GQ-6 Rekuvr Nite Time by Unique

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. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies show that intake of calcium supplements or dietary calcium modestly reduces 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 salt-sensitive people and patients with low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221). Also, a meta-analysis of clinical research shows that calcium intake during pregnancy reduces systolic blood pressure in offspring by 1-2 mmHg (38852). 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 supplement 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).
• 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 in high risk pregnancies, especially if calcium intakes are low. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces pregnancy-related hypertension and pre-eclampsia (973,1833,8828,39043,39319,39426,96480). Calcium appears to reduce the risk of pre-eclampsia by about 50% when compared with placebo. One meta-analysis of 19 controlled trials involving over 29,000 pregnancies found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (96480). Calcium appears to have the greatest effect in individuals at high-risk of pre-eclampsia or with low calcium levels, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,96480,99714). 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. 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 supplementation 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low, in order to prevent pre-eclampsia (97347).
• 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 does not seem to be beneficial for breast cancer prevention. Details: Although some population research disagrees (15631,39041,95811,107237), most research shows that increased calcium intake is not associated with a reduced risk of breast cancer (15631,16715,98895,107236,107237). Subgroup analyses of population research suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237). Another subgroup analysis in a large meta-analysis of population research also suggests that dietary intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most other 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: The most recent and robust meta-analysis of clinical research shows that calcium supplementation with or without vitamin D is NOT associated with reduced fractures in older adults without osteoporosis (95822). A large-scale study in postmenopausal females aged 50-79 years suggests 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 Women's Health Initiative study found that, in older females with the lowest genetic susceptibility to low bone mineral density (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. 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), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). The most recent 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).

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).
• 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 oral calcium is beneficial for type 2 diabetes prevention. Details: Some population research has found that a higher intake of calcium from 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). However, population research is often limited by confounding variables. For example, one analysis found that any beneficial effect might be influenced by concomitant magnesium intake (96473). 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. This study is limited because it was not determined whether increased serum calcium was due to increased calcium intake or another factor such as parathyroid function (95815).
• 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).
• 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).
• Hypercholesterolemia. It is unclear if oral calcium is beneficial for hypercholesterolemia. Details: Some evidence shows that taking calcium carbonate 400 mg three times daily reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% after 6 weeks of treatment when used in combination with a low-fat diet (American Heart Association Step 1) (2557). In contrast, a study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years might INCREASE total cholesterol levels by about 12 mg/dL when compared with placebo. This same study showed an association between calcium supplementation and an increase in total cholesterol levels and carotid intimal thickness in postmenopausal females, but not premenopausal females (97350). A recent meta-analysis of randomized controlled trials which included both healthy patients and patients with 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 more effective in patients with dyslipidemia at baseline. It is unclear if this effect is due to calcium, vitamin D, or the combination (107227). However, other research shows that taking a specific supplement containing calcium 600 mg plus vitamin D 200 IU (Caltrate 600 D, Wyeth Consumer Healthcare Inc.) twice daily in combination with calorie restriction does not reduce total or LDL cholesterol levels when compared with placebo (15601).
• 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).
• 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)

EFFECTIVE

• Bowel preparation. Various magnesium salts are used for cleansing the bowel prior to procedures such as colonoscopy. Details: Various magnesium salts, including citrate, hydroxide, oxide, and sulfate, are ingredients in bowel preparation products available over-the-counter or by prescription only.
• Constipation. Magnesium salts are effective when used orally to treat constipation short-term. It is unclear if magnesium is beneficial for chronic idiopathic constipation (CIC). Details: Magnesium citrate, sulfate, and hydroxide salts are commonly used as laxatives. Magnesium citrate 8.75-25 grams has been used; magnesium hydroxide 2.4-4.8 grams, as 30-60 mL of milk of magnesia, has also been used (15). Magnesium sulfate, which seems to have the most potent effect, has been used as 10-30 grams (15,6430). Magnesium salts should only be used for occasional treatment of constipation, and doses should be taken with a full 8-ounce glass of water. There is also interest in using magnesium for symptomatic relief of CIC. A small clinical study in patients with CIC who are not taking chronic medications shows that taking magnesium oxide 1.5 grams in three divided doses daily for 28 days increases spontaneous bowel movements when compared with placebo (104397). It is unknown if magnesium is beneficial for CIC when used long-term.
• Dyspepsia. Magnesium salts are effective when used orally as antacids. Details: Magnesium carbonate, hydroxide, oxide, or trisilicate salts are used orally as antacids to reduce symptoms of gastric hyperacidity or gastroesophageal reflux. Magnesium hydroxide has the fastest onset of action. The onset for magnesium carbonate is slower due to its crystal structure. Magnesium trisilicate has the slowest onset and longest duration of action due to poor solubility (6844). Doses used include magnesium hydroxide 400-1200 mg (5-15 mL of milk of magnesia) up to four times daily, or magnesium oxide 800 mg daily (15).
• Eclampsia. Magnesium sulfate is considered the drug of choice for control of seizures. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (15,12591,12592,61012,61184). Typical doses include 4-6 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). Meta-analyses of clinical research show that treatment with IV or IM magnesium reduces the risk of seizure recurrence by 33% to 69% when compared with phenytoin, and by 47% to 60% when compared with diazepam (19960,60818,60954,60964,61105). One preliminary clinical study shows that lower doses of IV magnesium sulfate (9 grams loading dose and maintenance of 2.5 grams every 4 hours for 24 hours) are as effective as higher doses (14 grams loading dose and maintenance of 5 grams every 4 hours for 24 hours) for reducing the recurrence of eclamptic seizures (89383). It is generally recommended that treatment be continued for at least 24 hours after the last seizure (15). Oral magnesium has not been evaluated for eclampsia.
• Hypomagnesemia. Hypomagnesemia can be effectively treated with oral or parenteral magnesium. Details: Taking magnesium orally or parenterally is helpful for treating and preventing hypomagnesemia associated with alcoholism, cirrhosis of the liver, congestive heart failure (CHF), severe or prolonged diarrhea or vomiting, kidney dysfunction, inflammatory bowel disease (IBD), pancreatitis, malabsorption syndromes, and other conditions (6280,6281,8088,8089). The dose and salt of magnesium for oral replacement therapy should be chosen carefully to avoid causing diarrhea. The gluconate and chloride salts cause less diarrhea, while the oxide salt is more likely to cause diarrhea and should be avoided. Magnesium chloride should also be avoided due to poor solubility which decreases absorption (6430,8099,10664). Orally, magnesium sulfate 3 grams every 6 hours for four doses has been used for hypomagnesemia (15). Parenteral magnesium doses must be individualized according to serum magnesium levels, but a typical starting dose for mild deficiency is 1 gram of magnesium sulfate intramuscularly (IM) every 6 hours for 4 doses (15). For more severe deficiency, 5 grams of magnesium sulfate may be given as an intravenous (IV) infusion in 1 liter of dextrose 5% or normal saline solution over 3 hours (15).
• Pre-eclampsia. Magnesium sulfate is considered the drug of choice for seizure prophylaxis in patients with pre-eclampsia. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during pre-eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (12591,12592,61012,61184). Some meta-analyses show that IV administration of magnesium sulfate reduces the risk of eclampsia when compared with placebo, phenytoin, or diazepam in patients with pre-eclampsia (19960,60818,60960,60979). A typical initial dose is 4-5 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams of magnesium sulfate per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). The optimal duration of prophylaxis has not been determined. A meta-analysis suggests that using a shorter duration of 12 hours or less is not associated with an increase in risk of eclamptic seizures when compared with regimens of 24 hours or longer (108732). However, studies are likely underpowered due to the low incidence of eclampsia. Oral magnesium has been evaluated for the prevention of pre-eclampsia in healthy adults, but taking magnesium citrate 300 mg daily, starting at 12-20 weeks' gestation and continuing until delivery, does not reduce the incidence of pre-eclampsia when compared with placebo (103724).

LIKELY EFFECTIVE

• Cerebral palsy. Most evidence shows that antenatal magnesium reduces the risk of cerebral palsy in preterm infants, although there are some inconsistent results. Details: Most clinical studies and meta-analyses show that antenatal magnesium sulfate reduces the risk of cerebral palsy by about 32% and the risk of motor dysfunction by about 45% in preterm infants (60882,60915,60927,60931,61001,97485,103734,103754). However, some studies have inconsistent results (8093,19998,98293,98295). The lowest effective dose of magnesium sulfate seems to be 4 grams intravenously, with or without a maintenance dose of 1 gram/hour until birth or for 24 hours. In obese females, a higher dose, based on body weight, may be needed (97485,97495,103734,103754). Oral magnesium has not been evaluated for this purpose.
• Seizures. Intravenous magnesium sulfate is used for treating seizures of various etiologies. Details: Intravenous magnesium sulfate may be useful for controlling seizures associated with epilepsy, glomerulonephritis, hypothyroidism, and acute nephritis in children (15). Oral magnesium has not been evaluated for this purpose.
• Torsades de pointes. Intravenous magnesium sulfate is the first-line treatment for torsades de pointes after measures to correct precipitating factors have been unsuccessful. Details: Intravenous magnesium sulfate has been used successfully to treat the life-threatening ventricular tachycardia, torsades de pointes (15,6844). The Advanced Cardiac Life Support (ACLS) guidelines of the American Heart Association recommend a dose of 1 to 2 grams diluted in 50-100 mL Dextrose 5% solution given IV over 5-60 minutes, followed by a continuous IV infusion of 0.5-1 gram/hour.

POSSIBLY EFFECTIVE

• Arrhythmia. Magnesium sulfate is effective for the specific type of ventricular tachycardia known as torsades de pointes, and seems to be helpful for treating other types of arrhythmias. Evidence for the role of oral or intravenous magnesium in preventing postoperative arrhythmias is conflicting. Details: Administering magnesium intravenously or orally may be helpful for treating atrial and ventricular tachycardia and fibrillation, and supraventricular tachycardia (9497,13352,13354,13355,13356,60804,60829,60877,61113). Arrhythmias associated with congestive heart failure have been treated with magnesium sulfate 8 grams infused over 12 hours (9497). For rate control in atrial fibrillation, magnesium sulfate 2.5 grams IV over 20 minutes, followed by 2.5 grams IV over 2 hours has been used (13356). For paroxysmal supraventricular tachycardia, single doses of 1-4 grams of magnesium chloride have been used (13352). For atrial tachycardia, 2 grams of magnesium sulfate in 10 mL of dextrose 5% solution has been given IV over 1-10 minutes, followed by 5-10 grams of magnesium sulfate in 250-500 mL dextrose 5% solution as an IV infusion over 5 hours (13354,13355). Research on the effects of intravenous magnesium for preventing arrhythmias after cardiac surgery is conflicting. Some clinical trial meta-analyses show that intravenous magnesium reduces the risk of atrial fibrillation, ventricular arrhythmias, or supraventricular arrhythmias following cardiac surgery by 23% to 48% when compared with placebo (60814,60826,60828,60838,61008,61033,61181,97487,97490). Doses of magnesium sulfate used include 30 mg/kg in 500 mL normal saline (97490), or 80-100 mg/kg added to the cardioplegia solution (97487). Also, one small study in adults after CABG surgery suggests that taking magnesium hydroxide 1600 mg orally reduces arrhythmia as effectively as receiving magnesium sulfate 2000 mg intravenously (99315). However, other meta-analyses that only include higher-quality trials show that magnesium supplementation does not reduce the risk of ventricular or supraventricular arrhythmias following cardiac surgery (61010,61024,61031,105081).
• Asthma. Parenteral magnesium sulfate can help to reverse severe acute asthma attacks and reduce the need for hospital admission. Oral or nebulized magnesium, however, does not seem to be beneficial. Details: Overall, a single dose of intravenous magnesium seems to improve pulmonary function in acute asthma exacerbation and reduce the risk of hospitalization, particularly in patients with severe asthma, and those who have failed initial treatment with nebulized albuterol and intravenous corticosteroids (60888,90023,96483,104398,107365). The typical dose used for adults is 2 grams of magnesium sulfate infused over 20 minutes (15). For children, 25-75 mg/kg, to a maximum of 2 grams, infused over 20-30 minutes has been used (15,96483,107365). However, a post-hoc analysis of one large clinical trial (104400) designed to assess nebulized magnesium in children with acute asthma has found that adding IV magnesium to nebulized magnesium is associated with greater odds of hospitalization when compared with no IV magnesium (105919). This post-hoc analysis did not differentiate between precautionary and necessary hospitalizations. Although some clinical research in patients with acute asthma exacerbation shows that nebulized magnesium in combination with albuterol significantly improves airway function when compared with albuterol alone, the benefit is not likely to be clinically relevant (90016). Most evidence, including larger clinical trials, has not shown benefit of adjunct nebulized magnesium for acute asthma in adults or children (60888,90002,96484,104400,105920). Oral magnesium also does not seem to be beneficial. A meta-analysis of small clinical trials in children and adults with asthma shows that taking magnesium supplements orally does not improve lung function or reduce bronchodilator use when compared with control (104404).
• Colorectal cancer. Increasing dietary magnesium intake seems to lower the risk of colon cancer but not rectal cancer. Details: Epidemiological research shows that increased dietary magnesium intake is associated with a reduced risk of colon cancer, but the risk of rectal cancer is not affected (89387,90017,90027,101355).
• Diabetes. Low dietary magnesium may increase the risk of developing type 2 diabetes, but evidence on the use of supplements for treating type 2 diabetes is conflicting. Details: Higher dietary magnesium intake is associated with lower fasting insulin concentrations and a reduced risk of developing type 2 diabetes in adults and obese children (13369,15548,96473,97486,98294,103736,105918,106920). In people with existing type 2 diabetes, hypomagnesemia is found in 25% to 38% of patients, especially in those with poorly controlled diabetes (1172). Population research in adults with type 2 diabetes also shows that a dietary magnesium intake of less than 250 mg daily is associated with a 56% higher risk of mortality. Preliminary subgroup analyses suggest that the risk of mortality is higher in those with glycated hemoglobin (HbA1C) levels above 7% (110051). A meta-analysis of small, heterogeneous clinical studies in adults with type 2 diabetes suggests that magnesium may modestly reduce HbA1C in patients with hypomagnesemia, but not in patients with normal magnesium levels, when compared with control (105075). Individual clinical studies using magnesium supplements in patients with type 2 diabetes or insulin resistance have shown mixed results. Some research suggests magnesium supplements can decrease fasting blood glucose and improve insulin sensitivity, as well as reduce the risk of developing diabetes in high-risk patients (10664,12582,13376,60854,99313,106920), but other research shows no effect (1171,1172,13379,13380). Discrepancies in these findings might reflect differences in magnesium salts and doses used, or differences in baseline magnesium status in study subjects.
• Hypercholesterolemia. Magnesium may help improve lipid levels by a small amount in people with this condition. Details: There is some evidence that taking magnesium oxide 1 gram orally daily for 6 weeks can produce small decreases in low-density lipoprotein (LDL) and total cholesterol levels, and small increases in high-density lipoprotein (HDL) levels in patients with hypercholesterolemia. However, magnesium does not seem to improve lipoprotein (a) levels (1193). Magnesium may also lower triglycerides in people with hypertriglyceridemia (97494).
• Metabolic syndrome. Low dietary and serum levels of magnesium seem to be associated with the development of metabolic syndrome. Details: Higher magnesium intake from diet and supplements is associated with a 27% lower risk of developing metabolic syndrome in healthy females (13371) and a 31% lower risk in healthy young adults (14304). Additional epidemiological research suggests that people with low serum magnesium levels are 6-7 times more likely to have metabolic syndrome than people with normal magnesium levels (13372). In a population analysis of over 6000 individuals without metabolic syndrome at baseline, the risk of developing this condition over a 6-year follow-up period was reduced by 16% in the highest quintile of dietary magnesium intake (median intake 371 mg daily) when compared with the lowest quintile (median intake 203 mg daily). Some, but not all, research suggests that the hazard ratio for metabolic syndrome in relation to magnesium intake may be U-shaped, with higher risk at intakes below about 150 mg daily and above 600 mg daily (108963).
• Osteoporosis. Increased dietary and supplemental magnesium intake seems to increase bone mineral density and decrease bone loss in postmenopausal patients. Details: Preliminary clinical research shows that taking magnesium hydroxide orally, 300-1800 mg daily for 6 months, then 600 mg daily for 18 months, or magnesium citrate orally 1830 mg daily for 30 days, might reduce bone loss and bone turnover in postmenopausal patients with osteoporosis (9104,60928). Some epidemiological research also suggests that magnesium intake is related to increased bone mineral density (12501,12502,12503,12504,90014), although not all studies have found an association (12505,98286).
• Postoperative pain. Injectable magnesium has been used with promising results for reducing pain postoperatively. Details: Intravenous magnesium sulfate, 5-50 mg/kg bolus followed by a continuous infusion of 6 mg/kg or 500 mg hourly during surgery, seems to reduce the 24-hour postoperative use of intravenous morphine by 24% when compared with placebo (19968). Adding intravenous magnesium sulfate 3.7-5.5 grams to patient-controlled analgesia for 24 hours after surgery has also been used (19968). Meta-analyses also support that adjunctive intravenous and intrathecal administration of magnesium improves pain relief and sensory nerve block, and decreases the need for other analgesics, when compared with control (89390,90012,90015,98287,103728); however, it appears to be less effective than dexmedetomidine (105082). A moderate-sized clinical study in patients undergoing total knee arthroplasty in China shows that adding magnesium sulfate 2.5 mg/mL to the periarticular infiltration analgesia (PIA) cocktail reduces pain scores, limits the use of postoperative morphine, prolongs analgesia, and reduces markers of inflammation when compared with the usual PIA cocktail (111181). Administering magnesium intravenously also seems to be helpful for pain control after hysterectomy. A 3-gram IV bolus of magnesium sulfate followed by an infusion of 0.5 grams per hour for 20 hours has been used. Lower doses were not effective (6848). However, intravenous magnesium might not alleviate postoperative pain in children. Two small clinical studies show that administering a magnesium intravenous infusion does not reduce pain when compared with saline in children after tonsillectomy or after elective strabismus surgery (98282,105077).
• Premenstrual syndrome (PMS). Taking magnesium orally seems to relieve symptoms of PMS. Details: There is some evidence that magnesium supplementation can improve symptoms, including mood changes and fluid retention, in some patients with PMS (1187,1188,6847). Doses used include magnesium oxide 333 mg daily for 2 menstrual cycles, or magnesium pyrrolidone carboxylic acid equivalent to 360 mg elemental magnesium three times daily, from the 15th day of the menstrual cycle until onset of menstrual flow (1187,1188). Taking magnesium orally in a dose of 360 mg (elemental magnesium) three times daily for 2 months seems to prevent premenstrual migraine (1186,6847). A combination of magnesium 200 mg daily plus vitamin B6 50 mg daily seems to reduce anxiety-related premenstrual symptoms, including nervous tension, mood swings, irritability, and anxiety, when compared with placebo (8555).
• Vasospastic angina. Intravenous magnesium seems to prevent coronary spasm in patients with this condition. Details: Clinical research shows that administration of intravenous magnesium sulfate 65 mg/kg infused over 20 minutes dilates coronary arteries and suppresses acetylcholine-induced coronary spasms when compared with infusion of a dextrose solution in patients with vasospastic angina (8091).

