Creatine is a naturally occurring compound that plays major roles in the storage and release of cellular energy. It also participates in a wide range of biological processes involved in improving pregnancy outcomes, maintaining bone mineral density and muscle mass in the elderly, improving neurological function, and aiding the immune system to fight cancer. Creatine is perhaps best known for its widespread use as a dietary supplement to enhance physical performance.
Creatine uptake, synthesis, storage, and supplementation
Creatine can be supplied exogenously (from dietary or supplemental sources) and taken up directly into cells by the creatine transporters designated as CreaT1 and CreaT2. Dietary sources of creatine include meat, such as red meat and poultry, as well as fish. Meat contains approximately 4 to 5 grams of creatine per kilogram of the animal's weight while fish contains approximately 4 to 10 grams of creatine per kilogram of the animal's weight. However, creatine converts to creatinine when heated, so estimates of creatine content in commonly eaten foods vary as a function of cooking time. An 8-ounce cut of lean beef or a 4-ounce cut of salmon contains roughly 1.5 to 2.5 grams of creatine before cooking. An 8-ounce serving of 1 percent fat milk contains approximately 0.05 grams of creatine. Fruits and vegetables provide only trace amounts of creatine.  Creatinine is an end product of creatine metabolism and is excreted in the urine.
Creatine can also be synthesized in the liver from the amino acids arginine, glycine, and methionine. Endogenous synthesis of creatine is necessary to replace creatine that spontaneously converts to creatinine in the liver. Roughly half of the daily creatine requirement for a person who regularly eats meat (approximately 1 gram) is synthesized in the liver, while the other half must be obtained from the diet.  Due to the regular excretion of creatine, the need for endogenous creatine synthesis places a burden on methionine and arginine metabolism. In particular, studies demonstrate that creatine synthesis consumes about 40 percent of the body's S-adenosylmethionine, an enzyme that transfers a methyl group from methionine to creatine for synthesis. Creatine synthesis may further burden methionine metabolism in situations of low protein intake such as among the elderly or vegetarians, since methionine is an essential amino acid and must be consumed through the diet.
Although creatine content and excretion rates vary according to differences in muscle mass according to age, gender, daily activity levels, and dietary patterns, the body of a male in the 20 to 39 year age range and weighing approximately 70 kilograms contains about 120 grams of creatine with a turnover rate of about 2 grams of creatine per day. Data indicate that the creatine content of muscles in adult males who adhere to a vegetarian diet is 30 percent lower than those who eat meat, fish, and dairy products, suggesting that vegetarians or vegans may require creatine supplementation to completely replace lost creatine stores. 
Inside the body creatine exists as either free creatine or as creatine phosphate (also known as phosphocreatine), the latter of which contains a phosphate group – a chemical compound made up of one phosphorus and four oxygen atoms. Approximately 40 percent of creatine in the body is stored as free creatine while the remaining 60 percent is stored as creatine phosphate. The creatine/creatine phosphate system serves a critical role in normal muscle energy metabolism by acting as a buffer to the cellular ATP concentrations. In addition, creatine kinase, an enzyme that catalyzes the reversible phosphorylation of creatine by ATP, helps maintain steady ATP levels in the cell, as shown in this reaction:
Creatine kinase, an enzyme that catalyzes the reversible phosphorylation of creatine by ATP, helps maintain steady ATP levels in the cell.
The hydrogen produced in this reaction can serve as a buffer for the pH of exercising muscle. Whereas muscle concentrations of creatine are transporter-dependent, the concentration of creatine phosphate is dependent upon ATP and creatine concentrations. More than 90 percent of creatine is stored in skeletal and cardiac muscle, while the remainder is stored in various organs such as the brain, liver, and kidneys.  
Creatine supplements are typically sold and utilized as creatine monohydrate – which contains one molecule of water per molecule of compound – to increase the solubility and absorption of creatine. Hundreds of studies have shown that creatine monohydrate supplementation elicits no adverse health risks. Research indicates that creatine monohydrate supplementation with a loading phase of 5 grams (or approximately 0.3 grams per kilogram of body weight) of creatine taken approximately four times daily for five to seven days increases creatine stores in muscle tissue by 20 to 40 percent, with continued supplementation of 3 to 5 grams per day required to maintain elevated levels. Although creatine monohydrate is typically used for supplementation, one study suggests that salt forms, specifically creatine hydrochloride, can lead to a 60 percent increase in oral absorption compared to creatine monohydrate. While creatine hydrochloride has the potential to improve creatine supplementation options, more safety and efficacy studies utilizing creatine hydrochloride are needed.
