Creatine

Looking to buy Creatine? Buy from Amazon.com

According to the International Society of Sports Nutrition, creatine (monohydrate) is the most effective ergogenic (performance-enhancing) nutritional supplement currently available to athletes for increasing high-intensity exercise capacity and lean body mass during training.^[1] A variety of forms are available and are discussed in the complete summary, but have not been shown to exert significant benefits over basic monohydrate supplementation.

Creatine's main action in the body is to store high-energy phosphate groups in the form of phosphocreatine. During periods of stress, phosphocreatine releases this energy to aid cellular function. This mechanism of action is what causes creatine to increase strength, but can benefit almost every body system, including the brain, bones, muscles, and liver. Most benefits of creatine occur through this energy mechanism.

Creatine is produced naturally in the body, and it is also found in foods (mostly meats, eggs, and fish; some in dairy).

Creatine has been shown to increase DHT (dihydrotestosterone) levels by 40% with a dosage of 5g per day. DHT is directly involved in hair loss in men, so long-term creatine usage could accelerate hair loss.

Creatine supplementation at normal dosages and with adequate hydration has been shown to have no harmful effects in any population tested (see its safety profile). The only observed side effects are stomach cramping if consumed with insufficient water, and diarrhea if too much is consumed at once. Controlled usage of creatine with adequate water may actually reduce cramping over the long term.

Looking to buy Creatine? Buy from Amazon.com

Follow this Page for updates

Most studies use a "loading protocol" of 0.3g/kg bodyweight for 5-7 days followed by 5g of creatine monohydrate afterwards. For a 200lb individual, this translates to 27g a day for 5-7 days, followed by a period of time with 5g a day. Loading is used for quicker saturation of cells with creatine, and it should be noted that 5g is simply what is used traditionally and in studies, whereas 2g daily may suffice to maintain average stores.

Saturation can also be achieved at a slower rate with a constant dose of 3-10g creatine monohydrate for an extended period of time.

Most benefits associated with creatine supplementation come secondary to the state of saturation, so you can feel free to use a loading protocol or a constant maintenance dose to just "keep the tank full."

Creatine is not a highly water-soluble compound in general, so buying powders may be slightly unappetizing. Using warm water can increase the rate of dissolving, and buying micronized creatine can aid in dissolving the powder; micronization is a process that reduces the particle size of creatine powders without affecting the molecular structure, which increases the rate at which the powder dissolves.

I honestly see no reason why somebody shouldn't supplement creatine, nor do I see any logical basis for the seeming 'fear' of this compound in society.

It's safe, it's healthy, it's cheap, and for most people, it just works. Get some Creatine Monohydrate, take 5g a day, and you're good to go.

If humans didn't make any in the body, this thing would be a vitamin. There do exist deficiency symptoms that result in mental retardation.^[2] They're rare, but they pretty much establish the importance of this molecule as a vitamin-like compound.

Kurtis Frank

• What beneficial compounds are primarily found in animal products?
• Is creatine a steroid?
• Can creatine cause cancer?
• Do you need to cycle creatine?
• Does caffeine counteract creatine?
• What happens if I go off of creatine?
• Does creatine cause kidney problems?
• Is creatine safe?
• When should I take creatine?
• Does creatine cause baldness?
• What is the best form of creatine?
• Do I need to load creatine?
• What is Creatine Nitrate?

The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Creatine has in your body, and how strong these effects are.

Level of Evidence	Effect	Change	Magnitude of Effect Size	Scientific Consensus	Comments
A	Weight		Strong	100% See all 18 studies	Appears to have a large effect on increasing overall weight due to water retention in persons who respond to creatine supplementation. Degree of increase is variable.
A	Hydration		Notable	100% See all 9 studies	Appears to be quite notable due to the increase in water weight in skeletal muscle tissue following creatine supplementation.
A	Power Output		Strong	100% See all 43 studies	Creatine is the reference compound for power improvement, with numbers from one meta-analysis to assess potency being "Able to increase a 12% improvement in strength to... show 20% and able to increase a 12% increase in power to 26% following a training regiment using creatine monohydrate". There does appear to be a high degree of variability, which is correlated with the amount of creatine reaching muscle tissue. There does not appear to be much difference between trained and untrained persons. An acute study noted an increase in peak torque by 33.4% and reduction in the time to reach peak torque by 54.7%; perhaps useful as comparator.
A	Lean Mass		Minor	100% See all 14 studies	Does appear to have inherent lean mass building properties, but a large amount of research is confounded with water weight gains (difficult to assess potency).
A	Anaerobic Running Capacity		Minor	57% See all 20 studies	Appears to increase anaerobic cardiovascular capacity, not to a remarkable degree however.
B	VO2 max		Minor	33% See all 4 studies	Improvements in VO2 max are not wholly reliable, and appear to be low in magnitude.
B	Muscle Creatine Content		Strong	100% See all 10 studies	Creatine supplementation is the reference compound for increasing muscular creatine levels; there is variability in this increase, however, with some nonresponders.
B	Kidney function			100% See all 10 studies	Appears to be unable to influence kidney function according to the trials conducted.
B	Subjective Well-being		Minor	50% See all 9 studies	Unreliable and not overly potent.
B	Testosterone		Minor	66% See all 4 studies	Degree of testosterone spike is not overly notable, although it appears to be present
B	Cognition (Omnivores)			40% See all 5 studies	No inherent benefit to omnivore cognition appears apparent, but it may benefit cognition in the sleep deprived.
B	Glycemic control		Minor	100% See all 3 studies	Appears to be somewhat effective in diabetics for improving glycemic control.
B	Fatigue Resistance		Minor	60% See all 6 studies	Small degree of fatigue reduction during exercise, but appears unreliable.
B	Exercise Capacity in COPD			100% See all 4 studies	The cardiovascular system does not appear to have greater exercise capacity following supplementation with creatine in persons with COPD
B	Muscle Damage		Minor	50% See all 4 studies	Not overly protective, but there appears to be a degree of protection.
B	Muscular Endurance		Minor	66% See all 3 studies	Somewhat effective.
B	Blood Pressure			100% See all 3 studies	Does not appear to significantly influence blood pressure.
B	Aerobic exercise			100% See all 4 studies	Does not appear to confer any apparent benefit to prolonged cardiovascular exercise.
C	DNA damage		Minor	100% See study	Appears to reduce exercise-induced DNA damage; practical relevance unknown but potentially promising for cancer prevention.
C	Lipid Peroxidation		Minor	50% See 2 studies	A minor reduction, nothing to a remarkable degree.
C	DNA methylation		Minor	100% See study	Lack of comparator prevents proper assessment of potency; practical relevance unknown
C	Proteinuria			100% See study	No significant influence on protein losses in the urine (proteinuria)
C	Symptoms of Osteoarthritis		Minor	100% See study	Appeared to increase functionality, although not to a remarkable degree.
C	Cognition (Vegetarians)		Minor	100% See 2 studies	Appears to be reliable in increasing cognition in vegetarians, but is based on limited evidence and not yet compared to a reference drug.
C	DHT		Minor	100% See study	An increase in DHT has been noted in one study independent of an increase in testosterone, requires replication
C	Symptoms of Duchenne Muscular Dystrophy		Notable	100% See 2 studies	Preliminary evidence suggests that the improvement in symptoms of Duchenne muscular dystrophy are quite notable, with more evidence required to assess reliability.
C	Total Cholesterol			100% See study
C	Uric Acid		Minor	100% See 2 studies	Minor reductions in uric acid.
C	IGF-1			100% See all 4 studies	Insufficient evidence to support a role of creatine in increasing IGF-1
C	Depression		Notable	100% See all 3 studies	Notable due to seeming to be related to serotonin and augmenting SSRI therapy, and appears to have a gender difference (efficacy in females) which needs to be explored more.
C	Schizophrenia			100% See study	Insufficient evidence to support a role in schizophrenia
C	Treatment of Parkinsons			100% See study	Insufficient evidence to support an improvement in cognitive symptoms of Parkinson's (may aid physical capacities)
C	Body Cell Mass		Minor	100% See study	Limited evidence measuring cell volume, but creatine may increase the cell mass.
C	Exercise Capacity (with Heart Conditions)		Minor	50% See 2 studies	May improve power output, limited evidence suggests little to no benefit for persons in regards to cardiovacular exercise performance (including HIIT)
C	Satellite Cell Recruitment		Minor	100% See study	Unable to assess potency of this change based on comparisons to reference drugs.
C	Myonuclei proliferation		Minor	100% See study	Appears to induce myonuclei proliferation, unknown potency relative to other agents.
C	Functionality in Elderly or Injured		Minor	50% See 2 studies	Possibly an effect, but the less reliable effects of creatine in the older population (which seem to respond less) seems to manifest here.
C	Bone Mineral Density		Minor	100% See study	Limited evidence in favor of improvements in bone mineral density with creatine supplementation
C	Treatment of Huntington's Disease			100% See 2 studies	Insufficient evidence to support a rehabilitative role of creatine.
C	Treatment of Amyotrophic lateral sclerosis (ALS)			100% See study
C	Homocysteine		Minor	100% See study	Decrease in homocysteine (biomarker of inflammatory cardiovascular disease) was present, but not to a remarkable magnitude
C	Glycogen Resynthesis		Notable	100% See study	Degree of improvement is somewhat more potent than other supplemental options, and may be related to the improvements in glycemic control seen with creatine.
C	Myostatin		Notable	100% See study	Notable as it may be a reference compound (17% reduction in circulating Myostatin) although it is uncertain what practical relevance this holds.
D	Alertness		Minor	100% See 2 studies	Increases in alertness tend to be during sleep deprivation or stress, rather than outright increases in alertness. Not overly potent
D	Blood Flow		Minor	100% See study	Lack of comparator prevents assessment of potency.
D	Range of Motion		Minor	100% See study	One study noting a reduction in range of motion with creatine supplementation, needs to be replicated.
D	Skeletal Muscle Atrophy		Minor	100% See study	Appeared to reduce the rate of muscle loss during deloading, practical significance unknown, but suggestive of being an anti-catabolic agent which may be useful during... show fat loss diets.
D	Symptoms of Cystic Fibrosis		Minor	100% See study	Benefit that has been noted is in regards to muscular function, there is no apparent benefit to lung function and power associated with creatine supplementation

Looking to buy Creatine? Buy from Amazon.com or BodyBuilding.com | Life Extension Formula | VitaCost | Puritan's Pride

Edit1. Sources and Structure

1.1. Sources in the Diet

Creatine can be found in meat products, such as:

• Steak or beef with minimal visible connective tissue; about 5g of creatine per 1.1kg of uncooked ^[3] or a range of 2.15-2.5g/lb^[4]

• Chicken at around 3.4g/kg uncooked^[5]

• Rabbit at around 3.4g/kg uncooked^[5]

• Cardiac tissue (ox heart) at around 2.5g/kg^[5]. Pig heart is lower at 1.5g/kg^[4]

Conversely, some meats are poor sources of creatine, including:

• Liver, with negligible amounts^[5] around 0.2g/kg^[4]

• Kidney, at around 0.23g/kg^[4]

• Lung, at around 0.19g/kg^[4]

• Blood, at about 0.04%^[4]

Other compounds that possess creatine levels include:

• Skim milk, with dried skim milk (no water content) having a 0.88% creatine content^[4]

• Breast milk of humans^[6]

According to the NHANES III survey of American adults, the daily (average) consumption of creatine from food sources is about 7.9mmol and 5mmol for men and women, respectively, in the 19-39 year age group.^[7] This is below the "2g consumed via the diet" estimate that many studies reference; specifically, these values correlate to 1.08g and 0.64g of creatine, respectively.

Creatine is found in food products, and by far the best source is skeletal muscle (meat) with some found in dairy. In order to reach about 2g of dietary creatine, one would need to consume about 0.64kg (1.4lbs) of chicken or up to a pound of lean red meats daily; most Americans are not meeting these numbers.

Although consumption of creatine in food reduces the uptake rate due to being associated with chyme, there are no differences in total bioavailability.^[8]

1.2. Food Processing

During cooking, creatine can be degraded to methylamine which can then be incorporated into the toxic substance N-methylacrylamide by binding to acrylic acid and acrylamides (produced from carnosine and aspartic acid cooking).^[9] The intermediates, acrylamides and acrylic acid, are dependent on the cooking temperature and the presence of a reducing sugar, such as glycogen.^[9]

Creatine may also be converted to the biologically inactive creatinine through removal of a water molecule.^[10] Approximately 30% of meat-bound creatine can be lost in exudate or degraded into creatinine when cooking to medium-well.^[11]

Creatine can also participate in the formation of heterocyclic amines. ^[12] Heterocyclic amine formation can be partially inhibited by marination.^[13][14][15]

1.3. Biological Significance

Creatine is an energy intermediate. It exists in cells to donate a phosphate (energy) group to adenosine diphosphate (ADP) molecules to turn them into adenosine triphosphate (ATP). ATP can be seen as the cellular energy "currency," and is the molecule that is synthesized after breakdown of any energy substrate (carbohydrates, fatty acids, ketones) for metabolizable energy.^[16][17] Meanwhile, carbohydrates are able to provide quick energy in an anaerobic environment (high-intensity exercise), and fats are mobilized to provide energy during periods of high oxygen availability at a slower rate (low-intensity exercise or rest). In both cases, available creatine is used to rapidly replenish ATP.^[18][19]

Creatine storage in the body is limited. Over 95% of the body's creatine is stored in muscle at a maximum cellular concentration of 30uM. As such, creatine storage capacity increases with increasing muscle mass,^[20] and if were are to assume a 70kg male with an average physique, whole-body creatine stores are about 120g.^[21] In contrast to creatine, one can accumulate dozens of pounds of body fat, and glycogen is only stored in the liver, brain, and muscles.^[22][23]

Creatine is an energy substrate. Creatine, glucose (carbohydrate), and fatty acids (dietary fat) all serve to replenish ATP, which is the energy "currency" of the cell. Creatine replenishes ATP at a faster rate than either glucose or fatty acids, and is the first line of cellular ATP replenishment; stores are limited, however, and glucose or fatty acids quickly take over energy replenishment. Creatine serves a vital role in the very first stages of energy replenishment, preventing a depletion of ATP.

1.4. Synthesis of Creatine in vivo

Without supplementation, creatine is formed primarily in the liver, with minor contribution from the pancreas and kidneys. The two amino acids glycine and Arginine combine via the enzyme Arginine:Glycine amidinotransferase (AGAT) to form Ornithine and guanidoacetate. This is the first of two steps in creatine synthesis, and although rare, any deficiency of this enzyme can result in mild mental retardation and muscular weakness.^[24] AGAT is also the primary regulatory step, and an excess of dietary creatine can suppress activity of AGAT to reduce creatine synthesis^[25] via reducing AGAT mRNA levels, rather than competitive inhibition.^[26]

Guanidoacetate (made by AGAT) then receives a methyl donation from S-adenylmethionine via the enzyme guanidinoacetate methyltransferase (GAMT) which produces S-adenylhomocysteine and creatine. Deficiencies in GAMT are a bit more severe (although equally rare) relative to AGAT, resulting in severe mental retardation and autism-like symptoms.^[27]

For the most part, the above reactions occur in the liver^[28] (where most systemic creatine is synthesized), but the AGAT and GAMT enzymes have been located in lesser amounts in kidney and pancreatic tissue (the extra-hepatic synthesis locales^[29]); neurons also possess the capability to create their own creatine.^[30]

A binding of two amino acids yields guanidoacetate, and then methylation of this molecule results in creatine; two enzymes mediate this process, ornithine is formed, and S-adenylmethione (a methyl donor) is used up. Any error in synthesis of creatine results in mental retardation.

As mentioned before, S-adenylmethionine must be converted to S-adenylhomocysteine in order for guanidoacetate to convert into creatine during a process known as methylation.^[31] It has been suggested that the production of creatine accounts for up to 40% of the S-adenylmethionine used in the body for methylation processes.^[31][32]

Creatine supplementation alleviates the intrinsic burden of producing creatine. Supplementation reduces the expected increase in homocysteine^[33] after intense exercise and may be a reason why creatine is seen as cardioprotective around the time of exercise.

After supplementation of creatine monohydrate (loading phase, followed by 19 weeks maintenance), creatine precursors are decreased by up to 50% (loading) or 30% (maintenance), which suggests a decrease in endogenous creatine synthesis during supplementation.^[34] This appears to occur through creatine's own positive feedback and suppression of the l-arginine:glycine amidinotransferase enzyme, the rate-limiting step in creatine synthesis, as levels of intermediates before this stage are typically elevated by up to 75%.^[34]

A suppression of creatine synthesis is seen when creatine is supplemented enough to cover all vital needs (approximately 4g daily, 2g of which would have been synthesized). This suppression may be beneficial to health, due to inherent costs associated with creatine synthesis.

1.5. Vegetarian and Veganism

The main storage area of creatine in the human body is the skeletal (contractile) muscle, which holds true for other animals. Therefore, consumption of skeletal muscle (meat products) is the main human dietary source of creatine. Sice vegetarianism and veganism lack the main source of dietary creatine intake, which has been estimated to supply half of the daily requirements of creatine in normal persons, both vegetarians and vegans have been reported to have lower levels of creatine;

^[35][36] this also applies to other meat-exclusive nutrients, such as L-Carnitine.^[35]

Due to this relative deficiency-state in vegetarians and vegans, some aspects of creatine supplementation are seen that are more akin to normalizing a deficiency rather than benefits of supplementation. In young vegetarians, but not omnivores, creatine supplementation can enhance cognition,^[37][38] and the increased gain in lean mass may be more significant in vegetarians relative to omnivores.^[36] Supplementation of creatine in vegetarians appears to normalize the gap in storage between vegetarians and omnivores.^[39] This is possibly related to a correlation seen in survey research where vegetarianism and veganism appear to be more commonly affected by some mental disorders like anxiety and depression.^[40]

The importance of supplemental creatine is elevated in vegetarian and vegan diets due to elimination of the main dietary sources.

1.6. Properties and Structure

Creatine is a peptide compound, made of the two amino acids known as glycine and Arginine that combine to form the backbone known as guanidinoacetate; creatine's skeleton structure is depicted below.

