Creatine supplements are athletic aids used to increase high-intensity athletic performance. Researchers have known of the use of creatine as an energy source by skeletal muscles since the beginning of the 20th century. They were popularized as a performance-enhancing supplement in 1992.
History of creatine supplements 
In 1912, Harvard University researchers Otto Folin and Willey Glover Denis found proof 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 creatine phosphate, and determined that creatine is a key player in the metabolism of skeletal muscle. The substance creatine is naturally formed in vertebrates.
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. 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. In 1998, MuscleTech Research and Development launched Cell-Tech, the first creatine-carbohydrate-alpha lipoic acid supplement. Alpha lipoic acid has been demonstrated to enhance muscle phosphocreatine levels and total muscle creatine concentrations. This approach to creatine supplementation was supported by a study performed in 2003.
Creatine and athletic performance 
There is scientific evidence that short term creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5 to 15%. This is mainly bouts of running/cycling sprints and multiple sets of low RM weightlifting. Single effort work shows an increase of 1 to 5%. This refers mainly to single sprints and single lifting of 1-2RM weights. However, some studies show no ergogenic effect at all. Studies in endurance athletes have been less than promising, most likely because these activities are sustained at a given intensity and thus do not allow for significant intra-exercise synthesis of additional creatine phosphate molecules. Ingesting creatine can increase the level of phosphocreatine in the muscles up to 20%. Creatine has no significant effect on aerobic endurance, though it will increase power during short sessions of high-intensity aerobic exercise.
Since body mass gains of about 1 kg can occur in a week's time, many studies suggest that the gain is simply due to greater water retention inside the muscle cells. Other studies, however, have shown that creatine increases the activity of satellite cells, which make muscle hypertrophy possible. 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.
In another study, researchers concluded that changes in substrate oxidation may influence the inhibition of fat mass loss associated with creatine after weight training when they discovered that fat mass did not change significantly with creatine but decreased after the placebo trial in a 12-week study on ten active men. The study also showed that 1-RM bench press and total body mass increased after creatine, but not after placebo. The underlying effect of creatine on body composition has yet to be determined, as another study with a similar timeframe suggests no effect on body composition, but had less overall emphasis on metabolic effects.
Creatine use is not considered doping and is not banned by the majority of sport-governing bodies. However, in the United States, the NCAA recently ruled that colleges could not provide creatine supplements to their players, though the players are still allowed to obtain and use creatine independently.
Endocrine and other effects 
Decrease in myostatin levels 
In a study from 2010 it was found that 8 weeks of resistance training together with creatine supplementation resulted in lower serum myostatin levels compared to 8 weeks of resistance training and placebo as well as to control (no resistance training or supplementation), ~98 ng/ml, ~110 ng/ml and ~120 ng/ml respectively. In a study from 2011 where broiler chickens were fed creatine for 42 days, myostatin levels were significantly decreased compared to control. Myostatin is a protein that has catabolic effects on skeletal muscle to limit the growth of muscle.
Increase in dihydrotestosterone 
A 2009 study showed that after a 7 day loading phase of creatine supplementation, followed by a further 14 days of creatine maintenance supplementation, while testosterone levels in blood serum were unchanged, levels of dihydrotestosterone increased by 56% after the initial 7 days of creatine loading and remained 40% above baseline after 14 days maintenance. The ratio of dihydrotestosterone to testosterone was therefore increased by 36% after the 7 day creatine supplementation and remained elevated by 22% after the maintenance dose.
Increase in testosterone 
One study in 2006 showed a 22% increase, from 20.0 to 24.4 nmol/L, in resting testosterone levels after a 10 week resistance training program in the creatine supplemented group compared to placebo. However, results similar to these have never been seen in other studies measuring endocrine changes.
Increase in muscle insulin-like growth factor-I (IGF-I) 
One study done in 2008 showed that levels of insulin-like growth factor-1 (IGF-I) in muscle increased by 15% with creatine supplementation compared to placebo after 8 weeks of resistance training. In the same study on broiler chickens mentioned above, IGF-I levels increased compared to control after being fed with creatine for 42 days.