Creatine and methyl metabolism
Methyl groups are chemical structures containing three hydrogen atoms and one carbon atom. Methyl groups are used in multiple processes such as creatine synthesis, protein synthesis, and DNA methylation. DNA methylation creates a biological record of the varied molecular processes that participate in an individual's development, maintenance, and decline. Endogenous creatine synthesis requires the transfer of a methyl group from methionine and, as a result, will generate one molecule of homocysteine after multiple enzymatic reactions. Homocysteine is a branch point molecule that can be used to generate cysteine and glutathione or converted back to methionine. Therefore, exogenous creatine supplementation can free up methyl groups to be used in other processes such as DNA methylation, or it can methylate homocysteine back to methionine. Very limited evidence suggests that people who carry mutations in the MTHFR gene (which impairs homocysteine metabolism) may benefit from creatine supplementation.
Creatine and cellular energy production
Creatine phosphate acts as a cellular energy reserve. Under circumstances of high energy demand such as intense physical activity, the phosphate group is removed from creatine phosphate and is made available to convert ADP into adenosine triphosphate ATP (as described above). The conversion of creatine to creatine phosphate is carried out by an enzyme called creatine kinase. The regeneration of ATP from creatine phosphate can help delay fatigue during short term (a few seconds) of maximal activity because the cell is able to maintain its ATP levels for a longer period of time.
Creatine and physical performance
Since the 1980s, oral creatine supplementation has been routinely used to enhance physical performance. Many studies have shown that muscle creatine uptake improves exercise performance while low levels of creatine phosphate are closely related to muscle fatigue during physical activity.   In particular, evidence suggests that those participating in heavy resistance training while supplementing with 20 to 30 grams of creatine per day can maintain higher intensity training, increase fat-free mass, and increase endurance strength.    Furthermore, creatine supplementation promotes muscle recovery after exercise training.  
Creatine and age-related muscle loss
The degenerative loss of skeletal muscle mass, bone density, and strength are commonly associated with aging. While resistance training alone has been shown to improve musculoskeletal health during aging, the combination of creatine supplementation and exercise has been shown to lead to greater physiological benefits, specifically in the elderly. A meta-analysis – a type of statistical analysis that combines the results of multiple scientific studies – found that resistance training along with creatine supplementation can improve lower and upper body strength, increase fat-free mass, increase muscular endurance, and increase bone mineral density. These studies suggest that creatine supplementation in combination with resistance training can slow age-related muscular decline compared to resistance training alone.
Creatine and metabolic regulation
Creatine supplementation has also been tested as a potential agent to lower blood lipids and enhance glycemic control. In adults between the ages of 32 and 70 years old who had total blood cholesterol levels exceeding 200 milligrams per deciliter and who supplemented with 5 grams of creatine plus 1 gram of glucose for 56 days saw a 6 percent reduction in total blood cholesterol. Furthermore, those who supplemented experienced a 23 percent reduction in triacylglycerides and a 22 percent reduction in very-low-density lipoprotein (VLDL) – the lipoproteins that can be converted into the atherosclerotic low-density lipoproteins – compared to baseline.
In people diagnosed with type 2 diabetes, 5 grams of creatine supplementation per day for 12 weeks in conjunction with exercise training resulted in reduced HbA1c – a measure of long-term blood glucose control – and reduced blood glucose concentrations during a glucose tolerance test, compared to people who took a placebo in conjunction with exercise training.  Creatine supplementation may also improve metabolic parameters in healthy people. Specifically, in healthy collegiate athletes who supplemented daily for four weeks with 15.75 grams of creatine mixed with glucose, taurine, and an electrolyte supplement experienced a 13 percent increase in high-density lipoproteins (HDL) – proteins that deliver cholesterol back to the liver – and a 13 percent decrease in VLDL.
