Secret Sauce Orange by MuscleMeds

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Oral agaricus mushroom has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in people with IgE-positive birch pollen allergy shows that taking a specific agaricus mushroom product (Andosan, Immunopharma) containing 82% agaricus mushroom, 15% Hericium erinaceus mushroom, and 3% maitake mushroom extracts, 60 mL daily for 7 weeks starting before the pollen season, reduces symptoms of allergic rhinitis and allergic asthma and decreases use of anti-allergy medications when compared with placebo. During the allergy season, birch-specific IgE levels were reduced, and basophils were less sensitive to allergen activation (102919).
• Cancer. Although there is interest in using oral agaricus mushroom for the treatment of various types of cancer, there is insufficient reliable information about the clinical effects of agaricus mushroom for this purpose. Cardiovascular disease (CVD).Although there is interest in using oral agaricus mushroom for the management of CVD and CVD risk factors, there is insufficient reliable information about the clinical effects of agaricus mushroom for this purpose.
• Chemotherapy-induced adverse effects. It is unclear if oral agaricus mushroom is beneficial for reducing adverse effects in patients undergoing chemotherapy treatment. Details: Preliminary clinical research in females with gynecologic cancers shows that taking an agaricus mushroom extract three times daily while receiving chemotherapy for 6 weeks might improve some of the adverse effects of chemotherapy, such as generalized weakness, decreased appetite, and emotional instability, when compared with chemotherapy alone (15404).
• Crohn Disease. It is unclear if oral agaricus mushroom is beneficial for Crohn disease. Details: Preliminary clinical research in patients with Crohn disease shows that taking an oral agaricus mushroom extract (AndoSan, ACE Co. Ltd.) 30 mL twice daily for 21 days does not improve fatigue, quality of life, or symptom severity when compared with placebo (94721).
• Diabetes. It is unclear if oral agaricus mushroom is beneficial for type 2 diabetes. Details: Preliminary clinical research in patients with type 2 diabetes shows that taking an agaricus mushroom extract 500 mg orally three times daily for 12 weeks, in combination with metformin and the sulfonylurea gliclazide, decreases insulin resistance and lowers fasting insulin levels more than metformin and gliclazide alone (15421).
• Hepatitis B. It is unclear if oral agaricus mushroom is beneficial for hepatitis B. Details: Preliminary clinical research in adults with chronic hepatitis B infection shows that taking agaricus mushroom extract 500 mg three times daily for 12 months decreases aspartate aminotransferase (AST) from 246 IU/L to 61 IU/L and alanine aminotransferase (ALT) from 151 IU/L to 46 IU/L (94719). However, these results are limited by small study size and the lack of a comparator group.
• Hyperlipidemia. Although there is interest in using oral agaricus mushroom for hyperlipidemia, there is insufficient reliable information about the clinical effects of agaricus mushroom for this condition.
• Multiple myeloma. It is unclear if oral agaricus mushroom is beneficial for multiple myeloma. Details: Preliminary clinical research in patients with multiple myeloma undergoing stem cell transplantation with high-dose chemotherapy shows that taking an agaricus mushroom extract (AndoSan, ACE Co. Ltd.) 60 mL orally daily for about 7 weeks during chemotherapy does not improve treatment response or overall survival when compared with placebo (94716).
• Osteoporosis. Although there is interest in using oral agaricus mushroom for osteoporosis, there is insufficient reliable information about the clinical effects of agaricus mushroom for this condition.
• Peptic ulcers. Although there is interest in using oral agaricus mushroom for peptic ulcers, there is insufficient reliable information about the clinical effects of agaricus mushroom for this condition.
• Ulcerative colitis. It is unclear if oral agaricus mushroom is beneficial for ulcerative colitis. Details: Preliminary clinical research in patients with symptomatic ulcerative colitis shows that taking an agaricus mushroom extract (AndoSan, ACE Co. Ltd.) 30 mL orally twice daily for 21 days improves fatigue, quality of life, and overall symptom scores when compared with placebo (94715). More evidence is needed to rate agaricus mushroom for these uses.

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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))

LIKELY EFFECTIVE

• Chromium deficiency. Oral or parenteral chromium is effective for the treatment and prevention of chromium deficiency. Details: Chromium is effective for preventing and treating symptoms of chromium deficiency, including hyperglycemia, glycosuria, sudden weight loss, peripheral neuropathy, and confusion (7135).

POSSIBLY EFFECTIVE

• Diabetes. Oral chromium seems to be modestly beneficial for improving glycemic control in diabetes, especially when used in doses greater than 200 mcg daily and in patients with poorly controlled diabetes. It is unclear if chromium helps to prevent the development of diabetes. Details: Epidemiological research has found that lower toenail chromium levels are associated with an increased risk of diabetes and cardiovascular disease (11908). In 2005, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that chromium picolinate may reduce the risk of type 2 diabetes. However, the FDA has determined that any relationship between chromium picolinate and type 2 diabetes is highly uncertain and is based on limited scientific evidence (102362). Research on the use of chromium for the treatment of type 2 diabetes is conflicting but seems to show modest benefit in some patients. Several clinical studies, most including fewer than 80 patients with type 2 diabetes, show that taking chromium decreases fasting blood glucose, postprandial glucose, insulin, and glycated hemoglobin (HbA1c) levels and increases insulin sensitivity (6867,7137,12390,14440,15169,42628,42638,95097,103745). However, other small clinical studies show that chromium is no better than placebo for improving most glycemic indices in patients with diabetes (7060,14325,42679,42707,90059,103746,103749). Some of these studies may not have been adequately powered and some had a high risk of bias. Furthermore, these studies had high heterogeneity related to study population and size, chromium supplementation duration, formulation, and dose, and accepted standards of diabetes care. Multiple meta-analyses pooling results of these small clinical trials also show mixed results (90055,90063,95098,105026,110610,111420). The most recent of the aforementioned meta-analyses show that chromium picolinate lowers HbA1c by about 0.6%, with conflicting findings related to fasting blood glucose and measures of insulin resistance (110610,111420). It is unclear if chromium yeast, chromium dinicocysteinate, or chromium with biotin or other natural ingredients are beneficial. Chromium seems to be most beneficial in doses of greater than 200 mcg taken for 12 weeks or longer, and in patients with poorly controlled diabetes with a baseline HbA1c of 8% or greater (90063,105026). There is also speculation that chromium might primarily benefit patients with low chromium levels; however, there has not been an analysis specifically evaluating this population (6867,7058,13725,14325,95098). Some research suggests that chromium might also modestly improve lipid levels in patients with type 2 diabetes (1934,6867,95098). A meta-analysis of clinical trials in patients with type 2 diabetes shows that taking chromium 42-1000 mcg daily for 5-26 weeks decreases triglyceride levels by 7 mg/dL and increases high-density lipoprotein cholesterol levels by 2 mg/dL when compared with control. Taking chromium did not affect low-density lipoprotein cholesterol levels. However, the validity of these results is limited by high heterogeneity (110605). Another meta-analysis failed to demonstrate any effects of chromium on lipid levels (110610). Research on chromium's effect on blood pressure in patients with type 2 diabetes is mixed. A meta-analysis of clinical trials in patients with type 2 diabetes shows that taking chromium 200-1000 mcg daily for 8-25 weeks lowers diastolic blood pressure by 2 mmHg, but does not improve systolic blood pressure or body mass index, when compared with placebo (110607). Preliminary clinical research shows that chromium picolinate might improve metabolic parameters in patients with other forms of diabetes as well. This includes those with type 1 diabetes (1935), diabetes secondary to corticosteroid use (5039,42829), and gestational diabetes (42817).

