Creatine ( or ) is an organic compound that facilitates recycling of adenosine triphosphate (ATP) in vertebrates, primarily in their muscle and brain tissue. It is a popular dietary supplement.
Its phosphorylated form, phosphocreatine, donates phosphate groups to adenosine diphosphate (ADP), turning it back into ATP. Creatine also acts as a buffer. It has the nominal formula . In solutions, it exists in various tautomers, including a neutral form and zwitterionic forms.
History Creatine was first identified in 1832 when Michel Eugène Chevreul isolated the precipitate from the basified water-extract of skeletal muscle. He later named the crystallized precipitate after the Greek word for meat, (). 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. The discovery of phosphocreatine was reported in 1927.
In the 1960s, the enzyme creatine kinase was shown to phosphorylate ADP using phosphocreatine to generate ATP and thus buffering the ATP/ADP ratio.
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 7 August 1992 article in The Times reported that Linford Christie, the gold medal winner at 100 metres, had used creatine before the Olympics. An article in Bodybuilding Monthly named Sally Gunnell, who was the gold medalist in the 400-metre hurdles, as another creatine user. In addition, The Times also noted that 110 metre 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 the company Experimental and Applied Sciences (EAS) introduced the compound to the sports nutrition market under the name Phosphagen. In 1996, researchers found that carbohydrate consumption augments the effects of creatine supplementation on skeletal muscle creatine accumulation.
Metabolic role 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, so people need about 1-3 grams of creatine a 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.
Biosynthesis Creatine is not an essential nutrient. It is an amino acid derivative, naturally produced in the 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.
Phosphocreatine system 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 has the ability to increase muscle stores of PCr, potentially increasing the muscle's ability to resynthesize ATP from ADP to meet increased energy demands..
Creatine supplementation, when combined with strength training, has been reported in humans to augment training-induced increases in satellite cell content and myonuclei number per muscle fiber, changes that may support increases in muscle fiber size. In a separate study of rehabilitative strength training following immobilization, creatine supplementation was associated with increased muscle MRF4 protein expression; however, whether changes in MRF4 directly mediate myonuclear accretion or hypertrophy remains uncertain.
Genetic deficiencies
Genetic defects in the creatine biosynthetic pathway enzymes lead to various severe neurological defects. Defects in the two synthesis enzymes cause L-arginine:glycine amidinotransferase deficiency and guanidinoacetate methyltransferase deficiency. Both biosynthetic defects are inherited in an autosomal recessive manner. Creatine transporter defect, characterized by insufficient transport of creatine to the brain, is caused by mutations in SLC6A8 and is inherited in an X-linked manner.
Vegans and vegetarians Vegan and vegetarian diets are associated with lower levels of muscle creatine, and athletes on these diets may benefit from creatine supplementation.
Pharmacokinetics Most of the research on creatine so far has focused on its pharmacological properties. There has been less research into the pharmacokinetics of creatine. Studies have not established pharmacokinetic parameters for clinical usage of creatine such as volume of distribution, clearance, bioavailability, mean residence time, absorption rate, and half life. A clear pharmacokinetic profile would need to be established prior to determine optimal clinical dosing.
Dosing
Loading phase
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. It has also been shown that taking a lower dose of 3 grams a day for 28 days can also increase total muscle creatine storage to the same amount as the rapid loading dose of 20 g/day for 6 days. However, a 28-day loading phase does not allow for ergogenic benefits of creatine supplementation to be realized until fully saturated muscle storage.
This elevation in muscle creatine storage has been correlated with ergogenic benefits discussed in the research section. However, higher doses for longer periods of time are being studied to offset creatine synthesis deficiencies and mitigating diseases.
Maintenance phase After the 5–7 day loading phase, muscle creatine stores are fully saturated and supplementation only needs to cover the amount of creatine broken down per day. This maintenance dose was originally reported to be around 2–3 g/day (or 0.03 g/kg/day), however, some studies have suggested 3–5 g/day maintenance dose to maintain saturated muscle creatine.
Absorption
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.
Exercise and sport
Creatine is a widely researched dietary supplement that increases muscle phosphocreatine stores; it thus enhances short bursts of high-intensity exercise and facilitates strength adaptations. It is most effective in monohydrate form using a loading phase followed by a maintenance dosing protocol. (Creatine supplements are marketed in ethyl ester, gluconate, monohydrate, and nitrate forms.) According to a 2018 review article in the Journal of the International Society of Sports Nutrition creatine monohydrate is the most effective nutritional supplement to increase high intensity exercise capacity and muscle mass during training.
Creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5% to 15%. Creatine supplementation exerts positive ergogenic effects on single and multiple bouts of short-duration, high-intensity exercise activities, in addition to potentiating exercise training adaptations. Creatine has no significant effect on aerobic endurance.
Creatine supplementation for sporting performance enhancement is considered safe for short-term and long-term use, but there is a lack of safety data for use in children and in pregnancy.
A 2014 survey of 21,000 US college athletes showed that 14% of athletes take creatine supplements.
Research
Cognitive performance Creatine is sometimes reported to have a beneficial effect on brain function and cognitive processing, although the evidence is difficult to interpret systematically and the appropriate dosing is unknown. The greatest effect appears to be in individuals who are stressed (due, for instance, to sleep deprivation) or cognitively impaired.
A 2018 systematic review found that "generally, there was evidence that short-term memory and intelligence/reasoning may be improved by creatine administration", whereas for other cognitive domains "the results were conflicting".
A 2023 meta-analysis including 8 randomized controlled trials found that creatine supplementation improved memory performance with dosing parameters such as intake amounts and duration having no additional effects. Any positive effects on cognition from creatine supplementation seem to be greater for older adults.
A 2024 systematic review found no significant effect for healthy, unstressed individuals and mixed results for people under stress, suggesting that more research is needed to determine optimal dosing parameters and quantify changes in brain creatine levels during supplementation.
In a 2024 scientific opinion article, the European Food Safety Authority Panel on Nutrition, Novel Foods and Food Allergens determined that a cause and effect relationship cannot be established between creatine supplementation and increased cognitive function based on existing studies. In particular, it ruled that there is currently insufficient evidence on the mechanisms by which creatine can impact cognition.
Depression Creatine may have a small positive effect on depressive symptoms, but the benefit is likely not clinically significant.
Sports injuries