Creatine
1. Identity
Chemical Name and Structure
Creatine is commonly known chemically as N-(amidino-N-methylglycine), methylglycosyamine, or N-methyl-guanidino acetic acid. Creatine and phosphorylated creatine are generally present in the muscular tissue, brain, and other organs of many vertebrates. Its molecular formula is C₄H₉N₃O₂ (PubChem CID 586). Creatine is a nitrogenous organic acid, derived from glycine, L-arginine, and S-adenosyl-L-methionine, which is involved in energy transfer in the form of phosphocreatine (PCr) and which is metabolized to creatinine to be excreted by the kidney.
Natural Sources
The bulk of creatine is stored in muscle—hence creatine's name, derived from the Greek word for flesh (κρέας). The mammalian body derives about half of its creatine stores from meat sources in food; the other half is made in the kidney and liver. Creatine is biosynthesized mainly in the liver and kidneys from three amino acids: glycine, which provides the carbon skeleton; arginine, which releases the amidino group; and methionine, which releases the methyl group. Natural food sources such as red meat, poultry, and fish also provide creatine, but only in small amounts. In order to obtain 10 grams per day of creatine from food alone, approximately 2.5 kg of meat would need to be consumed. The exogenous supply and endogenous biosynthesis must compensate for the daily turnover of creatine to creatinine, which in a 70-kg male subject can be estimated at about two grams per day.
Approximately more than 95% of the human body's total creatine is located in skeletal muscle and brain.
Common Forms and Preparations
The main creatine formulations include creatine monohydrate, creatine anhydrous, and micronized creatine monohydrate; creatine monohydrate is the most common and well-studied form. Other variants include creatine hydrochloride, liquid creatine, buffered creatine (Kre-Alkalyn), creatine ethyl ester, magnesium-chelated creatine, and creatine nitrate, though many of these have not been proven to be more effective than creatine monohydrate.
- Creatine Monohydrate: The term "monohydrate" simply means the creatine molecule is bound to one molecule of water to ensure chemical stability. It is the most popular form and is considered affordable, safe, and the most researched.
- Micronized Creatine Monohydrate: The same compound processed into smaller particles to improve dissolution in liquids without altering the underlying molecule.
- Creatine Hydrochloride (HCl): Creatine HCl is bound to hydrochloric acid, which increases its solubility in water by roughly 38-fold compared to monohydrate. Proponents claim this allows for lower dosing and reduced gastrointestinal side effects. However, the solubility claim is accurate, but solubility and bioavailability are not the same thing. A 2022 review found no evidence that creatine HCl produces superior muscle creatine loading or performance outcomes compared to monohydrate when both are taken at effective doses.
- Creatine Ethyl Ester (CEE): Manufacturers of creatine ethyl ester promote their product as being able to bypass the creatine transporter due to improved sarcolemmal permeability. However, a study analyzing the effects of a 5-day loading protocol followed by a 42-day maintenance phase showed that ethyl ester was not as effective as creatine monohydrate in enhancing serum and muscle creatine stores.
- Buffered Creatine (Kre-Alkalyn): Buffered creatine has a higher pH level than creatine monohydrate, accomplished by adding alkaline powder to creatine. It is touted to enhance the effects of creatine monohydrate. However, this claim has not been scientifically proven. In fact, a 2012 study comparing buffered creatine to creatine monohydrate in 36 resistance-trained individuals found no significant differences between the two with regard to the accumulation of creatine in muscle tissue, training adaptations, or adverse effects.
- Liquid Creatine: Liquid creatine has been found to be less effective than creatine monohydrate. The reduced effect is likely due to the passive breakdown of creatine over a period of days into creatinine, which occurs when creatine is suspended in solution.
- Creatine Effervescent: Another form is creatine effervescent, which is creatine citrate or creatine monohydrate with citric acid and bicarbonate. The citric acid and bicarbonate react to produce an effervescent effect. When mixed with water, the creatine separates from its carrier, leaving a neutrally charged creatine and allowing it to dissolve to a higher degree in water.
