Search tips
Search criteria 


Logo of procbThe Royal Society PublishingProceedings BAboutBrowse by SubjectAlertsFree Trial
Proc Biol Sci. 2003 October 22; 270(1529): 2147–2150.
PMCID: PMC1691485

Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial.


Creatine supplementation is in widespread use to enhance sports-fitness performance, and has been trialled successfully in the treatment of neurological, neuromuscular and atherosclerotic disease. Creatine plays a pivotal role in brain energy homeostasis, being a temporal and spatial buffer for cytosolic and mitochondrial pools of the cellular energy currency, adenosine triphosphate and its regulator, adenosine diphosphate. In this work, we tested the hypothesis that oral creatine supplementation (5 g d(-1) for six weeks) would enhance intelligence test scores and working memory performance in 45 young adult, vegetarian subjects in a double-blind, placebo-controlled, cross-over design. Creatine supplementation had a significant positive effect (p < 0.0001) on both working memory (backward digit span) and intelligence (Raven's Advanced Progressive Matrices), both tasks that require speed of processing. These findings underline a dynamic and significant role of brain energy capacity in influencing brain performance.

Full Text

The Full Text of this article is available as a PDF (194K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Benton D, Owens DS, Parker PY. Blood glucose influences memory and attention in young adults. Neuropsychologia. 1994 May;32(5):595–607. [PubMed]
  • Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol. 1999 Sep;277(3 Pt 2):R698–R704. [PubMed]
  • Delanghe J, De Slypere JP, De Buyzere M, Robbrecht J, Wieme R, Vermeulen A. Normal reference values for creatine, creatinine, and carnitine are lower in vegetarians. Clin Chem. 1989 Aug;35(8):1802–1803. [PubMed]
  • Dienel GA, Hertz L. Glucose and lactate metabolism during brain activation. J Neurosci Res. 2001 Dec 1;66(5):824–838. [PubMed]
  • Dringen R, Verleysdonk S, Hamprecht B, Willker W, Leibfritz D, Brand A. Metabolism of glycine in primary astroglial cells: synthesis of creatine, serine, and glutathione. J Neurochem. 1998 Feb;70(2):835–840. [PubMed]
  • Ferrier CH, Alarcón G, Glover A, Koutroumanidis M, Morris RG, Simmons A, Elwes RD, Cox T, Binnie CD, Polkey CE. N-Acetylaspartate and creatine levels measured by (1)H MRS relate to recognition memory. Neurology. 2000 Dec 26;55(12):1874–1883. [PubMed]
  • Fox PT, Raichle ME, Mintun MA, Dence C. Nonoxidative glucose consumption during focal physiologic neural activity. Science. 1988 Jul 22;241(4864):462–464. [PubMed]
  • Gjedde A, Poulsen PH, Ostergaard L. On the oxygenation of hemoglobin in the human brain. Adv Exp Med Biol. 1999;471:67–81. [PubMed]
  • Griffiths WJ. Estimation of creatine in red cells. J Clin Pathol. 1968 May;21(3):412–413. [PMC free article] [PubMed]
  • Guerrero-Ontiveros ML, Wallimann T. Creatine supplementation in health and disease. Effects of chronic creatine ingestion in vivo: down-regulation of the expression of creatine transporter isoforms in skeletal muscle. Mol Cell Biochem. 1998 Jul;184(1-2):427–437. [PubMed]
  • Harris RC, Söderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond) 1992 Sep;83(3):367–374. [PubMed]
  • Jost Carolina R, Van Der Zee Catharina E E M, In 't Zandt Henricus J A, Oerlemans Frank, Verheij Michel, Streijger Femke, Fransen Jack, Heerschap Arend, Cools Alexander R, Wieringa Bé Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility. Eur J Neurosci. 2002 May;15(10):1692–1706. [PubMed]
  • Kennedy DO, Scholey AB. Glucose administration, heart rate and cognitive performance: effects of increasing mental effort. Psychopharmacology (Berl) 2000 Mar;149(1):63–71. [PubMed]
  • Lowry JP, Fillenz M. Evidence for uncoupling of oxygen and glucose utilization during neuronal activation in rat striatum. J Physiol. 1997 Jan 15;498(Pt 2):497–501. [PubMed]