POSSIBLY INEFFECTIVE

• Altitude sickness. Taking magnesium citrate orally does not seem to reduce acute altitude sickness risk. Details: Clinical research shows that taking magnesium citrate 1200 mg daily orally in three divided doses, beginning 3 days prior to mountain ascent and continuing until mountain descent, does not reduce the risk of acute altitude sickness when compared with placebo (60801).
• Athletic performance. Taking magnesium orally does not seem to improve energy or endurance during athletic activity. Details: Most evidence suggests that taking magnesium orally doesn't increase energy and endurance during athletic activity. Magnesium oxide, aspartate, and orotate salts don't seem to improve exercise performance when used alone or in combination with potassium (2825,2826,2828,2829,2830,60751).
• Bronchiolitis. Intravenous or nebulized magnesium is not beneficial in infants with this condition. Details: Clinical research shows that administering a single IV dose of magnesium sulfate 100 mg/kg to infants with acute bronchiolitis does not improve, and may actually worsen, symptoms when compared with placebo (97482). A clinical study in infants with moderate to severe bronchiolitis shows that adding nebulized magnesium sulfate 40 mg/kg to nebulized epinephrine does not reduce hospital stay or the need for ventilator or oxygen support when compared with epinephrine alone (99317). Oral magnesium has not been evaluated for this use.
• Chemotherapy-induced peripheral neuropathy. Research on the effects of intravenous infusions of magnesium and calcium for preventing oxaliplatin neurotoxicity are inconsistent, but higher quality studies seem to show no benefit. Details: Pooled analyses of cohort studies and clinical trials show that calcium and magnesium infusions can decrease the incidence of severe oxaliplatin-induced neurotoxicity (90028,90029,90031). However, when only clinical trials are considered, the infusions do not appear to be helpful (90005,90029,90031,96474,96479).
• Complex regional pain syndrome. Intravenous magnesium is not beneficial in complex regional pain syndrome type 1. Details: Clinical research shows that receiving magnesium sulfate 70 mg/kg intravenously at the rate of 25 mL/hour for 4 hours each day for 5 days does not improve pain or level of impairment when compared with placebo in patients with chronic complex regional pain syndrome type 1 (89395).
• Emergence delirium. Small clinical studies in adults and children undergoing various surgeries suggest that intravenous (IV) magnesium doesn't reduce the risk of emergence delirium. Details: A small clinical study in adults undergoing surgery for endovascular aortic aneurysm repair shows that administering IV magnesium 30 mg/kg as a loading dose, followed by a 10 mg/kg/hour infusion for the duration of surgery, does not improve agitation or delirium scores when compared with administering saline (111182). Similarly, a small clinical study in children ages 2-5 years undergoing elective strabismus surgery shows that administering IV magnesium during anesthesia does not seem to prevent the occurrence of emergence delirium when compared with administering saline (105077). In a meta-analysis of 8 clinical trials in children aged 2-16 years undergoing general anesthesia for oral or ophthalmic surgery, giving IV magnesium as a 30 mg/kg loading dose followed by a 10 mg/kg/hour infusion, or as a single dose of 15-30 mg/kg, does not reduce emergence delirium scores, and may actually prolong emergence times (108729).
• Menopausal symptoms. Oral magnesium oxide does not seem to be beneficial for menopausal hot flashes. Details: A small, low quality study in postmenopausal patients with a history of breast cancer shows that taking magnesium oxide 400-800 mg orally daily reduces hot flashes when compared with baseline (102454). However, a larger, higher quality clinical study using magnesium oxide 800-1200 mg daily did not show any benefit when compared with placebo (98290).
• Muscle cramps. Oral magnesium does not seem to improve muscle cramp frequency or intensity. Details: Meta-analyses of small clinical trials show that magnesium supplementation for 3-6 weeks does not decrease the frequency or intensity of skeletal muscle cramps, whether the cramps are idiopathic or due to liver cirrhosis or pregnancy, when compared with placebo (90022,104395).
• Sickle cell disease. Intravenous magnesium does not add any benefit to standard therapy for sickle cell disease in children. Details: Clinical research shows that giving magnesium sulfate 40-100 mg/kg (maximum of 2 grams per dose) intravenously every hour for 6-8 doses as an adjunct to standard therapy does not decrease hospital stay, pain, or opioid use, or improve quality of life, when compared with standard therapy and placebo in children with sickle cell disease (89399,98283,101356). Oral magnesium has not been evaluated for this purpose.
• Stillbirth. Magnesium administered during pregnancy does not reduce stillbirth risk. Details: A meta-analysis of clinical research shows that magnesium supplementation does not significantly decrease the risk of stillbirths when administered during pregnancy (60925,60978).
• Tetanus. Intravenous magnesium sulfate does not seem to improve outcomes in patients with this condition. Details: A meta-analysis of clinical research shows that intravenous magnesium sulfate does not reduce mortality when compared with placebo or diazepam in patients with tetanus (61020). While some research shows that magnesium reduces the duration of hospitalization and the need for ventilation when compared with diazepam (61170), magnesium does not seem to improve these outcomes when compared with placebo (60860).
• Traumatic brain injury (TBI). Magnesium does not improve clinical outcomes in patients with moderate to severe TBI. Its effect in patients with concussions is unclear. Details: A meta-analysis of four clinical trials shows that treatment with magnesium does not significantly improve neurological outcomes or reduce the risk of mortality when compared with placebo in patients with moderate to severe TBI (60905). A small observational cohort study in adolescents with concussions has found that adding oral magnesium 400 mg twice daily for 5 days to standard treatment with acetaminophen and ondansetron is associated with a trend toward reduced symptom severity when compared with standard treatment alone (104401). The validity of this study is limited by its observational nature and small cohort size.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Intravenous magnesium does not seem to help reduce symptoms of alcohol withdrawal but may reduce the duration of alcoholic delirium. Details: Preliminary clinical research shows that administration of four intramuscular injections of magnesium sulfate 2 grams at 6-hour intervals does not reduce symptoms of alcohol withdrawal when compared with saline (61063). A small observational study in patients with alcoholic delirium has found that administering magnesium sulfate IV 50 mg/kg every 8 hours, in addition to usual sedation, is associated with a reduction of delirium by approximately 2 days, or 4 days when given every 12 hours in addition to dexmedetomidine, when compared with usual sedation alone (111180). However, half of patients had hypomagnesemia at baseline; it is unclear if effects would be similar for patients with normal magnesium levels. Oral magnesium has not been evaluated for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral magnesium for allergic rhinitis, there is insufficient reliable information about the clinical effects of magnesium for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral magnesium is beneficial in children with ADHD. Details: Children with ADHD seem to have lower magnesium levels in their blood and hair (9969,100262,100263). A small clinical study in children aged 7-12 years with ADHD and magnesium deficiency shows that taking magnesium aspartate and lactate 6 mg/kg daily for 6 months might improve hyperactivity and magnesium levels when compared with control (1189). Another small clinical study in children with ADHD but without magnesium deficiency shows that taking magnesium 6 mg/kg daily along with vitamin D 50,000 IU weekly for 8 weeks may modestly improve emotional problems, but not inattention or hyperactivity, as measured on the strength and difficulties questionnaire (SDQ), when compared with placebo (105914).
• Back pain. It is unclear if oral or intravenous magnesium is beneficial for acute or chronic back pain in adults. Details: One open-label clinical study in adults with acute low-back pain shows that taking magnesium 365 mg once daily in addition to taking etodolac 400 mg twice daily for 10 days does not further reduce pain when compared with taking etodolac alone (105913). Magnesium has also been tried for chronic back pain. A small clinical study in patients with chronic low-back pain shows that receiving magnesium sulfate 1 gram in 250 mL normal saline intravenously every 4 hours for 2 weeks, followed by magnesium gluconate 100 mg and magnesium oxide 400 mg by mouth daily for 4 weeks, reduces pain severity when compared with placebo (90035). It is unclear if oral magnesium used alone is beneficial.
• Bariatric surgery complications. It is unclear if oral magnesium supplementation improves metabolic parameters after bariatric surgery. Details: A retrospective study of over 3000 post-bariatric surgery patients suggests that those who take oral magnesium supplements providing 100-450 mg elemental magnesium daily may have improved metabolic parameters over 4 years of follow-up. When patients taking magnesium supplements were compared with those not taking supplements, 11% and 18% had type 2 diabetes, respectively, 30% and 42% had hypertension, respectively, and 16% and 23% had elevated low-density lipoprotein (LDL) cholesterol levels, respectively. For patients with hypomagnesemia at baseline, supplementation seemed to result in greater benefits (108968).
• Bipolar disorder. Taking magnesium orally might improve manic symptoms in some people with bipolar disorder; however, it is unclear how it compares to current standard of care. Details: One preliminary clinical study shows that magnesium 40 mEq daily (Magnesiocard) for 32 weeks has similar effects to lithium in up to 50% of patients treated for rapid cycling bipolar affective disorder (61022). Another preliminary clinical study shows that magnesium oxide 375 mg orally daily plus verapamil 80 mg taken four times daily reduces manic symptoms more effectively than verapamil alone in patients with mania (60742).
• Cancer-related neuropathic pain. It is unclear if intravenous magnesium is beneficial for this condition. Details: Single 500 mg to 1 gram doses of magnesium sulfate seem to relieve neuropathic pain for up to four hours when compared to baseline (6846). The validity of this finding is limited by the lack of a comparator group.
• Chemotherapy-induced leukopenia. It is unclear if oral magnesium is beneficial in pediatric patients at risk for cisplatin-induced febrile neutropenia. Details: A small clinical study in children with solid tumors aged 9 years and older shows that taking magnesium 250 mg daily while receiving cisplatin-based chemotherapy reduces febrile neutropenia by 47% and septic shock by 57% when compared with not receiving magnesium. Results from this study suggest that four pediatric patients need to take oral magnesium to avoid one case of febrile neutropenia (104394).
• Cardiac arrest. Intravenous magnesium does not seem to be helpful in cardiac arrest; however, the risk of sudden cardiac death seems to be inversely correlated to higher plasma magnesium levels or dietary intake. It is unclear if magnesium supplementation is associated with similar risk reduction. Details: Administering magnesium intravenously doesn't seem to improve successful resuscitation in people with cardiac arrest (1190). However, higher plasma magnesium levels and higher dietary magnesium intake might reduce the risk of sudden cardiac death, possibly by protecting against fatal ventricular arrhythmias. In the Nurses' Health Study, the risk of sudden cardiac death was 77% lower in females with the highest quartile of plasma magnesium levels when compared with the lowest quartile. Also, the risk was 37% lower in females with the highest quartile of dietary magnesium intake when compared with the lowest quartile (17132).
• Cardiovascular disease (CVD). Evidence regarding the effect of dietary magnesium on CVD risk is conflicting. Details: Epidemiological research in some populations shows that increased dietary magnesium intake is associated with decreased mortality due to strokes, coronary heart disease, ischemic heart disease, and heart failure, but other epidemiological research does not show any effect on these risks (89391,90003,90009,90030,90036,103735). Reasons for the discrepancies may be related to serum levels of magnesium at baseline, risk of cardiovascular disease at baseline, use of concomitant medications such as diuretics, or the presence of concomitant conditions such as kidney dysfunction. A population analysis conducted in Denmark has found that magnesium intake from drinking water may be associated with cardiovascular mortality. The overall risk of cardiovascular death and death due to stroke was reduced by 4% in the lowest 3 quintiles of intake when compared with the highest quintile. However, the risk of death due to acute myocardial infarction was increased by 22% in the lowest quintile when compared with the highest (108726). The relevance of these results is unclear, given that the main dietary source of magnesium is food rather than drinking water.
• Chronic fatigue syndrome (CFS). Limited evidence suggests that magnesium may help improve CFS symptoms, but this is controversial. Details: In people with low red blood cell magnesium, there is some evidence that intramuscular injections of 1 gram magnesium sulfate given once weekly for 6 weeks might improve CFS symptoms (7556). However, there is additional evidence that most patients with CFS have normal magnesium stores, and measurement of red cell magnesium is a poor indicator of total magnesium stores (7557,8084,8085,8086,8087).
• Chronic obstructive pulmonary disease (COPD). Intravenous, but not nebulized, magnesium may be helpful in acute exacerbations of COPD. Details: Administering magnesium sulfate intravenously, 1.2-2.5 grams over 20 minutes, might be helpful for treating acute exacerbations of COPD (1208,6844,103733). Also, giving magnesium sulfate 2 grams intravenously seems to improve exercise capacity when compared with placebo (89384). A meta-analysis of studies using intravenous magnesium sulfate for COPD exacerbations shows that it reduces hospital admission and mean length of stay and improves dyspnea scores when compared with placebo. Based on the relative risk identified in the included studies, seven patients would need to receive intravenous magnesium to prevent one hospitalization. However, intravenous magnesium sulfate does not change the need for non-invasive ventilation and the available research did not evaluate intensive care unit (ICU) admission (108967). Nebulized magnesium has also been evaluated. In patients experiencing a COPD exacerbation, clinical research shows that administering nebulized magnesium sulfate with albuterol three times at 30-minute intervals does not improve pulmonary function as measured by the forced expiratory volume in 1 second (FEV1) when compared with placebo (89393). Also, a meta-analysis of a small number of low-quality studies shows that nebulized magnesium does not reduce hospital admission or the need for ventilatory support, although it might modestly improve dyspnea scores and reduce ICU admissions, when compared with placebo (108967).
• Cluster headache. It is unclear if a single intravenous dose of magnesium sulfate is beneficial for cluster headaches. Details: Administering magnesium sulfate intravenously, 1 gram over 5 minutes, seems to improve cluster headaches when compared with baseline(1184). The validity of this finding is limited by the lack of a comparator group.
• Coronary heart disease (CHD). It is unclear if magnesium supplementation is beneficial for CHD. Details: Clinical research shows that magnesium oxide 800-1200 mg daily for 3 months reduces platelet-dependent thrombosis by 35% when compared with placebo in patients with CHD (60759). It is unclear if this effect improves clinical outcomes. The effect of magnesium supplementation on coronary artery calcium has also been studied. A meta-analysis of 3 clinical studies in 196 patients with chronic kidney disease (CKD) shows that taking magnesium or increasing the concentration of magnesium in dialysate does not improve coronary artery calcification (CAC) scores when compared with standard therapy. However, magnesium reduced carotid intima-media thickness (111179). Similarly, a large clinical study in patients with CKD shows that taking slow-release magnesium hydroxide (Mablet, Denmark) 360 mg twice daily for 12 months does not slow the progression of CAC scores when compared with placebo (111178). This study may not have been adequately powered to detect a difference between groups.
• Depression. It is unclear if magnesium is beneficial for the treatment or prevention of depression in adults. Details: Some population research shows that dietary intake of elemental magnesium between 76-360 mg daily is associated with a reduced risk of depression, but there was no association with greater amounts of magnesium, and other population research shows no association at any intake level (96480,98289). For treatment of mild to moderate depression, one preliminary clinical study shows that taking magnesium chloride 2 grams orally daily for 6 weeks reduces depression scores by 56% and anxiety scores by about 52% when compared to baseline (96477). The validity of these findings is limited by the lack of a comparator group. However, a small clinical study in adults with recurrent depression shows that taking magnesium aspartate 120 mg daily for 8 weeks, along with fluoxetine, does not improve depression scores when compared with patients taking fluoxetine and placebo (111185). Similarly, a very small crossover clinical study in adults with mild or moderate treatment-resistant depression shows that administering a single dose of IV magnesium sulfate 4 grams does not improve depression scores when compared with an infusion of 5% dextrose (96481). However, scores were evaluated 24 hours post-infusion which may be too soon to detect improvement. Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that elemental magnesium in doses of 100-400 mg is not recommended for adjunctive or monotherapy use in patients with depression (110318).
• Diabetic foot ulcers. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with grade 3 diabetic foot ulcers shows that taking magnesium oxide 250 mg plus vitamin E 400 IU daily for 12 weeks modestly reduces ulcer size when compared with placebo (101436). It is unclear if this effect is due to magnesium, vitamin E, or the combination.
• Exercise-induced muscle soreness. It is unclear if oral magnesium reduces muscle soreness in adults after resistance training. Details: A very small study in healthy adults, ages 19-23, shows that taking magnesium glycinate 350 mg daily for 10 days seems to reduce muscle soreness after bench press exercise when compared with placebo (104399).
• Fibromyalgia. It is unclear if oral magnesium is beneficial for this condition. Details: A small clinical study shows that taking magnesium chloride orally 100 mg once daily for one month reduces mild to moderate, but not severe, stress associated with fibromyalgia when compared with placebo. It also reduces pain levels, but not to a clinically significant extent, and it does not affect sleep, fatigue, or quality of life (108964). Another small clinical study shows that taking magnesium citrate 300 mg daily for 8 weeks improves some symptoms of fibromyalgia, such as number of tender points and depression, when compared to baseline (89385). The validity of this finding is limited by the lack of a comparator group. A small clinical study shows that taking a combination of magnesium hydroxide and malic acid (Super Malic tablets) orally decreases fibromyalgia-related pain and tenderness in some patients when compared with placebo (3262). It is unclear if this effect is due to magnesium, malic acid, or the combination.
• Fractures. Population research suggests that higher intakes of magnesium may reduce fracture risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is associated with a 34% lower odds of fracture when compared with lower magnesium intake (101395).
• Gastric cancer. Population research suggests that higher intakes of magnesium may reduce gastric cancer risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is not associated with a reduced risk for gastric cancer when compared with lower intake (103730).