In supplements, creatine is made synthetically in laboratories from sarcosine and cyanamide through controlled chemical reactions. Both natural and synthetic creatine have the same chemical structure. The key difference lies in the source (food/body versus lab synthesis) and the level of purity achievable through modern manufacturing processes.
2. Historical Discovery and Use
Scientific Discovery (1832–1927)
Creatine was first identified in 1832 when Michel Eugène Chevreul isolated the precipitate from the basified water-extract of skeletal muscle. He later named the crystallized precipitate after the Greek word for meat, κρέας (kreas).
In 1847, the German chemist Justus von Liebig replicated Chevreul's findings that creatine can be extracted from animal flesh. Building from this conclusion, he was able to discover that wild animals have more creatine in their muscles than their domestic counterparts.
In 1912, Harvard University researchers Otto Folin and Willey Glover Denis found evidence that ingesting creatine can dramatically boost the creatine content of the muscle. In 1928, creatine was shown to exist in equilibrium with creatinine. Studies in the 1920s showed that consumption of large amounts of creatine did not result in its excretion, which pointed to the ability of the body to store creatine—suggesting its use as a dietary supplement.
In 1927, phosphocreatine (PCr) was discovered by Eggleton and Eggleton, and by Fiske and Subbarow. In the 1960s, the enzyme creatine kinase was shown to phosphorylate ADP using phosphocreatine to generate ATP and thus buffer the ATP/ADP ratio.
Pre-Supplementation Era: Anecdotal and Traditional Uses
During the period following early scientific discovery, some bodybuilders and weightlifters reportedly resorted to "sweated beef," a method to extract creatine from meat by hot steam, resulting in a highly creatine-enriched meat juice that was anecdotally said to be beneficial for muscle growth and performance. Also notable is the so-called "Jewish medicine," a concentrated chicken soup from a fresh chicken boiled to perfection, used as a traditionally inherited panacea that served to "cure" almost everything. These accounts represent informal, non-clinical practices and should not be equated with scientifically validated use.
Entry into Athletic and Commercial Use (1992–Present)
While creatine's influence on physical performance had been documented since the early twentieth century, it came into public view following the 1992 Olympics in Barcelona. An article in The Times reported that Linford Christie, the gold medal winner at 100 meters, had used creatine before the Olympics. An article in Bodybuilding Monthly named Sally Gunnell, who was the gold medalist in the 400-meter hurdles, as another creatine user. The Times also noted that 100-meter hurdler Colin Jackson began taking creatine before the Olympics. These media reports triggered widespread public and commercial interest in creatine supplementation.
3. Key Constituents and Mechanisms of Action
Phosphocreatine and the ATP-PCr Energy System
Creatine, when phosphorylated by creatine kinase with adenosine triphosphate (ATP), forms high-energy phosphocreatine (creatine phosphate), which is a significant cellular energy reserve, and adenosine diphosphate (ADP). Phosphorylation by creatine kinase is reversible, thus phosphocreatine helps to supply energy to cells in the body by increasing the formation of ATP as needed. This interaction maintains the ATP concentration at a constant level at the moments of its intense consumption.
The principal role of phosphocreatine (PCr) in skeletal muscle energy metabolism is that of a "temporal" energy buffer at sites of high energy translocation, which operates when the rate of ATP utilisation outstrips the rate of production by mitochondrial respiration. Thus, at the onset of steady-state contraction, or during non-steady-state conditions, PCr maintains ATP homeostasis at specific sites of high energy turnover.
The creatine kinase system has a dual role in intracellular energy metabolism: functioning as an energy buffer to restore depleted ATP levels at sites of high ATP hydrolysis, and to transferring energy in the form of phosphocreatine from the mitochondria to other parts of the cell by a process involving intermediate energy carriers, several enzymatic reactions, and diffusion through various intracellular structures.
