Glycocyamine and Betaine: Superstack for “non-responders”

Glycocyamine (Guanidinoacetic acid or GAA) is a direct precursor of creatine and is naturally occurring in the human body.[1,2] It has gained its popularity from a well-know pre-workout supplement that is now discontinued.

Some experts believe that among the population there are about 20% or more so-called creatine “non-responders“.[2] Creatine responders naturally respond to creatine and have better effects when using creatine. Some individuals (a.k.a. non-responders) show little or no increase in total muscle creatine concentration. Glycocyamine is believed to benefit both responders and non-responders favourably.[3]

How Can Glycocyamine help non-responders?

Several studies evaluated the metabolic and clinical effects of glycocyamine. Research in rats has shown that short-term oral glycocyamine administration increases the serum level of creatine to a similar extent like the same dose of creatine.[4] Stead and co-workers [4], and Fukada and co-workers [5] observed moderate hyperhomocysteinemia (elevated levels of homocysteine) after oral administration of guanidinoacetic acid in rats.

Glycocyamine is basically a creatine without a methyl group (CH₃).[6] In the conversion of glycocyamine to creatine, the enzyme Guanidinoacetate N-methyltransferase (GAMT) catalyzes the transfer of a methyl group from S-adenosylmethionine  [SAM (methyl donor)] to glycocyamine to form creatine and S-adenosylhomocysteine (SAH) mainly in the liver.[7] This process consumes more methyl groups than all other methylation reactions combined and can deplete liver of methyl groups. S-adenosylhomocysteine is subsequently metabolized to homocysteine. Stead LM and co-workers found that homocysteine was significantly increased (cca. 50%) in rats maintained on glycocyamine-supplemented diets, whereas rats maintained on creatine-supplemented diets showed a significantly lower (~25%) plasma homocysteine level.[8] Elevated levels of homocysteine have been associated with a number of disease states like congestive heart failure [9], Alzheimer’s disease and stroke [10], etc. Vigneaud and associates were the first who found that exhaustion of methyl groups may occur when the demand for methyl groups is artificially raised by an excess of methyl acceptors (e.g., glycocyamine). They also reported that the addition of glycocyamine to an otherwise adequate diet resulted in the production of fatty livers (fat accumulation in liver cells) and in the reduction of liver choline (source for methyl groups).[11]

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Glycocyamine Side Effects and Health Risks

Ostojic, Sergej M., et al. [12] administered 2,4 grams of glycocyamine or placebo to 24 healthy volunteers. In a six-week trial, they concluded that exogenous glycocyamine supplementation resulted in a significant increase of fasting serum creatine with an acceptable side-effects profile and low biochemical abnormalities. As previously stated animal studies show increased fat accumulation in liver cells and reduction of liver choline.

Derek Cornelius [3] suggests taking betaine (trimethylglycine) in combination with glycocyamine in order to provide the liver with more methyl groups so that homocysteine would be adequately detoxified as well as making more efficient glycocyamine to creatine conversion. He even came up with “the best” ratio; 4:1 of betaine to glycocyamine.

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(Other common names: Guanidinoacetic acid, GAA)

References

1. Borsook, Henry, and Jacob W. Dubnoff. “The formation of creatine from GAA in the liver.” Journal of Biological Chemistry 132.2 (1940): 559-574.
2. Hespel, Peter, et al. “Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans.” The Journal of physiology 536.2 (2004): 625-633.
3. Derek C. “Straight talk GAA: Let the truth be revealed.” Bodybuilding.com Retrieved 21. Feb 2013
4. Stead, Lori M., et al. “Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate.” American Journal of Physiology-Endocrinology And Metabolism 281.5 (2001): E1095-E1100.
5. Fukada, Shin-ichiro, et al. “Dietary eritadenine suppresses guanidinoacetic acid-induced hyperhomocysteinemia in rats.” The Journal of nutrition 136.11 (2006): 2797-2802.
6. Borsook, Henry, and Jacob W. Dubnoff. “Creatine formation in liver and in kidney.” Journal of Biological Chemistry 134.2 (1940): 635-639.
7. Walker, James B. “Creatine: biosynthesis, regulation, and function.” Adv Enzymol Relat Areas Mol Biol 50 (1979): 177-242.
8. Stead, Lori M., et al. “Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate.” American Journal of Physiology-Endocrinology And Metabolism 281.5 (2001): E1095-E1100.
9. Vizzardi, Enrico, et al. “Homocysteine and heart failure: an overview.” Recent patents on cardiovascular drug discovery 4.1 (2009): 15-21.
10. Morris, Martha Savaria. “Homocysteine and Alzheimer’s disease.” The Lancet Neurology 2.7 (2003): 425-428.
11. Hoagland, Charles L., Helena Gilder, and Robert E. Shank. “The synthesis, storage, and excretion of creatine, creatinine, and glycocyamine in progressive muscular dystrophy and the effects of certain hormones on these processes.” The Journal of Experimental Medicine 81.5 (1945): 423-438.
12. Ostojic, Sergej M., et al. “Creatine Metabolism and Safety Profiles after Six-Week Oral Guanidinoacetic Acid Administration in Healthy Humans.” International journal of medical sciences 10.2 (2013): 141.