• Hearing loss. Oral magnesium may prevent and improve hearing loss due to environmental factors or loud noises. Details: Clinical research in healthy military recruits shows that taking magnesium aspartate 167 mg daily for 2 months prevents hearing loss from exposure to loud noises during basic military training when compared with placebo (1205). Also, in patients with acute-onset hearing loss that was not caused by environmental factors, taking magnesium aspartate 167 mg daily for 8 weeks seems to improve hearing loss when compared with placebo (60813).
• Hypertension. Oral magnesium supplementation may modestly reduce blood pressure, although these changes are not likely to be considered clinically significant. Details: Most research shows that taking oral magnesium supplements in daily doses that are at least as high as the Recommended Dietary Allowance (RDA) for adults and up to 1000 mg daily can lower diastolic blood pressure by about 2 mmHg in adults with or without hypertension (1192,1199,9465,15165,18111,96482). Significantly lower doses do not seem to have this effect (1180,1195,1197,8098). The effect of magnesium on systolic blood pressure is conflicting. One meta-analysis shows that taking magnesium 240-970 mg daily does not lower systolic blood pressure (15165). However, more recent meta-analyses show that taking magnesium 120-970 mg daily can lower systolic blood pressure in a dose-dependent manner by about 2-4 mmHg in patients with or without hypertension (18111,96482). In 2022, the US Food and Drug Administration (FDA) approved a qualified health claim stating that inconsistent and inconclusive evidence suggests that diets with adequate magnesium may reduce the risk of high blood pressure. Products bearing this claim must provide at least 84 mg of magnesium daily, but no more than 350 mg daily (107451).
• Hypokalemia. It is unclear if intravenous or oral magnesium is beneficial for hypokalemia in patients with normal magnesium levels. Details: A preliminary retrospective observational study in patients with hypokalemia and unknown serum magnesium levels has found that administering oral or intravenous magnesium is not associated with improved time to normalization of serum potassium levels when compared with no magnesium treatment (110049). However, hypokalemia with concurrent hypomagnesemia can impede potassium repletion and exacerbate hypokalemia-induced rhythm disturbances. Standard of care in patients with hypokalemia and known hypomagnesemia includes prompt treatment with magnesium (110063).
• Impaired glucose tolerance (prediabetes). It is unclear if oral magnesium is beneficial for prediabetes. Details: Preliminary clinical research in patients with prediabetes shows that taking magnesium oxide 250 mg orally daily for 12 weeks does not improve fasting blood glucose levels, insulin resistance, or glycated hemoglobin (HbA1C) levels when compared with placebo. Taking magnesium also did not affect blood pressure, body weight, triglyceride levels, or low-density lipoprotein cholesterol levels; however, it did modestly improve high-density lipoprotein cholesterol levels (110053).
• Insomnia. Oral magnesium may modestly improve sleep complaints in adults, but evidence is conflicting. Details: A meta-analysis of two small clinical studies in healthy older adults with or without insomnia suggests that taking magnesium reduces the time to fall asleep by an average of 17 minutes when compared with placebo (105917). However, it does not increase the time spent asleep. Also, these findings are limited by imprecision and a high risk of bias. Studies included in the analysis used elemental magnesium 500-729 mg daily (as magnesium oxide) for up to 8 weeks (102458,105917). Another small clinical study in patients with poor sleep quality and low magnesium status shows that taking elemental magnesium 320 mg (as magnesium citrate) in divided doses daily for 7 weeks does not improve sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), when compared with a sodium citrate placebo (102456). A very small crossover clinical study in patients aged 18-40 years without a sleep disorder shows that taking a combination of magnesium 300 mg, L-tryptophan 1000 mg, glycine 3000 mg, tart cherry 220 mg, and theanine 200 mg for 3 days reduces the time to fall asleep by about 24 minutes, increases total time asleep by about 22 minutes, and improves sleep efficiency, but does not improve the total time in bed or wakefulness after falling asleep when compared with cellulose placebo (111184). It is unclear if these effects are due to magnesium, other ingredients, or the combination.
• Intraventricular hemorrhage. It is unclear if antenatal intravenous magnesium sulfate can reduce the risk for intraventricular hemorrhage in neonates. Details: A meta-analysis of clinical research in premature infants shows that if the mother received antenatal intravenous magnesium sulfate, the infant had a non-significant trend toward a reduced risk of intraventricular hemorrhage when compared with infants whose mothers received placebo (103727). This analysis may have been insufficiently powered to detect a difference between groups.
• Kidney stones (nephrolithiasis). Taking magnesium orally may prevent the recurrence of kidney stones, although evidence is conflicting. Details: Prophylactic treatment with magnesium hydroxide, 200 mg twice daily for one year, followed by 500 mg daily for another year, might decrease the recurrence rate of calcium stone formation (2007). However, magnesium oxide does not seem to benefit patients considered to be recurrent calcium stone formers when compared with placebo, no treatment, or chlorthalidone (8097,38501,61199). Magnesium oxide 300 mg in combination with vitamin B6 10 mg daily seems to decrease urinary oxalate levels in people with hyperoxaluria who have previously had kidney stones (1201), but it is unclear if this effect translates into a reduced incidence of kidney stones.
• Liver cancer. Increased dietary magnesium intake is linked with a lower risk of liver cancer. Details: Observational research in retired older Americans has found that higher dietary magnesium intake is associated with a 35% lower risk of liver cancer when compared with lower intake. This association was especially strong in persons who were moderate or heavy alcohol users (105080).
• Migraine headache. Oral magnesium may help prevent migraine in some adults and children. Also, intravenous magnesium may help treat migraine in adults, but evidence is conflicting. Details: Small clinical studies in adults with migraine suggest that taking oral high-dose magnesium citrate 600-1830 mg daily in divided doses for up to 3 months seems to modestly reduce the frequency and severity of headaches when compared with baseline or placebo (4891,9498,60902). Limited evidence suggests that adding oral magnesium to conventional treatment may also be beneficial. A clinical study in adults with migraine living in Iran shows that taking magnesium oxide 250 mg twice daily in addition to sodium valproate 200 mg twice daily for 12 weeks modestly reduces severity and duration of migraine, but not migraine frequency, when compared with taking sodium valproate alone (105915). It is unclear if these improvements would be considered clinically significant. In contrast, one small clinical study shows that taking magnesium does not reduce migraine frequency and severity by at least 50% in adults when compared with placebo (10661). For treatment of migraine, some adults with normal magnesium levels respond to intravenous (IV) magnesium sulfate 1 gram over 5 minutes, but most patients who benefit have low magnesium levels at baseline (1185,6844). Effects of IV magnesium in patients with unknown magnesium levels are conflicting. Some preliminary clinical research shows that magnesium 1-2 grams IV alleviates acute migraine for up to 2 hours, but other research has found no benefit (89388,97493,98285). In children, treatment with magnesium oxide orally 15 mg/kg daily in 3 divided doses for up to 16 weeks reduces the frequency and severity of migraine headaches when compared with placebo (10663). However, adding magnesium sulfate 400 mg orally daily to ibuprofen or acetaminophen does not further reduce migraine severity in children (89396).
• Myocardial infarction (MI). Research on the effects of intravenous or oral magnesium after myocardial infarction are conflicting. Details: Administering magnesium intravenously doesn't seem to reduce mortality after an acute MI (8999,13357,13358,13359,13360,19990,60872,61082), although there is some conflicting evidence from a meta-analysis of clinical research that shows that intravenous magnesium sulfate may reduce short-term mortality by 55% when compared with placebo (60795,60895). Clinical research with oral magnesium supplementation has found no benefit (1198,6844).
• Neonatal encephalopathy. Intravenous magnesium may improve short-term outcomes in neonates with encephalopathy. Details: A meta-analysis of clinical research shows that intravenous magnesium may improve short term outcomes of neonatal encephalopathy (hypoxic ischemic encephalopathy, HIE). However, long term outcomes are not affected (90025).
• Nocturnal leg cramps. It is unclear if oral magnesium is helpful for nocturnal leg cramps. Details: Some clinical research in adults with nocturnal leg cramps shows that taking magnesium oxide 865 mg daily at bedtime for 4 weeks does not reduce the frequency of leg cramping episodes when compared with placebo (96478). However, four weeks may be too short a time to see a benefit. In other clinical research, taking oral magnesium oxide monohydrate 226mg daily at bedtime for 60 days reduces the frequency of leg cramps when compared with placebo. This reduction was not seen after 30 days. Magnesium also reduced cramp duration and improved sleep quality, but did not affect pain scores, at 60 days when compared with placebo (106919).
• Nonalcoholic fatty liver disease (NAFLD). Oral magnesium hydroxide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with NAFLD shows that taking magnesium hydroxide 150 mg and L-carnitine 2000 mg daily for 16 weeks does not improve liver stiffness scores when compared with baseline or controls who took placebo for 8 weeks followed by this magnesium and L- carnitine combination for 8 weeks. Taking magnesium and L-carnitine also did not improve levels of aspartate aminotransferase (AST) or alanine transaminase (ALT) when compared to baseline (111177).
• Obesity. Evidence on the use of magnesium for weight loss in obese patients is conflicting; any benefit is likely small at best. Details: A meta-analysis of 7 clinical studies in obese patients shows that taking magnesium reduces body mass index (BMI) by 0.3 when compared with control (103723). Another meta-analysis of 7 studies in obese patients shows that while magnesium supplementation does not reduce weight, it reduces waist circumference by 2 cm when compared with placebo (103729). Interestingly, subgroup analyses did not find that the dose of magnesium or baseline magnesium levels impacted effectiveness. One subgroup analysis found that magnesium supplementation lasting 12 weeks or less seemed to be more beneficial for obesity than supplementation lasting longer than 12 weeks (103723).
• Overall mortality. It is unclear if oral or IV magnesium reduces the risk of overall mortality. Details: A meta-analysis of heterogeneous observational studies has found that increased dietary magnesium intake, but not supplemental magnesium intake, is associated with a modestly reduced risk of overall mortality (105073). A meta-analysis of 3 small, low-quality clinical studies in ICU patients shows that administering IV magnesium 24-30 mmol or as a target-directed dose for 3 days reduces overall mortality when compared with patients who did not receive magnesium (111290). However, some studies included patients with hypomagnesemia; it is unclear if effects would be similar for patients with normal levels of magnesium.
• Osteoarthritis. Population research has not found a link between magnesium intake and osteoarthritis risk. Details: Observational research has found that dietary and supplemental magnesium intake is not associated with the risk of developing osteoarthritis (101395).
• Pain (acute). It is unclear if intravenous magnesium is helpful for acute pain associated with kidney dysfunction. Details: Preliminary clinical research in patients with renal colic shows that intravenous (IV) magnesium sulfate, 50 mg/kg infused over 20 minutes, is as effective as IV morphine sulfate 0.1 mg/kg for controlling acute renal pain at 20 minutes after the dose (107367).
• Pain (chronic). Population research suggests that higher intakes of magnesium may modestly reduce the risk for chronic pain. Details: A cross-sectional observational study has found that increased magnesium intake is associated with a 7% to 8% reduced risk for chronic pain. The association was found to be stronger in females than in males (103732).
• Perioperative anxiety. It is unclear if oral magnesium is beneficial for perioperative anxiety. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves anxiety and depression scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Physical performance. Oral magnesium may modestly improve physical performance in otherwise healthy, elderly females. Details: Clinical research in otherwise healthy elderly females shows that taking a magnesium oxide supplement (Easymag, Sanofi-Aventis) 900 mg daily for 12 weeks modestly improves walking speed and chair stand speed in elderly females when compared with no treatment (90026).
• Polycystic ovary syndrome (PCOS). It is unclear if oral magnesium is beneficial for improving metabolic indices in patients with PCOS. Details: Two small clinical studies in patients with PCOS show that taking magnesium oxide orally, 250 mg daily for 8 weeks, does not affect insulin resistance, beta-cell function, lipid levels, or insulin sensitivity when compared with placebo (103725,105887). Other clinical research in patients with PCOS shows that taking magnesium oxide orally, 250 mg daily for 10 weeks, improves subjective measures of quality of life, fatigue, and emotional functioning, but not objective measures such as alopecia, abnormal uterine bleeding, or acne, when compared with placebo (108965). A clinical study using a combination of magnesium 250 mg with vitamin E 400 mg daily for 12 weeks shows a modest reduction in insulin resistance, insulin levels, and triglyceride levels, but not other lipid levels, when compared with placebo (100264). It is unclear if these beneficial effects are due to magnesium, vitamin E, or the combination.
• Postoperative sleep disturbance. It is unclear if oral magnesium is beneficial for postoperative sleep disturbances. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves sleep scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Pregnancy-related leg cramps. It is unclear if oral magnesium reduces leg cramps during pregnancy; evidence is conflicting. Details: One small clinical study in patients with pregnancy-related leg cramps shows that taking magnesium bisglycinate chelate 300 mg daily for 4 weeks reduces the frequency and intensity of leg cramps when compared with placebo (99318). A smaller clinical study in this population shows that taking a specific mixture of magnesium lactate and citrate (Nycoplus Magnesium) providing elemental magnesium 120 mg in the morning and 240 mg in the evening for 3 weeks reduces the frequency of cramps when compared with placebo (1194). However, not all research agrees. One small clinical study using this same supplement and dose for 2 weeks found no benefit when compared with placebo (17463). It is possible that a 2-week duration of treatment is too short to be beneficial. Finally, a meta-analysis of these studies and one other more recent clinical study shows that taking magnesium does not reduce the frequency or improve the resolution of pregnancy-related leg cramps when compared with placebo (105916). This analysis may not have been adequately powered to detect a difference between treatment groups.
• Preterm labor. The use of magnesium sulfate to inhibit uterine contractions in preterm labor (tocolysis) is controversial. However, its use for the purpose of fetal neuroprotection for up to 48 hours is supported by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine. Details: Magnesium is given intravenously during preterm labor in an effort to improve fetal neurological outcomes. The typical dosage of magnesium sulfate is 4 grams infused IV over 10-30 minutes, followed by a maintenance infusion of 1-4 grams/hour for 48 hours or until birth. Use beyond 5-7 days has been associated with hypocalcemia and bone abnormalities in the fetus (15,12590,12594). Some meta-analyses of clinical research suggest that magnesium sulfate is more effective at delaying delivery by 48 hours when compared with oxytocin receptor blockers, nitrates, beta-mimetics, and/or placebo (20263,61021). Administration of magnesium during preterm labor has been shown to reduce the risk of cerebral palsy and motor dysfunction in the infant (60882,60915,60927,60931,61001,97485,103734,103754).
• Pseudoxanthoma elasticum (PXE). It is unclear if oral magnesium is beneficial for PXE. Details: Preliminary clinical research in patients with PXE shows that taking magnesium oxide 800 mg (500 mg of elemental magnesium) twice daily for one year tends to reduce calcification of elastic skin fibers when compared with placebo, but the effect is not statistically significant (101393). This study was limited by small size and insufficient power to detect smaller effects.
• Restless legs syndrome (RLS). It is unclear if oral magnesium is beneficial for RLS. Details: Some observational research has found that hypomagnesemia is associated with RLS; however, not all research agrees (8096,9472). Preliminary clinical research in adults with RLS who are beginning treatment with pramipexole shows that also taking magnesium oxide 250 mg orally daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052). Other low-quality clinical research in adults with RLS or periodic limb movement during sleep shows that taking magnesium 12.4 mmol orally in the evening for 4-6 weeks decreases movement and increases sleep when compared with baseline (9466). The validity of this finding is limited by the lack of a comparator group.
• Sarcopenia. It is unclear if oral magnesium is beneficial for the prevention or treatment of sarcopenia. Details: Population research in older adults has found that lower dietary intake of magnesium is associated with sarcopenia. However, the effect of magnesium supplementation on sarcopenia prevention or treatment has not been evaluated (110055).
• Stroke. Increased dietary magnesium may decrease stroke risk, and using a magnesium-containing salt substitute may improve neurological performance post-stroke. However, intravenous magnesium has not demonstrated benefit. Details: Most population research has found that increased dietary intake of magnesium is associated with decreased stroke risk and decreased mortality from stroke (9001,9002,90013,90030,90036,92107,103736). In patients who have had a stroke, a preliminary clinical study shows that using a salt substitute providing the Dietary Reference Intake (DRI) of magnesium and potassium for 6 months improves neurological performance when compared with using regular salt (97491). However, intravenous (IV) magnesium does not seem to be beneficial in patients who have had a stroke. Large prospective clinical trials show that IV magnesium given within 12 hours of acute stroke does not reduce mortality or disability in most patients when compared with placebo. However, one subgroup analysis suggested that IV magnesium might benefit patients with lacunar (non-cortical) stroke (13361,90021). IV magnesium also doesn't seem to reduce cardiovascular complications after acute stroke. A secondary analysis of a clinical trial in patients after ischemic and hemorrhagic stroke shows that giving IV magnesium does not reduce serious cardiac adverse events when compared with placebo (104393). Another secondary analysis of this trial shows that giving IV magnesium prior to arrival at the hospital and within 2 hours of a hemorrhagic stroke does not reduce hematoma volume on hospital arrival, hematoma expansion during hospital admission, or functional outcomes at 3 months (108733).
• Subarachnoid hemorrhage. Intravenous magnesium sulfate may reduce the risk of adverse outcomes in people with subarachnoid hemorrhage, but evidence is conflicting. Details: There is mixed evidence regarding the effect of magnesium sulfate in managing aneurysmal subarachnoid hemorrhage. One meta-analysis of clinical research shows that intravenous magnesium sulfate 64-144 mmol/day for 10-18 days reduces the risk of poor outcomes following aneurysmal subarachnoid hemorrhage, including death, vegetative state, or dependency, by 46% when compared with control (60932). Also, meta-analyses of clinical research show that intravenous magnesium reduces the risk of delayed cerebral ischemia by 27% when compared with placebo (60944,89398). However, these results were not confirmed in other meta-analyses (60973,90034).
• Urinary incontinence. Although there has been interest in using oral magnesium for urinary incontinence, there is insufficient reliable information about the clinical effects of magnesium for this purpose. More evidence is needed to rate magnesium for these uses.

