Methylguanidine-acetic acid

Creatine/Drug Interactions:

  • AminoglycosidesAminoglycosides: In theory, a combination of aminoglycosides and creatine may increase the risk of nephrotoxicity (67; 68; 33). Renal function should be monitored.
  • Antiaging drugsAntiaging drugs: In vivo, creatine supplementation had a greater effect on phosphocreatine availability and resynthesis rate in middle-aged persons vs. younger persons; therefore, creatine may have additive effects (156). In vivo, aging was associated with lower total creatine and phosphocreatine concentrations (310; 82), and loading may be more efficient in subjects with a lower basal creatine level (311; 312).
  • Antidiabetic agentsAntidiabetic agents: According to secondary sources, creatine may alter activities of insulin and other blood glucose-lowering agents. In a controlled study, changes were lacking in humans taking hydroxymethylbutyrate (HMB) plus creatine for six weeks (313). Decreased blood glucose and plasma insulin levels in creatine-supplemented animals have been reported (42). In humans, neither acute nor short-term creatine supplementation influenced glucose tolerance or levels (197; 314; 193). In human research, insulin levels increased after 120 and 240 minutes (43); however, this effect was not present in another trial (44). High concentrations of insulin may enhance muscle creatine accumulation (315). This is a result of an insulin-induced transport of creatine from circulation to skeletal muscle (315) vs. creatine delivery (316). In humans, neither acute nor short-term creatine supplementation influenced measures of insulin sensitivity (314).
  • AntiepilepticsAntiepileptics: In animal studies, creatine injections reduced hypoxia-induced seizures; therefore, they may have an additive effect in patients taking medication for seizures (73).
  • Antigout agentsAntigout agents: According to secondary sources, use of creatine with probenecid in humans may increase the levels of creatine in the body, leading to increased side effects (67; 68; 33).
  • Anti inflammatory agentsAnti inflammatory agents: In an animal study, the combination of indomethacin with creatine, as measured by the carrageenan-induced paw edema test, showed that the drug combination was more effective at reducing inflammation than either drug alone (7). According to secondary sources, the combination of creatine with nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, indomethacin, naproxen, and piroxicam (Feldene?), may adversely affect renal function and be harmful to the kidneys. Renal function should be monitored. NSAIDs reduce renal blood flow (via prostaglandin inhibition), and creatine may be nephrotoxic, so adverse effects may be reciprocal.
  • Antilipemic agentsAntilipemic agents: In vitro, daily supplementation with creatine may reduce plasma total cholesterol, triacylglycerides, LDL, and VLDL cholesterol (8; 317) and thus may potentiate the effects of lipid-lowering agents.
  • Antineoplastic agentsAntineoplastic agents: In vivo, cyclocreatine, an analog of creatine, increased tumor growth delay in SW2 small-cell lung cancer cells when added to standard anticancer agents, including cis-diamminedichloroplatinum(II), cyclophosphamide, Adriamycin, or 5-fluorouracil (37). Addition of creatine and phosphocreatine analogs to the MCF-7 breast adenocarcinoma and the HT-29 colon adenocarcinoma cell lines delayed the growth of rat mammary adenocarcinomas comparably to effects seen with currently used anticancer drugs (36). Thus, concomitant use with these or other antineoplastic agents may potentiate effects or lead to toxicity.
  • Antiviral agentsAntiviral agents: According to secondary sources, a combination of valacyclovir and creatine may increase the risk of nephrotoxicity (67; 68; 33). Renal function should be monitored. A combination of valacyclovir and creatine may result in increased valacyclovir and acyclovir levels, resulting in increased toxicity if renal function is impaired.
  • Athletic performance-enhancing drugsAthletic performance-enhancing drugs: In vitro, creatine supplementation may accelerate phosphocreatine resynthesis following intense muscle contractions (318). Creatine supplementation has been shown to increase muscle creatine levels (311); therefore, additive effects may occur in combination with other performance-enhancing herbs or supplements.
  • CaffeineCaffeine: Phosphocreatine resynthesis is possibly inhibited by creatine. In randomized controlled trials, caffeine antagonized the ergogenic effects of creatine and counteracted its benefits on intense, intermittent exercise performance (4; 5). It is unclear whether caffeine consumption as found in the average cup of coffee or tea also has this effect. A combination of caffeine, ephedra, and creatine may increase the risk for adverse side effects. In a case series, ischemic stroke was reported in a body builder who consumed ma huang extract (400-600mg of caffeine, 40-60mg of ephedra, and other supplements) and creatine monohydrate (6g) for six weeks. In one case series, an athlete who consumed 6g of creatine monohydrate, 400-600mg of caffeine, and 40-60mg of ephedra for six weeks had a stroke (319). A combination of caffeine and creatine may increase risk of dehydration. In humans, caffeine had ergogenic effects after withdrawal from creatine supplementation (320). In humans, combined use of creatine and caffeine had no effect on caffeine pharmacokinetics. Combined use had no effect on heart rate or blood lactate (187).
  • Calcium-channel blockersCalcium-channel blockers: According to secondary sources, combined use of nifedipine and creatine may improve stroke and cardiac indices and may be useful for the treatment of myocardial infarction. Like creatine, nifedipine has been shown to have positive effects when added to cardioplegic solution (321).
