis when compared with no supplementation (96639). However, another small clinical study in patients with breast cancer who have had both chemotherapy and surgery shows that taking oral glutamine 5 grams three times daily, starting 1 week before radiation and continuing until 1 week after radiation, is associated with a reduction in grade 1 and grade 2 radiation dermatitis when compared with placebo (97366).
• Radiation-induced esophagitis. It is unclear if oral glutamine reduces the risk of developing esophagitis from radiation therapy. Details: A small clinical study in patients with advanced non-small cell lung cancer shows that taking glutamine 10 grams three times daily for 12 months along with a palliative dose of chemoradiotherapy (total 30 Gy) results in a 7% incidence of symptomatic (grade 2 or higher) radiation-induced esophagitis, compared with a 53% incidence with palliative chemoradiotherapy alone. The glutamine group also had a 5.8-day delay in the onset of esophagitis (100942). However, a lower dose of glutamine in patients receiving higher doses of radiotherapy might not be beneficial. A small clinical study in patients with advanced thoracic malignancies shows that taking glutamine 4 grams mixed in water twice daily for 4 weeks along with radiotherapy (total dose of at least 45 Gy) to the esophagus, with or without chemotherapy, does not slow the onset of radiation-induced esophagitis or reduce its severity when compared with a glycine placebo (105011).
• Short bowel syndrome. It is unclear if oral glutamine improves symptoms of short bowel syndrome. Details: Although small clinical studies suggest that glutamine plus growth hormone can decrease dependence on parenteral nutrition in some patients (2334,2361,2362,2703), it has not shown benefit for improving intestinal absorption of energy in all studies (8185). Additionally, glutamine alone doesn't appear to be beneficial (7730).
• Traumatic Brain injury (TBI). It is unclear if intravenous glutamine is beneficial in patients hospitalized with severe TBI. Details: A clinical trial in patients hospitalized for a severe TBI shows that adherence to a hypocaloric, low-protein diet supplemented with daily intravenous glutamine 0.3 g/kg for 7 days does not improve 28-day mortality when compared with standard nutritional support alone. However, it may reduce the length of ventilator use, hospitalization, and duration of intensive care unit stay (108034).
• Vincristine-induced neuropathy. It is unclear if oral glutamine reduces the risk of developing neuropathy from treatment with vincristine in children. Details: Preliminary clinical research in children ages 1-21 years receiving vincristine for various cancer types shows that taking glutamine 6 grams/m2 twice daily orally for 21 days reduces sensory neuropathy when compared with placebo. There was a significant improvement in self-reported, but not parent-reported, quality of life scores as measured by the PedsQL scale. However, there was no effect on motor neuropathy with the use of glutamine (96517).
• Wound healing. It is unclear if oral glutamine improves wound healing. Details: Preliminary clinical research in trauma patients with wound healing disorders shows that taking glutamine 20 grams orally daily in combination with ascorbic acid 500 mg, vitamin E 166 mg, beta-carotene 3.2 mg, selenium 100 mcg, and zinc 6.6 mg (Glutamine Plus, Fresenius Kabi) for 14 days reduces the time to wound closure by 29 days when compared with placebo. However, there is no difference in length of stay (97364). More evidence is needed to rate glutamine for these uses.

(Read more about GLUTAMINE)

POSSIBLY EFFECTIVE

• Angina. Oral L-arginine seems to improve symptoms and exercise tolerance in patients with angina. Details: Clinical research shows that taking L-arginine orally seems to decrease symptoms and improve exercise tolerance and quality of life in patients with mild to severe angina (3593,7815,7816,31866,31923). Some patients with severe angina who have frequent attacks at rest despite treatment with standard antianginal agents might also benefit from L-arginine (3593). However, L-arginine does not seem to improve objective measures of blood vessel dilation or increase circulating concentrations of nitric oxide (7817,99262). Also, when used in combination with ten 200 mcg injections of vascular endothelial growth factor (VEGF)-165 plasmid DNA, L-arginine 6 grams daily orally for 3 months does not improve angina severity in patients with coronary artery disease who underwent surgical angiogenesis compared to patients who did not receive this combination (32001). In addition, intravenous infusion of arginine 10% solution does not improve exercise capacity in patients with stable angina when compared with placebo (31843,32293).
• Erectile dysfunction (ED). Oral L-arginine might improve symptoms of ED. When taken with phosphodiesterase type 5 (PDE5) inhibitors, L-arginine seems to provide a small additional benefit. Details: Taking L-arginine orally in high doses, 5 grams daily, improves subjective assessment of sexual function in males with organic ED when compared with placebo (222,102586). Additionally, a meta-analysis of 4 small clinical studies in patients with ED, including those with diabetes and/or cardiovascular disease risk factors, shows that although PDE5 inhibitors improve sexual function better than L-arginine, the combination of PDE5 inhibitors and L-arginine may be more effective than either treatment alone (105065). In most clinical trials, doses of L-arginine 2.5-5 mg daily for 6-12 weeks were used alone or in addition to PDE5 inhibitors such as sildenafil 50 mg or tadalafil 5-10 mg daily (102586,102587,102592,104222). Higher doses have also been investigated. One clinical trial shows that taking L-arginine (Bioarginina, Farmaceutici Damor S.p.A., Napoli, Italy), 2 grams three times daily for 3 months improves sexual function compared with placebo (110387). However, taking lower doses, 1.5 grams daily, might not be effective in patients with mixed-type ED (2038). L-arginine has also been examined in combination with other ingredients. A meta-analysis of 2 small clinical studies in males with mild-to-moderate ED shows that taking L- arginine, up to 3 grams daily, in combination with maritime pine for 1-6 months improves a subjective assessment of sexual function when compared with control (112715). Some preliminary clinical evidence suggests that taking L-arginine orally in low doses, 1.7 grams daily in combination with maritime pine bark extract (Pycnogenol) or taking 0.69 grams daily along with maritime pine bark extract and aspartic acid (Edicare, Kobayashi Pharmaceutical Co. Ltd.) modestly improves symptoms of ED (10416,50924). Another preliminary clinical trial has investigated the effects of a combination of L-arginine 2.5 grams daily for 6 months and tadalafil 5 mg daily for 3 months, both starting with the initiation of weekly extracorporeal shock wave (ESW) therapy. When compared with ESW alone, this combination modestly improves sexual function for up to 12 months (110388). The effect of L-arginine alone is not clear from these studies.
• Hypertension. Oral L-arginine can modestly reduce systolic and diastolic blood pressure. Details: Oral L-arginine seems to have additive vasodilating effects when used with angiotensin converting enzyme (ACE) inhibitors or nitrate vasodilators such as isosorbide mononitrate (7822,20192,31916). A meta-analysis of clinical research in a variety of populations shows that taking L-arginine reduces systolic and diastolic blood pressure (SBP; DPB) by an average of 6.40 mmHg and 2.64 mmHg, respectively. Sub-analyses show that these reductions occur in both normotensive and hypertensive individuals. Beneficial effects were limited to adults with a body mass index (BMI) of 18.5 to 19.9 kg/m² (110384). The effect of L-arginine on blood pressure levels in adults exposed to traffic-related air pollution (TRAP) has also been investigated. Clinical research in adults with hypertension shows that taking L-arginine 3 grams three times daily for 2 weeks modestly reduces SBP and DBP elevations following a 2-hour exposure to TRAP during an outdoor walk compared with taking placebo (110383). Doses have included 4-24 grams daily, with the best evidence of benefit for doses of less than 9 grams daily, for 2-24 weeks (7818,10636,31871,31923,32167,32201,110383,110384).
• Necrotizing enterocolitis (NEC). Oral L-arginine may help prevent NEC in premature infants. Details: In a meta-analysis of 3 clinical trials, L-arginine 260 mg/kg orally in a single dose or two divided doses daily reduces the absolute risk of NEC in premature infants by about 62% when compared with placebo. To prevent one case of NEC, 6 infants would need to be treated with L-arginine (8474,91194,96803).
• Peripheral arterial disease (PAD). Short-term use of intravenous or oral L-arginine may improve symptoms of PAD, but long-term use does not seem to be beneficial. Details: Clinical research shows that using L-arginine intravenously or orally for up to 8 weeks increases flow-mediated dilation and improves symptoms of intermittent claudication associated with PAD (3465,31857,31905). However, long-term administration of L-arginine orally for up to 6 months does not improve walking speed, walking distance, or absolute claudication distance in patients with PAD and intermittent claudication (31957,31985).
• Pre-eclampsia. Intravenous L-arginine may have beneficial effects in pre-eclampsia. However, it is unclear if oral L-arginine is effective. Details: One small clinical study shows that intravenous L-arginine 30 grams as a one-time dose decreases systolic blood pressure (SBP) by 5 mmHg and diastolic blood pressure by 11 mmHg when compared to baseline in pregnant patients with hypertension or pre-eclampsia (31847), while intravenous L-arginine 20 grams daily for 5 days decreases SBP and DBP by about 2% when compared with placebo (31978). Another small clinical study shows that oral use of L-arginine 3 grams daily for 3 weeks reduces SBP and DBP by around 7 and 5 mmHg, respectively, when compared with placebo (31938); however, taking L-arginine 12 grams daily by mouth for 5 days does not seem to improve blood pressure in these patients (11828). Another preliminary clinical trial allowing for both oral and intravenous dosing shows that taking L-arginine 3.5 grams by mouth every 6 hours or 10 grams via intravenous infusion every 8 hours shortly before or immediately after delivery and continuing until postpartum day 3 does not improve blood pressure when compared with placebo (31959). The reasons for the disparate findings are unclear, but the small study sizes, as well as variations in the dose, duration, and timing of therapy before and/or after delivery, may explain some of the differences. Oral L-arginine has also been evaluated for the prevention of pre-eclampsia. One clinical study in patients at high risk for pre-eclampsia shows that taking L-arginine 3 grams daily starting the 20th week of gestation reduces the risk of pre-eclampsia by about 74% when compared with placebo (96811). Based on these results, one case of pre-eclampsia is prevented for every 6 high-risk pregnant patients treated with L-arginine 3 grams daily. Another clinical study also shows that taking two bars of a specific medical food (Heart Bars, Nellson Nutraceutical) containing L-arginine 6.6 grams and antioxidant vitamins daily starting at 14-32 weeks gestation and continuing until delivery reduces the risk of pre-eclampsia by 44% when compared with a bar containing antioxidant vitamins alone in patients at high risk of pre-eclampsia (91197). Based on these results, one case of pre-eclampsia is prevented for every 11 high risk patients treated with this L-arginine-containing medical food.
• Pregnancy-induced hypertension. Intravenous L-arginine may have beneficial effects in pregnancy-induced hypertension. Details: Some clinical research in patients with pregnancy-induced hypertension shows that intravenous infusion of L-arginine 20 grams daily for up to 5 days decreases systolic blood pressure by 2% to 3% and diastolic blood pressure by about 3% when compared with placebo (31933,31961,31978). Clinical research in patients with pre-existing hypertension has also been conducted. One clinical trial shows that taking L-arginine 4 grams by mouth daily for 10-12 weeks does not seem to reduce blood pressure in those with pre-existing hypertension or mild gestational hypertension. However, these results are confounded by the fact that more patients taking placebo needed to be placed on antihypertensive therapy during the study. L-arginine reduced the risk of being placed on antihypertensive drug therapy during the pregnancy by 47% when compared with placebo (32191). Based on this study, for every 5 patients with pregnancy-induced hypertension treated with L-arginine over placebo, antihypertensive drug therapy is avoided in one additional patient. L-arginine has also been investigated in combination with other ingredients in patients with pre-existing hypertension. Preliminary clinical research in patients with pre-existing hypertension and a previous history of pre-eclampsia, stillbirth, intrauterine growth restriction (IUGR), or other placenta vascular disorder shows that taking L-arginine and other ingredients starting at 14 weeks gestation prevents an increase in blood pressure and reduces the percentage of patients requiring new antihypertensive medication by about 73% compared with 24.5% of those not taking this combination. In this study, L-arginine 3 grams daily was taken with magnesium 350 mg and salicylate 100 mg. Therefore, the effect of L-arginine alone is unclear. All patients in the study were taking low dose aspirin 100 mg daily (110382).

POSSIBLY INEFFECTIVE

• Chronic kidney disease (CKD). Oral or intravenous L-arginine does not seem to improve CKD. Details: Most preliminary clinical research shows that taking L-arginine, either orally for up to 6 months or intravenously short-term, does not improve kidney function, glomerular filtration rate, or renal plasma flow in patients with CKD, although proteinuria may be reduced in some patients (31844,31904,32235,32303).
• Hypercholesterolemia. Oral L-arginine does not seem to reduce cholesterol levels. Details: Preliminary clinical research in patients with hypercholesterolemia shows that taking L-arginine 21 grams daily for 4 weeks does not reduce plasma lipids (1363). Furthermore, meta-analyses of clinical research show that taking L-arginine for up to about 6 months does not reduce total or low-density lipoprotein (LDL) cholesterol levels in populations of healthy individuals or those with cardiovascular disease risk factors. However, there was a very small effect on fasting triglyceride levels (102590,102591).
• Myocardial infarction (MI). Oral L-arginine does not seem to improve outcomes after MI. Details: Patients who have had an ST-segment MI who take L-arginine within 24 hours to 21 days, titrated up to a dose of 3 grams three times a day for up to 6 months, do not seem to have reduced vascular stiffness or increased ejection fraction (13221,32137). Also, there is some concern that long-term use of L-arginine might actually worsen outcomes and increase mortality in these patients (13221). Population studies also suggest that intake of L-arginine does not reduce the risk of experiencing an acute coronary event such as MI or coronary heart disease-related mortality (3332,6896,7821,10637).
• Tuberculosis. Oral L-arginine does not seem to improve symptoms or the clearance of tuberculosis infection. Details: Clinical research shows that taking L-arginine (ArgimaxH) 6 grams daily orally for 8 weeks, with or without vitamin D, does not improve symptoms of tuberculosis or the clearance of tuberculosis infection when used with standard treatment (91196).
• Wound healing. Oral L-arginine does not seem to improve wound healing. Details: Clinical research shows that taking L-arginine (as arginine aspartate) 17 grams orally in three divided doses daily for 2 weeks does not improve epithelialization in healthy, elderly patients with catheter wounds, although it may improve collagen deposition (32247). Also, taking L-arginine (as L-arginine hydrochloride) 26 grams daily for 5 days perioperatively does not improve angiogenesis, re-epithelialization, or neutrophil count in patients undergoing skin graft donation when compared with placebo (20692). In addition, taking a wound-specific oral nutrition supplement containing L-arginine 4.5 grams, zinc, and vitamin C twice daily for 4 weeks, along with standard wound care for 8 weeks, is no more effective for wound healing than a standard oral nutrition supplement along with standard wound care (90198). L-arginine has also been studied in combination with other ingredients. Taking L-arginine enterally or orally, before or after surgery, in combination with ribonucleic acid (RNA) and either eicosapentaenoic acid (EPA) or fish oil, seems to improve wound healing when compared with a control group (5531,32174). Another observational study conducted in Italy in newborns shows that applying a specific topical powder containing L-arginine, arnica extract, zinc oxide, and other ingredients (Cicaben, Orsana Italia S.r.l.) to the newborn's umbilical cord stump 3 to 4 times daily until stump detachment reduces the rates of mild complications 48 hours after discharge such as a wet cord stump but does not change the time to cord stump detachment or the rates of purulent secretions or umbilical granulomas when compared with standard dry care. However, no differences were noted between the groups one week after discharge (113662). The validity of these results is limited by the observational nature of the study and the ability of the parents to select a treatment group. It is unclear if the effects in these studies are due to L-arginine, other ingredients, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). Small clinical studies suggest that oral L-arginine may prevent ARDS. Details: A meta-analysis of three small studies shows that taking L-arginine 3 grams daily, starting in the second or third trimester usually until delivery, reduces the risk of ARDS in the infant by about 54% when compared to control, including placebo or no treatment (110379).
• Altitude sickness. It is unclear if oral L-arginine is beneficial in patients with altitude sickness. Details: Preliminary clinical research shows that taking L-arginine 4 grams orally three times daily for 2 days while ascending to a high altitude and for 24 hours while at high altitude does not reduce altitude sickness when compared with placebo (31955).
• Anthracycline cardiotoxicity. Although there is interest in using oral L-arginine for anthracycline cardiotoxicity, there is insufficient reliable information about the clinical effects of L-arginine for this purpose.
• Anemia of chronic disease. It is unclear if oral L-arginine is beneficial for anemia in patients with chronic kidney disease. Details: One very small clinical study in elderly adults with chronic kidney disease and anemia shows that taking L-arginine orally 1.3 grams daily might increase hemoglobin and erythropoietin levels in some patients when compared to baseline (31988). The validity of these findings is limited by the small study size and the lack of a comparator group.
• Asthma. It is unclear if oral L-arginine is beneficial in patients with asthma. Details: Preliminary clinical research in adults with severe asthma shows that taking L-arginine 0.05 gram/kg ideal body weight twice daily does not reduce asthma exacerbations when compared with placebo (104223). This study may have been inadequately powered to detect a difference in exacerbation rates between groups. While other studies have shown adverse airway effects in patients with asthma (121,31849), this study demonstrated no change in exacerbations and reported no adverse airway effects.
• Athletic performance. Small clinical studies suggest that oral L-arginine may improve measures of athletic performance. Details: A meta-analysis of 5 small clinical trials shows that taking L-arginine seems to modestly improve measures of cardiorespiratory fitness, as measured by a 0.07 L/minute increase in maximal oxygen uptake, when compared with control (105064). L-arginine has also been examined for its effects on athletic performance. Most research suggests that taking L-arginine does not improve athletic performance. However, clinical trials are small and may not be adequately powered to detect a difference in these outcomes Taking L-arginine as a single dose of 5 or 6 grams or as 5-10 grams daily for 2-4 weeks does not improve grip strength, strength during resistance exercise, power output during cycling, or muscle function during recovery from intense resistance exercise in healthy adults (91190,97393,99265,110381,110389). Also, taking L-arginine 5 grams daily for 4 weeks (Bioarginina Farmaceutici Damor) or 8 grams daily for 8 days does not increase swim speed (110381,110386). In contrast, some research suggests that drinking a single beverage containing the same dose of L-arginine 6 grams increases the time to exhaustion during high-intensity exercise when compared with placebo (32180). Also, a meta-analysis of small clinical trials shows that supplementation with L-arginine has a large beneficial effect on aerobic performance and a small beneficial effect on anaerobic performance. However, publication bias was evident in the aerobic performance data, limiting these conclusions. Doses found to be beneficial in this analysis included an acute dose of L-arginine 0.15 gram/kg 60-90 minutes before performance or chronic dosing of 1.5 grams to 2 grams daily for 4-7 weeks for aerobic performance. The chronic dose of L-arginine most likely to be beneficial for anaerobic performance is unclear from this analysis due to inclusion of studies using arginine alpha-ketoglutarate (110395). With the exception of a few studies which include a very small number of healthy females (99265,110395,110386), research on the use of L-arginine for athletic performance has focused almost exclusively on healthy males. Also, studies are heterogeneous with respect to sport and endpoints. Therefore, whether results can be applied to females or specific athletes is unclear. L-arginine has also been evaluated in overweight males. One small clinical study shows that taking a single dose of L-arginine 6 grams 90 minutes prior to high-intensity interval training seems to improve exercise tolerance by improving ventilation, heart rate, and oxygen uptake when compared with placebo (105060). L-arginine has also been evaluated in combination with other ingredients. Research in male soccer players shows that taking L-arginine 1.2 grams and L-citrulline 1.2 grams daily for 7 days increases total power output over a 10-minute cycling test and improves subjective perceptions of exertion when compared with placebo (100956). Another study shows that taking L-arginine 1.5 or 3 grams daily, in combination with grape seed extract, increases physical working capacity at fatigue threshold when compared with pretreatment in untrained, college-aged males (32164).
• Beta-thalassemia. It is unclear if oral L-arginine is beneficial in children with beta-thalassemia. Details:Preliminary clinical research in children aged 6-18 years treated conventionally for pulmonary hypertension related to beta-thalassemia shows that taking L-arginine 0.1 mg/kg daily for 60 days reduces Doppler echocardiography pulmonary arterial pressure by 35% compared with baseline. This measurement was increased by up to 15% in children given conventional treatments only; however, a statistical comparison between these treatment groups was lacking (110391).
• Breast cancer. It is unclear if oral L-arginine is beneficial in patients with breast cancer. Details: Preliminary clinical research shows that taking L-arginine 30 grams daily for 3 days prior to chemotherapy does not improve the clinical response rate in breast cancer patients when compared with placebo (32282).
• Cognitive impairment. It is unclear if oral L-arginine is beneficial in patients with cognitive impairment. Details: A small clinical trial in frail adults aged 65 years of age and up with hypertension shows that taking L-arginine (Bioarginina) 1.66 grams twice daily for 4 weeks modestly improves cognitive function when compared to placebo (110385).
• Congestive heart failure (CHF). It is unclear if oral L-arginine is beneficial in patients with CHF. Details: One small clinical study in patients with CHF stage 2-3 shows that taking L-arginine 15 grams daily for 5 days, in combination with conventional treatment, seems to improve glomerular filtration rate (GFR), creatinine clearance, and sodium and water elimination after saline loading, indicating an improvement in kidney function (3596).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral L-arginine is beneficial in patients with severe COVID-19 infection. Details: A small clinical trial in patients with severe COVID-19 shows that receiving oral L-arginine (Argin, Nutrigrow, India) 3 grams daily for a maximum of 10 days while on oxygen support does not affect the percentage of patients weaned off oxygen support after 10 days, the length of time requiring oxygen support, the duration of hospitalization, or the incidence of adverse thrombotic events, compared with placebo (110392). This study may not have been adequately powered to detect differences between groups. An interim analysis of a small clinical trial in patients hospitalized with severe COVID-19 shows that adding oral L-arginine (Bioarginina, Farmaceutici Damor) 1.66 grams twice daily to standard therapy throughout hospitalization increases the rate of respiratory support reduction by 60% after 10 days of therapy, but not after 20 days of therapy, when compared with placebo. L-arginine also significantly reduced the length of hospital stay. The median hospital stay was 25 days and 46 days, respectively, for L-arginine and placebo (106500). L-arginine has also been investigated in combination with other ingredients for post-acute COVID symptoms. Preliminary clinical research in adults with persistent fatigue following a COVID infection shows that taking L-arginine 1.66 grams plus vitamin C 500 mg (Bioarginina C, Farmaceutici Damor) twice daily for 28 days increases the distance walked in 6 minutes by 30 meters and reduces the percentage of patients with fatigue by about 89%, when compared with placebo. Grip strength was also increased (110390).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral L-arginine is beneficial for preventing complications after CABG surgery. Details: Preliminary clinical research shows that venous infusion of L-arginine hydrochloride 30 grams as a 10% solution over 15 minutes helps maintain mean arterial pressure, coronary vascular resistance, and graft blood flow when compared with a placebo infusion in patients that have undergone CABG (31840). Administering L-arginine 7.5 grams in 500 mL of cardioplegic solution also seems to reduce wedge pressure and intensive care unit stay in patients undergoing CABG; however, it does not reduce hospital stay duration or postoperative complications when compared with cardioplegic solution alone (31958,31886).
• Critical illness (trauma). Oral L-arginine has only been evaluated in combination with other ingredients; its effects when used alone are unclear. Details: A meta-analysis of clinical research shows that taking L-arginine orally with glutamine, nucleotides, and omega-3 fatty acids reduces the recovery time, the need for ventilation, and infection rates in critically ill patients, but does not reduce the risk of mortality (31853).
• Cyclosporine-induced nephrotoxicity. Although there is interest in using oral L-arginine for cyclosporine-induced nephrotoxicity, there is insufficient reliable information about the clinical effects of L-arginine for this purpose.
• Cystic fibrosis. It is unclear if oral L-arginine is beneficial in patients with cystic fibrosis. Details: Preliminary clinical research in teens and adults with cystic fibrosis shows that twice daily inhalation with L-arginine 500 mg for 2 weeks does not improve lung function when compared with inhaling 2.6% hypertonic saline twice daily (96807).
• Dental caries. Small clinical studies suggest that using a dentifrice containing L-arginine might prevent dental caries. Details: A meta-analysis of small studies shows that use of a dentifrice containing L-arginine 1.5% w/w in combination with calcium base (Dical or calcium carbonate) and fluoride 1450 ppm 2-3 times daily for up to 2 years reduces the risk of developing dental caries by a small to moderate amount when compared with a dentifrice containing only fluoride in children and adults (96806). Also, preliminary clinical research shows that using a confection containing an L-arginine complex (CaviStat) for one year reduces the number of dental caries in molars of children when compared with a sugarless mint control (32011). L-arginine has also been investigated as a prebiotic in combination with probiotics. In 5- to 9-year-old children with low caries risk, clinical research shows that taking one lozenge daily for 10-12 months containing arginine 20 mg along with Lacticaseibacillus paracasei and Lacticaseibacillus rhamnosus, modestly reduces caries severity, but does not reduce caries progression, active caries lesions, plaque, or gingivitis, when compared with placebo (113241,113242).
• Dental hypersensitivity. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a toothpaste containing L-arginine, calcium, and fluoride twice daily reduces dentin hypersensitivity when compared with pretreatment or control (32130,32131,32132,32177). Another moderate-sized clinical study in adults shows that applying a topical combination of L-arginine 10% and ibuprofen to tooth enamel surfaces for 10 minutes prior to in-office tooth bleaching reduces the risk and intensity of tooth sensitivity when compared with placebo (115354). It is unclear whether the effects are due to L-arginine, other ingredients, or the combination.
• Diabetes. Small, low-quality studies suggest that oral L-arginine does not improve glycemic control in people with type 2 diabetes. Details: A meta-analysis of small, low-quality studies shows that taking L-arginine 2-20 grams daily for up to 77 weeks decreases fasting blood glucose and serum insulin levels in adults without diabetes. However, no improvements occurred in adults WITH type 2 diabetes. This may be explained by previous studies which suggest L-arginine affects glucose control only in the early steps of beta-cell dysfunction. L-arginine did not improve insulin resistance or glycated hemoglobin (HbA1c) in patients with or without diabetes (104225). Also, a prospective observational study in patients with type 1 or type 2 diabetes has found that taking a specific product (Flebotrofine, AMNOL Chimica Biologica) containing L-arginine for 3 months is not associated with improvements in HbA1c, cholesterol, or triglyceride levels when compared with baseline. Other ingredients in this product included diosmin, troxerutin, hesperidin, black currant extract, and gotu kola extract (108151). The validity of these findings is limited by the lack of a comparator group.
• Diabetic foot ulcers. It is unclear if oral or subcutaneous L-arginine is beneficial in patients with diabetic foot ulcers. Details: A very small clinical study shows that administering L-arginine subcutaneously at the site of diabetic foot ulcers does not decrease healing time or rate of amputation when combined with conventional therapies (14914). Also, taking a specific drink containing L-arginine 7 grams, L-glutamine 7 grams, and calcium hydroxymethylbutyrate (HMB) 1.5 grams (Juven/Abound, Abbott Nutrition) orally twice daily for 16 weeks does not improve diabetic foot ulcer healing when compared with a control drink in non-ischemic patients or those with normal albumin levels. However, in specific populations with low albumin and/or poor limb perfusion, up to 74% more patients had total wound healing when compared with the control drink (96637).
• Diabetic neuropathy. It is unclear if oral L-arginine is beneficial in patients with diabetic neuropathy. Details: Preliminary clinical research shows that taking L-arginine 3 grams daily for 3 months does not improve circulation, disability, or nerve function in patients with diabetic neuropathy when compared with placebo (32145).
• Head and neck cancer. It is unclear if oral L-arginine is beneficial in patients with head and neck cancer. Details: Small clinical studies suggest that enteral nutrition supplemented with L-arginine does not seem to have any beneficial effects on markers of immune function such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), length of postoperative hospital stay, or fistula rates; however, it seems to reduce wounds and general infections after surgery in patients with head and neck cancer when compared with control (10160,32008).
• Heart failure. It is unclear if oral L-arginine is beneficial in patients with heart failure. Details: Preliminary clinical research in adults with heart failure shows that taking L-arginine 3.0-12.6 grams orally daily for 6-12 weeks does not consistently improve exercise tolerance or peripheral vascular resistance (3595,6028,32138). However, some research shows that taking L-arginine 1000 mg three times daily for 10 weeks modestly improves measures of cardiac function compared with placebo (110380). Although some research disagrees (32138), most research shows that taking L-arginine modestly improves quality of life (3595,110380).
• Heart transplant complications. It is unclear if oral L-arginine is beneficial in patients that have received a heart transplant. Details: Preliminary clinical research shows that taking L-arginine 6 grams orally twice daily for 6 weeks increases walking distance and oxygen uptake and delays the ventilatory threshold in heart transplant patients when compared with baseline (32150).
• HIV/AIDS-related wasting. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in patients with HIV/AIDS shows that taking L-arginine orally, in combination with hydroxymethylbutyrate (HMB) and glutamine for 8 weeks, increases body weight, particularly lean body mass, and positively affects immune status when compared with placebo (1909). However, other clinical research in HIV-positive patients shows that taking L-arginine 7.4 grams daily orally, in combination with omega-3 fatty acids and a balanced oral nutritional supplement for 6 months, does not improve body weight or fat mass, total energy intake, or immune status when compared to taking the nutritional supplement alone (113).
• Impaired glucose tolerance (prediabetes). It is unclear if oral L-arginine can prevent the development of type 2 diabetes in adults with prediabetes. Details: Clinical research shows that taking L-arginine (Bioarginine, Farmaceutici Damor) 3.2 grams orally twice daily for 18 months does not reduce the incidence of diabetes in patients with impaired glucose tolerance (prediabetes). However, when assessed one year after treatment discontinuation, patients who took L-arginine had a 58% lower risk of developing diabetes when compared with placebo (91195).
• Infertility. It is unclear if oral L-arginine improves outcomes in people undergoing an assisted reproductive technology (ART) program. Details: Some preliminary clinical research shows that taking L-arginine 16 grams daily decreases the cancellation rate of in vitro fertilization (IVF) and increases the number of oocytes collected in females undergoing an ART program when compared with control. However, taking L-arginine does not seem to improve the number of viable pregnancies (31842). A small clinical study of females undergoing an ART program shows that taking a combination product containing L-arginine 1 gram with folate 200 mcg or L-arginine 2 grams, folate 400 mcg, and vitamin E 10 mg daily for 12 weeks does not affect the hCG-positive rate or clinical pregnancy rate when compared with placebo. A subgroup analysis suggests that taking these combination products might improve HCG-positive and clinical pregnancy rates in females who are undergoing ART due to male infertility (104224). However, this small study was not adequately powered to detect a difference in these outcomes, limiting the validity of these findings.
• Interstitial cystitis. Small clinical studies suggest that oral L-arginine may improve pain in interstitial cystitis. Details: Taking L-arginine orally seems to reduce some symptoms, especially pain, that are associated with interstitial cystitis (107,114,3460,31855,32267). Research shows that patients with interstitial cystitis having a bladder capacity greater than 800 mL and/or a history of recurrent genitourinary infections might respond more favorably to L-arginine than patients with bladder capacity less than 800 mL and/or no history of recurrent genitourinary infections. Three months of treatment may be necessary before significant symptom improvement occurs (3460). However, L-arginine does not seem to reduce the need to urinate at night or improve urgency or frequency of urination (3460,31855).
• Intrauterine growth restriction (IUGR). Small clinical studies suggest that oral or intravenous L-arginine may increase birthweight in IUGR. Details: A meta-analysis of mainly small studies shows that L-arginine given orally or intravenously in the third trimester for a time period of 7 days or until delivery increases the birthweight by up to 650 grams in patients with an IUGR pregnancy. Furthermore, there is evidence from a small number of these studies that L-arginine supplementation decreases the risk of neonatal respiratory distress syndrome and fetal intracranial hemorrhage (96804). A more recent meta-analysis of small studies also shows that taking L-arginine 3 grams daily, starting in the second or third trimester usually until delivery, reduces the risk of an IUGR infant by about 32% when compared to control, including placebo or no treatment (110379). Doses used in clinical research have usually been 3 grams daily orally, although some studies have used up to 20 grams intravenously (31930,31937,96804,110379). However, supplementation with L-arginine does not seem to increase birthweight or reduce neonatal mortality or morbidity when compared with placebo in patients with severe IUGR (32083).
• Kidney transplant. Small clinical studies suggest that oral L-arginine may not improve kidney function in patients after kidney transplantation. Details: Although preliminary clinical research showed some benefit, evidence from other clinical research shows that infusion with L-arginine does not increase renal plasma flow or glomerular filtration rate in kidney transplant patients treated with cyclosporine, including those experiencing transplant dysfunction (112,31876,32229). Other evidence suggests that intravenous L-arginine improves kidney function only in transplant patients receiving organs with a short cold ischemia time or those receiving kidneys from young donors (31887).
• Male infertility. It is unclear if oral L-arginine is beneficial in males with infertility. Details: Preliminary clinical research shows that taking L-arginine 4 grams daily for 12 weeks does not improve semen quality in males with oligospermia when compared with placebo (32209). However, one small clinical study shows that a specific formulation of L-arginine aspartate and maritime pine bark extract (Prelox), taken for 6 months, improves sperm quality in males with idiopathic male infertility when compared to baseline (32061). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to L-arginine, maritime pine bark, or the combination.
• Mitochondrial myopathies. Small clinical studies suggest that intravenous L-arginine may modestly improve symptoms in patients with MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes syndrome). Details: Preliminary clinical research shows that infusions of L-arginine, 0.5 grams/kg administered within one hour of stroke-like symptoms, improves headaches, nausea, vomiting, transient blindness, and the appearance of bright spots when compared to pretreatment in patients with MELAS (31943,99263). Also, taking oral L-arginine 4-24 grams daily for 18 months seems to reduce the frequency and severity of stroke-like symptoms associated with MELAS when compared to baseline (31943). However, other preliminary clinical research shows that taking oral L-arginine 0.3-0.5 grams/kg daily in three divided doses for 2 years does not reduce the severity of MELAS symptoms, including migraine and stroke-like episodes. If a stroke-like episode did occur, administration of intravenous L-arginine 0.5 grams/kg improved headache, nausea, vomiting, and visual disturbance (99263). The validity of this research is limited by the small study sizes and the absence of comparator groups.
• Migraine headache. Although there is interest in using oral L-arginine for migraine, there is insufficient reliable information about the clinical effects of L-arginine for this condition.
• Muscular dystrophy. There is limited evidence on the oral use of L-arginine in patients with Duchenne muscular dystrophy. Details: A very small study in five children with Duchenne muscular dystrophy, shows that drinking a beverage containing L-arginine hydrochloride (L-Arginine Hydrochloride, Selectchemie) 2.5 grams three times daily, in addition to metformin 250 mg twice daily, for 16 weeks improves motor function by 4% and increases distance walked in two minutes by 9.6 meters when compared to baseline (96805). The validity of these findings is limited by the very small study size and lack of a comparator group.
• Nitrate tolerance. It is unclear if oral L-arginine is beneficial for nitrate tolerance. Details: A very small crossover study in adults with stable angina shows that taking L-arginine orally 700 mg four times daily for up to 10 days seems to prevent tolerance to transdermal nitrate when compared with placebo (8475).
• Obesity. Small clinical studies suggest that oral L-arginine may be beneficial for weight loss. Details: A meta-analysis of mainly small clinical trials shows that taking L-arginine daily for at least 8 weeks modestly reduces body weight, body mass index (BMI), and waist circumference when compared with placebo. However, when taking L-arginine for less than 8 weeks, BMI and body weight were not affected. The optimal dose of L-arginine was 2-6 grams (110398). An additional small clinical study suggests that taking a specific arginine supplement (NOW Foods) 3 grams by mouth three times daily for 12 weeks, in addition to receiving dietary counseling, reduces waist circumference by 4-6 cm and reduces body weight by 1.8-2.9 kg when compared to baseline in obese females 18-40 years of age (91193). The validity of these findings is limited by the lack of a comparator group.
• Oral mucositis. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study shows that taking a specific combination of L-arginine 7 grams, L-glutamine 7 grams, and hydroxymethylbutyrate (HMB) 1.2 grams (Abound; Abbott) in water twice daily during chemoradiotherapy treatment for head and neck cancer does not reduce the incidence of severe oral mucositis when compared with a historical control (99243). The validity of this finding is limited by the lack of a placebo control. Additionally, a small open-label study in patients undergoing chemoradiation for head and neck cancer shows that taking a specific combination product (Abound, Abbot) containing L-arginine, glutamine, and HMB twice daily throughout chemoradiation treatments decreases the incidence of grade 3 or higher oral mucositis and ameliorates body weight loss when compared with no intervention (113726). However, the incidence of grade 2 or higher oral mucositis was not reduced. It is unclear if this effect is due to L-arginine, other ingredients, or the combination. Additionally, the validity of the study is limited by the lack of blinding.
• Periodontitis. It is unclear if oral L-arginine is beneficial in patients with periodontitis. Details: Preliminary clinical research in patients with chronic periodontitis shows that using L-arginine aspartate (Yuria-Pharm, Ukraine) 1 gram three times daily orally for 10 days after scaling and root planing, modestly reduces bleeding on probing but not periodontal pocket depth, when compared with untreated controls (108926).
• Physical performance. It is unclear if oral L-arginine is beneficial for improving physical performance in older adults. Details: A small study in physically active females 65 years of age and older shows that taking L-arginine 8 grams as a single dose does not improve lower body strength, measured by knee flexion and extension tests, or functional performance, measured by sit-stand, tandem gait, and timed up-and-go tests, when compared with placebo (96812).
• Polycystic ovary syndrome (PCOS). Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of N-acetylcysteine 1200 mg daily plus L-arginine 1600 mg daily for 6 months modestly improves menstrual function and decreases insulin resistance in patients with PCOS when compared to baseline (32094). The validity of these findings is limited by the lack of a comparator group.
• Postoperative infection. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies show that taking L-arginine, enterally or orally, either before or after surgery, in combination with fish oil, or with ribonucleic acid (RNA) and eicosapentaenoic acid (EPA), seems to reduce the rate of perioperative infection when compared with a control group. The risk of infection was 41% lower when compared to taking no arginine-based formulations. However, there is no good evidence to support the use of L-arginine alone for this purpose, and it is possible that this effect is due to the other ingredients or the combination of ingredients (5531,32174,32196).
• Postoperative recovery. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies show that taking L-arginine, enterally or orally, either before or after surgery, in combination with fish oil, or with ribonucleic acid (RNA) and eicosapentaenoic acid (EPA), seems to reduce the recovery time after surgery or serious illness when compared with a control group. This seems to be related to a reduced number of perioperative infections and improved wound healing. However, there is no good evidence to support the use of L-arginine alone for this purpose, and it is possible that this effect is due to the other ingredients or the combination of ingredients (5531,32174,32196). The effect of another combination product containing L-arginine is unclear. In one clinical study, taking a combination product (Abound, Abbott) containing L-arginine 7 grams, glutamine 7 grams, and hydroxymethylbutyrate 1.2 grams orally daily for 3 days before and 7 days after abdominal surgery did not reduce the incidence of wound infection or other complications when compared with placebo (99413). However, when a similar combination of L-arginine 14 grams, glutamine 14 grams, and hydroxymethylbutyrate 3 grams (Heallagen) was taken orally daily for one month before heart surgery, the length of hospital and ICU stay were reduced by about one day. Recovery, based on some but not all biochemical or other measurements, was also improved. However, there was no difference in risk of overall postoperative complications (110394). The discrepancies between these two studies may be related to differences in the dose or duration of the combination product and/or the type of surgery.
• Pressure ulcers. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Oral L-arginine has been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients show that administering an oral nutritional supplement enriched with L-arginine, zinc, and vitamin C improves ulcer healing when compared with a standard diet (31953,87173). A small preliminary clinical study in sedentary older adults in care facilities shows that giving an oral or enteral combination of L-arginine 7.4 grams, L-glutamine 7.4 grams, and hydroxymethylbutyrate (HMB) 1.3 grams (Abound, Abbott) daily for 20 weeks reduces median time to healing by 48 days when compared with standard care only (110396). Also, preliminary clinical research in patients living in long-term care facilities with grade II-IV pressure ulcers shows that taking an oral nutritional supplement enriched in protein, energy, L-arginine, vitamin C, and zinc daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
• Preterm labor. Small clinical studies suggest that oral L-arginine may prevent preterm labor. Details: A meta-analysis of three small studies shows that taking L-arginine 3-6.6 grams daily, starting in the second or third trimester usually until delivery, reduces the risk of preterm labor by about 50% when compared to control, usually placebo (110379).
• Pulmonary hypertension. It is unclear if oral L-arginine is beneficial in children with pulmonary hypertension related to beta-thalassemia. Details: Preliminary clinical research in children aged 6-18 years treated conventionally for pulmonary hypertension related to beta-thalassemia shows that taking L-arginine 0.1 mg/kg daily for 60 days reduces Doppler echocardiography pulmonary arterial pressure by 35% compared with baseline. This measurement was increased by up to 15% in children given conventional treatments only; however, a statistical comparison between these treatment groups was lacking (110391).
• Radiation dermatitis. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with head and neck cancer shows that taking a combination of L-arginine 7 grams, L-glutamine 7 grams, and hydroxymethylbutyrate (HMB) 1.2 grams (Abound, Abbott) in water twice daily from the first day of radiation to approximately 1 week after completion does not reduce the number of patients with severe dermatitis when compared with taking no supplement. However, there was a 34% reduction in the incidence of moderate dermatitis and the overall duration of dermatitis was reduced (96639).
• Restenosis. It is unclear if intravenous L-arginine helps to prevent restenosis after stent implantation. Details: Some clinical research suggests that intravenous and intracoronary infusion of L-arginine during stent implantation followed by oral L-arginine for 2 weeks does not reduce the risk of restenosis when compared with placebo (31925). However, local delivery of 6 mL of L-arginine 100 mg/mL for 15 minutes after stent deployment seems to reduce neointimal formation at 6 months after stent placement when compared with placebo (31883).
• Respiratory tract infections. Although there is interest in using oral L-arginine for respiratory tract infections, there is insufficient reliable information about the clinical effects of L-arginine for these conditions.
• Schizophrenia. It is unclear if oral L-arginine is beneficial in patients with schizophrenia. Details: A small clinical study shows that taking L-arginine 3 grams twice daily for 3 weeks, in conjunction with an individualized medication regimen, does not improve positive, negative, or depressive symptoms associated with schizophrenia when compared with taking the medication regimen alone (99264).
• Sexual dysfunction. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in females with sexual dysfunction who are taking oral contraceptives shows that taking a specific combination product (Lady Prelox, Horphag Research) containing L-arginine, maritime pine bark extract, L-citrulline, and rose hip extract daily for 8 weeks improves symptoms of sexual dysfunction by 18% when compared with a control group (91963). Taking the same product in a dose of 2 tablets twice daily for 8 weeks, in addition to the lifestyle management program, improves vaginal dryness in pre- and post-menopausal patients when compared with lifestyle management alone (103611). It is unclear if this effect is due to L-arginine, the other ingredients, or the combination.
• Sickle cell disease. Small clinical studies suggest that oral or intravenous L-arginine may modestly improve complications in patients with sickle cell disease. Details: Two small clinical studies in hospitalized children aged 3-19 years with sickle cell disease-related veno-occlusive crisis shows that administering L-arginine intravenously or orally 100 mg/kg three times daily for 5 days or until discharge reduces total opioid use by 26% to 54%, pain scores at discharge by 23%, and median length of hospital stay by about 36 hours when compared with placebo (97392,105063). Another very small clinical study in patients aged 13-63 years with sickle cell disease shows that taking L-arginine 0.1 grams/kg orally three times daily for 5 days reduces pulmonary hypertension when compared to baseline (11428).
• Stress. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in healthy adults shows that taking a single dose of L-arginine 50 mg plus L-theanine 200 mg modestly reduces stress associated with a stress-loading test when compared with placebo, but was no more effective than taking L-theanine alone (110393).
• Valproic acid-induced toxicities. Although there is interest in using intravenous L-arginine for valproic acid toxicity, there is insufficient reliable information about the clinical effects of L-arginine for this purpose. More evidence is needed to rate L-arginine for these uses.