  • Madsen PL, Cruz NF, Sokoloff L, Dienel GA. Cerebral oxygen/glucose ratio is low during sensory stimulation and rises above normal during recovery: excess glucose consumption during stimulation is not accounted for by lactate efflux from or accumulation in brain tissue. J Cereb Blood Flow Metab. 1999 Apr;19(4):393–400. [PubMed]
  • Mata M, Fink DJ, Gainer H, Smith CB, Davidsen L, Savaki H, Schwartz WJ, Sokoloff L. Activity-dependent energy metabolism in rat posterior pituitary primarily reflects sodium pump activity. J Neurochem. 1980 Jan;34(1):213–215. [PubMed]
  • Merboldt KD, Bruhn H, Hänicke W, Michaelis T, Frahm J. Decrease of glucose in the human visual cortex during photic stimulation. Magn Reson Med. 1992 May;25(1):187–194. [PubMed]
  • Möller A, Hamprecht B. Creatine transport in cultured cells of rat and mouse brain. J Neurochem. 1989 Feb;52(2):544–550. [PubMed]
  • Moss MC, Scholey AB, Wesnes K. Oxygen administration selectively enhances cognitive performance in healthy young adults: a placebo-controlled double-blind crossover study. Psychopharmacology (Berl) 1998 Jul;138(1):27–33. [PubMed]
  • Parker PY, Benton D. Blood glucose levels selectively influence memory for word lists dichotically presented to the right ear. Neuropsychologia. 1995 Jul;33(7):843–854. [PubMed]
  • Rango M, Castelli A, Scarlato G. Energetics of 3.5 s neural activation in humans: a 31P MR spectroscopy study. Magn Reson Med. 1997 Dec;38(6):878–883. [PubMed]
  • Rooney Kieron B, Bryson Janet M, Digney Alison L, Rae Caroline D, Thompson Campbell H. Creatine supplementation affects glucose homeostasis but not insulin secretion in humans. Ann Nutr Metab. 2003;47(1):11–15. [PubMed]
  • Saks VA, Kongas O, Vendelin M, Kay L. Role of the creatine/phosphocreatine system in the regulation of mitochondrial respiration. Acta Physiol Scand. 2000 Apr;168(4):635–641. [PubMed]
  • Salomons GS, van Dooren SJ, Verhoeven NM, Cecil KM, Ball WS, Degrauw TJ, Jakobs C. X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet. 2001 Jun;68(6):1497–1500. [PubMed]
  • Sappey-Marinier D, Calabrese G, Fein G, Hugg JW, Biggins C, Weiner MW. Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab. 1992 Jul;12(4):584–592. [PubMed]
  • Scholey AB, Harper S, Kennedy DO. Cognitive demand and blood glucose. Physiol Behav. 2001 Jul;73(4):585–592. [PubMed]
  • Shomrat A, Weinstein Y, Katz A. Effect of creatine feeding on maximal exercise performance in vegetarians. Eur J Appl Physiol. 2000 Jul;82(4):321–325. [PubMed]
  • Silver IA, Erecińska M. Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals. J Neurosci. 1994 Aug;14(8):5068–5076. [PubMed]
  • Stöckler S, Hanefeld F, Frahm J. Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet. 1996 Sep 21;348(9030):789–790. [PubMed]
  • Terjung RL, Clarkson P, Eichner ER, Greenhaff PL, Hespel PJ, Israel RG, Kraemer WJ, Meyer RA, Spriet LL, Tarnopolsky MA, et al. American College of Sports Medicine roundtable. The physiological and health effects of oral creatine supplementation. Med Sci Sports Exerc. 2000 Mar;32(3):706–717. [PubMed]
  • Valenzuela Michael J, Jones Megan, Wen Wei, Rae Caroline, Graham Scott, Shnier Ronald, Sachdev Perminder. Memory training alters hippocampal neurochemistry in healthy elderly. Neuroreport. 2003 Jul 18;14(10):1333–1337. [PubMed]
  • Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis. Biochem J. 1992 Jan 1;281(Pt 1):21–40. [PubMed]
  • Watanabe Airi, Kato Nobumasa, Kato Tadafumi. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci Res. 2002 Apr;42(4):279–285. [PubMed]
  • Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev. 2000 Jul;80(3):1107–1213. [PubMed]
  • Wyss Markus, Schulze Andreas. Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience. 2002;112(2):243–260. [PubMed]

Articles from Proceedings of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society