  • Cardiovascular agentsCardiovascular agents: In a randomized, equivalence human trial, favorable effects on clinical symptoms were observed with phosphocreatine alone (when combined with digoxin, these improvements were additive), and a significant 40% increase in exercise tolerance in the digoxin + diuretics + phosphocreatine group was observed (45). Both the digoxin + creatine and the creatine groups showed a significant decrease in frequency of angina attacks compared to the digoxin-only group (44.4% vs. 61%, p<0.05). The amount of nitroglycerin consumed decreased significantly in the digoxin + creatine and creatine-only groups compared to placebo (41.2% vs. 60%, p<0.05). Various clinical studies, case series, and randomized trials reported that creatine supplementation may have use in congestive heart failure (263; 101; 265; 45; 264; 266; 262); therefore, additive effects may be possible with heart failure medications. In vitro, daily supplementation with creatine may reduce plasma total cholesterol, triacylglycerides, LDL, and VLDL cholesterol (8; 317) and thus may potentiate the effects of lipid-lowering agents. According to secondary sources, combined use of nifedipine and creatine may improve stroke and cardiac indices and may be useful for the treatment of myocardial infarction. Like creatine, nifedipine has been shown to have positive effects when added to cardioplegic solution (321).
  • CimetidineCimetidine: In vivo, cimetidine competed with creatinine (metabolic product of creatine) for renal tubular secretion and may increase the risk of adverse renal effects (70).
  • CNS stimulantsCNS stimulants: According to secondary sources, a combination of creatine with CNS stimulants may increase the risk of serious adverse effects and may decrease creatine efficacy. Phosphocreatine resynthesis is possibly inhibited by creatine. In randomized, controlled human trials, caffeine antagonized the ergogenic effects of creatine and counteracted its benefits on intense, intermittent exercise performance (4; 5). It is unclear whether caffeine consumption as found in the average cup of coffee or tea also has this effect. According to secondary sources, a combination of caffeine, ephedra, and creatine may increase risk for adverse side effects. According to secondary sources, in a case series, ischemic stroke was reported in a body builder who consumed ma huang extract (400-600mg of caffeine, 40-60mg of ephedra, and other supplements) and creatine monohydrate (6g) for six weeks. In one case series, an athlete who consumed 6g of creatine monohydrate, 400-600mg of caffeine, and 40-60mg of ephedra for six weeks had a stroke (319). A combination of caffeine and creatine may increase risk of dehydration. In humans, caffeine had ergogenic effects after withdrawal from creatine supplementation (320). In humans, combined use of creatine and caffeine had no effect on caffeine pharmacokinetics. Combined use lacked an effect on heart rate or blood lactate (187).
  • DigoxinDigoxin: In a randomized, equivalence human trial, favorable effects on clinical symptoms were observed with phosphocreatine alone (when combined with digoxin these improvements were additive), and a significant 40% increase in exercise tolerance in the digoxin + diuretics + phosphocreatine group was observed (45). Both the digoxin + creatine and the creatine groups showed a significant decrease in frequency of angina attacks compared to the digoxin-only group (44.4% vs. 61%, p<0.05). The amount of nitroglycerin consumed decreased significantly in the digoxin + creatine and creatine-only groups compared to placebo (41.2% vs. 60%, p<0.05). Various clinical studies, case series, and randomized trials reported that creatine supplementation may have use in congestive heart failure (263; 101; 265; 45; 264; 266; 262); therefore, additive effects may be possible with heart failure medications.
  • DiureticsDiuretics: Concomitant use with diuretic medications may increase diuretic effects, due to increased diuretic effects with creatine use (7). In a controlled trial, blood electrolytes showed no changes in those taking HMB plus creatine for six weeks (313). Changes were lacking in blood electrolytes over 21 months of creatine supplementation in a human study (289).
  • Ergot derivativesErgot derivatives: According to secondary sources, a combination of ergotamine and creatine may increase the risk of adverse effects and decrease creatine efficacy. Phosphocreatine resynthesis is possibly inhibited by creatine.
  • Gallium nitrateGallium nitrate: A combination of gallium nitrate and creatine may increase the risk of nephrotoxicity (67; 68; 33). Renal function should be monitored.
  • Glutamate inhibitorsGlutamate inhibitors: In human research, creatine supplementation lowered levels of glutamate in the brain of patients with Huntington's disease (322); therefore, it may have additive effects with glutamate inhibitors such as Rilutek?.
  • Hepatotoxic agentsHepatotoxic agents: According to secondary sources, creatine use may increase liver enzymes. Animal studies indicate that transamidase activity is inhibited during creatine supplementation but returns to normal after removal of endogenous creatine. Similar studies in humans have not been performed (40). In a controlled trial, changes were lacking over 21 months of creatine use (289). In other controlled trials, no changes were observed in hepatic function indices (290; 323; 242). Nonsignificant increases in liver enzymes have also been noted in a human study (118). In a case study, a young patient developed acute mixed liver injury (hepatocellular and cholestatic) after ingestion of various products to increase muscle mass and physical performance such as NO Xplode?, creatine, L-carnitine, and Growth Factor ATN? (54).
  • ImmunosuppressantsImmunosuppressants: According to secondary sources, a combination of tacrolimus and creatine may increase the risk of nephrotoxicity (67; 68; 33). Renal function should be monitored.
