Pumped-AF Strawberry Watermelon [Discontinued] by Steel

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Although there has been interest in using oral agmatine for alcohol use disorder, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Alzheimer disease. Although there has been interest in using oral agmatine for Alzheimer disease, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Anxiety. Although there has been interest in using oral agmatine for anxiety, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Athletic performance. Although there has been interest in using oral agmatine for improving athletic performance, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Autism spectrum disorder. Although there has been interest in using oral agmatine for autism spectrum disorder, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Bipolar disorder. Although there has been interest in using oral agmatine for bipolar disorder, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Depression. Although there has been interest in using oral agmatine for depression, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Epilepsy. Although there has been interest in using oral agmatine for epilepsy, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Herniated disc. It is unclear if oral agmatine is beneficial in patients with herniated disc. Details: A small clinical study in patients with radicular pain associated with lumbar disc herniation shows that taking agmatine sulfate 890 mg three times daily for 14 days decreases pain scores by around 20% and increases health-related quality of life scores by around 50% when compared with placebo (94736).
• Muscle strength. Although there has been interest in using oral agmatine for increasing muscle strength, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Parkinson disease. Although there has been interest in using oral agmatine for Parkinson disease, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Peripheral neuropathy. It is unclear if oral agmatine is beneficial in patients with peripheral neuropathy. Details: A small, open-label study in patients with peripheral neuropathy of mixed etiologies shows that taking a specific agmatine sulfate product (AgmaSet, Gilad&Gilad LLC) 2.67 grams daily, in divided doses, for 2 months reduces pain intensity by around 46% and improves symptom scores for burning, numbness, and tingling when compared to baseline (111144). The validity of these findings is limited by a lack of comparator group.
• Schizophrenia. Although there has been interest in using oral agmatine for schizophrenia, there is insufficient reliable information about the clinical effects of agmatine for this purpose.
• Stroke. Although there has been interest in using oral agmatine for neuroprotection against stroke, there is insufficient reliable information about the clinical effects of agmatine for this purpose. More evidence is needed to rate agmatine for these uses.

(Read more about AGMATINE)

