Skip to main content
SpringerLink
Log in

Guanidinoacetic acid as a performance-enhancing agent

  • Minireview Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Guanidinoacetic acid (GAA; also known as glycocyamine or guanidinoacetate) is the natural precursor of creatine, and under investigation as a novel dietary agent. It was first identified as a natural compound in humans ~80 years ago. In the 1950s, GAA's use as a therapeutic agent was explored, showing that supplemental GAA improved patient-reported outcomes and work capacity in clinical populations. Recently, a few studies have examined the safety and efficacy of GAA and suggest potential ergogenic benefits for physically active men and women. The purpose of this review is to examine possible applications of GAA supplementation for exercise performance enhancement, safety, and legislation issues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ADP:

Adenosine diphosphate

AGAT:

l-arginineglycine amidinotransferase

ATP:

Adenosine triphosphate

CRF:

Chronic renal failure

GAA:

Guanidinoacetic acid

GABA:

Gamma-amino butyric acid

GAMT:

Guanidinoacetate N-methyltransferase

GH:

Growth hormone

SAH:

S-adenosylhomocysteine

References

  • Aldes JH (1957) Glycocyamine betaine as an adjunct in the treatment of neuromuscular disease patients. J Ark Med Soc 54(5):186–194

    CAS  PubMed  Google Scholar 

  • Almeida LS, Verhoeven NM, Roos B, Valongo C, Cardoso ML, Vilarinho L, Salomons GS, Jakobs C (2004) Creatine and guanidinoacetate: diagnostic markers for inborn errors in creatine biosynthesis and transport. Mol Genet Metab 82(3):214–219

    Article  CAS  PubMed  Google Scholar 

  • Alsever RN, Georg RH, Sussman KE (1970) Stimulation of insulin secretion by guanidinoacetic acid and other guanidine derivatives. Endocrinology 86(2):332–336

    Article  CAS  PubMed  Google Scholar 

  • Álvares TS, Meirelles CM, Bhambhani YN, Paschoalin VM, Gomes PS (2011) l-Arginine as a potential ergogenic aid in healthy subjects. Sports Med 41(3):233–248

    Article  PubMed  Google Scholar 

  • Aynsley-Green A, Alberti KG (1974) In vivo stimulation of insulin secretion by guanidine derivatives in the rat. Horm Metab Res 6(2):115–120

    Article  CAS  PubMed  Google Scholar 

  • Bailey RL, Fulgoni VL 3rd, Keast DR, Dwyer JT (2012) Examination of vitamin intakes among US adults by dietary supplement use. J Acad Nutr Diet 112(5):657–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker DH (2009) Advances in protein–amino acid nutrition of poultry. Amino Acids 37(1):29–41

    Article  CAS  PubMed  Google Scholar 

  • Basom WC, Breck LW, Leonard MH (1955) The effect of betaine and glycocyamine in the management of chronic anterior poliomyelitis. Int Rec Med Gen Pract Clin 168(2):70–71

    CAS  PubMed  Google Scholar 

  • Beard HH, Barnes BO (1931) The influence of feeding proteins, amino acids, and related substances upon creatine–creatinine metabolism. J Biol Chem 94(1):49–69

    Google Scholar 

  • Boehm EA, Radda GK, Tomlin H, Clark JF (1996) The utilisation of creatine and its analogues by cytosolic and mitochondrial creatine kinase. Biochim Biophys Acta 1274(3):119–128

    Article  PubMed  Google Scholar 

  • Borsook ME, Borsook H (1951) Treatment of cardiac decompensation with betaine and glycocyamine. Ann West Med Surg 5(10):830–855

    CAS  PubMed  Google Scholar 

  • Borsook ME, Billig HK, Golseth JG (1962) Betaine and glycocyamine in the treatment of disability resulting from acute anterior poliomyelitis. Ann West Med Surg 6(7):423–427

    Google Scholar 

  • Braisant O (2012) Creatine and guanidionoacetate transport at blood–brain and blood–cerebrospinal fluid barriers. J Inherit Metab Dis 35(4):655–664

    Article  Google Scholar 

  • Braissant O, Henry H, Loup M, Eilers B, Bachmann C (2001) Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Brain Res Mol Brain Res 86(1–2):193–201

    Article  CAS  PubMed  Google Scholar 

  • Christie DL (2007) Functional insights into the creatine transporter. Subcell Biochem 46:99–118

    Article  PubMed  Google Scholar 

  • Committee on the Framework for Evaluating the Safety of Dietary Supplements, Food and Nutrition Board, Board on Life Sciences, Institute of Medicine, National Research Council of the National Academies (2004) Dietary supplements: a framework for evaluating safety. The National Academies Press, Washington