Edit2. Creatine-Kinase System

2.1. Overview

Creatine is stored in the body in the form of creatine and as creatine phosphate, otherwise known as phosphocreatine, which is the creatine molecule bound to a phosphate group.^[41] Creatine phosphate is thought to maintain the ATP/ADP ratio by acting as a phosphorus reservoir.^[42] The more ATP a muscle has relative to ADP, the higher its contractility is, and thus its potential strength output in vivo.^[43][44] Beyond skeletal muscle, this pro-energetic mechanism also affects nearly all body systems. ^[41] During periods of rest and anabolism, creatine can gain a phosphate group through the creatine-kinase enzyme pathway up to a cellular concentration of 30uM^[20] to be later used for quick ATP resupply when needed.^[45][46] Creatine kinase enzymes (of which there are numerous isozymes) exist in both the mitochondria and the cytosol of the cell.^[47][42] The four isozymes of creatine kinase include the Muscle Creatine Kinase (MCK), present in contractile muscle and cardiac muscle, and the Brain Creatine Kinase (BCK), expressed in neuron and glial cells and some other non-muscle cells; these two Creatine Kinases are met with Sarcolemmic Mitochondrial Creatine Kinase (sMitCK), expressed alongside MCK, and the ubiquitous Mitochondrial Creatine Kinase (uMitCK), which is expressed alongside BCK everywhere else.^[21][41]

Supplementation with creatine monohydrate increases stores of both these compounds in myocytes, neurons, eyes, kidneys and testes; of which muscle comprises >95% of bodily creatine stores.^[48][49]

Creatine and creatine phosphate form a couplet in cells that sequesters phosphate groups, which are then donated to ADP to quickly reform it into the main energy molecule known as ATP; this donation is faster than any other process in a cell for replenishing energy, and higher cellular creatine levels result in more phosphate donation and subsequent energy replenishment.

Increasing cellular survival (by preventing ATP depletion, cells survive longer) against hypoxia, oxidative damage, and some toxins against neurons and skeletal muscle cells is a mechanism of creatine supplementation mediated via creatine-kinase.^[41][50][51] This has also been shown to have efficacy against toxin-induced seizures.^[52]

Expressing the creatine-kinase enzyme in cells that do not normally express it (and thus enabling these cells to use creatine) exerts protective effects,^[53] while inhibiting this enzyme reduces survival rates.^[54]

Creatine and phosphocreatine surplus within a cell serves as an energy reservoir that can protect cells under periods of acute stress, and may enhance cell survival secondary to its bioenergetic effects.

The creatine kinase system appears to be subject to sexual dimorphism, where differences exist in males and females, with males having more activity.^[55][56][57]

When looking at race interactions, black persons appear to have higher activity of the creatine kinase system when compared to both white and hispanic persons, with hispanic persons having greater levels than whites.^[55][57] The differences between races are more pronounced in men.^[58]

When splitting a sample into exercisers and non-exercisers, it appears that exercise as a pre-requisite precedes a higher range of activity. Those who are inactive tend to be on the lower end of creatine kinase activity and relatively clustered in magnitude while exercises generally increases activity, but introduces a larger range of possible activity.^[58]

Men appear to have higher active Creatine-Kinase systems, and racial differences favor Blacks over Hispanics over Whites for the activity of the Creatine-Kinase system; which is more variable in men (independent of supplementation). Exercise may increase the activity of the Creatine-Kinase system independent of supplementation

2.2. Creatine Receptor and Non-Response

The Creatine Transporter is a sodium/chloride-dependent transporter; dependent on both sodium^[59][60] and chloride^[61][62] and belongs to the Na+/Cl-dependent family of neurotransmitter transporters.^[63] On the muscle cells and most others,^[64][61] the isomer of the creatine transporter is known as SLC6A8 and due to it being a sodium-dependent transporter it is involved with sodium flux across the membrane.^[65] This isomer is coded by the gene present on Xq28 of the human chromosome and applies to most tissues^[66] which the other gene capable of encoding for the Creatine Transpoter, 16p11.1, creates transporters that are testicle exclusive;^[67] these two transporters share 98% homology.^[66][67]

General information on the receptor and its genetic regulation

This transport appears to be more active in states of creatine deficiency (in the muscle) and more active at levels closer to baseline.^[68] Some creatine transporters may exist in the sarcolemma of the muscle which indicates that they may abide by vesicle transport similar to GLUT4 translocation.^[69][70] The study itself^[71] indicates that 'some internal staining is evident' (when staining creatine transporters).

There are actually two 'bands' of creatine transporter that tend to not be differentiated between in past studies, a 55kDa band and a 70kDa band (73kDa in humans).^[71][72] The 73kDa band appears to be more numerous in humans, with no difference in gender.^[72]

Creatine uptake into cells is wholly regulated by the Creatine Transporter, of which the most common isoform is SLC6A8. The creatine receptor is expressed on the cytoplasmic membrane, but may also be sequestered inside a muscle cell. It is regulated based on creatine status and other factors (to be expanded upon)

Creatine nonresponse affects up to 30% of persons, but this number may be inflated due to being based on a study with a small sample,^[73] and is defined as having less than a 10mmol/L increase in creatine stores after a short loading period. The differentiation of response and nonresponse is a threshold, and people have variable levels of creatine uptake into muscles; more of a spectrum rather than a dichotomy.^[74] However, those classified as non-responders tend to not have power increased in response to creatine supplementation^[75] and are an underlying reason for some studies suggesting no physical improvement by creatine; which do subsequently see significant benefit when controlling for muscle creatine content.^[76] There exists some quasi-responders to creatine (between 10-20mmol/L increase) which get some benefit from creatine supplementation but not to the level of the responders (20mmol increase or more).^[74]

In comparing responders against nonresponders, it is noted that responders have a higher percentage of type II muscle fibers relative to nonresponders; a positive correlation existed between overall muscle mass and weight and being a creatine responder and no differnces existed for dietary protein intake (suggesting it is unrelated).^[74] Those that respond to creatine also tend to be younger, suggesting a mechanism of creatine uptake may be perturbed during aging.^[77]

Creatine non-response is when muscular loading of creatine is under a certain threshold (10mmol/L) with 'response' to creatine having more muscular creatine loading (20mol/L or more) with a grey area between where some benefits are achieved but less than pure responders. Response appears to be positively related to muscle mass and type II muscle fibers

2.3. Positive Regulation of the Creatine Transporter

The CrT is induced (activity increased) by activation of the Mammalian Target of Rapamycin (mTOR), a molecular target of Leucine and HMB.^[78] Activation of mTOR appears to induce activity of SGK1 and SGK3,^[79][80] which then appears to work through PIKfyve^[81] and possibly produced PI(3,5)P₂^[82] to induce the CrT.^[81]

SGK1 activity is increased by intracellular calcium^[83] and ischemia,^[84] two targets that increase during muscle contraction which is known to increase creatine uptake into muscle cells.^[85]

Stress-inducible Kinases (SGK1, SGK3) as well as mTOR, a nutrient sensor that responds to dietary amino acids, both play a role in increasing the activity of the creatine transporter and subsequent creatine uptake into a muscle cell

Growth Hormone (GH) appears to be able to increase the activity of the CrT,^[86] and activating the GH receptor increases production of the protein called Src^[87][88] which appears to phorphorylate the CrT and may be the mechanism by which GH increases receptor activity.^[89] Phosphorylation of the Creatine Receptor by Src appears to be direct, applicable to the 55kDa isomer (with no influence on the rat 70kDa isomer), and requires CD59 in concert.^[90]

Growth Hormone, possibly via Src phorphorylation, appears to increase the activity of the Creatine Receptor

Both Growth Hormone and mTOR appear to positively influence already existent receptors, without influencing the transcription of new CrTs. An orphan nuclear receptor dubbed TIS1 appears to positively influence transcription,^[91] and the influence of TIS1 on the Muscle Creatine Kinase (MCK) promoter in C2C12 myotubes is increased by Forskolin, the active ingredient in Coleus Forskohlii, in a relatively dose dependent manner and was found to enhance activity of the MCK at 20uM 3-fold.^[91][92]

The creatine promoter is positively influenced by TIS1, which may be increased by Forskolin; practical relevance of this nutraceutical combination is unknown

Oddly, starvation (absolute nutrient deprivation for 4 days) is associated with an increase in the activity of the creatine transporter which is secondary to decreased serine phosphorylation.^[93] This increase of creatine influx (+279%) was disconnected from an increase in phosphocreatine (-18.4%) because of the state of nutrient deprivation.^[93] No changes were observed in receptor tyrosine phorphorylation, which is mediated by Src.^[93]

Starvation appears to increase creatine uptake in the cell, but its disconnect from phosphocreatine precludes any ergogenic benefit from starvation

2.4. Negative Regulation of the Creatine Transporter

AMPK appears to reduce the activity of CrT,^[94] which may be through activating TSC2^[95] which can negatively regulate mTOR; an inducer of CrT.^[78] Injection of a cell with AMPK activators reduces the V_max of the CrT by 38+/-2%, with no alerations in receptor affinity for creatine; it appears to be secondary to reduced receptor expression on the cytoplasmic membrane.^[94] The addition of Rapamycin at 50uM (an mTOR antagonist) also inhibits Creatine uptake, but is maxed at 30% with no additive effects with AMPK activators; suggesting a limit to the reduction in CrT that AMPK can induce.^[94] Since creatine appears to be regulated in part by cytosolic factors^[63] and Supraphysiological concentrations of creatine (achieved at around 5g oral intake) itself activates AMPK,^[96] this may form a negative-feedback loop.

AMPK activation, induced by many phytochemicals, appears to negatively influence the Creatine Transporter and may be secondary to suppressing mTOR, which increases uptake; AMPK may also be activated by high Creatine levels and establish negative feedback

Another negative regulator appears to be involved with the CrT, since cytoplasmic regulators cannot account for all regulation^[63] and serum regulation appears to exist.^[60] Protein synthesis inhibitors prevent this downregulation, implicating a serum protein^[60] that has later been thought to be JAK2.^[97] Inhibition of JAK2 fails to alter the affinity of the CrT but increases the rate of the CrT, which validates the hypothesis that it plays a role in CrT regulation from serum, secondary to kinase actions of JAK2.^[97]

JAK2 is a regulatory protein involved in receptor stabilization and is increased under conditions of ischemia, oxidative stress, and hypertonicity^{[98][99][100]} (again implicating negative-feedback from creatine in a muscle cell) and interacts with the Growth Hormone (GH) receptor to induce activity via the JAK2-STAT pathway. Activation of the Growth Hormone receptor also induces Src,^[88][101] which appears to increase uptake of creatine by phorphorylating its receptor (again showing potential for negative feedback).^[89] Increasing Src via the GH receptor does not require JAK2 coactivation,^[87][88] and elimination of JAK2 interaction with the GH receptor does not actually hinder Src production.^[102] It is plausible that JAK2 activation may favorably direct signalling via the GH receptor to the JAK-STAT pathway rather than Src/ERK and indirectly suppress creatine uptake.^[88]

JAK2 (Janus-Activating Kinase 2) may negatively regulate Creatine uptake into cells, which may be tied into negative regulation of GH inducing Src

Cyclosporin A may also reduce activity of CrT.^[103]

Edit3. Mechanisms Independent of Creatine-Kinase

Creatine exerts most of its benefits through acting as an ATP (energy) reservoir in cells, benefits and mechanisms of creatine are not limited to this despite acting as an energy reservoir being Creatine's main role.

3.1. Cytoprotection

Phosphocreatine, the higher energy form of creatine, can associate with and protect cell membranes.^[104] This was first observed in Drosophilia which do not express the creatine kinase enzyme (and cannot use creatine for energy purposes) yet still received cellular protection from creatine^[105] and later when using a research membrane mimicking the mitochondrial membrane (and later cytosolic), it was found that at biologically relevant concentrations of 10-30mM exerting concentration-dependent binding to the membrane; phosphocreatine was more effective than creatine in this regard, although both bound (as well as cyclocreatine and phosphorylated cyclocreatine)^[104] and secondary to the binding the membranes appeared to be stabilized.

Due to the phosphate group, phosphocreatine can bind to cellular membranes. This seems to protect membranes, and exerts protective effects on the cell

Cyclocreatine (an analogue) has been shown to protect microtubules in a cell and protect its structure, but it is not known whether these benefits can be expanded to creatine.^[106]

Edit4. Pharmacology

4.1. Gastrointestinal Tract and Bioavailability

In the stomach, creatine can degrade about 13% due to the digestive hormone pepsin; as assessed by simulated digestion.^[107] Gastric digestion does not result in an increase of creatinine, however; but said increase of creatinine is noted with pancreatic buffer.^[107] There seems to be non-creatinine intermediate(s).

Stomach acid can degrade a small amount of creatinine, which does not appear to be too practically relevant (judging by the multitude of studies noting benefits with oral creatine monohydrate that is subject to the stomach)

The overall bioavailability of creatine is quite good, ranging from 80%^[108] upwards to near 100%^[109] depending on dose ingested (higher acute doses becoming less efficiently absorbed).

The specific mechanism of intestinal uptake of creatine is not clear, although human mRNA for gut transporters and the presence of rat jujenum transporters suggests that humans have them in the jujenum^[110][111] and the observation that creatine can be absorbed against a concentration gradient to a max ratio of 8:1 (8 times more creatine in the intestinal cell post absorption, relative to the lumen) supports transporter-mediated uptake, and the dependence on sodium and chloride implicated SLC6A8 (Creatine Transporter 1) as the mechanism.^[112]

In standard dosages (5-10g creatine monohydrate) the bioavailability of creatine in humans is ~99%^[113][109] although this value is subject to change with different conjugates (forms) of creatine and dosage.^[109] Coingestion of cyclocreatine (an analogue) can reduce uptake by about half^[64] and coincubation of Taurine, Choline, glycine, or Beta-Alanine had minimal attenuation of absorption, likely not practically relevant.^[64] The inhibition noted with cyclocreatine may be due to receptor saturation.

There is also evidence that increased ingestion of creatine leads to an increasing fecal creatine value, suggesting that the intestinal uptake can be saturated.^[48]

Most likely, intestinal uptake is mediated by SLC6A8 or a close variant (a sodium chloride dependent transporter) and doesn't appear to hindered by other common supplements, although too much creatine at one time (greater than 10g) can saturate the receptors and will 'waste' excess creatine

4.2. Serum

After ingestion of 5g creatine in otherwise healthy humans, serum levels of creatine were elevated from fasting levels (0.05-0.1mmol/L) to 0.6-0.8mmol/L within one hour after consumption.^[114] The receptor follows Michaelis-Menten kinetics with a V_max obtained at concentrations higher than 0.3-0.4mmol/L,^[115] with prolonged serum concentrations above this amount exerting most of its saturation within two days.^[116]

2.5 hours after ingestion of a 20g bolus of creatine, serum levels can increase up to 2.17mmol/L.^[117]

Creatine in serum follows a dose-dependent relationship, with more oral creatine ingested causing more serum increases; the rate of accrual into muscle cells may be maximized at a serum concentration achievable with 5g

4.3. Cytology

The creatine molecule is charged which indicates that it cannot passively diffuse through a cell membrane. Instead, creatine relies on the creatine transporter, a sodium-chloride dependent transporter that works against a concentration gradient.^[118] This transporter (dubbed either Creatine Transporter, or SLC6A8^[119]) and its mRNA has been found to be expressed in muscles, eyes, the brain, red blood cells, kidneys, testes, and the gut. Another creatine transporter (regulated by different genes, but overall 97% structurally similar) is found only in the testes of men.^[120][67]

Creatine is taken into cells by the Creatine Transpoter; the more common variant being called SLC6A8

In most situations and for people who respond to creatine, muscle content of creatine tends to be elevated to 15-20% above baseline in response to oral supplementation.^{[121][122][123][124]}

4.4. Brain Tissue

Creatine is vital for proper neural functioning, and true creatine deficiency results in mental retardation.^[2] Deficiency can occur by either hindered synthesis (lack of enzymes to make creatine, can be treated with supplementation) or lack of transport into brain (untreatable with standard creatine).

Entry into neural tissues (in general) is mediated by the secondary Creatine Transporter (CrT-2) known as SLC6A10^[125] with an mRNA sequence of BC012355^[126] and (CrT2) is the same transporter that is active in male testicles.^[67] It belongs to the family of SLC6 transports that acts to move solutes across the membrane by coupling transport with sodium and chloride.^[127][128] Deletion of the gene at 16p11.2 (ie. a genetic flaw), which mediates both SLC6A8^[129] and SLC6A10^[125] production, can result in mental retardation in humans and is one of the causes of 'Creatine Deficiency Syndrome' (although blame cannot be placed on a lack of either transport, as both as well as synthesis important neurally^[130]).^[129] The other cause of retardation being lack of creatine synthesis,^[27] which can be reversed with creatine supplementation and dietary changes.^[131]

In regards to the blood brain barrier (BBB) which is a tightly woven mesh of non-fenestrated microcapillary endothelial cells (MCECs) that prevents passive diffusion of many water-soluble or large compounds into the brain, creatine can be taken into the brain via the SLC6A8 transporter^[132] whereas its precursor (guanidinoacetate, or GAA) only appears to enter this transporter during creatine deficeincy.^[132] More creatine is taken up than creatine is effluxed, and more GAA is effluxed rather than taken up, suggesting creatine utilization in the brain from blood-borne sources^[132] and this is seen as the major source of neural creatine usage.^[133][132] However, 'capable of passage' differs from 'unregulated passage' and creatine appears to have tightly regulated entry into the brain in vivo^[133] and after injection into rats of a large dose of creatine, creatine levels increased and plateaued at 70uM above baseline levels (where baseline levels are about 10mM, this equates to an 0.7% increase when superloaded).^[133] These kinetics may be a reason for relatively lacklustre results of creatine supplementation on neural effects in creatine sufficient populations.