POSSIBLY EFFECTIVE

• Athletic performance. Oral beet may improve athletic performance associated with aerobic activities. However, it is not clear who is most likely to benefit, for which type of competition it is most useful, or what dose or duration of use is most appropriate. Details: Several small clinical trials, most of which enrolled elite athletes, recreational athletes, and sedentary males, as well as meta-analyses of some of these and other studies, show that beet improves various measures of athletic performance, including ability, muscular endurance, power output, sprinting, and strength (93844,94464,94468,94469,100143,100150,100152,105761,113422). Clinical research also shows that drinking beetroot juice improves the use of oxygen during exercise testing in recreationally-trained athletes, especially with severe exercise testing (94460,94463,94467,100147,105762). Also, in obese adolescents, taking beetroot juice daily for 6 days increases the time to exhaustion from severe exercise, but does not improve moderate exercise (100145). Not all research shows that beet supplementation benefits athletic performance. Another meta-analysis of several small clinical studies, including some of the studies above, shows that taking beetroot does not improve performance in high-intensity or sprint interval training (111159). Additionally, the majority of research in elite athletes does not support the use of beetroot juice to decrease the time needed to complete a task, aid in some sort of graded exercise test, or improve the use of oxygen during exercise testing (94455,94458,94460,94461,94464,94465,94466,94469,94473,100142,100153,105763). The supposed lack of effect of beetroot juice in elite athletes might be related to the natural production of nitrates and nitrites in the body or the increased ability to use oxygen that comes from extensive training (94458,94463). Alternatively, any changes might be very small (<1%) and not identified with statistical comparisons, although even very small changes might be beneficial in competition (94464). The most commonly used doses in all studies, regardless of effect, have included an acute dose of beetroot juice 70-500 mL up to 3 hours prior to exercise (93844,94463,94464,94466,94467,94473,97726,100142,100143,105761)(105762,111159,113422) or chronic dosing of up to 500 mL daily for 3-6 days (94459,94464,94469,100145,100147,100153,111159,113422). Less commonly, beetroot juice 70-140 mL daily, betalain-rich concentrate 100 mg daily, or a beetroot-based nutritional gel 100 grams daily, have been taken for longer dosing schedules of 7-15 days (97720,100144,100148,100152,105763,113422). Benefits in elite athletes, most often related to time trials, are usually limited to studies using chronic dosing of 7-15 days, which is longer than the duration of 6 days used in the majority of studies (94473,97720,100144,100148). Brands of juice used in clinical trials have included Beet It Sport (James White Drinks Ltd.) (94455,94458,94465,100142,100143,100144,100148,105761,105763), Beet It Stamina Shot (James White Drinks Ltd.) (93844), Beet It (James White Drinks Ltd) (94457,94459,94460,94467,94469,97726,100145,100153,105762,111159), and Love Beets Beetroot Juice (Gs Fresh Ltd.) (94461,94462). Although plasma levels have not been analyzed in all studies, the majority of studies suggest that these doses are adequate to increase levels of nitrates or nitrites, which is thought to be essential for increasing athletic potential (93844,94455,94458,94459,94460,94465,94467,94469,94466,94473,97726). The evidence also suggests benefit in both normoxic and hypoxic environments (94465,100148,105763).
• Exercise-induced muscle soreness. Drinking beetroot juice 7-8 times over 48 hours after strenuous exercise may reduce exercise-induced muscle soreness, but evidence is conflicting. Details: Some clinical research shows drinking beetroot juice (Love Beets Beetroot Juice, Gs Fresh Ltd.) 125 mL or 250 mL seven times over 48 hours after strenuous box jumps improves muscle soreness when compared with placebo and sodium nitrite (96964,97722). Other small clinical studies show that drinking beetroot juice 50-250 mL as eight separate doses over 48 hours after strenuous exerciseimproves muscle soreness and reduces tissue edema when compared with placebo (94461,113424). However, drinking beetroot juice 250 mL as seven separate doses over 48 hours after running a marathon does not appear to reduce muscle soreness when compared with placebo (94462). A meta-analysis of 4 small studies, mostly in healthy or physically active males, shows that drinking beetroot juice improves the pressure pain threshold, which is a measure of muscle soreness, at 48- and 72-hours post-exercise when compared with a fruit-flavored drink. However, beetroot juice does not improve subjective muscle soreness scores (111160). The validity of the findings from this meta-analysis is limited by the heterogeneity of the beetroot juice regimens among the included studies. Further, these results should not be generalized to elite athletes.

