Guanidinoacetic acid: Benefits and Risks
By Adin Smith, MS | Posted July 22, 2023
- Estimated reading time 7 minutes
Guanidinoacetic acid
Guanidinoacetic acid (GAA, or glycocyamine) is a natural creatine precursor that supplies energy to skeletal muscle and brain cells. Only small amounts of GAA are found in foods. The kidneys produce most of the GAA your body needs from the amino acids glycine and arginine. However, there is emerging interest in how GAA supplements may provide additional health benefits.
Introduction
Researchers first evaluated GAA supplementation in 1951 in patients with heart failure.[1]BORSOOK H, et al. The biochemical basis of betaine-glycocyamine therapy. Ann West Med Surg. 1951 Oct;5(10):825-9. After a year of treatment, the participants reported feeling more energized and experienced improvements in mental and physical performance. Still, these anecdotal results came from a non-rigorous study. It was decades later when researchers conducted higher-quality trials.
Benefits
Creatine production
Dietary GAA supplementation promotes creatine synthesis for delivery to skeletal muscles and brain cells. For instance, one study compared the effects of a GAA-creatine mixture versus a standalone creatine supplement in healthy young men.[2]Semeredi S, et al. Guanidinoacetic acid with creatine compared with creatine alone for tissue creatine content: A randomized, double-blind superiority trial. Nutrition. 2019 Jan;57:162-166. Upon trial completion, the combination treatment showed higher brain and skeletal muscle creatine levels than those taking creatine alone.
Physical performance
In one six-week study, young men and women received increasing doses of GAA, from 1.2 g, 2.4 g, and 4.8 g per day.[3]Ostojic SM, et al. Six-Week Oral Guanidinoacetic Acid Administration Improves Muscular Performance in Healthy Volunteers. J Investig Med. 2015 Dec;63(8):942-6. The results showed that handgrip strength and bench press endurance increased significantly in participants receiving GAA treatment compared to the placebo group. However, all doses were equally effective, suggesting that 1.2 grams was sufficient.
Another trial evaluated healthy elderly volunteers randomized to consume either a GAA-creatine supplement or a placebo for eight weeks.[4]Seper V, et al. Guanidinoacetate-Creatine Supplementation Improves Functional Performance and Muscle and Brain Bioenergetics in the Elderly. Ann Nutr Metab. 2021;77(4):244-247. Researchers found that the subjects taking the GAA-creatine mixture had significantly higher brain and muscle creatine levels than those ingesting the placebo. The combination treatment also improved walking speed and sit-to-stand ability more effectively than the placebo.
Risks
Elevated homocysteine
A few studies have reported that GAA supplementation may cause high homocysteine levels if not taken with b-vitamins.[5]Ostojic SM, et al. Co-administration of methyl donors along with guanidinoacetic acid reduces the incidence of hyperhomocysteinaemia. Br J Nutr. 2013 Sep 14;110(5):865-70. [6]Ostojic SM, et al. Effect of Creatine and Guanidinoacetate Supplementation on Plasma Homocysteine in Metabolically Healthy Men and Women. Ann Nutr Metab. 2021;77(5):307-308. Too much homocysteine can lead to cardiovascular complications such as blood clots or stroke. Sometimes high homocysteine results from a lack of b-vitamins, as they provide a source of methyl groups. Because methyl groups are required by cells to convert GAA into creatine, taking GAA may deplete these critical methyl molecules and increase homocysteine.
Hyperinsulinemia
Elevated insulin levels, called hyperinsulinemia, are associated with the adverse metabolism changes that commonly occur with health conditions such as obesity and type 2 diabetes.[7]Johnson JD. On the causal relationships between hyperinsulinaemia, insulin resistance, obesity and dysglycaemia in type 2 diabetes. Diabetologia. 2021 Oct;64(10):2138-2146. [8]Kolb H, Kempf K, Röhling M, Martin S. Insulin: too much of a good thing is bad. BMC Med. 2020 Aug 21;18(1):224. Environmental factors contributing to hyperinsulinemia may include air pollution and bisphenol A (BPA) exposure.[9]Thomas DD, et al. Hyperinsulinemia: An Early Indicator of Metabolic Dysfunction. J Endocr Soc. 2019 Jul 24;3(9):1727-1747.
