Studies on the safety of creatine supplementation

Abstract

Doubtful allegations of adverse effects of creatine supplementation have been released through the press media and through scientific publications. In the present review we have tried to separate the wheat from the chaff by looking for the experimental evidence of any such claims. Anecdotal reports from athletes have appeared on muscle cramp and gastrointestinal complaints during creatine supplementation, but the incidence of these is limited and not necessarily linked to creatine itself. Despite several unproved allegations, liver (enzymes, urea) and kidneys (glomerular filtration urea and albumin excretion rates) show no change in functionality in healthy subjects supplemented with creatine, even during several months, in both young and older populations. The potential effects (production of heterocyclic amines) of mutagenicity and carcinogenicity induced by creatine supplementation have been claimed by a French Sanitary Agency (AFSSA), which might put consumers at risk. Even if there is a slight increase (within the normal range) of urinary methylamine and formaldehyde excretion after a heavy load of creatine (20 g/day) this is without effect on kidney function. The search for the excretion of heterocyclic amines remains a future task to definitively exclude the unproved allegation made by some national agencies. We advise that high-dose (>3–5 g/day) creatine supplementation should not be used by individuals with pre-existing renal disease or those with a potential risk for renal dysfunction (diabetes, hypertension, reduced glomerular filtration rate). A pre-supplementation investigation of kidney function might be considered for reasons of safety, but in normal healthy subjects appears unnecessary.

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References

  1. Agence Française de Sécurité Sanitaire et Alimentaire (AFSSA) (2004) Avis relatif à la publicité portant sur des substances de développement musculaire et de mise en forme contenue dans un magazine spécialisé (Saisines 2003-SA-0385 & 2003-SA-0386)

  2. Almada A, Mitchell T, Earnest C (1996) Impact of chronic creatine supplementation on serum enzyme concentration. FASEB J 10:A791

    Google Scholar 

  3. American College of Sports Medicine (2000) The physiological and health effects of oral creatine supplementation. Med Sci Sports Exerc 32:706–717

    Article  Google Scholar 

  4. Bermon S, Venembre P, Sachet C, Valour S, Dolisi C (1998) Effects of creatine monohydrate ingestion in sedentary and weight-trained older adults. Acta Physiol Scand 164:147–155

    PubMed  Article  CAS  Google Scholar 

  5. Berode M, Sethre T, Laubli T, Savolainen T (2000) Urinary methanol and formic acid as indicators of occupational exposure to methyl formate. Int Arch Occup Environ Health 73(6):410–414

    PubMed  Article  CAS  Google Scholar 

  6. Boeniger MF (1987) Formate in urine as a biological indicator of formaldehyde exposure: a review. Am Ind Hyg Assoc J 48(11):900–908

    PubMed  CAS  Google Scholar 

  7. Camamori ML, Fioretto M (2000) The need for early predictors of diabetic nephrpathy risk. Diabetes 49:1399–1408

    Article  Google Scholar 

  8. Chanutin A (1926) The fate of creatine when asministered to man. J Biol Chem 67:29–41

    CAS  Google Scholar 

  9. Dalbo V, Roberts M, Stout J, Kerksick C (2008) Putting to rest the myth of creatine supplementation leading to muscle cramps and dehydration. Br J Sports Med 42:567–573

    PubMed  Article  CAS  Google Scholar 

  10. Deng Y, Boomsma F, Yu PH (1998) Deamination of methylamine and aminoacetone increases aldehydes and oxidative stress in rats. Life Sci 63(23):2049–2058

    PubMed  Article  CAS  Google Scholar 

  11. Derave W, Vanden Eede E, Hespel P, Carmella SG, Hecht DS (2006) Oral creatine supplementation in humans does not elevate urinary excretion of the carcinogen N-nitrososarcosine. Nutrition 22:332–333

    PubMed  Article  CAS  Google Scholar 

  12. Duarte JA, Neuparth MJ, Soares JMC, Appell HJ (1999) Oral creatine supplementation and liver metabolism. Int J Sports Med 20:S50

    Google Scholar 

  13. Edmunds JW, Jayapalan S, DiMarco NM, Saboorian MH, Aukema HM (2001) Creatine supplementation increases renal disease progression in Han:SPRD-cy rats. Am J Kidney Dis 37:73–79

    PubMed  Article  CAS  Google Scholar 

  14. Engelhardt M, Neumann G, Berbalk A, Reuter I (1998) Creatine supplementation in endurance sports. Med Sci Sports Exerc 30:1123–1129