(Read more about L-ARGININE)

POSSIBLY EFFECTIVE

• Age-related macular degeneration (AMD). When used alone or in combination with other ingredients, oral lutein seems to improve some aspects of vision in patient with AMD. However, it does not seem to slow the progression of AMD. Details: Epidemiological research has found that people who consume higher amounts of lutein plus zeaxanthin in the diet have a reduced risk of developing AMD (219,2394,60238,106353). The association between intake of lutein specifically and the development of AMD is not clear; however, dietary lutein levels are much higher than dietary zeaxanthin levels. Although one study found no association between increased dietary lutein consumption and a reduced risk for age-related maculopathy, people in this study already had high lutein intake at baseline (14007). Some research has assessed whether lutein supplements can reduce symptoms and progression of existing AMD. Clinical research, including pooled analyses, in adults with AMD shows that taking supplemental lutein 10-20 mg daily for up to 36 months modestly improves some aspects of vision, such as macular pigment optical density, the ability of the eyes to adapt to varying light conditions (glare recovery), the ability to see details of near objects (near vision acuity), and the ability to see under low-contrast conditions (contrast sensitivity) (11798,48213,60185,60242,60245,60268,60270,60280,90678,91160)(91165,97225,102887,106366). Meta-analyses of these and other studies shows that taking lutein or a related xanthophyll carotenoid (zeaxanthin or meso-zeaxanthin) improves macular optical density when compared with placebo in patients with or without AMD. Treatment duration of at least 3 months, doses greater than 5 mg, and/or combination treatment with all three carotenoids are associated with a greater improvement in macular optical density (97225,106366). However, lutein supplements do not appear to affect the progression of AMD (60281). A meta-analysis of 6 studies in patients with AMD shows that taking supplemental lutein 10 or 20 mg daily, with or without zeaxanthin, for 0.5-5 years does not reduce the risk of progression to visual loss or late-stage AMD, neovascular AMD, or geographic atrophy, nor does it improve visual acuity when compared with placebo (113088). Lutein has also been evaluated in combination with other ingredients, with conflicting findings. Although not all research agrees, lutein-containing combination supplements might improve some symptoms of AMD (19196,60134,60180,60207,60237,60244,97226). A specific supplement (AZYR SIFI) containing lutein 10 mg, vitamin C 180 mg, vitamin E 30 mg, zinc 22.5 mg, copper 1 mg, zeaxanthin 1 mg, and astaxanthin 4 mg has been used daily for 1-2 years in some research with moderate evidence of benefit (19196,60244). Taking lutein 10 mg plus zeaxanthin 2 mg in addition to the original Age-Related Eye Disease Study (AREDS) formulation (vitamins C and E, beta carotene, and zinc) does not seem to prevent the progression to advanced AMD more than the AREDS formulation alone. However, this progression was modestly inhibited in individuals with low dietary intakes of lutein and zeaxanthin. While progression to late AMD was only modestly inhibited at 5 years when these doses of lutein and zeaxanthin were included in a revised formulation devoid of beta-carotene (AREDS2) (60281), results of an additional 5 years of follow up showed that this revised formulation reduces the risk of progression to late AMD by 15% when compared with the formulation containing beta-carotene (108615). This suggests that lutein with or without zeaxanthin may be a suitable replacement for beta-carotene, which is associated with an increased risk of lung cancer in people who have smoked or have a history of exposure to asbestos (113088). Reasons for these discrepancies are not clear but may relate to lutein dose, dietary lutein intake, treatment duration, or the other ingredients included in the combination products. The effect of lutein on children of parents with AMD is unclear. In first-generation offspring of parents with neovascular AMD, taking lutein 10 mg, zeaxanthin 2 mg, vitamin C 180 mg, vitamin E 30 mg, zinc 15 mg, and copper 1 mg daily for 6 months does not improve the macular pigment optical density (106347).
• Cataracts. Increased dietary lutein seems to reduce the odds of developing cataracts. It is unclear if oral lutein supplementation is beneficial in those who already have cataracts. Details: Observational research and a meta-analysis of this evidence suggests that higher blood levels and/or higher dietary intake of lutein are associated with a 25% lower odds of developing age-related cataracts, and more specifically, a 25% to 27% decreased risk of developing nuclear cataracts (90944,91161,91162,112095). Population research has also found that people who consume higher amounts of lutein (6.9-11.7 mg daily) as part of their diet have a reduced risk of developing severe cataracts that require surgical removal (2395,3219,3220). Clinical research shows that taking lutein 10 mg and zeaxanthin 2 mg per day orally for an average of 4.7 years decreases the risk of needing cataract surgery by 32% in patients with low dietary intake of lutein and zeaxanthin; however, it doesn't benefit patients with higher dietary intake of lutein and zeaxanthin (94703). Some evidence shows that supplemental lutein might benefit patients who already have cataracts. Preliminary clinical research in adults with grade 2 or 3 senile cataracts shows that taking lutein 15 mg orally three times weekly for up to 2 years can improve the ability to see clearly when compared to baseline (60133).

POSSIBLY INEFFECTIVE

• Bronchopulmonary dysplasia. Oral lutein does not seem to prevent bronchopulmonary dysplasia in preterm and low birth weight infants. Details: Clinical research shows that giving preterm and low birth weight infants a specific product (LUTEINofta, SOOFT Italia SpA) containing lutein 0.14 mg and zeaxanthin 0.0006 mg orally once daily, starting at birth and continuing until 36 weeks corrected gestational age, does not decrease the incidence of bronchopulmonary dysplasia when compared with placebo (91163).
• Necrotizing enterocolitis (NEC). Oral lutein does not seem to prevent NEC in preterm and low birth weight infants. Details: Clinical research shows that giving preterm and low birth weight infants a specific product (LUTEINofta, SOOFT Italia SpA) containing lutein 0.14 mg and zeaxanthin 0.0006 mg orally once daily, starting at birth and continuing until 36 weeks corrected gestational age, does not decrease the incidence of NEC when compared with placebo (91163).
• Retinitis pigmentosa. Oral lutein does not seem to improve vision or slow down retinal degeneration in patients with this condition. Details: While some preliminary clinical evidence suggests that oral lutein might be helpful in the treatment of retinitis pigmentosa (10279), most clinical research shows that taking lutein does not improve vision or other markers of retinal degeneration in patients with retinitis pigmentosa (60117,60165,60225).
• Retinopathy of prematurity. Oral lutein does not seem to prevent retinopathy of prematurity in preterm and low birth weight infants. Details: Clinical research in preterm and low birth weight infants shows that giving 0.5 mL or 1.8 mL/kg of a specific product (LUTEINofta, SOOFT Italia SpA) providing lutein 0.14 mg, or giving 0.5 mg/kg plus zeaxanthin 0.0006 mg or 0.02 mg/kg orally once daily, starting at birth and continuing until 36-40 weeks corrected gestational age, does not decrease the incidence or severity of retinopathy of prematurity when compared with placebo (60240,60243,91163,102889).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral lutein is beneficial for attenuating cognitive decline in older adults. Details: Clinical research in adults 40-75 years old shows that taking lutein 10 mg with zeaxanthin 2 mg daily for 6 months improves some, but not all, measures of visual memory when compared with placebo. However, other measures of memory and cognitive function were not improved (109763). Preliminary clinical research in older adults shows that taking the same dose of lutein and zeaxanthin for one year modestly improves some measures of cognitive function, such as complex attention and cognitive flexibility, when compared with placebo (106367). Other preliminary clinical research in older females shows that taking lutein 12 mg alone or with docosahexaenoic acid (DHA) 800 mg daily for 4 months can improve verbal fluency and memory scores when compared to baseline (48216). Also, some observational research in patients 50 years and older has found that higher dietary lutein and zeaxanthin intake is associated with greater word recall when compared with lower intake (102891). However, clinical research in patients over 60 years old shows that taking lutein 10 mg with zeaxanthin 2 mg daily for 5 years in addition to vitamins C and E, beta-carotene, and zinc (AREDS) does not improve markers of cognitive function, such as memory and verbal fluency, when compared with AREDS alone (94702). More research is needed to determine whether lutein is beneficial for specific measures of cognitive function in older adults.
• Alzheimer disease. Oral lutein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking lutein 10 mg, zeaxanthin 2 mg, meso-zeaxanthin 10 mg, fish oil 1 gram (providing docosahexaenoic acid 500 mg and eicosapentaenoic acid 150 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 lutein alone is unclear.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if oral lutein is beneficial for ALS prevention. Details: Population research has found that higher dietary intake of lutein is associated with a 21% lower risk of developing ALS when compared with lower dietary intake (90412). It is unknown if supplemental lutein has any effect on the risk of developing ALS.
• Asthenopia (eye strain). It is unclear if oral lutein is beneficial for eye strain. Details: Preliminary clinical research shows that some combination lutein supplements might reduce symptoms of eye strain. Results from one clinical trial show that taking a combination product containing lutein, zeaxanthin, and black currant extract daily for 2 weeks improves visual fatigue and eye stress when compared with placebo in patients completing a two-hour visual proof reading task (60214). Other clinical research shows that taking lutein 17.5 mg plus omega-3 fatty acids (standardized to contain docosahexaenoic acid 783 mg and eicosapentaenoic acid 162 mg) and bilberry extract (standardized to contain anthocyanidin 59 mg) daily for 4 weeks reduces symptoms of eye strain when compared with placebo (35470). The effect of lutein alone on eye strain is unclear.
• Asthma. It is unclear if oral lutein is beneficial for asthma prevention. Details: Population research has found that a higher dietary intake of lutein plus zeaxanthin is associated with up to 30% lower odds of having asthma when compared with a lower dietary intake (109765). The effects of lutein intake alone or lutein supplementation are unclear.
• Cardiovascular disease (CVD). Eating more lutein in the diet seems to reduce the risk of CVD. However, taking oral lutein supplements does not seem to prevent CVD events or mortality. Details: One observational study has found that increased intake of dietary lutein is marginally associated with a reduced risk of developing coronary heart disease (14108). A meta-analysis including this and other studies shows that high dietary lutein intake or high lutein serum concentrations are associated with a 12% reduction in the incidence of coronary heart disease, an 18% reduction in stroke, and a 25% reduction in the incidence of metabolic syndrome when compared with low lutein intake or serum concentrations (97227). However, clinical research shows that taking lutein 10 mg plus zeaxanthin 2 mg daily for an average of 4.8 years does not decrease the risk of CVD-related mortality or cardiovascular events such as stroke, myocardial infarction, or angina when compared with no supplementation in patients 50-85 years old (94701). Unlike the analysis above, individual cardiovascular outcomes were not separately evaluated in this study. The effect of lutein on CVD in younger patients or in doses greater than 10 mg is unknown.
• Central serous retinopathy. Oral lutein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a supplement containing lutein 15 mg, vitamin C 288 mg, vitamin E 150 IU, zinc 9 mg, and copper 1.2 mg (Sante Lutax 15, Santen Pharmaceutical Co. Ltd) three times daily after meals for 6 months has no effect on mean best-corrected visual acuity, serous retinal detachment, or subfoveal fluid remission when compared with placebo in patients with central serous retinopathy (97224).
• Cervical cancer. It is unclear if oral lutein is beneficial for cervical cancer prevention. Details: Epidemiological research has found that low dietary intake of lutein is not associated with an increased risk for developing cervical cancer (60297).
• Child development. It is unclear if oral lutein is beneficial for child development. Details: Epidemiological research has found that a higher dietary intake of lutein in the first and second trimesters of pregnancy is associated with increased verbal intelligence and improved behavior in the child at 6-10 years of age. However, the ability to discriminate between a novel or familiar visual stimulus was reduced at about 6 months of age, and there were no effects on most cognitive outcomes in children aged 3-6 years (107106). Other epidemiological research has found that a higher dietary intake of lutein plus zeaxanthin in children aged 3-6 years may be associated with modestly improved executive function at 6-10 years. However, there were no effects on most cognitive outcomes in children aged 3-6 years or 6-10 years (109761). Additionally, a small clinical study conducted in India in children aged 5-12 years shows that taking lutein 10 mg with zeaxanthin 2 mg (Lutemax Kids, Omniactive) daily for 180 days improves some measures of cognitive performance, such as attention and focus, when compared with placebo (114698).
• Choroideremia. It is unclear if oral lutein is beneficial for improving vision. Details: Preliminary clinical research shows that taking lutein 20 mg daily for 6 months does not improve vision in patients with choroideremia (60124).
• Cognitive function. It is unclear if oral lutein is beneficial for improving cognitive function. Details: A meta-analysis of clinical research shows that increased dietary lutein does not improve cognitive function measures, such as attention, executive function, or memory, when compared with placebo or an isocaloric meal (107082). However, the dietary source of lutein used in the included studies was heterogeneous and any conclusions remain unclear. Doses of lutein ranged from 8-12 mg daily, alone or in combination with daily zeaxanthin 2-26 mg and/or meso-zeaxanthin 10 mg and docosahexaenoic acid (DHA) 800 mg (107082). However, some preliminary clinical research in younger adults shows that taking lutein 10 mg and zeaxanthin 2 mg for one year modestly improves some measures of cognitive function, such as spatial memory, when compared with placebo (106348). Also, observational research has found that intake of choline and lutein plus zeaxanthin is positively associated with cognitive flexibility task performance speed. However, this association is not present with the intake of lutein plus zeaxanthin in the absence of choline (106354). Reasons for these discrepancies are not clear but may relate to lutein dose, treatment duration, or the addition of other nutrients to the diet or supplements.
• Colorectal cancer. It is unclear if oral lutein is beneficial for colorectal cancer prevention. Details: Some epidemiological research has found that higher dietary intake of lutein is associated with a reduced risk of developing colon cancer (3962). However, most epidemiological research has found that higher dietary intake of lutein is not associated with a reduced risk of colorectal cancer (34481,106372). It is not known if supplemental lutein has any effect on colorectal cancer risk.
• Depression. It is unclear if oral lutein is beneficial for depression. Details: A cross-sectional study in 8655 adults with cardiometabolic disease including diabetes, hypertension, coronary heart disease, heart failure, and stroke suggests that higher dietary lutein and zeaxanthin intake is associated with a 31% reduced risk of depression when compared with lower dietary intake. The study also found that adults with depression had lower dietary lutein and zeaxanthin intake than those without depression. Additionally, the study found a nonlinear U-shaped relationship between total dietary carotenoid intake and the risk of depression among patients with cardiometabolic disease, where the risk of depression decreased with increasing total dietary carotenoid intake up until an inflection point where the risk of depression increased with increasing total dietary carotenoid intake (112098). Further research is needed to establish causality.
• Diabetes. Observational research suggests that oral lutein may not be beneficial for the prevention of diabetes or diabetic complications. Details: Some epidemiological research has found that low serum levels of carotenoids, including lutein, are associated with impaired glucose tolerance. This may indicate that taking carotenoids such as lutein might reduce the risk of diabetes development (60161). However, population research has found that increasing intake of dietary lutein plus zeaxanthin does not decrease the risk of developing type 2 diabetes (14004,97227). Other epidemiological research in patients with type 2 diabetes has found that an increased serum concentration of lutein is not associated with reduced cardiovascular mortality over 14 years (109768).
• Diabetic retinopathy. It is unclear if oral lutein is beneficial in diabetic retinopathy. Details: Preliminary clinical research shows that taking lutein 10 mg daily for 36 weeks has no effect on visual acuity or glare sensitivity in patients with non-proliferative diabetic retinopathy (97223). Observational research in a small group of patients with non-proliferative diabetic retinopathy has also found that taking lutein 4 mg with zeaxanthin 0.5 mg daily for 4 months does not improve visual acuity, contrast sensitivity, or glare sensitivity when compared with zeaxanthin alone (100986).
• Esophageal cancer. It is unclear if oral lutein is beneficial for esophageal cancer prevention. Details: Population research has found that people who consume higher amounts of lutein and zeaxanthin in their diet have a 29% lower risk of developing esophageal squamous cell cancer when compared with those with lower intake (91159). It is unknown if supplemental lutein has any effect on esophageal cancer risk.
• Exercise-induced muscle soreness. It is unclear if oral lutein is beneficial in relieving muscle soreness due to exercise. Details: Some clinical research shows that taking a specific lutein-containing combination product (BioAstin, Cyanotech Corp.) containing haematococcus algae extract with astaxanthin 4 mg and lutein 480 mg daily for 3 weeks prior to exercise does not significantly reduce post-exercise muscle soreness when compared with placebo (19199). The effect of lutein alone is unclear.
• Fractures. It is unclear if oral lutein is beneficial for fracture prevention. Details: A meta-analysis of observational research has found that increased dietary intake of lutein and/or zeaxanthin is not associated with a reduced risk of hip fractures (97228).
• Gastric cancer. It is unclear if oral lutein is beneficial for gastric cancer prevention. Details: Two meta-analyses of observational research have found that increased dietary intake of lutein and/or zeaxanthin is not associated with a reduced risk of developing gastric cancer (97231,114694). The validity of these findings is limited by the heterogeneity of the included studies, including populations and outcomes.
• Glaucoma. Oral lutein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with open-angle glaucoma shows that taking oral lutein 10 mg, zeaxanthin 2 mg, and meso-zeaxanthin 10 mg daily for 18 months increases macular pigment density, but does not affect visual function, when compared with placebo (109756).
• Hyperlipidemia. It is unclear if oral lutein is beneficial for hyperlipidemia. Details: A meta-analysis of clinical research shows that supplementation with lutein does not reduce the levels of total, low-density lipoprotein (LDL), or high-density lipoprotein (HDL) cholesterol when compared with placebo (109757). Most publications included in this analysis evaluated lutein alone in healthy adults or in patients with age-related macular degeneration, two studies combined lutein with another ingredient, and one study evaluated zeaxanthin alone. The effect of lutein in patients with existing hyperlipidemia is unclear.
• Infertility. It is unclear if oral lutein is beneficial for infertility. Details: An observational study suggests that there is no association between dietary lutein intake and in-vitro fertilization (IVF) outcomes including good oocyte quality, embryo transfer success rates, clinical pregnancy rates, and successful term pregnancy rates in subfertile couples who are candidates for IVF (112097).
• Lung cancer. Research is conflicting whether oral lutein is beneficial for lung cancer prevention. Details: Epidemiological research has found that low serum levels of carotenoids, including lutein, are associated with an increased risk of lung cancer (12874). However, other epidemiological research has found that higher serum levels or higher dietary intake of lutein are not associated with a reduced risk of developing or dying from lung cancer (39690,60090,60160). Another large epidemiological cancer screening trial with a mean follow-up of over 12 years suggests that dietary intake of lutein and zeaxanthin is protective against lung cancer as shown by a non-linear dose response curve, where lower doses of lutein and zeaxanthin are associated with a sharp decrease in the incidence of lung cancer, followed by a more gradual decrease in incidence at higher doses (112096).
• Macular telangiectasia type 2. It is unclear if oral lutein is beneficial for macular telangiectasia type 2. Details: In patients with macular telangiectasia type 2, observational research has found that taking a specific combination of lutein 10 mg, meso-zeaxanthin 10 mg, and zeaxanthin 2 mg (MacuShield; Alliance Pharmaceuticals) for at least 6 months, with an average duration of 15.7 months, was associated with a stabilization of visual acuity. Also, the number and size of cavitations in the macula were reduced (106355).
• Metabolic syndrome. Oral lutein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of observational research shows that high dietary lutein intake or high lutein serum concentrations are associated with a 25% reduction in the incidence of metabolic syndrome when compared with low lutein intake or serum concentrations (97227). Additional population research in females shows that the highest dietary intake of lutein plus zeaxanthin is associated with 54% reduced odds of developing metabolic syndrome when compared with the lowest intake. However, when supplements containing lutein plus zeaxanthin were included in the total intake, there was no association with metabolic syndrome (109760).
• Myopia. It is unclear if oral lutein is beneficial for myopia. Details: A very small clinical study in adults aged 20-50 years with high myopia shows that taking lutein 20 mg daily for 6 months does not improve macular pigment optical density, visual acuity, contrast sensitivity, or electroretinogram measurements when compared with placebo (112099). The validity of these findings is limited by the very small sample size and short study duration.
• Non-Hodgkin lymphoma. It is unclear if oral lutein is beneficial for Non-Hodgkin lymphoma prevention. Details: A meta-analysis of observational population research has found that increased intake of lutein/zeaxanthin in the diet is associated with an 18% lower risk of developing non-Hodgkin lymphoma when compared with low dietary intake. However, no dose-response relationship was reported (97229). It is unknown if supplemental lutein has any effect on non-Hodgkin lymphoma risk.
• Obesity. It is unclear if oral lutein is beneficial for obesity. Details: A small clinical trial in obese middle-aged individuals shows that taking lutein 20 mg daily in addition to following a low-calorie diet for 10 weeks does not affect most anthropometric or cardiometabolic indices when compared with a low-calorie diet alone. However, there was a small beneficial effect on body fat and total cholesterol levels (107107).
• Pancreatic cancer. It is unclear if oral lutein is beneficial for pancreatic cancer prevention. Details: A meta-analysis of population research has found that increased dietary intake of lutein and/or zeaxanthin is not associated with a reduced risk of pancreatic cancer (97230). The effects of supplemental lutein are unclear.
• Parkinson disease. It is unclear if oral lutein is beneficial for Parkinson disease prevention. Details: Population research has found that higher dietary intake of lutein is not associated with the risk of developing Parkinson disease (91164). The effects of supplemental lutein are unclear.
• Pre-eclampsia. It is unclear if oral lutein is beneficial for pre-eclampsia prevention. Details: Some epidemiological research has found that high plasma concentrations of lutein are associated with a decreased risk of pre-eclampsia (60142). Other epidemiological research has found that the highest dietary intake of lutein plus zeaxanthin during pregnancy is associated with 68% reduced odds of having pre-eclampsia when compared with the lowest intake (109762). The effects of lutein supplements are unclear.
• Respiratory tract infections. It is unclear if oral lutein is beneficial in respiratory tract infection prevention or treatment. Details: Epidemiological research has found that high serum levels of lutein are not associated with a decreased incidence or severity of respiratory tract infections in the elderly (60152). The effects of supplemental lutein are unclear.
• Ulcerative colitis. It is unclear if oral lutein is beneficial for ulcerative colitis. Details: In patients in the remission phase of ulcerative colitis, observational research has found that a higher dietary intake of lutein plus zeaxanthin is associated with a reduced incidence of constipation, but not flatulence or feelings of urgency (tenesmus) (106362). The effects of supplemental lutein are unclear.
• Visual development. It is unclear if taking oral lutein during pregnancy can improve the visual acuity or vision health of children. Details: Some observational research has found that higher maternal lutein levels are associated with a 22% to 40% lower risk of poor visual acuity in children at 3 years of age when compared with lower maternal lutein levels (102888). However, other epidemiological research has found that dietary intake of lutein plus zeaxanthin during the first or third trimesters of pregnancy is not associated with contrast vision or visual acuity in the child at 11-12 years of age (109759). The effects of lutein supplements taken in pregnancy are unclear. A small clinical study conducted in India in children aged 5-12 years shows that taking lutein 10 mg with zeaxanthin 2 mg (Lutemax Kids. Omniactive) daily for 180 days improves a key biomarker of vision health (macular pigment optical density, MPOD)when compared with placebo (114698). More evidence is needed to rate lutein for these uses.

