Guanidinoacetic Acid (GAA) Administration in Physically Active Men and Women
Condition: Athletic Performance
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Glycocyamine (guanidinoacetic acid - GAA) is the biochemical precursor of creatine, which is
      phosphorylated and plays an important role as a high-energy carrier in the muscle. Since GAA
      can be administered in liquid solutions, such as sports drinks, it could be hypothesised that
      GAA could easily enhance creatine biosynthesis with clear physiological effects yet to be
      determined. No single study has examined the influence of GAA on health, human performance or
      body composition indicators in healthy human subjects. Moreover, the most effective dose of
      GAA is yet to be find. Finally, the adverse effects of GAA supplementation in humans are not
      determined. The main aims of the present study will be to identify if the 6-weeks of GAA
      supplementation improves human performance and body composition, to determine most effective
      dose regimens of GAA, and to analyze adverse effects of GAA supplementation. Forty eight
      healthy, trained (> 2 yr training experience) male and female subjects (aged 20 to 25 years)
      will give their informed consent and volunteer to participate in the study, which will obtain
      the approval of the University's Ethical Advisory Commission. The subjects will be allocated
      to four randomly assigned trials: ingesting GAA (1.2, 2.4, 4.8 g of GAA in a single dose) or
      placebo (PLA) for 6 weeks in a double-blind design. All testing including blood and urine
      samples, body composition and muscle strength and exercise performance (both aerobic and
      anaerobic) will be conducted at presupplementation (baseline), at 1 week, at 2 weeks, at 4
      weeks, at 6 weeks of supplementation and at 8 and 10 weeks (2 and 4 weeks after the end of
      supplementation) to analyze wash-out period. According to previous investigations, the
      investigators expect that ingestion of GAA will significantly increase both serum creatine
      and total homocystein. The investigators expect that ingestion of GAA will significantly
      improve muscle strength parameters and exercise performance results as compared to placebo in
      long term. The investigators also expect to find prevalence of side-effects (i.e.
      gastrointestinal distress, retention of fluid).
    

Detailed description: 
      For the last two decades, top athletes first, then sport professionals and amateur sports
      participants have been using oral creatine supplementation on regular basis as an ergogenic
      aid to improve performance (Poortmans & Francaux 2000). Up to 90% of team-game athletes are
      regular consumers of creatine (Striegel et al. 2006), with nearly 60% of recreational
      athletes have tried creatine (Froiland et al. 2004). Supplementation with oral creatine, that
      currently is viewed to be safe, augments skeletal muscle creatine concentrations in most
      individuals, which has been shown to promote gains in lean body mass when used in conjunction
      with resistance training, to enhance power and strength, and to improve performance in
      intense exercise, especially during repeated bouts (Racette 2003; Ostojic 2004). Yet,
      creatine is not stable in solution and as such is only offered in a variety of non-liquid
      forms including powder, tablets, gel, chewing gum, and candy (Benzi & Ceci 2001). Although
      creatine synthesis is a proprietary process among manufacturers, it is quite common to use
      another muscle-related compounds (i.e. sarcosine, cyanamide), as the principal starting
      materials for the commercial synthesis of creatine (Williams & Branch 1998). Glycocyamine
      (guanidinoacetic acid - GAA) along with L-ornithine is formed from arginine and glycine in
      the kidney, with this reaction is believed to be the regulated step of creatine biosynthesis
      (Edison et al. 2007). The second enzyme in the pathway is GAA N-methyltransferaze which
      catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to GAA to form
      S-adenosylhomocysteine (SAH) and creatine (Walker 1979). It has been estimated that about 75%
      of labile methyl groups is used to synthetize creatine by a reaction catalyzed by GAA
      N-methyltransferaze (Mudd et al. 1975). It seems that creatine synthesis is an interorgan
      process whereby GAA, produced by the kindey, is released into the circulation and is
      methylated to creatine in the liver. Creatine is then released from the liver and into the
      circulation where it can be taken up, via a specific transporter, by various tissues.
      According to previous studies in animals (da Silva et al. 2009) and preliminary research in
      humans (AlzChem 2009), short-term oral intake of GAA increases serum level of creatine, with
      level of increase interrelated with GAA dose supplemented. GAA is the biochemical presursor
      of creatine, which is phosphorylated and plays an important role as a high-energy carrier in
      the muscle (Edison et al. 2007). Since GAA can be administred in liquid solutions, such as
      sports drinks, it could be hypothesised that GAA could easily enhance creatine biosynthesis
      with clear physiological effects yet to be determined. Moreover, it seems that GAA has a
      significantly better bioavailability than creatine, developing maximal activity at a dosage
      at which creatine leads to no observable effects (AlzChem 2009). Several human studies
      (Borsook & Borsook 1951; Graybiel & Patterson 1951; Higgins et al. 1952; Dixon et al. 1954)
      found beneficial effects of creatine precursors oral administration on cardiac
      decompensation, arthritis, anxiety and depression patients. Authors speculated that benefical
      effects of GAA intake could be due to boosting energy levels and/or increased availability of
      dimethylglycine for incorporation into tissue proteins, providing repair of damaged muscle
      cells. Yet, no single study has examined the influence of additive-free GAA (e.g. without
      betaine or choline) on health, human performance or body composition indices. The amount
      taken of this supplementation ranges typically from a few grams to tens of grams per day for
      weeks or months in previous research in humans. Although, the most effective dose is yet to
      be find. Finally, the adverse effects of GAA supplementation in both animals and humans are
      yet to be determined. Several studies showed moderate hyperhomocysteinemia (Stead et al.
      2001; Fukada et al. 2006; Setoue et al. 2008; AlzChem 2009), disturbances in antioxidant
      system (Zugno et al. 2008), modulation of inflammatory responses (Glorieux et al. 2004) after
      GAA supplementation. If GAA have ergogenic properties it could become new effective
      performance-enhancing substance for both professional and recreational athletes, stable in
      water solutions, where creatine at neutral to slightly acidic pH-values is rapidly being
      metabolised to creatinine, which is meaningless for the energy production (AlzChem 2009).
    

Intervention name(s): guanidinoacetic acid; GAA-4; GAA-1; PLACEBO
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): 2.4 grams of guanidinoacetic acid; 4.8 grams of guanidinoacetic acid; 1.2 grams of guanidinoacetic acid; celulose
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: strength, anaerobic performance, recovery, ergogenic