    PubMed  Article  CAS  Google Scholar 

  15. European FSA (2004) Creatine monohydrate for use in foods for particular nutrional uses (Question number EFSA-Q-2003–125). EFSA J 36:1–6

    Google Scholar 

  16. Evans G, Greaves I (1999) Microalbuminuria as predictor of outcome. Br Med J 318:207–208

    CAS  Google Scholar 

  17. Ferreira LG, Bergamaschi CT, Lazaretti-Castro M, Heilberg IP (2005) Effects of creatine supplementation on body composition and renal function in rats. Med Sci Sport Exerc 37:1525–1529

    Article  CAS  Google Scholar 

  18. Friesen MD, Rothman N, Strickland PT (2001) Concentration of 2-amino-1-methyl-6-phenylimidazo(4, 5-b)pyridine (PhIP) in urine and alkali-hydrolyzedn urine after consumption of charbroiled beef. Cancer Lett 173:43–51

    PubMed  Article  CAS  Google Scholar 

  19. Garpenstrand H, Bergqvist M, Brattstrom D, Larsson A, Oreland L, Hesselius P, Wagenius G (2004) Serum semicarbazide-sensitive amine oxidase (SSAO) activity correlates with VEGF in non-small-cell lung cancer patients. Med Oncol 21(3):241–250

    PubMed  Article  CAS  Google Scholar 

  20. Gooderham NJ, Murray S, Lynch AM, Yadollahi-Farsani M, Shao K, Boobis AR, Davies DS (2001) Food-derived heterocyclic amine mutagens: Variable metabolism and significanbce to humans. Drug Metab Dispos 29:529–534

    PubMed  CAS  Google Scholar 

  21. Gotschalk LA, Volek JS, Staron RS, Denegar CR, Hagerman F, Kraemer WJ (2002) Creatine supplementation improves muscular performance in older men. Med Sci Sport Exerc 34:537–543

    Article  Google Scholar 

  22. Greenhaff P (1998) Renal dysfunction accompanying oral creatine supplements. Lancet 352:233

    PubMed  Article  CAS  Google Scholar 

  23. Greenwood M, Kreider RB, Melton C, Rasmussen C, Lancaster S, Cantler E, Milnor P, Almada A (2003) Creatine supplementation during college footbal training does not increase the incidence of cramping or injury. Mol Cell Biochem 244:83–88

    PubMed  Article  CAS  Google Scholar 

  24. Groeneveld GJ, Beijer C, Veldink JH, Kalmijn S, Wokke JHJ, Van den Berg LH (2005) Few adverse effects of long-term creatine supplementation in a placebo-controlled trial. Eur J Sports Med 26:307–313

    Article  CAS  Google Scholar 

  25. Gualano B, Ugrinowitsch C, Novaes R, Artioli G, Shimizu M, Seguro A, Harris R, Lancha A Jr (2008) Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial. Eur J Appl Physiol 103:33–40

    PubMed  Article  CAS  Google Scholar 

  26. Headlam HA, Mortimer A, Easton CJ (2000) Beta-scission of C-3 (beta carbon) alkoxyl radicals on peptides and proteins: a novel pathway which results in the formation of alpha-carbon radicals and the loss of amino acid side chains. Chem Res Toxicol 13:1087–1095

    PubMed  Article  CAS  Google Scholar 

  27. Heddle JA, Knize MG, Dawod D, Zhang XB (2001) A test of the mutagenicity of cooked meats in vivo. Mutagenesis 16:103–107

    PubMed  Article  CAS  Google Scholar 

  28. Hoberman HD, Sims EAH, Peters JH (1948) Creatine ans creatinine metabolism in the normal male adult studied with the aid of isotopic nitrogen. J Biol Chem 172:45–58

    PubMed  CAS  Google Scholar 

  29. Hultman E, Söderlund K, Timmons J, Cederblad G, Greenhaff P (1996) Muscle creatine loading in men. J Appl Physiol 81:232–237

    PubMed  CAS  Google Scholar 

  30. Hyde E (1942) Creatine feeding and creatine-creatinine excretion in males and females of different age groups. J Biol Chem 143:301–310

    CAS  Google Scholar 

  31. Juhn MS, Tarnopolsky M (1998) Potential side effects of oral creatine supplementation: a critical review. Clin J Sport Med 8:298–304

    PubMed  Article  CAS  Google Scholar 

  32. Juhn MS, O’Kane JW, Vinci DM (1999) Oral creatine supplementation in male collegiate athletes: a survey of dosing habits and side effects. J Am Diet Assoc 99:593–595