(Read more about LUTEIN)

EFFECTIVE

• Hypokalemia. Oral or intravenous potassium can treat and prevent hypokalemia. Details: Administering potassium orally or intravenously is effective for treating and preventing hypokalemia (15,107970). Oral potassium 20 mEq (780 mg of elemental potassium) is typically taken once daily to prevent hypokalemia (15,95010). Oral potassium 40-100 mEq (1560-3900 mg of elemental potassium) is typically taken in 2-5 divided doses daily to treat hypokalemia (95010). Doses should be limited to 40 mEq (1560 mg of elemental potassium), and the total dose should not exceed 200 mEq (7800 mg of elemental potassium) in 24 hours (95010). Potassium supplementation and route of administration should be individualized based on serum potassium level and patient status (15,107970).

LIKELY EFFECTIVE

• Hypertension. Oral potassium, via dietary intake or supplementation, reduces blood pressure. Details: Population research has found that higher dietary potassium consumption is associated with a lower risk of developing hypertension (1310,8817,69512). Additionally, most clinical research shows that potassium, taken orally as part of the diet or as a supplement, reduces systolic blood pressure by about 3-9.5 mmHg and diastolic blood pressure by about 2-6.4 mmHg in patients with or without hypertension (3385,92104,92106,95624,107974). In most of these studies, daily intake of potassium typically ranged from about 1500-7800 mg, with the most common intake being about 2340-2540 mg daily (92104,95624). However, some research shows that taking potassium does not lower systolic or diastolic blood pressure (69541,69550,107966). Differences in the patient populations, potassium intake, and salt intake could have contributed to the conflicting results. Potassium seems to be more effective for people with hypertension, low potassium levels, high daily sodium intake, and for Black adults (3384,3385,3386,92104,92106). Some research also shows that the greatest blood pressure-lowering effects of potassium occur at doses of about 3900-7800 mg daily (95624). A meta-analysis of clinical trials using a novel computational technique to assess both potassium intake and excretion suggests that the optimal blood pressure reduction occurs when taking about 1500 mg supplemental potassium daily or an overall intake of 4500-6500 mg potassium daily (105448). This analysis is limited by the heterogeneity and short duration of the included trials. There is also interest in utilizing low-sodium, high-potassium food substitutes to treat hypertension. Research shows that using salt substitutes containing 25% to 30% potassium chloride reduces systolic and diastolic blood pressure by 3-4.6 mmHg and 1 mmHg, respectively, when compared with regular table salt (107971,107976). In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) published guidelines recommending that patients with hypertension consume 3500-5000 mg of potassium daily (95680). This intake of potassium is expected to lower systolic blood pressure by about 4-5 mmHg in patients with hypertension and by about 2 mmHg in normotensive patients (3385). Although potassium supplements and dietary potassium both seem to be beneficial, the guidelines recommend getting potassium from dietary sources, since potassium-rich diets are usually heart-healthy (95680). Additionally, the US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Kidney stones (nephrolithiasis). Oral prescription potassium citrate reduces the risk of kidney stone recurrence. It is unclear if non-prescription potassium citrate would be beneficial. Details: The American Urological Association (AUA) recommends potassium citrate therapy for patients with recurrent calcium stones and low urinary citrate, those with recurrent calcium or calcium oxalate stones without current metabolic abnormalities, and those with uric acid or cystine stones. The citrate component reduces urine calcium excretion and increases urine citrate and urine pH, which in turn alleviates crystal growth, formation, and aggregation. Sodium citrate may also be used to prevent stone recurrence; however, due to sodium's propensity to increase urine calcium excretion, potassium citrate remains the preferred salt formulation (107972). It is important to note that potassium citrate supplements are not equivalent to prescription potassium citrate products. Dose and duration of treatment is determined by a healthcare professional and individualized based on a patient's urinary citrate levels (107975,107989). Serum potassium levels should be monitored prior to starting potassium citrate, within 2 weeks of treatment initiation, and every 12 months (107975).

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Eating foods high in potassium and low in sodium might reduce the risk of cardiovascular disease. It is unclear if taking potassium supplements has the same benefit. Details: Large population studies in adults without prior CVD have found that higher dietary potassium intake is associated with a lower risk of cardiovascular events (109395,109399). One study found that daily potassium intake of about 3300 mg is associated with a 13% reduction in CVD risk when compared with intake of about 1920 mg (109399). The other study found that each additional 1000 mg of daily urinary potassium excretion, which is a marker of dietary intake, is associated with an 18% reduction in CVD risk (109395). Another observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Stroke. Eating foods high in potassium and low in sodium might reduce the risk of stroke. It is unclear if taking potassium supplements has the same benefit. Details: Higher dietary intake of potassium seems to be associated with a lower risk of stroke. Population research has found that increasing dietary potassium intake by 1-1.5 grams daily is associated with up to a 20% reduced risk of stroke (92105,92107). Some population research has found that higher supplemental intake of potassium is associated with a 29% reduced risk of ischemic stroke. However, supplemental potassium intake is not found to be associated with a lower risk of hemorrhagic or total stroke (92107). An observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dental hypersensitivity. It is unclear if topical potassium improves dental hypersensitivity. Details: One meta-analysis of clinical research shows that using a dentifrice containing 5% potassium nitrite reduces dentin sensitivity when compared with a dentifrice that does not contain potassium nitrite (69549). Other clinical research published in a systematic review shows that potassium-containing toothpastes might reduce dentin sensitivity more than controls that do not contain potassium. However, these toothpastes might be less effective than other active toothpastes, such as those containing sodium monofluorophosphate, and the effect may result from a placebo effect, since the mechanism of action of potassium is unclear (69456).
• Diabetes. It is unclear if increasing dietary potassium reduces the risk of diabetes. Details: A meta-analysis of 7 large population studies has found that consuming dietary potassium 3300-3500 mg daily is associated with a 20% reduction in the risk of diabetes when compared with consumption below 1000 mg daily. Results were similar when studies that measured potassium intake with a dietary questionnaire were analyzed separately from those that measured intake based on urinary potassium excretion (110776). However, the validity of this finding is limited by the heterogeneity of the included studies. Furthermore, despite use of data from various databases, most studies included in the analysis were conducted by the same author.
• Impaired glucose tolerance (prediabetes). It is unclear if oral potassium improves glycemic control in prediabetes. Details: A small clinical study in Black patients with prediabetes shows that taking extended-release potassium (Klor-Con M10, Cardinal Health) 40 mEq daily as potassium chloride for 3 months does not improve glucose tolerance when compared with placebo. Although fasting glucose levels were slightly reduced in the potassium group when compared with placebo, both groups experienced a worsening of glucose intolerance, with no change in insulin levels or glycated hemoglobin (98533).
• Osteoporosis. Although there is interest in using oral potassium for osteoporosis, there is insufficient reliable information about the clinical effects of potassium for this condition.
• Physical performance. It is unclear if oral potassium improves physical performance in older adults. Details: Observational research in older adults has found that decreased dietary potassium intake and increased dietary sodium intake over 5 years is associated with worsened physical performance (105450).
• Systemic lupus erythematosus (SLE). It is unclear if oral potassium is beneficial in patients with SLE. Details: Observational research in patients with SLE has found that increased dietary potassium intake is not associated with improvements in disease activity scores or markers of cardiovascular disease, including lipid levels and blood pressure, when compared with low dietary potassium intake. However, higher potassium intake does seem to reduce the odds of having elevated levels of C-reactive protein, a marker of inflammation, in these patients (109397). More evidence is needed to rate potassium for these uses.

(Read more about POTASSIUM)

POSSIBLY INEFFECTIVE

• Athletic performance. Oral quercetin does not seem to improve athletic performance. Details: A pooled analysis of data from seven clinical trials shows that intake of quercetin does not improve maximal oxygen consumption or capacity to perform prolonged exercise in trained or untrained athletes when compared with placebo (91577). Additionally, one small clinical study in male soldiers shows that taking quercetin 500 mg twice daily for 8.5 days before a loaded treadmill marching test and a cycling time trial test does not affect ratings of perceived exertion, cycling time, or peak oxygen consumption during treadmill testing when compared with placebo (91578). Quercetin has also been evaluated in combination with another ingredient. A small clinical study in trained athletes shows that taking a single dose of quercetin (Quercetin Powder from Sophora Japonica Flower, Aki Organics) 140 mg and mangiferin 84 mg, a mango constituent, one hour prior to an intermittent high-intensity exercise test improves performance as measured by circuit time and reduces perceived exertion, but does not improve heart rate, sprint time, or subjective muscle soreness when compared with placebo (113077). It is unclear whether these effects are due to quercetin, mangiferin, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral quercetin is beneficial in older adults with age-related cognitive decline. Details: Preliminary research in healthy adults aged 60 to 80 years with age-related forgetfulness shows that drinking 500 mL of a barley-based beverage containing 110 mg quercetin glycoside calculated as isoquercitrin, daily for 40 weeks seems to improve reaction times when compared with placebo. However, increase in score on the mini-mental state examination (MMSE), reduction in accumulation of amyloid beta in the brain, and prevention of reduction in cerebral blood flow occur to a similar extent with quercetin and placebo (110008).
• Allergic rhinitis (hay fever). It is unclear if oral quercetin is beneficial in patients with allergic rhinitis. Details: A small clinical study in Japanese adults with allergic rhinitis shows that taking a specific quercetin product (Quercetin Phytosome, Indena SpA) 100 mg twice daily for 4 weeks does not improve scores related to quality of life, activities of daily living, nasal symptoms, or ocular symptoms on the Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ). However, scores related to fatigue and sleep quality improved when compared with placebo. Additionally, sneezing, rhinorrhea, and activities of daily living scores improved when another scale was used to assess the severity of allergic rhinitis (109620). Quercetin has also been evaluated in combination with other ingredients. A small clinical study in children aged 6-12 years with allergic rhinitis who had gone through a treatment phase with antihistamines and a specific combination of quercetin, perilla, and vitamin D3 (Lertal) 1 tablet daily for 4 weeks shows that taking this specific combination for an additional 4-12 weeks reduces the chance of having symptom exacerbations by approximately 50% when compared with no further treatment past the first 4 weeks. The number of days requiring rescue medication was also reduced from 28.5 days to an average of 9.6 days (104676).
• Alzheimer disease. Although there has been interest in using oral quercetin for Alzheimer disease, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Asthma. It is unclear if oral quercetin is beneficial in patients with asthma. Details: Preliminary clinical research in patients with mild-to-moderate asthma shows that taking a specific quercetin product (QFit, Indena SpA) 250 mg or 500 mg daily for 30 days along with conventional therapy reduces daytime and nighttime asthma symptoms, improves spirometry measures, and decreases the use of rescue inhalers when compared to baseline. Significant improvements in these outcomes were lacking in patients receiving conventional therapy alone (102540).
• Atherosclerosis. Although there has been interest in using oral quercetin for atherosclerosis, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Autism spectrum disorder. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children aged 4-10 years with autism shows that taking a combination of luteolin 10 mg/kg, quercetin 7 mg/kg, and rutin 3 mg/kg in olive oil for 26 weeks improves hyperactivity, irritability, and lethargy by a moderate to large amount, and improves some indices of functioning, such as daily living and social behavior, by a small amount when compared with baseline. The validity of these findings is limited by the lack of a comparator group (96765).
• Benign prostatic hyperplasia (BPH). Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking one tablet of a specific combination product (Difaprost) containing quercetin, beta-sitosterol, and saw palmetto daily for 3 months does not improve general symptoms of BPH when compared to baseline (96784). The validity of these findings is limited by the lack of a comparator group.
• Beta-thalassemia. It is unclear if oral quercetin is beneficial in patients with beta-thalassemia. Details: Preliminary clinical research in transfusion-dependent patients with beta-thalassemia shows that taking quercetin 500 mg daily for 12 weeks reduces iron and ferritin levels, increases transferrin levels, and decreases transferrin saturation when compared with placebo. However, total iron binding capacity was not improved. These results suggest that quercetin might reduce iron overload, which is a complication of frequent blood transfusions in these patients (102541).
• Cancer. Although there has been interest in using intravenous or intraperitoneal quercetin for cancer, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Canker sores. Topical quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a cream containing quercetin, glycol, zinc, and Myristica (Rootage skin cream, Elsi-Si) three times daily results in complete healing of minor canker sores and reduces pain in 100% of patients within 7-10 days, compared with only 60% of patients using a benzydamine hydrochloride mouthwash three times daily (104677).
• Cardiovascular disease (CVD). It is unclear if oral quercetin is beneficial for CVD prevention. Details: Population research has found that increasing dietary intake of quercetin from food sources such as tea, onions, and apples is associated with a significantly reduced risk of heart disease-related mortality in elderly males (7726). However, preliminary clinical research shows that quercetin 1 gram daily for 28 days does not significantly improve platelet aggregation, thromboxane B2 production, blood pressure, heart rate, or serum lipid levels when compared with placebo in healthy people (1998).
• Cataracts. Although there has been interest in using oral quercetin for cataracts, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Chemotherapy-induced cystitis. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with bladder cancer undergoing intravesical chemotherapy shows that taking a specific combination product (Ialuril, IBSA Farmaceutici) containing quercetin 400 mg, hyaluronic acid 40 mg, chondroitin sulfate 400 mg, and curcumin 400 mg every morning, starting 7 days before the first instillation and ending 30 days after the last instillation, improves lower urinary tract symptoms as measured using a visual analog scale and the International Prostate Symptom Score (IPSS) at 13 months when compared with placebo (109622).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral quercetin for CFS, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Chronic venous insufficiency (CVI). Although there has been interest in using oral quercetin for CVI, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Colorectal cancer. Although there has been interest in using oral quercetin for colorectal cancer prevention, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Contrast induced nephropathy. It is unclear if oral quercetin is beneficial for the prevention of contrast induced nephropathy. Details: Preliminary clinical research in patients undergoing coronary catheterization shows that taking quercetin 500 mg every 8 hours, starting two days prior to contrast imaging and continuing for two days after, does not appear to prevent contrast induced nephropathy when compared with a control group not receiving quercetin (102539). Given its small size, this study may have been inadequately powered to detect significant differences for this outcome.
• Coronavirus disease 2019 (COVID-19). Analysis of several small, open-label clinical studies suggest that oral quercetin may modestly reduce hospitalizations and intensive care unit (ICU) admissions in patients with COVID-19. Whether quercetin is beneficial in patients with severe COVID-19 is unclear. Details: A meta-analysis of 6 open-label clinical studies in patients with COVID-19 shows that taking quercetin 260-1000 mg daily for 7-30 days along with standard therapy with analgesics, antipyretics, antibiotics, remdesivir, or favipiravir reduces the odds of intensive care unit (ICU) admission by 69% and the odds of hospitalization by 75% but does not decrease the rate of all-cause mortality or the rate of recovery upon follow-up when compared with standard care (111412). However, the interpretation of these findings is limited by differences in the severity of COVID-19, doses and durations of quercetin therapy, and standard of care regimens used across the included studies. In outpatients in the early stages of COVID-19, two small, open-label clinical studies included in the meta-analysis above show that taking quercetin 200 mg two or three times daily for 14-30 days along with standard care reduces time to symptom resolution when compared with standard care alone. However, these studies show mixed results with respect to prevention of hospitalization, ICU admission, and death (106498,106499). More recent research in patients with early-stage, mild to moderate COVID-19 symptoms shows that taking quercetin 500 mg three times daily for 1 week, followed by 500 mg twice daily for 1 week, increases the rate of symptom resolution and achieving a negative COVID-19 test at 1 week by 116% and 183%, respectively, when compared with placebo (110009). Quercetin has also been evaluated in patients with severe COVID-19. A small, open-label clinical study of patients with severe COVID-19 who have not been admitted to the ICU shows that taking quercetin 500 mg twice daily for 7 days along with remdesivir or favipiravir shortens the time to discharge by around 1.5 days and improves symptoms of weakness and lethargy, but does not improve other symptoms of COVID-19 or reduce the risk of ICU admission or death, when compared with remdesivir or favipiravir alone (107450).
• Depression. It is unclear if oral quercetin is beneficial for depression in patients with a recent myocardial infarction (MI). Details: A moderate-sized clinical study in adults 6-8 weeks post-MI conducted in Iran shows that taking quercetin 500 mg daily for 8 weeks does not improve self-reported depression scores when compared with placebo (112228). However, the severity of patients' depression was minimal at baseline, which limits the power to detect a difference between groups.
• Diabetes. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with type 2 diabetes who are not using hypoglycemic agents shows that taking a specific combination of quercetin, myricetin, and chlorogenic acid (Emulin, Anderson Global Group LLC) 250 mg daily for 7 days reduces levels of fasting and postprandial glucose by about 5% when compared to baseline. These changes were significantly different than the slight increases seen in the placebo group. In patients taking metformin along with the combination supplement, fasting blood glucose levels decreased by about 20%, compared with a decrease of less than 1% with metformin alone (96779).
• Exercise-induced muscle damage. It is unclear if oral quercetin is beneficial for preventing muscle damage associated with exercise. Details: Some clinical research shows that taking quercetin 500 mg twice daily for 3 weeks prior to and during an endurance run or cycling event does not attenuate exercise-induced muscle damage, soreness, or inflammation (16429,16431). However, a series of two small clinical trials show that taking quercetin 1000 mg daily for 14 days prior to eccentric exercise modestly attenuates the decline in the maximal intensity of a contraction when compared with placebo (99236,104226). Additionally, this dosing regimen appears to modestly accelerate the recovery of muscle strength and neuromuscular function after exercise when compared with placebo (104226).
• Exercise-induced respiratory infections. It is unclear if oral quercetin is beneficial for prevention of respiratory infections induced by exercise. Details: Preliminary clinical research shows that taking quercetin 500 mg twice daily for 3 weeks before, and continuing during 3 days of prolonged, intense cycling, reduces the incidence of upper respiratory infections in the 14 days following the heavy exercise (16430).
• Gout. Although there has been interest in using oral quercetin for gout, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Herpes labialis (cold sores). Although there has been interest in using oral quercetin for herpes labialis, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Hypercholesterolemia. It is unclear if oral quercetin is beneficial for improving cholesterol levels. Details: Multiple meta-analyses show that taking quercetin does not affect total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides (TG) when compared with placebo (96783,104229). However, a subgroup analysis shows that taking quercetin for at least 8 weeks seems to reduce TG levels by 13 mg/dL and increase HDL levels by 3 mg/dL, compared with no change in patients who took quercetin for less than 8 weeks (104229). It is unclear these patients had elevated cholesterol levels at baseline.
• Hypertension. It is unclear if oral quercetin is beneficial for reducing blood pressure. Details: Three meta-analyses show that taking quercetin 100-1000 mg daily for 4-12 weeks decreases systolic and diastolic blood pressure by 2-4 mmHg and 2-3 mmHg, respectively, when compared with placebo. However, only two of the studies included in these analyses evaluated patients with hypertension (16424,96775,104229,109617). Additional clinical research in patients with mild hypertension shows that taking a single dose of quercetin 1095 mg can lower systolic and diastolic blood pressure by 7 mmHg and 3 mmHg, respectively, when measured 10 hours later (96780). Overall, the benefit of quercetin on blood pressure seems modest; it is unclear whether the improvement is clinically significant for patients with hypertension.
• Kidney transplant. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific product containing a combination of quercetin 20 mg and curcumin 480 mg (Oxy-Q, Farr Labs) taken once or twice daily in combination with anti-rejection medications, starting within 24 hours of a kidney transplant and continuing for one month, improves early function of the graft and reduces serum creatinine when compared with taking placebo in combination with anti-rejection medications (16420).
• Lung cancer. It is unclear if oral quercetin is beneficial in lung cancer prevention. Details: Epidemiologic research has found that increasing dietary intake of quercetin is associated with a reduced risk of lung cancer in smokers (96778).
• Metabolic syndrome. It is unclear if oral quercetin is beneficial in patients with metabolic syndrome. Details: A meta-analysis of small clinical studies shows that taking quercetin 100-1000 mg daily for 4-12 weeks does not improve fasting blood glucose, glycated hemoglobin, or insulin levels when compared with placebo in patients with risk factors for metabolic syndrome, such as type 2 diabetes, prehypertension, polycystic ovary syndrome, and/or obesity (100967). Additional research is needed to determine if quercetin is beneficial in patients with existing metabolic syndrome.
• Niacin-induced flushing. Although there has been interest in using oral quercetin for niacin-induced flushing, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Obesity. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking quercetin 500 or 1000 mg daily for 12 weeks, in addition to niacin 5 mg or 10 mg and vitamin C 125 mg or 250 mg, does not reduce body weight or fat mass when compared with placebo in adults considered overweight or obese based on body mass index (BMI) (104678).
• Oral mucositis. It is unclear if oral quercetin is beneficial in patients with oral mucositis. Details: One small clinical study shows that taking quercetin 250 mg twice daily for 4 weeks does not prevent oral mucositis associated with chemotherapy when compared with placebo (96776).
• Ovarian cancer. It is unclear if oral quercetin is beneficial for ovarian cancer prevention. Details: One epidemiologic study found no association between dietary intake of quercetin and related flavonols and the risk of ovarian cancer (16428).
• Pancreatic cancer. It is unclear if oral quercetin is beneficial for pancreatic cancer prevention. Details: Epidemiologic studies have found that a high dietary intake of quercetin and related flavonols might reduce the risk of pancreatic cancer, especially in male smokers (16426,16427).
• Peptic ulcers. Although there has been interest in using oral quercetin for peptic ulcers, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Physical performance. It is unclear if oral quercetin is effective for improving physical performance in older adults. Details: A small clinical study in Japanese individuals 50-74 years of age shows that taking quercetin glycosides 200 mg or 500 mg daily along with low-intensity resistance training 3 days weekly for 24 weeks does not improve muscle size or lean body mass, but may reduce muscle stiffness, when compared with placebo (109621).
• Polycystic ovary syndrome (PCOS). It is unclear if oral quercetin is beneficial for improving hormone levels or pregnancy rates in patients with PCOS. Details: Clinical research in patients with PCOS shows that taking quercetin 1000 mg daily for 12 weeks reduces testosterone and luteinizing hormone (LH) levels by 9% and 3%, respectively, when compared to baseline; both of these improvements were significant when compared with placebo. Insulin resistance also improved by 18% when compared to baseline, which was significant when compared with placebo (96782). In a similar group of patients with higher levels of insulin resistance at baseline, taking the same dose of quercetin modestly reduced testosterone and LH levels when compared with placebo; however, there was no improvement in insulin resistance (99237). These disparate outcomes might be due to different baseline levels of insulin resistance. Also, it is unclear if these changes are associated with an improvement in the clinical symptoms of PCOS. Quercetin has also been evaluated for improving pregnancy rates in adults with PCOS and infertility. A small clinical study shows that taking quercetin 500 mg daily for 40 days increases pregnancy rates when compared with placebo. Quercetin supplementation also improves the grading of oocytes, but not the quality of embryos, in those undergoing in vitro fertilization (IVF). Nearly 84% of patients taking quercetin became pregnant spontaneously or via IVF in the 6 months following initiation of quercetin supplementation. Only 11% of patients taking placebo became pregnant during the study, all through IVF (109618). Due to a short duration of follow-up, it is unclear whether quercetin improves live birth rates.
• Prostatitis. It is unclear if oral quercetin is beneficial in patients with prostatitis. Details: Preliminary clinical research shows that taking quercetin 500 mg twice daily for one month reduces pain and improves quality of life, but does not seem to affect voiding dysfunction, in patients with chronic, nonbacterial prostatitis when compared with placebo (481).
• Rheumatoid arthritis (RA). It is unclear if oral quercetin is beneficial in patients with RA. Details: In patients with RA, clinical research shows that taking quercetin 500 mg daily for 8 weeks improves morning stiffness, morning pain, and after-activity pain when compared with placebo. However, taking quercetin does not seem to improve the number of swollen or tender joints or the disease activity score when compared with placebo (96774).
• Schizophrenia. Although there has been interest in using oral quercetin for schizophrenia, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Upper respiratory tract infection (URTI). Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking quercetin 500 mg or 1000 mg daily for 12 weeks, in combination with vitamin C 500 mg or 1000 mg daily or niacin 20 mg or 40 mg daily, does not reduce the frequency or severity of URTIs. However, in a subgroup analysis of physically fit individuals 40 years and older, the severity of URTIs and the number of sick days related to URTIs were reduced by 36% and 31%, respectively, when quercetin 1000 mg was compared with placebo (104679).
• Urethral syndrome. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking one tablet daily of a specific formulation containing quercetin, bromelain, chondroitin sulfate, gotu kola, rhodiola, and barbed skullcap (Cistiquer, Deakos) for 7 weeks reduces urinary urgency by 91% when compared with baseline. Also, 55% of patients reported no discomfort associated with urination. This combination product was reported to be at least as effective as intravesical administration of betamethasone 8 mg plus gentamicin 80 mg twice weekly (96777).
• Urinary tract infections (UTIs). Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking 1-2 capsules of a combination of hyaluronic acid, chondroitin sulfate, curcumin, and quercetin daily for 15 days each month, in combination with the use of local topical estrogen therapy (0.005% estriol vaginal gel) for up to 12 months, increases the number of women cured of recurrent UTIs to 66%, compared with only 34% of those taking the oral combination product or the vaginal estrogen product alone (96781). More evidence is needed to rate quercetin for these uses.