POSSIBLY INEFFECTIVE

• Hypertension. Meta-analyses of small clinical trials suggest that oral chromium does not lower blood pressure by a clinically meaningful amount. Details: A meta-analysis of randomized clinical trials in adults with different metabolic disorders shows that taking chromium 42-1000 mcg daily for 12-24 weeks does not lower systolic or diastolic blood pressure when compared with placebo (110609). A meta-analysis of randomized clinical trials in adults with different chronic disorders shows that taking chromium 42-1000 mcg daily for 4-25 weeks lowers systolic and diastolic blood pressure by 3 mmHg and 1 mmHg, respectively, when compared with placebo. However, the validity of this meta-analysis is limited by high heterogeneity (110604). Another meta-analysis of randomized clinical trials including patients with type 2 diabetes shows that taking chromium 200-1000 mcg daily for 8-25 weeks lowers diastolic blood pressure by 2 mmHg, but not systolic blood pressure, when compared with placebo (110607). In addition, the validity of these results is limited by inclusion of patients with and without hypertension at baseline (110604,110607,110609).
• Impaired glucose tolerance (Prediabetes). Oral chromium does not seem to improve glycemic indices in patients with prediabetes. Details: Some clinical research shows that adults with impaired glucose tolerance do not have improved glycemic parameters or insulin sensitivity after taking chromium picolinate 500-1000 mcg daily for up to 6 months when compared with placebo (13053,42670). Likewise, a small clinical study in elderly patients with impaired glucose tolerance shows that chromium supplements do not improve glucose tolerance or triglyceride or cholesterol levels when compared with placebo (13722). Finally, a preliminary clinical study in overweight or obese adults with prediabetes shows that taking two capsules of a combination product containing chromium, cinnamon, and carnosine (Glycabiane, PiLeJe) daily for 4 months decreases fasting plasma glucose by approximately 4 mg/dL when compared with placebo, but does not improve fasting plasma insulin, measures of insulin sensitivity or resistance, or glycated hemoglobin (HbA1C) (94234). The small effect on fasting plasma glucose is clinically insignificant and may be due to the other ingredients in this product.
• Schizophrenia. Oral chromium does not seem to improve psychological measures in patients with schizophrenia. Details: Clinical research in patients with schizophrenia shows that taking chromium polynicotinate 400 mcg daily for 3 months does not affect weight or mental status when compared with placebo (42613).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antiretroviral-induced insulin resistance. It is unclear if oral chromium is beneficial for preventing antiretroviral-induced insulin resistance. Details: Preliminary clinical research in patients with HIV treated with highly active antiretroviral therapy (HAART) shows that taking chromium nicotinate 200 mcg or chromium picolinate 1000 mcg daily for 8-16 weeks may help decrease insulin resistance and increase glucose disposal when compared to baseline (42630,42662). The validity of this finding is limited by the lack of a control group.
• Athletic performance. It is unclear if chromium enhances athletic performance, although some research suggests that it may improve body composition when used in conjunction with exercise. Details: One large clinical study shows taking chromium 400 mcg daily, in conjunction with resistance training, can increase weight loss, body fat loss, and lean body mass when compared with placebo in conjunction with resistance training (6868). However, other, very small clinical studies show that adding chromium picolinate or chromium chloride 177-400 mcg daily to a weight-training program does not improve body composition when compared with weight-training alone (6860,6861,6862,42747). These studies may not have been adequately powered to detect a difference in outcomes.
• Atypical depression. It is unclear if oral chromium is beneficial in patients with atypical depression. Details: Preliminary clinical research in patients with atypical depression shows that taking chromium picolinate 400 mcg daily for 2 weeks followed by 600 mcg daily for an additional 6 weeks improves response and remission rates when compared with placebo (10309). However, other clinical research shows that taking elemental chromium 400 mcg in the form of chromium picolinate daily for 2 weeks followed by 600 mcg daily for an additional 6 weeks does not improve most symptoms of atypical depression, although appetite and sexual drive may improve, when compared with placebo (42600).
• Beta blocker-induced dyslipidemia. It is unclear if oral chromium is beneficial in patients with dyslipidemia due to beta-blocker use. Details: One small clinical study in patients who take beta-blockers shows that taking glucose tolerance factor (GTF)-chromium 600 mcg daily for 2 months increases high-density lipoprotein (HDL) cholesterol levels by 16%, but does not affect other lipid parameters, when compared with placebo (5040).
• Binge eating disorder. It is unclear if oral chromium is beneficial in patients with binge eating disorder. Details: One small clinical study in adults with overweight and binge eating disorder shows that taking chromium picolinate 600 or 1000 mcg daily for 6 months does not affect binge eating frequency, body weight, or depressive symptoms when compared with placebo (90057).
• Bipolar disorder. It is unclear if oral chromium is beneficial in patients with treatment-resistant bipolar disorder. Details: Preliminary clinical research in patients with treatment-resistant, rapid-cycling bipolar disorder shows that taking chromium chloride (Hypo-A Chrom, Hypo-A GmbH) 600-800 mcg daily for up to 2 years can decrease the frequency of affective episodes by approximately three episodes annually when compared to baseline (42618). The validity of this finding is limited by the lack of a control group.
• Cognitive impairment. It is unclear if oral chromium prevents or treats cognitive impairment. Details: Some clinical research shows that taking chromium picolinate standardized to contain elemental chromium 1000 mcg daily for 12 weeks does not improve memory or depression in elderly patients with mild cognitive impairment when compared with placebo. However, results from neuroimaging scans suggest that chromium increases the activity of certain regions of the brain during memory tasks when compared with placebo (42666).
• Hyperlipidemia. Small clinical studies suggest that oral chromium may modestly reduce lipid levels in patients with hyperlipidemia. Details: One small clinical study in patients with atherosclerotic disease shows that taking chromium 250 mcg as chromium chloride daily for 7-16 months decreases triglycerides and increases high-density lipoprotein (HDL) cholesterol, but not other lipid parameters, when compared with placebo (7060). Other small clinical studies in adults with hyperlipidemia show that taking chromium picolinate 200 mcg daily for 6 weeks, chromium polynicotinate 200 mcg twice daily, or brewer's yeast containing 48 mcg elemental chromium daily for 6-8 weeks decrease total and low-density lipoprotein (LDL) cholesterol when compared to baseline (37178,42585,42710). The validity of this finding is limited by the lack of comparison with a control group. A meta-analysis of small heterogeneous clinical studies in patients mostly without hyperlipidemia shows that taking chromium does not affect lipid levels when compared with placebo (105029). A meta-analysis of randomized clinical trials including patients with type 2 diabetes shows that taking chromium 42-1000 mcg daily for 5-26 weeks modestly improves triglyceride and HDL cholesterol levels, but not LDL cholesterol levels, when compared with control. However, the validity of these results is limited by high heterogeneity and inclusion of patients with and without hyperlipidemia (110605). In addition, some meta-analyses have failed to demonstrate any effects of chromium on lipid levels in adults with diabetes (110610). Limited research has tested high-dose chromium in children. One small clinical study in children with hypercholesterolemia shows that taking chromium polynicotinate 400-600 mcg with glucomannan 1000-1500 mg twice daily for 8 weeks reduces total and LDL cholesterol when compared to baseline (90061). It is unclear if this effect is due to chromium, glucomannan, or the combination.
• Hypoglycemia. It is unclear if oral chromium helps to reverse or prevent hypoglycemia. Details: One very small clinical study in patients with reactive hypoglycemia shows that taking chromium chloride 200 mcg daily for 3 months increases blood glucose levels and improves insulin binding and hypoglycemic symptoms following an oral glucose load (6859). Another small clinical study in patients with symptomatic hypoglycemia shows that taking chromium yeast (Biochrome, Pharma-Nord) 125 mcg daily for 3 months improves symptoms, including chilliness, trembling, and disorientation, when compared with baseline (42711). The validity of this finding is limited by the lack of a control group.
• Metabolic syndrome. It is unclear if oral chromium is beneficial in patients with metabolic syndrome. Details: One small clinical study in patients with metabolic syndrome shows that taking a particular chromium picolinate product (Chromax, Nutrition 21) 500 mcg twice daily for 16 weeks does not affect weight, waist circumference, insulin sensitivity, glycated hemoglobin (HbA1C), or lipid levels when compared with placebo (42654).
• Myocardial infarction (MI). It is unclear if oral chromium helps to prevent MI. Details: Epidemiological research has found that low toenail chromium concentrations are associated with an increased risk of MI (13728). However, toenail chromium concentrations might not be a reliable predictor of body stores of chromium. There is also no reliable research showing that chromium supplements can prevent MI.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral chromium slows NAFLD progression. Details: One small clinical study in patients with NAFLD shows that taking chromium picolinate 200 mcg two times daily after meals for 12 weeks does not affect liver enzyme levels or body weight when compared with placebo (105027).
• Obesity. Although some research suggests that oral chromium may increase weight loss, this increase in weight loss is not likely to be considered clinically relevant. Details: Meta-analyses of clinical studies in adults with overweight or obesity show that taking chromium picolinate 200-1000 mcg daily for 12-16 weeks might result in a cumulative weight loss of about 0.5-1 kg when compared with placebo (90062,90065). However, this small reduction in weight is unlikely to be considered clinically significant. Additionally, small clinical studies in healthy adults and children with overweight or obesity show that taking oral chromium 200-1000 mcg daily for 6-24 weeks does not reduce weight when compared with control (6860,13727,17224,42680). Some of these studies may not have been adequately powered to detect a smaller effect. A meta-analysis of randomized clinical trials among adults with type 2 diabetes shows that taking chromium 200-1000 mcg daily for 8-25 weeks does not lower body mass index when compared with placebo. However, the validity of these results is limited by inclusion of patients with and without obesity at baseline (110607).
• Polycystic ovary syndrome (PCOS). It is unclear if oral chromium improves symptoms of PCOS. Details: One small clinical study in patients with PCOS shows that taking chromium picolinate 1000 mcg daily for 6 months along with diet and exercise counseling decreases body mass index and improves rates of ovulation and regular menstruation when compared with placebo (95094). Also, some clinical research shows that taking chromium picolinate (21st Century HealthCare, Inc. or Nature Made) 200 mcg daily for 8 weeks increases insulin sensitivity when compared with placebo (95095,98687). However, other preliminary clinical research shows that taking chromium picolinate 200 mcg daily for 4 months does not affect insulin sensitivity or improve ovulation rates (42603). Although chromium picolinate at doses of less than 1000 mcg might have very small effects on fasting glucose, these doses do not seem to have clinically beneficial effects on fasting glucose, pregnancy rate, or testosterone levels (95094,95095,98687). A lower dose of chromium has also been studied in combination with carnitine. One small clinical study in adults with overweight and PCOS shows that taking chromium picolinate 200 mcg daily with carnitine 1000 mg daily for 12 weeks modestly reduces fasting blood glucose, insulin resistance, and body weight, and slightly increases insulin sensitivity, when compared with placebo (103747). However, it is unclear if this benefit is clinically significant. Additionally, it is unclear if these effects are due to chromium, carnitine, or the combination. Carnitine has demonstrated clinical benefit when used alone in PCOS.
• Turner syndrome. It is unclear if oral chromium is beneficial in patients with this condition. Details: A small clinical study shows that taking brewer's yeast 30 grams containing chromium 50 mcg daily for 8 weeks might improve abnormalities in glucose and lipid metabolism when compared with baseline in patients with Turner syndrome, a genetic disorder that has a high incidence of diabetes (13729). The validity of this finding is limited by the lack of a comparator group. More evidence is needed to rate chromium for these uses.