Creatine is vital for functioning of the brain, and has mechanisms to be both taken up as well as highly regulated. Although the diet appears to be the major source of creatine (and thus lack of dietary intake could cause a non-clinical deficiency) excess levels of creatine do not appear to 'super-load' the brain similar to muscle tissue. Due to kinetics, creatine appears to be more 'preventative' or 'restoring a deficiency' in regards to the brain, rather than its effects in muscle cells where it can affect a person drastically and acutely

After the BBB, SLC6A8 is also expressed on neurons and oligodendrocytes,^[132] but it is relatively absent from astrocytes, including the astrocytic feet^[133][134] which line 98% of the BBB.^[135] Creatine can still be transported into astrocytes (as well as cerebellar granule cells) via SLC6A8, as incubation with an SLC6A8 inhibitor prevents accumulation in vitro; just seems to be less active in a whole brain model relative to other brain cells.^[136]

That being said, many brain cells express both AGAT and GAMT; the two enzymes responsible for creatine synthesis. Neural cells have the capacity to synthesize their own creatine^[137][130]

4.5. Elimination and Excretion

Without supplementation, approximately 14.6mmol (2g) of creatinine, creatine's urinary metabolite, are lost on a daily basis in a standard 70kg male aged 20-39, which the value slightly lower in females and the elderly due to less muscle mass;^[31] this amount is seen as necessary to reach in either food or supplemental form to remain sufficient in creatine, and may be increased in persons with higher than normal lean mass.^[31][138] Excretion rates on a daily basis are correlated with muscle mass, and the value of 2g a day is derived from the aforemention male population with about 120g creatine storage capacity.^[31] Specifically, the rate of daily creatine losses is about 1.6%^[139]-1.7%,^[21] and mean losses for women are approximately 80% that of men due to less lean mass^[31] and for weight-matched elderly men (70kg, 70-79 years of age) the rate of loss of 7.8mmol/day^[51] is about half (53%) that of younger men.

Creatine appears to have a 'Daily Requirement' like a vitamin to maintain sufficient levels, at or around 2 grams assuming a 'normal' 70kg male body

Creatine levels in the blood tend to return to baseline (after a loading with or without the maintenance phase) after 28 days (4 weeks) without creatine supplementation.^{[123][140][141]} This number may vary slightly from one individual to another, and for some may exceed 30 days.^[142] Assuming an elimination rate of creatinine (creatine's metabolite) at 14.6mmol per day^[31][141] six weeks of cessation is nearing the upper limit for serum creatine to completely return to baseline.

Despite this decrease to baseline levels, muscle creatine and phosphocreatine levels may still be elevating and give ergogenic effects.^[142]

Creatine can be elevated above baseline after supplementation of more than 2 grams, and depending on the degree of loading it may elevate bodily creatine stores for up to 30 days

Edit5. Interactions with Neurology

Creatine is also a neurological nutrient. Individuals who cannot produce endogenous creatine suffer from from mental retardation^[143]. In surplus, creatine has been shown to partially alleviate the neurological decline associated with aging and is being studied as a treatment for Alzhemier's disease. Vegetarians and vegans who typically have reduced dietary creatine intake also get neurological benefits and anecdotal 'greater feelings of well-being' with creatine supplementation.

Creatine is outright essential for proper cognitive functioning, but a true deficiency is only genetic in nature; dietary deficiencies may expose the body to slightly greater risk on some parameters, and a dietary surplus may attenuate these pathological changes

5.1. Neuroprotection

Creatine, through its ability to act as an energy reserve, attenuates neuron death induced by the MPTP toxin that can produce Parkinson's Disease-like effects in research animals,^[144] reduces glutamate-induced excitotoxicity,^[145] attenuates rotenone-induced toxicity,^[105] L-DOPA induced dyskinesia,^[146] 3-nitropropinoic acid,^[147] and preserves growth rate of neurons during exposure to corticosteroids (like cortisol) which can reduce neuron growth rates.^[148] Interestingly, the energetic effect also applies to Alzheimer's Disease where creatine phosphate per se attenuates pathogenesis in vitro yet creatine per se did not.^[149]

These effects are secondary to Creatine being a source of phosphate groups, and acting as an energy reserve; the longer a cell has energy, the longer it can preserve the integrity of the cell membrane by preserving integrity of Na⁺/K^+-ATPase and Ca^2+-ATPase enzymes.^{[150][144][145]}

A protective effect on neurons by creatine, secondary to its ability to donate phosphate groups, exists; appears to be quite general in its protective effects

When assessing the antioxidant effects of creatine, it does not appear to sequester superoxide and may not be a direct antioxidant.^[150] Additionally, Creatine failed to protect neurons from H₂O₂ incubation to induce cell death via prooxidative means.^[150] These results are in contrast to previously recorded results suggesting creatine as a direct anti-oxidant.^[151]

Some reports exist that Creatine may be a direct anti-oxidant, but these have failed to be replicated; Creatine most likely does not possess anti-oxidant potential

5.2. NMDA-mediated Effects

At 1uM glutamate (low concentrations) the increase in Ca²⁺ was abolished when intraneuronal creatine stores were at 5mM and was attenuated at higher concentrations,^[150] which may underlie the ability of creatine to preserve cellular survival under periods of glutamate-induced excitotoxicity.^{[150][152][153]} This appears to extend to glial cells,^[154] and are additively protective with COX2 inhibitors,^[155] of which a potent nutraceutical COX2 inhibitor is Spirulina.

Conversely, incubation with hippocampal neurons with 10mM creatine (or direct injection of 5mM) was able to increase the activity of the Na⁺/K⁺ ATPase enzyme of the mitochondria which produces ATP.^[156] This action was mediated via the NMDA-Calcineurin pathway, as incubation with an inhibitor of NMDA or its N2BM subunit or inhibitors of Calcineurin reduced the observed effects.^[156]

Although Creatine can reduce the activity of NMDA receptors at or near resting excitation potentials, it is possible that Creatine serves a modulatory role at NMDA receptors.^[157]

Creatine may possess a role as NMDA receptor modulator

In a prolonged study on mice,^[158] it was found that there was a two-fold upregulation of the transport SLC1A6 which mediates glutamate uptake into cells and depleting extracellular levels; this may underlie the reduction of brain glutamate levels by creatine seen in Huntingtons Disease.^[159]

5.3. Depression

Creatine has been sought after for its effects on depressive due to significant changes occurring in brain morphology and neuronal structure associated with depression^[160] and low brain bioenergetic turnover in depression^[161] perhaps related to abnormal mitochondrial functioning, which reduces available energy for the brain.^[162][163] The general association of low or otherwise impaired phosphate energy systems (of which Creatine forms the energetic basis of) with depression, a less round-about way of saying things, has been noted previously.^{[164][161][165]} Due to associations with cellular death and impaired bioenergetics with depression, creatine was subsequently investigated.

Oral ingestion of 1-1000mg/kg bodyweight creatine to mice was able to exert an anti-depressive effect which was blocked by dopamine receptor antagonists, and a low dose of creatine (0.1mg/kg) was able to enhance the dopaminergic effects of dopamine receptor activators, suggesting supplemental creatine can positively influence dopamine signalling and neurotransmission.^[166]

Mechanistically, creatine may exert anti-depressant effects via a mixed dopaminergic (via dopamine) and serotonergic (via serotonin) mechanisms; exact mechanisms are not clear yet

Anti-depressive effects have been noted in humans, where 5g of creatine monohydrate daily for 8 weeks was able to augment the efficay of SSRI anti-depressants, where benefits were seen at week two and maintained until the end of the 8 week trial^[167] and was noted before in a preliminary study in depressed adolescents (with no placebo group) showing a 55% reduction in depressive symptoms at 4g daily when brain phosphocreatine levels increased.^[168] Other human studies suggest lessening the depressive side of bipolar disorder (although a preliminary study)^[169] and one study on Post-Traumatic Stress Disorder (PTSD) noting improved mood as assessed by the Hamilton Depression Rating Scale.^[170]

It is possible that females could benefit more than males due to a combined lower creatine kinase activity as well as having altered purine metabolism during depression,^[171] but no human comparative studies have been conducted yet; one rat study noted that creatine monohydrate at 2-4% of feed had 4% creatine able to exert anti-depressive and anxiolytic effects in female rats only.^[172]

Intervention studies with Creatine supplementation and Depression show promise, but only one well conducted study (used alongside SSRI pharmaceuticals) has been done while other studies have flaws. Promising, but no conclusions can be made yet

5.4. Serotonergic Interactions

One mouse study that compared male and female rats and used a forced swim test (measure of serotonergic activity of anti-depressants^[173]) found that a sexual dimorphism existed, and females exerted a serotonin mediated anti-depressant response while male rats did not.^[172] It appears that these anti-depressive effects are mediated via the 5-HT_1A subset of serotonin receptors, as the antidepressant effects can be abolished by 5-HT_1A inhibitors.^[174]

In females, the combination of SSRIs (to increase serotonin levels in the synapse between neurons) and creatine shows promise in augmenting the anti-depressive effects of SSRI therapy^[175] and another pilot study conducted on depression and females showed efficacy of creatine supplementation.^[168] The one study measuring male subjects noted an increase in mood and minimal anti-depressive effects, but it is not know whether this is due to gender differences or the model studies (Post-Tramautic Stress Disorder).^[170]

There is insufficient evidence to refute the notion that creatine supplementation only exerts anti-depressive effects in females; or put in other terms, the evidence to suggest that creatine is an anti-depressant (via serotonergic mechanisms) appears to be much stronger for women rather than men

In humans, studies that investigate links between serotonin and creatine supplementation find that 21 trained males given creatine at 22.8g creatine monohydrate (20g creatine equivalent) with 35g glucose, relative to a placebo of 160g glucose, was found to reduce the perception of fatigue in hot endurance training possible secondary to serotonergic modulation, specifically attentuating the increase of serotonin seen with exercise (normally seen to hinder exercise capacity in the heat^[176]) while possibly increasing dopaminergic activity (conversely seen to benefit activity in the heat^[177]).^[76]

Conversely, the suppression of serotonin spikes seen in males may enhance physical performance during periods when the body would normally overheat; the notion that this does not work in females cannot be refuted right now

5.5. Heat Tolerance

Beneficial effects on exercise in the heat appear to be independent of whether somebody is a 'responder' or a 'nonresponder' to creatine.^[76]

5.6. Parkinson's Disease and Dopamine

Creatine has been shown before in vitro to protect from MPTP induced toxicity, which targets dopaminergic neurons in the substantial nigra and induce Parkinson's Disease in research animals^[144] and also protected these cells from death induced by low oxygen or glucose.^[178] One study noted that dopaminergic cell survival under the influence of creatine was 1.32-fold higher than control cells, and the soma (cell body) was enlarged by 1.12-fold in these cells,^[178] and creatine showed some growth-enhancing effects as well as reducing destruction of dopaminergic neurons by various insults.^[178]

Additionally, creatine may enhance dopamine synthesis in the striatum of mice (while protecting against dopaminergic depletion)^[175] possibly secondary to increasing tyrosine hydroxylase activity, the rate-limiting step of dopamine biosynthesis.^[179][144]

5.7. Drug Abuse

Due to a combination of its neuroprotective effects and dopaminergic modulatory effects, creatine has been hypothesized in at least one review article to be of benefit to drug rehabilitation.^[180] This study used parallels between drug abuse (usually methamphetamines) and tramautic brain injury^[181][182] and make note of creatine being able to reduce symptoms of brain trauma such as headaches, fatigue, and dizziness in clinical settings in two pilot studies.^[183][184] No studies currently existed looking at creatine supplementation and drug rehabilitation.

5.8. Memory and Learning

Acute administration of creatine (intra-cranial) appears to enhance learning from a previous stimuli vicariously through the NDMA receptor and was enhanced via coincubation of spermidine,^[185] which amplifies NMDA currents.^[186]

In rats, an enhancement of spatial learning appears to be apparent and mediated via the NMDA receptor; a similar mechanism to preliminary studies in D-Aspartic Acid

Studies conducted in vegetarians tend to show cognitive enhancement in youth, possibly due to a creatine deficiency relative to omnivores.^{[187][37][38]} Vegetarian diets have lesser levels of circulating creatine prior to supplementation, but attain similar circulating levels as omnivores when both supplement.^[187][188] Building on this latter point, supplementation of creatine monohydrate in a loading protocol (20g daily in orange juice) in omnivores does not alter levels of creatine in white matter tissue in the brain (test subjects competitive sportsmen).^[189] On most of the parameters that vegetarians experience benefit, omnivores fail to experience statistically significant benefits^[190] except possibly when sleep deprived, where the cognitive improvements rival that seen in vegetarians.^[191] Elderly persons who are omnivorous may also experience increases in cognitive to a similar level (in regards to long-term memory as well as forward number and spatial recall), although this study failed to find any significant benefit on backwards recall or random number generation,^[34] the latter of which is a test for executive working memory.^[192]

Creatine has been demonstrated to increase cognition (memory, learning, and performance) in persons with no dietary creatine intake (vegetarians/vegans); this also appears to extend to a degree to the sleep deprived and elderly persons without any saliant cognitive decline

In a rested state, young omnivores may have an increase in reaction speed.^[37]

One study that did not control for vegetarian or omnivore, but was conducted in young healthy adults, noted that 8g of creatine supplementation daily (spread out in multiple doses) for 5 days was able to reduce fatigue on a mathematical test (Uchida-Kraepelin test), but this was not associated with the observed increase of deoxygenated hemoglobin relative to oxygenated.^[193] The authors hypothesized that the latter was secondary to increased oxygen consumption in the brain, which has been noted in vitro to be correlated with cellular creatine stores.^[194]

Limited potential for creatine to increase cognition in otherwise healthy young omnivores, but it does possess a general pro-cognitive effect

Edit6. Cardiovascular Health

6.1. Cardiac Tissue

Creatine appears to be a cardioprotective agent, as evidenced by overexpression of the Creatine Transporter (allowing more creatine into cardiac muscle cells) exerting protective effects in rats subject to Ischemia/Reperfusion injury, reducing necrosis and increasing post-insult functionality by approximately 30%.^[195]

Edit7. Interactions with Glucose Metabolism

7.1. Mechanisms

Creatine may influence Adenosine Monophosphate Kinase (AMPK); a cytoplasmic protein that acts as a nutrient sensor and, when activated, increases glucose uptake into a cell.^[96] In vitro with L6 Myoblasts (muscle cell line), elevating creatine concentrations to 687% of baseline (46.39-62.36ug protein, achieved with 0.5mM creatine in medium) failed to significantly modify glucose uptake in conjunction with or independent of insulin, yet increased glucose oxidation as measured by CO2 (140% of baseline).^[196] This was claimed to be due to a 2-fold increase in AMPK subunits α1 and α2, and was as potent as 1mM AICAR (which did increase glucose uptake 1.7-fold).^[196] This study was conducted in non-contracting cells, and studies in rats fed creatine without any exercise also fail to note increases in glucose uptake;^{[197][198][199]} this is in contrast to data suggesting that creatine can augment exercise-induced glucose uptake into cells.^[124][200]

The above concentrations, achived via diffusion into the cell with a medium containing 0.5mM, is equivalent to a 5g oral dose.^[114] This dose was subsequently tested in non-vegetarian type II diabetics (n=10) in conjunction with a light exercise regiment, and although the expression of AMPKα was approximately 7-fold the level of placebo it failed to reach statistical significance (P=0.06); a significant inverse relationship was found between HbA1c and AMPKα levels.^[201]

Creatine supplementation appears to enhance glucose oxidation within a muscle cell at physiologically relevant concentrations, and this has been noted in vivo with 5g Creatine Monohydrate

Creatine has the ability to increase glucose uptake into a cell, but this must be accompanied by muscle contraction as well; no glucose uptake is apparent in muscle cells at rest

7.2. Insulin

Creatine has been implicated in causing more insulin secretion when incubated with isolated pancreatic cells,^[202][203] but no increases in insulin secretion have been noted with dietary intakes of 3-5g creatine acutely in humans.^[204][205]

7.3. Interventions

One intervention in non-vegetarian type II diabetics using 5g creatine daily for 12 weeks in conjunction with a twice weekly exercise regimen noted an increase of AMPKα that trended towards statistical significance (P=0.06) but with the magnitude of approximately 7-fold greater expression than control; this insignificant result may have been due to 5 participants per group, an underpowered study.^[201] This study established a significant correlation between AMPKα and increased GLUT4 translocation as well as decreased HbA1c.^[201]

Edit8. Exercise and Performance

8.1. Resistance Exercise

Resistance exercise enhances the rate of creatine uptake into muscle cells in the muscles that are actively engaged. Initially thought to be a byproduct of enhanced blood flow^[3], the enhanced creatine uptake is now thought to be due to allosteric modifications of the creatine transporter which enhance its maximal capacity.^[206]

One study reported elevated creatine uptake in response to supplementation (and independent of exercise) in athletes versus non-athletes, suggesting that long-term modifications in muscle tissue is a by-product of exercise.^[207]

8.2. Anaerobic cardiovascular exercise

Defined as high-intensity cardio such as sprints or wingate tests, creatine supplementation appears to be effective at increasing power output,^{[208][209][210][211][212]} and has been implicated in increasing the lactate threshold as well as time to volitional fatigue within 6 days after stating supplementation (20g daily, divided into 4 doses with 15g glucose).^[213]

Some studies note no significant benefit,^[214][215] although at least one author has suggested this may be due to calcuation errors.^[216] Regardless, there is still some counter evidence that is not subject to said calculation errors that suggest no statistically significant benefit.^[217]

8.3. Aerobic exercise

Creatine supplementation does not appear to influence VO2 max or running economy, even after increases in water weight are accounted for.^[218][219] Increases in VO2 max may occur in patients of chronic heart failure, but the results of the study that noted these benefits were confounded with CoQ10.^[220]

8.4. Power Output

Using information from Meta-Analysis' conducted on creatine and its influence on power and strength,^[221][222] a Meta-Analysis of 16 studies (with or without exercise in all age groups above 16, but placebo controlled and without crossover^[221]) studies that tended to have a 5-7 day loading period with continued maintenance thereafter noted that, in regards to studies assessing 1-3 rep bench press strength in trained young men, that 7 studies (Four of which are online^{[223][224][225][226]}) totalling 70 persons using creatine and 73 persons in placebo resulted in a 6.85kg increase in strength relative to placebo; benefits of which peaked at 8 weeks.^[221] This meta-analysis also quantified a significant increase in squat strength (9.76kg) yet failed to find a significant influence on peak biceps contraction power, which may have been influenced by the two null studies^[227][228] being in elderly persons while the positive study^[229] was statistically outweighed, but noted 1.8-fold larger increases in power associated with creatine over placebo. The other meta-analysis conducted the following year^[222] calculated effect sizes for creatine supplementation and noted no significant differences between gender or when comparing trained against untrained individuals and found the mean effect size of exercises lasting below 30s (those that use the creatine-phosphate system) to have an effect size of 0.24+/-0.02 and performed significantly better than placebo, where exercise increased performance by 4.2+/-0.6% while the addition of creatine enhanced this to 7.5+/-0.7%.^[222]

According to the two meta-analysis' on the topic, Creatine (overall) significantly increases power when supplemented in both sexes over a period of time up to 8 weeks (where improvement over placebo is maintained, rather than being enhanced further). The rate of which power is derived from a resistance training regimen appears to be up to 78.5% greater with creatine relative to placebo, and in active trained men who are naive to creatine this can be quantified at about 7kg for bench and 10kg for squat over 8 weeks

Edit9. Contractile Muscle and Hypertrophy

9.1. Myostatin

One study on 27 otherwise healthy men supplementing creatine (0.3g/kg loading for a week, 0.05g/kg thereafter for 8 weeks) with a thrice weekly exercise regiment noted that alongside greater increase in lean mass and power relative to placebo at 4 and 8 weeks that Myostatin in serum decreased to a greater extent with Creatine (around 17% at 8 weeks; derived from graph) than it did with placebo (approximately 7%).^[230] Increases in GASP-1, a serum protein that inhibits the actions of Myostatin via directly binding to it,^[231] was not different between groups.^[230]

9.2. Muscle Hypertrophy and Size

Creatine supplementation can also increase muscle fiber size independent of protein synthesis, as increasing water content in muscle cells increases their diameter; after 20g ingestion (alongside dextrose at a 1:7.5 ratio) type I, IIa and IIx fibers increased in diameter by 9, 5, and 4% respectively.^[232]

This cellular influx may also decrease protein oxidation rates, which lead to increases in nitrogen balance and indirectly increases muscle mass.^[233] This lowering of protein oxidation is from signalling changes vicariously through cell swelling^[234][235] and appears to upregulate 216 genes^[232] in a range of 1.3 to 5-fold increases, with the largest increase seen in the protein involved in satellite cell recruitment, sphingosine kinase-1. Most importantly for muscle hypertrophy, the protein content of PKBa/Akt1, p38 MAPK, and ERK6 increased 2.8+/-1.2 fold.^[232] 69 genes are also downregulated after creatine supplementation, to less notable degrees.