  • InsulinInsulin: According to secondary sources, creatine may alter activities of insulin and other blood glucose-lowering agents. In a controlled study, changes were lacking in humans taking HMB plus creatine for six weeks (313). Decreased blood glucose and plasma insulin levels in creatine-supplemented animals have been reported (42). In humans, neither acute nor short-term creatine supplementation influenced glucose tolerance or levels (197; 314; 193). In human research, insulin levels increased after 120 and 240 minutes (43); however, this effect did not occur in another trial (44). High concentrations of insulin may enhance muscle creatine accumulation (315). This is a result of an insulin-induced transport of creatine from circulation to skeletal muscle (315) vs. creatine delivery (316). In humans, neither acute nor short-term creatine supplementation influenced measures of insulin sensitivity (314).
  • Nephrotoxic agentsNephrotoxic agents: In theory, the combination of creatine with nephrotoxic drugs, such as cyclosporin, aminoglycosides (amikacin, gentamicin, and tobramycin), gallium nitrate, and tacrolimus, may adversely affect renal function and may be harmful to the kidneys, due to the potential for increased nephrotoxic effects (67; 68; 33).
  • Neurologic agentsNeurologic agents: In human research, following a creatine supplement (8g daily for five days), repeated performance of simple mathematical calculations decreased cerebral oxygenated hemoglobin in the brains of subjects, suggesting increased oxygen utilization (324). A case study reported that long-term use of creatine when started early in diagnosis may improve neurologic abilities (278).
  • NifedipineNifedipine: According to secondary sources, combined use of nifedipine and creatine may improve stroke and cardiac indices and may be useful for the treatment of myocardial infarction. Like creatine, nifedipine has been shown to have positive effects when added to cardioplegic solution (321).
  • Osteoporosis drugsOsteoporosis drugs: In a human study examining the effect of creatine in the elderly, it was determined that creatine may increase bone density in combination with resistance training (83); therefore, additive effects may occur in patients taking osteoporosis agents such as bisphosphonates.
  • ProbenecidProbenecid: According to secondary sources, use of creatine with probenecid in humans may increase the levels of creatine in the body, leading to increased side effects (67; 68; 33).
  • RenallyeliminateddrugsRenallyeliminateddrugs: In theory, the combination of creatine with renally cleared drugs such as valacyclovir may impair the renal clearance of the drug and may increase blood levels (67; 68; 33).
  • Sodium bicarbonateSodium bicarbonate: In humans, there is a potential for additive performance enhancement effects with creatine in regard to swimming performance (325)
  • TacrolimusTacrolimus: According to secondary sources, a combination of tacrolimus and creatine may increase the risk of nephrotoxicity (67; 68; 33). Renal function should be monitored.
  • ValacyclovirValacyclovir: According to secondary sources, a combination of valacyclovir and creatine may increase the risk of nephrotoxicity (67; 68; 33). Renal function should be monitored. A combination of valacyclovir and creatine may result in increased valacyclovir and acyclovir levels, resulting in increased toxicity if renal function is impaired.

    • Creatine/Herb/Supplement Interactions:

  • Alpha-lipoic acidAlpha-lipoic acid: Addition of alpha-lipoic acid (1,000mg daily) to creatine and sucrose has been found to enhance glucose uptake into skeletal muscle in animal models (326). Muscle total creatine content increased compared to creatine alone or creatine with sucrose.
  • Antiaging herbs and supplementsAntiaging herbs and supplements: In vivo, creatine supplementation had a greater effect on phosphocreatine availability and resynthesis rate in middle-aged persons vs. younger persons; therefore, creatine may have additive effects (156). In vivo, aging was associated with lower total creatine and phosphocreatine concentrations (310; 82), and loading may be more efficient in subjects with a lower basal creatine level (311; 312).
  • AntiepilepticsAntiepileptics: In animal studies, creatine injections reduced hypoxia-induced seizures and therefore may have an additive effect in patients taking medication for seizures (73).
  • Antigout agentsAntigout agents: According to secondary sources, use of creatine with probenecid in humans may increase the levels of creatine in the body, leading to increased side effects (67; 68; 33).
  • Anti-inflammatory herbsAnti-inflammatory herbs: In an animal study, the combination of indomethacin with creatine, as measured by the carrageenan-induced paw edema test, showed that the drug combination was more effective at reducing inflammation than either drug alone (7). According to secondary sources, the combination of creatine with nephrotoxic herbs may adversely affect renal function and be harmful to the kidneys. Renal function should be monitored.
  • AntilipemicsAntilipemics: Daily supplementation with creatine may reduce plasma total cholesterol, triacylglycerides, and VLDL cholesterol (8) and thus may potentiate the effects of lipid-lowering agents.
  • AntineoplasticsAntineoplastics: Cyclocreatine, an analog of creatine, increased tumor growth delay in SW2 small-cell lung cancer cells when added to standard anticancer agents, including cis-diamminedichloroplatinum(II), cyclophosphamide, Adriamycin, or 5-fluorouracil (37). Thus, concomitant use with these or other antineoplastic agents may potentiate effects or lead to toxicity.
  • Antiviral agentsAntiviral agents: According to secondary sources, a combination of valacyclovir and creatine may increase the risk of nephrotoxicity (67; 68; 33). Renal function should be monitored. A combination of valacyclovir and creatine may result in increased valacyclovir and acyclovir levels, resulting in increased toxicity if renal function is impaired.
  • Athletic performance-enhancing herbs and supplementsAthletic performance-enhancing herbs and supplements: In vitro, creatine supplementation may accelerate phosphocreatine resynthesis following intense muscle contractions (318). Creatine supplementation has been shown to increase muscle creatine levels (311); therefore, additive effects may occur in combination with other performance-enhancing herbs or supplements.