POSSIBLY INEFFECTIVE

• Chronic obstructive pulmonary disease (COPD). Drinking beetroot juice for up to 14 days may not improve exercise capacity in patients with COPD. Details: A meta-analysis of eight small clinical trials in patients with COPD shows that taking nitrate-rich beetroot juice does not improve most measures of exercise capacity, including the 6-minute walk test, cycling ergometry endurance time, and maximum rate of oxygen consumption (VO2 max), when compared with placebo. Additionally, beetroot juice did not reduce blood pressure or heart rate. However, the analysis did show a significant improvement in scores on the Borg Rating of Perceived Exhaustion scale with beetroot juice over placebo. Nitrate-rich beetroot juice doses ranged from 70-140 mL daily for up to 14 days (104200).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cognitive function. It is unclear if drinking beetroot juice is beneficial for cognitive function. Details: A small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days improves the time to complete part B of the trail making test, which is a test of cognitive function, but not part A, when compared with controls (111158). However, the duration and size of this study limits its validity. Further, it is unclear whether any improvement is clinically significant. The effect of acute beet administration on cognitive function has also been studied. A very small clinical study in healthy adults shows that taking beet extract (RedNite, Enovate Biolife) chewable tablets 3 grams 90 minutes prior to neuropsychological testing improves immediate and delayed memory capacity, frontal lobe function, and lexical flexibility but does not improve working memory, information processing speed, or subjective reports of memory performance when compared with placebo (113427).
• Coronary heart disease (CHD). It is unclear if oral beetroot extract is beneficial in patients with CHD. Details: A small clinical trial in patients with CHD shows that taking red beetroot extract 500 mg, containing around 25 mg betalains, twice daily for 2 weeks reduces total cholesterol and low-density lipoprotein (LDL) cholesterol by 15 mg/dL and reduces triglycerides by 8 mg/dL when compared to baseline. Slight improvements in blood pressure and blood glucose were also reported, but these changes were not clinically significant (103883). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear whether beetroot can reduce the risk of cardiovascular events in patients with CHD.
• Dyslipidemia. It is unclear if oral beetroot is beneficial in patients with dyslipidemia. Details: A meta-analysis of small clinical studies in healthy individuals or patients with dyslipidemia, cardiovascular disease, or overweight or obesity, shows that consuming beetroot juice or leaves does not improve levels of triglycerides or total, low-density lipoprotein, or high-density lipoprotein cholesterol when compared with controls (111163). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the enrolled patients and beetroot regimens.
• Exercise-induced muscle damage. It is unclear if oral beetroot juice improves recovery from muscle damage after exercise. Details: A meta-analysis of 4 small clinical studies in healthy or physically active individuals, most of which enrolled males only, shows that drinking beetroot juice improves measures of muscle recovery at 72 hours post-exercise when compared with a fruit-flavored drink. However, beetroot juice does not consistently improve recovery at earlier time points post-exercise, nor does it reduce levels of creatine kinase or markers of inflammation (i.e., interleukin-6, interleukin-8, c-reactive protein, or tumor necrosis factor-alpha) (111160). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the beetroot juice regimens among the included studies, which usually varied from 210-250 mg of nitrate in 7-11 servings over 3-7 days. Further, these results should not be generalized to elite athletes. Another very small clinical study in semi-professional female athletes shows that ingesting beetroot juice 50 mL 8 times over 48 hours after exercise-induced muscle damage enhances the recovery of some functional parameters such as muscle endurance but not others such as flexibility and vertical jump performance when compared with placebo (113424).
• Hypertension. Oral beet may slightly reduce blood pressure in healthy individuals, but it is unclear if it is beneficial in patients with hypertension. Details: Meta-analyses of small studies show the potential for a minor reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in healthy adults taking beetroot juice (94470,97718,97728). The average reduction in SBP and DBP with beetroot juice consumption is about 4 mmHg and 1 mmHg, respectively, which is greater than the effect seen with consuming blackcurrant juice or nitrate-depleted beetroot juice. The most benefit is seen when beetroot juice is taken for at least 2 weeks or at doses of 500 mL daily (97728). The effect of acute beet supplementation on blood pressure is conflicting. A small clinical study in healthy adults shows that drinking beet juice (Beet It, James White Company) 140 mL two hours prior to cardiovascular measurements reduces resting SBP by about 4 mmHg but does not improve resting or post-exercise DBP, central blood pressure, or arterial stiffness nor does it improve post-exercise SBP when compared with placebo. Subgroup analysis suggests that the reductions in