9.3. Aging and Sarcopenia

Creatine supplementation is being explored as a treatment for sarcopenia, the passive loss of lean mass that occurs with aging.^[236] The effects of creatine on alleviating sarcopenia seem to be more significant when paired with resistance training.^[237] Creatine is also being researched as a method for slowing cachexia and wasting syndromes.^[238]

In a study using lifelong creatine supplementation in SAMP8 mice (a model used to research aging), no significant preventative effect was found on sarcopenia rates at 2% dietary intake^[239]

Edit10. Interactions with Hormones

10.1. Androgens

Creatine has been shown to influence androgen levels. Three weeks of creatine supplementation has been shown to increase dihydrotestosterone (DHT) levels, as well as the DHT:testosterone ratio with no effects on testosterone levels^[240]. Furthermore, creatine supplementation when paired with Beta-Alanine has been shown to increase testosterone levels.^[241] Both of these studies effects were chronic in nature, as low dose creatine supplementation does not acutely increase androgen levels.^[242]. However acute dosing of creatine at higher levels (100mg/kg) has been shown to elicit a moderate increase in testosterone levels.^[243]

Creatine appears to increase DHT and androgen-like effects in the body of men, no studies currently exist in women.

DHT is involved in male pattern baldness (receding hairline in men), although no studies exist in men examining a causal link between creatine and hair growth or loss (see FAQ in regards to this inquiry)

Edit11. Longevity and Life Extension

11.1. Mechanisms

Creatine supplementation may be able to enhance lifespan secondary to increasing intracellular Carnosine stores, Carnosine is the metabolic compound formed from Beta-Alanine supplementation, and in senescence-accelerated (premature aging, SAMP8) animals, Creatine supplementation without any beta-alanine may increase cellular Carnosine storages.^[244] This study used dietary creatine at 2% and noted significantly higher levels of carnosine during middle age, but this was no longer significant during old age. This study also notes that a previously conducted human study using 1 week of 20g creatine monohydrate failed to change carnosine stores in healthy young humans.^[244]

May increase Carnosine stores which could theoretically lead to anti-aging effects, but the lack of effect seen in the eldest cohort of mice and the lack of proof that Carnosine extends overall lifespan limit conclusions on creatine as an anti-aging molecule

Edit12. Inflammation and Immunology

12.1. Mechanisms

In vitro on macrophage cells when measuring the receptors that detect antigens (TLR2, 3, 4, and 7), it was found that both 0.1mM creatine and 0.1mM creatinine (the metabolite of creatine) can rapidly downregulate expression of TLR2 mRNA and receptor content, less reliable but still present suppression of TLR4 and TLR7, while creatine and creatinine had mixed effects on TLR3 dependening on the time of incubation.^[245] This study noted that Creatine Ethyl Ester was immunostimulatory, but practical significance of this is unknown (as creatine ethyl ester does not get absorbed in that form, but rather as creatinine).^[245]

Edit13. Interactions with Cancer

13.1. Formaldehyde Production

Several review studies assessing the safety of Creatine supplementation tend to make note of increases in formaldehyde and possible carcinogenic results due to that.^[246][247] Specifically, creatine is metabolized to an intermediate called methylamine which can be converted to formaldehyde by the SSAO enzyme.^[248]

One intervention in older men noted that creatine at 0.3g/kg (20g for a 150lb person) for 10 weeks failed to influence urinary formaldehyde concentrations,^[249] yet a study conducted in youth with similar doses (21g) for a week noted increases in urinary formaldehyde (+350%) and methylamin (+820%), but failed to note any adverse effects to the kidneys secondary to them.^[250]

There is biological plausiblity that creatine can increase formaldehyde formation, and this has been confirmed in one study using 21g daily but failed to be noted in another using similar doses; there is currently no evidence to draw an association between formaldehyde and harm as a result of creatine supplementation, and the one study noting increased urinary levels failed to note harm to the kidneys

13.2. Mechanisms

Anti-cancer effects have been observed with the creatine analogue cyclocreatine^{[251][252][253]} and have been replicated with creatine itself, and these effects tend to be a reduction in which the rate of implanted tumors progresses.^[254][255] It is suspected that these observed effects (inhibition of growth, or attenuation of the rate of growth) are not due to bioenergetic effect of creatine secondary to Creatine-Kinase, and these anti-cancer effects do not have a known reliability as the expression of Creatine-Kinase varies widely based on the type of tumor.^[256] However, some studies suggest an inverse relationship between tumor progression in mice and concentrations of creatine in cells; creatine depletion coinciding with tumor development.^[256]

The anti-cancer effects of creatine are currently directed towards it being anti-tumor, and being negatively correlated with tumor production (with higher concentrations of creatine being associated with less tumor progression)

In regards to genetic damage, Creatine has been shown in vitro to reduce mitochondrial DNA damage secondary to buffering stores of ATP; ATP depletion preceded genetic damage to mitochondrial DNA.^[257] This reduction of oxidative DNA damage has been noted in vivo following a short loading period in exercising humans.^[258]

It has also been noted that supplementing creatine (which reduces internal synthesis of creatine and methylation requirements) preserved folate and tetrahydrofolate status (42% and 23%)^[259] which acted to preserve methyl groups for other processes. Despite this, global DNA methylation decreases 22% (Assessed by the 5-methylcytosine/cytosine ratio) following creatine supplementation, usually seen as an anti-cancer effect in developed mammals;^[260] this study was unable to demonstrate why this reduction occured,^[260] and opposing effects have been noted in females with Rett syndrome supplementing 200mg/kg creatine for 1 year where global methylation increased secondary to preserving other methyl donors.^[261]

Appears to reduce oxidative damage to DNA, but unclear effects on DNA methylation; practical significance of these mechanisms to cancer prevention is not clear

Creatine supplementation appears to augment the anti-cancer effects of Vitamin C and Methylglyoxal,^[262] a metabolic by-product of glycolysis.^[263] Methylglycoxal appears to inhibit step 1 of the electron transport chain in isolated mitochondria and cancerous mitochondria but has not been implicated in doing so in normal tissue, as protective measures in normal cells appear to exist.^[264][263]

May by synergistic with Methylglycoxal

13.3. Interventions

In rats currently using toxic levels of doxorubicin (a chemotherapeutic agent), creatine supplementation at 0.2g/kg for 30 days appeared to significantly protect rats from death and reduced serum levels of LDH and ALT, the two enzymes were further reduced with the addition of 0.25mg/kg Vitamin C and 400IU/kg Vitamin E.^[265]

In a sample of persons with Colorectal Cancer in which creatine supplementation was given for 8 weeks to assess its interactions with Chemothreapy, creatine failed to benefit muscle function or Quality of Life; benefit was seen in body cell mass and phase angle (indicative of cellular viability), but only in the subsample with less aggressive chemotherapy.^[266]

In children with lymphoblastic leukemia who are currently maintaining corticosteroid chemotherapy, creatine monohydrate at 0.1g/kg is able to significantly attenuate the chemotherapy-induced gain in fat mass over 16 weeks.^[267]

Edit14. Interactions with Organ Systems

14.1. Species differences

Minor liver lesions (grade I, no grade II or III; pathology not indicative of toxicity) have been noted in SOD1 G93A transgenic mice (a research model for amyotrophic lateral sclerosis, but used in this study to assess a state of chronic pro-oxidative stress) for 159 days with 2% of feed intake and in CD-1 rats (seen as normal) over 56 days with 0.025-0.5mg/kg in CD-1 mice, although in Sprague-Dawley rats (also seen as normal) there were no significant differences noted even after 2% of feed intake for 365 days.^[268] These observations were reported to be species-specific in rats,^[269][268] and despite no renal pathology noted in any of these three tested strains a previous report in hypertensive Han:SPRD rats noted renal pathology.^[270] The doses used in this study were within human consumption rages (8g of creatine per 2000kcal mixed diet assuming a 70kg person) but currently no reports exist of hepatoxicity in humans.

There appear to be species-related responses to creatine supplementation in rat livers, where some strains experience non-pathological lesions (minor, but indicative of hepatitis). These do not appear to influence all strains, and have not yet been reported following human consumption despite similar dosages

Edit15. Interactions with Aesthetics

15.1. Skin

Skin degradation and loss of integrity is due to a loss of collagen and degradation of the extracellular matrix^[271] which is enhanced by UV radiation (produces reactive oxygen species which stimulate MMPs^[272]) and contributes to skin integrity loss and wrinkling; due to the stimulation of collagen being associated with a cellular surplus of energy^[273] and intracellular stores of energy declining with age^[274][275] creatine has been investigated as a topical anti-aging agent. In vitro, creatine appears to be rapidly absorbed through the skin (52% within an hour, remaining similar at 3 hours) with most creatine found in the stratum corneum (79.6-86.5%) follwed by the epidermis (9-13.2%) and dermis (4.5-7.1%)^[276] and is successful in stimulating collagen expression and procollagen secretion in fibroblasts, with the latter increasing to 449+/-204% of control.^[276]

The increased cellular storage of creatine may also confer antioxidative effects secondary to enhancing mitochondrial function^[277] and may play a preventative role in addition to rehabilitative.

A study using creatine at 0.02% of a face cream (confounded with 8% glycerol and 0.4% Guarana) was able to exert a skin tightening effect over 6 weeks, reducing wrinkles and jowl volume.^[276] Combination therapy has also been used with creatine and folic acid (both in vitro^[278] and in vivo resulting in increased skin firmness and reduced coarse and fine wrinkles^[279])

Creatine may have a role in topical anti-aging skin products at around 0.02% of the cream, and theoretically can enhance the effects of other agents by providing more energy for a skin cell to use. Creatine may inhernetly have a pro-collagen effect and reduce wrinkle formation and improve skin integrity

Edit16. Nutrient-Nutrient Interactions

16.1. Creatine with Carbohydrates

Insulin secretion seems to have interplay with creatine supplementation, however this is only clinically significant during the first few days of loading when myocyte stores of creatine are depleted.^[280] The effect is mediated through high level of insulin release^[281] and it appears to be independent of the creatine transporter.^[282]

During a creatine loading phase, it is possible for insulin secretion to enhance the rate of uptake into myocytes. When the myocytes are saturated with creatine (seen after 3 days of loading), then this insulin effect seems to disappear.

16.2. Creatine with Caffeine

Co-ingesting creatine with Caffeine appears to partially negate the benefits of creatine supplementation (at 5mg/kg bodyweight) during the loading phase.^[283] The exact mechanism is not known, but might be related to opposing actions on muscle contraction time.^[284]

However, caffeine does not negate the benefits of creatine loading when not coingested, but just taken before exercise in the same dosage.^[285] This result indicates that loading creatine without caffeine on a daily basis, but saving caffeine for select workouts, may be an effective strategy as creatine does not adversely affect Caffeine's ergogenic effects^[285][286] and may enhance creatine's effectiveness in anaerboic exertion if the two compounds are alternated.^[287]

16.3. Creatine with Beta-alanine

The combination of creatine and beta-alanine appears to augment prolonged (4 week) beneficial changes in body composition (more muscle, less fat) relative to creatine alone.^[241]

16.4. Creatine and HMB

Creatine seems to be additive with beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of Leucine in regards to muscle synthesis but not synergystic; although the metabolism of the two are linked.^[288]

16.5. Creatine and Alpha-Lipoic Acid

In a study with Alpha-Lipoic Acid, 1g of ALA paired with 100g sucrose and 20g creatine monohydrate was more effective in increasing muscular creatine levels relative to creatine alone and creatine combined with sucrose.^[289] This apparent augmentation of creatine uptake into muscle cells was used alongside a loading period. Another study investigating a nutrient mixture (150g glucose, 20g creatine, 2g/kg bodyweight glycerol) on heat tolerance in trained athletes found that replacing one third (50g) of the glucose with 1g ALA resulted in no significant differences between groups (in regards to heat tolerance and cardiovascular performance) despite the reduction of 50g carbohydrate.^[290]

A study in swine noted increased water retention (via a PY value) in the group fed both creatine and alpha-lipoic acid^[291] at a dose of 24g and 600mg daily; respectively.

16.6. Cyclooxygenase Inhibitors

COX-2, a pro-inflammatory enzyme, is sometimes a therapeutic target for both muscle soreness and some degenerative diseases that are exacerbated by inflammation. COX-2 inhibitors (in this study, rofecoxib) and creatine monohydrate both appear to protect dopaminergic neurons from being destroyed by toxins, and can protect in an additive manner; suggesting possible usage of both to reduce the risk of Parkinson's Disease.^[175]

Edit17. Different forms of creatine and creatine supplements

Creatine is sold in various forms which are purported to either increase plasma levels of creatine or to otherwise aid in cellular absorption. The standard of which most scientific studies and supplements is based upon is creatine monohydrate, as it is the most prevalently used and has a nearly maximal intestinal uptake rate.^[292][8]

Note that different creatine supplements provide varying quantities of creatine per gram. As such, each creatine source has an isomolar multiplication factor. For example, creatine monohydrate is 87.9% creatine by weight (12.1% water). A lower percentage provides less creatine per gram, and thus more grams must be ingested to get an equal creatine dosage.

17.1. Creatine Monohydrate

Creatine monohydrate is the most common form of creatine and is used in most of the scientific studies mentioned in this article. Creatine monohydrate is generally the standard to which all all other creatine formulations are compared.^[293]

17.2. Creatine Anhydrous

Anhydrous creatine is Creatine monohydrate without the water molecule attached. This form is sometimes used to reduce the weight of creatine in a supplement, and is able to convert to creatine monohydrate in aqueous and humid environments.^[294][295] It is 100% creatine by weight ^[113]

17.3. Liquid (Serum) Creatine

Liquid creatine has been shown to be less effective than creatine monohydrate.^[296] This reduced effect is due to the passive breakdown of creatine over a period of days into creatinine when it is suspended in solution.^[297] This breakdown is not an issue for at-home use when creatine is added to shakes, but is a concern from a manufacturing perspective in regards to self-life before use.

17.4. Buffered Creatine

Buffered Creatine (Kre-Alkylyn as brand name) is touted to enhance the effects of creatine monohydrate due to a higher pH level, which enables better translocation across the cytoplasmic membrane and more accumulation in muscle tissues.

This claim has currently not been demonstrated, and a recent comparative study of buffered creatine against basic creatine monohydrate found no significant differences between the two in 36 resistance trained in regards to the effects or the accumulation of creatine in muscle tissue.^[298] There were no significant differences in the amount of adverse side-effects reported.

17.5. Creatine Ethyl Ester

Creatine ethyl ester increases muscle levels of creatine to a lesser degree than creatine monohydrate.^[299] It may also result in higher serum creatinine levels^[300] due to creatine ethyl ester being converted into creatinine via non-enzymatic means in an environment similar to the digestive tract,^[301][302] and at equal doses to creatine monohydrate ethyl ester has failed to increase water weight after 28 days of administration (indicative of muscle deposition rates of creatine, which are seemingly absent with ethyl ester).^[303]

Creatine ethyl ester is more a pronutrient for creatinine rather than creatine,^[301] and was originally created in an attempt to bypass the creatine transporter, and is currently being studied as treatment for situations in which there are a lack of creatine transporters (alongside cyclocreatine as another possible example);^[304] its efficacy may rely on intravenous administration, however.

Creatine Ethyl Ester (CEE) may legitimately be the only available form of creatine which actually doesn't confer any benefits following oral ingestion

For the general population, supplementation creatine ethyl ester is likely to have negligible effects. Direct studies on creatine ethyl ester show it less effective than creatine monohydrate, on par with placebo.^[299]

Creatine ethyl ester is 82.4% creatine by weight, and thus would give 8.24g of active creatine for a dosage of 10 grams.^[113]

17.6. Creatine-Magnesium Chelate

Magnesium chelated creatine typically exerts the same ergogenic effects as creatine monohydrate at low doses.^[305] It was made because carbohydrates tend to beneficially influence creatine metabolism and magnesium is also implicated in carbohydrate metabolism and creatine metabolism.^[306][307] Magnesium chelated creatine may be useful in increasing muscle strength output in a similar potency to creatine monohydrate, but without the water weight gain (noted differences, but statistically insignificant).^[307][308]

17.7. Creatine Nitrate

Creatine Nitrate is a form of creatine where a nitrate (NO3) moiety is supposedly bound to the creatine molecule, which has been demonstrated to enhance solubility in water by approximately 10-fold with the pH of 2.5 or 7.5 not significantly affecting the solubility.^[309] Beyond increased solubility, no other studies have been conducted using creatine nitrate.

