Creatine supplements
Encyclopedia
Creatine supplements are athletic aids used to increase high-intensity athletic performance. Though researchers have known of the use of creatine
Creatine
Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...

 as an energy source by skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

s 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
Harvard University
Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country...

 researchers Otto Folin
Otto Folin
Otto Knut Olof Folin was a Swedish-born American chemist who is best known for his groundbreaking work at Harvard University on practical micromethods for the determination of the constituents of protein-free blood filtrates and the discovery of creatine phosphate in muscles.-Background:Folin was...

 and Willey Glover Denis
Willey Glover Denis
Dr. Willey Glover Denis was an American biochemist and physiologist. She was noted particularly for her collaborations with Otto Folin studies of the protein metabolism. In addition, she was a pioneer in the field of clinical chemistry and the measurement of protein in biological fluids Dr. Willey...

 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
Phosphocreatine
Phosphocreatine, also known as creatine phosphate or PCr , is a phosphorylated creatine molecule that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle and brain.-Chemistry:...

, and determined that creatine is a key player in the metabolism of skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth 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
1992 Summer Olympics
The 1992 Summer Olympic Games, officially known as the Games of the XXV Olympiad, were an international multi-sport event celebrated in Barcelona, Catalonia, Spain, in 1992. The International Olympic Committee voted in 1986 to separate the Summer and Winter Games, which had been held in the same...

 in Barcelona
Barcelona
Barcelona is the second largest city in Spain after Madrid, and the capital of Catalonia, with a population of 1,621,537 within its administrative limits on a land area of...

. An August 7, 1992 article in The Times
The Times
The Times is a British daily national newspaper, first published in London in 1785 under the title The Daily Universal Register . The Times and its sister paper The Sunday Times are published by Times Newspapers Limited, a subsidiary since 1981 of News International...

reported that Linford Christie
Linford Christie
Linford Cicero Christie OBE is a former sprinter from the United Kingdom. He is the only British man to have won gold medals in the 100 metres at all four major competitions open to British athletes: the Olympic Games, the World Championships, the European Championships and the Commonwealth Games...

, the gold medal winner at 100 meters, had used creatine before the Olympics. An article in Bodybuilding Monthly named Steven Murphy, 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
Colin Jackson
Colin Ray Jackson CBE is a British former sprint and hurdling athlete who specialised in the 110 metres hurdles. Over his career representing Great Britain and Wales he won an Olympic silver medal, became world champion three times, went undefeated at the European Championships for 12 years and...

 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
Experimental and Applied Sciences
EAS is a large distributor of performance based nutritional supplements with approximately 300 staff, annual sales exceeding $300 million dollars and offices/distributors in 54 countries.-History:...

 (EAS) introduced the compound to the sports nutrition market under the name Phosphagen. Research conducted afterward showed that the consumption of high glycemic
Glycemic index
The glycemic index, glycaemic index, or GI is a measure of the effects of carbohydrates on blood sugar levels. Carbohydrates that break down quickly during digestion and release glucose rapidly into the bloodstream have a high GI; carbohydrates that break down more slowly, releasing glucose more...

 carbohydrates in conjunction with creatine increases creatine muscle stores. In 1998, MuscleTech Research and Development
MuscleTech
MuscleTech is a brand of sports nutrition supplements marketed by Iovate Health Sciences Inc.- History :Some products bearing the MuscleTech brand name include Anator P70, Anabolic Halo, Gakic Hardcore, Leukic Hardcore, Vitakic, supplements containing creatine and protein supplements .The brand...

 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
Phosphocreatine
Phosphocreatine, also known as creatine phosphate or PCr , is a phosphorylated creatine molecule that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle and brain.-Chemistry:...

 in the muscles up to 20%. It must be noted 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
Satellite cells
Myosatellite cells or satellite cells are small mononuclear progenitor cells with virtually no cytoplasm found in mature muscle. They are found sandwiched between the basement membrane and sarcolemma of individual muscle fibers, and can be difficult to distinguish from the sub-sarcolemmal nuclei...

