Creatine was first identified in 1832 whenMichel Eugène Chevreul isolated it from the basified water-extract ofskeletal muscle. He later named the crystallized precipitate after theGreek word for meat,κρέας (kreas). In 1928, creatine was shown to exist inequilibrium withcreatinine.[3] 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.[4]
In the 1960s, the enzymecreatine kinase (CK) was shown to phosphorylate ADP using phosphocreatine (PCr) to generate ATP. It follows that ATP - not PCr - is directly consumed in muscle contraction. CK uses creatine to buffer the ATP/ADP ratio.[9]
While creatine's influence on physical performance has been well documented since the early twentieth century, it came into public view following the1992 Olympics inBarcelona. An 7 August 1992 article inThe Times reported thatLinford Christie, the gold medal winner at 100 meters, had used creatine before the Olympics (however, it should also be noted that Christie was found guilty of doping later in his career).[10] An article inBodybuilding Monthly namedSally Gunnell, who was the gold medalist in the 400-meter hurdles, as another creatine user. In addition,The Times also noted that 100 meter hurdlerColin Jackson began taking creatine before the Olympics.[11][12]
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 calledExperimental and Applied Sciences (EAS) introduced the compound to the sports nutrition market under the namePhosphagen.[13] In 1996, researchers found that carbohydrate consumption augments the effects of creatine supplementation on skeletal muscle creatine accumulation.[14]
The cyclic derivative creatinine exists in equilibrium with its tautomer and with creatine.
Creatine is a naturally occurring non-protein compound and the primary constituent of phosphocreatine, which is used to regenerateATP 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 theblood, brain, testes, and other tissues.[15][16] 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.[17] 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.[17][18][19] An omnivorous diet provides roughly half of this value, with the remainder synthesized in the liver and kidneys.[15][16][20]
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 ofATP in skeletal muscle is usually 2–5 mM, which would result in a muscle contraction of only a few seconds.[22] During times of increased energy demands, thephosphagen (or ATP/PCr) system rapidly resynthesizes ATP fromADP with the use ofphosphocreatine (PCr) through a reversible reaction catalysed by the enzymecreatine 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.[22] 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.[23][24][25]
Creatine supplementation, when combined withstrength training, has been reported in humans to augment training-induced increases insatellite cell content andmyonuclei number permuscle fiber, changes that may support increases in muscle fiber size.[26] In a separate study of rehabilitative strength training following immobilization, creatine supplementation was associated with increased muscleMRF4 protein expression; however, whether changes in MRF4 directly mediate myonuclear accretion or hypertrophy remains uncertain.[27]
Vegan and vegetarian diets are associated with lower levels of muscle creatine, and athletes on these diets may benefit from creatine supplementation.[30]
Most of the research to-date on creatine has predominantly focused on the pharmacological properties of creatine, yet there is a lack of 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 optimal clinical dosing.[31]
Approximate muscle total creatine levels in mmol/kg dry weight muscle reported in the literature for vegetarians, individuals following a normal diet, and in response to creatine loading with or without carbohydrate (CHO) or CHO and protein (PRO). Dietary supplementation of creatine serves to increase muscle creatine and PCr by 20–40%.
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.[32][17] 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.[17] However, a 28-day loading phase does not allow forergogenic 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.[33][34][29]
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),[17] however, some studies have suggested 3–5 g/day maintenance dose to maintain saturated muscle creatine.[14][19][35][36]
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.[citation needed]
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.[39][40]
According to a 2018review article in theJournal 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.[41]
Creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5% to 15%.[42][43][44] 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.[45] Creatine has no significant effect on aerobicendurance.[46][obsolete source][47][obsolete source]
A 2014 survey of 21,000 US college athletes showed that 14% of athletes take creatine supplements.[48]
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.[49][50] The greatest effect appears to be in individuals who arestressed (due, for instance, tosleep deprivation) or cognitively impaired.[49][50][51]
A 2018systematic 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".[52]
A 2023meta-analysis including 8randomized controlled trials found that creatine supplementation improvedmemory performance with dosing parameters such as intake amounts and duration having no additional effects.[53] Any positive effects on cognition from creatine supplementation seem to be greater for older adults.[53]
A 2024systematic 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.[54]
A 2024 randomized trial involving 15sleep-deprived subjects found that a single large dose of creatine (0.35 g/kg) may partially restore cognitive performance and resolve aberrant brain metabolism parameters.[55]
In a 2024 scientific opinion article, theEuropean 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.[56] In particular, it ruled that there is currently insufficient evidence on the mechanisms by which creatine can impact cognition.
