Glycocyamine, more commonly known as guanidinoacetate (GAA), is a member of a group of compounds known as guanidino compounds and is the immediate precursor to creatine in the body. It is formed in the body from arginine and glycine by glycine amidinotransferase, mainly in the kidney, and then a portion of the formed GAA is transported to the liver, where it is methylated to creatine by guanidinoacetate methyltransferase (GAMT) [1]. Glycocyamine is included in many creatine products, and it is claimed that it increases endogenous creatine production, thus operating synergistically with creatine. This article will examine whether or not this claim has any basis, and the potential risks and benefits of glycocyamine supplementation.

It is important to note that the limiting factor in the effectiveness of creatine is creatine transport. Muscle tissue cannot synthesize creatine, so it must be transported to muscle cells from circulating blood by the creatine transporter. Past a certain point, increasing the dosage of creatine yields no additional effect because the muscle creatine transporters are saturated. Therefore, any supplement designed to improve the effectiveness of creatine should increase creatine transport. Glycocyamine does the opposite – it is described in the literature as a "potent inhibitor of CRT [the creatine transporter]." For example, in one study it inhibited creatine uptake across the BBB by 69.8%, confirming the results of earlier studies. This is most likely due to the fact that GAA also uses the creatine transporter, and this results in a competitive inhibition of creatine transport. Glycocyamine is transported to muscle tissue in the place of creatine, and the enzymes necessary to convert glycocyamine to creatine are not present in muscle tissue. In other words, creatine alone would be expected to increase muscle creatine levels more than the combination of creatine and glycocyamine. [2]

Few studies have been conducted on the effects of glycocyamine administration. In one study, rats were given diets with either ~.4 g/kg daily of creatine or ~.36 g/kg daily of GAA (these are rough approximations). Muscle creatine levels were increased by 46% is in the creatine group and 39% in the GAA group relative to control, but muscle ATP was only significantly elevated in the creatine group [3]. The similar increase in muscle creatine levels is likely due to a high rate of conversion of ingested GAA to creatine, which is in line with the fact that GAMT is found in abundance in the liver [4]. This makes GAA the equivalent of expensive creatine. It is likely that supplementing with both GAA and creatine together will increase blood creatine levels, but as stated earlier, this is not a limiting step in how much creatine is stored in muscle tissue.

In addition, GAA carries an added risk when compared to creatine. The conversion of GAA to creatine via GAMT requires the presence of S-adenosylmethionine (SAMe), which is the methyl donor in virtually all known biological methylation reactions. The amount of SAMe normally used for endogenous creatine biosynthesis is greater than the amount used for all other methylation reactions combined. When this reaction takes place, homocysteine is produced as one of the end products. Increased blood concentrations of homocysteine have been associated with an increased risk for developing vascular disease. Rats on a GAA supplemented diet have blood homocysteine concentrations 49% higher than control levels. On the other hand, creatine supplementation was associated with a 27% decrease in homocysteine. This is because creatine supplementation downregulates GAA biosynthesis, thus decreasing methylation demand. Although there may be ways of reducing this negative effect (such as inclusion of betaine), it seems much more practical to just supplement with creatine. [3]

If glycocyamine does get past the liver intact, the effects will probably not be desirable. The fact that it competitively inhibits creatine transport is not the only reason. Glycocyamine is also transported across the blood brain barrier (BBB). This may be associated with a variety of negative effects, and the most well-known property of GAA in the brain is as a convulsant [1, 5-7]. GAA increases the production of reactive oxygen species (ROS) in the brain [1]. Other mechanisms of neurotoxicity include inhibition of Na+,K+-ATPase, decreased membrane fluidity, and interaction with the GABA-A receptor [8-9]. It is unknown whether these effects are relevant at doses used for supplementation, but it seems unlikely. They primarily become a problem in GAMT deficiency, which results in both elevated brain GAA and creatine deficiency. Still, those with a history of epilepsy should definitely stay away from glycocyamine.

Not all of the effects of glycocyamine supplementation are necessarily negative. It has been investigated as an antidiabetic, and improves glucose disposal in a mouse model of diabetes [10]. However, given the bulk of the information, creatine alone still seems to be the best choice. Still, those that regularly use cell volumizing supplements can rest easy, as the inclusion of glycocyamine in many formulas probably does not cause any significant decrease in effectiveness or safety, since most or all of it is converted to creatine in the liver.

If you have any questions or comments regarding this article, please email dvdtlsn@bulknutrition.com.


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