17.8. Creatine Malate

Creatine Malate is the creatine molecule bound to malic acid. There might be some ergogenic benefits of Malic acid on its own^[310] but this has not been investigated in conjunction with creatine. Malic acid/Malate also confers a sour taste^[311] and may negate the sensation of bitter, common among some supplements.

17.9. Creatine Citrate

Creatine Citrate is creatine bound to Citric Acid/citrate. Creatine Citrate does not differ greatly from monohydrate in regards to absorption or kinetics.^[109] Note that creatine citrate is more water-soluble than monohydrate,^[312], but creatine absorption is generally not limited by solubility. The increased water solubility may play a factor in palatability, however.

It can be found in varying ratios of creatine:citrate, including 1:1 (creatine citrate^[313][314]), 2:1 (dicreatine citrate^{[218][315][316]}), 3:1 (tricreatine citrate^[317])

17.10. Creatine Pyruvate

Creatine pyruvate (also known as Creatine 2-oxopropanoate), in an isomolar dose relative to creatine monohydrate, produces higher plasma levels of creatine (peak and AUC) yet has no discernible differences in absorption or excretion values.^[109] The same study noted increased performance from creatine pyruvate at low (4.4g creatine equivalence) doses relative to citrate and monohydrate, possibly due to the pyruvate group.

Creatine pyruvate is 60% creatine by weight.^[113]

17.11. Creatine α-ketoglutarate

Creatine α-ketoglutarate is the creatine molecule bound to an alpha-ketoglutaric acid moiety. Little research has been done with creatine α-ketoglutarate ^[318]

Creatine α-ketoglutarate is 53.8% creatine by weight.^[113]

17.12. Sodium creatine phosphate

Sodium creatine phosphate is 51.4% creatine by weight.^[113]

17.13. Polyethylene Glycosylated Creatine

Polyethylene glycosylated creatine seems to be as effective as creatine monohydrate at a lower dose (1.25-2.5g relative to 5g monohydrate), but does not seem to be comparable in all aspects.^[319][320]

17.14. Creatine Gluconate

Creatine Gluconate is a form of creatine supplementation where the creatine molecule is bound to a glucose molecule; it currently does not have any studies conducted on it.

17.15. Cyclocreatine

Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) is an analogue of creatine in a cyclic form, and synthetically made. It serves as a substrate for the creatine kinase enzyme system, serving as a creatine mimetic. Cyclocreatine may compete with creatine in the CK enzyme system to transfer phosphate groups to ADP, as coincubation of both can reduce cyclocreatine's anti-motility effects on some cancer cells.^[321]

Creatine mimetic, not commonly available for sales, interesting research properties

The structure of Cyclocreatine is fairly planar (flat) structure which aids in passive diffusion across membranes; it has been used with success in an animal study where mice suffered from SLC6A8 (creatine transporter at the blood brain barrier) deficiency which is not responsive to standard creatine supplementation.^[322] This study reported failed to report increases in creatine stores in the brain, but noted a reduction of mental retardation associated with increased cyclocreatine and phosphorylated cyclocreatine storages.^[322] As demonstrated by this animal study and previous ones, cyclocreatine is bioactive after oral ingestion^[322][323] and may merely be a creatine mimetic able to phosphorylate ADP via the creatine kinase system.^[322]

This increased permeability is noted in glioma cells where it exerts anti-cancer effects related to cell swelling^[324][325] and in other membranes such as breast cancer cells^[326] and skeletal (contractile) muscle cells.^[112] The kinetics of cyclocreatine appear to be first-order,^[326] with a relative V_max of 90, K_m of 25mM and a K_D of 1.2mM.^[327]

When looking at kinetics, cyclocreatine appears to be passively diffused through membranes and not subject to the creatine transporter; this can be beneficial for cases where the creatine transporter is hindering goals; creatine non-response and SLG6A8 deficiency

In regards to bioenergetics, phosphorylated cyclocreatine appears to have less affinity for the creatine kinase enzyme than phosphorylated creatine in donating the high energy phosphate group (about 160-fold less affinity) despite the process of receiving phosphorylation being similar.^[252][328] When fed to chickens, phosphorylated cyclocreatine can accumulate up to 60mM in skeletal muscle^[329] which suggests a sequestering of phosphate groups before reaching equilibrium.^[328] Cyclocreatine still has the capacity to donate phosphate, however, as beta-adrenergic stimulated skeletal muscle (which depletes ATP and glycogen) had an attenuation of glycogen depletion (indicative of preservation of ATP) with phosphocreatine.^[112]

Can act similar to creatine in preserving ATP levels, with unknown relative efficacy (ie. which is better or if there is even a difference)

Edit18. Safety and Toxicology

18.1. General Safety Profile

There are no clinically significant side-effects of creatine supplementation acutely. Numerous trials have been conducted in humans with varying dosages, and the side-effects have been limited to gastrointestinal distress (from too much creatine consumption at once) and cramping (from insufficient hydration).^{[330][331][332]}

A dose of 5g daily has strong evidence for not causing any adverse side effects^[333] and 10g has been used daily for 310 days in older adults (aged 57+/-11.1) with no significant differences from placebo.^[330] Such a dose has also been demonstrated for long-term safety in Parkinson's Disease,^[334] and at least one small retrospective study in athletes (surverying persons taking creatine for up to or over a year) failed to find any significant differences in a battery of serum health parameters.^[335] Other studies measuring serum parameters also fail to find abnormalities outside the normal range.^[336]

18.2. Case Studies

A case-study has reported that creatine co-ingestion with the medication metformin caused a case of metabolic acidosis^[337] although there was no proven connection between the acidosis and creatine as either a contributing or causative factor.

A relative lack of case studies on possible uncommon side effects of creatine, with none establishing a decent connection to the creatine itself

18.3. Creatine and Creatinine; Clarification

There is a compound in the body called 'creatinine', which is a byproduct (waste product) of muscle metabolism. It is routinely filtered out of the blood via the kidneys and thus a normal blood level is maintained.

When the kidneys start to fail (whatever the reason) they will excrete less creatinine. Less kidney excretion of creatinine will cause backlogging and higher blood levels, and thus normal blood levels of creatinine (from basic metabolic processes, like muscle turnover) can eventually become elevated. Because of this, creatinine is a clinical marker of kidney failure; meaning that if you have elevated creatinine levels (due to the aforementioned backlogging) you might have kidney failure.^[338][339]

Creatine does break down into creatinine, and then gets excreted via the kidneys. However, creatine suplementation is generally at too low a dose to cause significant changes in creatinine levels in healthy adults,^[340][341] although supplementation may cause a false positive result when take at a high dose.^[342]

Increased creatinine levels due to high dose supplementation of creatine is a diagnostic error, as no actual damage is done to the kidneys during these periods of higher blood creatinine.^{[343][344][345][346][347]} There have even been reports that a loading protocol does not hinder those with a single kidney^[348] and animal models suggest that even those with pre-existing renal failure are fine^[349]. Kidney failure causes high blood creatinine, but high blood creatinine does not cause kidney failure,^[350] it is a unidirectional relationship.

18.4. Water weight gain

Studies that use a dosage range typical of creatine supplementation (in the range of 5g a day following an acute loading period) note increases to total body water of 6.2% (3.74lbs) over 9 weeks,^[351] 1.1kg over 42 days,^[352]. Interestingly, some studies comparing creatine paired with training against training itself fail to find a significant difference in percentage of water gained (which is inherently to activity) with standard oral doses of creatine^{[352][336][353]} (although low dose creatine supplementation of 0.03g/kg or 2.3g daily doesn't appear to increase water retention^[354]) despite more overall water weight being gained; due to an equal gain of dry mass in muscles. One study has quantified the percentage increase in mass of muscle cells to be 55% water, suggesting they are fairly equal.^[352]

In regards to the loading period, two reviews suggest that the range of weight gain associated with creatine supplementation at 20g for 7 days is in the range of 0.9-1.8kg (1.98-3.96lbs).^[355][356] The highest reported increase in water weight associated with creatine loading, although measured a month after loading started (after a maintenance phase) was 3.8kg (8.36lbs).^[357]

Studies measuring extracellular water versus intracellular water note similar increases in both associated with creatine, and creatine does not tend to disturb the ratios of water to dry mass in various tissues measured.^[352] At least one study in older men (48-72yrs) has failed to find a significant difference in both intracellular and extracellular water concentration after 14 weeks of 5g daily (with gatorade) relative to gatorade in isolation; the ratio being maintained.^[358]