Neurological and Broader Cellular Roles
Phosphocreatine energy transfer sites include membranes that engage in ion transport, axonal regions involved in transporting material along microtubules to and from presynaptic endings, and presynaptic endings where energy is required for neurotransmission. Neurons synthesize creatine, however the amount of creatine can be severely depleted during injury. As with skeletal and heart muscle, neuronal creatine stores can to some extent be increased by oral supplementation. The creatine kinase system also serves as an intracellular spatial energy transport mechanism.
Creatine may enhance cognitive function through various mechanisms, such as increasing brain energy supply, regulating neurotransmitter levels, and improving neuronal function.
Creatine supplementation may increase serum creatinine concentration for some individuals, but this does not necessarily indicate kidney dysfunction, as creatine is spontaneously converted into creatinine.
4. Scientific Evidence by Area of Use
4.1 High-Intensity Exercise and Muscular Strength
Creatine is one of the most rigorously studied and efficacious nutritional supplements in exercise and sport science, particularly with respect to its ergogenic effects during high-intensity, short-duration activities. The primary mechanism of creatine supplementation's ability to enhance exercise performance is attributed to its role in elevating intramuscular phosphocreatine stores, thereby facilitating a greater capacity to rapidly resynthesize ATP during short durations of repeated bouts of muscular effort.
Over the past three decades, numerous randomized controlled trials (RCTs) and review studies have investigated the effects of creatine supplementation on muscle strength, power output, and overall exercise performance across diverse populations and training backgrounds. One systematic review and meta-analysis included 69 RCTs assessing the impact of creatine supplementation on bench/chest press strength, handgrip strength, leg press strength, squat performance, vertical jump height, and Wingate test performance.
A 2025 network meta-analysis (PubMed PMID 41901084) comparing creatine, protein, and omega-3 supplementation across 35 randomized controlled trials enrolling 1,211 participants found that creatine supplementation demonstrated superior effects for muscle strength (SMD = 0.46, 95% CI: 0.29 to 0.63, SUCRA = 82.4%).
Regardless of the form, supplementation with creatine has regularly been shown to increase strength, fat-free mass, and muscle morphology with concurrent heavy resistance training more than resistance training alone.
Evidence strength: Strong. Multiple large-scale meta-analyses of RCTs consistently demonstrate significant improvements in maximal and repetitive strength output with creatine monohydrate supplementation, particularly for activities relying on the ATP-PCr energy system.
4.2 High-Intensity Anaerobic Performance (Sprint, Power)
A meta-analysis of nine studies (168 soccer players) found that creatine supplementation did not present beneficial effects on aerobic performance tests (SMD, −0.05; 95% CI, −0.37 to 0.28; p = 0.78) or phosphagen metabolism performance tests (strength, single jump, single sprint, and agility: SMD, 0.21; 95% CI, −0.03 to 0.45; p = 0.08). However, creatine supplementation showed significant beneficial effects on anaerobic performance tests (SMD, 1.23; 95% CI, 0.55–1.91; p <0.001), with a large and significant effect on Wingate test performance (SMD, 2.26; 95% CI, 1.40–3.11; p <0.001).
Evidence also shows that creatine demonstrated a more pronounced effect during aerobic or anaerobic exercise compared to placebo groups. Furthermore, in sports that demand significant cumulative energy, such as long-distance races, biking, or triathlons, some athletes have observed performance enhancements with creatine supplementation.
Evidence strength: Strong for repeated sprint/anaerobic performance; modest to mixed for single-sprint and aerobic endurance.
4.3 Muscle Hypertrophy (Muscle Mass Gains)
Creatine supplementation is the most popular ergogenic aid for athletes in recent years and is used for improving sport performance and muscle growth. However, creatine supplementation is not always effective in all populations.
Supplementation with creatine has regularly been shown to increase strength, fat-free mass, and muscle morphology with concurrent heavy resistance training more than resistance training alone. Creatine may also be of benefit in other modes of exercise such as high-intensity sprints or endurance training.
Evidence strength: Moderate to strong. Creatine supplementation combined with resistance training augments lean body mass gains compared to resistance training alone, though the magnitude of hypertrophy varies by population, age, and training status.