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POSSIBLY EFFECTIVE

• Athletic performance. Oral creatine monohydrate seems to modestly improve rowing, jumping, and soccer performance. It is unclear if it is beneficial for sprinting, cycling, swimming, or tennis performance. Details: In competitive rowers, most clinical research shows that taking creatine 20 grams or 240-250 mg/kg daily for 5 days significantly improves aerobic and anaerobic performance (4605,4607,46569,46605,46833). Specifically, creatine decreases 1000-meter rowing time by 2.4 seconds and 2500-meter rowing time by 6.5 seconds and increases time to fatigue by 9.7 seconds when compared with placebo (4607,46605,46833). To improve rowing performance, creatine 20 grams (or 240-250 mg/kg) daily for 5 days has been used (4605,4607,46605,46833). Additionally, most clinical research shows that taking creatine 20-30 grams daily for 5-7 days improves jumping height by up to 6 cm when compared with placebo in active males (11331,13661,46626,46704), although some conflicting results exist (6924,46601). When compared with placebo, creatine also appears to improve spike jumping and block jumping in male volleyball players (46762), as well as peak and mean power of stationary roundhouse kicks in male trained taekwondo athletes (108333). In young male soccer players, preliminary clinical research shows that taking creatine 10 grams three times daily for 7 days can increase performance on a specific dribbling speed test by up to 2.8 seconds when compared with placebo (46626). In young female soccer players, preliminary clinical research shows that taking creatine 5 grams four times daily for 7 days followed by 5 grams daily for 5 weeks in conjunction with plyometric training modestly increases body mass index, jump and power performance, and repeated sprinting performance when compared with either plyometric training with placebo or standard soccer drills (95961). Research evaluating creatine supplementation for sprinting, cycling, high-intensity-interval training (HIIT), and swimming has been inconsistent. The reason for these mixed findings is unclear. A meta-analysis of small clinical trials shows that taking creatine decreases the peak oxygen uptake (VO2 max) during running and cycling, suggesting a worsening of aerobic fitness (108330). However, another meta-analysis of randomized controlled trials shows that taking creatine up to 20 grams orally daily for 3-7 days modestly improves mean power, but not peak power or fatigue, during repeated running or cycling sprint intervals when compared with placebo (112206). In addition, a meta-analysis of randomized clinical trials in trained athletes shows that taking creatine up to 20 grams orally daily for 5-42 days does not improve endurance running or cycling performance when compared with control (112214). A potential explanation for these conflicting results is that the studies failing to show an improvement are likely underpowered, with sample sizes of only 6-32 subjects (4582,4601). For instance, some small clinical trials show that taking creatine 20-30 grams daily for 5-7 days can improve sprint times by up to 3% and decrease time to exhaustion by up to 13% when compared with placebo in trained athletes (6924,11331,46558,46567,46626,46819); however, others show that taking creatine 20-25 grams daily for 3-7 days does not improve sprint velocity, 60-meter or 150-meter sprint times, or fatigue in these individuals (46603,46656,46797,46806,112216). In trained athletes, untrained yet healthy adults, and sedentary adults, some clinical research shows that taking creatine 10-35 grams daily for 4-7 days significantly improves power output, peak power, and fatigue indices while cycling (4591,4592,4593,4594,4602,4604,6926,10064,46522,46528) (46547,46568,46601,46614,46820); however, significant improvements in cycling performance with creatine are lacking in other studies (4582,4595,4596,4597,4598,4599,4600,4606,46520,46538) (46646). Similarly, in trained swimmers, some clinical research shows that creatine improves swimming performance (4601,4603,46600,46655,46725,46805), with a few studies reporting improvements of 1.3-2 seconds in 100-meter swim times when compared with placebo (46600,46725,46805). However, creatine does not improve 25-, 50-, or 100-meter swim performance in other trials (2106,4601,46798). To improve swimming performance, creatine 9-25 grams daily for 4-9 days has been used (4601,4603,46600,46655,46725,46805), with lower maintenance doses of 2.25-10 grams daily for 8-9 days used in some cases (4601,46600). Preliminary clinical research in trained tennis players shows that taking creatine 5 grams four times daily for 5 days or 0.3 grams/kg daily for 6 days followed by 0.03 grams/kg daily for 4 weeks does not appear to improve stroke power, stroke precision, serving speed, sprinting, or shuttle run time when compared with placebo (46536,46673). Taking creatine (Creapure, AlzChem AG) 0.3 grams/kg daily for 5 days, followed by 0.1 grams/kg daily for 23 days, while undergoing HITT 3 days each week does not improve physical performance outcomes when compared with placebo in healthy young females (95965). A preliminary clinical trial in elite female handball players shows that the beneficial effects of creatine monohydrate 0.3 grams/kg for 5 days followed by 0.03 grams/kg are not dependent on the time of day of supplementation (108332). Although this suggests that the circadian rhythm does not influence the ergogenic effect of creatine, this study was small and may have been underpowered to detect any differences. One clinical study compared the efficacy of creatine monohydrate with that of creatine nitrate. At equivalent doses of 12 grams daily for 7 days, followed by 3 grams daily for 21 days, creatine nitrate and creatine monohydrate produce similar increases in fat-free mass, lean mass, and intramuscular creatine concentrations, and similar improvements in bench press lifting volume and average power output. The lower dose of creatine nitrate 6 grams daily for 7 days followed by 1.5 grams daily for 21 days does not demonstrate performance improvement benefits or result in increased intramuscular creatine (95959). In 2018, the International Society of Sports Nutrition (ISSN) recommended creatine monohydrate, but not creatine nitrate, as an ergogenic nutritional supplement for increasing athletic capacity and lean body mass (101009). Creatine has also been evaluated in combination with a variety of other ergogenic supplement ingredients. However, research is conflicting and variable and any benefits may be dose- and/or population-dependent.
• Cerebral creatine deficiency syndromes. Oral creatine seems to improve some symptoms of the cerebral creatine deficiency syndromes guanidinoacetate methyltransferase (GAMT) deficiency and arginine-glycine amidinotransferase (AGAT) deficiency. It is unclear if oral creatine is beneficial for creatine transporter defect. Details: Three inborn errors of metabolism, GAMT deficiency, AGAT deficiency, and creatine transporter defect, cause low cerebral creatine levels, resulting in mental retardation, seizures, autism, and movement disorders. In children with GAMT deficiency, taking creatine orally, 400-500 mg/kg daily for up to 8 years or 4-8 grams daily for up to 25 months, increases brain creatine levels and improves movement disorders and seizure frequency, but has little effect on intellectual ability (46722,46796,46804). Children with AGAT deficiency who take creatine 400-800 mg/kg daily for up to 8 years seem to have improved attention, language development, and academic performance (46584,46769). However, research in children up to 10 years of age with creatine transporter defect shows that taking a mixture of creatine, L-arginine, and glycine orally for 4-6 years does not increase brain creatine levels or improve motor or cognitive functioning (46757).
• Muscle strength. Oral creatine seems to modestly improve muscle strength. It is unclear if topical creatine is beneficial. Details: Pooled analyses of clinical trials assessing upper limb strength, lower limb strength, and body composition have evaluated creatine provided in typical loading doses of 20 grams daily or 0.3 grams/kg daily, although doses up to 26 grams daily have been used, in single or divided doses for 5-7 days (90323,90330,93626,93627,108316,108336,112213). Creatine maintenance doses ranged from 1.25-27 grams daily for up to 24 weeks (90323,90330,93626,93627,108316,108336). In some studies, creatine doses of usually 0.1 grams/kg have been taken daily for up to 12 months in the absence of a loading dose. In others, creatine was taken only on training days (108316). Meta-analyses of research in the general adult population show that taking creatine with or without resistance training seems to improve upper limb strength and lower limb strength, with a small-to-moderate overall effect (93626,93627). Benefits in combination with resistance training have also been shown on upper and/or lower limb strength in older adults, although benefits on both have not been demonstrated in all analyses (90323,90330,108316,108336). A meta-analysis limited to studies involving older females shows that while taking creatine with resistance training increases upper body strength when compared with placebo, improvements to lower body strength are limited to those studies providing supplementation for at least 24 weeks (108336). Meta-analyses of studies involving middle-aged and older adults show that creatine supplementation combined with resistance training appears to increase total body mass by 1 kg and lean body mass by 0.9-1.3 kg when compared with placebo (90323,90330,108316). However, a meta-analysis of studies limited to older females shows that there was no effect of creatine on muscle mass (108336). Also, significant decreases in fat mass are lacking and effects on body fat percentage are inconsistent (90323,108335). While the analyses above provide a good estimate of creatine's effect on muscle strength, it is important to note that a large number of clinical trials assessing strength in patients taking creatine have been published. These studies included varying methodologies, small sample sizes, and a wide range of creatine doses, dosing times, and study durations. These differences may explain why some studies have found a benefit with creatine supplementation (2100,2101,4580,6015,6924,6928,10062,13661,46507,46510)(46523,46528,46550,46551,46561,46562,46567,46570,46581,46589)(46601,46613,46615,46618,46626,46628,46667,46709,46720,46725)(46761,46762,46801,46815,90321,90327,95958,95960,102162,103279)(104668,104670,108329,112213), while others have not (4569,4570,4571,4572,4588,6183,46520,46539,46554,46569)(46579,46594,46656,46665,46673,95963,95967,95968,95969,102168,104669)(104671,108334). Topical creatine has also been evaluated. Applying 3.5 mL of a specific cream (Delivra, LivCorp Inc.) containing creatine 1% daily for 7 days moderately improves peak and average muscle power in males when compared with a placebo cream. However, some study participants were also taking oral creatine monohydrate 7 grams three times daily and others were taking an oral placebo. An acute application of the cream at doses of 3.5 mL or 7 mL 30 minutes before exercise does not seem to improve power (104669).
• Sarcopenia. When used for up to 12 weeks in combination with resistance training, oral creatine seems to modestly improve muscle strength in older adults. It is unclear if oral creatine is beneficial when used as a single dose or for more than 12 weeks. Details: Most research shows that taking creatine while taking part in a resistance training program can increase upper and/or lower body muscle strength in older adults (90323,90330,95958,102162,108316,108336). One meta-analysis of research in adults 50 years of age and older taking part in resistance training programs shows that creatine supplementation improves chest press strength with a moderate effect size, but does not improve leg press strength, when compared with placebo (90330). Also, another meta-analysis focusing on adults 45 years of age and older taking part in resistance training shows that creatine supplementation improves chest press strength by 1.74 kg and leg press strength by 3.25 kg when compared with placebo, with no effect on knee extension or biceps curl measurements (90323). A meta-analysis limited to studies involving older females shows that while taking creatine with resistance training increases upper body strength when compared with placebo, improvements to lower body strength are limited to those studies providing supplementation for at least 24 weeks (108336). However, some negative findings exist. Some clinical research in postmenopausal females with osteopenia shows that taking creatine monohydrate 1-3 grams (Creapure, AlzChem AG) daily for 1-2 years without participation in resistance training does not alter muscle function when compared with placebo (95969,102168). In addition, in healthy males aged 49-69 years, a small clinical trial shows that taking creatine monohydrate (Rivalus Inc.) 0.05 grams/kg twice daily, while undergoing supervised resistance training three days each week for one year, does not alter muscle strength when compared with placebo (104671). One clinical study shows that a single loading dose of creatine monohydrate 20 grams (Creapure, AlzCHem AG) taken 3 hours prior to exercise does not improve leg press or chest press muscle endurance in aging males (95968). Also, lower doses of creatine added to whey protein supplementation do not seem to be beneficial. One small study in adults 65 years or older shows that adding creatine monohydrate 2.5 grams twice daily along with whey protein 10 grams twice daily and resistance training for 14 weeks does not improve muscle function when compared with whey protein and resistance training alone (95966). Most research also suggests that creatine improves total muscle mass in older adults, although conflicting research exists. Some studies show that taking creatine while taking part in a resistance training program seems to increase muscle mass in older adults (90323,90330,108316,108329). Meta-analyses of studies involving middle-aged and older adults show that creatine supplementation combined with resistance training appears to increase total body mass by 1 kg and lean body mass by 0.9-1.3 kg when compared with placebo (90323,90330,108316). However, a meta-analysis of studies limited to older females shows that there was no effect of creatine on muscle mass (108336). Also, in healthy males aged 49-69 years, a small clinical trial shows that taking creatine monohydrate (Rivalus Inc.) 0.05 grams/kg twice daily, while undergoing supervised resistance training three days each week for one year, does not alter body composition when compared with placebo (104671). Despite these generally beneficial findings, significant decreases in fat mass following creatine supplementation in older adults are lacking, and effects on body fat percentage are inconsistent (90323,95958,108335).