References

1. Buford TW, et al. International Society of Sports Nutrition position stand: creatine supplementation and exercise. J Int Soc Sports Nutr. (2007)
2. Creatine Deficiency Syndrome
3. Harris RC, Söderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). (1992)
4. Dahl O. Estimating protein quality of meat products from the content of typical amino-acids and creatine. J Sci Food Agric. (1965)
5. Harris RC, et al. The concentration of creatine in meat, offal and commercial dog food. Res Vet Sci. (1997)
6. Jenness R. The composition of human milk. Semin Perinatol. (1979)
7. Dietary Reference Intakes
8. Deldicque L, et al. Kinetics of creatine ingested as a food ingredient. Eur J Appl Physiol. (2008)
9. Yaylayan VA, et al. The role of creatine in the generation of N-methylacrylamide: a new toxicant in cooked meat. J Agric Food Chem. (2004)
10. Influence of creatine, amino acids and water on the formation of the mutagenic heterocyclic amines found in cooked meat
11. Mora L, Sentandreu MA, Toldrá F. Effect of cooking conditions on creatinine formation in cooked ham. J Agric Food Chem. (2008)
12. Pais P, et al. Formation of mutagenic/carcinogenic heterocyclic amines in dry-heated model systems, meats, and meat drippings. J Agric Food Chem. (1999)
13. Smith JS, Ameri F, Gadgil P. Effect of marinades on the formation of heterocyclic amines in grilled beef steaks. J Food Sci. (2008)
14. Melo A, et al. Effect of beer/red wine marinades on the formation of heterocyclic aromatic amines in pan-fried beef. J Agric Food Chem. (2008)
15. Gibis M. Effect of oil marinades with garlic, onion, and lemon juice on the formation of heterocyclic aromatic amines in fried beef patties. J Agric Food Chem. (2007)
16. Guzun R, et al. Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function. Amino Acids. (2011)
17. Adhihetty PJ, Beal MF. Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromolecular Med. (2008)
18. Mujika I, Padilla S. Creatine supplementation as an ergogenic aid for sports performance in highly trained athletes: a critical review. Int J Sports Med. (1997)
19. Terjung RL, et al. American College of Sports Medicine roundtable. The physiological and health effects of oral creatine supplementation. Med Sci Sports Exerc. (2000)
20. Schlattner U, Tokarska-Schlattner M, Wallimann T. Mitochondrial creatine kinase in human health and disease. Biochim Biophys Acta. (2006)
21. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev. (2000)
22. Gruetter R. Glycogen: the forgotten cerebral energy store. J Neurosci Res. (2003)
23. Roser W, et al. Absolute quantification of the hepatic glycogen content in a patient with glycogen storage disease by 13C magnetic resonance spectroscopy. Magn Reson Imaging. (1996)
24. Edvardson S, et al. l-arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation. Mol Genet Metab. (2010)
25. Guthmiller P, et al. Cloning and sequencing of rat kidney L-arginine:glycine amidinotransferase. Studies on the mechanism of regulation by growth hormone and creatine. J Biol Chem. (1994)
26. McGuire DM, et al. Repression of rat kidney L-arginine:glycine amidinotransferase synthesis by creatine at a pretranslational level. J Biol Chem. (1984)
27. Nasrallah F, et al. Guanidinoacetate methyltransferase (GAMT) deficiency in two Tunisian siblings: clinical and biochemical features. Clin Lab. (2012)
28. COHEN S, BUCKLEY P. The synthesis of creatine by preparations of liver from embryos and adults of various species. J Biol Chem. (1951)
29. Koszalka TR. Extrahepatic creatine synthesis in the rat. Role of the pancreas and kidney. Arch Biochem Biophys. (1967)
30. Braissant O, Henry H. AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: A review. J Inherit Metab Dis. (2008)
31. Brosnan JT, da Silva RP, Brosnan ME. The metabolic burden of creatine synthesis. Amino Acids. (2011)
32. Mudd SH, et al. Methyl balance and transmethylation fluxes in humans. Am J Clin Nutr. (2007)
33. Deminice R, et al. Creatine supplementation reduces increased homocysteine concentration induced by acute exercise in rats. Eur J Appl Physiol. (2011)
34. McMorris T, et al. Creatine supplementation and cognitive performance in elderly individuals. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. (2007)
35. Delanghe J, et al. Normal reference values for creatine, creatinine, and carnitine are lower in vegetarians. Clin Chem. (1989)
36. Venderley AM, Campbell WW. Vegetarian diets : nutritional considerations for athletes. Sports Med. (2006)
37. Benton D, Donohoe R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br J Nutr. (2011)
38. Rae C, et al. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc Biol Sci. (2003)
39. Watt KK, Garnham AP, Snow RJ. Skeletal muscle total creatine content and creatine transporter gene expression in vegetarians prior to and following creatine supplementation. Int J Sport Nutr Exerc Metab. (2004)
40. Vegetarian diet and mental disorders: results from a representative community survey
41. Wallimann T, Tokarska-Schlattner M, Schlattner U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids. (2011)
42. Sahlin K, Harris RC. The creatine kinase reaction: a simple reaction with functional complexity. Amino Acids. (2011)
43. Ortenblad N, Macdonald WA, Sahlin K. Glycolysis in contracting rat skeletal muscle is controlled by factors related to energy state. Biochem J. (2009)
44. Hultman E, Greenhaff PL. Skeletal muscle energy metabolism and fatigue during intense exercise in man. Sci Prog. (1991)
45. Saks VA, et al. Functional coupling as a basic mechanism of feedback regulation of cardiac energy metabolism. Mol Cell Biochem. (2004)
46. Chance B, et al. Skeletal muscle energetics with PNMR: personal views and historic perspectives. NMR Biomed. (2006)
47. Wallimann T, et al. Some new aspects of creatine kinase (CK): compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology. Biofactors. (1998)
48. McCall W, Persky AM. Pharmacokinetics of creatine. Subcell Biochem. (2007)
49. Kreider RB. Effects of creatine supplementation on performance and training adaptations. Mol Cell Biochem. (2003)
50. Wyss M, et al. Creatine and creatine kinase in health and disease--a bright future ahead. Subcell Biochem. (2007)
51. Brosnan JT, Brosnan ME. Creatine: endogenous metabolite, dietary, and therapeutic supplement. Annu Rev Nutr. (2007)
52. Rambo LM, et al. Acute creatine administration improves mitochondrial membrane potential and protects against pentylenetetrazol-induced seizures. Amino Acids. (2012)
53. Miller K, Halow J, Koretsky AP. Phosphocreatine protects transgenic mouse liver expressing creatine kinase from hypoxia and ischemia. Am J Physiol. (1993)
54. Lenz H, et al. Inhibition of cytosolic and mitochondrial creatine kinase by siRNA in HaCaT- and HeLaS3-cells affects cell viability and mitochondrial morphology. Mol Cell Biochem. (2007)
55. Black HR, Quallich H, Gareleck CB. Racial differences in serum creatine kinase levels. Am J Med. (1986)
56. Meltzer HY. Factors affecting serum creatine phosphokinase levels in the general population: the role of race, activity and age. Clin Chim Acta. (1971)
57. Wong ET, et al. Heterogeneity of serum creatine kinase activity among racial and gender groups of the population. Am J Clin Pathol. (1983)
58. Gledhill RF, et al. Race-gender differences in serum creatine kinase activity: a study among South Africans. J Neurol Neurosurg Psychiatry. (1988)
59. Daly MM, Seifter S. Uptake of creatine by cultured cells. Arch Biochem Biophys. (1980)
60. Extracellular creatine regulates creatine transport in rat and human muscle cells
61. Guimbal C, Kilimann MW. A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression. J Biol Chem. (1993)
62. Dai W, et al. Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Arch Biochem Biophys. (1999)
63. Nash SR, et al. Cloning, pharmacological characterization, and genomic localization of the human creatine transporter. Receptors Channels. (1994)
64. Peral MJ, et al. Human, rat and chicken small intestinal Na+ - Cl- -creatine transporter: functional, molecular characterization and localization. J Physiol. (2002)
65. Odoom JE, Kemp GJ, Radda GK. The regulation of total creatine content in a myoblast cell line. Mol Cell Biochem. (1996)
66. Eichler EE, et al. Duplication of a gene-rich cluster between 16p11.1 and Xq28: a novel pericentromeric-directed mechanism for paralogous genome evolution. Hum Mol Genet. (1996)
67. Iyer GS, et al. Identification of a testis-expressed creatine transporter gene at 16p11.2 and confirmation of the X-linked locus to Xq28. Genomics. (1996)
68. Brault JJ, Abraham KA, Terjung RL. Muscle creatine uptake and creatine transporter expression in response to creatine supplementation and depletion. J Appl Physiol. (2003)
69. Dodd JR, Zheng T, Christie DL. Creatine accumulation and exchange by HEK293 cells stably expressing high levels of a creatine transporter. Biochim Biophys Acta. (1999)
70. Creatine uptake, metabolism, and efflux in human monocytes and macrophages
71. Murphy R, et al. Creatine transporter protein content, localization, and gene expression in rat skeletal muscle. Am J Physiol Cell Physiol. (2001)
72. Murphy RM, et al. Human skeletal muscle creatine transporter mRNA and protein expression in healthy, young males and females. Mol Cell Biochem. (2003)
73. Greenhaff PL, et al. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol. (1994)
74. Syrotuik DG, Bell GJ. Acute creatine monohydrate supplementation: a descriptive physiological profile of responders vs. nonresponders. J Strength Cond Res. (2004)
75. Effect of creatine supplementation on sprint exercise performance and muscle metabolism
76. Hadjicharalambous M, Kilduff LP, Pitsiladis YP. Brain serotonin and dopamine modulators, perceptual responses and endurance performance during exercise in the heat following creatine supplementation. J Int Soc Sports Nutr. (2008)
77. Rawson ES, et al. Differential response of muscle phosphocreatine to creatine supplementation in young and old subjects. Acta Physiol Scand. (2002)
78. Shojaiefard M, Christie DL, Lang F. Stimulation of the creatine transporter SLC6A8 by the protein kinase mTOR. Biochem Biophys Res Commun. (2006)
79. Hong F, et al. mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol Cell. (2008)
80. García-Martínez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J. (2008)
81. Strutz-Seebohm N, et al. PIKfyve in the SGK1 mediated regulation of the creatine transporter SLC6A8. Cell Physiol Biochem. (2007)
82. Seebohm G, et al. Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels. Circ Res. (2007)
83. Klingel K, et al. Expression of cell volume-regulated kinase h-sgk in pancreatic tissue. Am J Physiol Gastrointest Liver Physiol. (2000)
84. Nishida Y, et al. Alteration of serum/glucocorticoid regulated kinase-1 (sgk-1) gene expression in rat hippocampus after transient global ischemia. Brain Res Mol Brain Res. (2004)
85. Derave W, et al. Electrolysis stimulates creatine transport and transporter cell surface expression in incubated mouse skeletal muscle: potential role of ROS. Am J Physiol Endocrinol Metab. (2006)
86. Omerovic E, et al. Growth hormone induces myocardial expression of creatine transporter and decreases plasma levels of IL-1beta in rats during early postinfarct cardiac remodeling. Growth Horm IGF Res. (2003)
87. Fresno Vara JA, et al. Stimulation of c-Src by prolactin is independent of Jak2. Biochem J. (2000)
88. Rowlinson SW, et al. An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway. Nat Cell Biol. (2008)
89. Wang W, et al. Cr supplementation decreases tyrosine phosphorylation of the CreaT in skeletal muscle during sepsis. Am J Physiol Endocrinol Metab. (2002)
90. Wang W, Shang LH, Jacobs DO. Complement regulatory protein CD59 involves c-SRC related tyrosine phosphorylation of the creatine transporter in skeletal muscle during sepsis. Surgery. (2002)
91. Yang WL, Lim RW. Modulation of muscle creatine kinase promoter activity by the inducible orphan nuclear receptor TIS1. Biochem J. (1997)
92. Lim RW, Zhu CY, Stringer B. Differential regulation of primary response gene expression in skeletal muscle cells through multiple signal transduction pathways. Biochim Biophys Acta. (1995)
93. Zhao CR, et al. Myocellular creatine and creatine transporter serine phosphorylation after starvation. J Surg Res. (2002)
94. Li H, et al. Regulation of the creatine transporter by AMP-activated protein kinase in kidney epithelial cells. Am J Physiol Renal Physiol. (2010)
95. Shaw RJ, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. (2004)
96. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. (2012)
97. Shojaiefard M, et al. Downregulation of the creatine transporter SLC6A8 by JAK2. J Membr Biol. (2012)
98. Garnovskaya MN, et al. Hypertonicity activates Na+/H+ exchange through Janus kinase 2 and calmodulin. J Biol Chem. (2003)
99. Gatsios P, et al. Activation of the Janus kinase/signal transducer and activator of transcription pathway by osmotic shock. J Biol Chem. (1998)
100. Kurdi M, Booz GW. JAK redux: a second look at the regulation and role of JAKs in the heart. Am J Physiol Heart Circ Physiol. (2009)
101. Zhang F, et al. Involvement of JAK2 and Src kinase tyrosine phosphorylation in human growth hormone-stimulated increases in cytosolic free Ca2+ and insulin secretion. Am J Physiol Cell Physiol. (2006)
102. Barclay JL, et al. In vivo targeting of the growth hormone receptor (GHR) Box1 sequence demonstrates that the GHR does not signal exclusively through JAK2. Mol Endocrinol. (2010)
103. Tran TT, Dai W, Sarkar HK. Cyclosporin A inhibits creatine uptake by altering surface expression of the creatine transporter. J Biol Chem. (2000)
104. Tokarska-Schlattner M, et al. Phosphocreatine interacts with phospholipids, affects membrane properties and exerts membrane-protective effects. PLoS One. (2012)
105. Hosamani R, Ramesh SR, Muralidhara. Attenuation of rotenone-induced mitochondrial oxidative damage and neurotoxicty in Drosophila melanogaster supplemented with creatine. Neurochem Res. (2010)
106. Martin KJ, et al. Microtubule stabilization and potentiation of taxol activity by the creatine analog cyclocreatine. Anticancer Drugs. (1995)
107. Purchas RW, Busboom JR, Wilkinson BH. Changes in the forms of iron and in concentrations of taurine, carnosine, coenzyme Q(10), and creatine in beef longissimus muscle with cooking and simulated stomach and duodenal digestion. Meat Sci. (2006)
108. MacNeil L, et al. Analysis of creatine, creatinine, creatine-d3 and creatinine-d3 in urine, plasma, and red blood cells by HPLC and GC-MS to follow the fate of ingested creatine-d3. J Chromatogr B Analyt Technol Biomed Life Sci. (2005)
109. Jäger R, et al. Comparison of new forms of creatine in raising plasma creatine levels. J Int Soc Sports Nutr. (2007)
110. Tosco M, et al. A creatine transporter is operative at the brush border level of the rat jejunal enterocyte. J Membr Biol. (2004)
111. Orsenigo MN, et al. Jejunal creatine absorption: what is the role of the basolateral membrane. J Membr Biol. (2005)
112. Turner DM, Walker JB. Enhanced ability of skeletal muscle containing cyclocreatine phosphate to sustain ATP levels during ischemia following beta-adrenergic stimulation. J Biol Chem. (1987)
113. Jäger R, et al. Analysis of the efficacy, safety, and regulatory status of novel forms of creatine. Amino Acids. (2011)
114. Persky AM, et al. Single- and multiple-dose pharmacokinetics of oral creatine. J Clin Pharmacol. (2003)
115. Sora I, et al. The cloning and expression of a human creatine transporter. Biochem Biophys Res Commun. (1994)
116. Kamber M, et al. Creatine supplementation--part I: performance, clinical chemistry, and muscle volume. Med Sci Sports Exerc. (1999)
117. Mesa JL, et al. Oral creatine supplementation and skeletal muscle metabolism in physical exercise. Sports Med. (2002)
118. Speer O, et al. Creatine transporters: a reappraisal. Mol Cell Biochem. (2004)
119. SLC6A8 solute carrier family 6
120. Snow RJ, Murphy RM. Creatine and the creatine transporter: a review. Mol Cell Biochem. (2001)
121. Casey A, et al. Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol. (1996)
122. Hultman E, et al. Muscle creatine loading in men. J Appl Physiol. (1996)
123. Febbraio MA, et al. Effect of creatine supplementation on intramuscular TCr, metabolism and performance during intermittent, supramaximal exercise in humans. Acta Physiol Scand. (1995)
124. Robinson TM, et al. Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle. J Appl Physiol. (1999)
125. Xu W, et al. Assignment of the human creatine transporter type 2 (SLC6A10) to chromosome band 16p11.2 by in situ hybridization. Cytogenet Cell Genet. (1997)
126. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences
127. Chen NH, Reith ME, Quick MW. Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch. (2004)
128. Reith ME, Zhen J, Chen N. The importance of company: Na+ and Cl- influence substrate interaction with SLC6 transporters and other proteins. Handb Exp Pharmacol. (2006)
129. Braissant O, et al. Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids. (2011)
130. Braissant O, et al. Creatine synthesis and transport during rat embryogenesis: spatiotemporal expression of AGAT, GAMT and CT1. BMC Dev Biol. (2005)
131. Gordon N. Guanidinoacetate methyltransferase deficiency (GAMT). Brain Dev. (2010)
132. Braissant O. Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers. J Inherit Metab Dis. (2012)
133. Ohtsuki S, et al. The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain. J Cereb Blood Flow Metab. (2002)
134. Tachikawa M, et al. Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis. Eur J Neurosci. (2004)
135. Cardoso FL, Brites D, Brito MA. Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev. (2010)
136. Carducci C, et al. In vitro study of uptake and synthesis of creatine and its precursors by cerebellar granule cells and astrocytes suggests some hypotheses on the physiopathology of the inherited disorders of creatine metabolism. BMC Neurosci. (2012)
137. Braissant O, Bachmann C, Henry H. Expression and function of AGAT, GAMT and CT1 in the mammalian brain. Subcell Biochem. (2007)
138. The nutritional biochemistry of creatine
139. Intake of 13C-4 creatine enables simultaneous assessment of creatine and phosphocreatine pools in human skeletal muscle by 13C MR spectroscopy
140. Muscle creatine loading in men
141. Preen D, et al. Creatine supplementation: a comparison of loading and maintenance protocols on creatine uptake by human skeletal muscle. Int J Sport Nutr Exerc Metab. (2003)
142. Rawson ES, et al. Effects of repeated creatine supplementation on muscle, plasma, and urine creatine levels. J Strength Cond Res. (2004)
143. Nasrallah F, Feki M, Kaabachi N. Creatine and creatine deficiency syndromes: biochemical and clinical aspects. Pediatr Neurol. (2010)
144. Matthews RT, et al. Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol. (1999)
145. Brustovetsky N, Brustovetsky T, Dubinsky JM. On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem. (2001)
146. Valastro B, et al. Oral creatine supplementation attenuates L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats. Behav Brain Res. (2009)
147. Matthews RT, et al. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. J Neurosci. (1998)
148. Roy BD, et al. Dietary supplementation with creatine monohydrate prevents corticosteroid-induced attenuation of growth in young rats. Can J Physiol Pharmacol. (2002)
149. Sawmiller DR, et al. High-energy compounds promote physiological processing of Alzheimer's amyloid-β precursor protein and boost cell survival in culture. J Neurochem. (2012)
150. Genius J, et al. Creatine protects against excitoxicity in an in vitro model of neurodegeneration. PLoS One. (2012)
151. Lawler JM, et al. Direct antioxidant properties of creatine. Biochem Biophys Res Commun. (2002)
152. Malcon C, Kaddurah-Daouk R, Beal MF. Neuroprotective effects of creatine administration against NMDA and malonate toxicity. Brain Res. (2000)
153. Brewer GJ, Wallimann TW. Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J Neurochem. (2000)
154. Juravleva E, et al. Creatine enhances survival of glutamate-treated neuronal/glial cells, modulates Ras/NF-kappaB signaling, and increases the generation of reactive oxygen species. J Neurosci Res. (2005)
155. Klivenyi P, et al. Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem. (2004)
156. Rambo LM, et al. Creatine increases hippocampal Na(+),K(+)-ATPase activity via NMDA-calcineurin pathway. Brain Res Bull. (2012)
157. Royes LF, et al. Neuromodulatory effect of creatine on extracellular action potentials in rat hippocampus: role of NMDA receptors. Neurochem Int. (2008)
158. Bender A, et al. Creatine improves health and survival of mice. Neurobiol Aging. (2008)
159. Bender A, et al. Creatine supplementation lowers brain glutamate levels in Huntington's disease. J Neurol. (2005)
160. Volz HP, et al. 31P magnetic resonance spectroscopy in the frontal lobe of major depressed patients. Eur Arch Psychiatry Clin Neurosci. (1998)
161. Iosifescu DV, et al. Brain bioenergetics and response to triiodothyronine augmentation in major depressive disorder. Biol Psychiatry. (2008)
162. Shao L, et al. Mitochondrial involvement in psychiatric disorders. Ann Med. (2008)
163. Rezin GT, et al. Mitochondrial dysfunction and psychiatric disorders. Neurochem Res. (2009)
164. Moore CM, et al. Lower levels of nucleoside triphosphate in the basal ganglia of depressed subjects: a phosphorous-31 magnetic resonance spectroscopy study. Am J Psychiatry. (1997)
165. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine
166. Cunha MP, et al. Antidepressant-like effect of creatine in mice involves dopaminergic activation. J Psychopharmacol. (2012)
167. Lyoo IK, et al. A Randomized, Double-Blind Placebo-Controlled Trial of Oral Creatine Monohydrate Augmentation for Enhanced Response to a Selective Serotonin Reuptake Inhibitor in Women With Major Depressive Disorder. Am J Psychiatry. (2012)
168. Kondo DG, et al. Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study. J Affect Disord. (2011)
169. Roitman S, et al. Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord. (2007)