4.4 Older Adults: Sarcopenia, Muscle Strength, and Function
Accumulating evidence indicates that creatine supplementation, with and without resistance training, has possible anti-sarcopenic and anti-dynapenic effects. Specifically, creatine supplementation increases aging muscle mass and strength (upper- and lower-body), possibly by influencing high-energy phosphate metabolism, muscle protein kinetics, and growth factors.
Meta-analyses have revealed that adding creatine supplementation to exercise training significantly increases one-repetition maximum (1RM) test results and muscle strength in older adults. One such meta-analysis included 20 RCTs with a total of 1,093 participants (69% female and 31% male) searched through August 2024.
There is accumulating evidence that creatine monohydrate (≥3 grams/day) combined with resistance training is a viable intervention for improving strength, whole-body lean mass, regional muscle size and density, and select measures of functional ability in older adults. Future research should determine whether creatine monohydrate, with and without exercise training, provides muscle and functionality benefits for those diagnosed with sarcopenia and associated age-related conditions. Creatine monohydrate during resistance training programs shows some potential to improve bone health and prevent falls, but there is a lack of evidence that it can improve strength, lean body mass, muscle accretion, or functional ability in those classified as frail.
Evidence strength: Moderate to strong for augmenting resistance training benefits in older non-frail adults; insufficient for frail or clinically sarcopenic populations.
4.5 Cognitive Function and Brain Health
Creatine, a nitrogenous organic acid naturally occurring in vertebrates, plays a critical role in the energy metabolism of brain cells.
Current evidence suggests that creatine monohydrate supplementation may confer beneficial effects on cognitive function in adults, particularly in the domains of memory, attention time, and information processing speed. Larger robust clinical trials are warranted to further validate these findings.
Previous studies have shown that supplementation increases brain creatine levels, which might increase cognitive performance. The results of studies that have tested cognitive performance differ greatly, possibly due to different populations, supplementation regimens, and cognitive tasks. One large double-blind, placebo-controlled, crossover, pre-registered RCT included daily supplementation of 5 g for 6 weeks each.
Creatine supplementation can increase brain creatine stores, which may help explain some of the positive effects on measures of cognition and memory, especially in aging adults or during times of metabolic stress such as sleep deprivation. Specifically, creatine supplementation has been shown to improve measures of cognition and memory, primarily in aging adults, and decrease symptoms of sleep deprivation in human and animal populations.
The current limited evidence suggests that creatine may be associated with benefits for cognition in generally healthy older adults. However, high-quality clinical trials are warranted to further validate this relationship.
Robust evidence that clearly demonstrates the importance of creatine on cognitive function comes from individuals with creatine-deficient syndromes, which are known to deplete brain creatine stores.
Evidence strength: Preliminary to moderate. Beneficial signals exist, especially in older adults and those under metabolic stress, but evidence is heterogeneous and larger, well-designed trials are needed.
4.6 Traumatic Brain Injury (TBI) and Concussion
An open-label randomized controlled trial found that creatine supplementation (0.4 g of creatine/kg/day) for 6 months had several positive effects. Specifically, creatine reduced the duration of post-traumatic amnesia, intubation time, and intensive care unit stay, in addition to improving disability, good recovery, self-care, communication, locomotion, sociability, personality and behavior, and neurophysical and cognitive function.
Although the current evidence is limited, the utilization of creatine supplementation for the management and protection of concussion and TBI appears promising. The safety of creatine supplementation in humans is well established, so future research examining its use in human clinical trials would be of value. Further exploration of creatine supplementation, both prior to and following TBI, is required to determine an optimal consumption protocol.
Evidence strength: Preliminary. Early RCT data are encouraging, but insufficient large-scale trials exist to draw firm conclusions.
4.7 Mood Disorders: Depression and Anxiety
Creatine supplementation also shows promise for alleviating some symptoms of TBI and characteristics of muscular dystrophy in humans. The efficacy of creatine for treating symptoms of depression and anxiety is also encouraging, but clinical trials examining the effects of creatine independent of pharmacological interventions on these mood disorders are needed before a consensus can be reached.