    Google Scholar 

  • Daly MM (1985) Guanidinoacetate methyltransferase activity in tissue and cultured cells. Arch Biochem Biphys 236(2):576–584

    Article  CAS  Google Scholar 

  • Davenport HW, Fisher RB, Wilhelmi AE (1938) The metabolism of creatine: the role of glycocyamine in creatine synthesis. Biochem J 32(2):262–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Derave W, Marescau B, Vanden Eede E, Eijnde BO, De Deyn PP, Hespel P (2004) Plasma guanidino compounds are altered by oral creatine supplementation in healthy humans. J Appl Physiol 97(3):852–857

    Article  CAS  PubMed  Google Scholar 

  • Dilger RN, Bryant-Angeloni K, Payne RL, Lemme A, Parsons CM (2013) Dietary guanidino acetic acid is an efficacious replacement for arginine for young chicks. Poult Sci 92(1):171–177

    Article  CAS  PubMed  Google Scholar 

  • Dixon HH, Dickel HA, Shanklin JG, Peterson RD, West ES (1954) Therapy in anxiety states and anxiety complicated by depression. West J Surg Obstet Gynecol 62(6):338–341

    CAS  PubMed  Google Scholar 

  • Edison EE, Brosnan ME, Meyer C, Brosnan JT (2007) Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo. Am J Physiol Renal Physiol 293(6):F1799–F1804

    Article  CAS  PubMed  Google Scholar 

  • European Food Safety Authority (2009) Safety and efficacy of guanidinoacetic acid as feed additive for chickens for fattening. EFSA J 988:1–30

    Google Scholar 

  • Fallis BD, Lam RL (1952) Betaine and glycocyamine therapy for the chronic residuals of poliomyelitis. J Am Med Assoc 150(9):851–853

    Article  CAS  PubMed  Google Scholar 

  • Future Market Insights (2015) Dietary supplements market: global industry analysis and opportunity assessment, 2014–2020. Future Market Insight, London. http://www.futuremarketinsights.com/reports/details/dietary-supplements-market. Accessed 16 June 2015

  • Graybiel A, Patterson CA (1951) Use of betaine and glycocyamine in the treatment of patients with heart disease: preliminary report. Ann West Med Surg 5(10):863–875

    CAS  PubMed  Google Scholar 

  • Heger J, Zelenka J, Machander V, de la Cruz C, Lestak M, Hampel D (2014) Effects of guanidinoacetic acid supplementation to broiler diets with varying energy content. Acta Univ Agric Silvic Mendelianae Brun 62(3):477–485

    Article  CAS  Google Scholar 

  • Higgins AR, Harper HA, Kline EF, Merrill RS, Jones RE, Smith TW, Kimmel JR (1952) Effects of creatine precursors in arthritis; clinical and metabolic study of glycocyamine and betaine. Calif Med 77(1):14–18

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hunter A (1928) Creatine and creatinine. Longman, London

    Google Scholar 

  • Joncquel-Chevalier Curt M, Cheillan D, Briand G, Salomons GS, Mention-Mulliez K, Dobbelaere D, Cuisset JM, Lion-François L, Des Portes V, Chabli A, Valayannopoulos V, Benoist JF, Pinard JM, Simard G, Douay O, Deiva K, Tardieu M, Afenjar A, Héron D, Rivier F, Chabrol B, Prieur F, Cartault F, Pitelet G, Goldenberg A, Bekri S, Gerard M, Delorme R, Porchet N, Vianey-Saban C, Vamecq J (2013) Creatine and guanidinoacetate reference values in a French population. Mol Genet Metab 110(3):263–267

    Article  CAS  PubMed  Google Scholar 

  • Lemme A, Tossenberger J, Ringel J (2007) Digestibility and availability of the creatine source guanidinoacetic acid in broilers. Poult Sci 86(Suppl 1):153

    Google Scholar 

  • Leuzzi V, Bianchi MC, Tosetti M, Carducci C, Cerquiglini CA, Cioni G, Antonozzi I (2000) Brain creatine depletion: guanidinoacetate methyltransferase deficiency (improving with creatine supplementation). Neurology 55(9):1407–1409

    Article  CAS  PubMed  Google Scholar 

  • Liversedge LA (1956) Glycocyamine and betaine in motor-neurone disease. Lancet 271(6953):1136–1138

    Article  CAS  PubMed  Google Scholar 

  • Michiels J, Maertens L, Buyse J, Lemme A, Rademacher M, Dierick NA, De Smet S (2012) Supplementation of guanidinoacetic acid to broiler diets: effects on performance, carcass characteristics, meat quality, and energy metabolism. Poult Sci 91(2):402–412

