(Markus Wyss and Rima Kaddurah-Daouk, 2000)

Chemical nature and synthesis

• Creatine (methylguanidoacetic acid) is a nitrogenous, non-proteinogenic amino acid derivative. 

• In humans, creatine is synthesized primarily in the kidneys, liver, and pancreas via a two-step pathway:

   1. Arginine:glycine amidinotransferase (AGAT) catalyzes transfer of an amidino group from arginine to glycine, producing guanidinoacetate + ornithine. 

   2. Guanidinoacetate N-methyltransferase (GAMT) methylates guanidinoacetate using S-adenosylmethionine (SAM) to form creatine. 

• Some tissues (e.g. brain, testes) have limited capacity for local creatine synthesis. 

• After synthesis or dietary absorption, creatine circulates via the bloodstream and is taken up into target tissues via a Na⁺/Cl⁻-dependent creatine transporter (CRT, also called SLC6A8). 

• Roughly 95 % of the body’s creatine pool is stored in skeletal muscle (in free creatine + phosphorylated form) with the remainder in brain, heart, testes, etc. 

• Creatine spontaneously (non-enzymatically) degrades to creatinine, which is excreted in urine (~1–2 % of creatine pool per day). 

Biochemical / physiological roles of creatine in the human body

Creatine (and its phosphorylated form, phosphocreatine) is central to high-flux energy metabolism, especially in tissues with rapidly fluctuating energy demand (muscle, brain, heart). Below are its main roles:

The phosphocreatine / creatine kinase (CK) system — an energy buffer and shuttle

The enzyme creatine kinase (CK) catalyses the reversible reaction:

Creatine + ATP —— Phosphocreatine (PCr) + ADP

This reaction provides a rapid buffer of high-energy phosphate, allowing ADP to be rephosphorylated to ATP during bursts of high energy demand. 

• In periods of high ATP consumption, phosphocreatine can donate its phosphate to ADP, rapidly regenerating ATP. Conversely, when ATP is abundant, excess phosphate is stored as PCr. 

• This buffering helps maintain the ATP/ADP ratio, avoiding precipitous drops in ATP during sudden energy demands (e.g., muscle contraction). 

• The PCr/Cr system also acts as a spatial energy shuttle: in larger cells, creatine/PCr may facilitate transport of high-energy phosphate from mitochondria (where ATP is generated) to sites of ATP consumption (e.g. contractile apparatus) via diffusion and local CK “relay” systems. 

Stabilisation of cellular energetics, mitochondrial function, and redox balance

• The creatine system helps stabilise mitochondrial membrane potential under periods of stress, reducing cellular damage from transient energy deficits or ischemia. 

• It may act as a cellular buffer against reactive oxygen species (ROS) by moderating metabolic stress and limiting overproduction of free radicals during energetic strain. 

• By shuttling phosphate and reducing local ADP accumulation, it can help maintain mitochondrial coupling and efficiency, and reduce fluctuations in local ADP concentrations that might otherwise inhibit oxidative phosphorylation. 

Role in excitable tissues: muscle contraction, brain neurotransmission, etc.

• In skeletal and cardiac muscle, the rapid regeneration of ATP via the CK / PCr system is essential to sustain contraction during brief high-power bursts (e.g. sprint, jump). 

• In the central nervous system, creatine helps maintain energy supply during synaptic activity, ion pumping (e.g. restoring membrane potentials), neurotransmitter cycling, and other energetically demanding processes. 

• Under conditions of metabolic stress (e.g. hypoxia, ischemia), the creatine/PCr system may help buffer energy supply shortfalls in neurons or glial cells. 

Other cellular roles (less firmly established)

• Some in vitro and theoretical studies suggest neuroprotective, anti-apoptotic, or membrane-stabilising effects of creatine, especially under pathological stress (oxidative stress, excitotoxicity) 

• There is speculation about creatine influencing cell signaling, gene expression, or mitochondrial biogenesis, though human evidence is still limited. 