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LIKELY EFFECTIVE

• Delayed sleep phase syndrome (DSPS). Oral melatonin shortens the time needed to fall asleep in children and adults with DSPS. Details: Most clinical research shows that taking melatonin orally reduces the length of time needed to fall asleep and advances sleep onset time in young adults and children with DSPS (8244,12226,15005,62714,62792,63055,88288,88290,89509). In adults, 0.3-5 mg daily for up to 9 months has been used (8244,62714,62792,63055,88290,89509). In children, 1-6 mg before bedtime for up to one month has been used (62714,62792,89509). In addition to improving sleep, melatonin also improves measures of quality of life such as mental health, vitality, and bodily pain in young adults with DSPS (8244,12226,15005). However, relapse to pre-treatment sleeping patterns seems to occur within one year after stopping supplementation (63048).
• Non-24-hour sleep wake disorder. Oral melatonin improves non-24-hour sleep wake disorder in blind children and adults. Details: Taking oral melatonin 0.5-4 mg daily in children and 0.5-10 mg daily in adults for up to 6 years helps improve circadian rhythm sleep disorders in blind children and adults (1082,1744,1749,6585,62346,62350).

POSSIBLY EFFECTIVE

• Beta blocker-induced insomnia. Oral melatonin seems to improve sleep in patients with insomnia related to the use of beta-blockers. Details: Beta-blockers such as atenolol and propranolol seem to decrease endogenous melatonin levels (1780). This might result in insomnia as a side effect. Clinical and preclinical research shows that taking a melatonin supplement might decrease the insomnia caused by beta-blockers (1062,89502). Taking melatonin 5 mg at night after taking atenolol 100 mg appears to attenuate the changes in sleep onset latency, total wake time, and wakefulness after sleep onset when compared with taking atenolol 100 mg alone (1062). Also, in patients taking atenolol or metoprolol, taking melatonin 2.5 mg one hour before bedtime for 20-28 days increases total sleep time by 13-37 minutes and decreases sleep latency by 8-14 minutes when compared with placebo (89502).
• Cancer. In patients with various types of cancer, most research shows that oral or combined intramuscular/oral melatonin in combination with chemotherapy or other treatments seems to improve tumor regression and survival rates. Details: There is some evidence that taking combined high-dose melatonin with conventional chemotherapy or with interleukin-2 (IL-2) might improve tumor regression rate in patients with breast, lung, kidney, liver, pancreatic, stomach, or colon cancer (1692,5854,5855,5857,7040,7043,8268,62407,62844). Melatonin plus chemotherapy in patients with metastatic solid tumors seems to increase the regression rate and one-year survival rate by about 40% to 50% when compared with chemotherapy alone (7040,62407,62844,89504). The addition of melatonin also seems to help reduce chemotherapy toxicities, including hematologic complications, cachexia, asthenia, and neuropathy (8268,62844,89504). There is also some preliminary evidence that melatonin alone, orally or intramuscularly, might improve stabilization rate and possibly one-year survival rate in patients with resistant or untreatable neoplasms of the lung, liver, pancreas, colon, breast, or brain (1080,1688,1693,2566). Also, when used in combination with radiotherapy, high-dose melatonin seems to increase the survival time and percent survival in patients with brain glioblastomas when compared with radiotherapy alone (62991). However, high-dose melatonin treatment does not seem to improve the survival of patients with brain metastases who receive radiation therapy (62455). Melatonin 10-40 mg daily has been used in most clinical trials (1080,1692,1693,2566,5854,5855,5857,7040,7043,8268)(62455,62844,62991,89504). In one study, melatonin 20 mg intramuscularly daily for 2 months, followed by oral melatonin 10 mg daily as maintenance, was used (1688). The effect of melatonin on quality of life and sleep quality in patients with cancer has also been investigated. A meta-analysis of six clinical trials shows that taking melatonin 20 mg daily does not improve sleep quality or quality of life when compared with a control, usually placebo. The duration of studies varied widely; from a period of 7 days or until death. However, there was a modest effect of melatonin on symptoms of depression in patients taking it for at least 14 days or those who underwent surgery (109697).
• Emergence delirium. Oral melatonin seems to be beneficial for reducing sevoflurane-induced agitation in children. Details: Clinical research in children aged 3-9 years shows that taking melatonin 0.3 mg/kg as part of a multimodal anxiolytic strategy reduces the incidence of sevoflurane-associated emergence delirium when compared with placebo or midazolam 0.3 mg/kg. Emergence delirium occurred in 27% of those children given melatonin, compared with 50% of those given placebo and 56% of those given midazolam (106292). In addition, a meta-analysis of three small clinical studies in children aged 2-9 years shows that taking melatonin 0.05-0.5 mg/kg 40-45 minutes prior to sevoflurane reduces the incidence of agitation when compared with placebo, with inconclusive outcomes when compared with midazolam and dexmedetomidine. A sub-group analysis indicates that doses of melatonin 0.2 mg/kg or greater may be most effective (97440). However, taking melatonin 0.5 mg/kg before surgery is 55% less effective than intranasal dexmedetomidine 2 mg/kg for reducing the incidence of sevoflurane-associated emergence delirium (109701).
• Endometriosis. Oral melatonin seems to reduce endometriosis-related pain. Details: Clinical research shows that taking melatonin 10 mg daily for 8 weeks reduces pain by about 39% and analgesic use by about 46%, as well as pain during menstruation, intercourse, and evacuation, when compared with placebo in adults with endometriosis (89503).
• Hypertension. Oral controlled-release melatonin seems to reduce blood pressure by a small amount in patients with hypertension. Immediate-release melatonin may not have the same effect. Details: Controlled-release melatonin 2-24 mg, taken before bedtime for up to 4 weeks, seems to lower systolic blood pressure by 4-6 mmHg and diastolic blood pressure by about 4 mmHg in individuals with essential hypertension or high blood pressure at nighttime (62359,62416,62441,62826,108947). However, most studies are small and the quality of the evidence is low (108947). Some evidence shows that immediate-release melatonin does not have this effect (62826). Melatonin also seems to reduce blood pressure in patients without hypertension, but to a lesser degree (103689).
• Insomnia. In patents with insomnia, oral melatonin seems to shorten the time it takes to fall asleep by about 7-12 minutes, although the effect on the amount of time asleep is inconclusive. Melatonin is more likely to be beneficial in older adults or people with certain comorbidities. Details: Short-term melatonin treatment appears to modestly reduce the time it takes to fall asleep (sleep latency) in otherwise healthy adults with insomnia. This reduction in sleep latency appears to amount to only about 7-12 minutes and might not be considered clinically relevant. Melatonin does not appear to improve sleep efficiency and may only increase total sleep time by about 8 minutes (15005,88290). Despite lack of substantial improvements in objective measures, some patients report minor improvement in subjective feelings of sleep quality (1070,1083,12226,88290). In children aged 6-12 years with insomnia due to delayed onset of sleep, melatonin 5 mg or 0.05-0.15 mg/kg at bedtime for up to 4 weeks seems to shorten the time that it takes to fall asleep and increases the duration of sleep (9708,62345,62770). More evidence is needed on the long-term effects of melatonin for insomnia. Some evidence shows that taking oral melatonin might be most beneficial for insomnia in elderly patients who could be melatonin deficient (1072,1729,1738,1754,7081,15005,62357,62465,62472,62613)(62776,62789). Taking sustained-release melatonin preparations 2 mg daily seems to improve sleep maintenance and sleep quality in elderly individuals (1738,1754,62465,62472,62613,62776), while immediate-release preparations seem to decrease sleep latency (1738,63041). In these clinical trials, controlled-release, fast-release, or slow-release melatonin 2-3 mg before bedtime for up to 29 weeks has been used (1072,1738,1754,7081,62357,62465,62472,62613,62776,62789). However, using a melatonin patch placed on the gums does not improve sleep parameters in elderly patients with insomnia (63062). Some research shows that taking melatonin when taken either alone or in combination with other sleep aids such as bright-light treatment seems to be beneficial for insomnia in patients with certain comorbid conditions. Taking melatonin 2-12 mg for up to 4 weeks has been used to improve insomnia in patients with depression (1053,1729), schizophrenia (8245,62452), bipolar disorder (62140), asthma (62375), cystic fibrosis (62708), hospitalization (9709,106295), and insomnia termed "ICU syndrome", which refers to sleep disturbances while in the intensive care unit (8240). Insomnia is also improved in children aged 3-12 years with epilepsy taking 6-9 mg of melatonin before bedtime for 4 weeks (62394,99342) and quality of sleep is modestly improved in adults with epilepsy taking 3 mg before bedtime for 8 weeks (110299). There is also evidence that melatonin can improve total sleep time and sleep-onset latency in children with tuberous sclerosis (1747), autism spectrum disorders (1056,62811,88286,96318,106293,110290), developmental disabilities (9707), and neurodevelopmental disorders (21819,62143,88283). It also appears to decrease sleep latency and increase sleep time in adults and children with intellectual disabilities, with or without epilepsy (62373,62561). While some evidence shows that fast-release melatonin is more effective for improving the time to fall asleep in children with sleep-wake cycle disturbances and neurodevelopmental disabilities, it is unclear if controlled-release melatonin provides any additional benefits in this population (62143,95746). However, there is conflicting evidence regarding the effects of melatonin in patients with insomnia and comorbid conditions such as Alzheimer disease or dementia. Some clinical research shows that taking melatonin 3-5 mg before bedtime for up to 10 weeks, either alone or in combination with bright-light treatment, improves impaired sleep related to Alzheimer disease or dementia (1729,62474,63059). But not all research agrees. Meta-analyses of several clinical studies show that taking melatonin 3-10 mg daily improves subjective sleep quality, but not objective outcomes such as number of awakenings at night and sleep efficiency in these patients. Also, immediate-release melatonin 2.5-10 mg or prolonged-release melatonin 1.5-2.5 mg for 10 days to 24 weeks shows inconsistent effects on total sleep time at night in patients with Alzheimer disease (96319,96320). There is also mixed evidence regarding the effects of melatonin in patients with Parkinson disease. Some subjective outcomes such as sleep quality seem to improve. However, the improvement might not be clinically significant, and objective outcomes such as sleep efficiency and total sleep time at night do not seem to improve (62403,62454,62829,96320). Melatonin has also been evaluated in postoperative patients and patients with traumatic brain injury (TBI). Taking melatonin before bed does not improve sleep quality soon after tracheostomy, laparoscopic cholecystectomy, or total knee arthroplasty (62439,62552,99343,100255) or 2-6 weeks after total joint arthroplasty (106305). In adults with TBI, one clinical study shows that taking prolonged-release melatonin (Circadin, Sigma Pharmaceuticals) 2 mg two hours prior to bedtime for 4 weeks improves sleep quality, efficiency, and fatigue when compared with placebo. However, melatonin did not improve sleep onset latency or daytime sleepiness. There appears to be no association between TBI severity and the effect of treatment (96317). There is mixed evidence regarding the effect of melatonin in patients undergoing hemodialysis. Some evidence shows that taking melatonin (Pharma Nord) 3 mg before bed for 6 weeks reduces time needed to fall asleep, improves sleep efficiency, and increases actual sleep time when compared with placebo (62521). Other clinical research in patients undergoing hemodialysis shows that taking immediate-release melatonin 3 mg (Puritans Pride, USA) for 3 months modestly improves various sleep measures when compared with placebo. After treatment, 63.0% of those taking melatonin had no insomnia compared with 7.7% of those taking placebo (110291). However, other evidence shows that taking immediate-release melatonin (Pharma Nord) 3 mg nightly for 12 months does not improve quality of life or sleep efficiency in these patients, indicating that melatonin may not improve sleep long-term (89501). Finally, limited evidence shows that melatonin does not improve insomnia in patients with substance use disorders (97441).
• Jet lag. Taking oral melatonin 2-3 mg daily while travelling seems to improve alertness and reduce daytime sleepiness in people with jet lag. It is unclear if it improves sleep efficiency in this population. Higher doses might have a hypnotic effect. Details: Most research shows that melatonin can modestly improve certain symptoms of jet lag such as alertness and psychomotor performance. Melatonin also seems to improve, to a lesser extent, other jet lag symptoms such as daytime sleepiness and fatigue (12226). Melatonin might not be effective for decreasing the time to fall asleep (sleep latency) or sleep efficiency in patients with jet lag (6496,14283), although some research shows a beneficial effect of melatonin on these outcomes (62364). Doses between 0.5-5 mg appear to be equally effective. Although doses of up to 8 mg have been used, doses greater than 5 mg do not seem to be more effective and seem to produce a greater hypnotic effect. Travelers traveling eastward through five or more time zones may find 2-3 mg of melatonin, either slow-release or fast-release, to be useful when taken at local bedtime on the day of arrival and for 2-5 nights thereafter. Taking melatonin in advance of travel does not help prevent jet lag. The usefulness of melatonin for westward travel or over fewer time zones is less clear, although some evidence suggests that slow-release formulations are less effective than fast-release preparations (1049,1077,1079,1085,1722,8273,9181,9750,62706).
• Migraine headache. Oral melatonin 3-4 mg seems to prevent migraines when used prophylactically. It is unclear if oral melatonin is beneficial for treating migraine. Details: Melatonin production might be altered in people with migraine headache (6712,96316). Meta-analyses and individual clinical studies in adults have shown that taking melatonin modestly reduces migraine severity, duration, and frequency, and increases the likelihood of a 50% reduction in the baseline frequency of migraine, when compared with placebo or baseline. Immediate- or prolonged-release melatonin (occasionally as Circadin, Sigma Pharmaceuticals) in doses of 3-4 mg each evening for up to 6 months have been used in these studies (12149,96316,97438,103486,110286). Meta-analyses have included two or three individual clinical trials (103486,110286). One meta-analysis shows that taking melatonin reduces the frequency of migraine days by about 1.7 (103486). An additional meta-analysis in adults with migraines shows that taking melatonin modestly reduces the use of analgesic medications from baseline, when compared with placebo (110286). In contrast, other clinical research shows that taking extended-release melatonin (Circadin, Neurim Pharmaceuticals Ltd.) 2 mg nightly for 8 weeks does not reduce migraine attack frequency when compared with placebo (62784). Some clinical research also shows that melatonin is as effective as standard treatment for migraine prevention. Some research shows that taking melatonin 3 mg daily for 12 weeks is as effective as amitriptyline 25 mg in reducing migraine frequency, intensity, and duration, as well as reducing analgesic use (96316). A meta-analysis of two clinical trials shows that taking melatonin 3 mg each evening for 8-12 weeks is as effective as standard treatment; however, only one study each compared melatonin with amitriptyline (96316) and valproate (110286). More research comparing melatonin with standard treatments is needed. Melatonin has also been investigated in children. Preliminary clinical research in children 5-15 years of age with migraine headache shows that taking melatonin 0.3 mg/kg daily for 90 days reduces migraine frequency, severity, and duration, and decreases analgesic use when compared to baseline (97446). Some research also suggests that melatonin might help to TREAT migraine headache in children and adolescents aged 9-17 years. Preliminary clinical research shows that taking melatonin 1-8 mg reduces pain by a small amount 2-4 hours later. The higher doses of 2 mg for children weighing less than 40 kg and 8 mg for children weighing at least 40 kg seemed to have the greatest benefit (103487). This study is limited by the lack of a comparator group and a very high drop-out rate.
• Pre-procedural anxiety. Most research shows that oral or sublingual melatonin reduces preoperative anxiety in adults. The benefit in children is unclear. Details: A meta-analysis of 18 clinical studies in adults shows that taking oral or sublingual melatonin 3-10 mg or 0.05-0.4 mg/kg 20-120 minutes prior to surgery reduces preoperative anxiety by an average of 12 points on a 100-point visual analogue scale when compared with placebo. It also reduces postoperative anxiety by about 5 points when compared with placebo. Furthermore, a meta-analysis of 7 small clinical trials suggests that melatonin is comparable to benzodiazepines such as midazolam, oxazepam, or alprazolam for reducing preoperative anxiety (105005). In some cases, melatonin might also be preferable to benzodiazepines because it does not cause anterograde amnesia, respiratory depression, or impairment of cognitive and psychomotor skills (88299,99337). However, research in children is conflicting. One small clinical study in children aged 2-8 years preparing to undergo outpatient elective surgery shows that taking melatonin 0.05-0.4 mg/kg 45 minutes before anesthesia is less effective than midazolam 0.5 mg/kg for reducing anxiety during separation from parents and when putting on the anesthesia mask (62601). In contrast, another small clinical study in children aged 2-5 years undergoing minor elective surgery shows that taking oral melatonin 0.25-0.5 mg/kg 1 hour before anesthesia is similar to midazolam 0.25-0.5 mg/kg for reducing anxiety when separating from parents and when putting on the anesthesia mask (62399). A third study in children aged 3-8 years found no differences between melatonin 0.3 mg/kg, midazolam 0.3 mg/kg, and placebo for reducing preoperative anxiety (106292).
• Pre-procedural sedation. Oral melatonin might reduce the sedative dose required to achieve adequate sedation in children. It is unclear if oral melatonin is beneficial for this purpose in adults. Details: A clinical study in children aged 5-14 years undergoing surgery shows that oral melatonin 0.5 mg/kg reduces the propofol dose required for adequate sedation by 0.77 mg/kg when compared with midazolam 0.5 mg/kg (97444). However, taking melatonin 0.5 mg/kg 45 minutes before surgery is less effective than intranasal dexmedetomidine 2 mg/kg for successful mask acceptance and parental separation (109701). A meta-analysis of clinical and observational studies in children undergoing non-operative procedures, such as electroencephalogram (EEG) and magnetic resonance imaging (MRI), suggests that enteral or parenteral melatonin is no better for adequate sedation than sleep deprivation or chloral hydrate (105884). This finding is limited by imprecision, inconsistency, and a high risk of bias. A small clinical study in adults undergoing total abdominal hysterectomy shows that taking extended-release melatonin 5 mg, 90 minutes before surgery, decreases the use of midazolam for sedation during surgery when compared with placebo (108945). However, the validity of this finding is unclear, as 0% of patients in the melatonin group required midazolam, compared with 100% of patients in the placebo group. In adults undergoing lower extremity orthopedic surgery with spinal anesthesia, a small study shows that giving melatonin 10 mg orally the night before surgery, followed by 10 mg 2 hours prior to surgery, increases the sedation score when compared with placebo (108951).
• Sunburn. Most research shows that topical melatonin seems to protect against erythema from ultraviolet (UV) light exposure. Details: When applied prior to UV light exposure, a gel containing melatonin 0.05% to 2.5% seems to significantly decrease erythema (1066,1768,1769). In one study, topically applied melatonin in combination with vitamin E 2% and/or vitamin C 5%, was modestly photoprotective when used prior to UV exposure, but had no effect when used during or after UV exposure (4713,4714). Other preliminary clinical research shows that applying a cream containing melatonin 12.5% prior to sun exposure reduces erythema in adults with high sun reactivity, but not in those with mild to moderate sun reactivity. Creams containing melatonin 0.5% or 2.5% did not reduce erythema in any skin types when compared with placebo (97443). The differences in these findings may be related to the different topical formulations used.
• Temporomandibular disorders (TMD). Oral melatonin seems to moderately reduce pain in females with TMD. Details: Clinical research shows that taking melatonin 5 mg at bedtime for 4 weeks reduces pain by 44% and increases the ability to withstand pain by 39% when compared with placebo in females with TMD. This results in reduced analgesic use and improved sleep quality (89508).
• Thrombocytopenia. Oral melatonin seems to improve and prevent thrombocytopenia associated with cancer, cancer treatment, and other disorders. Details: Clinical research shows that taking melatonin can improve thrombocytopenia associated with cancer, cancer treatment, and other disorders. Melatonin 20-40 mg daily beginning up to 7 days before chemotherapy and continuing for up to four chemotherapy cycles or until disease progression has been used (1694,1695,1696,1697,2564,8268).

POSSIBLY INEFFECTIVE

• Athletic performance. Most research suggests that oral melatonin does not improve athletic performance or physical strength. Details: Taking melatonin 6 mg one hour prior to heavy resistance exercise does not seem to improve maximal strength or maximal jumping ability (62424). Also, taking melatonin 5 mg at night does not appear to improve exercise performance the following morning in healthy athletes (62179). Furthermore, taking melatonin 5 mg 15 minutes prior to exercise does not appear to impact endurance during a cycling trial when compared with placebo (99338). However, some research disagrees. One small clinical trial in professional soccer players shows that taking melatonin 5 mg daily during a six-day training schedule modestly attenuates deterioration in physical performance, such as jumping, agility, and sprints, when compared with placebo (109700).
• Cachexia. Oral melatonin does not seem to improve appetite or body composition in patients with cachexia and cancer. Details: Clinical research in cachectic patients with advanced lung or gastrointestinal cancers shows that taking melatonin 20 mg each evening for 28 days does not improve appetite, body weight, or body composition when compared with placebo (88287).
• Cancer-related fatigue. Oral melatonin does not seem to improve fatigue in patients with cancer. Details: A meta-analysis of five clinical trials shows that taking melatonin does not reduce fatigue in patients with cancer (109697). Most studies used melatonin 20 mg daily, with a duration of 7 days to one year (99344,109697). Although most studies included in the analysis were small, one contained over 700 patients and lasted one year.
• Cancer-related pain. Oral melatonin does not seem to improve pain in patients with cancer. Details: A meta-analysis of five clinical trials shows that taking melatonin does not reduce pain in patients with cancer (109697). Most studies used melatonin 20 mg daily, with a duration of 10 days to one year (109697). Although most studies included in the analysis were small, one contained over 700 patients and lasted one year.
• Critical illness (trauma). Oral melatonin does not seem to be beneficial for reducing hospital stay in critically ill patients. Details: A meta-analysis of clinical research in critically ill patients shows that taking melatonin does not reduce the length of stay in the ICU or the hospital, or affect mortality or sleep quality, when compared with placebo (109696). One additional small clinical study shows that receiving melatonin 3 mg through a nasogastric tube once at 9 pm, followed by a 0.5 mg hourly maintenance dose for 6 hours during the overnight period, does not improve sleep when compared with placebo in patients in the ICU that are being weaned off sedatives and mechanical ventilation (104997).
• Dementia. Oral melatonin does not seem to improve behavior or cognition in patients with dementia. However, it might reduce evening confusion (sundowning). Details: Most clinical research shows that taking melatonin does not improve cognition or behavioral or affective symptoms in patients with probable Alzheimer disease or other forms of dementia (62421,62530,96319). However, some research shows that taking melatonin 2.5-3 mg before bedtime for up to 10 weeks reduces sundowning, which is the confusion and restlessness experienced by some dementia patients in the evening (62788).
• Infertility. Oral melatonin does not seem to increase fertility in females undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Details: Some clinical research shows that taking melatonin does not improve fertility rate or clinical pregnancy rate in adults undergoing IVF, although oocyte and embryo quality might be improved (62775,62818,62819,88297,89512). Also, results from meta-analyses of clinical research show that melatonin does not improve clinical pregnancy rate, total number of oocytes retrieved, or the rate of miscarriage, although it seems to increase the number of mature oocytes (89505,106304). Most studies have used single doses of 3 mg daily which may not be adequate (106304). Melatonin has also been evaluated in adults undergoing ICSI. Although one study shows that taking melatonin improves the fertilization rate, the clinical pregnancy rate was not evaluated (88297). Other research in females taking melatonin and undergoing ICSI does not show an increase in clinical pregnancy rate (97445).
• Shift work disorder. Oral melatonin does not seem to improve sleep in individuals doing shift work. Details: Taking melatonin orally doesn't seem to significantly improve the time it takes to fall asleep (sleep latency), sleep efficiency, or adjustment to rotating shift work. However, slight increases in total sleep time during the day or overall sleep quality may occur (1052,1054,1721,14283,62200,62401,62462,62942).