    Article  CAS  PubMed  Google Scholar 

  • Morris MS (2003) Homocysteine and Alzcheimer’s disease. Lancet Neurol 2(7):425–428

    Article  CAS  PubMed  Google Scholar 

  • Mousavi SN, Afsar A, Lotfollahian H (2013) Effects of guanidinoacetic acid supplementation to broiler diets with varying energy contents. J Appl Poult Res 22(1):47–54

    Article  CAS  Google Scholar 

  • Mudd SH, Brosnan JT, Brosnan ME, Jacobs RL, Stabler SP, Allen RH, Vance DE, Wagner C (2007) Methyl balance and transmethylation fluxes in humans. Am J Clin Nutr 85(1):19–25

    CAS  PubMed  Google Scholar 

  • Murakami AE, Rodrigueiro RJ, Santos TC, Ospina-Rojas IC, Rademacher M (2014) Effects of dietary supplementation of meat-type quail breeders with guanidinoacetic acid on their reproductive parameters and progeny performance. Poult Sci 93(9):2237–2244

    Article  CAS  PubMed  Google Scholar 

  • Neu A, Neuhoff H, Trube G, Fehr S, Ullrich K, Roeper J, Isbrandt D (2002) Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism. Neurobiol Dis 11(2):298–307

    Article  CAS  PubMed  Google Scholar 

  • Ostojic SM (2010) Guanidinoacetic acid (GAA) administration in physically active men and women. US National Library of Medicine. http://www.clinicaltrials.gov/ct2/show/NCT01133899. Accessed 16 June 2015

  • Ostojic SM, Stojanovic MD (2015) Guanidinoacetic acid loading affects plasma γ-aminobutyric acid in healthy men. Eur J Nutr 54(5):855–858

    Article  CAS  PubMed  Google Scholar 

  • Ostojic SM, Vojvodic-Ostojic A (2015) Single-dose oral guanidinoacetic acid exhibits dose-dependent pharmacokinetics in healthy volunteers. Nutr Res 35(3):198–205

    Article  CAS  PubMed  Google Scholar 

  • Ostojic SM, Niess B, Stojanovic M, Obrenovic M (2013a) Creatine metabolism and safety profiles after six-week oral guanidinoacetic acid administration in healthy humans.–. Int J Med Sci 10(2):141–147

    Article  PubMed  PubMed Central  Google Scholar 

  • Ostojic SM, Niess B, Stojanovic M, Obrenovic M (2013b) Co-administration of methyl donors along with guanidinoacetic acid reduces the incidence of hyperhomocysteinemia compared to guanidinoacetic acid administration alone. Br J Nutr 110(5):865–870

    Article  CAS  PubMed  Google Scholar 

  • Ostojic SM, Stojanovic MD, Drid P, Hoffman JR (2014) Dose-response effects of oral guanidinoacetic acid on serum creatine, homocysteine and B vitamins levels. Eur J Nutr 53(8):1637–1643

    Article  CAS  PubMed  Google Scholar 

  • Ostojic SM, Hoffman JR, Stojanovic M, Drid P (2015a) 28-day GAA supplementation improves clinical outcomes in patients with chronic fatigue syndrome. Med Sci Sport Exerc 48(5):S47

    Google Scholar 

  • Ostojic SM, Stojanovic MD, Hoffman JR (2015b) Six-week oral guanidinoacetic acid administration improves muscular performance in healthy volunteers. J Investig Med. doi:10.1097/JIM.0000000000000212. (in press)

  • Powers M (2012) GABA supplementation and growth hormone response. Med Sport Sci 59:36–46

    Article  CAS  PubMed  Google Scholar 

  • Refsum H, Ueland PM, Nygard O, Vollset SE (1998) Homocysteine and cardiovascular disease. Annu Rev Med 49:31–62

    Article  CAS  PubMed  Google Scholar 

  • Ringel J, Lemme A, Redshaw MS, Damme K (2008) The effects of supplemental guanidino acetic acid as a precursor of creatine in vegetable broiler diets on performance and carcass parameters. Poult Sci 87(Suppl 1):72

    Google Scholar 

  • Schulze A, Hoffmann GF, Bachert P, Kirsch S, Salomons GS, Verhoeven NM, Mayatepek E (2006) Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology 67(4):719–721

    Article  CAS  PubMed  Google Scholar 

  • Sonksen PH (2001) Insulin, growth hormone and sport. J Endocrinol 170(1):13–25

    Article  CAS  PubMed  Google Scholar 

  • Stacy JJ, Terrell TR, Armsey TD (2004) Ergogenic aids: human growth hormone. Curr Sports Med Rep 3(4):229–233