Evidence strength: Preliminary. Encouraging signals from early clinical work, particularly as an augmentation agent, but standalone efficacy trials are lacking.
4.8 Alzheimer's Disease and Neurodegeneration
In Alzheimer's disease (AD) mouse models, creatine monohydrate supplementation improved cognitive function and brain energy metabolism and reduced pathological biomarkers such as amyloid beta (Aβ) and phosphorylated tau. Despite the critical role of creatine in sustaining brain energy and these encouraging preclinical findings, no clinical trials had investigated creatine monohydrate as an adjuvant therapy for patients with AD prior to very recent pilot work.
Because a pilot single-arm trial without a placebo was conducted, improvements cannot rule out artifact (test–retest, placebo effects, and so on). These results merely provide preliminary support for the hypothesis that creatine monohydrate may be beneficial for cognitive function in AD and suggest that future efficacy trials are needed.
Evidence strength: Very preliminary. Animal model data are supportive; human clinical evidence is currently limited to pilot/feasibility studies.
5. Body Systems Associated with Creatine
- Musculoskeletal System: Creatine supplementation increases aging muscle mass and strength, possibly by influencing high-energy phosphate metabolism, muscle protein kinetics, and growth factors.
- Central Nervous System: Creatine plays a critical role in the energy metabolism of brain cells. Brain creatine stores support neuronal ATP homeostasis, particularly under conditions of heightened demand.
- Cardiovascular System: Cellular depletion of ATP stores, as occurs during tissue ischemia, results in impaired tissue functions and cell death. Of foremost medical relevance, ischemia-related cardiovascular disease such as stroke and heart attack remains a leading cause of death and morbidity. Phosphocreatine's role in maintaining cardiac ATP homeostasis has made it a subject of investigation in cardiac ischemia research, though clinical evidence for supplemental creatine in cardiovascular disease is not yet well established.
- Renal System: The majority (>90%) of creatine supplementation ingested is removed from the plasma by the kidney and excreted in the urine.
- Bone: Creatine supplementation has shown potential to enhance bone mineral density in some but not all studies, and seems to affect the activation of cells involved in bone remodeling.
6. Dosage Forms and Reported Dosages
Forms
Creatine is commercially available as powders (monohydrate being most common), capsules, tablets, effervescent tablets, and pre-mixed drinks, though pre-mixed liquid preparations are associated with creatine degradation over time.
Dosage Protocols Reported in Clinical Research
- Loading Phase: Creatine monohydrate is a dietary supplement that increases muscle performance in short-duration, high-intensity resistance exercises. The effective dosing for creatine supplementation includes loading with 0.3 g/kg/day for 5 to 7 days, followed by maintenance dosing at 0.03 g/kg/day most commonly for 4 to 6 weeks. However, loading doses are not necessary to increase intramuscular stores of creatine.
- Standard Loading (absolute dose): Oral creatine supplementation appears to be safe when used by healthy adults at recommended loading doses of 20 g/day for 5 days.
- Maintenance Phase: Maintenance doses of less than 3 g/day are considered standard recommended doses. Some studies have used maintenance doses of 5 g/day.
- Buffered Creatine (Manufacturer's Recommended): In a double-blind RCT, participants were assigned either creatine monohydrate at normal loading (4 × 5 g/day for 7 days) and maintenance (5 g/day for 21 days) doses, or Kre-Alkalyn at manufacturer's recommended doses (1.5 g/day for 28 days), or Kre-Alkalyn at equivalent loading and maintenance doses of creatine monohydrate.
- Older Adults: Evidence supports creatine monohydrate at ≥3 grams/day combined with resistance training as a viable intervention for improving strength and whole-body lean mass in older adults.
- Brain Health / TBI: An open-label RCT used creatine supplementation at 0.4 g of creatine/kg/day for 6 months in a TBI population.