Creatine ingestion 
Creatine is often taken by many fitness enthusiasts, athletes of all levels, and bodybuilders all around the world to increase one's performance in anaerobic type activities. There are a number of forms but the most common are creatine monohydrate (creatine complexed with a molecule of water) and creatine ethyl ester (CEE). A number of methods for ingestion exist: as a powder mixed into a drink, or as a capsule or caplet. Once ingested, creatine is highly bioavailable, whether it is ingested as the crystalline monohydrate form, the free form in solution, or even in meat. Creatine salts will become the free form when dissolved in aqueous solution. Conventional wisdom recommends the consumption of creatine with high glycemic index carbohydrates or a combination of 50% protein and 50% carbohydrate mixture for maximal insulin release and creatine retention.
Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 g (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 blood plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day. Creatine is consumed by the body fairly quickly, and if one wishes to maintain the high concentration of creatine, 2-5 g daily is the standard amount to intake.
Creatine ethyl ester 
CEE is a form of commercially available creatine touted to have higher absorption rates and a longer serum half-life than regular creatine monohydrate by several supplement companies. However, no peer-reviewed studies have emerged on creatine ethyl ester which conclusively prove these claims. A study presented at the 4th International Society of Sports Nutrition (ISSN) annual meeting demonstrated that the addition of the ethyl group to creatine actually reduces acid stability and accelerates its breakdown to creatinine. The researchers concluded that creatine ethyl ester is inferior to creatine monohydrate as a source of creatine.
Buffered creatine 
Buffered creatine monohydrate (trademarked as Kre-Alkalyn®) is claimed to enhance the effects of creatine through the promotion of greater creatine retention and training adaptations with fewer side effects at lower doses (1.5 g/d for 28-days vs. 4 x 5 g/d for 7-days). Research performed found no significant difference in muscle creatine content, body composition, or training adaptations between buffered creatine monohydrate and creatine monohydrate. There was also no evidence that supplementing the diet with a buffered form of creatine resulted in fewer side effects.
Creatine hydrochloride 
Creatine hydrochloride is a hydrochloride salt patented in 2009 and marketed as an athletic and bodybuilding supplement. A study by Vireo Systems (commissioned by supplement manufacturer ProMera Health) found creatine hydrochloride to be 59 times more soluble in water than creatine monohydrate. Due to its higher solubility, the recommended dosage for creatine hydrochloride is much lower than that for creatine monohydrate.
Creatine nitrate 
Creatine Nitrate is a form of creatine where the molecule is bound to a nitrate group. No benefits have been noted except that it may be more water-soluble, and thus easier to ingest.
Synthetic creatine is usually made from sarcosine (or its salts) and cyanamide which are combined in a reactor with catalyst compounds. The reactor is heated and pressurized, causing creatine crystals to form. The crystalline creatine is then purified by centrifuge and vacuum dried. The dried creatine compound is milled into a fine powder for improved bioavailability. Milling techniques differ, resulting in final products of varying solubility and bioavailability. For instance, creatine compounds milled to 200 mesh are referred to as micronized.
Current studies indicate that short-term creatine supplementation in healthy individuals is safe, although those with renal disease should avoid it due to possible risks of renal dysfunction, and before using it healthy users should bear these possible risks in mind. Small-scale, longer-term studies have been done and seem to demonstrate its safety. There have been reports of muscle cramping with the use of creatine, though a study showed no reports of muscle cramping in subjects taking creatine on a 15-item panel of qualitative urine markers. Creatine did not cause any clinically significant changes in serum metabolic markers, muscle and liver enzyme efflux, serum electrolytes, blood lipid profiles, red and white whole blood cell hematology, or quantitative and qualitative urinary markers of renal function.
In addition, experiments have shown that creatine supplementation improved the health and lifespan of mice. Whether these beneficial effects would also apply to humans is still uncertain.
Creatine supplementation may accelerate the growth of cysts in humans with Polycystic Kidney Disease. PKD is prevalent in approximately 1 in 1000 people and may not be detectable until affected individuals reach their thirties.
In 2004 the European Food Safety Authority (EFSA) published a record that stated that oral long-term intake of 3 g pure creatine per day is risk-free. The reports of damage to the kidneys or liver by creatine supplementation have been scientifically refuted.
Creatine and cognitive performance 
Creatine administration was shown to significantly improve performance in cognitive and memory tests in vegetarian individuals involved in double-blind, placebo-controlled cross-over trials. Vegetarian supplementation with creatine seems to be especially beneficial as they appear to have lower average body stores, since meat is a primary source of dietary creatine. This study did not, however, compare the differing effects of creatine on vegetarians and non-vegetarians.
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