  • CaffeineCaffeine: In randomized controlled trials, caffeine antagonized the ergogenic effects of creatine and counteracted its benefits on intense, intermittent exercise performance (4; 5). It is unclear whether caffeine consumption as found in the average cup of coffee or tea also has this effect. A combination of caffeine, ephedra, and creatine may increase risk for adverse side effects. In a case series, ischemic stroke was reported in a body builder who consumed ma huang extract (400-600mg of caffeine, 40-60mg of ephedra, and other supplements) and creatine monohydrate (6g) for six weeks. In one case series, an athlete who consumed 6g of creatine monohydrate, 400-600mg of caffeine, and 40-60mg of ephedra for six weeks had a stroke (319). A combination of caffeine and creatine may increase risk of dehydration. In humans, caffeine had ergogenic effects after withdrawal from creatine supplementation (320). In humans, combined use of creatine and caffeine had no effect on caffeine pharmacokinetics. Furthermore, combined use had no effect on heart rate or blood lactate (187).
  • Cardiovascular agentsCardiovascular agents: In a randomized, equivalence human trial, favorable effects on clinical symptoms were observed with phosphocreatine alone (when combined with digoxin, these improvements were additive), and a significant 40% increase in exercise tolerance in the digoxin + diuretics + phosphocreatine group was observed (45). Both the digoxin + creatine and the creatine groups showed a significant decrease in frequency of angina attacks compared to the digoxin-only group (44.4% vs. 61%, p<0.05). The amount of nitroglycerin consumed decreased significantly in the digoxin + creatine and creatine-only groups compared to placebo (41.2% vs. 60%, p<0.05). Various clinical studies, case series, and randomized trials reported that creatine supplementation may have use in congestive heart failure (263; 101; 265; 45; 264; 266; 262); therefore, additive effects may be possible with heart failure medications. In vitro, daily supplementation with creatine may reduce plasma total cholesterol, triacylglycerides, LDL, and VLDL cholesterol (8; 317) and thus may potentiate the effects of lipid-lowering agents. According to secondary sources, combined use of nifedipine and creatine may improve stroke and cardiac indices and may be useful for the treatment of myocardial infarction. Like creatine, nifedipine has been shown to have positive effects when added to cardioplegic solution (321).
  • DiureticsDiuretics: Concomitant use with diuretic herbs and supplements may increase diuretic effects, due to increased diuretic effects with creatine use (7). In a controlled trial, blood electrolytes lacked changes in those taking HMB plus creatine for six weeks (313). Changes were lacking in blood electrolytes over 21 months of creatine supplementation in a human study (289).
  • EphedraEphedra: A combination of caffeine, ephedra, and creatine may increase the risk for adverse side effects. In a case series, ischemic stroke was reported in a body builder who consumed ma huang extract (400-600mg of caffeine, 40-60mg of ephedra, and other supplements) and creatine monohydrate (6g) for six weeks. In one study an athlete who consumed 6g of creatine monohydrate, 400-600mg of caffeine, and 40-60mg of ephedra for six weeks had a stroke (319).
  • HydroxymethylbutyrateHydroxymethylbutyrate: In a clinically controlled study, hydroxymethylbutyrate (HMB) supplementation with creatine for six weeks lacked adverse effects (313). HMB and creatine may have additive effects on lean body mass (121), and HMB may antagonize creatine-induced increases in creatine phosphokinase (121). However, additive effects were lacking in rugby players (327).
  • Hepatotoxic herbs and supplementsHepatotoxic herbs and supplements: Creatine use may increase liver enzymes. Animal studies indicate that transamidase activity is inhibited during creatine supplementation but returns to normal after removal of endogenous creatine. Similar studies in humans have not been performed (40). In a controlled trial, no changes were observed over 21 months of creatine use (289). In other controlled trials, no changes were observed in hepatic function indices (290; 323; 242). Nonsignificant increases in liver enzymes also have been noted in a human study (118).
  • HypoglycemicsHypoglycemics: Creatine may alter activities of insulin and other blood glucose-lowering agents. In a controlled study, no changes were observed in those taking HMB plus creatine for six weeks (313). Decreased blood glucose and serum insulin levels in creatine-supplemented animals have been reported (42). In humans, neither acute nor short-term creatine supplementation influenced glucose tolerance or levels (197; 314; 193). In human research, insulin level increased after 120 and 240 minutes (43); however, this effect did not occur in another trial (44). High concentrations of insulin may enhance muscle creatine accumulation (315). This is a result of an insulin-induced transport of creatine from circulation to skeletal muscle (315) vs. creatine delivery (316). In humans, neither acute nor short-term creatine supplementation influenced measures of insulin sensitivity (314).
  • L-arginineL-arginine: In vivo, a mutation in the X-linked cerebral creatine transporter (SLC6A8) gene has been reported to lead to a decrease in cerebral creatine levels (328). Creatine monohydrate has been reported to enhance cerebral creatine transport, and when combined with L-arginine and L-glycine, it enhanced cerebral creatine synthesis, leading to a complete resolution of seizures. In humans, supplementation with creatine, in combination with low arginine, may increase creatine status more dramatically (329).