Although studies suggest a role for creatine as a potential lipid-lowering agent, a separate study in healthy resistance-trained men found no effect of creatine supplementation on blood lipids. In one study, 19 healthy men who consumed 25 grams of creatine per day for one week and 5 grams of creatine for the following 11 weeks while performing heavy resistance training three to four times per week saw no change in serum total cholesterol, HDL, LDL, or triglycerides. These contradictory results may be due to the different health status of the individuals across studies or the dose and duration of creatine taken. While more studies are needed, creatine may be a promising supplement to help improve blood lipid levels as well as improve glycemic control in people who have type 2 diabetes or high cholesterol levels.
Creatine and pregnancy
During pregnancy in humans, creatine is transferred from the maternal circulation to the placenta and eventually to the fetus. The expression of creatine kinase in the placenta is significantly increased during the third trimester and is ten times higher in newborns compared to adults, suggesting that during pregnancy there may be a greater need for creatine cycling. 
Numerous animal studies have demonstrated that creatine during pregnancy can promote neural development and reduce complications resulting from birth asphyxia – a condition arising when the body is deprived of oxygen, which can cause unconsciousness or death.    A study of human preterm infants (babies born alive before 37 weeks' gestation) demonstrated that breastfed infants had higher creatine levels in the cerebellum, a brain region that supports high-order cognitive functions, compared to infants that were formula-fed. Furthermore, the percentage of days infants were fed breast milk was associated with significantly greater levels of creatine.
These data suggest that creatine may be beneficial in preventing poor pregnancy outcomes. However, in the absence of data from randomized controlled trials during pregnancy in humans, increased dietary intake of creatine sources may be more prudent than supplementation.
Creatine and neuroprotection
Numerous studies have also implicated creatine in brain development, function, and aging. Specifically, creatine has been shown to increase cognitive performance and aid in the treatment of brain-related disorders such as Huntington's disease and Parkinson's disease. Furthermore, impairments in creatine metabolism have been implicated in the progression of depressive and anxiety disorders. Many studies along with ongoing research are uncovering creatine's mechanisms of action in the brain and its potential use for the treatment of neurological disorders.
Creatine and cognitive performance
Some studies have shown the potential of creatine supplementation as a way to improve cognitive function in young and elderly adults and vegetarians. In one study, young adults (average age, 25 years) who supplemented with 8 grams of creatine per day for five days saw a reduction in mental fatigue when asked to continually complete a unique serial calculation compared to the subjects who took a placebo. In young vegetarian adults between the ages of 19 and 37 years old, 5 grams of creatine taken for six days significantly improved their results on the Raven’s Advanced Progressive Matrices cognitive test. Furthermore, subjects around the age of 21 who were sleep-deprived for 36 hours and supplemented with 5 grams of creatine four times a day for seven days saw an improvement in a random number generation cognitive task compared to the placebo group.
Although the studies referenced here along with others have shown an enhancement in cognitive function with creatine supplementation,   others have found that creatine supplementation in healthy individuals has no effect on cognitive function.   Potential reasons for the contradictory results may be due to the different parameters in which cognitive function is measured as well as the dose of creatine supplementation. Creatine supplementation has been shown to increase brain creatine levels as much as 10 percent. However, the optimal dose needed to increase brain creatine levels has not been established. While more studies are needed to determine in which circumstances creatine supplementation can increase brain creatine levels, some researchers believe that creatine is most likely to exert an influence in situations whereby cognitive processes may be stressed, such as in those who follow restrictive non-meat diets, the elderly, or those who are sleep-deprived.