resting SBP were only observed in males, not females (113423). Another small clinical study shows that consuming beet 100 grams baked into bread modestly decreases DBP over a 6-hour period when compared with white bread (97725). It is possible that genetics might play a role in the magnitude of effect seen with beetroot consumption. Adults with a specific gene polymorphism, eNOS Glu298Asp, experienced a greater reduction in DBP after consuming beet-containing bread (97724). Despite positive findings in studies of healthy individuals, research on the use of beetroot juice in patients with hypertension is unclear. A small clinical study in adults with hypertension who were taking antihypertensive medications shows that drinking nitrate-rich beetroot juice (Beet it; James White Drinks Ltd.) 70 mL twice daily for one week does not lower blood pressure when compared with nitrate-depleted beetroot juice (94457). Also, in patients with mild to moderate hypertension, clinical research shows that taking a combination of beetroot powder (Sensient) 300 mg, olive leaf extract 1000 mg, and green coffee bean extract 200 mg daily for 6 weeks does not lower blood pressure when compared with placebo (97723). However, some evidence suggests that at least part of the blood pressure lowering effects of beet might be independent of nitrate (97728). Furthermore, some research suggests that identifying effects on blood pressure might be dependent on the method of measurement, including clinic resting measurements, 24-hour monitoring, or morning/evening home resting measurements (97729).
• Hypertriglyceridemia. It is unclear if oral beet is beneficial in patients with hypertriglyceridemia. Details: A small clinical study in overweight or obese individuals with dyslipidemia shows that taking freeze-dried beet leaf 2.8 grams daily for 4 weeks in addition to nutritional guidance does not lower triglyceride levels when compared with nutritional guidance alone (100146). Beet has also been evaluated in combination with other ingredients. A small clinical trial in patients at risk for heart disease shows that a specific combination of beet and hawthorn berry (Neo40-Daily, Neogenis Labs), taken twice daily for 30 days, can modestly reduce blood triglyceride levels when compared to baseline (18222). It is unclear if these findings are due to beet, hawthorn berry, or the combination.
• Liver disease. Although there has been interest in using oral beet for liver disease, there is insufficient reliable information about the clinical effects of beet for this purpose.
• Muscle strength. It is unclear if oral beetroot juice is beneficial for muscle strength. Details: A meta-analysis of 18 clinical studies in healthy males shows that taking beetroot juice or beetroot gel 2-3 hours before exercise improves muscular strength when compared with placebo. Subgroup analysis suggests that beetroot-based supplements improve muscular strength in a fatigued but not resting state (113422). A small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days improves handgrip strength by approximately 18% compared with 4% in controls (111158). However, it is unclear whether any improvement is clinically significant.
• Obesity. It is unclear if oral beet leaf or beetroot juice is beneficial for weight loss. Details: A small clinical study in patients with overweight or obesity and dyslipidemia shows that taking freeze-dried beet leaf 2.8 grams daily for 4 weeks in addition to nutritional guidance does not reduce body weight or body mass index (BMI) when compared with nutritional guidance alone (100146). Similarly, a small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days does not improve weight loss when compared with controls (111158). However, the size and duration of this study may have been inadequate to detect differences between groups.
• Pregnancy-induced hypertension. It is unclear if oral beetroot juice is beneficial in patients with pregnancy-induced hypertension. Details: A small clinical trial in pregnant patients with hypertension who are at approximately 22-35 weeks gestation shows that taking beetroot juice (James White Drinks Ltd) 70 mL daily for 8 days does not reduce blood pressure when compared with a nitrate-depleted beetroot juice (100151). However, the study was small and designed to investigate the feasibility of using beetroot juice in this population.
• Pulmonary hypertension. It is unclear if oral beetroot juice is beneficial in patients with pulmonary hypertension. Details: A small clinical study shows that taking beetroot juice (Beet-It Sport; James White Drinks Ltd) 70 mL twice daily for 7 days does not improve right ventricular systolic function when compared with nitrate-depleted beetroot juice in patients with pulmonary hypertension (100149). However, this study was small and not adequately powered to detect differences between groups.
• Raynaud syndrome. It is unclear if oral beetroot juice is beneficial in patients with Raynaud syndrome. Details: A small clinical study in patients with Raynaud syndrome undergoing cold sensitivity tests shows that drinking beetroot juice (Beet-It, James White Drinks Ltd) 70 mL daily for 13 days, followed by 140 mL prior to testing, does not reduce pain in the hands or feet, but might improve thermal comfort in the feet, when compared to baseline (103884). The validity of this finding is limited by the lack of a comparator group. More evidence is needed to rate beet for these uses.