POSSIBLY INEFFECTIVE

• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Oral creatine does not seem to reduce ALS symptoms or increase survival. Details: Taking creatine orally, 5-10 grams daily for 9-16 months, or 20 grams daily for 5-7 days followed by 3-5 grams daily for 6 months, has no effect on disease progression, respiratory function decline, or survival in patients with ALS (11332,16389,46553,46574,46707). In one case series, some patients experienced temporary improvement in muscle strength while taking 20 grams daily during the first week, but this was not maintained (46553).
• Huntington disease. Oral creatine does not seem to reduce symptoms of this condition. Details: Taking creatine orally has no effect on motor function or symptom scores in people with Huntington disease (46598,46609,95957). Clinical research shows that taking creatine 5-40 grams daily (average dose of 31.6 grams) for 24 months does not improve total motor score or total functional capacity in patients with early manifest Huntington disease (95957).
• Osteopenia. Oral creatine does not seem to be beneficial for osteopenia. Details: In postmenopausal adults with osteopenia, taking creatine monohydrate (Creapure, AlzChem GmbH ) 1-3 grams daily for 1-2 years does not improve bone mineral density (BMD) when compared with placebo (95969,102168). Another clinical trial in postmenopausal adults with osteopenia or osteoporosis shows that taking creatine monohydrate (Probiotica) 20 grams daily for 5 days and then 5 grams daily for the next 23 weeks, with or without exercise training, does not improve bone mass when compared with placebo (90321). Also, a small clinical trial in older adults, most of which had osteopenia, shows that taking creatine monohydrate (Rivalus Inc.) 0.05 grams/kg twice daily in combination with resistance training for 12 months modestly improves some measures of bone area, but not BMD, when compared with placebo (108329). Other research has evaluated creatine in patients without a definite diagnosis of osteopenia. One study shows that taking creatine (Rivalus Inc.) 0.1 gram/kg daily for 12 months or creatine (Creapure AlzChem Trostberg GmbH) 0.1 grams/kg three times weekly does not affect BMD in adults age 50 and up taking part in resistance training (104671,104674). In contrast, a small clinical trial in postmenopausal patients shows that taking creatine monohydrate (Rivalus Inc.) 0.1 gram/kg daily for 12 months while undergoing a resistance training program has a small preventive effect on bone loss at the femoral neck, but not the hip or spine (104673). However, other preliminary clinical research in postmenopausal patients shows that taking creatine (Creapure, AlzChem AG) 0.14 grams/kg orally daily for 2 years does not improve BMD when compared with placebo (112219). Also, preliminary clinical research shows that taking creatine 0.3 grams/kg for 5 days and 0.07 grams/kg for the remainder of a 12-week resistance training session increases BMD in elderly males over 70 years (46664). More information is needed to determine if creatine is beneficial when used in combination with a resistance training program in older adults.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral creatine is beneficial for the treatment or prevention of age-related cognitive decline. Details: Population research in the US has found a positive association between dietary creatine intake and a specific measure of cognitive function, the WAIS III Digit Symbol Substitution Test (DSS). In addition, this measure of cognitive function was highest in individuals who consumed more than 0.95 grams daily (108331). However, clinical research is conflicting. A small clinical trial in older adults shows that taking creatine monohydrate (Creapure, Deguss AG) 5 grams four times daily for one week has modest beneficial effects on some measures of cognitive function, but not others, when compared with baseline or placebo (46686). Another small clinical trial shows that taking creatine monohydrate 5 grams four times daily for five days, and then 5 grams daily for a total of 4 weeks, does not improve cognitive function when compared with placebo (108339).
• Aging skin. Topical creatine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a cream containing creatine 0.2%, guarana 0.4%, and glycerol 8% to the face daily for 6 weeks reduces wrinkles and skin sagging when compared to baseline (46766). Other research shows that a specific cream containing creatine 0.2% and folic acid 0.03% (Nivea Visage DNAage, Beiersdorf AG) reduces wrinkles and roughness and improves firmness of photo-aged skin when compared to baseline (46696). The effect of topical creatine alone on aging skin is unclear. Also, the validity of these findings is limited by the lack of a comparator group.
• Arsenic poisoning. It is unclear if oral creatine is beneficial in patients with arsenic poisoning. Details: Preliminary clinical research in adults regularly consuming well water that contains arsenic shows that taking creatine 3 grams orally daily for 12 weeks lowers the concentration of certain serum arsenic metabolites when compared with control (112212). Creatine has not been studied for management of acute arsenic poisoning.
• Chronic kidney disease (CKD). It is unclear if oral creatine is beneficial in patients with CKD. Details: A small clinical study in CKD patients undergoing hemodialysis shows that taking creatine monohydrate 20 grams daily for a week alternating with taking 5 grams daily for a week, for a total of 4 weeks, attenuates loss of lean body mass and reduces the malnutrition-inflammation score when compared with taking a maltodextrin control (102166).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral creatine is beneficial in patients with COPD. Details: One clinical study shows that taking creatine 22 grams daily for 5 days, then 3.76 grams daily for 6 weeks, does not improve pulmonary function or walking distance when compared with placebo (46699). Another study shows taking creatine 5.7 grams three times daily for 2 weeks, then once daily thereafter, improves patient self-assessment of lung function, but not exercise capacity, when compared with placebo (46658). A third study shows taking creatine 0.3 grams/kg for 7 days, then 0.07 grams/kg for 7 weeks, improves walking time, but not measures of lung function, when compared with placebo (46691). A meta-analysis of the results from these and other clinical trials shows that creatine does not improve exercise capacity, muscle strength, or quality of life in COPD patients. However, the studies analyzed were of varying quality, which may limit the validity of these findings (46740).
• Cognitive function. It is unclear if oral creatine is beneficial for improving cognitive function. Details: Some preliminary clinical research in healthy adults shows that taking creatine possibly improves some measures of cognitive performance, specifically short-term memory and reasoning. However, findings related to most measures of cognitive function are inconsistent (108340). Other preliminary clinical research in healthy adults shows that taking a specific creatine (Creapure, AlzChem) 10-20 grams orally daily for 6 weeks does not improve cognitive function scores when compared with placebo (112215).
• Congestive heart failure (CHF). It is unclear if oral creatine is beneficial in patients with CHF. Details: Two very small clinical studies show that taking creatine orally 20 grams daily for 5-10 days improves skeletal muscle strength and endurance, but not ejection fraction or symptoms of CHF, when compared with placebo (4562,4563). Also a small clinical study in males with class II-IV heart failure shows that taking creatine 5 grams daily for 6 months does not improve exercise capacity or ejection fraction when compared with placebo (90328). However, it is possible that these small studies were inadequately powered to detect a difference in these clinical outcomes.
• Depression. It is unclear if oral creatine is beneficial for improving symptoms of depression. Details: Preliminary clinical research shows that taking creatine 5 grams daily for 8 weeks improves response to escitalopram in females with major depressive disorder. Hamilton Depression Rating Scale (HAM-D) scores decreased by 80% when compared to baseline in those receiving creatine plus escitalopram, compared to a decrease of only 63% in those taking placebo plus escitalopram (46777). However, the World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce recommend against use of creatine for depression until more conclusive data are generated (110318).
• Diabetes. It is unclear if oral creatine is beneficial for glycemic control. Details: A meta-analysis of preliminary clinical research shows that taking creatine does not affect levels of fasting blood glucose or measures of insulin resistance when compared with placebo (108338). However, most of the studies included in this analysis were not conducted in individuals with diabetes. In people with newly-diagnosed type 2 diabetes, preliminary clinical studies show a reduction in postprandial glucose levels after taking creatine 3-6 grams orally daily for 5 days (46732,46760). The studies show that creatine 3 grams once daily has similar effects to glyburide 3.5 mg daily, and that creatine 3 grams twice daily is similar to metformin 500 mg twice daily. The effects of treatment for longer than 5 days in patients with diabetes are unknown. However, in sedentary males without diabetes, taking creatine 10 grams daily for 3 months seems to improve glucose tolerance (46682).
• Fatigue. It is unclear if oral creatine is beneficial for cognitive fatigue prevention. Details: A small clinical study in healthy young adults with mental fatigue shows that taking creatine monohydrate (Sportimaxx) 20 grams daily for 7 days improves accuracy on prolonged cognitive tasks, but not cognitive measures that require a quick response, when compared with placebo (102170).
• Fibromyalgia. It is unclear if oral creatine is beneficial for improving exercise performance in patients with fibromyalgia. Details: Preliminary clinical research shows that taking creatine 5 grams orally four times daily for 5 days, followed by 5 grams daily for a total of 16 weeks, improves leg press strength by 10% and chest press strength by 8% when compared with placebo in patients with fibromyalgia. However, creatine supplementation does not appear to improve aerobic capacity, pain, sleep, quality of life, or cognitive function (90331).
• Gyrate atrophy. Anecdotal reports suggest that oral creatine may be beneficial in some patients with gyrate atrophy. Details: Gyrate atrophy of the choroid and retina is associated with elevated plasma ornithine levels, which inhibit creatine synthesis and result in muscle fiber atrophy and eye fundus damage. Left untreated, patients with this condition progressively lose their vision (4577,4578). A small case series suggests that taking creatine 1.5 grams daily for one year might slow eye damage and visual deterioration in some patients with this condition when compared to baseline (4578). The validity of this finding is limited by the small sample size and lack of a comparator group.
• Hereditary motor and sensory neuropathy. It is unclear if oral creatine is beneficial in patients with hereditary motor sensory neuropathies. Details: Preliminary clinical studies in people with hereditary motor sensory neuropathies, such as Charcot-Marie-Tooth Disease, suggest that taking creatine orally 5 grams daily for 1-12 weeks has no effect on muscle strength, endurance, or functional capacity when compared with placebo (46548,46630,46675,46695).
• HIV/AIDS-related wasting. It is unclear if oral creatine is beneficial in patients with muscle wasting associated with HIV. Details: A small clinical study shows that taking creatine orally 20 grams daily for 5 days, then 4.8 grams daily for 14 weeks, does not increase muscle mass or strength in patients with HIV with muscle wasting when compared with placebo (46718).
• Hyperhomocysteinemia. It is unclear if oral creatine is beneficial in patients with hyperhomocysteinemia. Details: Preliminary clinical research in strict vegan adults with hyperhomocysteinemia shows that taking micronized creatine monohydrate (Bioderm) 5 grams daily for 3 weeks reduces blood levels of homocysteine by 39% when compared with baseline (102169). The validity of this finding is limited by the lack of a comparator group.
• Inflammatory myopathies. It is unclear if oral creatine is beneficial in patients with idiopathic inflammatory myopathies. Details: Preliminary clinical research in people with dermatomyositis or polymyositis shows that taking creatine orally 20 grams daily for 8 days, followed by 3 grams daily for a total of 6 months, in addition to an exercise program, decreases aggregate functional performance time by around 7% and increases shoulder abduction and hip flexion strength when compared with placebo. However, no improvements in functional index or strength as measured by elbow flexion, knee extension, or dorsi flexion are reported (15520). Taking creatine does not seem to improve muscle strength or disease activity in patients aged 7-18 years with juvenile dermatomyositis. Preliminary clinical research shows that taking creatine (AlzChem) for 4 weeks to 6 months does not improve muscle strength or disease activity when compared with placebo. The doses used in this study were 150 mg/kg daily for children weighing up to 40 kg or 4.69 grams/m2 for those weighing over 40 kg (104672).
• Juvenile idiopathic arthritis (JIA). Oral creatine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In children with JIA, taking a specific supplement (Kre-Celazine; All American Pharmaceutical) containing creatine and fatty acids 750 mg twice daily for 30 days may improve pain and inflammation when compared to baseline. Pain scores were reduced to 0 or 1 in 81% of these patients, and laboratory measures of inflammation were normalized in nearly every patient (90322). However, the effect of creatine alone in JIA patients is unclear. Also, the validity of this study is limited by a lack of control group.
• McArdle disease. It is unclear if oral creatine is beneficial for this condition. Details: There is some preliminary clinical evidence that taking creatine orally, 150 mg/kg daily for 5 days, followed by 60 mg/kg daily for 5 weeks, improves frequency and/or severity of muscle pain in some, but not all, patients with McArdle disease (70). However, continuing with the higher dose of 150 mg/kg daily throughout the 5-week period seems to INCREASE muscle pain and exercise intolerance (46564).
• Memory. It is unclear if oral creatine is beneficial for improving memory. Details: A meta-analysis of randomized controlled trials in healthy adults shows that taking creatine 2.2-20 grams orally for 5 days to 24 weeks improves performance on certain memory tests when compared with placebo (112202). However, the validity of this study is limited by high heterogeneity. In addition, the statistical methods utilized in this meta-analysis are likely to increase the risk of false positive results (112203) and re-analysis using other methods failed to reproduce the significant effects of creatine (112204).
• Mitochondrial myopathies. It is unclear if oral creatine is beneficial in patients with mitochondrial myopathies. Details: Preliminary studies using creatine orally for mitochondrial myopathies, such as chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome, show mixed results. Using 150 mg/kg daily for 6 weeks or 20 grams daily for 4 weeks does not improve muscle function, exercise performance, or ease of completing activities of daily living when compared with placebo (46529,46650,104675). However, one very small clinical study shows that taking creatine 5 grams twice daily for 14 days, then 2 grams twice daily for 7 days, improves some measures of strength during high-intensity anaerobic and aerobic exercise, but not low-intensity exercise, when compared with baseline (4565).
• Multiple sclerosis (MS). It is unclear if oral creatine is beneficial in patients with MS. Details: A very small clinical study shows that taking creatine 20 grams orally daily for 5 days does not improve exercise capacity in people with relapsing-remitting multiple sclerosis when compared with placebo (46599).
• Muscle breakdown. It is unclear if oral creatine is beneficial for muscle breakdown prevention. Details: Preliminary clinical research shows that taking creatine 5 grams four times daily for 7 days seems to help maintain muscle mass and reduce loss of muscle strength associated with immobilization by a cast in young males aged 18-25 years (46713).
• Muscle cramps. It is unclear if oral creatine is beneficial in patients with muscle cramps related to hemodialysis. Details: Preliminary clinical research shows that taking creatine 12 grams orally 5 minutes before hemodialysis sessions for 4 weeks reduces the frequency of muscle cramps by around 60%, from an average of 6.4 episodes to 2.6 episodes over the course of 4 weeks of dialysis. No reduction in muscle cramp frequency is reported with placebo in these patients (46582).
• Muscular dystrophy. The evidence for the use of oral creatine in patients with various forms of muscular dystrophy is conflicting. Details: Preliminary studies have assessed oral creatine in patients with muscular dystrophy, including Duchenne dystrophy, Becker dystrophy, facioscapulohumeral dystrophy, sarcoglycan-deficient limb girdle muscular dystrophy, and myotonic dystrophies. Although a meta-analysis of available research shows that there is a small benefit of creatine on muscle strength in patients with muscular dystrophies, results of individual clinical trials have been inconsistent (104675). Some preliminary clinical research shows that measures of muscle strength or fatigue are improved after 8-16 weeks of treatment with creatine 3-5 grams or 0.1 gram/kg daily (6182,46596,46629,46739). Also, subjective improvement in muscle strength occurs in some people taking creatine 20 grams daily for one week, followed by 5 grams daily for 8 weeks (46639). The ability to perform activities of daily living improves only modestly, if at all (6182,46629,46739). Despite these positive results, some conflicting results exist. Some studies show no improvement in muscle strength or functional capacity with doses of 5 grams daily for 17-26 weeks (46616,46657), or 10.6 grams daily for 10 days followed by 5.3 grams daily for a total of 8 weeks (46587). Also, a dose of 10 grams daily for 12 weeks does not appear to improve muscle strength, although it seems to improve myalgia in some patients (10654). The inconsistent results reported in patients with muscular dystrophy may be explained by the different types of muscular dystrophies, the varied methodologies, or the small number of patients assessed. Studies failing to show an improvement with creatine may be underpowered, with sample sizes of only 20-60 (10654,46657).
• Neonatal apnea. It is unclear if oral creatine is beneficial for neonatal apnea treatment. Details: A preliminary clinical study shows that giving creatine orally 200 mg/kg daily for 2 weeks to premature infants with a gestational age of less than 32 weeks does not improve signs or symptoms of apnea of prematurity when compared with placebo (46623).
• Osteoarthritis. It is unclear if oral creatine is beneficial in patients with osteoarthritis. Details: In patients with osteoarthritis of the knee, preliminary clinical research shows that taking creatine 20 grams orally daily for one week, followed by 5 grams daily for 11 weeks, in combination with strengthening exercises, modestly improves physical functioning as measured by the number of stand-ups performed from a standard-height chair in 30 seconds when compared with exercise alone. Stiffness, pain, and quality of life were also improved with creatine supplementation; however, it is unclear if these improvements were significant when compared with exercise alone (46753).
• Parkinson disease. It is unclear if oral creatine is beneficial in patients with this condition. Details: Preliminary clinical research shows that taking creatine 5 grams twice daily for 12-18 months decreases the rate of disease progression when compared with placebo in patients who have not started conventional medications for symptom control (15353,46703). However, preliminary clinical research in patients with more advanced disease who have already started conventional medications shows that taking creatine 20 grams daily for 6 days followed by 2 grams daily for 6 months, and then 4 grams daily for 18 months does not decrease overall progression of symptoms or the need to start symptomatic treatment. However, increases in dopamine agonist doses were 3-fold lower over the course of the study in patients receiving creatine when compared with placebo (15354).
• Peripheral arterial disease (PAD). It is unclear if oral creatine is beneficial in patients with PAD. Details: A small clinical trial in patients with PAD shows that taking creatine monohydrate (Creapure, AlzChem Trostberg GmbH) 5 grams four times daily for one week, followed by 5 grams daily for the next 7 weeks, does not improve functional capacity based on walking distance, upper body strength, or lower body strength, when compared with placebo (108337). This study may have been inadequately powered to detect differences between groups.
• Post-stroke fatigue. It is unclear if oral creatine is beneficial in patients with post-stroke fatigue. Details: Very preliminary clinical research in patients undergoing progressive resistance training after a stroke shows that taking a specific creatine supplement (Creapure, AlzChem Trostberg GmbH) 0.3 grams/kg orally daily for 7 days, followed by 0.1 grams/kg orally daily for a total of 10 weeks modestly improves 6-minute walk test distance when compared with placebo (112207).
• Postoperative recovery. Small clinical studies suggest that oral creatine may not improve recovery of muscle strength after knee surgery. Details: Preliminary clinical research shows that taking creatine 20 grams daily for 7 days, followed by 5 grams daily for 11 weeks, does not improve recovery of muscle strength after anterior cruciate ligament (ACL) reconstruction surgery in young adults when compared with placebo (46622). Other preliminary research shows that taking creatine 10 grams daily for 10 days before total knee arthroplasty, followed by 5 grams daily for 30 days after surgery, does not improve muscle strength or functional recovery when compared with placebo (46659). These studies are limited by small size and variability in patient population and supplementation regimen.
• Rett syndrome. It is unclear if oral creatine is beneficial in patients with this condition. Details: Preliminary clinical research shows that taking creatine 200 mg/kg daily for 6 months does not improve symptom scores when compared with placebo in patients aged 3-25 years with Rett syndrome (46759).
• Rheumatoid arthritis (RA). Oral creatine does not seem to improve disease activity in patients with RA, but it might improve muscle strength. Details: Clinical research in adults with RA shows that taking creatine increases lean muscle mass, total body mass, and muscle strength, but does not alter disease activity or improve strength or physical function, when compared with placebo or a control group (6929,95964). Creatine was taken as 5 grams four times daily for 5 days, followed by 3 grams daily for 12 weeks, in one study and 5 grams four times daily for 5 days, followed by 0.5 grams four times daily for 16 days, in the other study (6929).
• Schizophrenia. It is unclear if oral creatine is beneficial in patients with schizophrenia. Details: Preliminary clinical research shows that taking creatine orally, 3 grams daily for one month followed by 5 grams daily for 2 months, does not improve symptom control or cognitive function in patients with schizophrenia when compared with placebo (16390).
• Spinal cord injury. It is unclear if oral creatine is beneficial in patients with spinal cord injury. Details: Preliminary clinical research shows that taking creatine orally, 20 grams daily for 7 days, increases exercise capacity by improving respiratory function in patients with spinal cord injury (cervical level C5-7) when compared with placebo (46563). However, other preliminary clinical research shows that patients with similar injuries taking creatine 10 grams twice daily for 6 days, followed by 5 grams daily, do not have significant improvements in wrist muscle or hand function (46660).
• Spinal muscular atrophy. It is unclear if oral creatine is beneficial in patients with spinal muscular atrophy. Details: Preliminary clinical research shows that children with type II or III spinal muscular atrophy do not benefit from taking creatine orally for 6 months (46841). Doses were 2 grams daily for children aged 2-5 years, and 5 grams daily for children aged 5-18 years.
• Traumatic brain injury (TBI). It is unclear if oral creatine is beneficial in children with a TBI. Details: In children and adolescents who have suffered a TBI, preliminary clinical research shows that taking creatine orally 0.4 grams/kg daily for 6 months reduces the duration of post-traumatic amnesia by 60 days. It also reduces the risk of headache by 88%, fatigue by 87%, and dizziness by 80% when compared with control. There is also a trend towards reduced duration of intubation and total time in the intensive care unit or hospital (46694). More evidence is needed to rate creatine for these uses.