  • L-glycineL-glycine: In vivo, a mutation in the X-linked cerebral creatine transporter (SLC6A8) gene has been reported to lead to a decrease in cerebral creatine levels (328). Creatine monohydrate has been reported to enhance cerebral creatine transport, and when combined with L-arginine and L-glycine, it enhanced cerebral creatine synthesis, leading to a complete resolution of seizures.
  • MagnesiumMagnesium: In a randomized controlled study, magnesium and creatine were used together to increase muscle strength and power (330).
  • Nephrotoxic agentsNephrotoxic agents: In theory, the combination of creatine with nephrotoxic herbs may adversely affect renal function and may be harmful to the kidneys, due to the potential for increased nephrotoxic effects (67; 68; 33).
  • Neurologic agentsNeurologic agents: In human research, following a creatine supplement (8g daily for five days), repeated performance of simple mathematical calculations decreased cerebral oxygenated hemoglobin in the brains of subjects, suggesting increased oxygen utilization (324). A case study reported that long-term use of creatine when started early in diagnosis may improve neurologic abilities (278).
  • Osteoporosis supplementsOsteoporosis supplements: In a human study examining the effect of creatine in the elderly, it was determined that creatine may increase bone density in combination with resistance training (83); therefore, additive effects may occur in patients taking osteoporosis supplements.
  • PhosphatidylcholinePhosphatidylcholine: In a human case report, two children with S-adenosylhomocysteine hydrolase deficiency were supplemented with phosphatidylcholine and creatine and followed a methionine-restricted diet; however, this combination did not affect survival outcome (331).
  • PyruvatePyruvate: In a randomized controlled study, creatine in combination with pyruvate has been shown to increase lean body mass and total body mass, as well as bench press and static vertical jump results (332).
  • Renally eliminated herbs and supplementsRenally eliminated herbs and supplements: In theory, the combination of creatine with renally cleared herbs may impair the renal clearance of the herb and may increase blood levels (67; 68; 33).
  • Vitamin AVitamin A: In humans, creatine plus vitamin supplements may lower homocysteine to a greater extent than vitamin supplements alone (333). Creatine may lower the effectiveness of vitamins A, D, E, and K.
  • Vitamin DVitamin D: In humans, creatine plus vitamin supplements may lower homocysteine to a greater extent than vitamin supplements alone (333). Creatine may lower the effectiveness of vitamins A, D, E, and K.
  • Vitamin EVitamin E: In humans, creatine plus vitamin supplements may lower homocysteine to a greater extent than vitamin supplements alone (333). Creatine may lower the effectiveness of vitamins A, D, E, and K.
  • Vitamin KVitamin K: In humans, creatine plus vitamin supplements may lower homocysteine to a greater extent than vitamin supplements alone (333). Creatine may lower the effectiveness of vitamins A, D, E, and K.

    • Creatine/Food Interactions:

  • CarbohydratesCarbohydrates: In humans, absorption of creatine appears to be enhanced by concurrent carbohydrate ingestion (334; 295; 183; 335). In a randomized, controlled human trial, postexercise supplementation with carbohydrate and creatine resulted in similar strength gains as protein and carbohydrate (336). In humans, ingesting creatine with carbohydrates augmented glycogen supercompensation in exercised muscle (337).
  • ProteinProtein: In pig animal studies, high dietary protein (16% crude protein) was added to creatine monohydrate supplementation combined with a high-glycemic carbohydrate to improve lean tissue deposition (338). After 28 days, the pigs supplemented with the combination diet gained the least 10th rib fat and expressed the highest percentage fat-free carcass lean. In human research, 12 weeks of creatine supplementation in resistance-trained subjects consuming a high-protein diet lacked an effect on kidney function (1).
  • Reduced food intakeReduced food intake: In humans, during recovery of body mass loss, creatine did not accelerate body mass restoration (339). In humans, creatine increased muscle total and phosphocreatine with dietary restriction (340). Urinary nitrogen losses were similar to placebo.
  • Vegetarian dietVegetarian diet: According to secondary sources, lower levels of creatine have been reported in vegetarians.
  • Vitamin AVitamin A: In humans, creatine plus vitamin supplements may lower homocysteine to a greater extent than vitamin supplements alone (333). Creatine may lower the effectiveness of vitamins A, D, E, and K.
  • Vitamin DVitamin D: In humans, creatine plus vitamin supplements may lower homocysteine to a greater extent than vitamin supplements alone (333). Creatine may lower the effectiveness of vitamins A, D, E, and K.
  • Vitamin EVitamin E: In humans, creatine plus vitamin supplements may lower homocysteine to a greater extent than vitamin supplements alone (333). Creatine may lower the effectiveness of vitamins A, D, E, and K.
  • Vitamin KVitamin K: In humans, creatine plus vitamin supplements may lower homocysteine to a greater extent than vitamin supplements alone (333). Creatine may lower the effectiveness of vitamins A, D, E, and K.

    • Creatine/Lab Interactions:

  • 3-Methylhistidine3-Methylhistidine: 3-Methylhistadine, a marker for myofibrillar protein catabolism, was measured in patients taking 6g of conjugated linoleic acid, 9g of creatine, and 36g of whey protein daily; 9g of creatine, 36g of whey protein, and placebo oil daily; or 36g of whey protein and placebo oil daily for five weeks (341). 3-Methylhistidine changed the least in patients taking creatine (p<0.05; CCP: -4.7 ? 70.2%, CP: -0.4 ? 81.4%, P: 20.3 ? 75.2%).