170. Amital D, et al. Open study of creatine monohydrate in treatment-resistant posttraumatic stress disorder. J Clin Psychiatry. (2006)
171. Renshaw PF, et al. Multinuclear magnetic resonance spectroscopy studies of brain purines in major depression. Am J Psychiatry. (2001)
172. Allen PJ, et al. Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology. (2010)
173. Detke MJ, Rickels M, Lucki I. Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl). (1995)
174. Cunha MP, et al. Evidence for the involvement of 5-HT(1A) receptor in the acute antidepressant-like effect of creatine in mice. Brain Res Bull. (2013)
175. Klivenyi P, et al. Additive neuroprotective effects of creatine and a cyclooxygenase 2 inhibitor against dopamine depletion in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. J Mol Neurosci. (2003)
176. Lin MT, et al. Changes in extracellular serotonin in rat hypothalamus affect thermoregulatory function. Am J Physiol. (1998)
177. Bridge MW, et al. Responses to exercise in the heat related to measures of hypothalamic serotonergic and dopaminergic function. Eur J Appl Physiol. (2003)
178. Andres RH, et al. Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. Neuroscience. (2005)
179. Klivenyi P, et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med. (1999)
180. D'Anci KE, Allen PJ, Kanarek RB. A potential role for creatine in drug abuse. Mol Neurobiol. (2011)
181. Gold MS, et al. Methamphetamine- and trauma-induced brain injuries: comparative cellular and molecular neurobiological substrates. Biol Psychiatry. (2009)
182. Licata SC, Renshaw PF. Neurochemistry of drug action: insights from proton magnetic resonance spectroscopic imaging and their relevance to addiction. Ann N Y Acad Sci. (2010)
183. Sakellaris G, et al. Prevention of complications related to traumatic brain injury in children and adolescents with creatine administration: an open label randomized pilot study. J Trauma. (2006)
184. Prevention of traumatic headache, dizziness and fatigue with creatine administration. A pilot study
185. Oliveira MS, et al. The involvement of the polyamines binding sites at the NMDA receptor in creatine-induced spatial learning enhancement. Behav Brain Res. (2008)
186. Maione S, et al. Effects of the polyamine spermidine on NMDA-induced arterial hypertension in freely moving rats. Neuropharmacology. (1994)
187. Lukaszuk JM, et al. Effect of a defined lacto-ovo-vegetarian diet and oral creatine monohydrate supplementation on plasma creatine concentration. J Strength Cond Res. (2005)
188. Maccormick VM, et al. Elevation of creatine in red blood cells in vegetarians and nonvegetarians after creatine supplementation. Can J Appl Physiol. (2004)
189. Wilkinson ID, et al. Effects of creatine supplementation on cerebral white matter in competitive sportsmen. Clin J Sport Med. (2006)
190. Rawson ES, et al. Creatine supplementation does not improve cognitive function in young adults. Physiol Behav. (2008)
191. McMorris T, et al. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology (Berl). (2006)
192. Towse JN. On random generation and the central executive of working memory. Br J Psychol. (1998)
193. Watanabe A, Kato N, Kato T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci Res. (2002)
194. Jacobus WE, Diffley DM. Creatine kinase of heart mitochondria. Control of oxidative phosphorylation by the extramitochondrial concentrations of creatine and phosphocreatine. J Biol Chem. (1986)
195. Lygate CA, et al. Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction. Cardiovasc Res. (2012)
196. Ceddia RB, Sweeney G. Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells. J Physiol. (2004)
197. Young JC, Young RE. The effect of creatine supplementation on glucose uptake in rat skeletal muscle. Life Sci. (2002)
198. Eijnde BO, et al. Effect of creatine supplementation on creatine and glycogen content in rat skeletal muscle. Acta Physiol Scand. (2001)
199. Rooney K, et al. Creatine supplementation alters insulin secretion and glucose homeostasis in vivo. Metabolism. (2002)
200. Op 't Eijnde B, et al. Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization. Diabetes. (2001)
201. Alves CR, et al. Creatine-induced glucose uptake in type 2 diabetes: a role for AMPK-α. Amino Acids. (2012)
202. Alsever RN, Georg RH, Sussman KE. Stimulation of insulin secretion by guanidinoacetic acid and other guanidine derivatives. Endocrinology. (1970)
203. Marco J, et al. Glucagon-releasing activity of guanidine compounds in mouse pancreatic islets. FEBS Lett. (1976)
204. Green AL, et al. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol. (1996)
205. Green AL, et al. Carbohydrate ingestion augments creatine retention during creatine feeding in humans. Acta Physiol Scand. (1996)
206. Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle
207. Zange J, et al. Creatine supplementation results in elevated phosphocreatine/adenosine triphosphate (ATP) ratios in the calf muscle of athletes but not in patients with myopathies. Ann Neurol. (2002)
208. Bogdanis GC, et al. Recovery of power output and muscle metabolites following 30 s of maximal sprint cycling in man. J Physiol. (1995)
209. Havenetidis K, Bourdas D. Creatine supplementation: effects on urinary excretion and anaerobic performance. J Sports Med Phys Fitness. (2003)
210. Koçak S, Karli U. Effects of high dose oral creatine supplementation on anaerobic capacity of elite wrestlers. J Sports Med Phys Fitness. (2003)
211. Eckerson JM, et al. Effect of creatine phosphate supplementation on anaerobic working capacity and body weight after two and six days of loading in men and women. J Strength Cond Res. (2005)
212. Okudan N, Gokbel H. The effects of creatine supplementation on performance during the repeated bouts of supramaximal exercise. J Sports Med Phys Fitness. (2005)
213. Oliver JM, et al. Oral Creatine Supplementation Decreases Blood Lactate during Exhaustive, Incremental Cycling. Int J Sports Physiol Perform. (2012)
214. Ahmun RP, Tong RJ, Grimshaw PN. The effects of acute creatine supplementation on multiple sprint cycling and running performance in rugby players. J Strength Cond Res. (2005)
215. Hoffman JR, et al. Effect of low-dose, short-duration creatine supplementation on anaerobic exercise performance. J Strength Cond Res. (2005)
216. Havenetidis K, et al. Incorrect calculation of power outputs masks the ergogenic capacity of creatine supplementation. Appl Physiol Nutr Metab. (2006)
217. Kinugasa R, et al. Short-term creatine supplementation does not improve muscle activation or sprint performance in humans. Eur J Appl Physiol. (2004)
218. Smith AE, et al. Ergolytic/ergogenic effects of creatine on aerobic power. Int J Sports Med. (2011)
219. Beis LY, et al. The effects of creatine and glycerol hyperhydration on running economy in well trained endurance runners. J Int Soc Sports Nutr. (2011)
220. Fumagalli S, et al. Coenzyme Q10 terclatrate and creatine in chronic heart failure: a randomized, placebo-controlled, double-blind study. Clin Cardiol. (2011)
221. Dempsey RL, Mazzone MF, Meurer LN. Does oral creatine supplementation improve strength? A meta-analysis. J Fam Pract. (2002)
222. Branch JD. Effect of creatine supplementation on body composition and performance: a meta-analysis. Int J Sport Nutr Exerc Metab. (2003)
223. Vandenberghe K, et al. Long-term creatine intake is beneficial to muscle performance during resistance training. J Appl Physiol. (1997)
224. Volek JS, et al. Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. Med Sci Sports Exerc. (1999)
225. Stone MH, et al. Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and body composition in American football players. Int J Sport Nutr. (1999)
226. Effect of oral creatine supplementation on near-maximal strength and repeated sets of high-intensity bench press exercise
227. Rawson ES, Clarkson PM. Acute creatine supplementation in older men. Int J Sports Med. (2000)
228. Rawson ES, Wehnert ML, Clarkson PM. Effects of 30 days of creatine ingestion in older men. Eur J Appl Physiol Occup Physiol. (1999)
229. Becque MD, Lochmann JD, Melrose DR. Effects of oral creatine supplementation on muscular strength and body composition. Med Sci Sports Exerc. (2000)
230. Saremi A, et al. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol. (2010)
231. Hill JJ, et al. Regulation of myostatin in vivo by growth and differentiation factor-associated serum protein-1: a novel protein with protease inhibitor and follistatin domains. Mol Endocrinol. (2003)
232. Safdar A, et al. Global and targeted gene expression and protein content in skeletal muscle of young men following short-term creatine monohydrate supplementation. Physiol Genomics. (2008)
233. Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis
234. Effects of hyper- and hypoosmolality on whole body protein and glucose kinetics in humans
235. Häussinger D, et al. Cell swelling inhibits proteolysis in perfused rat liver. Biochem J. (1990)
236. Morley JE, et al. Nutritional recommendations for the management of sarcopenia. J Am Med Dir Assoc. (2010)
237. Candow DG, Chilibeck PD. Effect of creatine supplementation during resistance training on muscle accretion in the elderly. J Nutr Health Aging. (2007)
238. Sakkas GK, Schambelan M, Mulligan K. Can the use of creatine supplementation attenuate muscle loss in cachexia and wasting. Curr Opin Clin Nutr Metab Care. (2009)
239. Derave W, et al. No effects of lifelong creatine supplementation on sarcopenia in senescence-accelerated mice (SAMP8). Am J Physiol Endocrinol Metab. (2005)
240. van der Merwe J, Brooks NE, Myburgh KH. Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. Clin J Sport Med. (2009)
241. Hoffman J, et al. Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes. Int J Sport Nutr Exerc Metab. (2006)
242. Op 't Eijnde B, Hespel P. Short-term creatine supplementation does not alter the hormonal response to resistance training. Med Sci Sports Exerc. (2001)
243. Cook CJ, et al. Skill execution and sleep deprivation: effects of acute caffeine or creatine supplementation - a randomized placebo-controlled trial. J Int Soc Sports Nutr. (2011)
244. Derave W, et al. Creatine supplementation augments skeletal muscle carnosine content in senescence-accelerated mice (SAMP8). Rejuvenation Res. (2008)
245. Leland KM, McDonald TL, Drescher KM. Effect of creatine, creatinine, and creatine ethyl ester on TLR expression in macrophages. Int Immunopharmacol. (2011)
246. Kim HJ, et al. Studies on the safety of creatine supplementation. Amino Acids. (2011)
247. Francaux M, Poortmans JR. Side effects of creatine supplementation in athletes. Int J Sports Physiol Perform. (2006)
248. Yu PH, Deng Y. Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance. Med Hypotheses. (2000)
249. Candow DG, et al. Low-dose creatine combined with protein during resistance training in older men. Med Sci Sports Exerc. (2008)
250. Poortmans JR, et al. Effect of oral creatine supplementation on urinary methylamine, formaldehyde, and formate. Med Sci Sports Exerc. (2005)
251. Schimmel L, et al. The synthetic phosphagen cyclocreatine phosphate inhibits the growth of a broad spectrum of solid tumors. Anticancer Res. (1996)
252. Kornacker M, et al. Hodgkin disease-derived cell lines expressing ubiquitous mitochondrial creatine kinase show growth inhibition by cyclocreatine treatment independent of apoptosis. Int J Cancer. (2001)
253. Lillie JW, et al. Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) inhibits growth of a broad spectrum of cancer cells derived from solid tumors. Cancer Res. (1993)
254. Kristensen CA, et al. Creatine and cyclocreatine treatment of human colon adenocarcinoma xenografts: 31P and 1H magnetic resonance spectroscopic studies. Br J Cancer. (1999)
255. Miller EE, Evans AE, Cohn M. Inhibition of rate of tumor growth by creatine and cyclocreatine. Proc Natl Acad Sci U S A. (1993)
256. Patra S, et al. A short review on creatine-creatine kinase system in relation to cancer and some experimental results on creatine as adjuvant in cancer therapy. Amino Acids. (2012)
257. Berneburg M, et al. Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences. J Invest Dermatol. (2005)
258. Rahimi R. Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise. J Strength Cond Res. (2011)
259. Taes YE, et al. Creatine supplementation decreases homocysteine in an animal model of uremia. Kidney Int. (2003)
260. Taes YE, et al. Lowering methylation demand by creatine supplementation paradoxically decreases DNA methylation. Mol Genet Metab. (2007)
261. Freilinger M, et al. Effects of creatine supplementation in Rett syndrome: a randomized, placebo-controlled trial. J Dev Behav Pediatr. (2011)
262. Ghosh M, et al. In vivo assessment of toxicity and pharmacokinetics of methylglyoxal. Augmentation of the curative effect of methylglyoxal on cancer-bearing mice by ascorbic acid and creatine. Toxicol Appl Pharmacol. (2006)
263. Talukdar D, et al. Critical evaluation of toxic versus beneficial effects of methylglyoxal. Biochemistry (Mosc). (2009)
264. Ray S, Biswas S, Ray M. Similar nature of inhibition of mitochondrial respiration of heart tissue and malignant cells by methylglyoxal. A vital clue to understand the biochemical basis of malignancy. Mol Cell Biochem. (1997)
265. Santos RV, et al. Chronic supplementation of creatine and vitamins C and E increases survival and improves biochemical parameters after Doxorubicin treatment in rats. Clin Exp Pharmacol Physiol. (2007)
266. Norman K, et al. Effects of creatine supplementation on nutritional status, muscle function and quality of life in patients with colorectal cancer--a double blind randomised controlled trial. Clin Nutr. (2006)
267. Bourgeois JM, et al. Creatine monohydrate attenuates body fat accumulation in children with acute lymphoblastic leukemia during maintenance chemotherapy. Pediatr Blood Cancer. (2008)
268. Tarnopolsky MA, et al. Histological assessment of intermediate- and long-term creatine monohydrate supplementation in mice and rats. Am J Physiol Regul Integr Comp Physiol. (2003)
269. Kreider RB. Species-specific responses to creatine supplementation. Am J Physiol Regul Integr Comp Physiol. (2003)
270. Edmunds JW, et al. Creatine supplementation increases renal disease progression in Han:SPRD-cy rats. Am J Kidney Dis. (2001)
271. El-Domyati M, et al. Intrinsic aging vs. photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin. Exp Dermatol. (2002)
272. Scharffetter-Kochanek K, et al. UV-induced reactive oxygen species in photocarcinogenesis and photoaging. Biol Chem. (1997)
273. Blatt T, et al. Stimulation of skin's energy metabolism provides multiple benefits for mature human skin. Biofactors. (2005)
274. Zwerschke W, et al. Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence. Biochem J. (2003)
275. Papa S. Mitochondrial oxidative phosphorylation changes in the life span. Molecular aspects and physiopathological implications. Biochim Biophys Acta. (1996)
276. Peirano RI, et al. Dermal penetration of creatine from a face-care formulation containing creatine, guarana and glycerol is linked to effective antiwrinkle and antisagging efficacy in male subjects. J Cosmet Dermatol. (2011)
277. Lenz H, et al. The creatine kinase system in human skin: protective effects of creatine against oxidative and UV damage in vitro and in vivo. J Invest Dermatol. (2005)
278. Fischer F, et al. Folic acid and creatine improve the firmness of human skin in vivo. J Cosmet Dermatol. (2011)
279. Knott A, et al. A novel treatment option for photoaged skin. J Cosmet Dermatol. (2008)
280. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans
281. Stimulatory effect of insulin on creatine accumulation in human skeletal muscle
282. Creatine uptake in brain and skeletal muscle of mice lacking guanidinoacetate methyltransferase assessed by magnetic resonance spectroscopy
283. Vandenberghe K, et al. Caffeine counteracts the ergogenic action of muscle creatine loading. J Appl Physiol. (1996)
284. Hespel P, Op't Eijnde B, Van Leemputte M. Opposite actions of caffeine and creatine on muscle relaxation time in humans. J Appl Physiol. (2002)
285. Doherty M, et al. Caffeine is ergogenic after supplementation of oral creatine monohydrate. Med Sci Sports Exerc. (2002)
286. Fukuda DH, et al. The possible combinatory effects of acute consumption of caffeine, creatine, and amino acids on the improvement of anaerobic running performance in humans. Nutr Res. (2010)
287. Lee CL, Lin JC, Cheng CF. Effect of caffeine ingestion after creatine supplementation on intermittent high-intensity sprint performance. Eur J Appl Physiol. (2011)
288. Jówko E, et al. Creatine and beta-hydroxy-beta-methylbutyrate (HMB) additively increase lean body mass and muscle strength during a weight-training program. Nutrition. (2001)
289. Burke DG, et al. Effect of alpha-lipoic acid combined with creatine monohydrate on human skeletal muscle creatine and phosphagen concentration. Int J Sport Nutr Exerc Metab. (2003)
290. Thermoregulatory and cardiovascular responses to creatine, glycerol and alpha lipoic acid in trained cyclists
291. Berg EP, Maddock KR, Linville ML. Creatine monohydrate supplemented in swine finishing diets and fresh pork quality: III. Evaluating the cumulative effect of creatine monohydrate and alpha-lipoic acid. J Anim Sci. (2003)
292. The fate of creatine when administered to man
293. Dash AK, Mo Y, Pyne A. Solid-state properties of creatine monohydrate. J Pharm Sci. (2002)
294. Sakata Y, Shiraishi S, Otsuka M. Effect of pulverization on hydration kinetic behaviors of creatine anhydrate powders. Colloids Surf B Biointerfaces. (2004)
295. Sakata Y, Shiraishi S, Otsuka M. Effect of pulverization of the bulk powder on the hydration of creatine anhydrate tablets and their pharmaceutical properties. Colloids Surf B Biointerfaces. (2005)
296. Astorino TA, et al. Is running performance enhanced with creatine serum ingestion. J Strength Cond Res. (2005)
297. Gill ND, Hall RD, Blazevich AJ. Creatine serum is not as effective as creatine powder for improving cycle sprint performance in competitive male team-sport athletes. J Strength Cond Res. (2004)
298. Jagim AR, et al. A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate. J Int Soc Sports Nutr. (2012)
299. Spillane M, et al. The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels. J Int Soc Sports Nutr. (2009)
300. Velema MS, de Ronde W. Elevated plasma creatinine due to creatine ethyl ester use. Neth J Med. (2011)
301. Giese MW, Lecher CS. Non-enzymatic cyclization of creatine ethyl ester to creatinine. Biochem Biophys Res Commun. (2009)
302. Katseres NS, et al. Non-enzymatic hydrolysis of creatine ethyl ester. Biochem Biophys Res Commun. (2009)
303. The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels
304. Adriano E, et al. Searching for a therapy of creatine transporter deficiency: some effects of creatine ethyl ester in brain slices in vitro. Neuroscience. (2011)
305. Selsby JT, DiSilvestro RA, Devor ST. Mg2+-creatine chelate and a low-dose creatine supplementation regimen improve exercise performance. J Strength Cond Res. (2004)
306. Balsom PD, et al. Skeletal muscle metabolism during short duration high-intensity exercise: influence of creatine supplementation. Acta Physiol Scand. (1995)
307. Brilla LR, et al. Magnesium-creatine supplementation effects on body water. Metabolism. (2003)
308. Silber ML. Scientific facts behind creatine monohydrate as sport nutrition supplement. J Sports Med Phys Fitness. (1999)
309. EQUILIBRIUM SOLUBILTY STUDIES OF CREATINE NITRATE, CREATINE MONOHYDRATE AND BUFFERED CREATINE
310. Wu JL, et al. Effects of L-malate on physical stamina and activities of enzymes related to the malate-aspartate shuttle in liver of mice. Physiol Res. (2007)
311. Neta ER, et al. Effects of pH adjustment and sodium ions on sour taste intensity of organic acids. J Food Sci. (2009)
312. Ganguly S, Jayappa S, Dash AK. Evaluation of the stability of creatine in solution prepared from effervescent creatine formulations. AAPS PharmSciTech. (2003)
313. Horecký J, et al. Effects of coenzyme Q and creatine supplementation on brain energy metabolism in rats exposed to chronic cerebral hypoperfusion. Curr Alzheimer Res. (2011)
314. Graef JL, et al. The effects of four weeks of creatine supplementation and high-intensity interval training on cardiorespiratory fitness: a randomized controlled trial. J Int Soc Sports Nutr. (2009)
315. Smith AE, et al. Effects of creatine loading on electromyographic fatigue threshold during cycle ergometry in college-aged women. J Int Soc Sports Nutr. (2007)
316. Jäger R, et al. The effects of creatine pyruvate and creatine citrate on performance during high intensity exercise. J Int Soc Sports Nutr. (2008)
317. Comparison of new forms of creatine in raising plasma creatine levels
318. Incledon T, Kreider RB. Creatine alpha-ketoglutarate is experimentally unproven. J Sports Med Phys Fitness. (2000)
319. Herda TJ, et al. Effects of creatine monohydrate and polyethylene glycosylated creatine supplementation on muscular strength, endurance, and power output. J Strength Cond Res. (2009)
320. Camic CL, et al. The effects of polyethylene glycosylated creatine supplementation on muscular strength and power. J Strength Cond Res. (2010)
321. Mulvaney PT, et al. Cyclocreatine inhibits stimulated motility in tumor cells possessing creatine kinase. Int J Cancer. (1998)
322. Kurosawa Y, et al. Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency. J Clin Invest. (2012)
323. Woznicki DT, Walker JB. Formation of a supplemental long time-constant reservoir of high energy phosphate by brain in vivo and in vitro and its reversible depletion by potassium depolarization. J Neurochem. (1979)
324. Cyclocreatine Accumulation Leads to Cellular Swelling in C6 Glioma Multicellular Spheroids: Diffusion and One-Dimensional Chemical Shift Nuclear Magnetic Resonance Microscopy
325. Cyclocreatine transport and cytotoxicity in rat glioma and human ovarian carcinoma cells: 31P-NMR spectroscopy
326. Maril N, et al. Kinetics of cyclocreatine and Na(+) cotransport in human breast cancer cells: mechanism of activity. Am J Physiol. (1999)
327. McLaughlin AC, Cohn M, Kenyon GL. Specificity of creatine kinase for guanidino substrates. Kinetic and proton nuclear magnetic relaxation rate studies. J Biol Chem. (1972)