Animal studies have shown that GAA exposure may stimulate insulin release. In one experiment, researchers measured pancreatic insulin secretion in rats injected with GAA, creatine, arginine, and guanidine hydrochloride.[10]Alsever RN, Georg RH, Sussman KE. Stimulation of insulin secretion by guanidinoacetic acid and other guanidine derivatives. Endocrinology. 1970 Feb;86(2):332-6. After analysis, GAA was shown to cause mean insulin levels to rise significantly more than guanidine, arginine, or creatine.
A human cross-sectional trial evaluating healthy adults found that higher serum GAA levels were associated with higher insulin levels.[11]Ostojic SM, et al. Guanidinoacetic Acid and Creatine are Associated with Cardiometabolic Risk Factors in Healthy Men and Women: A Cross-Sectional Study. Nutrients. 2018; 10(1):87. However, these findings come from an association study and cannot prove causation.
In another trial, safety biomarkers were examined among twenty healthy volunteers supplementing with 3 grams daily of GAA for ten weeks.[12]Ostojic SM, et al. Effects of Guanidinoacetic Acid Loading on Biomarkers of Cardiometabolic Risk and Inflammation. Ann Nutr Metab. 2018;72(1):18-20. Researchers found no adverse effects on insulin levels. Whether these findings will be repeatable in a larger population remains to be seen.
Low GABA
The central nervous system (CNS), which consists of the brain and spinal cord, is regulated by signaling molecules called neurotransmitters. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter of the central nervous system. GABA also influences motor control functions within the peripheral nervous system (PNS), such as gastrointestinal motility.[13]Tillakaratne NJ, et al. gamma-Aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol A Physiol. 1995 Oct;112(2):247-63. Other examples of GABA’s functional role in the PNS include regulating hormone release from the pancreas and adrenal glands.[14]Jin Z, Korol SV. GABA signalling in human pancreatic islets. Front Endocrinol (Lausanne). 2023 Feb 20;14:1059110. GABA receptors and transporters also exist in many tissues, such as the prostate gland and urinary bladder, liver, stomach, and blood vessels.
Because GAA is similar in structure to GABA, there is a concern that GAA supplementation may interfere with GABA metabolism. For instance, one human trial evaluated the impact of GAA supplementation on blood plasma GABA levels.[15]Ostojic SM, Stojanovic M. Guanidinoacetic acid loading affects plasma γ-aminobutyric acid in healthy men. Eur J Nutr. 2015 Aug;54(5):855-8. In this small study, eight healthy men consumed three grams of GAA powder or a placebo daily for three weeks. At the end of the study, plasma GABA levels declined significantly in the men taking the GAA supplement. In contrast, GABA concentrations remained unchanged in the placebo group.
Based on in-vitro and animal research, GAA administration may build up in the CNS and bind to the GABA-A receptors, eliciting adverse effects. However, human studies do not show that GAA supplementation leads to unwanted GAA buildup in the brain. For instance, a 2018 trial showed that GAA doses of up to 60 mg/kg (equating to 4,363 mg for a 160-pound adult) did not accumulate in the brain of healthy male participants.[16]Ostojic SM, et al. Dietary guanidinoacetic acid does not accumulate in the brain of healthy men. Eur J Nutr. 2018 Dec;57(8):3003-3005. Furthermore, the researchers measured brain glutamate levels, which remained unchanged throughout the study.
Conclusion
Skeletal muscle and brain creatine levels achieve higher concentrations when GAA and creatine are taken together. GAA-creatine mixtures also exert more favorable effects on physical performance than creatine alone.
Human studies suggest that GAA supplementation carries the risk of elevating homocysteine levels if not taken with b-vitamins. Furthermore, GABA levels may decline after GAA supplementation. Preliminary research also suggests that GAA stimulates insulin release.
The safety profile of GAA needs further investigation, especially concerning its long-term use as a dietary supplement.
References
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