  • Adenine nucleotidesAdenine nucleotides: In human research, a lack of changes has been reported in muscle (342; 203).
  • AlbuminAlbumin: In human research, serum levels remained unchanged with 12mg of creatine for four weeks in hemodialysis patients (115) and after approximately one year in patients with amyotrophic lateral sclerosis (291). In a creatine consumer group, differences were lacking vs. control for plasma contents and urine excretion rates of albumin (33). In a case report evaluating a young man with one kidney, albuminuria decreased after supplementation with creatine (303). In resistance-trained subjects consuming a high-protein diet, albuminuria was unchanged following 12 weeks of creatine supplementation (1).
  • AldosteroneAldosterone: In a human controlled trial, patients taking 0.3g/kg of creatine for seven days had a slightly greater increase of 263% in aldosterone response compared to 224% in those taking placebo (111).
  • Alkaline phosphataseAlkaline phosphatase: In a case report, a 27 year-old man had an elevated alkaline phosphatase of 436 U/L following a combination of whey protein and creatine supplements (55).
  • AmmoniaAmmonia: In human controlled trials, creatine lowered serum levels of ammonia during cycling exercises (160; 343; 344). No effects have also been shown (342).
  • Argininic acidArgininic acid: In a human controlled trial, argininic acid concentrations doubled following creatine supplementation for four weeks (114).
  • Aspartate aminotransferase (AST)Aspartate aminotransferase (AST): In humans, significant elevations in AST have been noted with creatine supplementation (345).
  • BicarbonateBicarbonate: Blood levels of bicarbonate significantly decreased in humans taking HMB (313). Thus, use of creatine may yield similar results.
  • BilirubinBilirubin: In a case report, a 27 year-old man had an elevated total bilirubin of 54.7mg/dL following a combination of whey protein and creatine supplements (55).
  • Bone mineral densityBone mineral density: Whole-body, leg bone, and arm bone mineral density increased by approximately 0.5% 1%, and 3.2%, respectively, after 12 weeks of creatine (83). In a human crossover study, creatine supplementation increased bone mineral density by 3% (233).
  • Brachial-ankle pulse wave velocity (baPWV)Brachial-ankle pulse wave velocity (baPWV): In a human controlled trial, creatine supplementation suppressed increases in baPWV after five minutes of exercise (-0.1 ? 0.4m/s) and after 15 minutes of exercise (-0.3 ? 0.3m/s) (94).
  • CarnosineCarnosine: In human trials, the content of carnosine in the gastrocnemius and soleus muscles lacked changes after creatine supplementation in type 2 diabetic patients (346).
  • Chromium-51-labeled ethylenediamine tetraacetic acidChromium-51-labeled ethylenediamine tetraacetic acid: In a human controlled trial, glomerular filtration rate, measured by (51)-Cr-EDTA, was unchanged after creatine supplementation (301) or lacked significant differences from placebo (302). In resistance-trained subjects consuming a high-protein diet, 51Cr-EDTA clearance lacked a significant change following 12 weeks of creatine supplementation (1).
  • CortisolCortisol: No changes in cortisol were observed in those taking HMB plus creatine for six weeks (313). However, in another clinical study, cortisol significantly increased after one week of 0.3g/kg of creatine (+29%), then returned to baseline at week 2 (41).
  • C-peptideC-peptide: In human trials, C-peptide concentrations increased after 120 and 240 minutes (43); however, there were no effects in a different randomized human trial (44).
  • CreatineCreatine: In humans, serum and urinary creatine increased significantly in those taking supplemental creatine (71; 119; 279; 323; 347; 127; 196; 112). Muscle creatine has been shown to increase in some human studies (311; 160; 192). Early studies reported that radiation-induced creatinuria in rats may be prevented by administration of creatine (348). Differences in creatine status after supplementation were lacking in young (24 years) vs. old (70 years) human subjects (349). After supplementation, muscle phosphocreatine increased further in the young subjects. In humans, increased muscle phosphocreatine has been reported, even after energy restriction (200; 340). A lack of effect on muscle phosphocreatine has been reported (203). In a clinical trial, vegetarians ingesting creatine (0.25g/kg for seven days, then 0.0625g/kg for 49 days) had a greater increase in total creatine and phosphocreatine than nonvegetarians (133).
  • Creatine kinaseCreatine kinase: In a case series, significant elevations in creatine kinase have been noted following creatine supplementation (345).
  • Creatinine (serum)Creatinine (serum): Creatine is metabolized to creatinine. Thus creatine supplementation may potentially result in higher-than-normal serum creatinine levels, despite normal renal function, according to secondary sources. Higher serum creatinine was noted in at least two randomized controlled trials (25g daily for seven days and then 5g daily for 11 weeks) (347; 71). However, in a creatine consumer group, differences were lacking vs. control for plasma contents and urinary excretion rates of creatinine (33). In humans taking creatine ethyl ester, plasma creatinine was elevated (350). In human trials, creatine was found to contribute to serum creatinine up to 20% (351). A comparison trial evaluated whole blood creatine by two different plasma enzymatic (Nova StatSensor) and definitive creatinine (Roche Modular) methods, to determine interferents with these methods (352). Creatine did not contribute to method differences; however, the plasma enzymatic creatinine method varied with certain substances, but creatine was not one of these interferences. Another study also suggested that drugs may interfere with chemical and enzymatic methods of measuring creatine (353). In a case report, a 27 year-old man had an elevated creatinine of 3.1mg/dL (55). In resistance-trained subjects consuming a high-protein diet, creatinine clearance was unchanged following 12 weeks of creatine supplementation (1).