Supplementation of creatine: rationale, evidence, and limitations

“Creatine supplementation” most commonly refers to oral creatine monohydrate (CrM), which increases total creatine and phosphocreatine in tissues above baseline. Many human (and animal) studies have explored its effects in exercise, disease, and healthspan.

Effects in healthy / athletic populations

• Meta-analyses and randomised controlled trials show that creatine supplementation combined with resistance training can lead to greater gains in muscle mass, strength, and power compared to placebo + training. 

• For example, a 2003 meta-analysis reported average improvements of ≈ +8 % in one-rep-max strength and +14 % in repetitions to exhaustion compared to placebo in strength training settings. 

• Creatine supplementation also improves performance in short-duration, high-intensity exercise (e.g. sprints, repeated bursts) by enhancing ATP resynthesis capacity. 

• Some evidence indicates creatine may help recovery, rehabilitation, or reduce muscle damage when used after injury or in heavy training cycles. 

• Safety data from many studies suggest that creatine, in recommended dosages, is generally well tolerated and not associated with clinically significant adverse effects in healthy individuals when renal function is normal. 

Therapeutic / clinical contexts: evidence and limitations

Below are select conditions in which creatine supplementation has been studied. The evidence is mixed and often preliminary.

 Summary & key takeaways

• Creatine is a central compound in human energetics, especially for tissues with high and rapidly fluctuating ATP demand (muscle, brain).

• Its main biochemical role is via the creatine kinase / phosphocreatine system, acting as an energy buffer, shuttle, and stabiliser of cellular energetics.

• Oral creatine supplementation (especially creatine monohydrate) reliably increases intramuscular creatine and PCr stores and augments strength and performance in many individuals, when paired with resistance training.

• In pathophysiological contexts, creatine supplementation shows promise in conditions involving energy deficits, mitochondrial dysfunction, or metabolic stress (e.g. TBI, neurodegenerative disease, neuromuscular disease, cognitive impairment). But the clinical evidence is still emerging, mixed, and often preliminary.

• Safety in healthy individuals appears good for standard doses. However, in people with impaired renal function or other comorbidities, caution is warranted and clinical monitoring is essential.

References:

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• Balsom, P.D., Söderlund, K. and Ekblom, B. (1994) ‘Creatine in humans with special reference to creatine supplementation’, Sports Medicine (Auckland, N.Z.), 18(4), pp. 268–280. Available at: https://doi.org/10.2165/00007256-199418040-00005.

• Bonilla, D.A. et al. (2021) ‘Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review’, Nutrients, 13(4), p. 1238. Available at: https://doi.org/10.3390/nu13041238.

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• Kreider, R.B. et al. (2017) ‘International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine’, Journal of the International Society of Sports Nutrition, 14(1), p. 18. Available at: https://doi.org/10.1186/s12970-017-0173-z.

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• Smith, A.N., Sullivan, D.K. et al. (2025) ‘Eight weeks of creatine monohydrate supplementation is associated with increased muscle strength and size in Alzheimer’s disease: data from a single-arm pilot study’, Frontiers in Nutrition, 12. Available at: https://doi.org/10.3389/fnut.2025.1670641.

• Tarnopolsky, M. and Martin, J. (1999) ‘Creatine monohydrate increases strength in patients with neuromuscular disease’, Neurology, 52(4), pp. 854–854. Available at: https://doi.org/10.1212/WNL.52.4.854.

• Woodcock, I.R. et al. (2025) ‘Effect of creatine monohydrate on motor function in children with facioscapulohumeral muscular dystrophy: A multicenter, randomized, double-blind placebo-controlled crossover trial’, Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 45(6), pp. 341–351. Available at: https://doi.org/10.1002/phar.70025.

• Wyss, M. and Kaddurah-Daouk, R. (2000) ‘Creatine and Creatinine Metabolism’, Physiological Reviews [Preprint]. Available at: https://doi.org/10.1152/physrev.2000.80.3.1107.