(Read more about BEET)

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)

LIKELY EFFECTIVE

• Constipation. Rectal glycerol is beneficial in children and adults with constipation. Details: Glycerol rectal suppositories and enemas are approved by the US Food and Drug Administration (FDA) for over-the-counter use to treat occasional constipation in adults and children at least 2 years of age (15).

POSSIBLY EFFECTIVE

• Athletic performance. Oral glycerol may improve hydration during exercise, but clinical studies evaluating glycerol for improving measures of athletic performance are limited and conflicting. Details: Several clinical studies show that glycerol increases serum osmolality and improves hydration status during exercise (2475,2476,93757,93760,93761,93765). One meta-analysis, including 14 studies and 99 patients, shows that glycerol-induced hyperhydration increases body water by approximately 2.5-fold when compared with water-induced hyperhydration (93757). Also, taking glycerol along with table salt 7.5 grams per liter fluid seems to improve hydration status when compared withg glycerol alone (99162). Research regarding the effects of glycerol on thirst, comfort, temperature regulation, sweating, and heart rate is conflicting (2475,2476,93760,99162). While glycerol may improve hydration status during exercise, it is unclear whether it can improve measures of athletic performance. An early meta-analysis including a total of 36 athletes shows that taking glycerol increases endurance performance by 2.6%. Although this is a small difference, it might be considered meaningful to athletes (93757). Some small clinical studies in athletes suggest that glycerol increases endurance and time to exhaustion, with no effect on heat regulation (2475,2479,93764). However, other small studies suggest that glycerol does not reduce perceived exhaustion or improve exercise performance (2476,93760). Also, glycerol has not been shown to increase time to exhaustion in triathletes (2492). When used to improve athletic performance, glycerol is most often taken at doses of 1-1.5 gram/kg in conjunction with approximately 1.5 L of fluid, 60-120 minutes before competition, and in some cases continued during the competition (2475,93757,93760,93764).
• Ichthyosis. Topical application of a specific product containing glycerol and paraffin may improve symptoms of ichthyosis in children. The benefits of topical glycerol alone in these patients is unknown. Details: A large clinical trial in children aged 1 month to 18 years shows that applying a specific product (Dexeryl, Pierre Fabre Laboratoires) containing glycerol 15% and paraffin 10% for 4 weeks reduces symptoms of non-bullous ichthyosis by at least 50% in an additional 17% of children when compared with a placebo cream. Applying this specific product also improves pruritus by an additional 45% when compared with placebo (93756). It is unclear if these findings are due to glycerol, paraffin, or the combination.

POSSIBLY INEFFECTIVE

• Meningitis. Some clinical research suggests that oral glycerol does not reduce the risk of mortality or seizures in adults and children with bacterial meningitis, although it may reduce certain sequelae. Details: A meta-analysis of five low-quality clinical trials including 1,270 patients shows that adjunctive treatment with glycerol as an oral osmotic agent does not reduce the risk of mortality, seizures, or gastrointestinal symptoms in adults and children with acute bacterial meningitis, although it may modestly reduce the risk of deafness and residual neurological deficit in surviving children (99160). Clinical research included in the meta-analysis has used glycerol 1.5 grams/kg every 6 hours in children aged 2 months to 16 years (93762,93763).
• Prematurity. Rectal glycerol does not appear to reduce the time to enteral feeding in premature infants. Details: Glycerol is used as an enema or given by suppository to facilitate the evacuation of meconium in premature infants in order to reduce the time to enteral feeding. However, two meta-analyses of small studies in preterm infants, that include some of the same studies, show that administering glycerol suppositories does not reduce the number of days to full enteral feeds when compared with placebo or no treatment (99166,112003). However, the interpretation of these findings is limited by the heterogeneity of dosages used in the included studies.