    PubMed  Article  CAS  Google Scholar 

  33. Kage S, Kudo K, Ikeda H, Ikeda N (2004) Simultaneous determination of formate and acetate in whole blood and urine from humans using gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 805(1):113–117

    PubMed  Article  CAS  Google Scholar 

  34. Kapeller-Adler R, Toda K (1932) Uber das vorkommen von monomethylamin im harn. Biochem Z 248:403–425

    CAS  Google Scholar 

  35. Keys S, Tyminski M, Davis J, Bacon C, Benglovanni J, Hussin A (2001) The effects of long-term creatine supplementation on liver architecture in mice. Med Sci Sport Exerc 33:S206

    Google Scholar 

  36. Kinemuchi H, Sugimoto H, Obata T, Satoh N, Ueda S (2004) Selective inhibitors of membrane-bound semicarbazide-sensitive amine oxidase (SSAO) activity in mammalian tissues. Neurotoxicology 25(1–2):325–335

    PubMed  Article  CAS  Google Scholar 

  37. Knize MG, Salmon CP, Pais P, Felton JS (1999) Food heating and the formation of heterocyclic aromatic amine and polycyclic aromatic hydrocarbon mutagens/carcinogens. Adv Exp Med Biol 459:179–193

    PubMed  CAS  Google Scholar 

  38. Knize MG, Kulp KS, Malfatti MA, Salmon CP, Felton JS (2001) Liquid chromatography-tandem mass spectrometry method of urine analysis for determining human variation in carcinogen metabolism. J Chromat 914:95–103

    Article  CAS  Google Scholar 

  39. Knize MG, Kulp KS, Salmon CP, Keating GA, Felton JS (2002) Factors affecting human heterocyclic amine intake and the metabolism of PhIP. Mutation Res 9377:1–10

    Google Scholar 

  40. Koshy KM, Griswold Schneeberger EE (1999) Interstitial nephritis in a patient taking creatine. New Engl J Med 340:814–815

    PubMed  Article  CAS  Google Scholar 

  41. Kreider R, Ferreira M, Wilson M, Grindstaff P, Plisk S, Reinardy J (1998) Effects of creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc 30:73–82

    PubMed  CAS  Google Scholar 

  42. Maganaris C, Maughan R (1998) Creatine supplementation enhances maximum volunbtary isometric force and endurance capacity in resistance trained men. Acta Physiol Scand 163:279–287

    PubMed  Article  CAS  Google Scholar 

  43. Mattock MB (1992) Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 41:736–741

    PubMed  Article  CAS  Google Scholar 

  44. Mihic S, MacDonald JR, McKenzie S, Tarnopolsky MA (1998) The effect of creatine supplementation on blood presure, plasma creatine kinase, and body composition. FASEB J 12:A652

    Google Scholar 

  45. Mitchell SC, Zhang AQ (2001) Methylamine in human urine. Clin Chim Acta 312(1–2):107–114

    PubMed  Article  CAS  Google Scholar 

  46. Mogensen CE (1990) Prediction in clinical diabetic nephropathy in IDDM patients. Diabetes 39:761–767

    PubMed  Article  CAS  Google Scholar 

  47. Ostojic S, Ahmetovic Z (2008) Gastrointestinal distress after creatine supplementation in athletes: are side effects dose dependent? Res Sports Med 16:15–22

    PubMed  Article  Google Scholar 

  48. Poortmans JR, Francaux M (1998) Renal dysfunction accompanying oral creatine supplements—reply. Lancet 352:234

    PubMed  Article  CAS  Google Scholar 

  49. Poortmans JR, Francaux M (1999) Long-term oral creatine supplementation does not impair renal function in healthy athletes. Med Sci Sports Exerc 31:1108–1110

    PubMed  Article  CAS  Google Scholar 

  50. Poortmans JR, Francaux M (2000) Adverse effects of creatine supplementation : Fact or fiction? Sports Med 30:155–170

    PubMed  Article  CAS  Google Scholar 

  51. Poortmans JR, Francaux M (2002) Renal implications of exogenous creatine monohydrate supplementation. Am J Med Sports 4:212–216

    Google Scholar 

  52. Poortmans JR, Francaux M (2008) Creatine consumption in health. In: Stout J, Antonio J, Kalman D (eds) Essentials of creatine in sports and health. Humana Press, Totowa, pp 137–172

    Google Scholar 

  53. Poortmans JR, Auquier H, Renaut V, Durussel A, Saugy M, Brisson GR (1997) Effects of short-term creatine supplementation on renal responses in men. Eur J Appl Physiol 76:566–567

