Few Adverse Effects of Long-Term Creatine Supplementation in a Placebo-Controlled Trial

Abstract

Although oral creatine supplementation is very popular among athletes, no prospective placebo-controlled studies on the adverse effects of long-term supplementation have yet been conducted. We performed a double-blind, placebo-controlled trial of creatine monohydrate in patients with the neurodegenerative disease amyotrophic lateral sclerosis, because of the neuroprotective effects it was shown to have in animal experiments. The purpose of this paper is to compare the adverse effects, and to describe the effects on indirect markers of renal function of long-term creatine supplementation. 175 subjects (age = 57.7 ± 11.1 y) were randomly assigned to receive creatine monohydrate 10 g daily or placebo during an average period of 310 days. After one month, two months and from then on every fourth month, adverse effects were scored using dichotomous questionnaires, plasma urea concentrations were measured, and urinary creatine and albumin concentrations were determined. No significant differences in the occurrence at any time of adverse effects due to creatine supplementation were found (23 % nausea in the creatine group, vs. 24 % in the placebo group, 19 % gastro-intestinal discomfort in the creatine group, vs. 18 % in the placebo group, 35 % diarrhoea in the creatine group, vs. 24 % in the placebo group). After two months of treatment, oedematous limbs were seen more often in subjects using creatine, probably due to water retention. Severe diarrhoea (n = 2) and severe nausea (n = 1) caused 3 subjects in the creatine group to stop intake of creatine, after which these adverse effects subsided. Long-term supplementation of creatine did not lead to an increase of plasma urea levels (5.69 ± 1.47 before treatment vs. 5.26 ± 1.44 at the end of treatment) or to a higher prevalence of micro-albuminuria (5.4 % before treatment vs. 1.8 % at the end of treatment).