LIKELY INEFFECTIVE

• Stroke. Intravenous glycerol may not improve mortality or symptoms in patients with acute ischemic stroke. Details: Several clinical studies show that intravenous administration of glycerol does not improve symptoms of acute stroke (2480,2481,2482,2484,2486). Additionally, one clinical study in elderly patients with acute ischemic stroke shows that while glycerol can improve initial survival, it does not reduce the risk of overall mortality when compared with placebo (2483).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dandruff. Topical glycerol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical trial in adults with dandruff shows that applying a leave-in hair lotion containing glycerol 10%, stearic acid 2.5%, and sunflower seed oil 0.6%, 3 times weekly for 8 weeks, modestly reduces dandruff severity throughout use and for up to one week after the last application when compared with a placebo lotion. The glycerol lotion also reduced total water loss from the scalp by 8% and increased moisturization by 23% (93758). It is unclear if these findings are due to glycerol, other ingredients, or the combination.
• Dry skin. Topical glycerol has only been evaluated in combination with other ingredients for the management of dry skin associated with kidney failure; its effect when used alone is unclear. Details: One small, open-label clinical study in adults with kidney failure and moderate to severe uremic xerosis shows that applying an emulsion containing glycerol 15% and paraffin 10% twice daily for 7 days reduces the severity of xerosis when compared with a placebo emulsion. The glycerol-containing emulsion produces a treatment response in an additional 29% of patients, improves quality of life, and reduces scale density and thickness when compared with placebo (93754). It is unclear if these findings are due to glycerol, paraffin, or the combination.
• Glaucoma. Although there has been interest in using oral glycerol for glaucoma, there is insufficient reliable information about the clinical effects of glycerol for this purpose.
• Intracranial hypertension. Although there has been interest in using intravenous glycerol to reduce intracranial pressure in patients with brain tumors, central nervous system (CNS) trauma, encephalitis, idiopathic intracranial hypertension, meningitis, and Reye syndrome, there is insufficient reliable information about the clinical effects of glycerol for this purpose.
• Meniere disease. It is unclear if intravenous glycerol is beneficial in patients with Meniere disease. Details: A small, uncontrolled clinical study in adults with unilateral, intractable Meniere disease shows that intravenous administration of glycerol 10% at a dose of 0.5 grams/kg once daily for 2 consecutive days, twice monthly for 6 months, reduces the frequency of vertigo attacks and improves quality of life when compared to baseline. Patients reported an average of 3.2 vertigo attacks per month at baseline and 1.2 vertigo attacks per month after 6 months of treatment (106649). The lack of a control group limits the validity of these findings.
• Neonatal jaundice. It is unclear if rectal glycerol improves jaundice-related outcomes in premature infants. Details: A small clinical study in neonates receiving phototherapy for jaundice shows that administering glycerol suppositories has no effect on the duration of phototherapy needed for jaundice treatment, or on bilirubin levels or the rate of bilirubin decline when compared with no glycerol suppositories (99165).
• Obesity. It is unclear if oral glycerol is beneficial in patients who are overweight or obese. Details: One small clinical study in adults on a low-calorie diet shows that taking glycerol 7.5 grams before meals for 6 weeks does not increase weight loss when compared with placebo (2485).
• Otitis externa. Topical glycerol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in adults with otitis externa shows that inserting ribbon gauze soaked in glycerol and ichthammol into the ear canal reduces pain and swelling as effectively as the application of antibiotic and steroid drops three times daily (93759). It is unclear if these findings are due to glycerol, ichthammol, or the combination. More evidence is needed to rate glycerol for these uses.

(Read more about GLYCEROL)

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.

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POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Agmatine sulfate has been used with apparent safety at doses up to 2.67 grams daily for up to 2 months and 3.56 grams daily for up to 3 weeks (94736,111144).

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

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LIKELY SAFE ...when used in amounts commonly found in foods.

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes, short term. Beetroot juice has been safely used in clinical trials in doses of up to 500 mL daily for up to 7 days and a beetroot-based nutritional gel has been used safely in doses of up to 100 grams daily for 8 days (94461,94462,94464,100149,100152,100153).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of beets used medicinally during pregnancy and 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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LIKELY SAFE ...when used rectally and appropriately. Glycerol rectal suppositories and enemas are approved by the US Food and Drug Administration (FDA) for over-the-counter use to treat occasional constipation (15,272). ...when used topically and appropriately as a lotion, emulsion, or humectant (15,272,93754,93758,93759,99164).

POSSIBLY SAFE ...when used orally, short-term. Glycerol has been used with apparent safety in clinical trials at doses of up to 1.5 grams/kg (2474,2475,99162).

POSSIBLY UNSAFE ...when used intravenously. While some research suggests that intravenous glycerol can be safely administered for two consecutive days twice monthly for up to 6 months (106649), in another study, hemolysis was reported in 98% of patients treated with intravenous glycerol for acute ischemic stroke (2482).

CHILDREN: LIKELY SAFE
when used rectally and appropriately. Glycerol rectal suppositories and enemas are approved by the US FDA for over-the-counter use to treat occasional constipation in children 2 years of age and older (15,272). ...when used topically and appropriately as an emulsion or humectant in children 1 month of age and older (15,272,93756).