  • Creatinine (urine)Creatinine (urine): Creatine supplementation may also potentially result in higher-than-normal urine creatinine levels, despite normal renal function. Higher urinary creatinine has been reported in a randomized controlled trial (196). However, in humans change was lacking in urinary creatinine output in 40 athletes ingesting 0.1g/kg of creatine in the heat daily for seven days (147), and there were no significant alterations in creatinine excretion rates obtained from 24-hour and exercise urine collection periods (111). In a creatine consumer group, differences were lacking vs. control for plasma contents and urine excretion rates of creatinine (33). In a systematic review and meta-analysis of creatine for dehydration, two studies showed that participants treated with creatine had greater urinary creatine levels following exercise (112).
  • ElectrolytesElectrolytes: In a controlled trial, blood electrolytes lacked changes in those taking HMB plus creatine for six weeks (313). Changes were lacking in blood electrolytes over 21 months of creatine supplementation in a human study (289). In resistance-trained subjects consuming a high-protein diet, electrolytes were unchanged following 12 weeks of creatine supplementation (1).
  • Free androgen indexFree androgen index: In a human controlled trial, the free androgen index decreased in patients taking creatine (41).
  • GlucagonGlucagon: Increased glucagon levels in creatine-supplemented animals have been suggested (42).
  • GlucoseGlucose: In a controlled study, no changes were observed in those taking HMB plus creatine for six weeks (313). Decreased glucose levels in creatine-supplemented animals have been suggested (42). In humans, neither acute nor short-term creatine supplementation influenced glucose tolerance or levels (197; 314; 193) or measures of insulin sensitivity (314), and fasting and postprandial glucose concentrations decreased (44). In a human controlled trial, patients taking 0.3g/kg of creatine daily for five days followed by 6mg/kg of caffeine had a significant increase in glucose (354).
  • GlutamateGlutamate: In human research, glutamate decreased by 17% in patients with amyotrophic lateral sclerosis following creatine monohydrate supplementation (93).
  • GlycogenGlycogen: In humans, muscle glycogen loading capacity was influenced by its initial levels of creatine (355). In a randomized controlled trial, neither acute nor short-term creatine supplementation influenced skeletal muscle glycogen content (314).
  • Growth hormoneGrowth hormone: In humans, the exercise-induced increase of serum growth hormone was not altered by acute creatine intake (356; 203; 342). In a human trial, participants drinking a combination sports drink containing creatine had significantly higher serum growth hormones 15 minutes after exercise (357).
  • Guanidino compoundsGuanidino compounds: In humans, plasma guanidinoacetate levels were reduced during the creatine loading and maintenance phases (358). Several circulating guanidino compound levels were significantly altered after creatine loading, but not during the maintenance phase: homoarginine (+35%), alpha-keto-delta-guanidinovaleric acid (+45%), and argininic acid (+75%) increased, whereas guanidinosuccinate was reduced (-25%). In a human controlled trial, guanidinoacetate concentrations decreased by 15%, but alpha-keto-delta-guanidinovaleric acid concentrations increased threefold (114).
  • Heart rateHeart rate: In a human controlled trial, patients taking 0.3g/kg of creatine daily for five days followed by 6mg/kg of caffeine had a significant increase in heart rate (354). In a human controlled trial, creatine supplementation lessened increases in heart rate after five minutes of exercise (16 ? 2 beats/min) and after 15 minutes of exercise (11 ? 2 beats/min) (94).
  • HematocritHematocrit: Hematocrit remained unchanged in hemodialysis patients after supplementation with 12mg of creatine for four weeks (115).
  • Hemoglobin A1CHemoglobin A1C: In a randomized human trial, creatine lacked effects on HbA1C (44).
  • HomocysteineHomocysteine: Creatine supplementation may lower homocysteine levels (359; 95).
  • HypoxanthineHypoxanthine: In a randomized controlled trial, creatine lowered serum levels of hypoxanthine during cycling exercise (160).
  • Insulin levelsInsulin levels: High concentrations of insulin may enhance muscle creatine accumulation (315). This is a result of an insulin-induced transport of creatine from circulation to skeletal muscle (315) vs. creatine delivery (316). Decreased insulin levels in creatine-supplemented animals have been suggested (42). In humans, neither acute nor short-term creatine supplementation influenced measures of insulin sensitivity (314). In human research, insulin increased after 120 and 240 minutes (43); however, this effect did not occur in another trial (44). In another human controlled trial, insulin was significantly depressed after one week (-24%) and drifted back toward baseline during weeks 2-4 (41). In a human trial, participants drinking a combination sports drink containing creatine had significantly higher insulin concentrations immediately after exercise (357). In patients undergoing creatine feeding, after 15 minutes, serum insulin concentrations increased (225).
  • Insulin-like growth factor-IInsulin-like growth factor-I: In human trials, muscle insulin-like growth factor-I (IGF-I) increased by 78% when resistance exercise training was combined with creatine supplementation (360).
  • LactateLactate: In human trials, measured lactate levels were similar between creatine and placebo (207; 138) or lacked significant changes (160; 344; 188; 203; 342; 195; 344; 177; 361; 187; 193; 200; 197). In a controlled trial, the lactate threshold rose significantly following creatine supplementation (171). Increased lactate has been reported in a controlled trial (347). Decreased lactate has been reported in controlled trials (343; 167; 362). In humans, plasma lactate increased by 20.8% in a randomized controlled trial (82) and also increased significantly when combined with caffeine (354).