, which make muscle hypertrophy
Muscle hypertrophy
Muscle hypertrophy is an increase in the size of muscle cells. It differs from muscle hyperplasia, which is the formation of new muscle cells.-Hypertrophy stimuli:A range of stimuli can increase the volume of muscle cells...

 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
One rep maximum
One rep maximum in weight training is the maximum amount of weight one can lift in a single repetition for a given exercise. One repetition maximum can be used for determining an individual's maximum strength and is the method for determining the winner in events such as powerlifting and...

 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
Doping (sport)
The use of performance-enhancing drugs in sport is commonly referred to by the term "doping", particularly by those organizations that regulate competitions. The use of performance enhancing drugs is mostly done to improve athletic performance. This is why many sports ban the use of performance...

 and is not banned by the majority of sport-governing bodies. However, in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, the NCAA
National Collegiate Athletic Association
The National Collegiate Athletic Association is a semi-voluntary association of 1,281 institutions, conferences, organizations and individuals that organizes the athletic programs of many colleges and universities in the United States...

 recently ruled that colleges could not provide creatine supplements to their players, though the players are still allowed to obtain and use creatine independently.

Creatine ingestion

Creatine is often taken by athletes to help as a supplement for those wishing to gain muscle mass (bodybuilding
Bodybuilding
Bodybuilding is a form of body modification involving intensive muscle hypertrophy. An individual who engages in this activity is referred to as a bodybuilder. In competitive and professional bodybuilding, bodybuilders display their physiques to a panel of judges, who assign points based on their...

). There are a number of forms but the most common are creatine monohydrate (creatine complexed with a molecule of water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...

) and creatine ethyl ester
Creatine ethyl ester
Creatine ethyl ester, also known as creatine ester, cre-ester and CEE, is a substance sold as an aid for athletic performance and for muscle development in bodybuilding. It is an ethyl ester derivative of creatine, from which it is made. In the body, CEE is converted back into creatine...

 (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
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

, 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
Glycemic index
The glycemic index, glycaemic index, or GI is a measure of the effects of carbohydrates on blood sugar levels. Carbohydrates that break down quickly during digestion and release glucose rapidly into the bloodstream have a high GI; carbohydrates that break down more slowly, releasing glucose more...

 carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...

s.

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. There are two scientifically proven ways to supplement with creatine. The first is through a loading phase, in which 20 grams is taken for 5–7 days, followed by a maintenance phase of 3-5 grams a day for periods of 2–3 months at a time. The second consists of taking 3-10 grams of creatine per day for a period of 2–3 months with no loading phase. It is generally recommended to take at least 1–2 weeks off from creatine supplementation in order to maintain a proper response mechanism in the body. After the "loading dose" period (1–2 weeks, 12-24 g a day), it is no longer necessary to maintain a consistently high serum level of creatine. As with most supplements, each person has their own genetic "preset" amount of creatine they can hold. The rest is eliminated out of the body as waste. Creatine is consumed by the body fairly quickly, and if one wishes to maintain the high concentration of creatine, Post-loading dose, 2-5 g daily is the standard amount to intake.

Creatine increases the conversion rate from testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...

 to dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...

 in the body. 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 also increased by 36% after 7 days creatine supplementation and remained elevated by 22% after the maintenance dose. This could explain the fact that creatine users tend to report a slight onset of acne after starting creatine supplementation. It could also be a factor when it comes to the increased athletic performance that has been correlated with creatine supplemenation, although dihydrotestosterone has only minor anabolic effects compared to testosterone.

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
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...

. The researchers concluded that creatine ethyl ester is inferior to creatine monohydrate as a source of creatine.

As a supplement, the compound was patented, and licensed through UNeMed
UNeMed
UNeMed Corporation is the technology transfer entity of the University of Nebraska Medical Center. Through licensing and other cooperative agreements, UNeMed builds relationships with industry partners to transfer UNMC intellectual property from the laboratory to the marketplace.-History:Owned by...

