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Chemical compound

Creatine ('/k//r//iː//ə//t//iː//n/ or '/k//r//iː//ə//t//ɪ//n/) is an organic compound with the nominal formula |(H2N)(HN)CN(CH3)CH2CO2H. It exists in various tautomers in solutions (among which are neutral form and various zwitterionic forms). Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate (ATP), primarily in muscle and brain tissue. Recycling is achieved by converting adenosine diphosphate (ADP) back to ATP via donation of phosphate groups. Creatine also acts as a buffer.

Creatine was first identified in 1832 when Michel Eugène Chevreul isolated it from the basified water extract of skeletal muscle. He later named the crystallized precipitate after the Greek word for meat, κρέας (kreas). In 1928, creatine was shown to exist in equilibrium with creatinine. Studies in the 1920s showed that consumption of large amounts of creatine did not result in its excretion. This result pointed to the ability of the body to store creatine, which in turn suggested its use as a dietary supplement. In 1912, Harvard University researchers Otto Folin and Willey Glover Denis found evidence that ingesting creatine can dramatically boost the creatine content of the muscle. In the late 1920s, after finding that the intramuscular stores of creatine can be increased by ingesting creatine in larger than normal amounts, scientists discovered phosphocreatine (creatine phosphate), and determined that creatine is a key player in the metabolism of skeletal muscle. It is naturally formed in vertebrates. The discovery of phosphocreatine was reported in 1927. While creatine's influence on physical performance has been well documented since the early twentieth century, it came into public view following the 1992 Olympics in Barcelona. An August 7, 1992 article in The Times reported that Linford Christie, the gold medal winner at 100 meters, had used creatine before the Olympics (however, it should also be mentioned that Linford Christie was found guilty of doping later in his career.). An article in Bodybuilding Monthly named Sally Gunnell, who was the gold medalist in the 400 meter hurdles, as another creatine user. In addition, The Times also noted that 100 meter hurdler Colin Jackson began taking creatine before the Olympics. At the time, low potency creatine supplements were available in Britain, but creatine supplements designed for strength enhancement were not commercially available until 1993 when a company called Experimental and Applied Sciences (EAS) introduced the compound to the sports nutrition market under the name Phosphagen. Research performed thereafter demonstrated that the consumption of high glycemic carbohydrates in conjunction with creatine increases creatine muscle stores.

Creatine is a naturally occurring non protein compound and the primary constituent of phosphocreatine, which is used to regenerate ATP within the cell. 95% of the human body's total creatine and phosphocreatine stores are found in skeletal muscle, while the remainder is distributed in the blood, brain, testes, and other tissues. The typical creatine content of skeletal muscle (as both creatine and phosphocreatine) is 120 mmol per kilogram of dry muscle mass, but can reach up to 160 mmol/kg through supplementation. Approximately 1–2% of intramuscular creatine is degraded per day and an individual would need about 1–3 grams of creatine per day to maintain average (unsupplemented) creatine storage. An omnivorous diet provides roughly half of this value, with the remainder synthesized in the liver and kidneys. Creatine is not an essential nutrient. It is an amino acid derivative, naturally produced in the human body from the amino acids glycine and arginine, with an additional requirement for S Adenosyl methionine (a derivative of methionine) to catalyze the transformation of guanidinoacetate to creatine. In the first step of the biosynthesis, the enzyme arginine:glycine amidinotransferase (AGAT, EC:2.1.4.1) mediates the reaction of glycine and arginine to form guanidinoacetate. This product is then methylated by guanidinoacetate N methyltransferase (GAMT, EC:2.1.1.2), using S adenosyl methionine as the methyl donor. Creatine itself can be phosphorylated by creatine kinase to form phosphocreatine, which is used as an energy buffer in skeletal muscles and the brain. A cyclic form of creatine, called creatinine, exists in equilibrium with its tautomer and with creatine.

Creatine is transported through the blood and taken up by tissues with high energy demands, such as the brain and skeletal muscle, through an active transport system. The concentration of ATP in skeletal muscle is usually 2–5 mM, which would result in a muscle contraction of only a few seconds. During times of increased energy demands, the phosphagen (or ATP/PCr) system rapidly resynthesizes ATP from ADP with the use of phosphocreatine (PCr) through a reversible reaction catalysed by the enzyme creatine kinase (CK). The phosphate group is attached to an NH center of the creatine. In skeletal muscle, PCr concentrations may reach 20–35 mM or more. Additionally, in most muscles, the ATP regeneration capacity of CK is very high and is therefore not a limiting factor. Although the cellular concentrations of ATP are small, changes are difficult to detect because ATP is continuously and efficiently replenished from the large pools of PCr and CK. Creatine supplementation appears to increase the number of myonuclei that satellite cells will 'donate' to damaged muscle fibers, which increases the potential for growth of those fibers. This increase in myonuclei probably stems from creatine's ability to increase levels of the myogenic transcription factor MRF4.

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects. Clinically, there are three distinct disorders of creatine metabolism. Deficiencies in the two synthesis enzymes can cause L arginine:glycine amidinotransferase deficiency caused by variants in GATM and guanidinoacetate methyltransferase deficiency, caused by variants in GAMT. Both biosynthetic defects are inherited in an autosomal recessive manner. A third defect, creatine transporter defect, is caused by mutations in SLC6A8 and inherited in a X linked manner. This condition is related to the transport of creatine into the brain.

Some studies suggest that total muscle creatine is significantly lower in vegetarians than non vegetarians. Research shows that supplementation is needed to raise the concentration of creatine in the muscles of lacto ovo vegetarians and vegans up to non vegetarian levels.

An approximation of 0.3 g/kg/day divided into 4 equal spaced intervals has been suggested since creatine needs may vary based on body weight.

Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 gram (5000 mg) oral dose in healthy adults results in a peak plasma creatine level of approximately 120 mg/L at 1–2 hours post ingestion. Creatine has a fairly short elimination half life, averaging just less than 3 hours, so to maintain an elevated plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day.

It has been shown that once supplementation of creatine stops, muscle creatine stores return to baseline in 4–6 weeks. Creatine supplementation for sporting performance enhancement is considered safe for short term use but there is a lack of safety data for long term use, or for use in children and adolescents. A 2018 review article in the Journal of the International Society of Sports Nutrition said that creatine monohydrate might help with energy availability for high intensity exercise. Creatine use can increase maximum power and performance in high intensity anaerobic repetitive work (periods of work and rest) by 5% to 15%. Creatine has no significant effect on aerobic endurance, though it will increase power during short sessions of high intensity aerobic exercise. Creatine is proven to boost the recovery and work capacity of an athlete, and multi applicable capabilities upon athletes have given it a lot of interest over the course of the past decade. A survey of 21,000 college athletes showed that 14% of athletes take creatine supplements to try to improve performance. Compared to normal athletes, those with creatine supplementation have been shown to produce better athletic performance. Non athletes report taking creatine supplements to improve appearance. The greatest effect appears to be in individuals who are stressed (due, for instance, to sleep deprivation) or cognitively impaired. Another 2023 review initially found evidence of improved memory function. However, it was later determined that faulty statistics lead to the statistical significance and after fixing the "double counting", the effect was only significant in older adults. A 2023 systematic review found no evidence that creatine improved cognitive performance. The researches criticized the methodology of previous reviews.

A meta analysis found that creatine treatment increased muscle strength in muscular dystrophies, and potentially improved functional performance. Creatine treatment does not appear to improve muscle strength in people who have metabolic myopathies.

Creatine's impact on mitochondrial function has led to research on its efficacy and safety for slowing Parkinson's disease. As of 2014, the evidence did not provide a reliable foundation for treatment decisions, due to risk of bias, small sample sizes, and the short duration of trials.

Several primary studies have been completed but no systematic review on Huntington's disease has been completed yet.

It is ineffective as a treatment for amyotrophic lateral sclerosis.

A 2021 systemic review of studies found that "the current body of evidence does not indicate that creatine supplementation increases total testosterone, free testosterone, DHT or causes hair loss/baldness".

Long term creatine supplementation has not been proven safe for kidney patients. A 2019 systematic review published by the National Kidney Foundation investigated whether creatine supplementation had adverse effects on renal function. They identified 15 studies from 1997 to 2013 that looked at standard creatine loading and maintenance protocols of 4–20 g/day of creatine versus placebo. They utilized serum creatinine, creatinine clearance, and serum urea levels as a measure of renal damage. While in general creatine supplementation resulted in slightly elevated creatinine levels that remained within normal limits, supplementation did not induce renal damage (P value< 0.001). Special populations included in the 2019 Systematic review included type 2 diabetic patients and post menopausal women, bodybuilders, athletes, and resistance trained populations. The study also discussed 3 case studies where there were reports that creatine affected renal function. In a joint statement between the American College of Sports Medicine, Academy of Nutrition and Dietetics, and Dietitians in Canada on performance enhancing nutrition strategies, creatine was included in their list of ergogenic aids and they do not list renal function as a concern for use. The most recent position stand on creatine from the Journal of International Society of Sports Nutrition states that creatine is safe to take in healthy populations from infants to the elderly to performance athletes. They also state that long term (5 years) use of creatine has been considered safe. It is important to mention that kidneys themselves, for normal physiological function, need phosphocreatine and creatine and indeed kidneys express significant amounts of creatine kinases (BB CK and u mtCK isoenzymes). At the same time, the first of two steps for endogenous creatine synthesis takes place in the kidneys themselves. Patients with kidney disease and those undergoing dialysis treatment generally show significantly lower levels of creatine in their organs, since the pathological kidneys are both hampered in creatine synthesis capability and are in back resorption of creatine from the urine in the distal tubules. In addition, dialysis patients lose creatine due to wash out by the dialysis treatment itself and thus become chronically creatine depleted. This situation is exacerbated by the fact that dialysis patients generally consume less meat and fish, the alimentary sources of creatine. Therefore, to alleviate chronic creatine depletion in these patients and allow organs to replenish their stores of creatine, it was proposed in a 2017 article in Medical Hypotheses to supplement dialysis patients with extra creatine, preferably by intra dialytic administration. Such a supplementation with creatine in dialysis patients is expected to significantly improve the health and quality of the patients by improving muscle strength, coordination of movement, brain function and to alleviate depression and chronic fatigue that are common in these patients.

A 2011 survey of 33 supplements commercially available in Italy found that over 50% of them exceeded the European Food Safety Authority recommendations in at least one contaminant. The most prevalent of these contaminants was creatinine, a breakdown product of creatine also produced by the body. Creatinine was present in higher concentrations than the European Food Safety Authority recommendations in 44% of the samples. About 15% of the samples had detectable levels of dihydro 1,3,5 triazine or a high dicyandiamide concentration. Heavy metals contamination was not found to be a concern, with only minor levels of mercury being detectable. Two studies reviewed in 2007 found no impurities.

A National Institutes of Health study suggests that caffeine interacts with creatine to increase the rate of progression of Parkinson's Disease.

When creatine is mixed with protein and sugar at high temperatures (above 148 °C), the resulting reaction produces carcinogenic heterocyclic amines (HCAs). Such a reaction happens when grilling or pan frying meat. Creatine content (as a percentage of crude protein) can be used as an indicator of meat quality.

Creatine monohydrate is suitable for vegetarians and vegans, as the raw materials used for the production of the supplement have no animal origin.