    Article  PubMed  Google Scholar 

  • Stead LM, Au KP, Jacobs RL, Brosnan ME, Brosnan JT (2001) Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am J Physiol Endocrinol Metab 281(5):E1095–E1100

    CAS  PubMed  Google Scholar 

  • Stromberger C, Bodamer OA, Stöckler-Ipsiroglu S (2003) Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J Inherit Metab Dis 26(2–3):299–308

    Article  CAS  PubMed  Google Scholar 

  • Torremans A, Marescau B, Kränzlin B, Gretz N, Billiouw JM, Vanholder R, De Smet R, Bouwman K, Brouns R, De Deyn PP (2006) Biochemical validation of a rat model for polycystic kidney disease: comparison of guanidino compound profile with the human condition. Kidney Int 69(11):2003–2012

    Article  CAS  PubMed  Google Scholar 

  • Tsubakihara Y, Suzuki A, Hayashi T, Shoji T, Togawa M, Okada N (1999) The effect of guanidinoacetic acid supplementation in patients with chronic renal failure. In: Mori A, Ishida M, Clark JF (eds) Guanidino compounds in biology and medicine, vol 5. Blackwell, Tokyo, pp 139–144

    Google Scholar 

  • Tsubakihara Y, Hayashi T, Shoji T (2012) Guanidinoacetic acid (GAA) in patients with chronic kidney disease (CKD) and diabetes mellitus (DM). Kid Res Clin Pract 31(Suppl):A81

    Article  Google Scholar 

  • Van Pilsum JF (1971) Evidence for a dual role of creatine in the regulation of kidney transamidinase activities in the rat. J Nutr 101(8):1085–1092

    PubMed  Google Scholar 

  • Van Zandt V, Borsook H (1951) New biological approach to the treatment of congestive heart failure. Ann West Med Surg 5(10):856–862

    Google Scholar 

  • Walker JB (1979) Creatine: biosynthesis, regulation, function. Adv Enzymol Relat Areas Mol Biol 50:177–242

    CAS  PubMed  Google Scholar 

  • Wallimann T, Tokarska-Schlattner M, Schlattner U (2011) The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40(5):1271–1296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang LS, Shi BM, Shan AS, Zhang YY (2012) Effects of guanidinoacetic acid on growth performance, meat quality and antioxidation in growing-finishing pigs. J Anim Vet Adv 11(5):631–636

    Article  CAS  Google Scholar 

  • Watkins AL (1953) Betaine and glycocyamine in the treatment of poliomyelitis. N Engl J Med 248(15):621–623

    Article  CAS  PubMed  Google Scholar 

  • Weber CJ (1934) Isolation of glycocyamine from urine. Exp Biol Med 32:172–174

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Zugno AI, Franzon R, Chiarani F, Bavaresco CS, Wannmacher CM, Wajner M, Wyse AT (2004) Evaluation of the mechanism underlying the inhibitory effect of guanidinoacetate on brain Na+, K+-ATPase activity. Int J Dev Neurosci 22(4):191–196

    Article  CAS  PubMed  Google Scholar 

  • Zugno AI, Stefanello FM, Scherer EB, Mattos C, Pederzolli CD, Andrade VM, Wannmacher CM, Wajner M, Dutra-Filho CS, Wyse AT (2008) Guanidinoacetate decreases antioxidant defenses and total protein sulfhydryl content in striatum of rats. Neurochem Res 33(9):1804–1810

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Serbian Ministry of Science (Grant No. 175037), Faculty of Sport and Physical Education, University of Novi Sad (2015 Annual Award), and AlzChem AG, Trostberg, Germany. The author is grateful to Theo Wallimann and Roger Harris for their assistance during the manuscript preparation.

Author information

Authors and Affiliations

  1. Biomedical Sciences Department, Faculty of Sport and Physical Education, University of Novi Sad, Lovcenska 16, Novi Sad, 21000, Serbia

    Sergej M. Ostojic

  2. University of Belgrade School of Medicine, Belgrade, Serbia

    Sergej M. Ostojic

Authors
  1. Sergej M. Ostojic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sergej M. Ostojic.

Ethics declarations

Conflict of interest

The author declares no conflict of interest.

Additional information

Handling Editors: T. Wallimann and R. Harris.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ostojic, S.M. Guanidinoacetic acid as a performance-enhancing agent. Amino Acids 48, 1867–1875 (2016). https://doi.org/10.1007/s00726-015-2106-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-015-2106-y

Keywords

Search

Navigation