, the technology transfer entity of the University of Nebraska Medical Center
University of Nebraska Medical Center
The University of Nebraska Medical Center is a public academic health sciences center located on 42nd and Emile Streets in Midtown Omaha, Nebraska. UNMC is the only public academic health science center in Nebraska.-Academics and rankings:...

.

Creatine hydrochloride

CrHCl 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 CrHCl to be 59 times more soluble in water than creatine monohydrate. Due to its higher solubility, the recommended dosage for CrHCl is much lower than that for creatine monohydrate.

Manufacture

Synthetic creatine is usually made from sarcosine
Sarcosine
Sarcosine, also known as N-methylglycine, is an intermediate and byproduct in glycine synthesis and degradation. Sarcosine is metabolized to glycine by the enzyme sarcosine dehydrogenase, while glycine-N-methyl transferase generates sarcosine from glycine. Sarcosine is a natural amino acid found in...

 (Sarcosine salts) and cyanamide
Cyanamide
Cyanamide is an organic compound with the formula CN2H2. This white solid is widely used in agriculture and the production of pharmaceuticals and other organic compounds. It is also used as an alcohol deterrent drug in Canada, Europe and Japan. The molecule features a nitrile group attached to an...

. Sarcosine is a naturally occurring amino acid like creatine, but manufacturers use a synthetic version. Sarcosine is usually made from chloroacetic acid
Chloroacetic acid
Chloroacetic acid, industrially known as monochloroacetic acid is the organochlorine compound with the formula ClCH2CO2H. This carboxylic acid is a useful building-block in organic synthesis.-Production:...

. Sarcosine is N-methylglycine (H3C-NH-CH2-COOH) which is also an endogenous antagonist of glycine transporter-1. Cyanamide is an amide of cyanogen
Cyanogen
Cyanogen is the chemical compound with the formula 2. It is a colorless, toxic gas with a pungent odor.The molecule is a pseudohalogen. Cyanogen molecules consist of two CN groups — analogous to diatomic halogen molecules, such as Cl2, but far less oxidizing...

, and has white crystalline composition.

The creatine made from sarcosine and cyanamise is made in a glass-lined vat called a reactor. Because of the cost of manufacturing reactors and the need for specialist technicians, most synthetic creatine is made by a few firms, which resell to a number of retailers. The reactor has a big rod-like whisk that shoots into the mix to agitate it. The reactor is filled with water, the sarcosine and cyanamide are put in with catalyst compounds. The reactor is heated and pressurized, causing synthetic creatine crystals to form. The crystalline creatine is then centrifuge
Centrifuge
A centrifuge is a piece of equipment, generally driven by an electric motor , that puts an object in rotation around a fixed axis, applying a force perpendicular to the axis...

d to spin out undesirable by-products like creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...

 and di-cyandiamide and subsequently vacuum dried
Drying
Drying is a mass transfer process consisting of the removal of water or another solvent by evaporation from a solid, semi-solid or liquid. This process is often used as a final production step before selling or packaging products. To be considered "dried", the final product must be solid, in the...

. The dried creatine compound is milled into a fine powder for improved bioabsorption. Milling techniques differ, resulting in final products of varying solubility
Solubility
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...

 and bioabsorbability. For instance, creatine compounds milled to 200 mesh are referred to as micronized.

Safety

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
Cramp
Cramps are unpleasant, often painful sensations caused by muscle contraction or over shortening. Common causes of skeletal muscle cramps include muscle fatigue, low sodium, and low potassium...

 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. Proper hydration will ensure no cramping occurs due to creatine. 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.

Studies have not yet determined if creatine supplementation will accelerate the growth of cysts in humans with Polycystic Kidney Disease
Polycystic kidney disease
Autosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...

. 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
European Food Safety Authority
The European Food Safety Authority is an agency of the European Union that provides independent scientific advice and communication on existing and emerging risks associated with the food chain, created by European Regulation 178/2002....

 (EFSA) published a record, that stated, that oral long-term intake of 3g 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 mental performance

Creatine administration was shown to significantly improve performance in cognitive and memory tests in vegetarian individuals involved in double-blind
Double-blind
A blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....

, 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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