(Read more about CREATINE)

POSSIBLY EFFECTIVE

• Schizophrenia. Oral glycine may improve negative, but not positive, symptoms of schizophrenia when used as adjunct to therapy with typical antipsychotics in patients resistant to monotherapy. However, glycine does not seem to provide additional benefit when used with clozapine. Details: Some small clinical trials show that taking glycine 0.4-0.8 grams/kg daily in divided doses along with conventional treatment seems to reduce negative symptoms of schizophrenia in patients that are resistant to monotherapy with typical antipsychotics such as thioridazine, haloperidol, and perphenazine (10250,10251,10252,98591). However, when used with the atypical antipsychotic clozapine, glycine appears to have a negligible effect on or worsen symptoms of schizophrenia (10253,11321). Additionally, glycine does not seem to improve positive symptoms of schizophrenia (10250,10251,10252,98591).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency. It is unclear if oral glycine is beneficial in patients with 3-PGDH deficiency. Details: A case series describing two patients with 3-PGDH deficiency who did not respond to serine supplementation suggests that taking oral glycine 0.2 grams/kg daily along with serine might reduce seizure frequency. 3-PGDH deficiency is a rare condition in which serine is not synthesized properly (10254).
• Aging. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults aged 61-80 years with overweight or obesity shows that taking a specific combination product (GlyNAC), providing glycine 100 mg/kg and N-acetyl cysteine 100 mg/kg, daily for 16 weeks improves some markers associated with aging, including glutathione levels, oxidative stress, mitochondrial impairment, genomic damage, inflammation, and endothelial dysfunction, when compared to baseline. Improvements in these measures were lacking in the placebo group (110624). The validity of these findings is limited by a lack of statistical comparison between groups. Also, it is unclear if these effects are due to glycine, N-acetyl cysteine, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral glycine for ADHD, there is insufficient reliable information about the clinical effects of glycine for this purpose.
• Benign prostatic hyperplasia (BPH). Although there has been interest in using oral glycine for BPH, there is insufficient reliable information about the clinical effects of glycine for this purpose.
• Cognitive function. Small clinical studies suggest that oral glycine may modestly improve memory and cognitive function in some patients. Details: Two small clinical studies in healthy young adults and adults with psychosis risk syndrome show that taking glycine 0.2-0.4 grams/kg once or twice daily for up to 24 weeks may improve some measures of memory and cognitive performance when compared with baseline or placebo (11322,92321).
• Cystic fibrosis. It is unclear if oral glycine is beneficial in patients with cystic fibrosis. Details: A small clinical trial in patients 6-23 years of age with cystic fibrosis shows that taking glycine 0.5 grams/kg daily for 8 weeks modestly improves some measures of lung function and reduces sputum and dyspnea by 15% and 23%, respectively, when compared with placebo. However, taking glycine does not improve appetite or energy (98583).
• Gout. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with mild hyperuricemia shows that taking a powder containing glycine 3 grams and L-tryptophan 0.2 grams nightly at bedtime for 6 weeks reduces serum uric acid levels by 0.3 mg/dL when compared with placebo. Improvements also occurred in the subgroup of patients with uric acid levels greater than 7 mg/dL, the point at which symptoms of gout can occur (99883). However, it is unclear if this combination improves gout-related pain. Also, it is not clear if these findings are due to glycine, L-tryptophan, or the combination.
• Insomnia. Small clinical studies suggest that oral glycine may modestly improve sleep quality and daytime feelings of fatigue in patients with poor sleep quality or a restricted sleep duration. Details: Two very small studies in patients who have reported a subjective reduction in sleep quality show that taking glycine 3 grams one hour before bedtime for 2-4 days improves overall sleep quality and sleep efficacy when compared with placebo (92318,92320). Another very small clinical study in healthy males shows that taking glycine 3 grams 30 minutes before bedtime for 3 nights, during which time sleep duration is restricted by 25%, modestly reduces feelings of fatigue after the first night, but not after the third night, when compared with placebo (92316). The effects of glycine on sleep measures have also been evaluated in combination with other ingredients. A very small crossover study in healthy adults without documented sleep disorders shows that taking a combination product containing glycine 3000 mg, tryptophan 1000 mg, magnesium 300 mg, tart cherry powder 220 mg, and L-theanine 200 mg before bed for 3 nights reduces sleep onset latency, increases total sleep time, increases sleep efficiency, and reduces morning sleepiness when compared with placebo (111184). It is unclear if these effects are due to glycine, other ingredients, or the combination.
• Isovaleric acidemia. Although there has been interest in using oral glycine for isovaleric acidemia, there is insufficient reliable information about the clinical effects of glycine for this purpose.
• Metabolic syndrome. Although there has been interest in using oral glycine for metabolic syndrome, there is insufficient reliable information about the clinical effects of glycine for this purpose.
• Obesity. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults aged 61-80 years with overweight or obesity shows that taking a specific combination product (GlyNAC), providing glycine 100 mg/kg and N-acetyl cysteine 100 mg/kg, daily for 16 weeks reduces waist circumference but does not improve body weight or body mass index (BMI) when compared to baseline. None of these outcomes were improved in individuals taking placebo (110624). The validity of these findings is limited by a lack of statistical comparison between groups. Also, it is unclear if these effects are due to glycine, N-acetyl cysteine, or the combination.
• Overactive bladder. It is unclear if oral glycine is beneficial in patients with overactive bladder. Details: One very small, non-randomized, crossover trial in patients with overactive bladder shows that taking glycine 3 grams twice daily for 4 weeks reduces urinary urgency, urinary incontinence, and nighttime urinary frequency and improves quality of life scores when compared with placebo (106497). The validity of these findings is limited by a lack of randomization.
• Physical performance. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults aged 61-80 years with overweight or obesity shows that taking a specific combination product (GlyNAC), providing glycine 100 mg/kg and N-acetyl cysteine 100 mg/kg, daily for 16 weeks improves upper and lower extremity strength and gait speed, but not walking distance, when compared to baseline. None of these outcomes were improved in individuals taking placebo (110624). The validity of these findings is limited by a lack of statistical comparison between groups. Also, it is unclear if these effects are due to glycine, N-acetyl cysteine, or the combination.
• Stroke. It is unclear if sublingual glycine is beneficial in patients with acute ischemic stroke. Details: One small clinical study in patients with acute ischemic stroke in the carotid artery territory shows that taking glycine 1-2 grams sublingually daily for 5 days, starting within 6 hours after the onset of stroke, modestly improves clinical outcomes on the Orgogozo Stroke Scale, the Scandinavian Stroke Scale, and the Barthel index when compared with placebo (11320).
• Venous leg ulcers. Topical glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that applying a cream containing glycine, L-cysteine, and DL-threonine to leg ulcers reduces pain and modestly improves healing when compared with a placebo cream (10255). It is unclear if these effects are due to glycine, other ingredients, or the combination.
• Wound healing. Although there has been interest in using topical glycine for wound healing, there is insufficient reliable information about the clinical effects of glycine for this purpose. More evidence is needed to rate glycine for these uses.