(Read more about QUERCETIN)

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)

EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Some research suggests that oral vitamin D reduces symptoms of allergic rhinitis in children and adults. It is unclear if oral vitamin D during pregnancy is beneficial for the prevention of allergic rhinitis in the child. Details: Preliminary clinical research in adults with allergic rhinitis and vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 8 weeks along with cetirizine improves overall symptom severity when compared with placebo and cetirizine. This improvement was not significant at 4 weeks, suggesting that symptom improvement might not occur until vitamin D has been adequately replenished (102120). Another moderate-sized clinical study conducted in China in adults with moderate to severe allergic rhinitis and vitamin D levels at the low end of the normal range shows that taking vitamin D 800 IU daily for 4 weeks along with mometasone nasal spray improves runny nose, itchy nose, and nasal congestion but does not reduce sneezing when compared with placebo and mometasone (112483). In children aged 5-15 years, 4 small- or moderate-sized clinical trials show that taking vitamin D 800 IU or 1000 IU daily for 1-6 months modestly reduces symptoms such as nasal congestion and rhinorrhea when compared with placebo or no supplementation (109728). It is unclear whether these children had vitamin D deficiency at baseline. Vitamin D supplementation during pregnancy has also been evaluated. A meta-analysis of three large clinical studies shows that prenatal vitamin D supplementation does not reduce the risk of the child developing allergic rhinitis when compared with low-dose vitamin D, placebo, or no intervention (108438).
• Dental caries. Some research suggests that oral vitamin D reduces the risk of dental caries in children. Details: A meta-analysis of clinical research suggests that vitamin D3 (cholecalciferol) reduces the risk of cavities by 49%, and vitamin D2 (ergocalciferol) reduces the risk by 36% when compared with placebo in infants, children, and adolescents (84690). The validity of this finding is limited by the heterogeneity of the included trials. Also, clinical research shows an inverse correlation between cord blood vitamin D status and the number of decayed primary teeth in the infant at 12 months of age (104620). However, this same research shows that taking two oral prenatal doses of vitamin D2 50,000 IU during pregnancy does not prevent dental caries in the infant at 12 months of age or increase vitamin D levels in the cord blood (104620).
• Heart failure. Limited research suggests that oral vitamin D reduces the risk of developing heart failure in some patients. However, vitamin D does not seem to improve outcomes in patients that have already developed heart failure. Details: Population research has found that vitamin D levels below 15 ng/mL are associated with increased risk of developing heart failure (16615). A meta-analysis of 17 trials, including the landmark Randomized Evaluation of Calcium Or vitamin D (RECORD) trial, shows that vitamin D reduces the risk of heart failure by 21% compared to not taking vitamin D in patients 60 years or older (91343). This finding is limited because none of the included trials were designed to determine effects on cardiovascular outcomes. In contrast, a secondary analysis of data from the Women's Health Initiative trial shows that taking vitamin D 400 IU with calcium 1000 mg daily is not associated with a reduced risk of heart failure in postmenopausal adults. However, a subgroup analysis of that trial shows that taking vitamin D plus calcium is associated with a 37% lower risk of developing heart failure in postmenopausal adults classified as low-risk for heart failure at baseline. It is speculated that high-risk patients might not benefit from vitamin D plus calcium due to negative interactions with medications used to manage cardiovascular risk factors in this group (97307). While vitamin D might be associated with a reduced risk of developing heart failure, most evidence suggests that vitamin D is not beneficial in patients already diagnosed with heart failure. In one small clinical trial, taking vitamin D3 50,000 IU weekly along with calcium citrate 800 mg daily for 6 months was not associated with an improvement in 6-minute walk test, timed get up and go test (TGUG), electrocardiographic variables, or health status when compared with placebo in adults with heart failure; mortality was not evaluated (97299,97300). In another clinical trial, taking vitamin D3 2000 IU daily did not decrease the risk of mortality when compared with placebo in New York Heart Association (NYHA) class 2 heart failure patients (16620).
• Hyperparathyroidism-related bone loss. Limited evidence suggests that oral vitamin D is beneficial in patients with this condition. Details: Taking vitamin D3 (cholecalciferol) orally seems to help decrease secondary hyperparathyroidism and bone turnover in females. In one study, supplementation with vitamin D3 increased serum levels of 25-hydroxyvitamin D, reduced levels of parathyroid hormone, and decreased production of markers of bone turnover (3463).
• Respiratory tract infections. Clinical research shows that oral vitamin D supplementation reduces the risk for respiratory tract infections in children but not in adults or older adults. Some clinical practice guidelines recommend vitamin D supplements or fortified foods for children to potentially lower the risk of respiratory tract infections. It is unclear if oral vitamin D is beneficial for the treatment of respiratory tract infections. Details: Prenatally, increased levels of vitamin D during pregnancy have been associated with a lower incidence of childhood respiratory tract infections (98197). However, two meta-analyses of small clinical studies and one meta-analysis of large clinical studies show no effect of prenatal vitamin D supplementation on the incidence of infant or childhood respiratory tract infections, including lower respiratory tract infections, when compared with control. Results related to risk of wheeze are conflicting (95910,95912,108438). In children, most research shows that vitamin D supplementation reduces the risk of respiratory infections. A meta-analysis of clinical trials in children aged 1-16 years shows that taking vitamin D decreases the odds of having a respiratory tract infection by about 29% when compared with control, although this study also identified a high likelihood of publication bias (105721). Daily or weekly vitamin D doses seem to be more beneficial than single bolus doses, although the largest meta-analysis failed to confirm this result (84689,93766,105721). One clinical study in preterm Black infants shows that taking vitamin D3 (cholecalciferol) 200 IU daily and then 400 IU daily until 6 months of age does not affect the rate of respiratory tract infections, but does reduce wheeze by 11%, when compared with a normal diet without vitamin D supplementation (98191). This study may not have been powered to detect a difference in respiratory tract infection between groups. Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from vitamin D fortified foods, vitamin D supplements, or vitamin formulations that contain vitamin D to potentially lower the risk of respiratory tract infections in children and adolescents aged 1 to 18 years. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502). In adults, vitamin D supplementation does not seem to reduce the risk of respiratory infections. Observational research in adults has found that low levels of vitamin D are associated with worsened respiratory tract infection complications, and even increased mortality from respiratory tract infections in older adults ages 50-75 years (103659). However, meta-analyses of prospective clinical trials in adults show that taking vitamin D supplements 300-4000 IU daily for 7 weeks to 5 years or taking vitamin D 30,000-100,000 IU monthly or 96,000-120,000 IU every 2 months for 1-5 years does not reduce the odds of developing a respiratory infection or severe respiratory complications, such as emergency department utilization, hospitalization, and death, when compared with placebo. These results were similar in subgroup analyses evaluating overall vitamin D dose and baseline vitamin D status (84689,105721,114506). The largest single clinical trial, conducted in adults at least 60 years of age, shows that taking vitamin D3 (cholecalciferol) 60,000 IU once monthly for up to 5 years reduces the duration of total and severe respiratory symptoms by approximately 0.5 days, but does not reduce the incidence of respiratory illness or hospitalization, when compared with placebo (105726,110825). A large meta-analysis of clinical studies in both children and adults shows that taking vitamin D does not reduce the risk of acute respiratory infections. While subgroup analyses revealed a reduced risk of acute respiratory infection in studies not exceeding 11 weeks' duration and with daily supplementation, these beneficial effects only persisted in studies considered to be of low quality (108435). Baseline vitamin D status was not assessed and the validity of these findings is limited by publication bias. Vitamin D has also been evaluated for the treatment of acute respiratory infections. A large meta-analysis of clinical studies in both children and adults shows that taking vitamin D improves outcomes (e.g., sputum conversion, survival rate, therapeutic success, need for intensive care admission) by a small, but not clinically relevant, amount. In subgroup analyses, these beneficial effects only persisted in studies considered to be of low quality (108436). The validity of these findings is limited by publication bias.
• Tooth retention. Oral vitamin D with calcium seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking vitamin D3 (cholecalciferol) 700 IU daily along with calcium citrate malate 500 mg daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if oral vitamin D is beneficial for acne. Details: A small clinical trial in patients with acne and vitamin D deficiency shows that taking cholecalciferol 1,000 IU daily for 2 months reduces the number of inflammatory lesions by about 35%, compared with 6% in those taking placebo. There was no effect on the total or non-inflammatory lesion count (106127). Other preliminary clinical research shows that taking alfacalcidol (One Alpha, LEO Company, Denmark) 0.25 mcg daily for 3 months modestly improves acne severity when compared with taking placebo (106128). In addition, population research has found that individuals with acne have modestly lower vitamin D levels than healthy controls. The odds of vitamin D deficiency were approximately three times higher in patients with acne when compared with healthy controls (106105).
• Age-related cognitive decline. It is unclear if oral cholecalciferol is beneficial for preventing age-related cognitive decline. Details: Pooled results of two large clinical sub-studies in community-dwelling adults aged 60 years or older show that taking cholecalciferol 2000 IU daily for 2-3 years has no effect on cognitive decline when compared with placebo. A subgroup analysis in Black patients suggests a modest effect of vitamin D when compared with placebo (108428).
• Alzheimer disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Some population research has found that lower serum concentrations of vitamin D are associated with higher risk of Alzheimer disease, and also with decreased cognition. People with Alzheimer disease seem to have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without Alzheimer disease (84672,103666). However, other population research has found that vitamin D deficiency (<25 nmol/L) or insufficiency (25-50 nmol/L) is not associated with increased risk of Alzheimer disease (100899).
• Asthma. Oral vitamin D might reduce asthma exacerbations in adults and children with mild, but not severe or persistent, asthma. Vitamin D supplementation during pregnancy or the first 6 months of an infant's life does not seem to prevent the development of asthma later in infancy or childhood. Details: Population research in patients with asthma suggests that low vitamin D levels are associated with an increased risk of exacerbations and increased need for medication therapy (94693). However, findings from clinical research are mixed. Some meta-analyses of clinical trials in adults and children with asthma show that taking vitamin D for 3 months to 1 year reduces the rate of asthma exacerbations by 31% to 36% when compared with control (92690,94686). However, findings from more recent meta-analyses show that vitamin D supplementation does not reduce the risk of asthma exacerbations when compared with placebo (109728,109732,110833). The reasons for this discrepancy are not clear. However, some clinical research suggests that vitamin D supplements might only prevent asthma in people with non-persistent asthma (92690,94685,94686,94688,104020). Also, many studies are small and do not represent patients with severe asthma exacerbations (92690,94687). Baseline levels of vitamin D may play a role. A clinical study in children aged 6-16 years with persistent asthma and low vitamin D levels shows that taking vitamin D 4000 IU daily for 48 weeks does not reduce severe asthma exacerbations when compared with placebo (104020). However, a meta-analysis including this study shows that taking vitamin D does reduce risk of asthma exacerbations in children with low baseline vitamin D levels (109728). One meta-analysis shows that taking vitamin D seems to modestly improve pulmonary function when compared with placebo (109732). Vitamin D doses have varied, with oral doses of 500-4000 IU daily, 1000 IU once weekly, 60,000 IU once monthly, 120,000 IU every 2 months, 100,000 IU 14 days apart, or 100,000 to 600,000 IU as a bolus dose followed by 400-4000 IU daily (92690,94686,104020,109728,110833). Vitamin D supplementation for the prevention of asthma in infants has also been evaluated. A meta-analysis of 4 large clinical studies shows that taking vitamin D 400-1200 IU daily for the first 6 months of life does not reduce the risk of asthma or wheezing at 6-30 months of age when compared with control (112031). Vitamin D supplementation during pregnancy has also been evaluated (97306,99763,102146,112031). A meta-analysis of 3 large clinical studies shows that taking vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy reduces the risk of recurrent wheezing by 23% but does not reduce the risk of asthma diagnosis within the first 3-6 years of life when compared with vitamin D 400 IU daily (112031). Some research suggests that the dose of vitamin D plays a role. A meta-analysis shows that prenatal vitamin D 800 IU daily reduces the odds of wheeze or asthma by 32%, while lower or higher vitamin D doses were not beneficial (103661).
• Athletic performance. It is unclear if oral vitamin D is beneficial for athletic performance. Details: One small clinical trial in athletes shows that taking vitamin D 20,000 or 40,000 IU once weekly for 2 doses does not affect performance on vertical jumps, sprints, or leg and bench presses when compared with placebo (98188). Another small clinical trial in professional rugby players shows that taking vitamin D3 (cholecalciferol) 50,000 IU once every two weeks over 12 weeks does not improve sprinting speed or the ability to perform bench presses, bench pulls, and chin-ups when compared with placebo (98189). Also, most research shows that taking vitamin D does not improve measures of cardiorespiratory fitness. One small study in young males undergoing resistance training shows that taking vitamin D 8000 IU daily for 12 weeks does not improve cardiorespiratory fitness compared with taking placebo (110812).
• Atopic dermatitis (eczema). Most research shows that oral vitamin D reduces eczema severity in children. However, most research shows that oral vitamin D, taken during pregnancy or infancy, does not prevent eczema in the child. Details: A meta-analysis of eight moderate-quality clinical trials in children shows that taking vitamin D, most commonly 1000-2000 IU daily for 4-12 weeks, modestly reduces severity of eczema when compared with placebo (109728). Most of the children in these studies were also given conventional medications. Oral vitamin D has also been evaluated for eczema prevention. A meta-analysis of two clinical studies shows that consuming vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy is not associated with a reduced risk for eczema in children during the first 3 years of life when compared with vitamin D 400 IU daily (97306). Another meta-analysis of five large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing eczema when compared with low-dose vitamin D, placebo, or no intervention (108438).
• Atrial fibrillation. It is unclear if oral vitamin D is beneficial for preventing atrial fibrillation. Details: A large clinical trial in adults without cardiovascular disease shows that taking vitamin D 2000 IU daily for an average of 5 years does not reduce the incidence of atrial fibrillation when compared with placebo or fish oil 840 mg daily (105209). However, observational research in postmenopausal adults with osteoporosis found that vitamin D supplementation is associated with a lower occurrence of atrial fibrillation when compared with not taking vitamin D (98922). Also, one large observational study in vitamin D-deficient patients with no history of atrial fibrillation has found that vitamin D supplementation for at least 6 months is associated with up to a 16% decreased risk of atrial fibrillation when compared with not taking vitamin D. There were also modest improvements in atrial fibrillation-free survival. In males 65 years and older with hypertension or diabetes at baseline, blood levels of at least 30 ng/mL following vitamin D supplementation were associated with decreased risk of atrial fibrillation; a post-supplementation blood level of 21-29 ng/mL was not associated with decreased risk (109043).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin D is beneficial for ADHD. Details: A small clinical trial in children 5-12 years of age with ADHD and vitamin D insufficiency shows that taking vitamin D 2000 IU daily along with methylphenidate for 8 weeks seems to improve parental ratings of evening, but not morning or overall, symptoms of inattentiveness and impulsivity when compared with methylphenidate alone. Vitamin D insufficiency was defined as levels less than 30 ng/mL (98196). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive use in children with ADHD, especially those with insufficient intake or skin exposure to sunlight (110318).
• Autism spectrum disorder. It is unclear if oral vitamin D is beneficial for autism spectrum disorder. Details: A small clinical study in children aged 2.5-8 years with autism spectrum disorder shows that taking vitamin D 2000 IU daily for 12 months modestly reduces irritability and hyperactivity when compared with placebo (99767).
• Autoimmune thyroiditis. It is unclear of oral vitamin D improves outcomes in patients with Hashimoto's thyroiditis. Details: A meta-analysis of 12 clinical trials in patients with Hashimoto's thyroiditis shows that taking vitamin D for at least 12 weeks increases free triiodothyronine (T3) and thyroxine (T4) levels, and reduces levels of thyroid stimulating hormone, thyroglobulin antibody, and anti-thyroid peroxidase antibody, when compared with placebo or no treatment (113593).
• Bacterial vaginosis. It is unclear if oral vitamin D is beneficial for bacterial vaginosis. Details: Preliminary clinical research in females at high risk for sexually transmitted disease shows that taking vitamin D along with standard therapy for bacterial vaginosis does not reduce the prevalence of bacterial vaginosis when compared with placebo. Patients in this study had been treated with metronidazole 500 mg orally twice daily for 7 days along with vitamin D3 (cholecalciferol) 50,000 IU each week for 4 weeks and then every 4 weeks for the remaining 20 weeks (91348).
• Breast cancer. It is unclear if oral vitamin D is beneficial for the prevention of breast cancer. Details: Some population research evaluating intake of calcium plus vitamin D suggests that higher vitamin D intake is not associated with a reduced risk of breast cancer in premenopausal or postmenopausal adults (15631). Similarly, a large observational study in females with a biological sibling with breast cancer has found that taking vitamin D recently or prior to enrollment is not associated with a reduced risk of breast cancer when compared with nonrecent vitamin D use or never taking vitamin D, respectively (107215). However, other research found that higher vitamin D intake is associated with a 17% reduced risk of breast cancer in premenopausal and perimenopausal, but not postmenopausal, adults (39001). Observational research has also examined the association between blood levels of vitamin D and risk of developing breast cancer. A meta-analysis found that those with serum levels of about 52 ng/mL had a 50% lower risk of developing breast cancer when compared with those with serum levels of less than 13 ng/mL. This high serum level of vitamin D corresponds to a high dose of about 4000 IU daily (16049). Other observational research has found that baseline vitamin D levels of more than 20 ng/mL are associated with a 48% reduced risk of developing breast cancer over approximately 9 years in Latina females in the US when compared with levels below 20 ng/mL; however, this association was not present in Black females (109058). Despite the contradictory findings from observational research, results from clinical research are generally negative. Evidence from one large-scale clinical trial (Women's Health Initiative) shows that postmenopausal adults who take vitamin D3 (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years do not have a significantly reduced risk of developing breast cancer (16715,98895). Also, a meta-analysis of two large-scale clinical trials, which did not include the Women's Health Initiative trial, shows that taking vitamin D 800-1000 IU daily, alone or with calcium, for 3-4 years does not reduce the incidence of breast cancer in postmenopausal adults, although there was a trend towards reduced risk with higher doses of vitamin D supplementation (97301). While vitamin D and calcium supplementation during the intervention period of the Women's Health Initiative trial was not associated with a reduced risk of developing breast cancer or ductal carcinoma in situ (DCIS), a precursor to breast cancer, a secondary post-hoc analysis of the data shows that supplementation reduces the risk of developing DCIS by 18% over a median follow-up of 19 years (107216). Additional research is needed regarding an optimal dose of vitamin D, timing of initiation, and whether any benefit is affected by menopausal status.
• Bronchopulmonary dysplasia. Limited research suggests that vitamin D deficiency is linked with bronchopulmonary dysplasia in the infant. Details: Observational research has found that vitamin D deficiency at birth is associated with about a 2-fold increased odds of developing bronchopulmonary dysplasia (104021). However, it is unclear if vitamin D supplementation is beneficial.
• Cancer. Vitamin D does not seem to reduce overall cancer risk. However, some research shows that vitamin D might slightly reduce the risk of metastatic cancer and cancer-related mortality. Details: There is interest in vitamin D for cancer PREVENTION, as observational research suggests that higher vitamin D intake and higher 25-hydroxyvitamin D levels are associated with a lower risk of cancer (111150). While individual clinical trials evaluating vitamin D for cancer have produced inconsistent findings, most meta-analyses and clinical trials show that taking vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol) alone or with calcium does not significantly reduce the risk of developing cancer (15629,91344,93943,97296,98916,104024,104618,110811). However, vitamin D supplementation might reduce the risk of metastatic cancer and cancer-related mortality. A large clinical trial shows that taking vitamin D3 2000 IU daily for a median of 5.3 years slightly reduces the risk of advanced metastatic or fatal cancers when compared with placebo (104618). Additionally, meta-analyses of several large clinical trials show that taking vitamin D 400-4000 IU daily, with or without calcium, for 1-7 years reduces the risk of cancer-related mortality by 12-13% when compared with control, while intermittent bolus dosing of vitamin D at high doses for 1-5 years does not appear to reduce the risk of cancer-related mortality (104024,111149). The role of vitamin D in cancer TREATMENT is unclear. A meta-analysis of clinical and observational research suggests that supplementation of vitamin D after a cancer diagnosis is associated with a modest improvement in overall survival, but not progression-free or cancer-specific survival (109726). Doses used in clinical research ranged between 1200 IU and 8000 IU daily or 100,000 IU every 50 days, after surgery and/or during treatment (99195,99196,109726). Other clinical research in patients with luminal gastrointestinal cancers shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse when compared with placebo (99195). It is unclear which, if any, types or stages of cancer respond best to vitamin D, and what dose of vitamin D is optimal.
• Child growth. It is unclear if oral vitamin D is beneficial for improving infant growth or bone structure. Details: Meta-analyses and individual clinical trials show that vitamin D supplementation during pregnancy modestly increases length at birth and bone mineral density at up to 6 years of age when compared with control, usually placebo or vitamin D 400 IU daily. However, there was no effect on length in the infant up to one year of age, weight at birth or up to one year of age, head circumference at birth or up to 6 years of age, bone mineral content at up to 6 years of age, or neonatal bone mineral density, bone mineral content, bone area, or femur or humoral length (98198,109737,112028). In the available research, vitamin D was taken in doses of 200 IU to 4400 IU daily, 4200 IU to 50,000 IU weekly, 50,000 IU every 2 weeks, or 60,000 IU every 4-8 weeks, starting from the early to late stages of pregnancy and usually continued until birth (98198,109737).
• Chronic kidney disease (CKD). It is unclear if oral vitamin D is beneficial in patients with CKD. Most research suggests that it does not reduce the risk for adverse cardiovascular events. Details: Population research in patients on dialysis has found that vitamin D levels less than 17.8 ng/mL are associated with a higher risk of all-cause mortality compared with higher levels (16619). A meta-analysis and individual clinical studies show that vitamin D and vitamin D analogues decrease parathyroid hormone (PTH) levels and urine protein levels in people with CKD (84376,84377,84628,98233,98236). However, taking vitamin D does not appear to decrease the risk of death or parathyroidectomy in CKD patients (84376,84377). Also, taking vitamin D increases the risk for hypercalcemia and hyperphosphatemia in this patient population (84376,84377,98236). Vitamin D has also been evaluated for the prevention of cardiovascular events in adults with CKD. Observational research has found that vitamin D deficiency in patients with CKD is associated with adverse cardiovascular events. However, vitamin D supplementation does not seem to be beneficial. One clinical study shows that taking paricalcitol, an active form of vitamin D, titrated to maintain adequate serum calcium levels, for 48 weeks does not affect the size of the left ventricle or heart function when compared with placebo (98233). Other clinical research in Japanese patients on hemodialysis for CKD shows that adding alfacalcidol, another active form of vitamin D, 0.5 mcg daily to standard treatment for 4 years does not affect mortality or cardiovascular events such as myocardial infarctions, stroke, aortic dissection, and others compared to standard treatment only (98920). Also, a large clinical trial in patients with CKD shows that taking vitamin D as cholecalciferol 2000 IU daily, alone or with omega-3 fatty acids 1 gram daily, does not affect major cardiovascular events or invasive cancer when compared with placebo (110811). Vitamin D has also been evaluated for musculoskeletal health in adults with CKD. A small clinical study shows that taking cholecalciferol 4000 IU daily, with or without physical activity, for 3 months improves bicep strength, but not back flexibility or aerobic fitness capacity, when compared with baseline. In patients taking cholecalciferol in combination with physical activity, musculoskeletal health was similar when compared with cholecalciferol alone (108431). However, this study was inadequately powered to detect a difference between groups, and it is unclear if the improvement from baseline differed between groups. Vitamin D has also been evaluated for the improvement of iron status in adults with CKD and secondary hyperparathyroidism. Clinical research shows that taking Vitamin D as cholecalciferol (Vitamin D3 Forte Renapharma) 8000 IU daily for 12 weeks does not improve iron status compared with taking placebo. However, a sub-analysis shows that hemoglobin levels are modestly improved in patients with a low Vitamin D status at baseline suggesting that Vitamin D might improve iron availability in these patients (110819).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin D is beneficial for COPD; benefits may be limited to patients with vitamin D deficiency. Details: Population research has found an association between low vitamin D levels and reduced lung function, increased risk of developing COPD, and worsening COPD severity (17685,96401). In contrast, 2 meta-analyses of clinical research in adults with COPD and with or without vitamin D deficiency show that oral vitamin D does not have beneficial effects on mortality, rate of COPD exacerbations, pulmonary function, or most measures of symptom severity when compared with placebo (109732,112485). However, other research suggests that vitamin D may be beneficial in patients with vitamin D deficiency. Some clinical research in patients with moderate to severe COPD and severe vitamin D deficiency shows that taking a specific vitamin D supplement (D-Cure, Laboratoires SMB) 100,000 IU once every 4 weeks for 1 year seems to reduce the rate of exacerbations by 43% when compared with placebo (98194).
• Cognitive function. It is unclear if oral vitamin D is beneficial for cognitive function. Details: Population research has found that low vitamin D levels are associated with worse cognitive performance and cognitive decline when compared to high vitamin D levels in healthy adults (84672,95916). However, the effect of vitamin D supplementation on cognitive function is unclear. One small meta-analysis of clinical research shows that vitamin D supplementation does not improve cognitive function (95916). However, the included trials evaluated a widely heterogeneous study population and utilized variable measures of cognitive function.
• Cognitive impairment. It is unclear if oral vitamin D is beneficial for older adults with mild cognitive impairment. Details: A small clinical study in older adults with mild cognitive impairment shows that taking vitamin D3 10,000 IU three times weekly for 20 weeks in addition to exercise and cognitive training does not improve cognitive function when compared with placebo and exercise with or without cognitive training. However, most participants had sufficient serum vitamin D levels at baseline (112489).
• Colorectal cancer. It is unclear if oral vitamin D is beneficial for the treatment or prevention of colorectal cancer. Details: Epidemiological research has found that a higher serum vitamin D level is associated with decreased risk of mortality and increased survival in patients with colorectal cancer (16101,99196). However, it is unclear whether vitamin D supplementation improves survival in patients with colorectal cancer, as research has generally involved small populations and results are somewhat conflicting. A subgroup analysis of one clinical study shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse or death, death due to any cause, or relapse over 5 years when compared with placebo in patients with colorectal cancer (99195). However, this subgroup may have been underpowered to detect between-group differences. Another small clinical trial in patients with advanced or metastatic colorectal cancer shows that taking high-dose vitamin D 8000 IU daily during the first cycle of chemotherapy, and then 4000 IU daily for subsequent cycles, does not increase median progression-free survival when compared with taking vitamin D 400 IU daily. However, patients taking high-dose vitamin D were 36% less likely to experience disease progression or death during follow-up when compared with patients taking the lower dose of vitamin D (99196). This latter result suggests that high-dose vitamin D supplementation might be beneficial for patients with advanced or metastatic colorectal cancer, but larger, multicenter studies are needed to confirm. The role of vitamin D in colorectal cancer prevention has also been investigated. A meta-analysis of epidemiological research has found that a higher serum vitamin D level is associated with a decreased colorectal cancer risk; however, sub-analyses suggest that this association only occurs in females, not males (109740). Most studies have evaluated vitamin D supplements in combination with calcium; the effects of vitamin D supplementation alone are unclear. One meta-analysis of clinical research suggests that taking vitamin D plus calcium is not associated with a decreased incidence of colorectal cancer in people with a low baseline risk of colorectal cancer (39042). Another meta-analysis of clinical research shows that vitamin D supplementation, with or without calcium, does not reduce the incidence of colorectal cancer or colorectal adenomas (109730). Additionally, a large clinical trial suggests that postmenopausal adults who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290,98895). One clinical study shows that taking calcium supplements reduces the risk of colorectal adenomas, but not in people with lower than average vitamin D levels (12118).
• Coronavirus disease 2019 (COVID-19). The evidence is mixed with respect to oral vitamin D supplementation for the prevention and treatment of COVID-19. Also, although some observational research has suggested a correlation between vitamin D status and risk for COVID-19, not all studies agree, and this association may be due to other confounders such as age and comorbidities. Details: Clinical and observational research has evaluated vitamin D supplementation for COVID-19 prevention. A preliminary clinical trial shows that oral vitamin D 800 IU or 3200 IU daily for 6 months in individuals with lower serum levels of vitamin D does not reduce the risk of COVID-19 or any respiratory tract infection when compared with no vitamin D supplementation (109721). However, groups were not matched for baseline vitamin D status and many individuals in the untreated group took their own vitamin D supplements. Two meta-analyses of clinical and observational studies show no relationship between vitamin D supplementation and the primary prevention of COVID-19 infection, although baseline vitamin D status is unclear (109040,112488), However, an umbrella meta-analysis of clinical and observational research suggests that vitamin D deficiency is associated with a greater risk of COVID-19 infection, COVID-19 severity, and mortality (114583). Also, a quasi-experimental cohort study in Italian adults who had supplemented with vitamin D in the 3 months prior to COVID-19 diagnosis found no reduction in risk for hospitalization, as well as a trend towards increased risk for in-hospital mortality, when compared with those who had not received vitamin D supplementation (104625). However, some research disagrees. Clinical research in highly exposed healthcare workers shows that taking vitamin D as cholecalciferol 4000 IU daily for 30 days reduces the risk of COVID-19 infection by 77% when compared with placebo (109052). Also, in the UK population, observational research has found that habitual use of vitamin D supplements between 2006 and 2010 is associated with a 34% lower risk of COVID-19 infection. This finding remained positive after adjusting for baseline health status and use of other micronutrients (104717). A meta-analysis of 16 studies in various populations shows that vitamin D reduces the risk of COVID-19 infection by 40% to 60% (113590). Vitamin D supplementation as treatment in outpatients with COVID-19 has also been evaluated. Preliminary clinical research discussed in a systematic review suggests that supplementation might be associated with less severe symptoms; however, there is inadequate information to determine if supplementation in patients with mild symptoms is associated with reduced hospital admission (109040). Conversely, a large cross-sectional study found an association between pre-hospital supplementation and increased risk for COVID-19, as well as increased rates of death and/or invasive mechanical ventilation. However, this association was no longer significant after adjusting for sex, age, and comorbidities (107205). Most research on vitamin D supplementation has been conducted in children and adults hospitalized with COVID-19. However, meta-analyses of clinical and observational research in these patients provides conflicting results on whether vitamin D supplementation as single dose or multiple doses is associated with a reduced risk of mortality, length of hospitalization, admission to the intensive care unit (ICU), or need for ventilation when compared with placebo or standard care alone (109040,109733,112488,112490,113579,114488,114583). The quality of evidence of most individual clinical trials is low to moderate due to a lack of placebo and blinding in many of the studies. Most individual studies evaluating single doses of vitamin D, administered either after diagnosis or after hospital admission, have not identified benefit for major outcomes, such as hospital length of stay, in-hospital mortality, or ICU admission. Many of these studies were small, low quality, and conducted in heterogenous populations, with doses ranging from 80,000 IU to 500,000 IU (104624,104626,107208,108434,109051,112490). Additionally, meta-analysis of 11 clinical studies primarily in patients hospitalized with mild to severe COVID-19 shows that taking vitamin D does not reduce the risk of all-cause mortality, regardless of baseline vitamin D status, when compared with control. However, sensitivity analysis shows that multiple administration of vitamin D reduces the risk of all-cause mortality by 33% when compared with single administration (114488). One small, unblinded study in at-risk older adults admitted to the hospital or living in a long-term care facility shows that taking a single dose of 400,000 IU within 72 hours of diagnosis modestly improves survival at 14 days, but not 28 days, when compared with 50,000 IU (109039). The evidence related to multi-dose regimens in hospitalized patients is mixed. A cohort study shows that giving calcifediol 0.532 mg at hospital admission, followed by calcifediol 0.266 mg on days 3 and 7 and then weekly until discharge or ICU admission, reduces odds of in-hospital death within 30 days by 78% when compared with those not given vitamin D (106099). A small clinical trial in patients with vitamin D deficiency shows that taking vitamin D 25,000 IU daily for 4 days and then weekly for up to 6 weeks reduces length of hospital stay and duration of supplemental oxygen by 4 days and 3 days, respectively, and also reduces disease severity and ICU admission after 7 days (109050). A small, unblinded study in patients with suboptimal vitamin D status and mild to moderate COVID-19 shows that taking vitamin D3 5,000 IU daily for 2 weeks reduces the time to recovery from cough and loss of taste by 2.9 and 5.5 days, respectively, when compared with vitamin D3 1,000 IU daily. However, there was no difference in time to recovery from fever, dyspnea, body aches, or other symptoms (106117). However, some research disagrees. A small unblinded study has found that although vitamin D status at 9 days is negatively associated with the number of bed days, vitamin D 50,000 IU on days 1 and 8 does not affect the number of bed days, time to discharge, or ICU admission when compared with no supplementation (109047). An additional preliminary study in patients with severe COVID-19 and low blood levels of vitamin D shows that taking vitamin D (Plivit D3, Pliva) 10,000 IU daily while in the ICU or for at least 14 days does not reduce the number of days on respiratory support, or in the ICU or hospital, or improve survival rates when compared with no supplementation (110813). A small, open-label study in patients hospitalized with COVID-19 pneumonia shows that taking alfacalcidol 2 mcg orally daily dose not reduce the duration of treatment or length of hospital stay (113579). The relationship between vitamin D levels and COVID-19 has also been evaluated in pregnant patients. A meta-analysis of observational research suggests that, while lower vitamin D levels are not associated with an increased risk of COVID-19, the presence of severe COVID-19 symptoms in pregnant patients may be linked to lower vitamin D levels when compared with non-severe COVID-19 symptoms (112025). Limited research has investigated the effect of vitamin D in combination with other ingredients. Preliminary clinical research in patients with mild to moderate COVID-19 shows that taking vitamin D3 (Davalindi, Medical Union Pharma, Cairo, Egypt) 2000 IU daily in combination with black seed (Baraka, Pharco Pharmaceuticals, Cairo, Egypt) 900 mg twice daily for 14 days modestly reduced the severity of some symptoms, including cough, diarrhea, fatigue, and pharyngitis, as well as the percent patients with viral positivity at day 7, but not headache, rhinorrhea, anosmia, or shortness of breath, or vomiting, when compared to standard care alone. However, taking vitamin D alone did not provide significant benefit (110265). The validity of individual studies is limited by generally poor designs. More research is needed to evaluate varying vitamin D dosing levels and schedules, as well as evaluated outcomes, and whether patients with vitamin D insufficiency are more likely to benefit from vitamin D supplementation. The relationship between vitamin D status and risk of COVID-19 infection or severe disease is unclear. Despite some observational research suggesting that low vitamin D levels are associated with an increased risk for COVID-19 mortality, development of severe disease, such as pulmonary involvement, and extended hospitalization or admission to intensive care (107206,107207,108434), several meta-analyses of observational research as well as individual observational studies have found that vitamin D deficiency in adults is not associated with a higher risk for COVID-19 infection or with disease severity or mortality (104627,107208,107209). Additional observational research has found no association between vitamin D status and hospital length of stay, need for mechanical ventilation, mortality, or experiencing persistent feelings of fatigue or reduced exercise tolerance, otherwise known as "long-COVID" (106102,106116,106120,107206). However, one meta-analysis has found that when compared with mild disease, 65% more individuals with severe disease had vitamin D deficiency. Also, vitamin D insufficiency, defined as blood levels less than 30 ng/mL, is associated with a more than 80% increased chance of hospitalization or mortality due to COVID-19. Notably, many of these studies did not control for patient age or other comorbidities (104627). A more recent observational study has found that vitamin D status in patients with severe COVID-19 symptoms is inversely correlated with both ICU admission and death, with a 1% reduction in risk of ICU admission and 4% reduction in risk of death for every 1 ng/mL increase in 25-hydroxyvitamin D (106112). In one individual observational study, the association between vitamin D status and COVID-19 infection is no longer significant after adjusting for socioeconomic status, age, health status, body mass index, ethnicity, and other covariates (104628). In contrast, a small observational study of adults admitted to the hospital with COVID-19 has found that low vitamin D levels are associated with an increased risk of mechanical ventilation and in-hospital mortality, even after adjustment for ethnicity and pre-existing conditions, such as cardiovascular disease, respiratory disease, and diabetes. However, this study is small and does not adjust for socioeconomic factors (105720). Also, another individual observational study has found that the likelihood of testing positive for COVID-19 is increased in Black, but not White, adults who had a vitamin D level of 30-40 ng/mL at some point in the past year when compared with a level of at least 40 ng/mL, with risk decreasing as levels increased from 30 ng/mL to 40 ng/mL (104716). Patients should be encouraged to maintain adequate vitamin D levels. A joint task force has recommended 400-1000 IU (10-25 mcg) daily for those who are unable to spend 15-30 minutes in the sun each day (103659,104629).