  • LDHLDH: In humans, significant elevations in lactate dehydrogenase (LDH) have been noted following creatine supplementation (345).
  • LipidsLipids: Daily supplementation with creatine may reduce plasma total cholesterol, triacylglycerides, and VLDL cholesterol (8). Reduced cholesterol was noted in at least one study (117). Cholesterol, triglycerides, and LDL cholesterol levels, and cholesterol:HDL ratios were significantly reduced with creatine supplementation (15.75g daily for five days followed by 5.25g for 20 days) (317). No changes in lipids were found in humans taking HMB plus creatine for six weeks (313). Changes were lacking in lipids after 21 months of creatine use in humans (289). Changes in serum total cholesterol, HDL, LDL, and triglycerides were lacking in other human controlled studies (71).
  • Liver enzymesLiver enzymes: Creatine use may increase liver enzymes. According to secondary sources, animal studies indicated that transamidase activity is inhibited during creatine supplementation but returned to normal after removal of endogenous creatine. Similar studies in humans have not been performed (40). In a controlled trial, changes were lacking over 21 months of creatine use (289). In other controlled trials, no changes were observed in hepatic function indices (290; 323; 242). Nonsignificant increases in liver enzymes have also been noted in a human study (118).
  • LymphocytesLymphocytes: In a human controlled trial, lymphocyte counts were within normal limits for those taking HMB plus creatine for six weeks (313). In a controlled trial, no changes were observed over 21 months of creatine use (289).
  • MonocytesMonocytes: In a controlled trial, monocyte counts were within normal limits for those taking HMB plus creatine for six weeks (313).
  • N-telopeptidesN-telopeptides: N-telopeptides, a urinary marker for bone absorption, was measured in patients taking 6g of conjugated linoleic acid, 9g of creatine, and 36g of whey protein daily; 9g of creatine, 36g of whey protein, and placebo oil daily; or 36g of whey protein and placebo oil daily for five weeks (341). Difference between groups for N-telopeptides was close to significance (p=0.055; CCP: -3.4 ? 66.6%, CP: -3.9 ? 64.9%, P: 26.0 ? 63.8%). In a human crossover study, creatine supplementation decreased urinary excretion of collagen type 1 cross-linking N-telopeptides by one-third (233).
  • Peak oxygen consumption (VO2)Peak oxygen consumption (VO2): Peak VO2 was significantly higher after eight weeks of taking 340mg of creatine daily (+1.8 ? 0.9mL/min/kg, 95% CI: 0.1-3.6, p<0.05) (363).
  • pHpH: An effect was lacking on pH following creatine use, in a human study (361).
  • PotassiumPotassium: In humans, creatine supplementation, in the heat, resulted in no significant alterations in potassium excretion rates obtained from 24-hour and exercise urine collection periods (111). In resistance-trained subjects consuming a high-protein diet, electrolytes were unchanged following 12 weeks of creatine supplementation (1).
  • ProteinProtein: In resistance-trained subjects consuming a high-protein diet, proteinuriawas unchanged following 12 weeks of creatine supplementation (1).
  • Sex hormone-binding globulinSex hormone-binding globulin: In a human controlled trial, sex hormone-binding globulin increased in patients taking creatine (41).
  • SodiumSodium: In humans, creatine supplementation, in the heat, resulted in no significant alterations in sodium, potassium, or creatinine excretion rates obtained from 24-hour and exercise urine collection periods (111). In resistance-trained subjects consuming a high-protein diet, electrolytes were unchanged following 12 weeks of creatine supplementation (1).
  • Systolic blood pressureSystolic blood pressure: In a human controlled trial, creatine supplementation lessened increases in systolic blood pressure after five minutes of exercise (5.6 ? 2.3mmHg) (94).
  • TestosteroneTestosterone: In a human controlled trial, changes were lacking with HMB plus creatine use over six weeks (313). In humans, the exercise-induced increase of serum testosterone was not altered by acute creatine intake (356). In a human controlled trial, total testosterone decreased in patients taking creatine (41).
  • TransaminaseTransaminase: In a case report, a 27 year-old man had minimally elevated transaminases following a combination of whey protein and creatine supplements (55).
  • UreaUrea: In human controlled trials, changes were lacking in those taking HMB plus creatine for six weeks to approximately one year (291; 313). In a creatine consumer group, differences were lacking vs. control for plasma contents and urine excretion rates of urea (33). In resistance-trained subjects consuming a high-protein diet, serum and urinary urea were unchanged following 12 weeks of creatine supplementation (1).
  • Uric acidUric acid: In humans, effects of creatine supplementation on pre- or postexercise uric acid were lacking (193). In a controlled trial, increases in urate in urine with high-dose creatine have been observed (60). In humans, decreased uric acid at exhaustion following creatine supplementation has been observed (364).
  • Ventricular premature beatsVentricular premature beats: The incidence of ventricular premature beats declined in 68% of 167 patients following supplemental creatine phosphate (2g daily intravenously for two weeks) (265).
  • Other (general)Other (general): In a controlled trial, changes were lacking in metabolic markers, muscle enzymes, and hematological markers over 21 months (289). No changes were observed in hematological indices, renal indices, or muscle damage indices in a randomized controlled trial (290).