title: Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial.
abstract: BACKGROUND
  Creatine synthesis from guanidinoacetate consumes ~50% of s-adenosylmethionine (SAM)-derived methyl groups, accounting for an equivalent proportion of s-adenosylhomocysteine (SAH) and total homocysteine (tHcys) synthesis. Dietary creatine inhibits the synthesis of guanidinoacetate, thereby lowering plasma tHcys in rats.
  
  
  OBJECTIVE
  We tested the hypotheses that creatine supplementation lowers plasma guanidinoacetate, increases blood SAM, lowers blood SAH, and lowers plasma tHcys.
  
  
  METHODS
  Bangladeshi adults were randomly assigned to receive 1 of 4 treatments for 12 wk: placebo (n = 101), 3 g/d creatine (Cr; n = 101), 400 μg/d folic acid (FA; n = 153), or 3 g/d creatine plus 400 μg/d folic acid (Cr+FA; n = 103). The outcomes of plasma guanidinoacetate and tHcys, as well as whole blood SAM and SAH, were analyzed at baseline and week 12 by HPLC. Treatment effects of creatine supplementation were examined with the use of the group comparisons of Cr vs. placebo and Cr+FA vs. FA.
  
  
  RESULTS
  Plasma guanidinoacetate declined by 10.6% (95% CI: 4.9, 15.9) in the Cr group while increasing nonsignificantly in the placebo group (3.7%; 95% CI: -0.8, 8.5) (Pgroup difference = 0.0002). Similarly, plasma guanidinoacetate declined by 9.0% (95% CI: 3.4, 14.2) in the Cr+FA group while increasing in the FA group (7.0%; 95% CI: 2.0, 12.2) (Pgroup difference < 0.0001). Plasma tHcys declined by 23.4% (95% CI: 19.5, 27.1) and 21.0% (95% CI: 16.4, 25.2) in the FA and Cr+FA groups, respectively (Pgroup difference = 0.41), with no significant changes in the placebo or Cr groups (Pgroup difference = 0.35). A decrease in guanidinoacetate over time was associated with a decrease in tHcys over time in the Cr+FA group (β = 0.30; 95% CI: 0.17, 0.43; P < 0.0001).
  
  
  CONCLUSIONS
  Our findings indicate that whereas creatine supplementation downregulates endogenous creatine synthesis, this may not on average lower plasma tHcys in humans. However, tHcys did decrease in those participants who experienced a decline in plasma guanidinoacetate while receiving creatine plus folic acid supplementation. This trial was registered at clinicaltrials.gov as NCT01050556.
authors: Department of Environmental Health Sciences.
authors: Brandilyn A
authors: BA
authors: Peters
authors: Department of Epidemiology, and.
authors: Megan N
authors: MN
authors: Hall
authors: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY; and.
authors: Xinhua
authors: X
authors: Liu
authors: Department of Environmental Health Sciences.
authors: Faruque
authors: F
authors: Parvez
authors: Columbia University Arsenic Project in Bangladesh, Dhaka, Bangladesh.
authors: Abu B
authors: AB
authors: Siddique
authors: Columbia University Arsenic Project in Bangladesh, Dhaka, Bangladesh.
authors: Hasan
authors: H
authors: Shahriar
authors: Columbia University Arsenic Project in Bangladesh, Dhaka, Bangladesh.
authors: Mohammad Nasir
authors: MN
authors: Uddin
authors: Columbia University Arsenic Project in Bangladesh, Dhaka, Bangladesh.
authors: Tariqul
authors: T
authors: Islam
authors: Department of Environmental Health Sciences.
authors: Vesna
authors: V
authors: Ilievski
authors: Department of Environmental Health Sciences.
authors: Joseph H
authors: JH
authors: Graziano
authors: Department of Environmental Health Sciences, mvg7@cumc.columbia.edu.
authors: Mary V
authors: MV
authors: Gamble
mesh_terms: D000328:Adult; D001459:Bangladesh; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003401:Creatine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019587:Dietary Supplements / Q000009:adverse effects; D004311:Double-Blind Method; D015536:Down-Regulation; D005260:Female; D005492:Folic Acid / Q000009:adverse effects / Q000627:therapeutic use; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000517:prevention & control*; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D010352:Patient Dropouts; D012435:S-Adenosylhomocysteine / Q000097:blood; D012436:S-Adenosylmethionine / Q000097:blood
chemical_list: D015415:Biomarkers; D006710:Homocysteine; D012436:S-Adenosylmethionine; D005492:Folic Acid; D012435:S-Adenosylhomocysteine; C004946:glycocyamine; D003401:Creatine; D005998:Glycine
keywords: Bangladesh; RCT; creatine; folate; folic acid; guanidinoacetate; homocysteine; hyperhomocysteinemia; s-adenosylmethionine