LIKELY INEFFECTIVE

• Benzodiazepine withdrawal. Oral melatonin does not facilitate benzodiazepine discontinuation in patients with insomnia. Details: Although some small studies show benefit (349,1751), results from larger clinical studies and a meta-analysis of clinical research show that taking melatonin 2-5 mg before bedtime for up to 6 weeks does not help facilitate benzodiazepine discontinuation in patients with insomnia (62464,62467,63075,88295,96321,96323).
• Depression. Most research shows that oral melatonin does not reduce symptoms of depression or prevent depression. In some patients, taking melatonin might make symptoms worse. Details: Most research shows that taking melatonin 5-10 mg daily before bedtime for 4-12 weeks, alone or with fluoxetine, does not improve depression symptoms in patients with rapid cycling bipolar disorder (1766) or major depressive disorder (MDD) (1053,62746,96326). However, some research shows that taking slow-release melatonin 3 mg in combination with immediate-release buspirone 15 mg daily for 6 weeks is more effective at improving depression severity and depression symptoms than placebo or buspirone alone in patients with MDD (88289). However, buspirone is not commonly used for the management of depression. Also, there is some concern that oral melatonin may worsen symptoms in some patients with unipolar or bipolar depression (1764). Evidence regarding the effects of melatonin for preventing depression is unclear. One clinical study shows that taking melatonin 6 mg daily for 12 weeks reduces the percentage of breast cancer patients who develop depression following a lumpectomy or mastectomy by about 75% when compared with placebo when an intention to treat analysis is used. However, when only patients who took all of the doses are considered, melatonin does not appear to have an effect (89511). Also, a meta-analysis of clinical research including two studies in patients with irritable bowel syndrome (IBS) who were at risk for depression shows that melatonin does not prevent depression when compared with placebo (96326).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). It is unclear if oral melatonin prevents vision loss in patients with AMD. Details: Preliminary clinical research shows that taking melatonin 3 mg daily for 3-6 months may delay the loss of clear vision in individuals with AMD when compared with baseline (62419). The validity of this finding is limited by the lack of a comparator group.
• Atopic dermatitis (eczema). Oral melatonin might improve some symptoms of atopic dermatitis. However, it is unclear if it improves sleep in this population. Details: Preliminary clinical research in children ages 1-18 years with atopic dermatitis and sleep disturbance shows that taking melatonin 3 mg daily for 4 weeks modestly reduces the overall atopic dermatitis symptom score by 19% when compared with placebo (97439). In another clinical study in children with atopic dermatitis, taking melatonin 6 mg daily 1 hour before bedtime for 6 weeks seems to improve disease severity and sleep quality when compared with placebo (99347). It is unclear whether melatonin improves sleep latency in this population, as conflicting results exist (97439,99347).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral melatonin is beneficial for ADHD. Details: Some small clinical studies in children with ADHD who are taking stimulants show that melatonin 3-5 mg daily for up to 3 months might reduce insomnia when compared with placebo (9980,15034). However, improved sleep related to melatonin treatment does not seem to result in fewer symptoms of ADHD (15034).
• Autism spectrum disorder. It is unclear if oral melatonin is beneficial for this condition. Details: One clinical trial in children aged 6-15 years with autism spectrum disorder shows that taking melatonin (Nobelpharma Co., Ltd) 1 mg or 4 mg before bedtime does not affect behavior when compared with placebo. However, this study was designed to evaluate sleep outcomes, not behavior, as a primary endpoint (106293). Also, a secondary analysis of results from a clinical trial in children with autism spectrum disorder shows that taking prolonged-release melatonin mini-tablets (PedPRM) 2-5 mg nightly for 13 weeks improves externalizing behavior in 26% more patients when compared with those taking placebo. There was no difference between groups in behaviors such as hyperactivity, inattention, emotional behavior, and relationships with peers (101256). The validity of these findings is limited by the secondary nature of the analysis, which was not designed to evaluate these outcomes.
• Benign prostatic hyperplasia (BPH). It is unclear if oral melatonin is beneficial for BPH. Details: One very small clinical study shows that taking controlled-release melatonin 2 mg nightly for 4 weeks reduces excessive urination at night in some men with BPH when compared with placebo. However, it is unclear if this improvement is clinically significant (62360).
• Bipolar disorder. It is unclear if oral melatonin is beneficial for this condition. Details: Preliminary clinical research shows that taking melatonin 3 mg at bedtime for 30 days increases sleep duration and reduces mania severity when compared to baseline in patients with bipolar disorder and treatment-resistant insomnia (62140). However, other research shows that melatonin is not beneficial in patients with bipolar disorder when compared with placebo. Taking melatonin 3-10 mg daily before bedtime for 3-12 weeks does not seem to improve mania or other symptoms when compared with placebo (1766,103694). Also, taking a specific brand of slow-release melatonin (Cronocaps, Productos Medix) 5 mg each evening for 8 weeks may attenuate the increase in blood pressure and fat mass that is associated with use of second-generation antipsychotics, but it does not appear to improve mania or depression in patients with bipolar disorder (88300). There is also some concern that oral melatonin may worsen symptoms in some patients with bipolar depression (1764).
• Bronchopulmonary dysplasia. It is unclear if oral melatonin reduces the risk of bronchopulmonary dysplasia (BPD) in premature infants. Details: A small clinical study in premature infants with respiratory distress syndrome who received surfactant shows that giving melatonin 3 mg daily for 7 days reduces the incidence of BPD to 45%, compared with 60% in those not receiving melatonin. Melatonin also reduced the duration of hospital stay, need for mechanical ventilation, and mortality (108948).
• Chronic fatigue syndrome (CFS). It is unclear if oral melatonin is beneficial for patients with CFS. Details: Many patients with CFS have circadian rhythm disturbances. Some very small clinical studies have evaluated the use of melatonin for addressing these disturbances. One study shows that taking melatonin 5 mg in the evening for 12 weeks might improve some measures of fatigue, concentration, motivation, and activity when compared with baseline (14437). However, other preliminary clinical research shows that taking the same dose of melatonin does not improve CFS symptoms when compared with placebo (9705). Melatonin has also been studied in combination with zinc. In patients with CFS, taking melatonin 1 mg plus zinc 10 mg before bedtime for 16 weeks modestly reduces self-reported levels of physical fatigue, but not self-reported cognitive or psychological symptoms, mood, sleep quality, or quality of life (QOL) measures, when compared with placebo. However, some measures of sleep quality and QOL worsened within 4 weeks of melatonin discontinuation, suggesting that there may have been a modest benefit (106241). It is unclear whether any benefit is related to melatonin, zinc, or the combination. Also, all patients in this study were White females, limiting the generalizability of the results.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral melatonin is beneficial for COPD. Details: Some clinical research shows that taking melatonin 3 mg daily for 3 months improves shortness of breath in patients with COPD when compared with placebo, although melatonin does not seem to improve lung function or exercise capacity (62854).
• Cluster headache. It is unclear if oral melatonin prevents cluster headaches. Details: A very small clinical study in adults with cluster headaches shows that taking melatonin orally 10 mg every evening for 14 days might reduce the frequency of episodic cluster headaches when compared with placebo (1127). However, 2 mg at bedtime does not seem to be effective (9702).
• Cognitive impairment. Oral melatonin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults 70 years and older with mild cognitive impairment shows that taking two capsules containing melatonin 5 mg, docosahexaenoic acid (DHA) 720 mg, eicosapentaenoic acid (EPA) 286 mg, vitamin E 16 mg, soy phospholipids 160 mg, and L-tryptophan 95 mg (IBSA Farmaceutici) before bedtime for 12 weeks modestly improves cognitive function and sensitivity to smells when compared with placebo. The observed improvement on the mini-mental state examination (MMSE) scale falls below the score generally considered to be indicative of true changes in cognitive function, and may not be clinically significant. Also, it is not known if any potential benefit is due to melatonin, other ingredients, or the combination (62847).
• Colorectal cancer. It is unclear if oral melatonin is beneficial for colorectal cancer prevention. Details: Population research suggests that any history of melatonin use is associated with an approximate 20% reduction in the incidence of colorectal cancer, especially rectal cancer, in individuals aged 60 years and older (106291).
• Contraception. Although there has been interest in using oral melatonin for contraception, there is insufficient reliable information about the clinical effects of melatonin for this use.
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral melatonin is beneficial for recovery from CABG surgery. Details: Clinical research shows that taking melatonin perioperatively during CABG surgery reduces the length of stay in the ICU by about 0.5 days and modestly reduces levels of creatine kinase-MB when compared with placebo. However, there was no effect on the length of hospital stay or levels of cardiac troponin-I, C-reactive protein, or erythrocyte sedimentation rate. Oral melatonin 3 mg was provided the night before and morning of surgery, as well as at bedtime for 3 days after surgery (109699).
• Coronavirus disease 2019 (COVID-19). Preliminary clinical studies suggest that oral melatonin may reduce disease severity in patients with COVID-19, although some conflicting findings exist. Details: A meta-analysis of mainly small and preliminary randomized clinical trials in patients with COVID-19 shows that taking melatonin improves clinical outcomes when compared with placebo. However, the clinical outcomes differed between individual trials, and included specific symptoms, hospital discharge, removal from quarantine, and survival. Dosing also varied, with doses of 2-24 mg daily in 1-4 divided doses for 6-14 days. There was no effect of melatonin on C-reactive protein levels or oxygen saturation (109695). Individual clinical trials have been conducted in hospitalized and/or non-hospitalized patients with mild to severe COVID-19. One clinical trial in outpatients with mild to moderate COVID-19 shows that taking melatonin 10 mg daily modestly reduces time to symptom resolution and quality of life improvement when compared with placebo (109462). However, it is unclear if any beneficial effects are clinically meaningful. In patients hospitalized and receiving standard care for mild to moderate COVID-19, a small clinical trial shows that taking melatonin 3 mg three times daily for 14 days reduces the mean time to hospital discharge by approximately 3.5 days when compared with placebo. Also, persistent symptoms of cough, dyspnea, and fatigue after 14 days occurred in only 0% to 8% of patients taking melatonin, compared with 15% to 30% of those taking placebo. However, there was no difference in the number of patients with other symptoms, including fever, myalgia, chill, and headache (106300). The validity of this study is limited by its high attrition rate. Another small clinical trial in patients hospitalized with COVID-19 shows that taking melatonin (Norm Life Vanatonin Melatonin) 3 mg nightly for 7 days does not reduce symptoms or prevent ICU admission or death when compared with standard care alone (106295). The low dose and short duration of use in this study might have played a role in the lack of benefit. Melatonin has also been evaluated in patients hospitalized for severe COVID-19. One large single-center preliminary clinical trial shows that taking melatonin 10 mg daily reduces the incidence of thrombosis at day 17 and the incidence of sepsis at day 11 when compared with standard care alone. Death occurred in approximately 17% of patients taking placebo, compared with 1% of those taking melatonin (106289). Another preliminary clinical trial in patients in the ICU for severe COVID-19 shows that taking melatonin (Danna Pharmaceutical Company, Iran) 5 mg twice daily for 7 days results in mortality and invasive mechanical ventilation rates of 67% and 51.4%, respectively, compared with 94% and 70.9% in patients given standard care only. There were also modest improvements in the time to improvement of clinical status and lengths of stay in the hospital and ICU (110297). The validity of these studies is limited by a lack of blinding.
• Delirium. It is unclear if oral melatonin is beneficial for preventing delirium in hospitalized patients; the available research is conflicting. Details: Although a large individual study disagrees (108952), a meta-analysis of 10 clinical trials shows that melatonin reduces the prevalence of delirium in critically ill patients in the ICU by 21% when compared with a control, usually placebo. However, there was no significant difference in the duration of delirium. Also, bias was a concern in many of the studies (109696). A previous meta-analysis of 9 small clinical studies shows that melatonin does not reduce delirium occurrence when compared with control, although there was a non-significant trend towards a reduction. Melatonin might be less beneficial in non-acute medical patients when compared with postoperative patients or those in the intensive care unit (ICU) (105003). This analysis is limited by substantial heterogeneity and a lack of dose-response evaluation. Most studies in these analyses have used doses of 0.5-10 mg daily for up to 14 days, although one study used a very high single dose of 50 mg/kg (105003,105891,107809,108949,109696). One additional small clinical study shows that receiving melatonin 3 mg through a nasogastric tube once at 9 pm, followed by a 0.5 mg hourly maintenance dose for 6 hours during the overnight period, does not reduce delirium or improve sleep when compared with placebo in patients in the ICU that are being weaned off sedatives and mechanical ventilation (104997). In contrast, two large clinical studies in older patients admitted to the ICU after acute heart failure or percutaneous coronary intervention (PCI) show that taking melatonin 3 mg once daily for up to 7 days is associated with a 27% incidence of delirium, compared with a 37% to 40% incidence with placebo (107809,108949). A small clinical study in patients undergoing coronary artery bypass graft (CABG) surgery suggests that taking prolonged-release melatonin (Webber Naturals) 3 mg twice before surgery and twice after surgery reduces the occurrence of delirium over the next 48 hours when compared with placebo (105891). The validity of this study is limited by a high risk of bias due to insufficient blinding and incomplete outcome data.
• Diabetes. Most research shows that oral melatonin is beneficial for improving glycemic control. However, it is unclear if oral melatonin is beneficial in patients with type 2 diabetes. Details: Most research on the use of melatonin for glycemic control has been conducted in mixed populations, such as those with schizophrenia, metabolic syndrome, nonalcoholic steatohepatitis (NASH), or perimenopause (103490,106294,106298). Two recent meta-analyses of clinical research in these populations show that taking melatonin modestly reduces fasting glucose and insulin, insulin resistance, and glycated hemoglobin (HbA1c), and improves insulin sensitivity (106294,106298). The most common doses of melatonin used were 3 -10 mg for 8-24 weeks; however, 10 mg may be more effective (106294,106298). This contrasts with an earlier meta-analysis showing only modest beneficial effects of melatonin on fasting glucose levels and insulin sensitivity (103490). Research on the use of melatonin in patients with type 2 diabetes is limited. One small clinical trial in patients with type 2 diabetes show that taking melatonin (NatureMade) 6 mg daily for 8 weeks does not improve glycemic control (104368). However, this trial may have been underpowered to detect a difference. Another small clinical trial shows that taking 6 mg of this product each evening seems to lower systolic blood pressure in patients with type 2 diabetes when compared with placebo (104368,105888).
• Diabetic neuropathy. It is unclear if oral melatonin is beneficial for improving pain in patients with diabetic neuropathy. Details: A clinical study in patients with painful diabetic neuropathy living in Iran shows that taking melatonin 3 mg nightly for 1 week and then 6 mg nightly for 7 weeks, in conjunction with pregabalin 150 mg daily seems to reduce pain and sleep interference to a greater degree than placebo and pregabalin (105895).
• Dry mouth. It is unclear if oral melatonin is beneficial for dry mouth caused by radiation treatment. Details: A small clinical study in patients with head and neck cancer undergoing chemoradiation shows that taking melatonin 20 mg orally at bedtime and using 10 mL of melatonin 0.2% oral gargle 15 minutes before each radiation session does not delay the onset or reduce the incidence of grade 2 dry mouth when compared with placebo. However, the incidence of grade 3 dry mouth is delayed by approximately 16 days (96314).
• Dysmenorrhea. It is unclear if oral melatonin is beneficial for dysmenorrhea. Details: A small clinical trial shows that taking melatonin 10 mg nightly before bed during the week of menstruation has a statistically significant effect on pain severity when compared with placebo. However, the pain reduction was not considered clinically significant (106301).
• Dyspepsia. It is unclear if oral melatonin is beneficial for dyspepsia in adults. Details: Preliminary clinical research shows that taking melatonin 5 mg nightly for 12 weeks improves dyspeptic symptoms in individuals with functional dyspepsia. However, the benefit seems to be decreased in patients with prior Helicobacter pylori infection (62456).
• Endotracheal intubation-associated adverse effects. It is unclear if oral melatonin is beneficial for endotracheal intubation-related hemodynamic effects. Details: Clinical research shows that taking immediate-release melatonin (Healthy Hey Nutrition) 6 mg, 2 hours prior to the induction of anesthesia, is as effective as clonidine 0.2 mg for attenuating the hemodynamic response to laryngoscopy and tracheal intubation (103483). It is not known if melatonin prevents other adverse effects associated with endotracheal intubation.
• Epilepsy. It is unclear if oral melatonin is beneficial for epilepsy in children or adults. Details: There is some low-quality evidence that taking melatonin 3 mg at bedtime for 3 months might reduce the frequency and duration of both nocturnal and daytime seizures in children aged 2-15 years with epilepsy (9699,9745,9746,62785). Also, taking melatonin 1.5 mg before bed for 3 months might reduce the seizure severity in children with epilepsy that is not successfully controlled with other treatment (62754). Furthermore, taking fast-release melatonin 10 mg daily for 3 weeks seems to reduce diurnal seizure frequency in both adults and children aged 9 years and up with intractable epilepsy (88291). Limited research has also assessed melatonin as an adjunct therapy in adults with seizure disorders. A small clinical study in adults with epilepsy involving generalized onset motor seizures that recurred within the last three days shows that adding melatonin 3 mg before bed to therapy with valproate 20 mg/kg in two divided doses daily for 8 weeks results in 82% of patients having at least a 50% reduction in seizure frequency, compared with only 53% of patients in the group taking valproate and placebo. Adding melatonin may also improve seizure severity (105006). However, other clinical research in adults under valproic acid treatment for idiopathic generalized tonic-clonic seizures alone shows that taking melatonin 3 mg before bed for 8 weeks modestly reduces seizure severity, but not frequency (110299).
• Fibromyalgia. It is unclear if oral melatonin is beneficial for this condition. Details: Preliminary clinical research shows that taking melatonin 3-5 mg daily for up to 60 days may decrease the severity of pain and stiffness, as well as the number of painful joints, in people with fibromyalgia when compared with placebo (9701,62797).
• Gastroesophageal reflux disease (GERD). It is unclear if oral melatonin is beneficial for GERD. Details: Clinical research shows that taking melatonin 3 mg daily at bedtime for 8 weeks may improve symptoms of GERD, including heartburn and epigastric pain. However, taking omeprazole 20 mg twice daily seems to be more effective (62723).
• Helicobacter pylori. It is unclear if oral melatonin is beneficial for Helicobacter pylori eradication. Details: One very small clinical study shows that taking melatonin 5 mg twice daily in combination with omeprazole 20 mg twice daily for 21 days improves ulcer healing rates when compared with omeprazole alone in individuals with H. pylori-associated gastroduodenal ulcers (62803).
• Heart failure. It is unclear if oral melatonin is beneficial for heart failure. Details: A small clinical study in adults with stable NYHA class II or III heart failure with reduced ejection fraction (HFrEF) and a left ventricular ejection fraction (LVEF) below 40%, shows that taking melatonin 10 mg orally every evening for 24 weeks improves a composite score reflecting all-cause mortality, hospitalization for exacerbation, and quality of life when compared with placebo. Melatonin also attenuates an increase in serum B-type natriuretic peptide levels, but does not affect LVEF or left ventricular end-diastolic or end-systolic diameter (108950).
• Irritable bowel syndrome (IBS). It is unclear if oral melatonin is beneficial for IBS. Details: In patients with IBS who also have poor sleep, taking melatonin 3 mg at bedtime for 2 weeks seems to decrease symptoms of IBS-related abdominal pain and increase the rectal pain threshold when compared with placebo. However, taking melatonin does not seem to influence stool frequency or consistency, bloating, mood, sleep, or overall quality of life (13112). In other small clinical studies, taking melatonin 3 mg at bedtime for 8 weeks decreased severity and frequency of pain, reduced bloating, improved bowel habits, decreased extracolonic symptoms such as headache, heartburn and nausea, and improved overall quality of life when compared with placebo (15216,62410). However, other clinical research shows that melatonin does not significantly affect the amount of time needed for food to travel through the colon in patients with IBS (62500). Also, one small clinical study shows that taking melatonin 3 mg in the morning and 5 mg in the evening for 6 months improves abdominal pain, bloating, and bowel habits in 50% to 70% of postmenopausal patients with constipation-predominant IBS when compared with placebo. However, beneficial effects were reduced in patients with diarrhea-predominant IBS (89510). The large number of endpoints in these studies makes it difficult to draw conclusions.
• Ischemia-reperfusion injury. It is unclear if intravenous or intracoronary melatonin is beneficial for ischemia-reperfusion injury. Details: A meta-analysis of 9 low-quality clinical trials in patients with myocardial ischemia-reperfusion injury shows that giving melatonin in doses of 2-50 mg by intravenous or intracoronary injection within 2.5-3.5 hours of ischemia onset improves left ventricular ejection fraction and reduces the infarct size, but does not improve left ventricular end-diastolic or end-systolic volumes, when compared with control. Also, giving melatonin orally for up to 12 weeks does not improve cardiac function. The patients in this study experienced injury as a result of an ST-elevation myocardial infarction, ischemic heart disease, acute coronary syndrome, or coronary heart disease (108946).
• Kidney failure. It is unclear if oral melatonin is beneficial for improving mood and quality of life in patients on hemodialysis. Details: A small clinical trial in patients undergoing hemodialysis shows that taking immediate-release melatonin 3 mg (Puritans Pride, USA) for 3 months modestly improves depression, anxiety, and quality of life when compared with placebo. After treatment, 73.1% and 57.7% of those taking placebo had severe depression and anxiety, respectively, when compared with 22.2% and 14.8% of those taking melatonin (110291).