• Crohn disease. Limited evidence suggests that vitamin D reduces relapses in patients with Crohn disease. Details: A meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). The validity of these findings is limited by the heterogeneity of the included studies.
• Dementia. It is unclear if oral vitamin D is beneficial for dementia. Details: Population research has found that patients with any type of dementia have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without dementia (84672). However, it is unclear if vitamin D supplementation is beneficial.
• Depression. It is unclear if oral vitamin D is beneficial for treating depression. Vitamin D does not seem to prevent the development of depression. Details: The role of vitamin D in the treatment of depression is unclear. Earlier meta-analyses of clinical research show that vitamin D supplementation does not improve overall symptoms of depression. However, some subgroup analyses suggest that vitamin D may be beneficial for improving the symptoms of depression in people with clinically significant symptoms, as well as those with baseline vitamin D deficiency (97295,97298). More recent meta-analyses of several clinical trials, that include some of the same studies, show that vitamin D modestly improves symptoms of depression in adults; however, subgroup analysis suggests that vitamin D does not improve depressive symptoms in older adults (110832,112786). These analyses are mixed over whether baseline vitamin D status affects results (110832,112786) and one of these analyses shows no evidence that the type of depression affects findings (110832). Another meta-analysis of generally small clinical trials in patients with type 2 diabetes and depression shows that taking vitamin D modestly improves depressive symptoms when compared with placebo or no intervention (110814). Although, results of an individual clinical trial in patients with type 2 diabetes are in contrast (108423). The evaluated research implemented one-time doses of 150,000-500,000 IU, as well as daily and weekly doses ranging between 400-5000 IU daily or 5000-100,000 IU weekly for 6 weeks to 2 years, with the most evidence of benefit related to one-time high doses. Cholecalciferol was the most common form of vitamin D used (97295,97298,108423,110814,110832,112786). Significant heterogeneity between studies and the wide variability in dosing strategies limit the validity of these findings, as well as identification of an effective dose or target population. Vitamin D has also been evaluated for the prevention of depression. One large clinical study (VITAL-DEP) in healthy patients 50 years and older shows that taking vitamin D 2000 IU daily for about 5.3 years does not prevent depression or depressive symptoms, or improve mood, when compared with placebo (103670). An analysis of a cohort of patients from the VITAL-DEP trial also shows that taking vitamin D 2000 IU daily for 2 years does not reduce the risk of major depressive disorder or improve mood scores in patients with subthreshold depression or risk factors for late-life depression when compared with placebo (112032). In addition, a meta-analysis of several clinical studies suggests that vitamin D supplementation does not prevent depression based on subgroup analysis of patients without depression at baseline (112786). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive or monotherapy use in patients with depression, especially those with insufficient intake or skin exposure to sunlight (110318).
• Diabetes. Oral vitamin D might improve glycemic indices in some patients with type 2 diabetes and gestational diabetes. It is unclear if oral vitamin D is beneficial for the prevention of type 1 or gestational diabetes. It is also unclear if intramuscular vitamin D is beneficial for the treatment of gestational diabetes. Details: Most meta-analyses of mainly small clinical trials show that vitamin D supplementation is beneficial for measures of glycemic control in patients with diabetes. However, the best evidence of benefit is in patients with baseline vitamin D deficiency. Three meta-analyses of small trials in patients with type 2 diabetes show that vitamin D supplementation reduces glycated hemoglobin (HbA1c) by 0.20% to 0.25%, and improves serum insulin, fasting blood glucose, and measures of insulin resistance when compared with control (96403,110822,112487). Supplemental vitamin D seems to be most beneficial in patients with baseline vitamin D deficiency (96403,110822,112487). Furthermore, correlation analysis suggests an inverse relationship between serum vitamin D levels and serum insulin, fasting blood glucose, and measures of insulin resistance (112487). However, another meta-analysis of small trials in patients with vitamin D insufficiency or deficiency and type 2 diabetes shows that oral vitamin D modestly improves fasting blood glucose and postprandial blood glucose, but not HbA1c, when compared with control (107210). Most of the evaluated research implemented daily or weekly doses of vitamin D for 4-48 weeks (96403,107210,110822). However, one meta-analysis of clinical research in patients with diabetes shows that vitamin D improves HbA1c, insulin resistance, and insulin measures in studies lasting less than 6 months, but not in studies lasting longer than 6 months (99764). An additional meta-analysis suggests that most evidence of benefit is associated with doses of more than 2000 IU daily for 4-12 weeks (110822). One small, long-term clinical study in middle-aged and elderly patients with type 2 diabetes shows that taking vitamin D 800 IU daily for 30 months reduces insulin levels and insulin resistance when compared with no supplementation. However, there was no effect on HbA1c or fasting blood glucose levels (109734). Thus, conflicting results may be related to the dose and duration of vitamin D supplementation, as well as patient characteristics at time of study entry, such as vitamin D status, baseline HbA1c levels, obesity, and medication regimen (97304,99764,109734,110822). Vitamin D has been evaluated for the prevention of type 1 diabetes. There is preliminary evidence that daily vitamin D supplementation (form not specified) in infants during the first year of life is associated with a reduced incidence of type 1 diabetes development later in life (10139). Also, a meta-analysis of population studies has found that vitamin D supplementation in early childhood is associated with a 29% reduced risk of developing type 1 diabetes later in life (84225). Vitamin D has been evaluated in patients with gestational diabetes. Some research has evaluated the effects of oral or intramuscular vitamin D on glycemic indices. The evidence from clinical research comparing vitamin D with placebo is mixed. Most studies show modest evidence of benefit for some markers of glycemic control. One clinical trial shows that vitamin D modestly reduces levels of insulin, as well as measures of insulin resistance, with no effect on fasting blood glucose (106125). However, other clinical research shows that taking vitamin D modestly reduces levels of fasting blood glucose and HbA1c, with no effect on insulin measures (106126). Two other trials show that taking vitamin D modestly improves all measures of glycemic indices (101775,106122). Additionally, a large clinical trial shows that taking vitamin D 1600 IU daily modestly reduces fasting blood glucose when compared with vitamin D 400 IU daily (112020). Some clinical research has also evaluated the effects of oral vitamin D on lipid indices in patients with gestational diabetes. Although some individual clinical research disagrees (106126), most research shows that taking vitamin D modestly improves levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides when compared with control (106125,110823). Also, a meta-analysis of clinical research in patients with gestational diabetes shows that taking vitamin D reduces the risk of premature birth and neonatal hospitalization by approximately 63% and 62%, respectively (110823). Oral vitamin D 50,000 IU (eg. D-Vitin50000; Zahravi Pharm Co.) once or twice monthly, starting at week 24 of gestation and continuing for 6 weeks, 8 weeks, or until delivery, has been used in most of these studies (106122,106125,106126). One study provided oral vitamin D 500 IU twice daily in yogurt from the beginning of the second trimester for 16 weeks (101775). However, other preliminary clinical research shows that giving vitamin D 300,000 IU as a single intramuscular injection at 24-28 weeks' gestation does not affect HbA1c (106124). Some research has examined the effect of vitamin D supplementation on insulin resistance during pregnancy in the absence of gestational diabetes. A meta-analysis of clinical research shows that taking vitamin D for 6 to 26 weeks modestly decreases measures of insulin resistance when compared with placebo. However, there was no evidence to suggest that higher doses were more beneficial than lower doses. Although this population did not have gestational diabetes, these results suggest that adequate vitamin D might be beneficial for its prevention (110821). Vitamin D has also been evaluated in combination with omega-3 fatty acids in adults with gestational diabetes. One study evaluated vitamin D in combination with eicosapentaenoic acid (EPA) 360 mg plus docosahexaenoic acid (DHA) 240 mg twice daily. There is some evidence that this combination offers benefit over vitamin D alone and plasma triglyceride levels were also improved (106122). Other clinical research in patients with gestational diabetes shows that taking vitamin D with omega-3 fatty acids 8,000 mg twice daily for 6 weeks modestly improves glycemic indices and most lipid markers when compared with placebo (106114). Vitamin D has also been evaluated for the prevention of gestational diabetes. A Cochrane analysis of one large clinical study shows that taking vitamin D during pregnancy does not lower the risk of gestational diabetes when compared with no supplementation (114587). In addition, a meta-analysis of population studies suggests that there is a U-shaped association between serum vitamin D concentrations and the risk of developing gestational diabetes, with serum concentrations between 40 and 90 nmol/L associated with the lowest risk (106109).
• Diabetic foot ulcers. It is unclear if oral vitamin D is beneficial for diabetic foot ulcers. Details: A meta-analysis of clinical research in patients with diabetic foot ulcers shows that taking vitamin D modestly reduces ulcer size and improves glycemic and lipid indices when compared with placebo (110835). This meta-analysis is limited by the availability of three small clinical trials, as well as the heterogeneous doses of vitamin D in the included studies.
• Diabetic nephropathy. Limited evidence suggests that vitamin D improves some markers of kidney function in patients with diabetic nephropathy. Details: A meta-analysis of small clinical studies in patients with diabetic nephropathy shows that taking vitamin D or its analogs reduces inflammatory markers and protein in the urine, but does not affect measures of kidney function such as serum creatinine or glomerular filtration rate, when compared to control (99771).
• Diabetic retinopathy. It is unclear if oral vitamin D is beneficial in diabetic retinopathy. Details: There is weak evidence from observational research suggesting a link between vitamin D deficiency and diabetic retinopathy (112095). However, clinical research addressing the effectiveness of vitamin D supplementation for treatment or prevention of diabetic retinopathy is lacking.
• Dysmenorrhea. Limited evidence suggests that oral vitamin D reduces pain in patients with dysmenorrhea. Details: A meta-analysis of 9 small clinical studies in patients with dysmenorrhea shows that taking vitamin D in doses ranging from 5000 IU daily to 300,000 IU monthly modestly reduces pain when compared with control (112029). However, the validity of these findings is limited by a high degree of heterogeneity across the studies, including differences in blinding and control interventions, vitamin D doses and frequency of supplementation, and baseline vitamin D levels. Another small clinical study in adolescent patients with dysmenorrhea shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces pain when compared to baseline (98912). The validity of this finding is limited by the lack of a control group.
• Erectile dysfunction (ED). It is unclear if oral vitamin D is beneficial for ED. Details: Although some data suggest ED is associated with low serum 25-hydroxy-vitamin D levels, preliminary research in males aged 60-84 years shows that taking vitamin D 60,000 IU once monthly for up to 5 years does not prevent or improve ED when compared with placebo (113580).
• Exercise-induced muscle damage. Small studies suggest that vitamin D does not improve exercise-induced muscle damage. Details: A meta-analysis of 6 small studies shows that taking vitamin D before and/or during exercise does not improve circulating levels of creatine kinase, lactate dehydrogenase, or myoglobin when compared with placebo (107218).
• Fall prevention. The role of vitamin D in fall prevention is confusing and controversial. Most clinical research shows that taking vitamin D 800-1000 IU daily decreases the risk of falls, with effects most apparent with daily over intermittent dosing and in those with vitamin D deficiency or insufficiency. Taking vitamin D at doses higher or lower than this may be associated with increased risk of falls. Details: Higher serum levels of vitamin D have been associated with improved lower-extremity function in elderly adults (15636). Clinical research in older adults shows that taking vitamin D or vitamin D analogues, with or without calcium, reduces the number of people who have a fall by up to 19% (39038,84215,84374,84539,94130,104023,113595,114504). Other research shows that vitamin D, with or without calcium, reduces number of falls by 19% to 50% (11939,16275,84404,93941,109053). The beneficial effect does not appear to depend on the form of vitamin D used (ergocalciferol, cholecalciferol, calcitriol, or alfacalcidol) (39038,84374,113595). Multiple meta-analyses of clinical research show that taking vitamin D leads to a decreased rate of falls in patients with low baseline levels of vitamin D, but not in those with adequate vitamin D levels (84670,84684,109053,114504). One meta-analysis also suggests that taking vitamin D as cholecalciferol up to 1000 IU daily reduces fall risk by up to 19%, whereas higher doses do not reduce fall risk (109053). Also, daily dosing, but not intermittent dosing, seems to be associated with a reduced risk of falling (109053,114504). Similarly, another meta-analysis of clinical research shows that taking vitamin D 800-1000 IU daily, with or without calcium, lowers the risk of falls by about 15-26% when compared with placebo, no treatment, or calcium alone. However, taking vitamin D 500 IU or less daily and vitamin D 1100 IU or more daily, with or without calcium, is not associated with a lower risk of falls and may even increase the risk of falls by 22-44% (114504). Despite the above meta-analyses, other clinical research shows that vitamin D does not reduce the risk of falling (84404,84670), the rate of falls overall (84670,93942), or the rate of injurious falls (93942) in elderly patients (93942). One study in adults over 70 years of age with a history of falling found that taking high-dose vitamin D, either as 60,000 IU monthly or 24,000 IU plus calcifediol 300 mcg monthly, increased both the risk of falling and the mean number of falls compared to a lower dose of 24,000 IU monthly (93940). One meta-analysis of 20 trials including nearly 30,000 patients shows that taking vitamin D, with or without calcium, does not reduce the risk of falling in elderly patients, regardless of baseline 25-hydroxyvitamin D levels, level of 25-hydroxyvitamin D achieved with treatment, duration of treatment, or residential status of the patients (91342). While a meta-analysis of 10 trials in nearly 6,000 patients shows that taking vitamin D 700-1000 IU daily with calcium 1000-2000 mg daily reduces the risk of falling in the elderly by 12% when compared with placebo or no treatment, a meta-analysis of 21 trials in nearly 52,000 patients shows that vitamin D alone is only associated with a reduced risk of falls in patients with baseline vitamin D levels of less than 50 nmol/L when compared with placebo or no treatment (107224). The 2018 US Preventative Services Task Force (USPSTF) guidelines for fall prevention acknowledges this research by recommending AGAINST vitamin D supplementation for fall prevention in community dwelling adults 65 years of age and older who do not have osteoporosis or vitamin D deficiency (95703). The reasons for the disparate study results may have to do with the way in which clinical trials have reported outcomes. Clinical trials assessing the effect of vitamin D on fall risk may report results as the number of patients who experience one or more falls, the total number of falls, or the rate of falls per individual. This can affect ultimate conclusions and, in some cases, can be misleading. For example, when studies report on only the total number of falls, it is unclear if vitamin D reduces the rate of falls across the study population, or if it only reduces falls in a small subset of patients. Also, analyses of research suggest that the size of the clinical study appears to affect the trial results. Most trials showing significant reductions in fall risk have been small and of short duration (91342,94132); whereas larger and longer-term studies tend to show no benefit (13073,84399).
• Fetal and premature infant mortality. Taking vitamin D during pregnancy might reduce the risk of fetal or early infant death. Details: A meta-analysis of clinical research shows that vitamin D supplementation during pregnancy reduces the risk of intrauterine or neonatal death by 31% when compared with not supplementing with vitamin D. A sub-analysis shows that this benefit was limited to doses of up to 4000 IU daily (109055). However, a Cochrane review suggests that the evidence linking vitamin D supplementation to a lower risk of fetal or neonatal death is very uncertain (114587). Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of intra-uterine and neonatal mortality, preeclampsia, preterm birth, and small for gestational age (SGA) birth. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Fibromyalgia. A small clinical study suggests that vitamin D might improve pain in patients with fibromyalgia. Details: A small clinical study in fibromyalgia patients with low vitamin D levels shows that taking vitamin D3 (cholecalciferol) 1200-2400 IU daily seems to reduce pain, but not mood or quality of life, when compared with placebo (91349).
• Food allergies. It is unclear if prenatal or infant oral vitamin D supplementation reduces the risk of developing food allergies. Details: A meta-analysis of two large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing food allergies when compared with low-dose vitamin D or no intervention (108438).
• Frailty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of frailty in older adults. Details: Frailty involves a combination of muscle loss and weakness, with exhaustion and reduced ability for physical activity. Some observational research has found that low vitamin D status is associated with frailty occurrence. However, clinical research in community dwelling older adults shows that taking vitamin D as 1000 IU, 2000 IU, or 4000 IU daily for 24 months does not prevent frailty or attenuate the worsening of frailty when compared with low-dose vitamin D 200 IU daily. Baseline vitamin D status did not affect these findings. Also, a sub-analysis suggests that vitamin D 2000 IU might increase frailty; however, only a small number of participants were randomized to this dose (109046). Other clinical research in community dwelling adults at least 70 years of age shows that taking cholecalciferol 2000 IU daily for 3 years does not reduce the odds of becoming pre-frail or frail over 36 months when compared with placebo. However, when taken in combination with omega-3 fatty acids 1 gram daily and a home exercise program, the odds of becoming pre-frail is reduced by 39% (110829).
• Generalized anxiety disorder (GAD). A small clinical study suggests that vitamin D may modestly improve anxiety in patients with GAD. Details: A small clinical study in patients with GAD shows that taking vitamin D 50,000 IU once weekly for 3 months, in addition to taking an antidepressant and an anxiolytic, moderately reduces anxiety scores when compared with taking these medications alone (103654).
• Hematopoietic stem cell transplant (HSCT). It is unclear if oral vitamin D is beneficial for improving outcomes in patients receiving HSCT. Details: A small clinical study in patients who have undergone an autologous HSCT shows that taking calcitriol 0.25 mcg three times daily for 30 days can reduce the time to absolute lymphocyte count recovery, but does not affect time to recovery of absolute neutrophil and platelet counts, when compared with placebo (103665).
• Hepatitis C. Low levels of vitamin D have been associated with an inadequate response to hepatitis C therapy. Adding vitamin D to standard therapy for hepatitis C may improve viral response, especially in specific genotypes. Details: A small clinical trial in patients with hepatitis C genotypes 2-3 receiving standard therapy with PEG-interferon and ribavirin shows that adding vitamin D 2000 IU daily for 24 weeks results in 95% of patients achieving undetectable levels of hepatitis C RNA, compared to only 77% of patients treated with standard therapy alone (98917). Another small clinical study in patients with hepatitis C genotype 1b receiving the same standard therapy shows that adding vitamin D 1000 IU daily for 16 weeks results in about 79% of patients achieving undetectable levels of hepatitis C RNA, compared to about 55% of patients treated with standard therapy alone. The TT genotype seems to be especially susceptible to vitamin D supplementation, while TG/GG genotype does not seem to be susceptible (98923).
• HIV/AIDS. It is unclear if oral vitamin D is beneficial for improving bone mineral density (BMD) in children and young adults with HIV. Details: Vitamin D deficiency and hyperparathyroidism are common in children and young adults with HIV. A meta-analysis of two clinical trials in this population shows that taking cholecalciferol for 12 months does not improve spine BMD when compared with placebo. Also, an analysis of two clinical trials shows that taking doses of 1600 IU to 4000 IU daily does not improve spine BMD when compared with taking doses of 400-800 IU daily. However, taking higher dose vitamin D has a small beneficial effect on total BMD when compared with taking lower doses. There was no improvement on parathyroid hormone levels (110824). This meta-analysis is limited by the availability of small clinical trials, as well as the heterogeneous doses of vitamin D used in the included studies.
• Hyperlipidemia. Although population research has found that higher vitamin D levels are associated with improved lipid levels, it is unclear if vitamin D supplementation is beneficial. Details: Population research has found that higher vitamin D levels are associated with lower low-density lipoprotein (LDL) cholesterol and triglyceride levels and higher high-density lipoprotein (HDL) cholesterol levels when compared with lower vitamin D levels (15630,98919). However, supplementation might not be beneficial. A meta-analysis of small clinical studies suggests that taking vitamin D as cholecalciferol, ergocalciferol, alfacalcidol, or calcitriol slightly increases LDL cholesterol, but does not affect total cholesterol, triglycerides, or HDL cholesterol, when compared with placebo (84642). The validity of these findings is limited by the variability in patient populations, vitamin D dose and formulation, and study duration. Also, none of the included studies were prospectively designed to test the effect of vitamin D on lipid levels. Another meta-analysis of clinical studies in a mixed population of healthy patients and patients with metabolic disease shows that taking vitamin D 1400-50,000 IU weekly with calcium 500-2000 mg daily results in very modest improvements in total cholesterol, triglyceride, and HDL cholesterol levels, but not LDL or very low-density lipoprotein (VLDL) cholesterol levels, when compared with placebo. Subgroup analyses suggest that effects are more pronounced in patients with metabolic disease (107227). The validity of these findings is limited by the heterogeneity of the included studies, which persisted throughout subgroup analyses.
• Hyperthyroidism. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research suggests that serum vitamin D levels are decreased in patients with newly diagnosed Graves' disease. A small preliminary clinical trial in patients with newly diagnosed Graves' disease taking methimazole and low levels of selenium and vitamin D shows that taking vitamin D as cholecalciferol for 270 days, in combination with selenium for the first 180 days, modestly reduces levels of serum free thyroxine and improves quality of life when compared with no vitamin D or selenium. However, taking vitamin D and selenium did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
• Hypothyroidism. It is unclear if oral vitamin D is beneficial in the treatment of subclinical hypothyroidism. Details: Preliminary clinical research in patients with vitamin D deficiency and subclinical hypothyroidism shows that taking vitamin D 50,000 IU weekly for 2-12 weeks decreases mean thyroid stimulating hormone levels by about 20% when compared with placebo, or by 3.55 mIU/L when compared to baseline (107213,113589).
• Ichthyosis. It is unclear if oral vitamin D is beneficial in patients with inherited ichthyosis. Details: A small clinical study in patients with congenital non-syndromic ichthyosis shows that taking vitamin D 2000 IU daily for 24 weeks reduces the clinical severity of disease at 12 weeks, but not 24 weeks, when compared with baseline. When compared with patients taking acitretin 0.5 mg/kg daily, results were similar at both 12 and 24 weeks, but it is unclear if the improvement from baseline differed between groups (108441).
• IgA vasculitis. It is unclear if oral alfacalcidol is beneficial in children with IgA vasculitis. Details: A clinical study in children with IgA vasculitis shows that taking alfacalcidol 0.25 mcg daily along with vitamin C, rutin, dipyridamole, cimetidine, calcium, and glucocorticoids for 4 weeks improves rates of recurrence and incidence of kidney damage when compared with those receiving the same regimen without alfacalcidol. Alfacalcidol also improves cellular immune function and reduces levels of inflammatory biomarkers (107212).
• Irritable bowel syndrome (IBS). It is unclear if oral vitamin D is beneficial for IBS; the available research is conflicting. Details: Although some meta-analyses show that taking vitamin D is moderately more effective than placebo for improving IBS symptom severity and quality of life, other analyses disagree. Doses of vitamin D have included 50,000 IU weekly or every 2 weeks or 2000-4000 IU daily for up to 6 months (109041,109054,109057). The reasons for these discrepancies might be attributed to the inclusion criteria related to the individual trials, the small sample sizes, and varied dosing strategies used in the available research.
• Kidney transplant. It is unclear if oral cholecalciferol is beneficial for improving allograft function or preventing non-skeletal complications in kidney transplant recipients. Details: Following a kidney transplant, patients are at increased risk of vitamin D insufficiency and related outcomes. A large clinical trial shows that taking a high dose of cholecalciferol for 2 years does not reduce the composite risk of developing type 2 diabetes, major cardiovascular events, or cancer, or death when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). The effect of a high dose of vitamin D on these outcomes individually is not clear. However, taking vitamin D does not seem to improve allograft function. A clinical study in kidney transplant recipients shows that taking cholecalciferol 4000 IU daily, beginning 1-month posttransplant and continuing for 11 months, has no effect on allograft function when compared with placebo (108425).
• Kidney transplant-related bone loss. Oral vitamin D might be beneficial for preventing bone loss associated with kidney transplantation. Details: A large clinical trial shows that taking a high dose of cholecalciferol for 2 years modestly reduces the odds of a fracture by 76% when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). A prespecified secondary analysis of a clinical study in patients at 1-month post-kidney transplant from a living donor in Japan shows that taking vitamin D (cholecalciferol) 4000 IU daily for months 1-12 posttransplant reduces whole blood parathyroid hormone levels by 15%, but does not alter levels of tartrate-resistant acid phosphatase 5-b or bone-specific alkaline phosphatase, when compared with placebo. The greatest effects on parathyroid hormone levels are observed in those with more severe vitamin D deficiency, hypocalcemia, and more preserved kidney function. Vitamin D supplementation also attenuates changes in bone mineral density (BMD) at the lumbar spine, but not the distal radius, from prior to transplant. Patients taking vitamin D had a loss of only 0.2%, compared with a loss of 2% in those receiving placebo. The greatest effects are observed in those with osteoporosis or osteopenia (107220). Conversely, a small clinical trial shows that taking calcitriol (1,25-dihydroxyvitamin D3) 0.25 mcg daily in combination with calcium carbonate 500 mg daily does not decrease bone loss associated with kidney transplantation. However, calcitriol might reduce osteoclast suppression, help maintain trabecular bone volume and wall thickness, and improve axial BMD (4823).
• Impaired glucose tolerance (prediabetes). Taking vitamin D might slow prediabetes progression to diabetes in people with low baseline levels of vitamin D or in people achieving high levels of vitamin D following supplementation. It is unclear if vitamin D supplementation is beneficial in people with prediabetes and sufficient vitamin D levels. Details: Observational research has found that low vitamin D levels are linked with a higher risk of prediabetes and higher dietary vitamin D is linked with a lower chance of developing diabetes (84594,103669). Meta-analyses and individual clinical studies in patients with prediabetes and unclear or sufficient vitamin D levels show that vitamin D supplementation might improve some glycemic indices, but does not seem to prevent progression of prediabetes to diabetes (84594,91347,99769,108421). However, a more recent meta-analysis of 3 clinical studies designed to evaluate the preventative effects of oral vitamin D shows that taking it in the form of cholecalciferol 4000 IU daily or 20,000 IU weekly or eldecalcitol 0.75 mcg daily reduces the risk of developing diabetes with an absolute risk reduction of 3.3% over 3 years when compared with placebo. However, the actual risk reduction is highly dependent on vitamin D status. Patients achieving the highest serum vitamin D levels have absolute 3-year risk reductions of 11.4% to 18.1% (110810). In patients with vitamin D deficiency and prediabetes, vitamin D might improve beta-cell function, suggesting reduced disease progression (99768,107210). One clinical study in adults with vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 3 months, and then monthly for 3 months, modestly improves insulin resistance and beta-cell function as measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), but does not affect fasting or postprandial glucose levels when compared with placebo (99768). Further, a meta-analysis of randomized controlled trials in patients with vitamin D deficiency and prediabetes shows that oral vitamin D at a median dose of 50,000 IU weekly for 26 weeks modestly improves fasting blood glucose and some markers of islet function, but not postprandial blood glucose or glycated hemoglobin (HbA1c) levels, when compared with control. Additionally, a significantly greater proportion of patients receiving vitamin D supplementation regressed from prediabetes to normal glucose status (107210). A meta-analysis of clinical studies in overweight or obese children and adolescents shows that high doses of vitamin D, 4000 IU daily or higher for 12-52 weeks, reduce HOMA-IR and C-reactive protein levels, but do not affect body weight, cholesterol, or parathyroid hormone (113596). A study in females with vitamin D deficiency and prediabetes shows that taking vitamin D 60,000 IU weekly for 8 weeks, followed by a maintenance dose of 200 IU daily, has no effect on the incidence of type 2 diabetes at 2 years (107211). Clinical practice guidelines from the Endocrine Society conditionally recommend, with moderate certainty of evidence, empiric vitamin D supplementation in addition to lifestyle modification for adults with high-risk prediabetes to reduce the risk of progression to diabetes. Empiric vitamin D supplementation is defined as vitamin D from supplements or fortified food above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Infant development. It is unclear if giving oral vitamin D in doses above the recommended dietary allowance during infancy is beneficial for improving neurodevelopment. It is also unclear if oral vitamin D during pregnancy is beneficial for improving cognitive development in the offspring. Details: Clinical research shows that giving vitamin D 1200 IU daily to healthy term infants of Northern European ethnicity starting at 2 weeks of age does not improve measures of neurodevelopment at 2 years of age when compared with giving the standard dose of vitamin D 400 IU (106121). Overall, the evidence from population research is mixed as to whether vitamin D status during gestation is associated with infant developmental outcomes. However, some population research has found that increased vitamin D status during pregnancy is associated with improved anthropomorphic and neurodevelopmental outcomes (104621,105724). Two meta-analyses of observational research show that low vitamin D status during pregnancy is associated with reduced head circumference and cognitive development scores, and higher odds of the offspring developing autism and attention deficit hyperactivity disorder (105724,105725). However, one meta-analysis suggests these risks may be limited to those with very low vitamin D status (serum level < 12 ng/mL) (105724). Multiple meta-analyses show that vitamin D status during pregnancy does not appear to affect motor development (105724,105725). In one observational study, plasma vitamin D concentrations in the second trimester of pregnancy was associated with increased IQ scores in the offspring at age 4-6 years. Each 10 ng/mL increase in vitamin D levels was associated with a 1.17-point increase in IQ (104621). In contrast, clinical research shows that taking vitamin D3 2800 IU daily during the third trimester does not improve neurodevelopmental outcomes in the first 6 years of life when compared to taking lower doses of 400 IU daily (104623).
• Infertility. It is unclear if oral or intramuscular vitamin D is beneficial in females with infertility. Details: Observational research in females undergoing in vitro fertilization suggests no association between dietary vitamin D intake and oocyte quality, successful embryo transfer, clinical pregnancy rate, or term pregnancy rate (112097). Additionally, a meta-analysis of clinical research in females with infertility shows that, although there was no effect of taking vitamin D on implantation rate or miscarriage, taking vitamin D increases the odds of clinical pregnancy by 49% when compared with placebo. However, sub-analyses of clinical and observational research found that benefits on clinical pregnancy rates were limited to populations with vitamin D insufficiency, but not vitamin D deficiency, and for doses between 1000 to 10,000 IU daily for 30-90 days (110818). Most studies included in the analysis used oral vitamin D; however, intramuscular vitamin D was used in one cohort study. A smaller meta-analysis of clinical studies in females with infertility and vitamin D insufficiency undergoing IVF shows that taking vitamin D increases the rate of chemical pregnancy by 50%, but has no effect on the clinical pregnancy rate (108432).
• Lichen planus. It is unclear if oral vitamin D is beneficial for lichen planus. Details: A small clinical study in patients with oral lichen planus and vitamin D deficiency or insufficiency shows that taking vitamin D 60,000 IU weekly in combination with systemic steroids for 1 month reduces pain severity and improves healing of lesions when compared with systemic steroids alone (114586). The validity of the study is limited by the lack of a placebo.
• Low birth weight. It is unclear if oral vitamin D can reduce the risk for low birth weight; the available evidence is conflicting. Details: A meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with lower birth weight and increased odds of SGA births. However, these risks have not been demonstrated in those with less severe vitamin D deficiency (serum level <20 ng/mL) (105724). Most research also shows that vitamin D supplementation during pregnancy reduces the risk of low birth weight. A meta-analysis of three clinical trials shows that supplementation with vitamin D 800-1000 IU daily starting between 27 and 32 weeks' gestation, or 200,000 IU administered as a single dose or in two divided doses during the seventh and eighth month of pregnancy, reduces the risk of delivering a low birth weight infant by 60% (84659). Other meta-analyses of clinical research show that supplementation with vitamin D during pregnancy results in a 31% to 60% reduced risk of low birth weight and a 103 gram greater average birth weight when compared with placebo or no intervention (99766,114587). However, some meta-analyses show that vitamin D supplementation during pregnancy does not reduce the risk of low birth weight when compared with no supplementation (95910,109055). One meta-analysis that included studies that did not directly measure birth weight shows no effect of vitamin D supplementation during pregnancy on the rate of low birth weight, despite showing an increase in overall birth weight of about 58 grams (95910).
• Lung cancer. It is unclear if oral vitamin D prevents lung cancer or improves lung cancer prognosis. Details: A small meta-analysis of randomized controlled trials and observational research has found that high intake of vitamin D is associated with a 10% reduction in the risk of developing lung cancer when compared with low vitamin D intake. In terms of prognosis, high vitamin D intake is associated with improvements in both overall survival and relapse-free survival (107217).
• Male infertility. It is unclear if oral cholecalciferol is beneficial in males with infertility. Details: A small clinical study in males with infertility shows that taking cholecalciferol 2500 IU daily for 6 months modestly improves progressive sperm motility, sperm concentration, and sperm morphology when compared with baseline (108427). The validity of these findings is limited by the lack of a comparator group.