(Read more about GLYCINE)

POSSIBLY EFFECTIVE

• Vitiligo. Small clinical studies suggest that oral or topical L-phenylalanine, when used in combination with UVA light, might modestly improve symptoms in adults and children with vitiligo. Details: Taking L-phenylalanine, as 50 mg/kg two to three times weekly or up to 100 mg/kg once daily orally for up to 3 months, or applying L-phenylalanine 10% cream topically, both in combination with UVA light exposure, seem to be effective for treating vitiligo in adults (2461,2463,2464,2466) and in children (2467).

POSSIBLY INEFFECTIVE

• Attention deficit-hyperactivity disorder (ADHD). Taking phenylalanine orally does not seem to be beneficial for ADHD. Details: Some research suggests that patients with ADHD have lower levels of amino acids such as phenylalanine (9948), but neither D-phenylalanine nor DL-phenylalanine appear to have any sustained effect on ADHD symptoms (9950,9951).
• Pain (chronic). Taking D-phenylalanine orally does not seem to be beneficial for chronic pain. Details: A small clinical study in patients with chronic pain of various etiologies shows that taking D-phenylalanine 250 mg four times daily for 4 weeks does not reduce pain when compared with placebo (2459). Additionally, a small clinical study in adults with chronic low back pain shows that taking D-phenylalanine 4 grams orally as a single dose prior to acupuncture does not enhance analgesic effects when compared with acupuncture alone (2456).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if topical undecylenoyl phenylalanine is beneficial for age spots. Details: Preliminary clinical research shows that applying undecylenoyl phenylalanine 2% cream to age spots, also known as solar lentigines, twice daily for 12 weeks significantly reduces the number of spots or their pigmentation when compared with controls (92704).
• Alcohol use disorder. Oral DL-phenylalanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients experiencing alcohol withdrawal symptoms shows that taking a combination of DL-phenylalanine 300 mg, L-glutamine 150 mg, and 5-HTP 5 mg orally daily for 40 days improves depression, hostility, and physical symptoms caused by psychological distress, when compared with placebo (30100).
• Depression. It is unclear if oral phenylalanine is beneficial in patients with depression. Details: Older clinical research conducted prior to 1985 suggests that taking L-phenylalanine 250 mg orally or intravenously daily for 14-96 days in combination with selegiline, or DL-phenylalanine 50-200 mg orally daily for 15-30 days, might improve symptoms of depression (2468,2469,68795,68825). However, taking D-phenylalanine, 50-100 mg daily for 15 days, does not seem to provide any benefit (68795,68830).
• Multiple sclerosis (MS). Oral L-phenylalanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that treatment with Cari Loder's regimen, which includes oral L-phenylalanine and lofepramine, plus intramuscular (IM) vitamin B12 for 24 weeks, does not improve disability in patients with MS when compared with placebo plus IM vitamin B12 (68796).
• Obesity. It is unclear if oral L-phenylalanine is beneficial in obese or overweight patients. Details: Preliminary clinical research in females with overweight or obesity shows that taking L-phenylalanine 5 grams or 10 grams orally 20 minutes before meals twice daily does not reduce energy intake or improve satiety when compared with placebo (92705).
• Osteoarthritis. Although there is interest in using oral phenylalanine for osteoarthritis, there is insufficient reliable information about the clinical effects of phenylalanine for this condition.
• Pain (acute). It is unclear if oral D-phenylalanine is beneficial for acute pain. Details: Preliminary clinical research shows that taking D-phenylalanine 2-4 grams orally as a single dose 30 minutes prior to tooth extraction modestly enhances the analgesic effects of acupuncture when compared with acupuncture alone (2456).
• Parkinson disease. Although there is interest in using oral phenylalanine for Parkinson disease, there is insufficient reliable information about the clinical effects of phenylalanine for this condition.
• Rheumatoid arthritis (RA). Although there is interest in using oral phenylalanine for RA, there is insufficient reliable information about the clinical effects of phenylalanine for this condition. More evidence is needed to rate phenylalanine for these uses.

(Read more about PHENYLALANINE)

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about SODIUM)

POSSIBLY SAFE ...when used orally and appropriately. Agaricus mushroom extract has been safely used in doses up to 1500 mg daily for up to 12 months (15404,15421,94715,94716,94719,94721). A specific agaricus lyophilized powder product (Sen-Sei-Ro Powder Gold, Kyowa Wellness Co., Ltd.) has been safely used in doses up to 5.4 grams daily for 6 months (17185).

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

(Read more about AGARICUS MUSHROOM)

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

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

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

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

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

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

LIKELY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Chromium has been safely used in doses up to 1000 mcg daily for up to 6 months (1934,5039,5040,6858,6859,6860,6861,6862,6867,6868)(7135,7137,10309,13053,14325,14440,17224,90057,90061)(90063,94234,95095,95096,95097,98687); however, most of these studies have used chromium doses in a range of 150-600 mcg. The Food and Drug Administration (FDA) and Institute of Medicine (IOM) evaluations of the safety of chromium suggest that it is safe when used in doses of 200 mcg daily for up to 6 months (13241,13242).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, long-term. Chromium has been safely used in a small number of studies at doses of 200-1000 mcg daily for up to 2 years (7060,7135,42618,42628,42666,110605,110607,110609). However, the Food and Drug Administration (FDA) and Institute of Medicine (IOM) evaluations of the safety of chromium suggest that it is safe when used in doses of 200 mcg daily for up to 6 months (13241,13242).

CHILDREN: LIKELY SAFE
when used orally and appropriately in amounts not exceeding the daily adequate intake (AI) levels by age: 0-6 months, 0. 2 mcg; 7-12 months, 5.5 mcg; 1-3 years, 11 mcg; 4-8 years, 15 mcg; males 9-13 years, 25 mcg; males 14-18 years, 35 mcg; females 9-13 years, 21 mcg; females 14-18 years, 24 mcg (7135). POSSIBLY SAFE...when used orally and appropriately in amounts exceeding AI levels. Chromium 400 mcg daily has been used safely for up to 6 weeks (42680).

PREGNANCY: LIKELY SAFE
when used orally and appropriately in amounts not exceeding adequate intake (AI) levels. The AI for pregnancy is 28 mcg daily for those 14-18 years of age and 30 mcg daily for those 19-50 years of age (7135).

PREGNANCY: POSSIBLY SAFE
when used orally in amounts exceeding the adequate intake (AI) levels. There is some evidence that patients with gestational diabetes can safely use chromium in doses of 4-8 mcg/kg (1953); however, patients should not take chromium supplements during pregnancy without medical supervision.

LACTATION: LIKELY SAFE
when used orally and appropriately in amounts not exceeding adequate intake (AI) levels. The AI for lactation is 44 mcg daily for those 14-18 years of age and 45 mcg daily for those 19-50 years of age (7135). Chromium supplements do not seem to increase normal chromium concentration in human breast milk (1937). There is insufficient reliable information available about the safety of chromium when used in higher amounts while breast-feeding.

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LIKELY SAFE ...when used orally and appropriately, short-term. Creatine supplementation appears to be safe when used at loading doses of up to 25 grams daily or 0.3 grams/kg daily for up to 14 days in healthy adults (1367,2100,2101,3996,4569,10064,15354,15520,46570,46587)(46673,46688,46719,46753,46801,103278,103279,108336). Creatine supplementation also appears to be safe when used at maintenance doses of 4-5 grams daily for up to 18 months (2101,4578,15353,15354,15520,46587,46673,46690,46753,46838,102164,103278,108336).

POSSIBLY SAFE ...when used orally and appropriately, long-term. Creatine supplementation has been safely used at doses of up to 10 grams daily for up to 5 years in some preliminary clinical research (1367,3996). There is insufficient reliable information available about the safety of creatine when used topically.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Creatine supplementation appears to be safe when used in appropriate doses in infants and children. Creatine 3-5 grams daily for 2-6 months has been safely used in children 5-18 years of age (6182,46596,46739,46841). Creatine 2 grams daily for 6 months has been safely used in children 2-5 years of age (46841). Additionally, weight-based dosing of creatine 0.1-0.4 grams/kg daily in infants and children or 4.69 grams/m2 in children weighing over 40 kg has been used safely for up to 6 months (46623,46629,46694,46759,104672).

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

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POSSIBLY SAFE ...when used orally and appropriately. Glycine has been used safely at doses up to 6 grams daily for 4 weeks (106497) and doses up to 9 grams daily for 3 days (10250,10251,10252,92319). There is insufficient reliable information available about the safety of glycine when used topically.

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

(Read more about GLYCINE)

LIKELY SAFE ...when L-phenylalanine is consumed in amounts typically found in foods (11120).

POSSIBLY SAFE ...when L-phenylalanine is used orally in doses up to 100 mg/kg daily for up to 3 months (2463,2464,2466,2467,2469). ...when D-phenylalanine is used orally in doses up to 1 gram daily for up to 4 weeks, or as a single dose of 4-10 grams (2455,2456,2459,68795,104792). ...when DL-phenylalanine is used orally in doses up to 200 mg daily for up to 4 weeks (2468,68795,68825). ...when phenylalanine cream is applied topically, short-term (2461,92704).

PREGNANCY: LIKELY SAFE
when L-phenylalanine is consumed in amounts typically found in foods by pregnant patients with normal phenylalanine metabolism (2020,11120).

PREGNANCY: UNSAFE
when L-phenylalanine is consumed in amounts typically found in foods by pregnant patients with high serum phenylalanine concentrations, such as those with phenylketonuria (PKU). Serum levels of phenylalanine greater than 360 micromol/L increase the risk of birth defects (1402,11468). Experts recommend that patients with high phenylalanine serum concentrations follow a low phenylalanine diet for at least 20 weeks prior to conception to decrease the risk for birth defects (1402). There is insufficient reliable information available about the safety of L-phenylalanine when taken by mouth in large doses during pregnancy; avoid using. There is insufficient reliable information available about the safety of oral D-phenylalanine during pregnancy; avoid using.

LACTATION: LIKELY SAFE
when L-phenylalanine is consumed in amounts typically found in foods by breast-feeding patients with normal phenylalanine metabolism (2020,11120). There is insufficient reliable information available about the safety of L-phenylalanine when taken by mouth in medicinal amounts during lactation; avoid using. There is insufficient reliable information available about the safety of oral D-phenylalanine during lactation; avoid using.

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

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

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

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

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

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

(Read more about SODIUM)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking agaricus mushroom with antidiabetes drugs might increase the risk of hypoglycemia.  Details In one clinical study in patients with type 2 diabetes who are stabilized on conventional oral hypoglycemic agents, 3 of 29 patients taking an agaricus mushroom extract 500 mg three times daily for 12 weeks reported hypoglycemia, compared to one of 29 patients in the placebo group (15421).