According to several studies, creatine supplements decrease or at least do not increase the incidence of musculoskeletal injury, muscle cramping, and dehydration. In a study, creatine users had fewer incidences that non-users of muscle pulls/strains, muscle tightness, cramping, heat illness/dehydration, non-contact injuries, and total injuries/missed practices.[57]
A meta-analysis found that creatine treatment increased muscle strength inmuscular dystrophies, and potentially improved functional performance.[58] Creatine treatment does not appear to improve muscle strength in people who havemetabolic myopathies.[58] High doses of creatine lead to increased muscle pain and an impairment inactivities of daily living when taken by people who haveMcArdle disease.[58]
Creatine's impact onmitochondrial function has led to research on its efficacy and safety for slowingParkinson'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.[59]
A 2021 systemic review of studies found that "the current body of evidence does not indicate that creatine supplementation increasestotal testosterone,free testosterone,DHT or causes hair loss/baldness".[64]
A 2011 systematic review evaluated the effectiveness of creatine and creatine analogues in adults with cardiovascular disease, includingheart failure andmyocardial infarction. The studies assessed the use of various creatine-based compounds—such as creatine, creatine phosphate, andphosphocreatinine—administered via oral, intravenous, or intramuscular routes, typically as adjuncts to standard therapy.
The analysis found no conclusive evidence that creatine or its analogues significantly affect mortality, myocardial infarction progression, or ejection fraction. However, some studies suggested a potential improvement in cardiacdysrhythmias anddyspnoea. The trials varied considerably in terms of drug formulation, dosage, treatment duration, and patient populations. Notably, no studies were identified that examined the effects of these compounds in patients with essential hypertension.
Due to the small sample sizes, clinical heterogeneity, and inconsistent outcomes across trials, the authors concluded that more rigorous and larger-scale studies are necessary to establish the clinical utility of creatine analogues in cardiovascular care.[65]
It has been found that women who consumed ≥13 mg of creatine per kg of body mass daily have a lower risk of obstetric conditions. Creatines properties support energy for production, stabilization of maternal plasma creatine, improved pregnancy outcomes, as well as reduced oxidative stress. It was also found to reduce risk of preterm birth, support immune function, and reduce risk of perinatal brain injury. Perinatal brain injury occurs after hypoxia events, creatine allows cells to recover faster.[66]
One well-documented effect of creatine supplementation is weight gain within the first week of the supplement schedule, likely attributable to greater water retention due to the increased muscle creatine concentrations by means ofosmosis.[68]
A 2009 systematic review discredited concerns that creatine supplementation could affect hydration status and heat tolerance and lead to muscle cramping and diarrhea.[69][70]
Despite weight gain due to water retention and potential cramps being two seemingly "common" side effects, new research indicates that these side effects are likely not the result of creatine usage. In addition, the initial water retention is attributed to more short-term creatine use (the "loading" phase). Studies have shown that creatine usage does not necessarily affect total body water relative to muscle mass in the long-term.[71]
A 2019 systematic review published by theNational Kidney Foundation investigated whether creatine supplementation had adverse effects on renal function.[72] 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[73] and post-menopausal women,[74] bodybuilders,[75] athletes,[76] and resistance trained populations.[77][78][79] The study also discussed 3 case studies where there were reports that creatine affected renal function.[80][81][82]
The most recent position stand on creatine from theJournal 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.[32]
A 2011 survey of 33 supplements commercially available in Italy found that over 50% of them exceeded theEuropean Food Safety Authority recommendations in at least one contaminant. The most prevalent of these contaminants wascreatinine, a breakdown product of creatine also produced by the body.[84] Creatinine was present in higher concentrations than theEuropean Food Safety Authority recommendations in 44% of the samples. About 15% of the samples had detectable levels ofdihydro-1,3,5-triazine or a highdicyandiamide 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.[85]
When creatine is mixed with protein and sugar at high temperatures (above 148 °C), the resulting reaction produces carcinogenicheterocyclic amines (HCAs).[86] Such a reaction happens when grilling or pan-frying meat.[87] Creatine content (as a percentage of crude protein) can be used as an indicator of meat quality.[88]
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