CHILDREN: POSSIBLY SAFE
when used orally, short-term. Glycerol has been used with apparent safety in clinical trials in children 2 months to 16 years of age at doses of 1.5 gram/kg, up to a maximum dose of 25 grams, taken every 6 hours (93762,93763).

PREGNANCY AND LACTATION:
Insufficient reliable information available; 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).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, agmatine might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal and in vitro research suggest that agmatine has mild hypoglycemic effects (94734).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, agmatine might increase the risk of hypotension when taken with antihypertensive drugs.  Details Animal research suggests that agmatine can modestly decrease heart rate and blood pressure (94734).

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CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, beet might decrease the levels and clinical effects of CYP1A2 substrates.  Details In vitro research suggests that beet induces CYP1A2 enzymes (111404).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, beet might increase the levels of CYP3A4 substrates.  Details In vitro research suggests that betanin, the major pigment in beet, competitively inhibits CYP3A4 in a dose-dependent manner similarly to strong CYP3A4 inhibitor ketoconazole (113425).

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

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

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

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

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

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General ...Orally, agmatine seems to be well tolerated when used in medicinal amounts, short-term.
Most Common Adverse Effects:
Orally: Diarrhea, dyspepsia, nausea.

Gastrointestinal ...Orally, agmatine has been reported to cause diarrhea, dyspepsia, and nausea in two small clinical studies (94736,94742). Mild-to-moderate diarrhea and nausea were reported in 3 out of 24 patients taking agmatine sulfate 3.56 grams daily. These adverse effects appeared within 2-3 days of therapy and resolved upon treatment discontinuation (94736).

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General ...Orally, beet seems to be well tolerated when used for medicinal purposes, short term.
Most Common Adverse Effects:
Orally: Red stools and red urine.
Serious Adverse Effects (Rare):
Orally: Hypocalcemia and kidney damage when ingested in large amounts.

Endocrine ...Theoretically, ingestion of large quantities of beets could lead to hypocalcemia because of the oxaluric acid content (18).

Gastrointestinal ...Orally, beet juice may cause red stools (94470,97726,100142,100145,105762). This red coloring of the stools is not harmful. Additionally, beet supplementation has been reported to cause black stools. In one case, a 79-year-old male on apixaban and clopidogrel presented with black stools, nausea, and vomiting after taking beet pills 2-3 days prior. The likelihood of upper gastrointestinal bleed was determined to be low based on factors such as normal vital signs and lack of severe anemia. The patient was diagnosed with beet-induced pseudo-hematochezia which was successfully treated with fluids and discontinuation of the beet supplement (113426).
Other less common gastrointestinal side effects include loose stools, constipation, and nausea (100149).

Genitourinary ...Orally, beet is known to produce red or pink urine (beeturia) in some people (32569,34134,94464,94470,97725,97726,100142,100145,100152,105762,113422). However, this red coloring of the urine is not harmful and dissipates after about 12 hours (113422).

Neurologic/CNS ...Orally, vivid dreams and worsening headaches have each occurred in one person in a clinical trial, although it is not clear if this is due to beet (97723).

Renal ...Theoretically, ingestion of large quantities of beets could lead to kidney damage due to its oxaluric acid content (18).

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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, rectally, and topically, glycerol seems to be well tolerated. Intravenously, glycerol may be unsafe.
Most Common Adverse Effects:
Orally: Bloating, diarrhea, nausea, vomiting, dizziness, and headache.
Topically: Burning, irritation, and pruritus.
Intravenously: Hemolysis in patients with acute ischemic stroke.

Dermatologic ...Topically, glycerol has been reported to cause burning, irritation, and pruritus (93754,93756). Rectally, the regular administration of glycerol 50% enemas has been reported to cause generalized urticaria in at least two patients; in both patients, symptoms resolved after discontinuation (110019,110025).

Gastrointestinal ...Orally, glycerol can cause bloating, nausea, vomiting, thirst, and diarrhea (15,2475).

Hematologic ...Intravenously, glycerol has been reported to caused hemolysis in people treated for acute ischemic stroke (2480,2482).

Neurologic/CNS ...Orally, glycerol can cause mild headache and dizziness (15,2475).

(Read more about GLYCEROL)

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

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

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

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

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

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

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

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

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