• Melanoma. It is unclear if oral vitamin D is beneficial in patients with melanoma. Details: A meta-analysis of 14 observational studies suggests that vitamin D deficiency is associated with a 45% greater risk of melanoma when compared with normal vitamin D levels (112027). However, a small clinical study in patients with newly resected stage II melanoma shows that taking vitamin D3 100,000 IU every 50 days for 3 years does not improve disease-free survival when compared with placebo. Most patients in this study had vitamin D deficiency or insufficiency at baseline (106113).
• Metabolic syndrome. It is unclear if oral vitamin D is beneficial for preventing or treating metabolic syndrome. Details: In patients with metabolic syndrome, clinical research shows that taking vitamin D 50,000 IU weekly for 16 weeks does not affect most metabolic or anthropometric factors when compared with placebo, although there was a modest decrease in triglyceride levels (106123). However, almost all of the individuals in this study were vitamin D deficient or insufficient, and many remained in that category even after supplementation. It is unclear if vitamin D supplementation is beneficial in vitamin D sufficient patients with metabolic syndrome. There is conflicting evidence about the association between vitamin D and metabolic syndrome (14265,16713,98234). Some population research has found that higher vitamin D levels are associated with a lower risk of metabolic syndrome, while other research found no association (14265,16713). Furthermore, a small clinical trial in patients with metabolic syndrome shows that taking vitamin D 20,000 IU or 40,000 IU weekly for 8 weeks does not affect metabolic risk factors when compared with placebo (98234).
• Migraine headache. It is unclear if oral vitamin D reduces the frequency of migraine. Details: A meta-analysis of three small high-quality clinical studies in patients with migraine shows that taking vitamin D 2000 or 4000 IU daily for 12-24 weeks or 500,000 IU weekly for 2 months reduces the frequency of migraines by 2-3 attacks monthly when compared with usual care or placebo (108439).
• Miscarriage. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in pregnant adults with threatened miscarriage between the 6th and 13th week of gestation shows that taking a specific combination product (DAV HA, Lo.Li pharma s.r.l) containing vitamin D 50 mcg, alpha-lipoic acid, hyaluronic acid, magnesium, and vitamin B6 daily in combination with conventional treatment of vaginal progesterone over 2 weeks of observation results in a faster resorption of the subchorionic hematoma and faster decrease of patient-reported vaginal bleeding, abdominal pain, and uterine contractions when compared with vaginal progesterone alone (113893). It is unclear if these effects are due to vitamin D, other ingredients, or the combination. Additionally, the validity of these findings is limited by the lack of a placebo for the control group.
• Multiple sclerosis (MS). Although vitamin D supplementation has been linked with a lower risk of developing MS, taking oral vitamin D supplements does not seem to reduce MS relapses. Details: Vitamin D deficiency appears to be linked to the risk of MS development and progression. Population research suggests that long-term supplementation with vitamin D 400 IU is associated with a 40% lower risk of MS in females. The effect seems to be dose-dependent. Consumption of at least 400 IU daily, mainly in the form of a multivitamin supplement, appears to have the greatest protective effect (11356). Additional population research in over 7 million people suggests that higher levels of calcifediol are associated with a lower risk of developing MS. In white adults, for every 20 ng/mL increase in vitamin D levels, there appears to be a 41% decrease in MS risk. However, this was not found in black and Hispanic adults (15159). Vitamin D supplementation has also been examined in patients with MS. Population research suggests that taking vitamin D supplements and the maintenance of optimal blood levels of vitamin D are associated with a reduction in the development of new areas of demyelination detected by magnetic resonance imaging (MRI) over 24 months. However, there are no correlations between vitamin D consumption or vitamin D blood levels and clinical outcomes (110816). Also, vitamin D supplementation does not seem to impact MS relapses or most symptoms in patients with MS. Meta-analyses of preliminary clinical research show that vitamin D supplementation does not affect the rate of MS relapses, overall symptoms, disability scores, or the number of MS nerve lesions detected by MRI, regardless whether the vitamin D was low-dose or high-dose (98192,98914,106119,113586). However, one meta-analysis of 6 small clinical studies shows that taking vitamin D for 8-96 weeks slightly improves fatigue scores when compared with placebo (112024). These analyses are limited by the small size and heterogeneity of most of the included studies and variability in dosing and duration of vitamin D regimens.
• Muscle strength. It is unclear if oral vitamin D improves muscle strength in middle aged or older adults with low or sufficient levels of vitamin D. The available research is conflicting. Details: Clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not increase muscle strength when compared with placebo (11814,104619,108429). In patients 40-80 years of age with low vitamin D levels, taking vitamin D3 100,000 IU (2500 mcg) once, followed by 20,000 IU (500 mcg) weekly for 4 months, does not improve muscle strength when compared with placebo (103658). Similarly, meta-analyses of clinical research show that vitamin D does not increase grip strength, muscle mass, global muscle strength, or back extensor strength when compared with control (91341,113595). However, some research has found some benefit with the use of vitamin D supplements. One meta-analysis shows that taking vitamin D increases grip strength after menopause when compared with placebo or low-dose vitamin D, although a sub-analysis shows that beneficial effects are limited to individuals aged 60-69 years, when vitamin D is taken without calcium, when baseline vitamin D levels are at least 30 ng/mL, or when the treatment consists of the vitamin D analog alfacalcidol. This suggests heterogeneity between studies (109048). Another meta-analysis in elderly adults shows that taking vitamin D as calcifediol 10-30 mcg daily for a median of 24 weeks modestly improves hand grip strength and leg extension, but not leg flexion, when compared with baseline (109042). Also, some individual clinical research in older adults with low levels of vitamin D at baseline shows that taking vitamin D3 800 IU daily or vitamin D2 (ergocalciferol) 1000 IU daily for 12 months in combination with calcium 1000 mg daily modestly improves lower extremity or hip strength by 8% to 23% when compared with calcium alone (38915,84530).
• Myalgia. It is unclear if oral vitamin D is beneficial for reducing myalgia associated with obesity. Details: Preliminary clinical research in obese individuals with vitamin D deficiency who are on a low-calorie diet shows that taking vitamin D 50,000 IU weekly, alone or in combination with an aerobic exercise program three times weekly for 12 weeks, modestly reduces muscle pain when compared with only aerobic exercise three times weekly (106118).
• Myelodysplastic syndromes. It is unclear if oral vitamin D is beneficial for patients with myelodysplastic syndromes. Details: A small observational study in patients with myelodysplastic syndromes has found that taking calcitriol or calcifediol orally is associated with slowed disease progression (11825).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral or intramuscular vitamin D is beneficial in children or adults with NAFLD. Details: Although findings from individual research are mixed, one meta-analysis of mainly small clinical trials in patients with NAFLD shows that vitamin D modestly improves insulin resistance and serum alanine aminotransferase (ALT) levels, with no effect on serum aspartate aminotransferase (AST) levels. Most studies included in the analysis used oral vitamin D 1000 IU daily or 50,000 IU weekly or biweekly for 3-6 months and compared with placebo; however, one study used a single intramuscular injection of vitamin D 600,000 IU compared with lifestyle modifications (109056). Vitamin D has also been evaluated in combination with fish oil. A clinical study in adults with NAFLD shows that taking oral vitamin D3 1680 IU daily in combination with fish oil or fish oil alone for 3 months improves serum ALT levels similarly to a control group (107186). Vitamin D has also been evaluated for use in children with NAFLD. One clinical study in children with obesity and biopsy-proven NAFLD shows that taking oral vitamin D3 2000 IU daily for 6 months with a hypocaloric diet improves liver histopathology in terms of steatosis, lobular inflammation, and NAFLD activity score at 6 months, but not hepatocyte ballooning or fibrosis, when compared with baseline. These improvements were not seen in the group receiving placebo with a hypocaloric diet, but it is unclear if the improvement from baseline differed between groups (107222).
• Nonmelanoma skin cancer. It is unclear if oral vitamin D is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking vitamin D3 1000 IU daily for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking vitamin D3 with calcium 1200 mg daily as calcium carbonate reduces the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but has no effect on the risk of basal cell carcinoma. Vitamin D taken alone has no effect on the risk for either type of cancer (104622).
• Obesity. The evidence for the use of oral vitamin D in obesity is conflicting and unclear. Details: Population research has found that people with lower vitamin D levels are significantly more likely to be obese when compared to people with higher vitamin D levels (15630). Also, a large-scale, high-quality clinical trial in postmenopausal adults taking calcium 1000 mg plus vitamin D3 (cholecalciferol) 400 IU daily for 3 years shows that these patients are more likely to lose weight and maintain their weight when compared with those taking placebo. This beneficial effect is mainly seen in females who have inadequate intake of calcium, less than 1200 mg/day, before starting a calcium supplement (15604). However, other evidence suggests that vitamin D alone does not improve weight loss. One clinical trial shows that taking vitamin D3 2000 IU/day without calcium for 12 months does not increase weight loss when compared with placebo in overweight and obese postmenopausal adults who are deficient in vitamin D at baseline (91345).
• Orthostatic hypotension. It is unclear if oral vitamin D is beneficial for prevention of orthostatic hypotension. Details: A secondary analysis of a clinical study in older patients with vitamin D insufficiency who are at an increased risk for falls shows that taking vitamin D 1000-4000 IU daily for up to 2 years has no effect on the risk of orthostatic hypotension or orthostatic symptoms when compared with those receiving vitamin D 200 IU daily (107223).
• Osteoarthritis. It is unclear if oral vitamin D is beneficial for osteoarthritis. Details: The evidence for the use of vitamin D in osteoarthritis is conflicting. Some clinical research shows that taking vitamin D3 (cholecalciferol) 2000 IU daily, or at a higher dose to reach serum vitamin D levels over 36 ng/mL, for 2 years does not reduce knee pain or loss of cartilage when compared with placebo in patients with symptomatic osteoarthritis (84688). However, another clinical study shows that taking vitamin D3 daily for 10 days and then vitamin D3 60,000 IU monthly for 12 months modestly reduces pain and improves function when compared with placebo in patients with osteoarthritis and vitamin D insufficiency (98199). It is possible that higher doses of vitamin D have an effect on osteoarthritis, while lower doses do not. Due to this conflicting and low-quality evidence, the American College of Rheumatology (ACR) recommends against the use of vitamin D for any form of osteoarthritis (102114).
• Otitis media. It is unclear if oral vitamin D is beneficial in patients with otitis media. Details: The relationship between vitamin D status and otitis media is unclear. Population research has found that having otitis media is associated with lower blood levels of vitamin D; however, lower vitamin D levels were not associated with greater risk of otitis media (98194).
• Overactive bladder. It is unclear if oral vitamin D is beneficial for overactive bladder. Details: A large clinical trial in older males shows that taking vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the odds of weekly overactive bladder when compared with placebo. In males with low serum vitamin D, taking vitamin D reduces the odds of overactive bladder at 5 years by 49%, including 34% reduced odds of overactive bladder with urinary incontinence and 81% reduced odds of overactive bladder without incontinence. However, urinary incontinence while sleeping or napping was increased (109738).
• Overall mortality. Taking oral vitamin D alone does not seem to reduce mortality; however, there is some evidence that taking certain forms of vitamin D with calcium might have a modest benefit. Details: While higher vitamin D levels have been associated with a small reduction in mortality when compared with lower vitamin D levels (98187), clinical research shows that taking vitamin D does not reduce the risk of mortality. A comprehensive meta-analysis shows that vitamin D supplementation alone does not reduce all-cause mortality when compared to control (100900). However, giving vitamin D with calcium may modestly reduce the risk of mortality. Meta-analyses show a 4% to 9% reduced risk of mortality when trials of vitamin D alone and vitamin D with calcium are pooled together (16102,97296,98186,112022). Finally, some research suggests that the type of vitamin D supplementation might influence the results. A meta-analysis of clinical research found that vitamin D3 (cholecalciferol) with or without calcium reduces mortality risk by 6%, while alfacalcidol, calcitriol, and vitamin D2 (ergocalciferol) do not have benefit (84595,98186). Other clinical research suggests that vitamin D supplementation in older adults may reduce the risk of all-cause mortality by about 4%, with an estimated effect size of 6 fewer deaths per 1000 individuals. This finding informed the 2024 Endocrine Society Clinical Practice Guidelines on vitamin D for the prevention of disease in the general population. The Endocrine Society conditionally recommends, with moderate certainty of evidence, empiric vitamin D supplementation from fortified foods or vitamin D-containing supplements in the general population aged 75 years and older to potentially lower the risk of mortality. Empiric vitamin D is defined as vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status. For empiric supplementation and for those who have indications for vitamin D treatment or supplementation, daily lower-dose versus intermittent higher doses was suggested (114502).
• Pain (chronic). It is unclear if oral vitamin D is beneficial for chronic pain. Details: A meta-analysis of clinical research in patients with chronic pain shows that taking vitamin D for 1-24 months produces a 43% greater decrease in pain score when compared with placebo. However, the final follow-up pain score is similar for both groups (96402). The effect of vitamin D on pain based on pain-related diagnosis, vitamin D status, or dose is unknown.
• Parkinson disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Population research found that higher levels of vitamin D are associated with milder Parkinson disease symptoms, while deficiency is associated with increased risk of Parkinson disease (97000,99772). One small study shows that taking vitamin D3 (cholecalciferol) 1200 IU daily for one year might modestly slow the progression of Parkinson disease based on the Hoehn and Yars staging criteria. However, there was no improvement in disease severity according to the more widely used Unified Parkinson Disease Rating Stage (UPDRS). The UPDRS includes measures of activities of daily living and non-motor symptoms. Vitamin D had no effect on most quality of life measures (95915).
• Periodontitis. It is unclear if oral vitamin D is beneficial for periodontal disease. Details: A meta-analysis of mostly observational research suggests that vitamin D levels are not associated with an increased or decreased risk of periodontitis (112026). Other population research suggests that higher blood levels of vitamin D may be associated with a reduced risk of periodontal disease in adults 50 years of age or older. However, this association was not found for adults younger than 50 years (15634).
• Physical performance. It is unclear if oral vitamin D improves muscle strength in elderly adults. Details: Some clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not improve physical performance when compared with placebo (11814,104619,108429). Also, results from one meta-analysis of clinical research in postmenopausal females with low levels of vitamin D shows that taking vitamin D does not improve the timed up and go test when compared with placebo or low-dose vitamin D (109048). One meta-analysis that included studies specifically evaluating the use of calcifediol in older adults shows a large benefit on gait speed; however, only one study included in the analysis used this endpoint and other measures of physical performance were not affected (109042).
• Pneumonia. High-dose oral vitamin D does not reduce pneumonia severity in children. Details: Although vitamin D supplementation might prevent respiratory tract infections in children, it might not prevent recurrent pneumonia. A small clinical study in children under 5 years of age with recurrent pneumonia and variable vitamin D blood levels shows that taking vitamin D 300,000 IU quarterly for 1 year does not reduce respiratory infections, severity of pneumonia, hospital admissions, or disease complications when compared with placebo (103667). However, it's unknown if vitamin D supplementation using lower and more frequent doses, or supplementation in patients with vitamin D deficiency, might be beneficial. Some observational research has found that having vitamin D deficiency is linked to a higher risk for developing community-acquired pneumonia (CAP) (102118). For information on other respiratory infections, refer to the Respiratory Tract Infection discussion.
• Polycystic ovary syndrome (PCOS). It is unclear if vitamin D improves pregnancy outcomes and symptoms in patients with PCOS. Details: Observational research in adults with infertility, PCOS, and insulin resistance suggests that normal vitamin D levels are associated with better embryo quality and increased pregnancy rate when compared with vitamin D deficiency or insufficiency (100834). It is unclear if supplementation with vitamin D improves pregnancy rates in patients with PCOS. A meta-analysis of clinical research shows that taking vitamin D 400-12,000 IU daily for 2-6 months improves follicular development when compared with placebo. Taking vitamin D in combination with metformin 1500 mg daily also appears to increase the number of regular menstrual cycles by 85% when compared with metformin alone, but without an effect on follicular development (96404). A meta-analysis of 9 studies also shows that combining vitamin D with metformin improves menstrual cycle regulation and reduces homeostatic model assessment for insulin resistance (HOMA-IR), body mass index, and testosterone levels when compared with metformin alone (113594). Vitamin D alone does not appear to improve menstrual cycle regularity. A meta-analysis of several mostly low quality clinical studies in patients with PCOS and vitamin D deficiency at baseline shows that taking intramuscular or oral vitamin D 200-10,000 IU daily for up to 24 weeks in addition to fertility treatment improves pregnancy rates and reduces premature miscarriage and premature delivery, but does not impact the incidence of pregnancy complications including gestational hypertension or gestational diabetes mellitus, when compared with control. This analysis also suggests vitamin D supplementation improves certain IVF-related outcomes including ovulation rate, fertilization rate, and number of mature oocytes (112787). The effects of vitamin D on the metabolic profile of patients with PCOS have been evaluated. A small clinical study in patients with PCOS and vitamin D deficiency or insufficiency shows that taking vitamin D 2000 IU daily in combination with diet and exercise for 12 weeks reduces insulin resistance, body mass index, waist to hip ratio, serum triglycerides, and total and low-density lipoprotein cholesterol when compared with diet and exercise alone (114580). The interpretation of these results is limited by the lack of a placebo.
• Post-stroke fatigue. It is unclear if oral vitamin D is beneficial for post-stroke fatigue. Details: A retrospective study in patients with post-stroke fatigue and vitamin D deficiency suggests that vitamin D (cholecalciferol) 600 IU daily is associated with improvements in fatigue severity at months 1 and 3 when compared with control. Neurologic disability also showed improvement at 3 months, but not at 1 month, when compared with control. It is unclear if improvements from baseline differed between groups (107225).
• Pre-eclampsia. It is unclear if oral vitamin D during pregnancy is beneficial for the prevention or treatment of pre-eclampsia. Details: While some clinical research suggests that taking vitamin D during pregnancy does not reduce the risk of pre-eclampsia (113585,114587), clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small for gestational age (SGA) birth, and neonatal mortality. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Precocious puberty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of precocious puberty. Details: A meta-analysis of 43 mostly observational studies from China suggests that vitamin D deficiency or insufficiency is associated with 2.25-fold greater odds of precocious puberty when compared with normal vitamin D levels. Taking vitamin D 200-1000 IU daily for 3-12 months along with a gonadotropic-releasing hormone analog (GnRHa) is associated with lower luteinizing hormone, follicle-stimulating hormone, and estradiol levels and reduced bone age when compared with GnRHa therapy alone (112019). Another meta-analysis of 15 studies, mainly from China and with high heterogeneity and publication bias, suggests that there is a negative correlation between serum 25-hydroxy-vitamin D concentrations and precocious puberty, and that vitamin D deficiency increases the risk of precocious puberty by about 53% (113578).
• Pregnancy-induced hypertension. It is unclear if oral vitamin D is beneficial for patients with gestational hypertension. Details: Meta-analyses of two low-quality clinical trials show that vitamin D supplementation during pregnancy does not reduce the risk for gestational hypertension when compared with control (95910,114587).
• Prematurity. It is unclear if taking vitamin D during pregnancy prevents respiratory complications in preterm neonates. Details: A large clinical study in pregnant patients with gestational age less than 34 weeks and at risk of preterm delivery shows that a single intramuscular injection of vitamin D 50,000 IU within 72 hours before delivery decreases the risk of respiratory distress syndrome treated by surfactant in the neonate by about 2.25-fold and increases the 5th minute APGAR scores, but not 1st minute APGAR scores, gestational age, neonatal intensive care unit admission, length of hospital stay, or delivery method, when compared with no treatment (114581).
• Premenstrual syndrome (PMS). It is unclear if oral vitamin D is beneficial in patients with PMS. Details: Observational research has found that increasing dietary intake of vitamin D above 706 IU daily is linked to a reduced risk of developing PMS when compared with consuming 112 IU daily (13094). Furthermore, a clinical study shows that taking vitamin D 400 IU daily in combination with calcium 1000 mg daily can decrease the severity of PMS symptoms (16869). Another clinical study in adolescent females with PMS shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces PMS symptoms when compared to baseline (98912). A small clinical study in young adults with PMS and vitamin D deficiency shows that taking vitamin D 50,000 IU every 2 weeks for 16 weeks reduces psychological symptom scores by 54% and physical symptom scores by 39% when compared with placebo (113582).
• Preterm labor. It is unclear if oral vitamin D is beneficial for preterm labor. Details: Vitamin D deficiency, defined as serum levels less than 20 ng/mL, during pregnancy has been associated with a 25% greater risk of preterm birth (95911). The risk seems to be especially prominent in those with darker colored skin (103662). However, meta-analyses of clinical research show that vitamin D supplementation during pregnancy does not reduce the risk of a preterm birth when compared with no supplementation with vitamin D (84659,95910,109055,114587). The effect vitamin D specifically in vitamin D-deficient patients is still unclear. Some small, heterogeneous, and low-quality studies show that vitamin D supplementation might reduce the rate of preterm birth in vitamin D-deficient patients (84659,95910). Additional studies are needed to determine the effect of vitamin D supplementation on the risk of preterm birth. Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of preterm birth, small for gestational age (SGA) birth, preeclampsia, intra-uterine mortality, and neonatal mortality. Empiric vitamin D supplementation iss defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Rheumatoid arthritis (RA). Small clinical studies suggest that oral vitamin D may not improve symptoms in patients with RA. Details: Population research has found that higher intake of vitamin D from foods or supplements is associated with a lower risk of developing RA (12206,98200). However, a meta-analysis of two small clinical trials shows that vitamin D supplementation does not reduce pain or recurrence of RA when compared with placebo (98190).
• Rhinosinusitis. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients over 12 years of age with chronic sinusitis shows that taking 1 or 2 sachets of a specific combination product (Flogostop Forte, Humana Italia) containing vitamin D 600 IU, black currant, Boswellia serrata, and bromelain along with a nasal corticosteroid daily for 15-30 days reduces symptoms of nasal hyperemia and rhinorrhea when compared with corticosteroid nasal spray alone (111501). It is unclear if these findings are due to vitamin D, other ingredients, or the combination.
• Sarcopenia. It is unclear if oral vitamin D is beneficial in older adults with sarcopenia. Details: A meta-analysis of randomized trials in older adults with sarcopenia shows that taking vitamin D3 (cholecalciferol) 100-800 IU daily, with protein 10-44 grams daily or amino acids 2.5-6 grams daily, for 2-6 months moderately improves muscle strength, but not muscle mass or walking speed, when compared with placebo (105727). The validity of this study is limited by high heterogeneity and an unreported baseline vitamin D status. Similarly, a small network meta-analysis of randomized trials shows that taking vitamin D 500-1600 IU daily or 2500-5000 IU weekly with protein 20-80 grams daily or amino acids 3-32 grams daily with and without exercise for 3-18 months increases hand grip strength and shortens time to chair-stand, respectively, but not gait speed or lower-limb mass when compared with usual care (107221). It is unclear if these effects are due to vitamin D, protein/amino acid supplementation, exercise, or the combinations.
• Schizophrenia. It is unclear if oral vitamin D is beneficial for schizophrenia. Details: Based on preliminary clinical evidence, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is not recommended for adjunctive use in patients with schizophrenia (110318). A moderate-sized clinical study in patients with schizophrenia shows that taking a specific combination product (BioZenD, Tak Gen Zist Pharmaceutical Company) containing vitamin D 400 IU in combination with a blend of probiotics (Lactobacillus acidophilus, Lacticaseibacillus rhamnosus, Limosilactobacillus reuteri, Lacticaseibacillus paracasei, Bifidobacterium longum, Bacillus coagulans) 2 x 10⁹ CFU daily for 12 weeks improves cognitive function scores but does not improve the severity of positive and negative schizophrenia symptoms when compared with placebo (114582). It is unclear if this effect is due to vitamin D, the probiotics, or the combination.
• Sciatica. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary research in adults up to 45 years of age with discogenic sciatica shows that taking cholecalciferol 800 IU with alpha-lipoic acid, acetyl-L-carnitine, and resveratrol daily for 30 days, in combination with a 20-session rehabilitation protocol, improves pain, disability, and quality of life when compared with the supplements alone or the rehabilitation protocol alone (112933).
• Seasonal affective disorder (SAD). One small study suggests that a large dose of oral vitamin D can improve symptoms of SAD. Details: A small clinical study in patients with SAD suggests that a single dose of vitamin D2 (ergocalciferol) 100,000 IU improves symptoms after one month when compared to baseline (83791). The validity of this finding is limited by the lack of a control group.
• Seborrheic keratosis. It is unclear if topical vitamin D analogues improve symptoms of seborrheic keratosis. Details: Preliminary clinical research suggests that topical ointments containing activated vitamin D in the form of tacalcitol, calcipotriol or maxacalcitol, applied for 3-12 months, can reduce tumor volume by at least 40% in 75% of patients with seborrheic keratosis. Additionally, over 30% of patients seem to experience complete tumor resolution or a reduction in tumor volume of at least 80% (84033). The validity of this finding is limited by the lack of a control group.
• Sexual dysfunction. One small study suggests that injecting a large dose of vitamin D might improve sexual function. Details: A small clinical study in females with vitamin D deficiency and sexual dysfunction shows that receiving an intramuscular injection of vitamin D as cholecalciferol 300,000 IU once at baseline and a second time 4 weeks later improves sexual function at 4 and 8 weeks when compared with placebo (100896).
• Sickle cell disease. One small study suggests that oral vitamin D reduces pain and improves quality of life in children with sickle cell disease with vitamin D insufficiency or deficiency. Details: A small clinical study in children with sickle cell disease shows that taking vitamin D3 (cholecalciferol) 40,000-100,000 IU weekly for 6 weeks reduces days with pain and improves physical activity and quality of life for up to 6 months when compared with placebo. Of the children included in the study, 82.5% had vitamin D insufficiency, while 52.5% were deficient in vitamin D (98918). It is unclear if vitamin D is effective for patients with sickle cell disease who have adequate levels of vitamin D.
• Small for gestational age (SGA). It is unclear if oral vitamin D can reduce the risk for SGA births; the available evidence is conflicting. Details: Two meta-analyses of clinical research show no effect of vitamin D on the risk of SGA birth (84659,109055). However, one meta-analysis shows a 40% reduction in the risk of SGA births with vitamin D supplementation (95910). Also, one meta-analysis shows that when vitamin D supplementation is initiated before the 20^th week of gestation, the risk of SGA is reduced by 54% (109055). Most individual clinical trials are small and heterogeneous. Also, the formulation of vitamin D and/or vitamin D status at baseline may explain part of the discrepant findings. For example, a meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with increased odds of SGA births. This association does not seem to be present with less severe vitamin D deficiency (serum level <20 ng/mL) (105724). Clinical practice guidelines from the Endocrine Society conditionally recommend, with low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of SGA births, as well as preeclampsia, intra-uterine mortality, preterm birth, and neonatal mortality. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Statin-induced myalgia. It is unclear if oral vitamin D is beneficial for patients with statin-induced myalgia. Details: Observational research has found that taking oral vitamin D supplements is associated with decreased symptoms of myalgia in patients taking statin drugs. In a small case series, patients who discontinued statins due to myalgia were able to resume statin therapy after starting vitamin D supplements. The majority of patients with myalgia were found to be vitamin D deficient, with vitamin D levels less than 12 ng/mL at baseline (16829). An observational study has also found that administering 50,000 units of vitamin D2 (ergocalciferol) once a week for 12 weeks reversed symptoms of myalgia in 92% of statin treated patients with low serum vitamin D levels of less than 32 ng/mL (16831).
• Stroke. Although low vitamin D levels are associated with higher risk of stroke, taking vitamin D supplements does not seem to reduce stroke risk. Details: Population research has found that low vitamin D levels are associated with an increased risk of stroke. Furthermore, increased dietary intake of vitamin D is associated with a reduced risk of stroke (15630,16618,93944,97303,106106). However, clinical research shows that vitamin D supplementation does not reduce stroke risk. Several meta-analyses and randomized controlled trials show that taking vitamin D alone or with calcium does not reduce the risk of stroke in patients with or without cardiovascular disease risk factors (16616,91343,97296,97308,106106,112022). It is difficult to draw firm conclusions from these studies, as they did not assess whether patients had adequate vitamin D levels at baseline. It is unclear if vitamin D supplementation might prevent strokes in patients with vitamin D deficiency.
• Sunburn. Although there is interest in using oral vitamin D for the treatment of sunburns, there is insufficient reliable information about the clinical effects of vitamin D for this purpose.
• Systemic lupus erythematosus (SLE). It is unclear if oral vitamin D is beneficial in patients with SLE. Details: While some observational research has found that adults with SLE are more likely to have vitamin D deficiency than healthy controls (102119), a small cross-sectional study in females has found no association between serum levels of 25-hydroxyvitamin D, SLE disease activity, and the presence or absence of lupus nephritis (107214). A meta-analysis of three small clinical studies shows that taking vitamin D3 (cholecalciferol) 2000 IU daily or 50,000 IU weekly seems to reduce anti-dsDNA positive, a marker of disease activity, when compared with placebo in patients with SLE (98190). However, the clinical significance of this finding is unclear. A small clinical trial in females with SLE shows that taking vitamin D3 5000 IU daily for 12 weeks modestly improves overall disease activity, but not quality of life, when compared with placebo (109735).
• Thyroid cancer. It is unclear if oral vitamin D is beneficial in patients with thyroid cancer. Details: Observational research in patients undergoing thyroidectomy for differentiated thyroid cancer suggests that taking vitamin D daily for at least 6 months after surgery is associated with a 38% lower risk of all-cause mortality and a 33% lower risk of total cancer-related mortality when compared with no vitamin D supplementation at around 10 years' follow-up. However, vitamin D does not appear to be linked to a lower risk of thyroid cancer-related mortality in these patients (112018).
• Ulcerative colitis. Limited evidence suggests that vitamin D may be beneficial in patients with ulcerative colitis. Details: A meta-analysis of mainly small clinical trials in patients treated with mesalazine shows that taking vitamin D for up to 24 weeks modestly increases clinical efficacy and reduces disease score when compared with mesalazine alone (109044). Also, a meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). These findings are limited because of the heterogeneity of the included studies.
• Upper respiratory tract infection (URTI). It is unclear if oral vitamin D is beneficial for dementia. Details: A large clinical trial shows that taking vitamin D 2800 IU daily, starting at gestational week 24 and continuing until one week after birth, reduces the risk of the child developing croup by 3 years of age by 40% when compared with olive oil as placebo. This risk reduction did not change after adjusting for the use of omega-3 fatty acids 2.4 grams daily, as well as for concomitant persistent wheeze and/or lower respiratory tract infections (109304).
• Urinary incontinence. Limited evidence suggests that vitamin D may be beneficial in middle-aged, but not older, adults with urinary incontinence. Details: Clinical research in middle-aged premenopausal females with stress urinary incontinence and low vitamin D status shows that taking vitamin D 5000 IU once weekly for 12 weeks has a moderate to large beneficial effect on the severity of incontinence and quality of life when compared with placebo. Kegel exercises were performed by all participants (109736). However, vitamin D supplementation does not seem to be beneficial for reducing urinary incontinence in older adults. In older females and males, a large clinical trial shows that vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the incidence or progression of urinary incontinence when compared with placebo (109738,109741). In older males with low vitamin D status, vitamin D supplementation may actually increase some types of incontinence (109738).
• Urinary tract infections (UTIs). It is unclear if oral vitamin D is beneficial for the prevention of UTIs in children. Details: A meta-analysis of 13 small observational studies in children suggests that lower levels of vitamin D are associated with 2.8-fold greater odds of UTI when compared with higher vitamin D levels. Further, this analysis shows that vitamin D deficiency in children is linked to 5.5-fold greater odds of UTI when compared with normal vitamin D levels (112030).
• Urticaria. It is unclear if oral vitamin D is beneficial for the prevention or treatment of urticaria. Details: A meta-analysis of population research has found that having urticaria is associated with a slightly lower vitamin D blood level and a greater likelihood of vitamin D deficiency when compared with individuals without urticaria. In addition, a meta-analysis of 6 clinical trials shows that taking high-dose vitamin D at an average daily dose of at least 4100 IU has a modest effect on the severity of urticaria symptoms (106115).
• Uterine fibroids. Some evidence suggests that the risk of developing uterine fibroids is linked to vitamin D status, and that fibroid size is reduced by vitamin D supplements. However, it is unclear if oral vitamin D is beneficial for preventing the recurrence of uterine fibroids. Details: Observational research suggests that uterine fibroids are linked to vitamin D deficiency, with normal vitamin D levels associated with 32% lower odds of developing uterine fibroids. A meta-analysis of 5 clinical trials shows that taking vitamin D for at least 8 weeks reduces uterine fibroid size when compared with placebo. One clinical study shows that the recurrence rate for uterine fibroids is about 9% with vitamin D supplementation, compared with 18% without. However, a clinical study in patients with low vitamin D levels undergoing hysteroscopic myomectomy for uterine fibroids shows that taking vitamin D 1000 IU daily for 12 months does not improve the rate of recurrence when compared with placebo (108422).
• Vaginal atrophy. It is unclear if oral vitamin D is beneficial for vaginal atrophy. There is limited evidence on the topical use of vitamin D in vaginal atrophy in postmenopausal adults or patients taking tamoxifen. Details: A small cross-sectional study in postmenopausal adults has found that taking a vitamin D supplement for at least one year improves the maturation index of superficial vaginal wall cells when compared with those who do not take vitamin D. However, symptoms of vaginal atrophy were not different between groups (16879). Vitamin D has also been evaluated for vaginal atrophy due to tamoxifen. A small clinical trial in females with breast cancer using tamoxifen shows that receiving vitamin D 1000 IU vaginal suppositories daily for 8 weeks improves maturation index of vaginal walls and self-reported symptoms when compared with placebo (99773).
• Vertigo. It is unclear if oral vitamin D is beneficial in patients with vertigo. Details: An analysis of observational research suggests that lower serum levels of vitamin D are associated with a higher risk of benign paroxysmal positional vertigo (BPPV) when compared with higher vitamin D levels (114579). However, it is unclear if vitamin D supplementation can reduce the risk of BPPV in individuals with low vitamin D levels. Vitamin D has been evaluated in combination with other ingredients for the treatment of BPPV. A large clinical study in adults with recurrent BPPV shows that taking vitamin D 400 IU and calcium 500 mg twice daily for one year reduces the risk of recurrence by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 4 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination.
• Vitiligo. Although there is interest in using oral vitamin D for vitiligo, there is insufficient reliable information about the clinical effects of vitamin D for this condition.
• Warts. Although there is interest in using topical vitamin D derivatives for warts, there is insufficient reliable information about the clinical effects of vitamin D for this condition. More evidence is needed to rate vitamin D for these uses.