328. Annesley TM, Walker JB. Cyclocreatine phosphate as a substitute for creatine phosphate in vertebrate tissues. Energistic considerations. Biochem Biophys Res Commun. (1977)
329. Griffiths GR, Walker JB. Accumulation of analgo of phosphocreatine in muscle of chicks fed 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine). J Biol Chem. (1976)
330. Groeneveld GJ, et al. Few adverse effects of long-term creatine supplementation in a placebo-controlled trial. Int J Sports Med. (2005)
331. Greenwood M, et al. Creatine supplementation during college football training does not increase the incidence of cramping or injury. Mol Cell Biochem. (2003)
332. Lopez RM, et al. Does creatine supplementation hinder exercise heat tolerance or hydration status? A systematic review with meta-analyses. J Athl Train. (2009)
333. Shao A, Hathcock JN. Risk assessment for creatine monohydrate. Regul Toxicol Pharmacol. (2006)
334. Bender A, et al. Long-term creatine supplementation is safe in aged patients with Parkinson disease. Nutr Res. (2008)
335. Schilling BK, et al. Creatine supplementation and health variables: a retrospective study. Med Sci Sports Exerc. (2001)
336. Kreider RB, et al. Effects of creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc. (1998)
337. Saidi H, Mani M. Severe metabolic acidosis secondary to coadministration of creatine and metformin, a case report. Am J Emerg Med. (2010)
338. Ronco C, et al. Oliguria, creatinine and other biomarkers of acute kidney injury. Contrib Nephrol. (2010)
339. Udani S, Lazich I, Bakris GL. Epidemiology of hypertensive kidney disease. Nat Rev Nephrol. (2011)
340. Pline KA, Smith CL. The effect of creatine intake on renal function. Ann Pharmacother. (2005)
341. Ropero-Miller JD, et al. Effect of oral creatine supplementation on random urine creatinine, pH, and specific gravity measurements. Clin Chem. (2000)
342. Poortmans JR, Francaux M. Adverse effects of creatine supplementation: fact or fiction. Sports Med. (2000)
343. Gualano B, et al. Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial. Eur J Appl Physiol. (2008)
344. Gualano B, et al. Creatine supplementation does not impair kidney function in type 2 diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial. Eur J Appl Physiol. (2011)
345. Poortmans JR, Francaux M. Long-term oral creatine supplementation does not impair renal function in healthy athletes. Med Sci Sports Exerc. (1999)
346. Farquhar WB, Zambraski EJ. Effects of creatine use on the athlete's kidney. Curr Sports Med Rep. (2002)
347. Neves M Jr, et al. Effect of creatine supplementation on measured glomerular filtration rate in postmenopausal women. Appl Physiol Nutr Metab. (2011)
348. Gualano B, et al. Effect of short-term high-dose creatine supplementation on measured GFR in a young man with a single kidney. Am J Kidney Dis. (2010)
349. Taes YE, et al. Creatine supplementation does not affect kidney function in an animal model with pre-existing renal failure. Nephrol Dial Transplant. (2003)
350. Persky AM, Rawson ES. Safety of creatine supplementation. Subcell Biochem. (2007)
351. Kutz MR, Gunter MJ. Creatine monohydrate supplementation on body weight and percent body fat. J Strength Cond Res. (2003)
352. Francaux M, Poortmans JR. Effects of training and creatine supplement on muscle strength and body mass. Eur J Appl Physiol Occup Physiol. (1999)
353. Bemben MG, et al. Creatine supplementation during resistance training in college football athletes. Med Sci Sports Exerc. (2001)
354. Rawson ES, et al. Low-dose creatine supplementation enhances fatigue resistance in the absence of weight gain. Nutrition. (2011)
355. Heymsfield SB, et al. Measurement of muscle mass in humans: validity of the 24-hour urinary creatinine method. Am J Clin Nutr. (1983)
356. Demant TW, Rhodes EC. Effects of creatine supplementation on exercise performance. Sports Med. (1999)
357. Earnest CP, et al. The effect of creatine monohydrate ingestion on anaerobic power indices, muscular strength and body composition. Acta Physiol Scand. (1995)
358. Eliot KA, et al. The effects of creatine and whey protein supplementation on body composition in men aged 48 to 72 years during resistance training. J Nutr Health Aging. (2008)
359. Diet and Refsum's disease. The determination of phytanic acid and phytol in certain foods and the application of this knowledge to the choice of suitable convenience foods for patients with Refsum's disease
360. Phytanic acid: measurement of plasma concentrations by gas–liquid chromatography–mass spectrometry analysis and associations with diet and other plasma fatty acids
361. Smith AE, et al. The effects of a pre-workout supplement containing caffeine, creatine, and amino acids during three weeks of high-intensity exercise on aerobic and anaerobic performance. J Int Soc Sports Nutr. (2010)
362. Spradley BD, et al. Ingesting a pre-workout supplement containing caffeine, B-vitamins, amino acids, creatine, and beta-alanine before exercise delays fatigue while improving reaction time and muscular endurance. Nutr Metab (Lond). (2012)
363. Vanakoski J, et al. Creatine and caffeine in anaerobic and aerobic exercise: effects on physical performance and pharmacokinetic considerations. Int J Clin Pharmacol Ther. (1998)
364. Candow DG, et al. Effect of ceasing creatine supplementation while maintaining resistance training in older men. J Aging Phys Act. (2004)
365. Greenwood M, et al. Cramping and Injury Incidence in Collegiate Football Players Are Reduced by Creatine Supplementation. J Athl Train. (2003)
366. Rathnayake D, Sinclair R. Male androgenetic alopecia. Expert Opin Pharmacother. (2010)
367. Wright AS, et al. Relative potency of testosterone and dihydrotestosterone in preventing atrophy and apoptosis in the prostate of the castrated rat. J Clin Invest. (1996)
368. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia. World J Urol. (2002)
369. Ryu HK, et al. Evaluation of androgens in the scalp hair and plasma of patients with male-pattern baldness before and after finasteride administration. Br J Dermatol. (2006)
370. Dallob AL, et al. The effect of finasteride, a 5 alpha-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. J Clin Endocrinol Metab. (1994)
371. Bang HJ, et al. Comparative studies on level of androgens in hair and plasma with premature male-pattern baldness. J Dermatol Sci. (2004)
372. Green G. Creatine supplementation and DHT:T ratio in male rugby players. Clin J Sport Med. (2010)
373. Volek JS, et al. The effects of creatine supplementation on muscular performance and body composition responses to short-term resistance training overreaching. Eur J Appl Physiol. (2004)
374. Lamontagne-Lacasse M, Nadon R, Goulet ED. Effect of Creatine Supplementation on Jumping Performance in Elite Volleyball Players. Int J Sports Physiol Perform. (2011)
375. Del Favero S, et al. Creatine but not betaine supplementation increases muscle phosphorylcreatine content and strength performance. Amino Acids. (2011)
376. Candow DG, et al. Effect of different frequencies of creatine supplementation on muscle size and strength in young adults. J Strength Cond Res. (2011)
377. Neves M Jr, et al. Beneficial effect of creatine supplementation in knee osteoarthritis. Med Sci Sports Exerc. (2011)
378. Sanchez-Gonzalez MA, et al. Creatine supplementation attenuates hemodynamic and arterial stiffness responses following an acute bout of isokinetic exercise. Eur J Appl Physiol. (2011)
379. Gualano B, et al. Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Med Sci Sports Exerc. (2011)
380. Sculthorpe N, et al. The effect of short-term creatine loading on active range of movement. Appl Physiol Nutr Metab. (2010)
381. Kingsley M, et al. Role of creatine supplementation on exercise-induced cardiovascular function and oxidative stress. Oxid Med Cell Longev. (2009)
382. Fukuda DH, et al. The effects of creatine loading and gender on anaerobic running capacity. J Strength Cond Res. (2010)
383. Al-Ghimlas F, Todd DC. Creatine supplementation for patients with COPD receiving pulmonary rehabilitation: a systematic review and meta-analysis. Respirology. (2010)
384. Banerjee B, et al. Effect of creatine monohydrate in improving cellular energetics and muscle strength in ambulatory Duchenne muscular dystrophy patients: a randomized, placebo-controlled 31P MRS study. Magn Reson Imaging. (2010)
385. Bemben MG, et al. The effects of supplementation with creatine and protein on muscle strength following a traditional resistance training program in middle-aged and older men. J Nutr Health Aging. (2010)
386. Bassit RA, et al. Effect of short-term creatine supplementation on markers of skeletal muscle damage after strenuous contractile activity. Eur J Appl Physiol. (2010)
387. Kerksick CM, et al. The effects of creatine monohydrate supplementation with and without D-pinitol on resistance training adaptations. J Strength Cond Res. (2009)
388. Bazzucchi I, Felici F, Sacchetti M. Effect of short-term creatine supplementation on neuromuscular function. Med Sci Sports Exerc. (2009)
389. Juhász I, et al. Creatine supplementation improves the anaerobic performance of elite junior fin swimmers. Acta Physiol Hung. (2009)
390. Kendall KL, et al. Effects of four weeks of high-intensity interval training and creatine supplementation on critical power and anaerobic working capacity in college-aged men. J Strength Cond Res. (2009)
391. Cooke MB, et al. Creatine supplementation enhances muscle force recovery after eccentrically-induced muscle damage in healthy individuals. J Int Soc Sports Nutr. (2009)
392. Cornish SM, et al. Conjugated linoleic acid combined with creatine monohydrate and whey protein supplementation during strength training. Int J Sport Nutr Exerc Metab. (2009)
393. Law YL, et al. Effects of two and five days of creatine loading on muscular strength and anaerobic power in trained athletes. J Strength Cond Res. (2009)
394. Sakkas GK, et al. Creatine fails to augment the benefits from resistance training in patients with HIV infection: a randomized, double-blind, placebo-controlled study. PLoS One. (2009)
395. Johnston AP, et al. Effect of creatine supplementation during cast-induced immobilization on the preservation of muscle mass, strength, and endurance. J Strength Cond Res. (2009)
396. Little JP, et al. Creatine, arginine alpha-ketoglutarate, amino acids, and medium-chain triglycerides and endurance and performance. Int J Sport Nutr Exerc Metab. (2008)
397. Gualano B, et al. Does creatine supplementation improve the plasma lipid profile in healthy male subjects undergoing aerobic training. J Int Soc Sports Nutr. (2008)
398. Cancela P, et al. Creatine supplementation does not affect clinical health markers in football players. Br J Sports Med. (2008)
399. Burke DG, et al. Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults. Int J Sport Nutr Exerc Metab. (2008)
400. Koenig CA, et al. Comparison of creatine monohydrate and carbohydrate supplementation on repeated jump height performance. J Strength Cond Res. (2008)
401. Walter AA, et al. Effects of creatine loading on electromyographic fatigue threshold in cycle ergometry in college-age men. Int J Sport Nutr Exerc Metab. (2008)
402. Deacon SJ, et al. Randomized controlled trial of dietary creatine as an adjunct therapy to physical training in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. (2008)
403. Eckerson JM, Bull AA, Moore GA. Effect of thirty days of creatine supplementation with phosphate salts on anaerobic working capacity and body weight in men. J Strength Cond Res. (2008)
404. Brault JJ, et al. Parallel increases in phosphocreatine and total creatine in human vastus lateralis muscle during creatine supplementation. Int J Sport Nutr Exerc Metab. (2007)
405. Rawson ES, Conti MP, Miles MP. Creatine supplementation does not reduce muscle damage or enhance recovery from resistance exercise. J Strength Cond Res. (2007)
406. Chilibeck PD, Magnus C, Anderson M. Effect of in-season creatine supplementation on body composition and performance in rugby union football players. Appl Physiol Nutr Metab. (2007)
407. Faager G, et al. Creatine supplementation and physical training in patients with COPD: a double blind, placebo-controlled study. Int J Chron Obstruct Pulmon Dis. (2006)
408. Cribb PJ, Williams AD, Hayes A. A creatine-protein-carbohydrate supplement enhances responses to resistance training. Med Sci Sports Exerc. (2007)
409. Stout JR, et al. Effects of creatine supplementation on the onset of neuromuscular fatigue threshold and muscle strength in elderly men and women (64 - 86 years). J Nutr Health Aging. (2007)
410. Gotshalk LA, et al. Creatine supplementation improves muscular performance in older women. Eur J Appl Physiol. (2008)
411. Cancela P, et al. Creatine supplementation does not affect clinical health markers in soccer players. Br J Sports Med. (2007)
412. Wright GA, Grandjean PW, Pascoe DD. The effects of creatine loading on thermoregulation and intermittent sprint exercise performance in a hot humid environment. J Strength Cond Res. (2007)
413. Cramer JT, et al. Effects of creatine supplementation and three days of resistance training on muscle strength, power output, and neuromuscular function. J Strength Cond Res. (2007)
414. Kaptsan A, et al. Lack of efficacy of 5 grams daily of creatine in schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. (2007)
415. Kilduff LP, et al. Reliability and detecting change following short-term creatine supplementation: comparison of two-component body composition methods. J Strength Cond Res. (2007)
416. Easton C, Turner S, Pitsiladis YP. Creatine and glycerol hyperhydration in trained subjects before exercise in the heat. Int J Sport Nutr Exerc Metab. (2007)
417. Armentano MJ, et al. The effect and safety of short-term creatine supplementation on performance of push-ups. Mil Med. (2007)
418. Gualano B, et al. Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training. Amino Acids. (2008)
419. Silva AJ, et al. Effect of creatine on swimming velocity, body composition and hydrodynamic variables. J Sports Med Phys Fitness. (2007)
420. Beck TW, et al. Effects of a drink containing creatine, amino acids, and protein combined with ten weeks of resistance training on body composition, strength, and anaerobic performance. J Strength Cond Res. (2007)
421. Branch JD, Schwarz WD, Van Lunen B. Effect of creatine supplementation on cycle ergometer exercise in a hyperthermic environment. J Strength Cond Res. (2007)
422. Hass CJ, Collins MA, Juncos JL. Resistance training with creatine monohydrate improves upper-body strength in patients with Parkinson disease: a randomized trial. Neurorehabil Neural Repair. (2007)
423. Cribb PJ, et al. Effects of whey isolate, creatine, and resistance training on muscle hypertrophy. Med Sci Sports Exerc. (2007)
424. Stout JR, et al. Effects of twenty-eight days of beta-alanine and creatine monohydrate supplementation on the physical working capacity at neuromuscular fatigue threshold. J Strength Cond Res. (2006)
425. Ferguson TB, Syrotuik DG. Effects of creatine monohydrate supplementation on body composition and strength indices in experienced resistance trained women. J Strength Cond Res. (2006)
426. Pan JW, Takahashi K. Cerebral energetic effects of creatine supplementation in humans. Am J Physiol Regul Integr Comp Physiol. (2007)
427. Weiss BA, Powers ME. Creatine supplementation does not impair the thermoregulatory response during a bout of exercise in the heat. J Sports Med Phys Fitness. (2006)
428. Cribb PJ, Hayes A. Effects of supplement timing and resistance exercise on skeletal muscle hypertrophy. Med Sci Sports Exerc. (2006)
429. McMorris T, et al. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiol Behav. (2007)
430. Bender A, et al. Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial. Neurology. (2006)
431. Zoeller RF, et al. Effects of 28 days of beta-alanine and creatine monohydrate supplementation on aerobic power, ventilatory and lactate thresholds, and time to exhaustion. Amino Acids. (2007)
432. Reardon TF, et al. Creatine supplementation does not enhance submaximal aerobic training adaptations in healthy young men and women. Eur J Appl Physiol. (2006)
433. Pluim BM, et al. The effects of creatine supplementation on selected factors of tennis specific training. Br J Sports Med. (2006)
434. Glaister M, et al. Creatine supplementation and multiple sprint running performance. J Strength Cond Res. (2006)
435. Watson G, et al. Creatine use and exercise heat tolerance in dehydrated men. J Athl Train. (2006)
436. Netreba I, et al. Creatine as a metabolic controller of skeletal muscles structure and function in strength exercises in humans. Ross Fiziol Zh Im I M Sechenova. (2006)
437. Kuethe F, et al. Creatine supplementation improves muscle strength in patients with congestive heart failure. Pharmazie. (2006)
438. Cornish SM, Chilibeck PD, Burke DG. The effect of creatine monohydrate supplementation on sprint skating in ice-hockey players. J Sports Med Phys Fitness. (2006)
439. Olsen S, et al. Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol. (2006)
440. Cañete S, et al. Does creatine supplementation improve functional capacity in elderly women. J Strength Cond Res. (2006)
441. Shi D. Oligosaccharide and creatine supplementation on glucose and urea nitrogen in blood and serum creatine kinase in basketball athletes. J Huazhong Univ Sci Technolog Med Sci. (2005)
442. Peyrebrune MC, et al. Effect of creatine supplementation on training for competition in elite swimmers. Med Sci Sports Exerc. (2005)
443. McConell GK, et al. Creatine supplementation reduces muscle inosine monophosphate during endurance exercise in humans. Med Sci Sports Exerc. (2005)
444. Murphy AJ, et al. Effects of creatine supplementation on aerobic power and cardiovascular structure and function. J Sci Med Sport. (2005)
445. Carter JM, et al. Does nutritional supplementation influence adaptability of muscle to resistance training in men aged 48 to 72 years. J Geriatr Phys Ther. (2005)
446. Chilibeck PD, et al. Creatine monohydrate and resistance training increase bone mineral content and density in older men. J Nutr Health Aging. (2005)
447. Perret C, Mueller G, Knecht H. Influence of creatine supplementation on 800 m wheelchair performance: a pilot study. Spinal Cord. (2006)
448. Anomasiri W, Sanguanrungsirikul S, Saichandee P. Low dose creatine supplementation enhances sprint phase of 400 meters swimming performance. J Med Assoc Thai. (2004)
449. Roy BD, et al. Creatine monohydrate supplementation does not improve functional recovery after total knee arthroplasty. Arch Phys Med Rehabil. (2005)
450. Fuld JP, et al. Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax. (2005)
451. Javierre C, et al. Creatine supplementation and performance in 6 consecutive 60 meter sprints. J Physiol Biochem. (2004)
452. Theodorou AS, et al. Effects of acute creatine loading with or without carbohydrate on repeated bouts of maximal swimming in high-performance swimmers. J Strength Cond Res. (2005)
453. Deldicque L, et al. Increased IGF mRNA in human skeletal muscle after creatine supplementation. Med Sci Sports Exerc. (2005)
454. Chilibeck PD, et al. Effect of creatine ingestion after exercise on muscle thickness in males and females. Med Sci Sports Exerc. (2004)
455. Taes YE, et al. Creatine supplementation does not decrease total plasma homocysteine in chronic hemodialysis patients. Kidney Int. (2004)
456. Shefner JM, et al. A clinical trial of creatine in ALS. Neurology. (2004)
457. Kilduff LP, et al. The effects of creatine supplementation on cardiovascular, metabolic, and thermoregulatory responses during exercise in the heat in endurance-trained humans. Int J Sport Nutr Exerc Metab. (2004)
458. Braegger CP, et al. Effects of creatine supplementation in cystic fibrosis: results of a pilot study. J Cyst Fibros. (2003)
459. Mendes RR, et al. Effects of creatine supplementation on the performance and body composition of competitive swimmers. J Nutr Biochem. (2004)
460. Santos RV, et al. The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race. Life Sci. (2004)
461. Korzun WJ. Oral creatine supplements lower plasma homocysteine concentrations in humans. Clin Lab Sci. (2004)
462. Tarnopolsky MA, et al. Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology. (2004)
463. Mero AA, et al. Combined creatine and sodium bicarbonate supplementation enhances interval swimming. J Strength Cond Res. (2004)
464. Chromiak JA, et al. Effect of a 10-week strength training program and recovery drink on body composition, muscular strength and endurance, and anaerobic power and capacity. Nutrition. (2004)
465. Eckerson JM, et al. Effect of two and five days of creatine loading on anaerobic working capacity in women. J Strength Cond Res. (2004)
466. Kilduff LP, et al. Effects of creatine on body composition and strength gains after 4 weeks of resistance training in previously nonresistance-trained humans. Int J Sport Nutr Exerc Metab. (2003)
467. Ayoama R, Hiruma E, Sasaki H. Effects of creatine loading on muscular strength and endurance of female softball players. J Sports Med Phys Fitness. (2003)
468. Rawson ES, Volek JS. Effects of creatine supplementation and resistance training on muscle strength and weightlifting performance. J Strength Cond Res. (2003)
469. Burke DG, et al. Effect of creatine and weight training on muscle creatine and performance in vegetarians. Med Sci Sports Exerc. (2003)
470. Verbessem P, et al. Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial. Neurology. (2003)
471. van Loon LJ, et al. Creatine supplementation increases glycogen storage but not GLUT-4 expression in human skeletal muscle. Clin Sci (Lond). (2004)

(Common misspellings for Creatine include Creatin, Craetine, creating, creetine, createen)

(Common phrases used by users for this page include types of creatine supplements literature, taking creatine monohydrate after colon cancer, make%20g%test%rubric, kreatine esther acryl, creatine and frequent urination, adverse effects of creatinine deficiency solutions)

(Users who contributed to this page include edozp, KurtisFrank, Insamity, raine, aaarum, Pwoolf, dbarvinok, Task_Master)