• Kidney transplant. It is unclear if oral melatonin is beneficial for improving post-transplant kidney function. Details: A small clinical study in patients that have received kidney transplants shows that taking melatonin 3 mg daily for an average of 25 days does not affect urine volume or kidney function, as measured by the blood urea nitrogen over creatinine (BUN/Cr) ratio, when compared with placebo (103693).
• Lung cancer. It is unclear if melatonin is beneficial in patients with early stage non-small cell lung cancer (NSCLC). Details: A clinical study in patients who have undergone complete surgical resection of early stage NSCLC shows that taking melatonin 20 mg daily for 1 year does not improve 2-5 year disease-free survival, pain, anxiety, fatigue, or quality of life when compared with placebo (105894). The validity of these findings is limited by a high study withdrawal rate.
• Melasma. Although there has been interest in using oral melatonin for melasma and other causes of hyperpigmentation, there is insufficient reliable information about the clinical effects of melatonin for these conditions.
• Menopausal symptoms. It is unclear if oral melatonin is beneficial for improving symptoms of menopause; evidence is conflicting. Details: A meta-analysis of 3-5 clinical studies in patients with menopausal symptoms shows that taking melatonin does not seem to improve vasomotor or psychological symptoms, but may modestly improve physical symptoms, when compared with placebo (105897). This analysis is limited due to inconsistent evidence and some risk of bias within the included studies. Studies included in the meta-analysis used melatonin 3 mg daily for 3-12 months alone or in combination with soy isoflavones 80 mg or fluoxetine 20 mg (11806,62840,105897).
• Metabolic syndrome. It is unclear if oral melatonin is beneficial for this condition. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking melatonin 5 mg nightly for 2 months reduces systolic and diastolic blood pressure, as well as low-density lipoprotein (LDL) cholesterol levels, when compared to baseline (62795). The validity of these findings is limited by the lack of a comparator group.
• Multiple sclerosis (MS). It is unclear if oral melatonin is beneficial for MS. Details: A small clinical study in patients with relapsing-remitting MS (RRMS) receiving interferon-beta once weekly shows that taking melatonin 3 mg daily for 12 months does not affect relapse rate, disability, brain lesions, fatigue, or depression when compared with placebo (99345). This small study may not have been adequately powered to detect a difference between groups.
• Myocardial infarction (MI). The benefits of administering oral or intravenous melatonin immediately after an MI are unclear. Details: A meta-analysis of 5 small clinical studies in patients after MI shows that oral or intravenous melatonin, used in conjunction with medical reperfusion, is associated with modestly lower troponin levels and modestly higher left ventricular ejection fraction when compared with control (105889). One clinical study included in this analysis that evaluated patients with ST-segment elevation myocardial infarction (STEMI) shows that intravenous administration of melatonin 51.7 mcmol over 60 minutes immediately prior to percutaneous coronary intervention, combined with a bolus intracoronary dose of melatonin 8.6 mcmol administered within 60 seconds after restoration of blood flow to the infarcted artery, does not reduce myocardial infarct size when compared with placebo. However, subgroup analyses suggest that the timing of melatonin administration after symptom onset may alter its effects (96324).
• Neonatal encephalopathy. It is unclear if oral or intravenous melatonin is beneficial for neonates with encephalopathy. Details: A meta-analysis of two small clinical studies in term or late preterm infants with neonatal encephalopathy who are receiving therapeutic hypothermia shows that receiving melatonin 5 mg/kg intravenously daily for 3 days, or 10 mg/kg orally daily for 5 days, does not reduce mortality when compared with hypothermia alone, although a nonsignificant trend towards a reduction was noted (104994). One of those small studies in term infants with neonatal encephalopathy also shows that receiving adjunct oral melatonin treatment results in fewer seizures and less white matter abnormalities when compared with hypothermia alone (99333).
• Nocturnal enuresis. It is unclear if oral melatonin is beneficial for reducing nighttime wettings. Details: Preliminary clinical research shows that taking melatonin 5 mg nightly before bedtime for 3 months does not reduce the number of wet beds when compared with placebo in children with nighttime wettings (nocturnal enuresis) (62824).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral melatonin is beneficial for NAFLD. Details: A meta-analysis of clinical research, as well as individual clinical trials, show that taking melatonin 6-18 mg daily for 4-56 weeks improves some liver indices, but not others (62853,88285,103484,103485). Overall, taking melatonin seems to modestly reduce levels of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). However, there is no effect on alanine aminotransferase (ALT) and levels of aspartate aminotransferase (AST) slightly increased (103485). One small clinical study shows that taking melatonin (Nature Made, USA) 6 mg daily for 12 weeks has a small benefit on systolic and diastolic blood pressure, body mass index (BMI), abdominal circumference, and liver enzymes, but not plasma lipid levels, when compared with placebo (103484). Larger studies are needed to determine the effect of melatonin in this population.
• Obesity. It is unclear if melatonin is beneficial for improving weight loss. Details: A meta-analysis of clinical research shows that taking melatonin up to 10 mg daily, usually for 4-24 weeks, modestly reduces body weight when compared with placebo. However, there was no effect on body mass index (BMI) or waist circumference. Also, the studies included in the analysis were not limited to overweight or obese individuals. Populations included those with metabolic syndrome, nonalcoholic steatohepatitis (NASH), schizophrenia, polycystic ovary syndrome (PCOS), and others, as well as postmenopausal adults (106288). A small clinical trial in overweight or obese individuals shows that although taking melatonin 3 mg daily for 12 weeks modestly reduces waist circumference and body fat mass when compared with placebo, there is no effect on body weight or BMI (106290).
• Oral mucositis. Most research shows that melatonin does not prevent or reduce the severity of oral mucositis in patients with head and neck cancer receiving radiation and chemotherapy. It is unclear if oral or topical melatonin is beneficial in patients with other types of cancer. Details: A meta-analysis of seven clinical trials including patients undergoing chemotherapy or radiotherapy shows that melatonin does not reduce the rate of oral mucositis when compared with a control, usually placebo (109697). Although a small clinical study in patients with head and neck cancer undergoing radiation and chemotherapy with cisplatin shows that melatonin delays the onset of severe mucositis by 16 days when compared with placebo (96314), a meta-analysis shows that melatonin does not reduce the rate of oral mucositis in patients with head and neck cancer (109697). A sub-analysis in one meta-analysis suggests that taking melatonin, usually 20 mg daily, reduces the rate of oral mucositis by 53% in patients with cancer types other than head and neck (109697). Most studies investigating the effect of melatonin have used oral melatonin 20 mg at bedtime. However, in one study, 10 mL of melatonin 0.2% oral gargle was also used 15 minutes before radiation (96314). In another, swishing with 10 mL of a melatonin 3% gel mouthwash for 2 minutes and then swallowing, starting 2-3 days before radiotherapy and continuing until 1-4 weeks after the end of radiotherapy, was used (105893). Melatonin has also been investigated for oral mucositis severity. Although some individual research disagrees (96314), a meta-analysis of three clinical trials shows that melatonin does not reduce the severity of oral mucositis when compared with placebo. However, the form of melatonin provided in these studies was heterogeneous, including oral, gargle, and gel formulations (96314,105893,109697).
• Osteopenia. It is unclear if oral melatonin is beneficial for improving bone mineral density. Details: A small clinical study in postmenopausal adults with osteopenia shows that taking melatonin 3 mg nightly for 1 year increases tibia thickness by 2.2% and volumetric bone mineral density (BMD) in the spine by 3.6% when compared with placebo. However, the BMD of other skeletal sites was not impacted. Additionally, a 1 mg melatonin dose was not beneficial (99334).
• Osteoporosis. Although there has been interest in using oral melatonin for osteoporosis, there is insufficient reliable information about the clinical effects of melatonin for this condition.
• Pain (acute). It is unclear if oral melatonin is beneficial for acute pain. Details: Clinical research in patients undergoing laparoscopic cholecystectomy shows that taking melatonin 6 mg two hours before induction with propofol reduces the number of patients requiring intraoperative fentanyl to 10%, compared with 35% of those taking placebo (106299). Also, preliminary clinical research in preterm infants also given standard treatments shows that oral melatonin (Syrup Trunap, Brio Bliss Life Science Pvt. Ltd) 20 minutes prior to retinopathy of prematurity screening, is not inferior to 24% sucrose for reducing pain (110295). However, the effect of sucrose itself is inconclusive and this study is limited by a lack of blinding. Also, it is unclear if melatonin is beneficial for other causes of acute pain.
• Pain (chronic). It is unclear if melatonin is beneficial for most causes of chronic pain. Details: A meta-analysis of 5 clinical studies shows that taking melatonin 3-12 mg daily for up to 12 weeks modestly reduces chronic pain when compared with placebo (103692). However, it is difficult to draw clinical conclusions from this analysis, as it pools the effects observed in various types of chronic pain, including migraine, burning mouth syndrome, endometriosis, and irritable bowel syndrome (IBS).
• Periodontitis. Small clinical studies suggest that oral melatonin may improve some measures of periodontitis severity. Details: A meta-analysis of 7 small clinical trials in patients with periodontitis treated with subgingival instrumentation to remove calculus and bacterial biofilms shows that adding oral melatonin in doses of 3-10 mg daily improves probing depth, clinical attachment loss, and gingival index when compared with instrumentation alone (108953).
• Polycystic ovary syndrome (PCOS). It is unclear if melatonin is beneficial for PCOS. Details: A prospective cohort study in patients with PCOS has found that taking melatonin (Armonia Fast, Nathura) 2 mg before bedtime for 6 months increases follicle-stimulating hormone and the total number of menstrual cycles from approximately 2.5 to 4 when compared to baseline (96313). The validity of this study is limited by its observational nature and the lack of a comparator group. Additionally, a small clinical study in patients with PCOS shows that taking melatonin 6 mg daily for 8 weeks does not affect insulin levels, fasting blood glucose, lipid levels, or weight, but might modestly reduce testosterone levels, when compared with placebo (105887). This study may have not been adequately powered to detect differences between groups.
• Postoperative nausea and vomiting (PONV). It is unclear if melatonin is beneficial for reducing PONV. Details: A small clinical trial shows that taking melatonin (Nature Made, USA) 3 mg, 5 mg, or 10 mg, one hour prior to lumbar discectomy surgery does not reduce postoperative nausea when compared with placebo (110294).
• Postoperative pain. It is unclear if melatonin is beneficial for reducing pain postoperatively. Details: Two meta-analyses, as well as most individual clinical studies, show that taking melatonin in addition to standard therapy modestly alleviates pain and reduces analgesic use after surgery when compared with placebo (62471,62512,62551,62743,88293,88294,103488,103691,103692,105892)(110294). However, any benefit is likely to be small and may not be clinically relevant (103488,109701). Melatonin has been used in doses of 1-10 mg daily for a duration of 1-21 days, usually starting the night before surgery (62471,62512,62743,103488,103691,105892,110294). This research is limited by poor methodology, as well as the heterogeneity of the included studies. The studies evaluated melatonin across a wide variety of surgeries, including abdominal hysterectomy, cataract surgery, caesarian section, prostatectomy, lumbar laminectomy, lumbar discectomy, laparoscopic cholecystectomy, wisdom teeth extraction, and corrective jaw surgery.
• Postoperative recovery. It is unclear if oral melatonin improves the rate of recovery after surgery. Details: In females undergoing total abdominal hysterectomy, taking extended-release melatonin 5 mg, 90 minutes before surgery, shortens hospital stay to a mean of 2.7 days, compared with 3.4 days for placebo (108945).
• Postoperative sleep disturbance. It is unclear if melatonin is beneficial for improving postoperative sleep disturbance. Details: A small clinical trial shows that taking melatonin (Nature Made) 5 mg each night before bed for 4 weeks, starting 2 weeks after surgery for orthopedic trauma, does not reduce postoperative sleep disturbance when compared with placebo. All patients were also given education related to sleep hygiene (110293).
• Postural tachycardia syndrome (POTS). It is unclear if melatonin is beneficial for POTS. Details: Preliminary clinical research in patients with POTS shows that taking a single dose of melatonin 3 mg reduces sitting and standing heart rate, after 2 and 4 hours, when compared with placebo. However, melatonin does not appear to affect blood pressure or orthostatic symptoms (88292). It is unclear if melatonin is beneficial when taken as more than a single dose.
• Pre-eclampsia. It is unclear if oral melatonin reduces the severity of pre-eclampsia. Details: A small clinical trial in patients with pre-eclampsia shows that taking sustained-release melatonin 10 mg with vitamin B6 10 mg three times daily, starting during recruitment and continuing until delivery, attenuates the need to increase the dose of antihypertensive medication on certain days, but does not affect overall pre-eclampsia severity, when compared with control (99341).
• Prostate cancer. Oral melatonin has only been evaluated in combination with medication; its effect when used alone is unclear. Details: One small clinical study in patients with metastatic prostate cancer that is refractory or resistant to treatment with the luteinizing hormone-releasing hormone (LHRH) analogue triptorelin shows that taking melatonin 20 mg daily in combination with intramuscular triptorelin injected every 28 days can decrease levels of prostate-specific antigen (PSA) and growth factors for prostate cancer when compared to baseline (7255). The validity of these findings is limited by the small study size and lack of a comparator group.
• Pruritus. Small clinical trials suggest that oral melatonin might be beneficial for some types of pruritus. Details: One small clinical trial in patients with pruritus due to various types of chronic liver disease shows that taking melatonin 10 mg nightly for 2 weeks modestly reduces the severity, frequency, and extent of pruritus when compared with placebo (106297). Another small clinical study in patients undergoing hemodialysis shows that taking melatonin 10 mg daily for 2 weeks reduces the severity of pruritus and reduces the affected body area when compared with placebo (104996).
• Radiation dermatitis. It is unclear if topical melatonin is beneficial for radiation-related dermatitis. Details: In females with breast cancer, a small clinical study shows that applying a specific melatonin emulsion cream (Praevoskin, PraevoMed GmbH) twice daily during radiation treatment and continuing for another 2 weeks results in fewer cases of grade 1 or 2 acute radiation dermatitis when compared with placebo (99336). In contrast, another clinical trial in patients with breast cancer shows that applying a cream providing melatonin 25 mg and dimethylsulfoxide 150 mg twice daily during and for 3 weeks after radiation treatment does not improve quality of life or breast symptoms at the end of treatment when compared with placebo. However, there was a modest reduction in breast symptoms over time (110298).
• Rapid eye movement sleep behavior disorder (RBD). It is unclear if oral melatonin is beneficial for RBD. Details: One very small clinical study shows that taking melatonin 3 mg before bed for 4 weeks increases the likelihood of muscle atonia during rapid eye movement (REM) sleep in patients with RBD when compared with placebo (62762). The validity of this finding is limited by the small study size.
• Restless legs syndrome (RLS). It is unclear if oral melatonin is beneficial for RLS. Details: One very small clinical study shows that taking melatonin 3 mg before bedtime does not improve symptoms of RLS and may actually worsen motor symptoms in individuals with RLS when compared with baseline (62753). The validity of this finding is limited by the small study size and lack of a comparator group.
• Rheumatoid arthritis (RA). It is unclear if oral melatonin is beneficial for RA. Details: A small clinical study in patients with RA shows that taking melatonin 6 mg daily for 12 weeks does not affect disease activity or erythrocyte sedimentation rate (ESR) when compared with placebo (105890).
• Sarcoidosis. It is unclear if oral melatonin is beneficial for this condition. Details: One very small clinical study shows that taking melatonin 20 mg daily for one year, followed by 10 mg daily for another year, improves lung function and skin lesions in patients with chronic sarcoidosis when compared with baseline (62435). The validity of this finding is limited by the small study size and lack of a comparator group.
• Schizophrenia. It is unclear if oral melatonin is beneficial for schizophrenia or for attenuating the adverse effects associated with antipsychotic medications. Details: Some clinical research shows that taking melatonin orally 3 mg each evening for 8 weeks reduces the weight gain and increased waist circumference associated with olanzapine when compared with placebo. It also seems to improve some symptoms of schizophrenia (88296). Other clinical research shows that taking a specific brand of slow-release melatonin (Cronocaps, Productos Medix) 5 mg each evening for 8 weeks reduces adverse effects from second generation antipsychotics, such as increased diastolic blood pressure and waist circumference, when compared with placebo. However, it does not seem to improve symptoms of schizophrenia (88300).
• Seasonal affective disorder (SAD). It is unclear if oral melatonin is beneficial for SAD. Details: Some preliminary clinical research shows that oral melatonin, 0.25-2 mg taken daily for 3 weeks, may decrease winter depression symptoms in patients with SAD (10670,62308). However, sublingual melatonin 0.5 mg daily for 6 days does not appear to improve this condition (62388). Reasons for these discrepancies may include the duration of treatment, route of administration, or the severity of SAD at baseline.
• Smoking cessation. It is unclear if oral melatonin is beneficial in patients trying to quit smoking. Details: One very small clinical study shows that taking melatonin 0.35 mg as a single oral dose 3.5 hours after initiation of nicotine withdrawal in smokers seems to reduce subjective symptoms of anxiety, restlessness, irritability, depression, and cigarette craving over the next 10 hours when compared with baseline (2424). The validity of these findings is limited by the small study size and lack of a comparator group.
• Sepsis. It is unclear if oral melatonin is beneficial for sepsis in neonates or adults. Details: There is conflicting research about the effect of melatonin on neonatal sepsis. While some preliminary research in Egypt shows that giving a single dose of melatonin 20 mg in addition to antibiotics reduces sepsis severity, another more recent study did not find a difference in outcomes between groups receiving antibiotics only or antibiotics with melatonin (99339,99340). In adults with early septic shock given standard care, a small clinical trial shows that taking melatonin 50 mg daily for 5 days increases the number of ventilator-free days by 6.9 and the number of vasopressor-free days by 2.6. ICU and hospital lengths of stay were reduced by 5.25 and 6.9 days, respectively. However, after 28 days there was no significant difference in the mortality rate, the number of patients requiring ventilation or renal replacement therapy, or the number of patients recovered from organ dysfunction (106296). Intravenous melatonin has also been investigated. A small clinical trial in patients with severe sepsis shows that a continuous infusion of melatonin, 60 mg over 24 hours, for 5 days following post-surgical sepsis diagnosis modestly reduces sepsis severity when compared with placebo. Hospital stay was reduced by approximately 5.2 days in patients given melatonin; however, it is unclear if this difference is statistically significant (110300).
• Stabbing headache. Although there has been interest in using oral melatonin for stabbing headaches, there is insufficient reliable information about the clinical effects of melatonin for this condition.
• Stress. It is unclear if oral melatonin is beneficial for stress reduction. Details: Preliminary clinical research shows that taking melatonin 3 mg one hour prior to stress modestly improves memory accuracy during a laboratory-induced stressful situation when compared with placebo (62509).
• Tardive dyskinesia. It is unclear if oral melatonin is beneficial for this condition. Details: One small clinical study shows that taking melatonin orally 10 mg daily for 6 weeks decreases symptoms by 24% to 30% in patients with tardive dyskinesia when compared with placebo (7082). However, other small clinical studies show that taking melatonin 2-20 mg daily for 4-12 weeks does not reduce abnormal, involuntary movement in patients with tardive dyskinesia when compared with placebo (62146,62825).
• Tension headache. It is unclear if oral melatonin is beneficial for reducing the frequency of tension headaches. Details: A small clinical study in patients with chronic tension headache shows that taking a specific melatonin supplement (Melaxen) 3 mg nightly for 30 days seems to reduce headache severity and reduce the median number of days with a headache by 6 when compared with baseline (104998). The validity of this finding is limited by the lack of a control group.
• Tinnitus. It is unclear if oral melatonin is beneficial for improving tinnitus intensity or severity. Details: Some clinical research shows that taking melatonin 3 mg nightly for one month reduces tinnitus intensity and improves the quality of sleep in individuals with chronic tinnitus when compared with placebo. The effect seems to be greatest in men, those who have not received prior treatment for tinnitus, and those with a history of noise exposure (62820). Other clinical research shows that taking melatonin 3 mg daily for 3 months is more effective for reducing tinnitus severity than sertraline 50 mg daily (97447). However, other clinical research shows that taking melatonin 3 mg nightly for 30-40 days does not significantly reduce tinnitus intensity when compared with placebo, although the effects might be significant when melatonin is combined with sulpiride or sulodexide (62469,62614).
• Traumatic brain injury (TBI). It is unclear if oral melatonin is beneficial for children who have experienced a concussion. Details: A small clinical study in children ages 8-18 years who have experienced a concussion shows that taking melatonin 3 mg or 10 mg one hour before bedtime for 28 days does not improve persistent post-concussive symptoms when compared with placebo (103690). One small observational study in children in the same age group who have experienced a concussion within 14 days has found that receiving a prescription for melatonin is not associated with improved symptoms and recovery at 15-35 days after concussion (105001). The validity of these findings is limited by small study size and short duration of follow-up.
• Ulcerative colitis. Oral melatonin may be modestly beneficial for reducing symptoms or sustaining remission in patients using the medication mesalazine. Details: A small clinical study shows that taking melatonin 5 mg daily in combination with mesalazine 1 gram twice daily for 12 months may help to sustain remission in patients with ulcerative colitis when compared with mesalazine alone (62821). Another small clinical trial in patients with mild to moderate ulcerative colitis shows that taking melatonin 3 mg daily for 3 months modestly improves overall symptoms, some measures of quality of life, and levels of fecal calprotectin when compared with placebo. However, there was no effect on other markers of inflammation, such as C-reactive protein and erythrocyte sedimentation rate (106303). More evidence is needed to rate melatonin for these uses.