(Read more about VITAMIN D)

POSSIBLY EFFECTIVE

• Age-related macular degeneration (AMD). Oral zeaxanthin, when used in low levels as part of multi-ingredient products containing lutein, seems to improve some aspects of vision in patient with AMD. It is unclear if oral zeaxanthin alone or in amounts similar to lutein is beneficial for slowing AMD progression. Details: Epidemiological research has found that people who consume higher amounts of zeaxanthin plus lutein in the diet have a reduced risk of developing late AMD, but not early or intermediate AMD (60238,106353,106359). However, any association between intake of zeaxanthin itself and the development of AMD is not clear. Some clinical research has assessed whether zeaxanthin alone can reduce symptoms and progression of AMD. A small clinical trial shows that taking supplemental zeaxanthin 8 mg daily for 12 months modestly improves some aspects of vision, such as macular pigment optical density, the ability to see details of near objects (near vision acuity), and resolution of scotoma (blind spot), when compared with placebo in patients with AMD (60245). Other clinical research in a healthy population shows that taking zeaxanthin alone (Optisharp) as 10 mg daily for 6-12 months increases macular pigment optical density (60175). Most clinical research in patients with AMD has assessed zeaxanthin in combination with lutein. In general, this combination has been shown to increase macular pigment optical density, as well as the ability to see under low-contrast conditions (contrast sensitivity) and visual acuity. However, most research has used much higher doses of lutein compared with zeaxanthin (60281,91160,97225,106366,108615). Use of near equal amounts, such as zeaxanthin 8-10 mg daily plus lutein 9-10 mg daily for up to 2 years, seems to improve macular density in adults with or without AMD (60175,60268,60270,106358); however, effects on vision when used for up to 2 years in patients with AMD are conflicting (60245,60268,60270,106358). Zeaxanthin has also been evaluated in combination with other ingredients, with conflicting findings. A specific supplement (AZYR SIFI) containing zeaxanthin 1 mg, lutein 10 mg, vitamin C 180 mg, vitamin E 30 mg, zinc 22.5 mg, copper 1 mg, and astaxanthin 4 mg has been used daily for 1-2 years with moderate evidence of benefit (19196,60244). Taking zeaxanthin 2 mg plus lutein 10 mg in addition to the original Age-Related Eye Disease Study (AREDS) formulation (vitamins C and E, beta-carotene, and zinc) does not seem to prevent the progression to advanced AMD more than the AREDS formulation alone. However, this progression was modestly inhibited in individuals with low dietary intakes of lutein and zeaxanthin. While progression to late AMD was only modestly inhibited at 5 years when these doses of lutein and zeaxanthin were included in a revised formulation devoid of beta-carotene (60281), results of an additional 5 years of follow up showed that this revised formulation reduces the risk of progression to late AMD by 15% when compared with the formulation containing beta-carotene (108615). Clinical research shows that adding meso-zeaxanthin 10 mg to this revised AREDS formulation (AREDS2) does not further improve contrast sensitivity in patients with non-advanced AMD (106369). In first-generation offspring of parents with neovascular AMD, taking zeaxanthin 2 mg, lutein 10 mg, vitamin C 180 mg, vitamin E 30 mg, zinc 15 mg, and copper 1 mg daily for 6 months does not improve the macular pigment optical density (106347). Reasons for these discrepancies are not clear but may relate to the patient population, zeaxanthin dose, treatment duration, or other ingredients included in combination products.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral zeaxanthin is beneficial for attenuating cognitive decline in older adults. Details: Clinical research in adults 40-75 years old shows that taking zeaxanthin 2 mg with lutein 10 mg daily for 6 months improves some, but not all, measures of visual memory when compared with placebo. However, other measures of memory and cognitive function were not improved (109763). Also, preliminary clinical research in older adults shows that taking the same dose of zeaxanthin and lutein for one year modestly improves some measures of cognitive function, such as complex attention and cognitive flexibility, when compared with placebo (106367). Some observational research in patients 50 years and older has found that higher dietary lutein and zeaxanthin intake is associated with greater word recall when compared with lower intake (102891). However, clinical research in patients over 60 years old shows that taking zeaxanthin 2 mg with lutein 10 mg daily for 5 years in addition to vitamins C and E, beta-carotene, and zinc (AREDS) does not improve markers of cognitive function, such as memory and verbal fluency, when compared with AREDS alone (94702).
• Alzheimer disease. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking zeaxanthin 2 mg, lutein 10 mg, meso-zeaxanthin 10 mg, fish oil 1 gram (providing docosahexaenoic acid 500 mg and eicosapentaenoic acid 150 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 in the number of patients experiencing either an improvement or attenuated decline in memory and mood (109764). The effect of zeaxanthin alone is unclear.
• Asthenopia (eye strain). Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Results from one clinical trial show that taking a combination product (Cerebos Pacific Limited) containing zeaxanthin 1 mg, lutein 5 mg, and black currant extract 200 mg daily for 2 weeks modestly improves visual fatigue and eye stress when compared with placebo in patients completing a two-hour visual proof reading task (60214). The effect of zeaxanthin alone on eye strain is unclear.
• Asthma. It is unclear if oral zeaxanthin is beneficial for asthma prevention. Details: Population research has found that a higher dietary intake of zeaxanthin plus lutein is associated with up to 30% lower odds of having asthma when compared with a lower dietary intake (109765). The effects of zeaxanthin intake alone or zeaxanthin supplementation are unclear.
• Breast cancer. It is unclear if oral zeaxanthin is beneficial for breast cancer prevention. Details: Epidemiological research has found that higher serum levels of lutein plus zeaxanthin are associated with a reduced risk of developing breast cancer (10132). The effects of supplemental zeaxanthin are unclear.
• Bronchopulmonary dysplasia. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that giving preterm and low birth weight infants a specific product (LUTEINofta, SOOFT Italia SpA) containing zeaxanthin 0.0006 mg and lutein 0.14 mg orally once daily, starting at birth and continuing until 36 weeks' corrected gestational age, does not decrease the incidence of bronchopulmonary dysplasia when compared with placebo (91163). The effect of zeaxanthin alone is unclear.
• Cardiovascular disease (CVD). Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults 50-85 years old shows that taking lutein 10 mg plus zeaxanthin 2 mg daily for an average of 4.8 years does not decrease the risk of CVD-related mortality or cardiovascular events such as stroke, myocardial infarction, or angina when compared with no supplementation (94701). Individual cardiovascular outcomes were not separately evaluated in this study. The effect of zeaxanthin alone on CVD prevention is unknown.
• Cataracts. Increased levels of zeaxanthin in the blood seems to reduce the odds of developing cataracts. It is unclear if dietary or supplemental zeaxanthin is beneficial for cataract treatment or prevention. Details: Some population research has found that higher blood levels of zeaxanthin are associated with a 30% lower odds of developing age-related cataracts, and more specifically, a 37% decreased risk of developing nuclear cataracts (90944,91161). Population research has also found that higher dietary combined intake of lutein plus zeaxanthin is associated with lower odds of developing cataracts. However, any association between intake of zeaxanthin itself and the development of cataracts is unclear (91162). Clinical research shows that taking zeaxanthin 2 mg and lutein 10 mg daily orally, in addition to the Age-Related Eye Disease Study (AREDS) formulation containing vitamin C 500 mg, vitamin E 400 IU, beta-carotene 15 mg, zinc 80 mg, and copper 2 mg, for an average of 4.7 years decreases the risk of needing cataract surgery by 32% when compared with the AREDS formulation alone in patients with low dietary intake of lutein and zeaxanthin, but not in those with higher dietary intake of lutein and zeaxanthin (94703).
• Child development. It is unclear if oral zeaxanthin is beneficial for child development. Details: Epidemiological research has found that a higher dietary intake of zeaxanthin in the first and second trimesters of pregnancy is associated with increased verbal intelligence and improved behavior in the child at 6-10 years of age. However, the ability to discriminate between a novel or familiar visual stimulus was reduced at about 6 months of age, and there were no effects on most cognitive outcomes in children aged 3-6 years (107106). Other epidemiological research has found that a higher dietary intake of zeaxanthin plus lutein in children aged 3-6 years may be associated with modestly improved executive function at 6-11 years. However, there were no effects on most cognitive outcomes in children aged 3-6 years or 6-11 years (109761).
• Cognitive function. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in younger adults shows that taking zeaxanthin 2 mg and lutein 10 mg for one year modestly improves some measures of cognitive function, such as spatial memory, when compared with placebo (106348). Observational research has found that intake of choline and lutein plus zeaxanthin is positively associated with cognitive flexibility task performance speed. However, this association is not present with the intake of lutein plus zeaxanthin in the absence of choline (106354). The effect of zeaxanthin alone is unclear.
• Colorectal cancer. It is unclear if oral zeaxanthin is beneficial for colorectal cancer prevention. Details: Although some individual epidemiological research disagrees (3962), most research has found that dietary intake of lutein plus zeaxanthin is not associated with a reduced risk of developing colorectal cancer (34481,106372). However, any association with intake of zeaxanthin alone, as supplements or in the diet, is unclear.
• Diabetes. Observational research suggests that oral zeaxanthin may not be beneficial for the prevention of diabetes or diabetic complications. Details: Some epidemiological research has found that low serum levels of carotenoids, including zeaxanthin and lutein, are associated with impaired glucose tolerance (60161). Other population research has found that increased dietary intake of zeaxanthin plus lutein does not decrease the risk of developing type 2 diabetes (14004,97227). Other epidemiological research in patients with type 2 diabetes has found that an increased serum concentration of zeaxanthin is not associated with reduced cardiovascular mortality over 14 years (109768).
• Esophageal cancer. It is unclear if oral zeaxanthin is beneficial for esophageal cancer prevention. Details: Population research has found that people who consume higher combined amounts of zeaxanthin and lutein in the diet have a 29% lower risk of developing esophageal squamous cell cancer when compared with lower intake (91159). The effects of supplemental zeaxanthin are unclear.
• Fractures. It is unclear if oral zeaxanthin is beneficial for fracture prevention. Details: A meta-analysis of observational research has found that increased dietary intake of zeaxanthin and/or lutein is not associated with a reduced risk of hip fractures (97228). The effects of supplemental zeaxanthin are unclear.
• Gastric cancer. It is unclear if oral zeaxanthin is beneficial for gastric cancer prevention. Details: A meta-analysis of observational research has found that increased dietary intake of lutein and/or zeaxanthin is not associated with a reduced risk of developing gastric cancer (97231). The effects of supplemental zeaxanthin are unclear.
• Glaucoma. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with open-angle glaucoma shows that taking oral zeaxanthin 2 mg, lutein 10 mg, and meso-zeaxanthin 10 mg daily for 18 months increases macular pigment density, but does not affect visual function, when compared with placebo (109756).
• Hyperlipidemia. Although there has been interest in using oral zeaxanthin for hyperlipidemia, there is insufficient reliable information about the clinical effects of zeaxanthin for this condition.
• Lung cancer. It is unclear if oral zeaxanthin is beneficial for lung cancer prevention. Details: Epidemiological research has found that low serum levels of carotenoids, including zeaxanthin, are associated with an increased risk of lung cancer (12874). However, other epidemiological research has found that higher serum levels of zeaxanthin are not associated with a reduced risk of dying from lung cancer (39690,60160).
• Macular telangiectasia type 2. It is unclear if oral zeaxanthin is beneficial for macular telangiectasia type 2. Details: In patients with macular telangiectasia type 2, observational research has found that taking a specific combination of lutein 10 mg, meso-zeaxanthin 10 mg, and zeaxanthin 2 mg (MacuShield; Alliance Pharmaceuticals) for at least 6 months, with an average duration of 15.7 months, was associated with a stabilization of visual acuity. Also, the number and size of cavitations in the macula were reduced (106355).
• Metabolic syndrome. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research in females shows that the highest dietary intake of zeaxanthin plus lutein is associated with 54% reduced odds of developing metabolic syndrome when compared with the lowest intake. However, when supplements containing zeaxanthin plus lutein were included in the total intake, there was no association with metabolic syndrome (109760).
• Necrotizing enterocolitis (NEC). Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that giving preterm and low birth weight infants a specific product (LUTEINofta, SOOFT Italia SpA) containing zeaxanthin 0.0006 mg and lutein 0.14 mg orally once daily, starting at birth and continuing until 36 weeks' corrected gestational age, does not decrease the incidence of NEC when compared with placebo (91163).
• Non-Hodgkin lymphoma. It is unclear if oral zeaxanthin is beneficial for non-Hodgkin lymphoma prevention. Details: A meta-analysis of observational research has found that increased intake of zeaxanthin/lutein in the diet is associated with an 18% lower risk of developing non-Hodgkin lymphoma when compared with low dietary intake. However, no dose-response relationship was reported (97229). It is unknown if supplemental zeaxanthin has any effect on non-Hodgkin lymphoma risk.
• Pancreatic cancer. It is unclear if oral zeaxanthin is beneficial for pancreatic cancer prevention. Details: A meta-analysis of population research has found that increased dietary intake of zeaxanthin and/or lutein is not associated with a reduced risk of pancreatic cancer (97230). The effects of supplemental zeaxanthin are unclear.
• Parkinson disease. It is unclear if oral zeaxanthin is beneficial for Parkinson disease prevention. Details: Population research has found that people who consume higher amounts of zeaxanthin in the diet do not have a lower risk of developing Parkinson disease (91164). The effects of supplemental zeaxanthin are unclear.
• Pre-eclampsia. It is unclear if oral zeaxanthin is beneficial for the prevention of pre-eclampsia. Details: Some epidemiological research has found that the highest intake of lutein plus zeaxanthin during pregnancy is associated with 68% reduced odds of having pre-eclampsia when compared with the lowest intake (109762). The effects of zeaxanthin supplements are unclear.
• Prostate cancer. It is unclear if oral zeaxanthin is beneficial for prostate cancer prevention. Details: Epidemiological research has found that low serum levels of carotenoids, including zeaxanthin, are not associated with an increased risk of prostate cancer (12874). The effects of supplemental zeaxanthin are unclear.
• Respiratory tract infections. It is unclear if oral zeaxanthin is beneficial for the treatment or prevention of respiratory tract infections. Details: Epidemiological research has found that high serum levels of zeaxanthin are not associated with decreased incidence or severity of respiratory tract infections in the elderly (60152). The effects of supplemental zeaxanthin are unclear.
• Retinopathy of prematurity. Oral zeaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in preterm and low birth weight infants shows that giving a specific product (LUTEINofta, SOOFT Italia SpA) providing lutein 0.14 mg or 0.5 mg/kg plus zeaxanthin 0.0006 mg or 0.02 mg/kg orally once daily, starting at birth and continuing until 36-40 weeks' corrected gestational age, does not decrease the incidence or severity of retinopathy of prematurity when compared with placebo (60240,60243,91163,102889).
• Ulcerative colitis. It is unclear if oral zeaxanthin is beneficial for ulcerative colitis. Details: In patients in the remission phase of ulcerative colitis, observational research has found that a higher dietary intake of lutein plus zeaxanthin is associated with a reduced incidence of constipation, but not flatulence or feelings of urgency (tenesmus) (106362). The effects of supplemental zeaxanthin are unclear.
• Visual development. It is unclear if taking oral zeaxanthin during pregnancy can improve the visual acuity of the child. Details: Some observational research has found that the highest maternal plasma zeaxanthin levels at delivery are associated with a 38% lower risk of poor visual acuity in children at 3 years of age when compared with the lowest maternal zeaxanthin levels (102888). However, other epidemiological research has found that dietary intake of zeaxanthin plus lutein during the first or third trimesters of pregnancy is not associated with contrast vision or visual acuity in the child at 11-12 years of age (109759). The effects of zeaxanthin supplements are unclear. More evidence is needed to rate zeaxanthin for these uses.

(Read more about ZEAXANTHIN)

LIKELY SAFE ...when used orally and appropriately. BCAAs 12 grams daily have not been associated with significant adverse effects in studies lasting for up to 2 years (68,72,73,74,10117,10146,10147,37120,92643,97531,103351,103352). ...when used intravenously and appropriately. BCAAs are an FDA-approved injectable product (13309).

CHILDREN: LIKELY SAFE
when used orally in dietary amounts of 71-134 mg/kg daily (11120,13308).

CHILDREN: POSSIBLY SAFE
when larger, supplemental doses are used orally and appropriately for up to 6 months (13307,13308,37127).

PREGNANCY:
Insufficient reliable information available; avoid using amounts greater than those found in food. Although adverse effects have not been reported in humans, some animal research suggests that consumption of supplemental isoleucine, a BCAA, during the first half of pregnancy may have variable effects on birth weight, possibly due to abnormal placental development (103350).

LACTATION:
Insufficient reliable information available; avoid using amounts greater than those found in food. Although the safety of increased BCAA consumption during lactation is unclear, some clinical research suggests that a higher concentration of isoleucine and leucine in breastmilk during the first 6 months postpartum is not associated with infant growth or body composition at 2 weeks, 2 months, or 6 months (108466).

(Read more about BRANCHED-CHAIN AMINO ACIDS (BCAA))

LIKELY SAFE ...when used orally or intravenously and appropriately. Calcium is safe when used in appropriate doses (7555,12928,12946,95817). However, excessive doses should be avoided. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: Age 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg; 19-50 years, 2500 mg; 51+ years, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stone, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).

POSSIBLY UNSAFE ...when used orally in excessive doses. The National Academy of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 19-50 years, 2500 mg; 51 years and older, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Calcium is safe when used in appropriate doses (17506).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (945,1586,3263,3264,17506). The World Health Organization (WHO) recommends prescribing oral calcium supplementation 1.5-2 grams daily during pregnancy to those with low dietary calcium intake to prevent pre-eclampsia (97347).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the same daily tolerable upper intake level (UL) for calcium according to age independent of pregnancy status: 9-18 years, 3000 mg; 19-50 years, 2500 mg (17506). Doses over these amounts might increase the risk of neonatal hypocalcemia-induced seizures possibly caused by transient neonatal hypoparathyroidism in the setting of excessive calcium supplementation during pregnancy, especially during the third trimester. Neonatal hypocalcemia is a risk factor for neonatal seizures (97345).

(Read more about CALCIUM)

LIKELY SAFE ...when used orally and appropriately. Glutamine has been safely used in clinical research in doses up to 40 grams per day or 1 gram/kg daily (2334,2337,2338,2365,5029,5462,7233,7288,7293), (52288,52307,52308,52311,52313,52337,52349,52350,96516,97366). A specific glutamine product (Endari) is approved by the US Food and Drug Administration (FDA) (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 600 mg/kg daily in clinical trials (2363,2366,5448,5452,5453,5454,5458,7293,52272,52275), (52283,52289,52304,52306,52316,52341), (52359,52360,52371,52377,52381,52284,52385,52408,96637,96507,96516).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Glutamine has been shown to be safe in clinical research when used in amounts that do not exceed 0.7 grams/kg daily in children 1-18 years old (11364,46657,52321,52323,52363,86095,96517). A specific glutamine product (Endari) is approved by the US Food and Drug Administration for certain patients 5 years of age and older (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 0.4 grams/kg daily in clinical research (52338,96508). There is insufficient reliable information available about the safety of glutamine when used in larger amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods. There is insufficient reliable information available about the safety of glutamine when used in larger amounts as medicine during pregnancy or lactation.

(Read more about GLUTAMINE)

POSSIBLY SAFE ...when used orally and appropriately. L-arginine has been used safely in clinical studies at doses of up to 24 grams daily for up to 18 months (3331,3460,3595,3596,5531,5532,5533,6028,7815,7816)(8014,8473,13709,31943,91195,91196,91963,99264,99267,110380)(110387). A tolerable upper intake level (UL) for arginine has not been established, but the observed safe level (OSL) of arginine intake established in clinical research is 20 grams (31996). ...when used intravenously and appropriately. Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically and appropriately. L-arginine appears to be safe when 5 grams is applied as a topical cream twice daily for 2 weeks or when a dentifrice is used at a dose of 1.5% w/w for up to 2 years (14913,96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks (96807).

CHILDREN: POSSIBLY SAFE
when used orally in premature infants and children (8474,32286,96803,97392,110391). ...when used intravenously and appropriately (97392). Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically, short-term. A dentifrice containing L-arginine appears to be safe when used at a dose of 1.5% w/w for up to 2 years in children at least 3.7 years of age (96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks in children at least 13 years of age (96807).

CHILDREN: POSSIBLY UNSAFE
when used intravenously in high doses. Parenteral L-arginine is an FDA-approved prescription product (15). However, when higher than recommended doses are used, injection site reactions, hypersensitivity reactions, hematuria, and death have occurred in children (16817).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term. L-arginine 12 grams daily for 2 days has been used with apparent safety in pregnancy during the third trimester (11828). L-arginine 3 grams daily has been taken safely during the second and/or third trimesters (31938,110379,110382). ...when used intravenously and appropriately, short-term. Intravenous L-arginine 20-30 grams daily has been used safely in pregnancy for up to 5 days (31847,31933,31961,31978).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about L-ARGININE)

LIKELY SAFE ...when used orally and appropriately. Consuming up to 20 mg of lutein daily from both dietary and supplemental sources appears to be safe (3219,3220,60167). Lutein supplements have been safely used in clinical trials at doses of up to 20 mg daily for up to 10 years (11798,60133,60177,94703,94701,100986,104570,107107,108615,109763).

CHILDREN: LIKELY SAFE
when used orally and appropriately. A specific product containing lutein (LUTEINofta, SOOFT Italia SpA) has been used with apparent safety in infants at a dose of 0.14 mg daily for 36 weeks (91163).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately in amounts found in foods. The high end of dietary lutein intake ranges from 6.9-11.7 mg/day (3219,3220).

(Read more about LUTEIN)

LIKELY SAFE ...when used orally in doses up to 100 mEq total potassium daily, not to exceed 200 mEq in a 24-hour period (95010,107989). Oral potassium chloride and potassium citrate are FDA-approved prescription products (95010,107989). Larger doses increase the risk of hyperkalemia (15). ...when administered intravenously (IV) at appropriate infusion rates (95011). Parenteral potassium is an FDA-approved prescription product (15,95011). A tolerable upper intake level (UL) for potassium has not been established; however, potassium levels should be monitored in individuals at increased risk for hyperkalemia, such as those with kidney disease, heart failure, and adrenal insufficiency (100310,107966).

CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established for healthy individuals (6243,100310).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in dietary amounts of 40-80 mEq daily (15). A tolerable upper intake level (UL) has not been established for healthy individuals (100310).

(Read more about POTASSIUM)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Quercetin has been used with apparent safety in doses up to 1 gram daily for up to 12 weeks (481,1998,1999,16418,16429,16430,16431,96774,96775,96782)(99237,102539,102540,102541,104229,104679,106498,106499,107450,109620)(109621). ...when used intravenously and appropriately. Quercetin has been used with apparent safety in doses less than 945 mg/m2. Higher doses have been reported to cause nephrotoxicity (9564,16418). There is insufficient reliable information available about the safety of quercetin when used topically.

POSSIBLY UNSAFE ...when used intravenously in large amounts. Doses greater than 945 mg/m2 have been reported to cause nephrotoxicity (9564,16418).

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

(Read more about QUERCETIN)

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)

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

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

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

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

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

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

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

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

(Read more about VITAMIN D)

LIKELY SAFE ...when used orally and appropriately in doses of up to 2 mg daily. Zeaxanthin supplements have been safely used in clinical trials at doses of up to 2 mg daily for up to 10 years (94701,94702,94703,108615).

POSSIBLY SAFE ...when used orally and appropriately in amounts greater than 2 mg daily. Zeaxanthin supplements in doses of 8-10 mg daily for up to 12 months have been used with apparent safety in clinical trials (60175,60245).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. A specific product containing zeaxanthin (LUTEINofta, SOOFT Italia SpA) has been used with apparent safety in infants at a dose of 0.0006 mg daily for 36 weeks (91163). There is insufficient reliable information available about the safety of zeaxanthin at higher doses or in older children.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately in amounts found in foods. Zeaxanthin is found in breast milk and levels correlate with infant status (106365). There is insufficient reliable information available about the safety of supplemental zeaxanthin.