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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))

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, chromium may have additive effects with antidiabetic agents and increase the risk of hypoglycemia.  Details Some research shows that taking chromium might lower blood glucose levels, especially in patients with poorly controlled type 2 diabetes (7137,14440,15169,94234,95097,95098,98687).

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = D Theoretically, aspirin might increase chromium absorption.  Details Animal research suggests that aspirin may increase chromium absorption and chromium levels in the blood (21055).

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of chromium and insulin might increase the risk of hypoglycemia.  Details In clinical research, chromium has been shown to increase insulin sensitivity (1952,14440,95095),

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Chromium might bind levothyroxine in the intestinal tract and decrease levothyroxine absorption.  Details Clinical research in healthy volunteers shows that taking chromium picolinate 1000 mcg with levothyroxine 1 mg decreases serum levels of levothyroxine by 17% when compared to taking levothyroxine alone (16012). Advise patients to take levothyroxine at least 30 minutes before or 3-4 hours after taking chromium.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D NSAIDs might increase chromium levels in the body.  Details Drugs that are prostaglandin inhibitors, such as NSAIDs, seem to increase chromium absorption and retention (7135).

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(Read more about CREATINE)

CLOZAPINE (Clozaril) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, glycine might decrease the effectiveness of clozapine.  Details One small clinical study in patients with schizophrenia shows that adding glycine to clozapine therapy worsens symptoms of schizophrenia when compared with clozapine alone (10253). The mechanism of this interaction is unclear.

(Read more about GLYCINE)

BACLOFEN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant intake of phenylalanine may reduce the intestinal absorption of baclofen.  Details Phenylalanine and baclofen share the same intestinal carrier for absorption; phenylalanine competitively inhibits the absorption of baclofen, reducing its plasma levels (23788).

LEVODOPA Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Phenylalanine, especially in high doses, can reduce the effectiveness of levodopa.  Details Phenylalanine competes with levodopa for carrier-mediated transport into the brain. The resulting reduction in levels of levodopa in the brain can exacerbate tremor, rigidity, and the "on-off" phenomenon in patients with Parkinson disease (3291,3294).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of L-phenylalanine and non-selective MAOIs might increase the risk of hypertensive crisis.  Details L-phenylalanine is metabolized to tyrosine (2052,9949). Some evidence suggests that L-phenylalanine, given with the non-selective MAOI pargyline, might prevent the elimination of tyramine, increasing the risk of hypertensive crisis (2021). However, this was not reported in a small number of patients when using L-phenylalanine with the partially selective MAO-B inhibitor, selegiline (2469).

(Read more about PHENYLALANINE)

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

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

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

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

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

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General ...Orally, agaricus mushroom is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal discomfort, diarrhea, and nausea.
Serious Adverse Effects (Rare):
Orally: Allergic reactions, hepatotoxicity, interstitial lung disease (ILD).

Gastrointestinal ...In one clinical trial, mild gastrointestinal side effects such as nausea, diarrhea, and abdominal discomfort were reported in 6 of 78 patients taking a specific agaricus powder product , Ltd.) 1.8-5.4 grams orally daily for 60 days. The causal relationship between this agaricus mushroom product and the associated gastrointestinal adverse effect was determined to be possible or probable in each case (17185).

Hepatic ...Three cases of severe hepatotoxicity have been reported in females with ovarian or breast cancer receiving chemotherapy who also took agaricus mushroom supplements. Two of the patients had increases in liver function tests a few days after starting agaricus mushroom, which then progressed rapidly to fatal, fulminant hepatitis. One of these patients was also an asymptomatic carrier of hepatitis B virus. In the third case, liver function improved when agaricus mushroom was stopped, worsened when it was restarted, and then recovered fully when the supplement was stopped permanently (16458).

Immunologic ...An allergic reaction has been reported in a female who took a specific agaricus powder product , Ltd.) 1.8 grams daily by mouth for 2 months. The patient developed an urticarial papular rash which resolved when the product was discontinued (17185). Allergic contact cheilitis was also reported in a patient taking a homemade agaricus mushroom extract orally. The reaction resolved upon discontinuation of agaricus mushroom (94720).

Pulmonary/Respiratory ...There is one case report of interstitial lung disease associated with the use of agaricus mushroom for approximately one month in a male with pancreatic ductal adenocarcinoma being treated with gemcitabine. Drug-induced lymphocyte stimulation test (DLST) was positive for agaricus mushroom extract and not gemcitabine. Pneumonitis improved upon discontinuation of agaricus mushroom (108313).

(Read more about AGARICUS MUSHROOM)

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, chromium is generally well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal irritation, headaches, insomnia, irritability, mood changes.
Serious Adverse Effects (Rare):
Orally: Rare cases of kidney and liver damage, rhabdomyolysis, and thrombocytopenia have been reported.

Dermatologic ...Orally, chromium-containing supplements may cause acute generalized exanthematous pustulosis (42561), skin rashes (42679), and urticaria (17224). Also, chromium picolinate or chromium chloride may cause systemic contact dermatitis when taken orally, especially in patients with contact allergy to chromium (6624,90058). In one clinical study, a patient taking chromium nicotinate 50 mcg daily reported itchy palms that improved after the intervention was discontinued. It is unclear of this effect was due to the chromium or another factor (95096).
Topically, hexavalent chromium, which can be present in some cement, leather products, or contaminated soil, may cause allergic contact dermatitis (42645,42789,90060,90064,110606).
A case of lichen planus has been reported for a patient following long-term occupational exposure to chromium (42688).

Endocrine ...Orally, cases of hypoglycemia have been reported for patients taking chromium picolinate 200-1000 mcg daily alone or 200-300 mcg two or three times weekly in combination with insulin (42672,42783). Chromium picolinate has also been associated with weight gain in young females who do not exercise and in those following a weight-lifting program (1938).

Gastrointestinal ...Orally, chromium in the form of chromium picolinate, chromium polynicotinate, chromium-containing brewer's yeast, or chromium-containing milk powder may cause nausea, vomiting, diarrhea, decreased appetite, constipation, flatulence, or gastrointestinal upset (14325,42594,42607,42622,42643,42679).
Long-term exposure to heavy metals, including chromium, has been associated with increased risk of gallbladder disease and cancer (42682,42704).

Genitourinary ...Orally, chromium polynicotinate has been associated with disrupted menstrual cycles in patients taking the supplement to prevent weight gain during smoking cessation (42643).

Hematologic ...Anemia, hemolysis, and thrombocytopenia were reported in a 33 year-old female taking chromium picolinate 1200-2400 mcg daily for 4-5 months (554). The patient received supportive care, blood product transfusions, and hemodialysis and was stabilized and discharged a few days later. Lab values were normal at a one-year follow-up.

Hepatic ...Liver damage has been reported for a 33-year-old female taking chromium picolinate 1200 mcg daily for 4-5 months (554). Also, acute hepatitis has been reported in a patient taking chromium polynicotinate 200 mcg daily for 5 months (9141). Symptoms resolved when the product was discontinued. Two cases of hepatotoxicity have been reported in patients who took a specific combination product (Hydroxycut), which also contained chromium polynicotinate in addition to several herbs (13037).

Musculoskeletal ...Acute rhabdomyolysis has been reported for a previously healthy 24-year-old female who ingested chromium picolinate 1200 mcg over a 48-hour time period (42786). Also, chromium polynicotinate has been associated with leg pain and paresthesia in patients taking the supplement to prevent weight gain during smoking cessation (42643).

Neurologic/CNS ...Orally, chromium picolinate may cause headache, paresthesia, insomnia, dizziness, and vertigo (6860,10309,14325,42594). Vague cognitive symptoms, slowed thought processes, and difficulty driving occurred on three separate occasions in a healthy 35-year-old male after oral intake of chromium picolinate 200-400 mcg (42751). Transient increases in dreaming have been reported in three patients with dysthymia treated with chromium picolinate in combination with sertraline (2659). A specific combination product (Hydroxycut) containing chromium, caffeine, and ephedra has been associated with seizures (10307). But the most likely causative agent in this case is ephedra.

Psychiatric ...Orally, chromium picolinate has been associated with irritability and mood changes in patients taking the supplement to lose weight, while chromium polynicotinate has been associated with agitation and mood changes in patients taking the supplement to prevent weight gain during smoking cessation (6860,42643).

Renal ...Orally, chromium picolinate has been associated with at least one report of chronic interstitial nephritis and two reports of acute tubular necrosis (554,1951,14312). Laboratory evidence suggests that chromium does not cause kidney tissue damage even after long-term, high-dose exposure (7135); however, patient- or product-specific factors could potentially increase the risk of chromium-related kidney damage. More evidence is needed to determine what role, if any, chromium has in potentially causing kidney damage.
Intravenously, chromium is associated with decreased glomerular filtration rate (GFR) in children who receive long-term chromium-containing total parenteral nutrition - TPN (11787). Topically, burns caused by chromic acid, a hexavalent form of chromium, have been associated with acute chromium poisoning with acute renal failure (42699). Early excision of affected skin and dialysis are performed to prevent systemic toxicity.

Other ...Another form of chromium, called hexavalent chromium, is unsafe. This type of chromium is a by-product of some manufacturing processes. Chronic exposure can cause liver, kidney, or cardiac failure, pulmonary complications, anemia, and hemolysis (9141,11786,42572,42573,42699). Occupational inhalation of hexavalent chromium can cause ulceration of the nasal mucosa and perforation of the nasal septum, and has been associated with pneumoconiosis, allergic asthma, cough, shortness of breath, wheezing, and increased susceptibility to respiratory tract cancer and even stomach and germ cell cancers (42572,42573,42601,42610,42636,42667,42648,42601,42788,90056,90066). Although rare, cases of interstitial pneumonia associated with chromium inhalation have been reported. Symptoms resolved with corticosteroid treatment (42614).

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General ...Orally, creatine is generally well-tolerated. Topically, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Dehydration, diarrhea, gastrointestinal upset, muscle cramps, and water retention.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about interstitial nephritis, renal insufficiency, rhabdomyolysis, and venous thrombosis.

Cardiovascular ...Some research suggests that creatine supplementation can cause edema. In a randomized controlled trial, 26% of patients with amyotrophic lateral sclerosis (ALS) receiving creatine 10 grams daily reported edema after 2 months of treatment compared to 9% with placebo. The difference between groups was statistically significant at 2 months but not at month 4 and beyond. Creatine is believed to cause slight water retention, which may have been more apparent in patients who were immobilized due to ALS (46647). While this adverse drug reaction did not lead to worsening cardiac function in these patients, theoretically, creatine-related water retention could worsen congestive heart failure or hypertension.
There is one case report of lone atrial fibrillation in a 30-year-old male vegetarian. He started powdered creatine 20 grams daily for 5 days, followed by 2.5 grams daily for a month. However, he discontinued powdered creatine due to severe cramping and diarrhea, and reinitiated creatine supplementation a month later with an encapsulated formulation. Aside from gelatin in the capsule, creatine was the only ingredient listed in both formulations. During the loading dose phase, the patient developed dyspnea and palpitations and was diagnosed with lone atrial fibrillation in the emergency department. Symptoms resolved with treatment and supplement discontinuation (13187). Theoretically, alterations in electrolyte balance due to dehydration or diarrhea could lead to conduction abnormalities and arrhythmia; however, in this case, the patient had normal electrolyte levels. Contaminants in dietary supplements might also be responsible for adverse reactions; this specific creatine product was not tested for contaminants. It remains unclear whether creatine was associated with this event.
Theoretically, taking creatine nitrate might reduce blood pressure and heart rate due to its nitrate component. However, clinical research shows that creatine nitrate 12 grams daily for 7 days followed by 3 grams daily for 21 days does not lower blood pressure or heart rate acutely or chronically when compared to creatine monohydrate or placebo (95959).