    Article  CAS  Google Scholar 

  54. Poortmans JR, Kumps A, Duez P, Fofonka A, Carpentier A, Francaux M (2005) Effect of oral creatine supplementation on urinary methylamine, formaldehyde, and formate. Med Sci Sport Exerc 37:1717–1720

    Article  CAS  Google Scholar 

  55. Pritchard N, Kalra P (1998) Renal dysfunction accompanying oral creatine supplementations. Lancet 351:1252–1253

    PubMed  Article  CAS  Google Scholar 

  56. Quievryn G, Zhitkovich A (2000) Loss of DNA-protein crosslinks from formaldehyde-exposed cells occurs through spontaneous hydrolysis and an active repair process linked to proteasome function. Carcinogenesis 21:1573–1580

    PubMed  Article  CAS  Google Scholar 

  57. Rawson ES, Gunn B, Clarkson PM (2001) The effects of creatine supplementation on exercise-induced muscle damage. J Strength Cond Res 15:178–184

    PubMed  CAS  Google Scholar 

  58. Rose WC, Ellis RH, Helming OC (1928) The transformation of creatine into creatinine by the male and female organism. J Biol Chem 77:171–184

    CAS  Google Scholar 

  59. Sale C, Harris RC, Florance J, Kumps A, Sanvura R, Poortmans JR (2009) “Urinary creatine and methylamine excretion following 4 × 5 g day−1 or 20 g × 1 g day−1 of creatine monohydrate for 5 days. J Sports Sci 27:759–766

    PubMed  Article  Google Scholar 

  60. Santos RVT, Bassit RA, Caperuro EC, Costa Rosa LFBP (2004) The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30 km race. Life Sci 75:1917–1924

    PubMed  Article  CAS  Google Scholar 

  61. Schmidt FH (1967) Faulty measurement of urinary glucose concentration by polarization. Dtsch Med Wochenschr 92(44):2025–2027

    PubMed  Article  CAS  Google Scholar 

  62. Skog K, Johansson M, Jägenstad M (1995) Factors affecting the formation and yield of heterocyclic amines. Princess Takamatsu Symp 23:9–19

    PubMed  CAS  Google Scholar 

  63. Taes YEC, Delanghe JR, Wuyts B, Van de Voorde J, Lameire NH (2003) Creatine supplementation does not affect kidney function in an animal model with pre-existing renal failure. Nephrol Dial Transplant 18:258–264

    PubMed  Article  CAS  Google Scholar 

  64. Tarnopolsky M, Bourgeois JM, Snow RJ, Keys S, Roy BD, Kwiecien JM, Turnbull J (2003) Histological assessment of intermediate- and long-term creatine monohydrate supplementation in mice and rats. Am J Physiol 285:R762–R769

    CAS  Google Scholar 

  65. Vandenberghe K, Goris M, Van Hecke P, Van Leemputte M, Vangerven L, Hespel P (1997) Long-term creratine intake is beneficial to muscle performance during resistance training. J Appl Physiol 83:2055–2063

    PubMed  CAS  Google Scholar 

  66. Wyss M (2004) Writing about creatine: is it worth the risk ? Toxicol Lett 152:273–274

    PubMed  Article  CAS  Google Scholar 

  67. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80(3):1107–1213

    PubMed  CAS  Google Scholar 

  68. Wyss M, Schulze A (2002) Health implications of creatine: Can oral creatine supplementation protect against neurological and atherosclerotic disease ? Neurosience 112:243–260

    Article  CAS  Google Scholar 

  69. Yu PH, Deng Y (2000) Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance. Med Hypotheses 54(5):726–728

    PubMed  Article  CAS  Google Scholar 

  70. Yu PH, Zuo DM (1996) Formaldehyde produced endogenously via deamination of methylamine. A potential risk factor for initiation of endothelial injury. Atherosclerosis 120(1–2):189–197

    PubMed  Article  CAS  Google Scholar 

  71. Yu PH, Wright S, Fan EH, Lun ZR, Gubisne-Harberle D (2003) Physiological and pathological implications of semicarbazide-sensitive amine oxidase. Biochim Biophys Acta 1647(1–2):193–199

    PubMed  CAS  Google Scholar 

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Correspondence to Jacques R. Poortmans.

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Kim, H.J., Kim, C.K., Carpentier, A. et al. Studies on the safety of creatine supplementation. Amino Acids 40, 1409–1418 (2011). https://doi.org/10.1007/s00726-011-0878-2

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Keywords

  • Sport
  • Creatine
  • Liver
  • Kidney
  • Health risks