(Read more about ZEAXANTHIN)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, BCAAs might alter the effects of antidiabetes medications.  Details Some evidence suggests that BCAAs might stimulate insulin release (10105,10110,10113,10114,10118). However, a small clinical study in adults with liver cirrhosis and high nocturnal levels of blood glucose suggests that BCAAs might increase blood glucose levels (103348).

LEVODOPA Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B BCAAs in large doses can reduce the effects of levodopa.  Details BCAAs may compete with levodopa for transport systems in the intestine and brain and decrease the effectiveness of levodopa (66,2719). Small clinical studies how that concomitant ingestion of protein or high doses of leucine or isoleucine (100 mg/kg) and levodopa can exacerbate tremor, rigidity, and the "on-off" syndrome in patients with Parkinson disease (3291,3292,3293,3294).

(Read more about BRANCHED-CHAIN AMINO ACIDS (BCAA))

ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium citrate might increase aluminum absorption and toxicity. Other types of calcium do not increase aluminum absorption.  Details Calcium citrate can increase the absorption of aluminum when taken with aluminum hydroxide. The increase in aluminum levels may become toxic, particularly in individuals with kidney disease (21631). However, the effect of calcium citrate on aluminum absorption is due to the citrate anion rather than calcium cation. Calcium acetate does not appear to increase aluminum absorption (93006).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium reduces the absorption of bisphosphonates.  Details Advise patients to take bisphosphonates at least 30 minutes before calcium, but preferably at a different time of day. Calcium supplements decrease absorption of bisphosphonates (12937).

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking calcipotriene with calcium might increase the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (12938). Theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcemia.

CALCIUM CHANNEL BLOCKERS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Intravenous calcium may decrease the effects of calcium channel blockers; oral calcium is unlikely to have this effect.  Details Intravenous calcium is used to decrease the effects of calcium channel blockers in the management of overdose. Intravenous calcium gluconate has been used before intravenous verapamil (Isoptin) to prevent or reduce the hypotensive effects without affecting the antiarrhythmic effects (6124). But there is no evidence that dietary or supplemental calcium when taken orally interacts with calcium channel blockers (12939,12947).

CEFTRIAXONE (Rocephin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Co-administration of intravenous calcium and ceftriaxone can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys.  Details Avoid administering intravenous calcium in any form, such as parenteral nutrition or Lactated Ringers, within 48 hours of intravenous ceftriaxone. Case reports in neonates show that administering intravenous ceftriaxone and calcium can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys. In several cases, neonates have died as a result of this interaction (15794,21632). So far there are no reports in adults; however, there is still concern that this interaction might occur in adults.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Using intravenous calcium with digoxin might increase the risk of fatal cardiac arrhythmias.  Details Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (12940). However, one retrospective analysis of clinical data suggests that intravenous calcium does not increase the risk of dysrhythmias or mortality in patients receiving digoxin (38960).

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of diltiazem.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, calcium might increase this risk of hypercalcemia and reduce the effectiveness of diltiazem.

DOLUTEGRAVIR (Tivicay) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of dolutegravir.  Details Advise patients to take dolutegravir either 2 hours before or 6 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium carbonate 1200 mg concomitantly with dolutegravir 50 mg reduces plasma levels of dolutegravir by almost 40%. Calcium appears to decrease levels of dolutegravir through chelation (93578).

ELVITEGRAVIR (Vitekta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of elvitegravir.  Details Advise patients to take elvitegravir either 2 hours before or 2 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium along with elvitegravir can reduce blood levels of elvitegravir through chelation (94166).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption and effectiveness of levothyroxine.  Details Advise patients to take levothyroxine and calcium supplements at least 4 hours apart. Calcium reduces levothyroxine absorption, probably by forming insoluble complexes (5082). Calcium carbonate supplements reduce effectiveness of levothyroxine in patients with hypothyroidism (5081,5082,6137).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of calcium and lithium may increase this risk of hypercalcemia.  Details Clinical research suggests that long-term use of lithium may cause hypercalcemia in 10% to 60% of patients (38953). Theoretically, concomitant use of lithium and calcium supplements may further increase this risk.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption of quinolone antibiotics.  Details Advise patients to take oral quinolones at least 2 hours before or 4-6 hours after calcium supplements or calcium-fortified foods. Taking calcium at the same time as oral quinolones can reduce quinolone absorption. Calcium binds to quinolones in the gut (4412,10339,21638,38570).

RALTEGRAVIR (Isentress) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Calcium may reduce levels of raltegravir.  Details Pharmacokinetic research shows that taking a single dose of calcium carbonate 3000 mg along with raltegravir 400 mg twice daily modestly decreases the mean area under the curve of raltegravir, but the decrease does not necessitate a dose adjustment of raltegravir (94164). However, a case of elevated HIV-1 RNA levels and documented resistance to raltegravir has been reported for a patient taking calcium carbonate 1 gram three times daily plus vitamin D3 (cholecalciferol) 400 IU three times daily in combination with raltegravir 400 mg twice daily for 11 months. It is thought that calcium reduced raltegravir levels by chelation, leading to treatment failure (94165).

SOTALOL (Betapace) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium seems to reduce the absorption of sotalol.  Details Advise patients to separate doses by at least 2 hours before or 4-6 hours after calcium. Calcium appears to reduce the absorption of sotalol, probably by forming insoluble complexes (10018).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium seems to reduce the absorption of tetracycline antibiotics.  Details Advise patients to take oral tetracyclines at least 2 hours before, or 4-6 hours after calcium supplements. Taking calcium at the same time as oral tetracyclines can reduce tetracycline absorption. Calcium binds to tetracyclines in the gut (1843).

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure.  Details Thiazides reduce calcium excretion by the kidneys (1902). Using thiazides along with moderately large amounts of calcium carbonate increases the risk of milk-alkali syndrome (hypercalcemia, metabolic alkalosis, renal failure). Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of verapamil.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, use of calcium supplements may increase this risk of hypercalcemia and reduce the effectiveness of verapamil.

(Read more about CALCIUM)

ANTICONVULSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, glutamine might antagonize the effects of anticonvulsant medications.  Details Glutamine is metabolized to the excitatory neurotransmitter glutamate. Glutamate might have antagonistic effects with anticonvulsant drugs (7292,7293,7294). However, this interaction has not yet been reported in humans.

(Read more about GLUTAMINE)

ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use of L-arginine and ACE inhibitors may increase the risk for hypotension and hyperkalemia.  Details Combining L-arginine with some antihypertensive drugs, especially ACE inhibitors, seems to have additive vasodilating and blood pressure-lowering effects (7822,20192,31854,31916). Furthermore, ACE inhibitors can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218). Theoretically, concomitant use of ACE inhibitors with L-arginine may increases the risk of hyperkalemia.

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use of L-arginine and ARBs may increase the risk of hypotension and hyperkalemia.  Details L-arginine increases nitric oxide, which causes vasodilation (7822). Combining L-arginine with ARBs seems to increase L-arginine-induced vasodilation (31854). Furthermore, ARBs can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218). Theoretically, concomitant use of ARBs with L-arginine may increases the risk of hyperkalemia.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of L-arginine with anticoagulant and antiplatelet drugs might have additive effects and increase the risk of bleeding.  Details Preliminary research suggests that L-arginine infusions reduce platelet aggregation in humans (32260,31864,32239,32220,32257,32263,32276,32188). The clinical significance of this effect is unclear.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of L-arginine might have additive effects with antidiabetes drugs.  Details Preliminary clinical research shows that L-arginine decreases blood glucose levels in patients with type 2 diabetes (31964,32085,31964,104225).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use of L-arginine and antihypertensive drugs may increase the risk of hypotension.  Details L-arginine increases nitric oxide, which causes vasodilation (7822). Clinical evidence shows that L-arginine can reduce blood pressure in some individuals with hypertension (7818,10636,31871,32201,32167,32225,31923,32232,110383,110384). Furthermore, combining L-arginine with some antihypertensive drugs seems to have additive vasodilating and blood pressure-lowering effects (7822,20192,31854,31916).

ISOPROTERENOL (Isuprel) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, concurrent use of isoproterenol and L-arginine might result in additive effects and hypotension.  Details Preliminary clinical evidence suggests that L-arginine enhances isoproterenol-induced vasodilation in patients with essential hypertension or a family history of essential hypertension (31932).

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically concomitant use of potassium-sparing diuretics with L-arginine may increases the risk of hyperkalemia.  Details Potassium-sparing diuretics can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218).

SILDENAFIL (Viagra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of sildenafil and L-arginine might increase the risk for hypotension.  Details In vivo, concurrent use of L-arginine and sildenafil has resulted in increased vasodilation (7822,8015,10636). Theoretically, concurrent use might have additive vasodilatory and hypotensive effects. However, in studies evaluating the combined use of L-arginine and sildenafil for erectile dysfunction, hypotension was not reported (105065).

TESTOSTERONE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of L-arginine and testosterone might have additive effects.  Details In clinical research, L-arginine increases the level of testosterone in male patients with erectile dysfunction (102586,104222). The clinical significance of this finding is unclear.

(Read more about L-ARGININE)

(Read more about LUTEIN)

ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = C Using ACEIs with high doses of potassium increases the risk of hyperkalemia.  Details ACEIs block the actions of the renin-angiotensin-aldosterone system and reduce potassium excretion (95628). Concomitant use of these drugs with potassium supplements increases the risk of hyperkalemia (15,23207). However, concomitant use of these drugs with moderate dietary potassium intake (about 3775-5200 mg daily) does not increase serum potassium levels (95628).

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = C Using ARBs with high doses of potassium increases the risk of hyperkalemia.  Details ARBs block the actions of the renin-angiotensin-aldosterone system and reduce potassium excretion (95628). Concomitant use of these drugs with potassium supplements increases the risk of hyperkalemia (15,23207). However, concomitant use of these drugs with moderate dietary potassium intake (about 3775-5200 mg daily) does not increase serum potassium levels (95628).

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = C Concomitant use increases the risk of hyperkalemia.  Details Using potassium-sparing diuretics with potassium supplements increases the risk of hyperkalemia (15).

(Read more about POTASSIUM)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of quercetin and antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research suggests that a combination of quercetin, myricetin, and chlorogenic acid reduce levels of fasting glucose in patients with type 2 diabetes, including those already taking antidiabetes agents (96779). The effect of quercetin alone is unknown.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking quercetin with antihypertensive drugs might increase the risk of hypotension.  Details Quercetin can modestly decrease blood pressure in people with mild hypertension (16424,96780). Theoretically, it might have additive blood pressure lowering effects when used with antihypertensive drugs.

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the levels and adverse effects of cyclosporine.  Details A small study in healthy volunteers shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of a single dose of cyclosporine, possibly due to inhibition of p-glycoprotein or cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporin (16434).

CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of CYP2C8 substrates.  Details In vitro research shows that quercetin inhibits CYP2C8 (16432,16435). Inhibition of paclitaxel (Taxol) metabolism via CYP2C8 has been reported in vitro (16436). However, a small study in humans found no effect of quercetin on rosiglitazone (Avandia), which is also a CYP2C8 substrate (16432).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the levels and adverse effects of CYP2C9 substrates.  Details A small clinical study in healthy volunteers shows that taking quercetin 500 mg twice daily for 10 days prior to taking diclofenac, a CYP2C9 substrate, increases diclofenac plasma levels by 75% and prolongs the half-life by 32.5% (97931). Animal research also shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of losartan (Cozaar), a substrate of CYP2C9 (100968). Furthermore, laboratory research shows that quercetin inhibits CYP2C9 (15549,16433).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of CYP2D6 substrates.  Details In vitro research show that quercetin inhibits CYP2D6 (15549,16433). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might alter the effects and adverse effects of CYP3A4 substrates.  Details A small clinical study in healthy volunteers shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of a single dose of cyclosporine (Neoral, Sandimmune), a substrate of CYP3A4 (16434). Animal research also shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of losartan (Cozaar) and quetiapine (Seroquel), substrates of CYP3A4 (100968,104228). Other laboratory research also shows that quercetin inhibits CYP3A4 (15549,16433,16435). However, one clinical study shows that quercetin can increase the metabolism of midazolam, a substrate of CYP3A4, and decrease serum concentrations of midazolam by about 24% in some healthy individuals, suggesting possible induction of CYP3A4 (91573).

DICLOFENAC (Voltaren, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use might increase the levels and adverse effects of diclofenac.  Details A small clinical study in healthy volunteers shows that taking quercetin 500 mg twice daily for 10 days prior to taking diclofenac increases diclofenac plasma levels by 75% and prolongs the half-life by 32.5%. This is thought to be due to inhibition of CYP2C9 by quercetin (97931).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of losartan and decrease the effects of its active metabolite.  Details Animal research shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of losartan (Cozaar) while decreasing plasma levels of losartan's active metabolite. This metabolite, which is around 10-fold more potent than losartan, is the result of cytochrome P450 (CYP) 2C9- and CYP3A4-mediated transformation of losartan. Additionally, in vitro research shows that quercetin may inhibit P-glycoprotein-mediated efflux of losartan from the intestines, resulting in increased absorption of losartan (100968). These results suggest that concomitant use of quercetin and losartan might increase systemic exposure to losartan while also decreasing plasma concentrations of losartan's active and more potent metabolite.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might decrease the levels and effects of midazolam.  Details A small clinical study in healthy volunteers shows that quercetin can increase the metabolism of midazolam, with a decrease in AUC of about 24% (91573).

MITOXANTRONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin might increase the effects and adverse effects of mitoxantrone.  Details In vitro research shows that quercetin increases the intracellular accumulation and cytotoxicity of mitoxantrone, possibly through inhibition of breast cancer resistance protein (BCRP), of which mitoxantrone is a substrate (107897). So far, this interaction has not been reported in humans.

ORGANIC ANION TRANSPORTER 1 (OAT1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of OAT1 substrates.  Details In vitro research shows that quercetin is a strong non-competitive inhibitor of OAT1, with half-maximal inhibitory concentration (IC50) values less than 10 mcM (104454). So far, this interaction has not been reported in humans.

ORGANIC ANION TRANSPORTER 3 (OAT3) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of OAT3 substrates.  Details In vitro research shows that quercetin is a strong non-competitive inhibitor of OAT3, with half-maximal inhibitory concentration (IC50) values as low as 0.75 mcM (104453,104454). So far, this interaction has not been reported in humans.

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of OATP substrates.  Details In vitro evidence shows that quercetin can inhibit organic anion-transporting peptide (OATP) 1B1-mediated uptake of estrone-3-sulfate and pravastatin (91581). Furthermore, clinical research in healthy males shows that intake of quercetin along with pravastatin increases the AUC of pravastatin by 24%, prolongs its half-life by 14%, and decreases its apparent clearance by 18%, suggesting that quercetin modestly inhibits the uptake of pravastatin in hepatic cells (91581).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might alter the effects and adverse effects of P-glycoprotein substrates.  Details There is preliminary evidence that quercetin inhibits the gastrointestinal P-glycoprotein efflux pump, which might increase the bioavailability and serum levels of drugs transported by the pump (16433,16434,16435,100968,104228). A small study in healthy volunteers reported that pretreatment with quercetin increased bioavailability and plasma levels after a single dose of cyclosporine (Neoral, Sandimmune) (16434). Also, two small studies have shown that quercetin might decrease the absorption of talinolol, a substrate transported by the gastrointestinal P-glycoprotein efflux pump (91579,91580). However, in another small study, several days of quercetin treatment did not significantly affect the pharmacokinetics of saquinavir (Invirase) (16433). The reason for these discrepancies is not entirely clear (91580). Until more is known, use quercetin cautiously in combination with P-glycoprotein substrates.

PRAVASTATIN (Pravachol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of pravastatin.  Details In vitro evidence shows that quercetin can inhibit OATP 1B1-mediated uptake of pravastatin (91581). Also, preliminary clinical research in healthy males shows that intake of quercetin along with pravastatin increases the maximum concentration of pravastatin by 24%, prolongs its half-life by 14%, and decreases its apparent clearance by 18%, suggesting that quercetin modestly inhibits the uptake of pravastatin in hepatic cells (91581).

PRAZOSIN (Minipress) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin might increase the effects and adverse effects of prazosin.  Details In vitro research shows that quercetin inhibits the transcellular efflux of prazosin, possibly through inhibition of breast cancer resistance protein (BCRP), of which prazosin is a substrate. BCRP is an ATP-binding cassette efflux transporter in the intestines, kidneys, and liver (107897). So far, this interaction has not been reported in humans.

QUETIAPINE (Seroquel) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of quetiapine.  Details Animal research shows that pretreatment with quercetin can increase plasma levels of quetiapine and prolong its clearance, possibly due to inhibition of cytochrome P450 3A4 (CYP3A4) by quercetin. Additionally, the brain-to-plasma ratio of quetiapine concentrations increased, possibly due to inhibition of P-glycoprotein at the blood-brain barrier (104228). This interaction has not been reported in humans.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might inhibit the effects of quinolone antibiotics.  Details In vitro, quercetin binds to the DNA gyrase site on bacteria (481), which may interfere with the activity of quinolone antibiotics.

SULFASALAZINE (Azulfidine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin might increase the effects and adverse effects of sulfasalazine.  Details Animal research shows that quercetin increases the maximum serum concentration (Cmax) and area under the curve (AUC) of sulfasalazine, possibly through inhibition of breast cancer resistance protein (BCRP), of which sulfasalazine is a substrate (107897). So far, this interaction has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin may increase the risk of bleeding if used with warfarin.  Details Animal and in vitro studies show that quercetin might increase serum levels of warfarin (17213,109619). Quercetin and warfarin have the same human serum albumin (HSA) binding site, and in vitro research shows that quercetin has stronger affinity for the HSA binding site and can theoretically displace warfarin, causing higher serum levels of warfarin (17213). Animal research shows that taking quercetin for 2 weeks before initiating warfarin increases the maximum serum level of warfarin by 30%, the half-life by 10%, and the overall exposure by 63% when compared with control. Concomitant administration of quercetin and warfarin, without quercetin pre-treatment, also increased these measures, but to a lesser degree. Researchers theorize that inhibition of CYP3A4 by quercetin may explain these effects (109619). So far, this interaction has not been reported in humans.

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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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ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin D might increase aluminum absorption and toxicity, but this has only been reported in people with renal failure.  Details The protein that transports calcium across the intestinal wall can also bind and transport aluminum. This protein is stimulated by vitamin D, which may therefore increase aluminum absorption (11595,11597,22916). This mechanism may contribute to increased aluminum levels and toxicity in people with renal failure, when they take vitamin D and aluminum-containing phosphate binders chronically (11529,11596,11597).

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin D might reduce absorption of atorvastatin.  Details A small, low-quality clinical study shows that taking vitamin D reduces levels of atorvastatin and its active metabolites by up to 55%. However, while atorvastatin levels decreased, total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels did not substantially change (16828). Atorvastatin is metabolized in the gut by CYP3A4 enzymes, and researchers theorized that vitamin D might induce CYP3A4, causing reduced levels of atorvastatin. However, this proposed mechanism was not specifically studied.

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Taking calcipotriene with vitamin D increases the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (15). Theoretically, combining calcipotriene with vitamin D supplements might increase the risk of hypercalcemia.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Vitamin D might induce CYP3A4 enzymes and reduce the bioavailability of CYP3A4 substrates.  Details There is some concern that vitamin D might induce CYP3A4. In vitro research suggests that vitamin D induces CYP3A4 transcription. Additionally, observational research has found that increased UV light exposure and serum vitamin D levels are associated with decreased serum levels of CYP3A4 substrates such as tacrolimus and sirolimus, while no association between UV light exposure or vitamin D levels and levels of mycophenolic acid, a non-CYP3A4 substrate, was found (110539). A small, low-quality clinical study shows that taking vitamin D reduces levels of the CYP3A4 substrate atorvastatin and its active metabolites by up to 55%; however, the clinical effects of atorvastatin were not reduced (16828). While researchers theorized that vitamin D might induce CYP3A4, this proposed mechanism was not specifically studied.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hypercalcemia induced by high-dose vitamin D can increase the risk of arrhythmia from digoxin.  Details High doses of vitamin D can cause hypercalcemia. Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (15). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and digoxin concurrently.

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of diltiazem for arrhythmia.  Details High doses of vitamin D can cause hypercalcemia. Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically this could also occur with diltiazem. Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and diltiazem concurrently.

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking thiazide diuretics and high-dose vitamin D can increase the risk of hypercalcemia.  Details Thiazide diuretics decrease urinary calcium excretion, which could lead to hypercalcemia if vitamin D supplements are taken concurrently (3072,11541,69580). This has been reported in people being treated with vitamin D for hypoparathyroidism, and also in elderly people with normal parathyroid function who were taking a thiazide, vitamin D, and calcium-containing antacids daily (11539,11540).

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of verapamil for arrhythmia.  Details Hypercalcemia due to high doses of vitamin D can reduce the effectiveness of verapamil in atrial fibrillation (10574). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and verapamil concurrently.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking zeaxanthin with antidiabetes drugs might increase the risk of hypoglycemia.  Details In an animal diabetic model, zeaxanthin has hypoglycemic effects (106363). However, population research has found that increasing intake of dietary zeaxanthin plus lutein does not decrease the risk of developing type 2 diabetes (14004,97227).

(Read more about ZEAXANTHIN)

General ...Orally or intravenously, BCAAs are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal distension, diarrhea, nausea, vomiting.
All routes of administration: High doses can lead to fatigue and loss of motor coordination.

Cardiovascular ...Orally, a single case of hypertension following the use of BCAAs has been reported (37143).

Dermatologic ...Orally, a single case of skin blanching following the use of BCAAs has been reported (681). It is not known if this effect was due to use of BCAAs or other factors.

Gastrointestinal ...Orally, BCAAs can cause nausea, vomiting, diarrhea, and abdominal distension. Nausea and diarrhea has been reported to occur in about 10% of people taking BCAAs (10117,37143,92643,97531).

Neurologic/CNS ...Orally and intravenously, BCAAs can cause fatigue and loss of motor coordination due to increased plasma ammonia levels (693,694,10117). Short-term use of 60 grams of BCAAs containing leucine, isoleucine, and valine for 7 days in patients with normal metabolic function seems to increase levels of ammonia, but not to toxic plasma levels (10117). However, liver function should be monitored with high doses or long-term use (10117). Due to the potential of increased plasma levels of ammonia and subsequent fatigue and loss of motor coordination, BCAAs should be used cautiously before or during activities where performance depends on motor coordination (75). Orally, BCAAs may also cause headache, but this has only been reported in one clinical trial (681).

(Read more about BRANCHED-CHAIN AMINO ACIDS (BCAA))

General ...Orally and intravenously, calcium is well-tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Belching, constipation, diarrhea, flatulence, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about calciphylaxis and kidney stones.

Cardiovascular ...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).

Gastrointestinal ...Orally, calcium can cause belching, flatulence, nausea, gastrointestinal discomfort, and diarrhea (1824,1843,12950,38803). Although constipation is frequently cited as an adverse effect of calcium, there is no scientific substantiation of this side effect (1824,1843,1844,1845,12950,38978). Calcium carbonate has been reported to cause acid rebound, but this is controversial (12935,12936).

Oncologic ...There is some concern that very high doses of calcium might increase the risk of prostate cancer. Some epidemiological evidence suggests that consuming over 2000 mg/day of dietary calcium might increase the risk for prostate cancer (4825,12949). Additional research suggests that calcium intake over 1500 mg/day might increase the risk of advanced prostate cancer and prostate cancer mortality (14132). Consumption of dairy products has also been weakly linked to a small increase in prostate cancer risk (98894). However, contradictory research suggests no association between dietary intake of calcium and overall prostate cancer risk (14131,14132,104630). More evidence is needed to determine the effect of calcium, if any, on prostate cancer risk.

Renal ...Kidney stones have been reported in individuals taking calcium carbonate 1500 mg daily in combination with vitamin D 2000 IU daily for 4 years (93943).

(Read more about CALCIUM)

General ...Orally and intravenously, glutamine is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, bloating, constipation, cough, diarrhea, flatulence, gastrointestinal pain, headache, musculoskeletal pain, nausea, and vomiting.

Endocrine ...One case of hot flashes has been reported in a patient taking glutamine 5-15 grams orally twice daily for up to 1 year (96520).

Gastrointestinal ...Orally, glutamine has been associated with belching, bloating, constipation, flatulence, nausea, vomiting, diarrhea, and gastrointestinal (GI) pain. Nausea, vomiting, constipation, diarrhea, and GI pain have been reported in clinical trials using high-dose glutamine 10-30 grams (0.3 grams/kg) in two divided doses daily to treat sickle cell disease (99414). One case of dyspepsia and one case of abdominal pain have been reported in patients taking glutamine 5-15 grams twice daily orally for up to 1 year (96520). In a small trial of healthy males, taking a single dose of about 60 grams (0.9 grams/kg of fat free body mass [FFM]) was associated with a 50% to 79% incidence of GI discomfort, nausea, and belching, compared with a 7% to 28% incidence with a lower dose of about 20 grams (0.3 gram/kg FFM). Flatulence, bloating, lower GI pain, and urge to regurgitate occurred at similar rates regardless of dose, and there were no cases of heartburn, vomiting, or diarrhea/constipation (105013). It is possible that certain GI side effects occur only after multiple doses of glutamine.

Musculoskeletal ...Orally, glutamine 30 grams daily has been associated with cases of musculoskeletal pain and non-cardiac chest pain in clinical trials for patients with sickle cell disease (99414).

Neurologic/CNS ...Orally, glutamine has been associated with dizziness and headache. A single case of dizziness has been reported in a patient treated with oral glutamine 0.5 grams/kg. However, the symptom resolved after reducing the dose to 0.25 grams/kg (91356). Mania and hypomania have been reported in 2 patients with bipolar disorder taking commercially purchased glutamine up to 4 grams daily (7291). Glutamine is metabolized to glutamate and ammonia, both of which might have neurological effects in people with neurological and psychiatric diseases or in people predisposed to hepatic encephalopathy (7293).

Oncologic ...There is some concern that glutamine might be used by rapidly growing tumors and possibly stimulate tumor growth. Although tumors may utilize glutamine and other amino acids, preliminary research shows that glutamine supplementation does not increase tumor growth (5469,7233,7738). In fact, there is preliminary evidence that glutamine might actually reduce tumor growth (5469).

Other ...Orally, glutamine has been associated with cough when a powdered formulation is used. It is unclear if this was due to accidental inhalation. One case of a burning sensation and one case of hypersplenism has been reported in a patient taking glutamine 5-15 grams twice daily orally for up to 1 year (96520).

(Read more about GLUTAMINE)

General ...Oral, intravenous, and topical L-arginine are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, nausea, diarrhea, headache, insomnia, flushing.
Intravenously: Excessively rapid infusion can cause flushing, headache, nausea and vomiting, numbness, and venous irritation.

Cardiovascular ...L-arginine taken orally by pregnant patients in a nutrition bar containing other antioxidants was associated with a 36% greater risk of palpitations when compared with a placebo bar (91197). It is unclear if this effect was due to L-arginine, other ingredients, or other factors.

Dermatologic ...Orally, arginine can cause flushing, rash, and hives (3460,32138,102587,104223). The skin reactions were likely of allergic etiology as oral L-arginine has been associated with eosinophilia (32138). In one case report, intravenous administration caused allergic reactions including urticaria, periorbital edema, and pruritus (11830). Excessively rapid infusion of L-arginine has caused flushing, local venous irritation, numbness. Extravasation has caused necrosis and superficial phlebitis (3330,16817).

Gastrointestinal ...Orally, L-arginine has been reported to cause nausea, diarrhea, vomiting, dyspepsia, gastrointestinal discomfort, and bloating (1363,31855,31871,31972,31978,32261,90198,91197,96811,99243)(102587,102592).
Orally, L-arginine has been reported to cause esophagitis in at least six adolescents. Symptoms, which included pain and dysphagia, occurred within 1-3 months of treatment in most cases (102588). There are at least two cases of acute pancreatitis possibly associated with oral L-arginine. In one case, a 28-year-old male developed pancreatitis after consuming a shake containing 1.2 grams of L-arginine daily as arginine alpha-ketoglutarate. The shake also contained plant extracts, caffeine, vitamins, and other amino acids. Although there is a known relationship between L-arginine and pancreatitis in animal models, it is not clear if L-arginine was directly responsible for the occurrence of pancreatitis in this case (99266).
Intravenously, excessively rapid infusion of L-arginine has been reported to cause nausea and vomiting (3330,16817).

Musculoskeletal ...Intravenous L-arginine has been associated with lower back pain and leg restlessness (32273). Orally, L-arginine has been associated with asthenia (32138).

Neurologic/CNS ...Orally, L-arginine has been associated with headache (31855,31955,32261,91197,102587,102592), insomnia, fatigue (102587,102592), and vertigo (32150,102592).

Oncologic ...In breast cancer patients, L-arginine stimulated tumor protein synthesis, which suggests stimulated tumor growth (31917).

Pulmonary/Respiratory ...When inhaled, L-arginine can cause airway inflammation and exacerbation of airway inflammation in asthma (121). However, two studies assessing oral L-arginine in patients with asthma did not detect any adverse airway effects (31849,104223).

Renal ...Intravenously, L-arginine has been associated with natriuresis, kaliuresis, chloruresis, and systemic acidosis (32225). Orally, L-arginine can cause gout (3331,3595).

Other ...Orally, L-arginine has been associated with delayed menses, night sweats, and flushing (31855).

(Read more about L-ARGININE)

General ...Orally, dietary and supplemental lutein is generally well tolerated. Doses up to 20 mg daily have not resulted in adverse effects.

(Read more about LUTEIN)

General ...Orally or intravenously, potassium is generally well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, belching, diarrhea, flatulence, nausea, and vomiting.
Serious Adverse Effects (Rare):
All ROAs: High potassium levels can cause arrhythmia, heart block, hypotension, and mental confusion.

Cardiovascular ...Orally or intravenously, high potassium levels can cause hypotension, cardiac arrhythmias, heart block, or cardiac arrest (15,16,3385,95011,95626,95630).

Gastrointestinal ...Orally or intravenously, high doses of potassium can cause, nausea, vomiting, abdominal pain, diarrhea, and flatulence (95010,95011). Bleeding duodenal ulcers have also been associated with ingestion of slow-release potassium tablets (69625,69672).

Neurologic/CNS ...Orally or intravenously, high potassium levels can cause paresthesia, generalized weakness, flaccid paralysis, listlessness, vertigo, or mental confusion (15,16,3385,95011).

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General ...Orally and intravenously, quercetin seems to be well tolerated in appropriate doses. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

Gastrointestinal ...Intravenous administration of quercetin is associated with nausea and vomiting (9564).

Neurologic/CNS ...Orally, quercetin may cause headache and tingling of the extremities (481,111500). Intravenously, quercetin may cause pain at the injection site. Injection pain can be minimized by premedicating patients with 10 mg of morphine and administering amounts greater than 945 mg/m² over 5 minutes (9564). In addition, intravenous administration of quercetin is associated with flushing and sweating (9564).

Pulmonary/Respiratory ...Intravenous administration of quercetin at doses as high as 2000 mg/m² is associated with dyspnea that may persist for up to 5 minutes (9564).

Renal ...Intravenously, nephrotoxicity has been reported with quercetin in amounts greater than 945 mg/m² (9563,9564,70304).

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

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

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

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

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

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

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

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

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

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

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General ...Orally, dietary and supplemental zeaxanthin are generally well tolerated. No adverse effects have been reported in clinical research.

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