- High-Dose Studies: A randomized, double-blind, placebo-controlled trial tested the renal effects of high-dose creatine supplementation of 10 grams/day for 3 months. The authors concluded that high-dose creatine supplementation daily for 90 days does not provoke renal dysfunction.
- Creatine Deficiency Syndromes: Creatine supplementation at 4–8 g/day for 25 months normalized plasma, urine, and brain creatine concentrations, as well as clinical symptoms.
- Long-Term Administration: Published studies have investigated the effects of creatine monohydrate supplementation from 5 to 20 g/day for up to 24 months on renal function in various populations.
7. Safety Considerations and Interactions
General Safety Profile
Creatine is a relatively safe supplement with few adverse effects reported. Available literature consistently shows that creatine monohydrate is safe when taken at recommended doses, even in clinical populations.
Renal Function
Despite a few case reports and animal studies suggesting that creatine may impair kidney function, clinical trials with controlled designs do not support this claim. Creatine supplementation may increase serum creatinine concentration for some individuals, but it does not necessarily indicate kidney dysfunction, as creatine is spontaneously converted into creatinine. Based on studies assessing kidney function using reliable methods, creatine supplements have been shown to be safe for human consumption.
Concern has been raised regarding creatine's potential for adverse effects on the kidneys, in part because creatine supplementation can increase urinary creatine and creatinine excretion. In response, Poortmans conducted studies showing that short-term supplementation does not alter glomerular filtration rate and that chronic supplementation of up to five years' duration did not impair renal function in healthy athletes.
Warnings about the potential harm of creatine supplementation on kidney health first emerged in the late 1990s, driven by case studies and preclinical trials in various animal models. However, most of these reports rely on retrospective observational data from individuals with pre-existing kidney conditions, who engaged in high-intensity and/or high-volume exercise, and/or who abused other substances known to affect renal function.
In terms of kidney health, studies consistently show no adverse effects on renal function in healthy individuals, though caution is advised for those with pre-existing kidney conditions and pregnant women, as evidence is lacking for these populations.
Animal studies have indicated that creatine could potentially exacerbate renal deterioration in pre-existing kidney conditions. Accordingly, individuals with known renal disease should not use creatine supplements without medical supervision.
Serum Creatinine as a Diagnostic Confound
In RCT data, serum creatinine levels increased in all groups receiving creatine, with higher doses promoting greater increases in serum creatinine, but the increases observed (0.1–0.2 mg/dL) were well within normal values for active individuals. Clinicians interpreting kidney function markers in creatine users should be aware that elevated serum creatinine may reflect exogenous creatine intake rather than renal pathology.
Gastrointestinal Effects
In published RCT data on buffered versus standard creatine monohydrate, no side effects were reported. Gastrointestinal discomfort (bloating, cramping, diarrhea) has been anecdotally reported with large loading doses; taking creatine with food and adequate hydration is commonly practiced by study participants.
Carcinogenicity
Although some theoretical risks, such as creatine's potential to form carcinogenic compounds, have been discussed, the available research does not support a link between creatine supplementation and cancer.
Quality and Impurities
Like other dietary supplements, creatine products may contain heavy metals such as lead, arsenic, and mercury. Impurities such as creatinine, dicyandiamide, and heavy metals can appear in poorly manufactured products. Third-party certification (e.g., NSF, Informed-Sport, USP) provides additional assurance of product purity.
Special Populations
Caution is advised for those with pre-existing kidney conditions and pregnant women, as evidence is lacking for these populations. Studies in children with TBI have been conducted; however, creatine use in pediatric populations more broadly requires further clinical evaluation.
Absence of Evidence for Interactions
Current peer-reviewed literature does not robustly document pharmacokinetic drug–nutrient interactions with creatine monohydrate at standard doses in healthy adults beyond the confounding of serum creatinine-based renal biomarkers noted above. Concerns about high-dose creatine's association with renal toxicity are based exclusively on two published case reports; in one of the cases the patient had a documented pre-existing kidney condition. Literature reviews and expert consensus panels have concluded there is no evidence supporting an association between creatine and renal disease.
References
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