(Read more about MELATONIN)

POSSIBLY EFFECTIVE

• Cognitive function. Oral L-theanine may improve some aspects of cognitive function. It is unclear if using L-theanine in conjunction with caffeine can enhance the effects of either ingredient. Details: A single dose of L-theanine 100 mg seems to improve vigilant attention, reducing error rates in cognitive tests when compared with placebo (91747). However, taking L-theanine (Suntheanine, Taiyo Kagaku) 200 mg daily for 4 weeks does not improve verbal fluency, memory, motor speed, or executive function in an adult population, although it may moderately improve verbal fluency in a subgroup of people with lower cognitive function at baseline (101986). When L-theanine is combined with caffeine, a meta-analysis and multiple individual clinical studies show that the combination improves alertness, as well as accuracy during a test that requires switching attention between different tasks, but does not improve reaction time (38116,91750,96335,96336). Some research also shows that L-theanine plus caffeine improves cognitive performance and reduces task-induced fatigue when compared with baseline and placebo. However, it is unclear if this is due to the individual ingredients or the combination (38116,96335,96336). Some research suggests that the combination is no better than either individual ingredient alone (91747,96335,96336).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral L-theanine, taken continuously or as a single dose, improves cognition in older adults. Details: A small clinical study in healthy, Japanese adults aged 50-69 years shows that taking a specific product (Suntheanine; Taiyo International.) containing L-theanine 101 mg daily after breakfast for 12 weeks does not improve mini-mental state exam (MMSE) scores when compared with placebo. However, a single-dose analysis from this study shows that administration of L-theanine 101 mg may improve the quality of working memory and reaction times during a cognitive function test when compared with placebo (108553). Patients were permitted to consume polyphenol-rich beverages during the study period; however, consumption was not documented, limiting the validity of this finding.
• Alzheimer disease. Although there is interest in using oral theanine for Alzheimer disease, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Anxiety. It is unclear if oral L-theanine is beneficial in patients with anxiety. Results of clinical research are conflicting. Details: A preliminary clinical study shows that taking a single dose of a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg does not reduce experimentally-induced anticipatory anxiety when compared with placebo (12188). However, another preliminary clinical study in healthy adults with stress-related anxiety shows that taking L-theanine 200 mg daily for 4 weeks reduces anxiety scale scores and sleep disturbance when compared with placebo (101986).
• Attention. It is unclear if oral theanine improves attention. Details: A small clinical study in healthy males shows that taking a single dose of L-theanine 200 mg improves selective attention similar to a single dose of caffeine 160 mg (96337). However, other small clinical studies in adults show that taking L-theanine 100-400 mg does not improve most measures of attention, especially sustained attention or attention in executive control tasks, but doses of 100-200 mg may improve performance in simple attentional tasks when compared with placebo (96338,111396). Some of these studies suggest that taking L-theanine with caffeine appears to provide more benefit than either individual ingredient alone (96337,96338).
• Attention deficit-hyperactivity disorder (ADHD). Oral L-theanine seems to improve some aspects of ADHD, including cognition and sleep. Details: Some preliminary clinical research in children with ADHD shows that taking a one-time dose of L-theanine 2.5 mg/kg increases cognition scores, but does not improve results on sustained attention or inhibitory control tests, when compared with placebo. Taking L-theanine with caffeine 2 mg/kg also increases cognition scores and improves performance on a sustained attention test, but does not improve inhibitory control, when compared with placebo (104141). Other preliminary clinical research in males aged 8-12 years with ADHD shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg orally twice daily for 6 weeks increases the percent of time spent in restful sleep by about 5% and decreases the number of bouts of nocturnal activity by about 6 when compared with placebo (91744).
• Cancer. Although there is interest in using oral theanine for cancer, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Chemotherapy-induced diarrhea. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with colon cancer shows that taking L-cystine 700 mg and L-theanine 280 mg (Ajinomoto Co. Inc.) orally once daily, starting one week before chemotherapy with TS-1 (Taiho Pharmaceutical) and continuing for 28 days, increases the rate of therapy completion by 49%, reduces the incidence of diarrhea by 37%, reduces appetite loss by 33%, and improves the reported tolerability of chemotherapy when compared with chemotherapy alone (96334). However, this combination does not appear to be beneficial in patients with gastric cancer, or in those with colorectal cancer receiving 4 courses of capecitabine-based adjuvant chemotherapy. (96334,101985).
• Cognitive impairment. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One very small clinical study in adults with mild cognitive impairment shows that taking a product containing L-theanine 120 mg and green tea extract 720 mg (LGNC-07, LG Household & Health Care, Ltd) orally twice daily after meals for 16 weeks modestly improves memory and attention when compared with baseline. However, taking this product does not appear to improve memory and attention when patients with self-reported memory problems, but without mild cognitive impairment, are also considered (96339).
• Depression. It is unclear if oral L-theanine is beneficial in patients with depression. Details: A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku Co. Ltd.) 250 mg orally at bedtime for 8 weeks reduces symptoms and improves sleep quality when compared to baseline in individuals with mild major depressive disorder (MDD) (96331). The validity of these findings is limited by the lack of a comparator group.
• Erythema. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy females with self-perceived skin sensitivity shows that taking a specific supplement containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne) daily for 8 weeks reduces facial pigmentation when compared to baseline (111399). The validity of this finding is limited by a lack of a placebo group. It is unclear if these effects are due to L-theanine, other ingredients, or the combination.
• Generalized anxiety disorder (GAD). It is unclear if oral L-theanine is beneficial for reducing anxiety in people with GAD. Details: One small clinical study in adults with GAD shows that taking L-theanine 225 mg twice daily for 4 weeks, then 450 mg twice daily for 4 weeks, in conjunction with prescribed antidepressants, does not reduce anxiety scores when compared with antidepressants and placebo (104976).
• Hypertension. Although there is interest in using oral theanine for hypertension, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Influenza. Oral L-theanine 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 green tea catechins (THEA-FLAN 90S, Ito-en Co.) 378 mg, standardized to contain epigallocatechin gallate 270 mg and L-theanine (Suntheanine, Taiyo Kagaku) 210 mg daily for 5 months reduces the risk of developing clinically diagnosed influenza when compared with placebo. However, the combination does not seem to prevent laboratory-confirmed influenza infection (54021).
• Insomnia. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with insomnia or disturbed sleep patterns shows that a specific product (RLX2; LiveLife Biosciences AG) containing L-theanine 50 mg and a specific casein peptide, alpha-s1-casein tryptic hydrolysate, 150 mg, taken one hour before bedtime for 4 weeks, increases sleep duration by 45 minutes and improves habitual sleep efficiency and daytime dysfunction when compared with baseline. However, it does not affect blood pressure, heart rate, or cortisol levels (108556). Another very small clinical study in healthy adults shows that taking a combination product containing tryptophan, glycine, magnesium, tart cherry powder, and L-theanine 2 hours before bedtime decreases sleep onset latency and increases total sleep duration, leading to better sleep efficiency and reduced morning sleepiness, when compared with placebo (111184). Another combination product containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne), taken daily for 8 weeks, seems to improve sleep quality when compared to baseline (111399). However, the validity of this finding is limited by a lack of a control group. It is unclear if the effects described above are due to L-theanine, other ingredients, or the combination.
• Postoperative recovery. Oral theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of adults with esophageal cancer undergoing esophagectomy shows that taking theanine 280 mg and cystine 700 mg daily, staring 4 days before surgery and continued for 13 days after surgery, does not improve measures of physical activity but does improve exercise tolerance and some measures of quality of life when compared with placebo (111400). It is unclear if these findings are due to theanine, cystine, or the combination.
• Schizophrenia. It is unclear if oral L-theanine is beneficial in patients with schizophrenia; the available evidence is limited and conflicting. Details: One preliminary clinical study in adults with schizophrenia or schizoaffective disorder shows that taking L-theanine (Biosynergy) 200 mg orally twice daily for 8 weeks along with antipsychotic medications improves positive symptoms, anxiety, and general psychopathology symptoms, such as poor impulse control and disorientation, when compared with placebo. However, theanine does not improve general disease severity, negative symptoms, depression, cognitive function, extrapyramidal side effects, or quality of life (96341). Another small clinical study shows that taking L-theanine 400 mg (Suntheanine, BioSynergy Health Alternatives) with pregnenolone 50 mg daily for 8 weeks, in addition to antipsychotic medications, improves negative symptoms, general psychopathology symptoms, and anxiety when compared with placebo in patients with schizophrenia or schizoaffective disorder. However, there were no improvements in positive schizophrenia symptoms or extrapyramidal side effects (97923). The inconsistency of results might be due to the small study sizes and the subjectivity of the outcomes measured.
• Stress. It is unclear if oral L-theanine is beneficial in patients with stress. Details: One very small clinical study shows that taking L-theanine 200 mg prior to a stress-inducing exam reduces tension-anxiety and may prevent blood pressure increases caused by psychological stress when compared with placebo (91746). Other preliminary clinical research in pharmacy students shows that taking theanine 200 mg twice daily for one week prior, and then for the first 10 days of a pharmacy practice period, decreases subjective stress scores when compared with placebo (91745). Another small clinical study in healthy young adults shows that drinking a beverage containing L-theanine 200 mg alone or combined with L-arginine 50 mg after a psychological stressor reduces stress, as measured by salivary alpha-amylase activity, when compared with placebo. The combination of L-arginine and L-theanine did not differ from L-theanine alone, suggesting that the combination does not act synergistically to reduce markers of stress (110393). However, not all research has been positive. A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg induces subjective feelings of tranquility in relaxed people, but not those with experimentally-induced anticipatory anxiety, when compared with placebo (12188). Also, a small, clinical crossover study in healthy, moderately stressed adults shows that taking a single dose of a specific product (Alphawave; Ethical Naturals) containing L-theanine 200 mg prior to a stress-inducing exam does not improve anxiety at any time point when compared with placebo (108554). Due to the single-dose nature of this study, the effects of continued administration of this product are unclear. L-theanine has also been evaluated in combination with other ingredients. A small clinical study in adults with stress shows that taking a specific combination product (Mg-Teadiola, Sanofi-Aventis Group), containing green tea extract 125 mg (providing 50 mg L-theanine), magnesium 150 mg, vitamin B6 0.2 mg, vitamin B9 0.1 mg, vitamin B12 1.25 mcg, and rhodiola 222 mg, orally once daily for 28 days modestly improves stress and anxiety scores when compared with placebo. Improvements in stress scores, but not anxiety scores, appear to persist at 28 days after treatment completion (108672). It is unclear if any effects are due to L-theanine, other ingredients, or the combination.
• Tourette syndrome. It is unclear if oral L-theanine is beneficial in children with Tourette syndrome. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing L-theanine 200 mg and vitamin B6 2.8 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate theanine for these uses.

(Read more about THEANINE)

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).

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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). 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). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (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). 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). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (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).

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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.

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LIKELY SAFE ...when used orally and appropriately. Oral magnesium is safe when used in doses below the tolerable upper intake level (UL) of 350 mg daily (7555). ...when used parenterally and appropriately. Parenteral magnesium sulfate is an FDA-approved prescription product (96484).

POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 350 mg daily frequently cause loose stools and diarrhea (7555).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Magnesium is safe when used in doses below the tolerable upper intake level (UL) of 65 mg daily for children 1 to 3 years, 110 mg daily for children 4 to 8 years, and 350 mg daily for children older than 8 years (7555,89396). ...when used parenterally and appropriately (96483).

CHILDREN: LIKELY UNSAFE
when used orally in excessive doses. Tell patients not to use doses above the tolerable upper intake level (UL). Higher doses can cause diarrhea and symptomatic hypermagnesemia including hypotension, nausea, vomiting, and bradycardia (7555,8095).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Magnesium is safe for those pregnant and breast-feeding when used in doses below the tolerable upper intake level (UL) of 350 mg daily (7555).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when prescription magnesium sulfate is given intramuscularly and intravenously prior to delivery for up to 5 days (12592,89397,99354,99355). However, due to potential adverse effects associated with intravenous and intramuscular magnesium, use during pregnancy is limited to patients with specific conditions such as severe pre-eclampsia or eclampsia. There is some evidence that intravenous magnesium can increase fetal mortality and adversely affect neurological and skeletal development (12590,12593,60818,99354,99355). However, a more recent analysis of clinical research shows that increased risk of fetal mortality seems to occur only in the studies where antenatal magnesium is used for tocolysis and not for fetal neuroprotection or pre-eclampsia/eclampsia (102457). Furthermore, antenatal magnesium does not seem to be associated with increased risk of necrotizing enterocolitis in preterm infants (104396). There is also concern that magnesium increases the risk of maternal adverse events. A meta-analysis of clinical research shows that magnesium sulfate might increase the risk of maternal adverse events, especially in Hispanic mothers compared to other racial and ethnic groups (60971,99319).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Tell patients to avoid exceeding the tolerable upper intake level (UL) of 350 mg daily. Taking magnesium orally in higher doses can cause diarrhea (7555). ...when prescription magnesium sulfate is given intramuscularly and intravenously prior to delivery for longer than 5 days (12592,89397,99354,99355). Maternal exposure to magnesium for longer than 5-7 days is associated with an increase in neonatal bone abnormalities such as osteopenia and fractures. The U.S. Food and Drug Administration (FDA) recommends that magnesium injection not be given for longer than 5-7 days (12590,12593,60818,99354,99355).

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LIKELY SAFE ...when used orally and appropriately, short-term or as a single dose. Melatonin seems to be safe when used up to 8 mg daily for up to 6 months. Melatonin 10 mg daily has been used safely for up to 2 months (1049,1068,1077,1085,1738,1754,5854,5855,5857,12226), (14283,15005,62850,89502,89503,88285,88289,88293,88294,88295)(88296,88299,89508,89510,89511,96313,96314,96316,96317,96319)(96321,97438,99345,103484,106301,106303,107811,110286,110299). ...when used topically and appropriately (1066,1768,1769,4713,4714,96314).

POSSIBLY SAFE ...when doses of up to 8 mg daily are used orally and appropriately for longer than 6 months, doses of 10 mg daily are used for longer than 2 months, or doses of 50 mg daily are used for up to 5 days (7040,7043,62435,106296,107811). There is some evidence melatonin can be used safely in doses of up to 10 mg daily for up to 2 years in some patients (7040,7043,62435). ...when used intravenously under the supervision of a healthcare professional. A one-time dose of intravenous melatonin combined with a single bolus of intracoronary melatonin has been used with apparent safety in one clinical trial (96324).

CHILDREN: POSSIBLY SAFE
when used orally in low doses, short-term (9980,15034,62792,88282,88283,88286,88288,95748,96318,97434)(97439,97446,106293,110292). Although melatonin has been safely used in clinical research in doses up to 12 mg daily (88283), it is often advised that daily doses of melatonin be limited to 3 mg daily for children and infants 6 months or older and 5 mg daily for adolescents (95746). There is some concern that taking melatonin might adversely affect gonadal development in children (1739,1740,1742,1743). While some evidence suggests that long-term use of melatonin in children may delay puberty, the available research includes only three small, observational studies with incomplete follow-up and poor measures of pubertal timing (95747). Although rare, pediatric overdose with melatonin has resulted in hospitalization, mechanical ventilation, and death (108145). Due to potential risks, melatonin should be used only in children with a medical reason for use; it should not be used to promote sleep in otherwise healthy children. There is insufficient reliable information available about the safety of melatonin when used long-term.

PREGNANCY: POSSIBLY UNSAFE
when used orally or parenterally in high doses or with frequent use. High doses of melatonin 75-300 mg daily seem to inhibit ovulation, causing a contraceptive effect (769,1740,6002,8271,95728). Advise pregnant patients and patients wishing to become pregnant to avoid using melatonin frequently or in high doses. There is insufficient reliable information available about the safety of melatonin in lower doses during pregnancy. Some research shows that taking melatonin 2 mg daily does not affect anterior pituitary hormone levels in females who are not pregnant; this suggests that low doses may not have a contraceptive effect (62898). Other research shows that taking melatonin 3 mg daily during the follicle stimulating stage of in vitro fertilization does not negatively impact pregnancy rates (62818,62819,88297,89512,88297). However, it is not known if melatonin is safe for use throughout pregnancy (95729). Until more is known about the safety of melatonin, avoid using during pregnancy.

LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. L-theanine has been used safely in clinical research in doses of up to 900 mg daily for 8 weeks (12188,36439,96331,96332,96334,96341,97923,101986,104976). There is insufficient reliable information available about the safety of L-theanine when used long-term.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg twice daily has been used safely in males aged 8-12 years for up to 6 weeks (91744).

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

(Read more about THEANINE)

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.

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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.

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AMINOGLYCOSIDE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Concomitant use of aminoglycoside antibiotics and magnesium can increase the risk for neuromuscular weakness.  Details Both aminoglycosides and magnesium reduce presynaptic acetylcholine release, which can lead to neuromuscular blockade and possible paralysis. This is most likely to occur with high doses of magnesium given intravenously (13362).

ANTACIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Use of acid reducers may reduce the laxative effect of magnesium oxide.  Details A retrospective analysis shows that, in the presence of H2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs), a higher dose of magnesium oxide is needed for a laxative effect (90033). This may also occur with antacids. Under acidic conditions, magnesium oxide is converted to magnesium chloride and then to magnesium bicarbonate, which has an osmotic laxative effect. By reducing acidity, antacids may reduce the conversion of magnesium oxide to the active bicarbonate salt.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, magnesium may have antiplatelet effects, but the evidence is conflicting.  Details In vitro evidence shows that magnesium sulfate inhibits platelet aggregation, even at low concentrations (20304,20305). Some preliminary clinical evidence shows that infusion of magnesium sulfate increases bleeding time by 48% and reduces platelet activity (20306). However, other clinical research shows that magnesium does not affect platelet aggregation, although inhibition of platelet-dependent thrombosis can occur (60759).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Magnesium can decrease absorption of bisphosphonates.  Details Cations, including magnesium, can decrease bisphosphonate absorption. Advise patients to separate doses of magnesium and these drugs by at least 2 hours (13363).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Magnesium can have additive effects with calcium channel blockers, although evidence is conflicting.  Details Magnesium inhibits calcium entry into smooth muscle cells and may therefore have additive effects with calcium channel blockers. Severe hypotension and neuromuscular blockades may occur when nifedipine is used with intravenous magnesium (3046,20264,20265,20266), although some contradictory evidence suggests that concurrent use of magnesium with nifedipine does not increase the risk of neuromuscular weakness (60831). High doses of magnesium could theoretically have additive effects with other calcium channel blockers.

DIGOXIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Magnesium salts may reduce absorption of digoxin.  Details Clinical evidence suggests that treatment with oral magnesium hydroxide or magnesium trisilicate reduces absorption of digoxin from the intestines (198,20268,20270). This may reduce the blood levels of digoxin and decrease its therapeutic effects.

GABAPENTIN (Neurontin) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B Gabapentin absorption can be decreased by magnesium.  Details Clinical research shows that giving magnesium oxide orally along with gabapentin decreases the maximum plasma concentration of gabapentin by 33%, time to maximum concentration by 36%, and area under the curve by 43% (90032). Advise patients to take gabapentin at least 2 hours before, or 4 to 6 hours after, magnesium supplements.

KETAMINE (Ketalar) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Magnesium might precipitate ketamine toxicity.  Details In one case report, a 62-year-old hospice patient with terminal cancer who had been stabilized on sublingual ketamine 150 mg four times daily experienced severe ketamine toxicity lasting for 2 hours after taking a maintenance dose of ketamine following an infusion of magnesium sulfate 2 grams (105078). Since both magnesium and ketamine block the NMDA receptor, magnesium is thought to have potentiated the effects of ketamine.

LEVODOPA/CARBIDOPA (Sinemet) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Magnesium can reduce the bioavailability of levodopa/carbidopa.  Details Clinical research in healthy volunteers shows that taking magnesium oxide 1000 mg with levodopa 100 mg/carbidopa 10 mg reduces the area under the curve (AUC) of levodopa by 35% and of carbidopa by 81%. In vitro and animal research shows that magnesium produces an alkaline environment in the digestive tract, which might lead to degradation and reduced bioavailability of levodopa/carbidopa (100265).

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Potassium-sparing diuretics decrease excretion of magnesium, possibly increasing magnesium levels.  Details Potassium-sparing diuretics also have magnesium-sparing properties, which can counteract the magnesium losses associated with loop and thiazide diuretics (9613,9614,9622). Theoretically, increased magnesium levels could result from concomitant use of potassium-sparing diuretics and magnesium supplements.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Magnesium decreases absorption of quinolones.  Details Magnesium can form insoluble complexes with quinolones and decrease their absorption (3046). Advise patients to take these drugs at least 2 hours before, or 4 to 6 hours after, magnesium supplements.

SEVELAMER (Renagel, Renvela) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Sevelamer may increase serum magnesium levels.  Details In patients on hemodialysis, sevelamer use was associated with a 0.28 mg/dL increase in serum magnesium. The mechanism of this interaction remains unclear (96486).