Creatine and depression
The etiology of depression remains unknown but is widely believed to be multifactorial, stemming from a confluence of psychological, physiological, and environmental elements. Multiple hypotheses have been developed to explain the molecular basis of depression, one of which implicates impairments in brain energy utilization. Therefore, compounds that can enhance brain energy storage such as creatine may be a promising supplement for the treatment of depression. With some exceptions, most of the clinical trials demonstrating the efficacy of creatine supplementation on ameliorating the symptoms of depression have supplemented with 4 to 10 grams of creatine per day for up to eight weeks. For example, a small study involving five female adolescents who had been on fluoxetine (Prozac) for more than eight weeks but still showed signs of depression demonstrated that a daily adjunctive dose of 4 grams of creatine for eight weeks reduced depressive symptoms by 56 percent. A larger, 8-week double-blind placebo-controlled clinical trial in which 52 participants took either 5 grams per day of creatine or a placebo as an adjunct to escitalopram (an antidepressant drug) demonstrated that the dual therapy with creatine reduced depressive symptoms by 79 percent as early as the second week of treatment. However, a dose-finding trial involving 18 women who were unresponsive to three weeks of antidepressant therapy demonstrated that creatine doses of 5 or 10 grams per day as an adjunct to their drug therapy had no effect on depressive symptoms.
Creatine and neurodegenerative disease
Neurodegenerative disease is an umbrella term used to describe diseases that cause the loss of structure and function of neurons that can affect memory, speech, and movement. Creatine supplementation has been shown to have neuroprotective effects in animal models of some neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, or ALS.  Unfortunately, the neuroprotective effect of creatine found in animals has not fully translated to human trials. While creatine supplementation has been shown to be safe and well-tolerated, there has been little to no therapeutic effect on patients with either Huntington's disease, Parkinson's disease, or ALS.   However, a few studies have suggested that creatine supplementation may be best as a preventive agent rather than a therapeutic, or it may have additive effects when used in combination with other drugs. 
Creatine as a therapy for traumatic brain injury
Traumatic brain injury, or TBI, due to accidents or sports-related head injuries can lead to mild to severe cognitive impairment. Evidence suggests that brain injury may lead to impairments in energy utilization for which creatine may possess some neuroprotective effects. A study in both mice and rats showed that creatine supplementation prior to TBI decreased the number of brain lesions formed by up to 50 percent. A prospective, randomized, pilot study investigated the effects of creatine given immediately after sustaining a TBI. The study involved 39 children and adolescents between the ages of 1 and 18 years who took 0.4 grams of creatine per kilogram of body weight for six months. Treatment was initiated within approximately four hours of injury. A control group received the normal standard of care without creatine. The participants who took creatine saw improvements in communication, locomotion, and cognitive function during creatine supplementation compared to those who did not. Furthermore, at six months post-injury, the creatine-treated participants had less dizziness, headaches, and fatigue compared to the controls. These studies indicate that creatine supplementation may be able to offset some of the damaging effects of TBI.
Creatine safety profile
Creatine appears to be safe and well-tolerated by most people and may have beneficial effects on performance as well as in some pathological conditions. The primary side effect is weight gain, which may be due to the increase in muscle mass commonly associated with creatine supplementation or an increase body water content due to the chemical structure of the molecule commonly present in the supplemental form. Although some case reports and anecdotal claims have reported adverse events such as musculoskeletal injuries, dehydration, muscle cramping, gastrointestinal issues, or kidney problems associated with creatine use, well-controlled clinical studies do not substantiate these claims.
Some evidence suggests that creatine supplementation may alter levels of male steroid hormones. For example, a study involving 20 college-aged rugby players found that after a week of creatine loading and two weeks of a maintenance dose, the men's serum testosterone levels did not change. However, their dihydrotestosterone, or DHT, levels increased by 56 percent after the loading phase and remained 40 percent above baseline after the maintenance period. The men's DHT to testosterone ratio increased by 36 percent during loading and was 22 percent higher than baseline during the maintenance phase. Although these findings have not been replicated in any other studies, they have raised concerns in the lay community about androgen-related conditions, such as androgenic alopecia, the most common form of hair loss in men. Whereas some evidence suggests that high levels of DHT are associated with androgenetic alopecia, the role of increased DHT in hair loss has been questioned by others.
Creatine participates in a wide variety of physiological functions. Although creatine is produced in the body, some creatine must be supplied in the diet or via the supplemental form. Creatine supplementation is widely practiced as a means to enhance exercise and sports performance. It is well-tolerated by most healthy people as well as those with pathological conditions. Numerous studies suggest that creatine may play critical roles in slowing bone and muscle decline in the elderly and providing neuroprotective effects.
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