Creatine monohydrate - side effects - randomised - renal function

References

• 1 Anderson G H, Catherine N L, Woodend D M, Wolever T M. Inverse association between the effect of carbohydrates on blood glucose and subsequent short-term food intake in young men.  Am J Clin Nutr. 2002;  76 1023-1030
• 2 Andres P L, Skerry L M, Thornell B, Portney L G, Finison L J, Munsat T L. A comparison of three measures of disease progression in ALS.  J Neurol Sci. 1996;  139 64-70
• 3 Beijer C. Creatine measurement in serum and urine with an automated enzymatic method.  Clin Chem. 1993;  39 1613-1619
• 4 Bemben M G, Bemben D A, Loftiss D D, Knehans A W. Creatine supplementation during resistance training in college football athletes.  Med Sci Sports Exerc. 2001;  33 1667-1673
• 5 Birch R, Noble D, Greenhaff P L. The influence of dietary creatine supplementation on performance during repeated bouts of maximal isokinetic cycling in man.  Eur J Appl Physiol. 1994;  69 268-276
• 6 Bosco C, Tihanyi J, Pucspk J, Kovacs I, Gabossy A, Colli R, Pulvirenti G, Tranquilli C, Foti C, Viru M, Viru A. Effect of oral creatine supplementation on jumping and running performance.  Int J Sports Med. 1997;  18 369-372
• 7 Brinkmann J R, Andres P, Mendoza M, Sanjak M. Guidelines for the use and performance of quantitative outcome measures in ALS clinical trials.  J Neurol Sci. 1997;  147 97-111
• 8 Doherty T J, Lougheed K, Markez J, Tarnopolsky M A. Creatine monohydrate does not increase strength in patients with hereditary neuropathy.  Neurology. 2001;  57 559-560
• 9 Fuller N J, Elia M. Factors influencing the production of creatinine: implications for the determination and interpretation of urinary creatinine and creatine in man.  Clin Chim Acta. 1988;  175 199-210
• 10 Grindstaff P D, Kreider R, Bishop R, Wilson M, Wood L, Alexander C, Almada A. Effects of creatine supplementation on repetitive sprint performance and body composition in competitive swimmers.  Int J Sport Nutr. 1997;  7 330-346
• 11 Groeneveld G J, Veldink J H, Van der Tweel I, Kalmijn S, Beijer C, De Visser M, Wokke J HJ, Van den Berg L H. A randomised sequential trial of creatine in amyotrophic lateral sclerosis.  Ann Neurol. 2003;  54 437-445
• 12 Haverkamp L J, Appel V, Appel S H. Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction.  Brain. 1995;  118 707-719
• 13 Hubbuch A. Results of the multicenter study of Tina-quant albumin in urine.  Wien Klin Wschr Suppl. 1991;  189 24-31
• 14 Hultman E, Soderlund K, Timmons J A, Cederblad G, Greenhaff P L. Muscle creatine loading in men.  J Appl Physiol. 1996;  81 232-237
• 15 Jacobs P L, Mahoney E T, Cohn K A, Sheradsky L F, Green B A. Oral creatine supplementation enhances upper extremity work capacity in persons with cervical-level spinal cord injury.  Arch Phys Med Rehabil. 2002;  83 19-23
• 16 Juhn M S, O'Kane J W, Vinci D M. Oral creatine supplementation in male collegiate athletes: a survey of dosing habits and side effects.  J Am Diet Ass. 1999;  99 593-595
• 17 Juhn M S, Tarnopolsky M. Potential side effects of oral creatine supplementation: a critical review.  Clin J Sport Med. 1998;  8 298-304
• 18 Klivenyi P, Ferrante R J, Matthews R T, Bogdanov M B, Klein A M, Andreassen O A, Mueller G, Wermer M, Kaddurah Daouk R, Beal M F. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis.  Nat Med. 1999;  5 347-350
• 19 Koshy K M, Griswold E, Schneeberger E E. Interstitial nephritis in a patient taking creatine.  N Engl J Med. 1999;  340 814-815
• 20 Kreider R B, Ferreira M, Wilson M, Grindstaff P, Plisk S, Reinardy J, Cantler E, Almada A L. Effects of creatine supplementation on body composition, strength, and sprint performance.  Med Sci Sports Exerc. 1998;  30 73-82
• 21 Lacomblez L, Bensimon G, Leigh P N, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II.  Lancet. 1996;  347 1425-1431
• 22 Pocock S J. Allocation of patients to treatment in clinical trial.  Biometrics. 1979;  35 183-197
• 23 Poortmans J R, Auquier H, Renaut V, Durussel A, Saugy M, Brisson G R. Effect of short-term creatine supplementation on renal responses in men.  Eur J Appl Physiol. 1997;  76 566-567
• 24 Poortmans J R, Francaux M. Long-term oral creatine supplementation does not impair renal function in healthy athletes.  Med Sci Sports Exerc. 1999;  31 1108-1110
• 25 Pritchard N R, Kaira P A. Renal dysfunction accompanying oral creatine supplements.  Lancet. 1998;  351 1252-1253
• 26 Romer L M, Barrington J P, Jeukendrup A E. Effects of oral creatine supplementation on high intensity, intermittent exercise performance in competitive squash players.  Int J Sports Med. 2001;  22 546-552
• 27 Swash M. Early diagnosis of ALS/MND.  J Neurol Sci. 1998;  160 33-36
• 28 Talke H, Schubert G E. Enzymatic urea determination in the blood and serum in the Warburg optical test.  Klin Wschr. 1965;  43 174-175
• 29 Tarnopolsky M J. Creatine monohydrate increases strength in patients with neuromuscular disease.  Neurology. 1999;  52 854-857
• 30 Vandenberghe K, Goris M, Van Hecke P, Van Leemputte M, Vangerven L, Hespel P. Long-term creatine intake is beneficial to muscle performance during resistance training.  J Appl Physiol. 1997;  83 2055-2063
• 31 Walter M C, Lochmuller H, Reilich P, Klopstock T, Huber R, Hartard M, Hennig M, Pongratz D, Muller-Felber W. Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study.  Neurology. 2000;  54 1848-1850
• 32 Zwang L, Bleijenberg B G. Assessment of a selected method for creatinine with special emphasis on bilirubin interference.  Eur J Clin Chem Clin Biochem. 1991;  29 795-800