SKELETAL MUSCLE RELAXANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Parenteral magnesium alters the pharmacokinetics of skeletal muscle relaxants, increasing their effects and accelerating the onset of effect.  Details Parenteral magnesium shortens the time to onset of skeletal muscle relaxants by about 1 minute and prolongs the duration of action by about 2 minutes. Magnesium potentiates the effects of skeletal muscle relaxants by decreasing calcium-mediated release of acetylcholine from presynaptic nerve terminals, reducing postsynaptic sensitivity to acetylcholine, and having a direct effect on the membrane potential of myocytes (3046,97492,107364). Magnesium also has vasodilatory actions and increases cardiac output, allowing a greater amount of muscle relaxant to reach the motor end plate (107364). A clinical study found that low-dose rocuronium (0.45 mg/kg), when given after administration of magnesium 30 mg/kg over 10 minutes, has an accelerated onset of effect, which matches the onset of effect seen with a full-dose rocuronium regimen (0.6 mg/kg) (96485). In another clinical study, onset times for rocuronium doses of 0.3, 0.6, and 1.2 mg/kg were 86, 76, and 50 seconds, respectively, when given alone, but were reduced to 66, 44, and 38 seconds, respectively, when the doses were given after a 15-minute infusion of magnesium sulfate 60 mg/kg (107364).

SULFONYLUREAS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Magnesium increases the systemic absorption of sulfonylureas, increasing their effects and side effects.  Details Clinical research shows that administration of magnesium hydroxide with glyburide increases glyburide absorption, increases maximal insulin response by 35-fold, and increases the risk of hypoglycemia, when compared with glyburide alone (20307). A similar interaction occurs between magnesium hydroxide and glipizide (20308). The mechanism of this effect appears to be related to the elevation of gastrointestinal pH by magnesium-based antacids, increasing solubility and enhancing absorption of sulfonylureas (22364).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Magnesium decreases absorption of tetracyclines.  Details Magnesium can form insoluble complexes with tetracyclines in the gut and decrease their absorption and antibacterial activity (12586). Advise patients to take these drugs 1 hour before or 2 hours after magnesium supplements.

(Read more about MAGNESIUM)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, melatonin may have anticoagulant effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details There are isolated case reports of minor bleeding and decreased prothrombin activity in people taking melatonin with warfarin (Coumadin) (63067). The mechanism, if any, of this interaction is unknown (9181). Taking melatonin orally seems to decrease coagulation activity within one hour of dosing in healthy men (62481).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking melatonin with antidiabetes drugs might increase the risk of hypoglycemia.  Details Some clinical research shows that melatonin reduces levels of fasting blood glucose and improves glycemic control (19034,19035,103490). However, other research suggests that melatonin might impair glucose utilization and increase insulin resistance (9713), while other research has found no effect on glucose levels (19036,104368). Until more is known, use melatonin cautiously in combination with antidiabetes drugs.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, taking melatonin with antihypertensive drugs might increase the risk of hypotension or hypertension.  Details Some clinical research suggests that taking melatonin decreases blood pressure in healthy adults (1724,62165,62187,63042). Also, melatonin seems to lower systolic and diastolic blood pressure in individuals with high blood pressure at nighttime or untreated essential hypertension (62359,62416,62441,62826). However, melatonin seems to worsen blood pressure in patients who are taking antihypertensive medications. Immediate-release melatonin 5 mg at night in combination with nifedipine GITS (Procardia XL) increases systolic blood pressure an average of 6.5 mmHg, diastolic blood pressure by an average of 4.9 mmHg, and heart rate by 3.9 bpm (6436). Also, results from animal research suggest that melatonin reduces the effectiveness of certain antihypertensive drugs, including methoxamine and clonidine (62432).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking caffeine with melatonin might increase levels of melatonin.  Details Some evidence suggests that caffeine consumption can decrease endogenous melatonin levels (8265,22303,37585), while other evidence suggests that caffeine increases endogenous melatonin levels (62328). When administered in combination with melatonin supplements, caffeine seems to increase melatonin effects and levels (62352,96315). The reason for this discrepancy is not completely clear. Part of the discrepancy may result from the fact that caffeine can inhibit melatonin synthesis as well as inhibit melatonin metabolism. By functioning as an adenosine receptor antagonist, caffeine may indirectly inhibit the synthesis of melatonin. Conversely, because melatonin and caffeine are both metabolized by cytochrome P450 1A2 (CYP1A2) enzyme, concomitant use of melatonin and caffeine may reduce the metabolism of melatonin, resulting in higher serum levels (22306,96315).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking melatonin might increase the sedative effects of CNS depressants.  Details Melatonin has sedative effects. Theoretically, concomitant use of melatonin with alcohol, benzodiazepines, or other sedative drugs might cause additive sedation (96315).

CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking contraceptive drugs with melatonin might increase the effects and adverse effects of melatonin.  Details Contraceptive drugs can increase the levels of endogenous melatonin (8265). Theoretically, these drugs may increase the effects and adverse effects of oral melatonin.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP1A2. Also, other CYP1A2 substrates might decrease the metabolism of melatonin, increasing melatonin levels.  Details Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes (62118,62405,96315). Theoretically, combined administration of melatonin with drugs metabolized by the CYP1A2 enzyme might reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP1A2 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP2C19. Also, other CYP2C19 substrates might decrease the metabolism of melatonin, increasing melatonin levels.  Details Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes (62118,62405). Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2C19 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP2C19 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP2D6.  Details Laboratory research suggests that certain lots of melatonin inhibit CYP2D6 (96315). Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2D6 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP3A4.  Details Laboratory research shows that certain lots of melatonin inhibit CYP3A4 (96315). Theoretically, combined administration of melatonin with certain drugs metabolized by CYP3A4 may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

FLUMAZENIL (Romazicon) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking flumazenil with melatonin might reduce the effects of melatonin.  Details Animal research shows that flumazenil may inhibit the effect of melatonin (9703).

FLUVOXAMINE (Luvox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking fluvoxamine with melatonin might increase levels of melatonin.  Details Fluvoxamine can significantly increase melatonin levels. In some cases, fluvoxamine might increase bioavailability of exogenously administered melatonin by up to 20 times (5038,6499,8251). Some researchers think this might be a beneficial interaction and be potentially useful for cases of refractory insomnia (6499). However, this interaction might also cause unwanted excessive drowsiness and possibly other adverse effects. Fluvoxamine is known to increase endogenous melatonin secretion (6498,22313). It seems to increase serum levels of exogenously administered melatonin possibly by decreasing melatonin metabolism by inhibiting cytochrome P450 (CYP450) 1A2 and 2C19 or by inhibiting melatonin elimination. This effect has been found in healthy people taking fluvoxamine 50-75 mg and melatonin 5 mg (5038,6498,6499,8251).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, melatonin might interfere with immunosuppressive therapy.  Details Melatonin can stimulate immune function. Theoretically, melatonin might interfere with immunosuppressive therapy (7040).

METHAMPHETAMINE (Desoxyn) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking melatonin with methamphetamine may increase the adverse effects of methamphetamine.  Details Animal research suggests that melatonin exacerbates the adverse effects of methamphetamine, resulting in greater depression of tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activity, as well as a significant reduction in dopamine levels (22307). This has not been shown in humans.

NIFEDIPINE GITS (Procardia XL) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking melatonin with extended release nifedipine reduces the effects of nifedipine.  Details Melatonin can decrease the effectiveness of extended release nifedipine (GITS). Immediate-release melatonin 5 mg at night in combination with nifedipine GITS 30-60 mg daily increases systolic and blood pressure by an average of 6.5 mmHg and 4.9 mmHg, respectively. Concomitant use with melatonin also increases heart rate by 3.9 bpm (6436). The mechanism of this interaction is not known.

SEIZURE THRESHOLD LOWERING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking melatonin with drugs that lower the seizure threshold might increase the risk of seizure activity.  Details Some clinical evidence suggests that melatonin may increase the frequency of seizures in certain patients, particularly children with neurological disabilities (8248,9744).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, melatonin may have antiplatelet effects and may increase the risk of bleeding with warfarin.  Details Three cases of increased prothrombin time have been reported for patients aged 48-72 years who took melatonin orally in combination with warfarin (9181). However, three cases of decreased prothrombin time have also been reported for patients aged 51-84 years who took melatonin orally in combination with warfarin (9181). Until more is known, use melatonin cautiously in patients taking warfarin.

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theanine might lower blood pressure, potentiating the effects of antihypertensive drugs.  Details Animal research shows that theanine can lower blood pressure in spontaneously hypertensive animals (7687,77354). Theoretically, concomitant use of theanine and antihypertensive drugs might potentiate the antihypertensive activity.

CNS DEPRESSANTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, theanine might have additive sedative effects when used in conjunction with CNS depressants. However, it is unclear if this concern is clinically relevant.  Details Theoretically, theanine may compete with glutamate and/or increase plasma gamma-aminobutyric acid (GABA) levels, which could cause CNS depression (96334). In one clinical study, some subjects taking oral theanine reported drowsiness (96331).

(Read more about THEANINE)

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 ...Magnesium is generally well tolerated. Some clinical research shows no differences in adverse effects between placebo and magnesium groups.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal irritation, nausea, and vomiting.
Intravenously: Bradycardia, dizziness, flushing sensation, hypotension, and localized pain and irritation. In pregnancy, may cause blurry vision, dizziness, lethargy, nausea, nystagmus, and perception of warmth.
Serious Adverse Effects (Rare):
All ROAs: With toxic doses, loss of reflexes and respiratory depression can occur. High doses in pregnancy can increase risk of neonatal mortality and neurological defects.

Cardiovascular ...Intravenously, magnesium can cause bradycardia, tachycardia, and hypotension (13356,60795,60838,60872,60960,60973,60982,61001,61031). Magnesium sulfate may cause rapid heartbeat when administered antenatally (60915).
In one case report, a 99-year-old male who took oral magnesium oxide 3000 mg daily for chronic constipation was hospitalized with hypermagnesemia, hypotension, bradycardia, heart failure, cardiomegaly, second-degree sinoatrial block, and complete bundle branch block. The patient recovered after discontinuing the magnesium oxide (108966).

Dermatologic ...Intravenously, magnesium may cause flushing, sweating, and problems at the injection site (including burning pain) (60960,60982). In a case study, two patients who received intravenous magnesium sulfate for suppression of preterm labor developed a rapid and sudden onset of an urticarial eruption (a skin eruption of itching welts). The eruption cleared when magnesium sulfate was discontinued (61045). Orally, magnesium oxide may cause allergic skin rash, but this is rare. In one case report, a patient developed a rash after taking 600 mg magnesium oxide (Maglax) (98291).

Gastrointestinal ...Orally, magnesium can cause gastrointestinal irritation, nausea, vomiting, and diarrhea (1194,4891,10661,10663,18111,60951,61016,98290). In rare cases, taking magnesium orally might cause a bezoar, an indigestible mass of material which gets lodged in the gastrointestinal tract. In a case report, a 75-year-old female with advanced rectal cancer taking magnesium 1500 mg daily presented with nausea and anorexia from magnesium oxide bezoars in her stomach (99314). Magnesium can cause nausea, vomiting, or dry mouth when administered intravenously or by nebulization (60818,60960,60982,104400). Antenatal magnesium sulfate may also cause nausea and vomiting (60915). Two case reports suggest that giving magnesium 50 grams orally for bowel preparation for colonoscopy in patients with colorectal cancer may lead to intestinal perforation and possibly death (90006).
Delayed meconium passage and obstruction have been reported rarely in neonates after intravenous magnesium sulfate was given to the mother during pregnancy (60818). In a retrospective study of 200 neonates born prematurely before 32 weeks of gestation, administration of prenatal IV magnesium sulfate, as a 4-gram loading dose and then 1-2 grams hourly, was not associated with the rate of meconium bowel obstruction when compared with neonates whose mothers had not received magnesium sulfate (108728).

Genitourinary ...Intravenously, magnesium sulfate may cause renal toxicity or acute urinary retention, although these events are rare (60818,61012). A case of slowed cervical dilation at delivery has been reported for a patient administered intravenous magnesium sulfate for eclampsia (12592). Intravenous magnesium might also cause solute diuresis. In a case report, a pregnant patient experienced polyuria and diuresis after having received intravenous magnesium sulfate in Ringer's lactate solution for preterm uterine contractions (98284).

Hematologic ...Intravenously, magnesium may cause increased blood loss at delivery when administered for eclampsia or pre-eclampsia (12592). However, research on the effect of intravenous magnesium on postpartum hemorrhage is mixed. Some research shows that it does not affect risk of postpartum hemorrhage (60982), while other research shows that intrapartum magnesium administration is associated with increased odds of postpartum hemorrhage, increased odds of uterine atony (a condition that increases the risk for postpartum hemorrhage) and increased need for red blood cell transfusions (97489).

Musculoskeletal ...Intravenously, magnesium may cause decreased skeletal muscle tone, muscle weakness, or hypocalcemic tetany (60818,60960,60973).
Although magnesium is important for normal bone structure and maintenance (272), there is concern that very high doses of magnesium may be detrimental. In a case series of 9 patients receiving long-term tocolysis for 11-97 days, resulting in cumulative magnesium sulfate doses of 168-3756 grams, a lower bone mass was noted in 4 cases receiving doses above 1000 grams. There was one case of pregnancy- and lactation-associated osteoporosis and one fracture (108731). The validity and clinical significance of this data is unclear.

Neurologic/CNS ...Intravenously, magnesium may cause slurred speech, dizziness, drowsiness, confusion, or headaches (60818,60960). With toxic doses, loss of reflexes, neurological defects, drowsiness, confusion, and coma can occur (8095,12589,12590).

Ocular/Otic ...Cases of visual impairment or nystagmus have been reported following magnesium supplementation, but these events are rare (18111,60818).

Psychiatric ...A case of delirium due to hypermagnesemia has been reported for a patient receiving intravenous magnesium sulfate for pre-eclampsia (60780).

Pulmonary/Respiratory ...Intravenously, magnesium may cause respiratory depression and tachypnea when used in toxic doses (12589,61028,61180).

Other ...Hypothermia from magnesium used as a tocolytic has been reported (60818).

(Read more about MAGNESIUM)

General ...Orally, melatonin is generally well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, headache, and nausea.
Serious Adverse Effects (Rare):
Orally: There is concern that melatonin may increase the risk for seizure.

Cardiovascular ...Melatonin might increase levels of very low-density lipoprotein (VLDL) cholesterol and triglycerides (62176). Several rare or poorly described cases of abnormal heart rhythms, palpitations, fast heart rate, or chest pain have been reported. However, in these cases, the patients were taking other drugs that could account for the symptoms, and melatonin was not thought to be the cause (1079,9181,62776,62789,63067).

Dermatologic ...Papular skin rash and pruritus has been reported with melatonin use. However, the effect was generally mild and did not require cessation of melatonin treatment (62450,62754,109696), and had similar rates as placebo (96316). Cutaneous flushing has also been reported (62770,62914). Two cases of fixed drug eruption on the genitalia have been reported for patients who used oral melatonin (Nature's Bounty Natural melatonin) for preventing jet lag (88284).

Endocrine ...A case of gynecomastia (increased breast size) has been reported for a 56 year-old patient with amyotrophic lateral sclerosis (ALS) who used oral melatonin, long-term (89430). Also, reduced sperm concentration and sperm motility has been reported for two men who used oral melatonin 3 mg daily for 6 months. Improvement in sperm quality was observed for only one of the two men following melatonin cessation (62231).

Gastrointestinal ...Orally, melatonin may cause nausea (62384,62770), abdominal cramps, or mild abdominal pain (62450,62754,62914,96316), diarrhea (62804,62811,62914), constipation (96316), or decreased appetite (62345,62792). Often these symptoms occur during the first few days of treatment and subside after a few days (62804). In some cases, rates of symptoms are similar between melatonin and placebo (96316). Less often, melatonin has been reported to cause abnormal feces (62450), odd taste in the mouth (1070), or reflux esophagitis (1745) when used orally. A case of exacerbated symptoms of Crohn disease, including increased diarrhea and abdominal cramps, has been reported for a patient who took oral melatonin 3 mg at bedtime for 4 days. Symptoms resolved within 24 hours of melatonin treatment cessation (62218).

Genitourinary ...Orally, melatonin may increase enuresis in adults and children (58685,62450,62710,62770,62804,62804,62811). In perimenopausal adults, melatonin has caused a resumption of spotting or menstrual flow (11806). Decreased libido has been noted for one patient treated with melatonin 3 mg daily for 8 weeks (15216).

Hematologic ...A case of nose bleed has been reported with oral melatonin (62450). Some melatonin preparations contain contaminants that are associated with eosinophilia-myalgia syndrome (9715,9716).

Hepatic ...A case of autoimmune hepatitis has been reported for a patient who took melatonin orally to treat insomnia (63037).

Musculoskeletal ...Preliminary clinical evidence shows that a single dose of melatonin 3 mg may increase fall risk due to increased postural swaying while standing on one or both feet in healthy adults ages 60-71 years (97442). A single case of ataxia has been reported for an 81-year-old female who used melatonin for 4 days (9181). Weakened muscle power has been reported for two patients treated with melatonin 5 mg in the evening (62456). Some melatonin preparations contain contaminants that are associated with eosinophilia-myalgia syndrome (9715,9716).

Neurologic/CNS ...Orally, melatonin may cause migraine-like headache (1070,1077,15034,62384,62450,62710,62754,62804,62792,62914,88288,88293,88294,96318)(106297) or dizziness (62345,62384,62450,62456,62770,62784,62792,62804,62811,89510)(110297). Often these symptoms occur during the first few days of treatment and subside after a few days (62804). Melatonin may also cause drowsiness or fatigue when taken orally (1077,8273,15216,62384,62456,62784,62804,62811,88288,89510,96314,96316,96318,97446)(106293,106297). These symptoms appear to be more common if melatonin is taken in the morning or at very high doses (greater than 50 mg) (8269,62874). A case of excessive drowsiness has been reported when melatonin was combined with citalopram, nortriptyline, and oxycodone. Sedation improved with discontinuation of melatonin (96315). Indiscriminate use of melatonin may cause irregular sleep-wake cycles to occur (62998). Less commonly, melatonin may also cause behavior worsening (62811), confusion or disorientation (63014,63067), nighttime awakening (62710,62811), mood swings or agitation (96318), stereotypy (96318), excitement before bedtime (62811), nightmares or more intense dreams (62401,62462,62780,62784,88283), feelings of a "rocking" sensation (62155), or reduced alertness when taken orally.
A case of generalized epilepsy has reportedly occurred after treatment with melatonin for 4 months (9708). Also, some case reports raise concerns about increased risk of seizure with melatonin treatment, but conflicting evidence suggests that melatonin may decrease the risk of seizures (1699,8248,9695,9697,9744,9746,62123,62256,62384,62754)(63070,63071,89431). One patient experienced hyponatremia with confusion and seizures after taking prolonged-release melatonin 2 mg. However, malnutrition and cannabis abuse were also thought to contribute to this reaction (96321).
Although there is concern that melatonin might affect cognitive function in healthy adults, research in humans suggests that oral or topical melatonin do not impact most measures of cognitive function (97442,97448).

Psychiatric ...Orally, melatonin may cause mood changes, including dysphoria (sadness) (1764), dips in mood (62345,62450,62792), nervousness (62784), or transient depression (1077). Delusions and hallucinations have also been reported in clinical research (62347). An isolated incident of aggressiveness was also noted in a child diagnosed with attention deficit-hyperactivity disorder (ADHD) who took melatonin in combination with methylphenidate (9980). Severe irritability has been reported in two children with autism spectrum disorder who had abruptly discontinued melatonin due to the completion of a clinical trial (106293).

(Read more about MELATONIN)

General ...Orally, L-theanine seems to be well tolerated.
Most Common Adverse Effects:
Orally: Drowsiness, headaches.

Neurologic/CNS ...Orally, L-theanine may cause headaches (36439). Patients have also reported drowsiness, increased duration of sleep, and increased dream activity after oral L-theanine use (96331).
A case of subtle facial tic starting within 4 days of taking L-theanine 400 mg daily has been reported for a pediatric patient. Although the tics reportedly ceased once theanine was discontinued, the child had exhibited tics in the past. Therefore, the adverse effect was not thought to be related to L-theanine (91744).

(Read more about THEANINE)