Dermatologic ...In a small clinical trial of older, healthy males, one subject out of the 10 receiving creatine 5 grams four times daily for 10 days followed by 4 grams daily for 20 days reported a skin rash during the study. The type and severity of rash and whether it resolved after creatine was discontinued were not discussed (4572). Also, skin rash has been reported by patients taking celecoxib and creatine; however, whether this effect was due to creatine or celecoxib is unclear (46706).
Topically, burning, itching, redness, irritation, and perception of changes in skin temperature have been reported (104669).

Endocrine ...Creatine may influence insulin production (11330). In human research, insulin levels increased 120 and 240 minutes after creatine supplementation (46760); however, there was no effect in another trial (46732). In a clinical study, 0.3 grams/kg of creatine daily for one week significantly increased cortisol levels by 29%. However, the levels returned to baseline at week 2 (46615).

Gastrointestinal ...Some small clinical studies have reported diarrhea and vomiting with oral creatine supplementation (4584,11332,46562,46684,46698,46704,104673). Also, gastrointestinal distress, transient abdominal discomfort, constipation, heartburn, and nausea have been reported by a small number of individuals in randomized, controlled clinical trials (4572,11332,46527,46528,46573,46589,46622,46668,46684,46695), (46704,46771,95964,104668,104669,104673,108316). However, most high-quality clinical research shows that creatine does not increase the incidence of gastrointestinal upset (103102,103278,103279).
Undissolved creatine powder may cause gastroenteritis (1368). Additionally, simultaneous intake of creatine and caffeine powder may increase the occurrence of gastrointestinal distress (95964).

Hematologic ...There are two case reports of creatine-related venous thrombosis in otherwise healthy adults. In the first case, an active 18-year-old male who had been taking an unspecified dose of creatine daily for 3 months was diagnosed with venous thrombosis via MRI. The patient reported increased thirst and fluid consumption when taking creatine. In the second case, an active 31-year-old male who had recently taken a 5-hour flight was diagnosed with deep vein thrombosis. He had been taking an unspecified dose of creatine. After stopping creatine and receiving anticoagulation therapy for 6 months, both patients' thromboses were resolved and did not recur. Researchers speculate that dehydration might be to blame for these adverse events, as dehydration increases the risk of thrombosis. In both cases, thrombophilic conditions were ruled out, and a temporal relationship between creatine consumption and thrombosis was established (90301). However, it remains unclear if creatine was responsible for these thrombotic events.

Hepatic ...Despite two case reports describing hepatic injury in patients taking creatine (46701,90319), meta-analyses and clinical studies specifically evaluating the safety of creatine have not identified an increased risk for hepatic injury (103278,103279). In addition, population research suggests that there is not an association between creatine intake and liver fibrosis, cirrhosis, or hepatic steatosis. However, this study largely included subjects consuming less than 4 grams daily (112208).
One preliminary clinical trial specifically evaluated the effect of creatine loading and maintenance doses on hepatic function indices in healthy adults. No clinically significant changes in hepatic indices were reported in patients taking creatine loading doses of 20 grams daily for 5 days followed by maintenance doses of 3 grams daily for 8 weeks (46521). Another clinical study evaluated the impact of creatine monohydrate and creatine nitrate on liver function enzymes, showing no change in levels within 5 hours after the first dose of 12 grams or after continued consumption of 12 grams daily for 7 days followed by 3 grams daily for 21 days (95959). The patients that experienced hepatic injury in the available case reports were also taking other exercise supplements. Whether the reported adverse hepatic effects were due to creatine or the other supplements patients were taking is unclear. Also, neither of these case reports addressed whether the supplements were tested for contamination (46701,90319).

Musculoskeletal ...Creatine-associated increase in body mass is well documented in randomized, controlled clinical trials and is often as large as 1-2 kg during the five-day loading period of creatine (2101,4569,4589,4591,4600,4605,46504,46561,46815,46827)(46830,46843,95962,103279,112201). This may be considered an unwanted adverse reaction in some individuals and a desired effect of supplementation in others. This weight gain may interfere with mass-dependent activities such as running and swimming (46504,46823). Muscle cramping due to creatine supplementation has been reported in controlled clinical trials and may result from water retention in skeletal muscle (2104,4572,4584,30915,46562,46695,46826,46827,104673). However, most high quality clinical research shows that creatine does not increase the incidence of musculoskeletal injuries or muscle cramping (103102). In one case report, rhabdomyolysis in a weight lifter using creatine 25 grams daily over a one-year period has been reported (12820). Another case report describes an adult male who developed acute compartment syndrome of the leg after regular consumption of an unspecified amount of creatine and cocaine (112210).

Neurologic/CNS ...In clinical research, thirst, sleepiness, mild headache, and syncope have been reported for patients taking creatine, although the events were uncommon (46578,46615,46820). More serious adverse events have been reported for patients taking creatine in combination with other ingredients. A case of ischemic stroke has been reported for an athlete who consumed creatine monohydrate 6 grams, caffeine 400-600 mg, ephedra 40-60 mg, and a variety of other supplements daily for 6 weeks (1275). In another case, a 26 year old male reported with a hemorrhagic stroke linked to taking the supplement Jack3d, which contains creatine, DMAA, schizandrol A, caffeine, beta-alanine, and L-arginine alpha-ketoglutarate (90318). It is likely that these adverse events were due to other ingredients, such as caffeine, ephedra, and DMAA, which are known to have stimulant and vasoconstrictive properties.

Oncologic ...Population research shows that use of muscle building supplements such as creatine, protein, and androstenedione is associated with an increased odds of testicular germ cell cancer. This risk appears to be more apparent in early users, those using two or more muscle building supplements, and those with long-term use of the supplements. The odds of testicular germ cell cancer may be increased by up to 155% in males taking both creatine and protein supplements (90329). The risk of testicular germ cell cancer from creatine alone is unclear from this study.

Psychiatric ...Anxiety, irritability, depression, aggression, and nervousness have been reported in clinical research for patients taking creatine, although the effects are not common (46518). A case of acute organic psychosis was reported in a 32-year-old soldier in Iraq who was consuming excessive amounts of caffeine coupled with use of creatine (Creatamax, MaxiNutrition) one tablet twice daily for 3 weeks plus a specific stimulant containing bitter orange, guarana seed extract, and St. John's wort extract (Ripped Fuel Ephedra Free, Twinlabs) two tablets three times daily for 2 days prior to admission. The psychosis was considered likely due to caffeine consumption in combination with the stimulant supplement rather than creatine (37982).

Renal ...Isolated cases of renal dysfunction in patients taking creatine have been reported, including a case of interstitial nephritis in a healthy male (184) and a case of renal insufficiency in a football player (46828). In contrast to these cases, several clinical studies and case reports have shown that creatine does not affect markers of renal function in healthy adults (2120,3996,4573,16535,46735,46749,46758,46779,46813,95959,103279). Doses studied included 5- to 7-day loading regimens of 12 to 21 grams daily (2120,46813), or maintenance doses of 3-10 grams daily for up to 2 years (16535,46712,46758,95959). In two additional studies, creatine supplementation 15.75 grams for 5 days followed by 4.25 grams daily for 20 days with carbohydrate and protein ingestion led to no change of renal stress markers (46844). Other clinical research has shown that ingestion of creatine up to 30 grams daily for 5 years is not associated with an increased incidence of renal dysfunction (103102).
Other case reports involve patients with pre-existing renal dysfunction. For example, in one case, a patient with a history of recurrent renal failure developed relapsing steroid-responsive nephritis syndrome after taking creatine (1368,2118). In another case, a patient with diabetic nephropathy who was taking creatine and metformin developed severe metabolic acidosis and acute renal failure. It is unclear if creatine contributed to this event, as metformin alone is known to cause metabolic acidosis (46738). These case reports have raised concern that individuals with pre-existing renal dysfunction may be at increased risk for renal injury with creatine supplementation. However, no prospective clinical trials have been conducted in this population to clarify this concern.
In addition, two cases of acute kidney injury and hypercalcemia have been reported in 16 year old males that took 1-4 servings of creatine for less than 4 weeks; however, the creatine product contained unlabeled, very high doses of vitamin D, which is the likely cause of these symptoms (109739).
In one survey, 13% of male collegiate athletes taking creatine reported dehydration (4584). The Association of Professional Team Physicians has warned that creatine may cause dehydration, heat-related illnesses, and electrolyte imbalances, and reduce blood volume. Mild transient dehydration resulting in an elevated serum creatinine was also reported in a single person in a clinical trial (104672). However, a study found that creatine supplementation during preseason football training had no effect on fluid or electrolyte status (46845). Additionally, most high quality clinical research shows that creatine does not increase dehydration (103102). A theoretical increase in risk of dehydration due to intracellular fluid shifts has led most creatine manufacturers to caution about adequate hydration with creatine supplementation (4576).

Other ...There have been reports of heat intolerance with oral creatine supplementation (46505). Increases in formaldehyde production have been reported with creatine use. A-24 year-old man taking supratherapeutic doses of creatine monophosphate in combination with an energy supplement developed malignant hyperthermia after undergoing anesthesia. His symptoms included tachycardia, hypertension, hypercarbia, and hyperthermia. Environmental factors are suspected to have played a role in the development of malignant hyperthermia, so whether this adverse event was due to creatine at all is unclear (46717).
In 1997, three collegiate wrestlers died after engaging in a rapid weight-loss program in order to qualify for competition (93628). Initially creatine supplementation was considered to have contributed to or caused these deaths (12820,93629); however, investigations by the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) did not confirm this belief (12820,93630). It appears that only one of the three wrestlers had been using creatine. Instead, the deaths were related to drastic, short-term weight loss in which the wrestlers wore rubber suits, avoided hydration, and performed workouts in rooms with temperatures up to 33 °C (1368,93631).

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General ...Orally and topically, glycine seems to be well tolerated.

Gastrointestinal ...Soft stools, nausea, vomiting, and upper gastrointestinal (GI) tract discomfort have occurred rarely with oral use of glycine. These symptoms resolve rapidly with discontinuation of glycine (10252,11320,92319). Dry mouth has also been reported but any association to glycine is unclear (92321).

Neurologic/CNS ...Mild sedation has occurred rarely with oral use of glycine. Symptoms resolve rapidly with discontinuation of glycine (10252,11320,92321). Irritability, insomnia, fatigue, memory impairment, headache, and sensory impairment have been reported, but any association with glycine is unclear (92321).

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General ...Orally, L-phenylalanine and D-phenylalanine are generally well tolerated when used in typical doses.
Most Common Adverse Effects:
Orally: Anxiety, constipation, headache, heartburn, insomnia, nausea, and sedation.
Topically: Burning, erythema, and itching.

Cardiovascular ...One patient in a small case series developed extrasystoles after 10 days of treatment with DL-phenylalanine, but this resolved on the 12th day of treatment without discontinuing phenylalanine (68825).

Dermatologic ...Topically, erythema, itching, and burning have been reported in some patients using an undecylenoyl phenylalanine 2% cream for treatment of age spots (92704).

Gastrointestinal ...Orally, constipation, heartburn, and nausea has been reported in some patients taking phenylalanine (2463,68827,68829,68830).

Neurologic/CNS ...Orally, headaches, which are typically transient and do not require treatment or dosage reduction, have been reported during the first 10 days of treatment with L-, D-, and DL-phenylalanine (68795,68825,68827,68829). Transient vertigo has also been reported with D- and DL-phenylalanine (68795).
In patients with Parkinson disease, taking DL-phenylalanine, especially in high doses, interferes with levodopa transport into the brain, causing increased rigidity, tremor, and occurrence of the on-off phenomenon. Akinesia has been reported more rarely (3291,3292,3293,3294,68828). In patients with schizophrenia, taking a single dose of L-phenylalanine 100 mg/kg has been associated with worsening of medication-induced tardive dyskinesia (2457).

Psychiatric ...Orally, L-phenylalanine has been associated with anxiety, insomnia, and, more rarely, hypomania (68827,68829). DL-phenylalanine has been associated with fatigue and sedation (9951).

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

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

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

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

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

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

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

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

(Read more about SODIUM)