Review of creatine research clarifies role in energy metabolism, clinical potential

Comprehensive review of creatine metabolism and supplementation has clarified its role in cellular energy systems, performance enhancement and emerging therapeutic research, while emphasising limits in efficacy and the need for further clinical trials

A comprehensive scientific review has clarified the physiological role of creatine, a widely used dietary supplement, and has outlined its expanding relevance beyond sport into cognitive and clinical domains. The analysis, conducted by Dr Mehdi Boroujerdi and presented in the Handbook of Creatine and Creatinine In Vivo Kinetics, published by the Routledge imprint of the Taylor & Francis Group, has consolidated current understanding of creatine metabolism, bioavailability and therapeutic potential.

Creatine is an endogenous compound synthesised primarily in the liver, kidneys and pancreas from the amino acids glycine, arginine and methionine. It circulates via the bloodstream to tissues with high energy demand, particularly skeletal muscle, where approximately 95 per cent of total body creatine is stored. The remaining fraction is distributed across the brain, heart and other organs.

Within cells, creatine converts to phosphocreatine, a high-energy molecule that supports the rapid regeneration of adenosine triphosphate, the principal cellular energy carrier. This system has enabled cells to sustain energy supply during periods of acute demand, particularly in skeletal and cardiac muscle as well as neural tissue. The capacity to replenish adenosine triphosphate efficiently has underpinned creatine’s long-standing association with high-intensity physical performance.

After participation in cellular energy transfer, creatine has degraded to creatinine, which the kidneys excrete in urine. The review has emphasised that creatine storage is finite and varies between individuals, with tissue saturation limits that constrain the extent of supplementation benefits.

“Creatine’s role in muscle development is solely to provide energy for contraction and respiration,” Dr Boroujerdi explained, addressing persistent misconceptions regarding its classification and mechanism of action.

Creatine monohydrate has remained the most extensively studied formulation. Evidence reviewed in this volume has demonstrated that supplementation can elevate intramuscular creatine and phosphocreatine concentrations, which in turn enhances adenosine triphosphate regeneration during short-duration, high-intensity exercise. These biochemical effects have translated into measurable improvements in power output, sprint capacity and training volume.

Beyond physical performance, the review examined evidence that creatine may support aspects of cognitive function, including memory, processing speed and mood. These effects have appeared most pronounced in populations with lower baseline creatine availability, such as older adults. The brain’s reliance on stable energy supply has provided a plausible mechanistic basis for these observations.

Emerging research has also positioned creatine as a candidate for therapeutic application in a range of clinical contexts, including neurodegenerative disorders such as Parkinson’s disease, mood disorders including depression, and musculoskeletal decline associated with menopause. However, the review has emphasised that these applications remain investigational.

“Creatine’s anti-inflammatory and antioxidant properties further underscore its promise in clinical settings, though more robust trials are needed to confirm these benefits,” said Boroujerdi.

“With sufficient justification, appropriate dosage form, and dosing regimen, creatine may eventually be recognised as an over-the-counter therapeutic agent rather than merely a dietary supplement,” he added.

Standard supplementation protocols have typically involved a loading phase of approximately 20 grams per day, divided into four doses for five to seven days, followed by a maintenance intake of 3 to 5 grams per day. This strategy has enabled rapid saturation of muscle creatine stores. However, the review has noted that a lower daily intake of 3 to 5 grams can achieve comparable saturation over a longer period of approximately 28 days.

Bioavailability has remained a critical consideration. Not all ingested creatine has been absorbed, with gastrointestinal stability and individual muscle storage capacity influencing retention. Co-administration with carbohydrates has enhanced uptake through insulin-mediated transport mechanisms which has increased intracellular creatine accumulation.

The review has also highlighted inter-individual variability in response to supplementation. Differences between men and women have reflected variations in muscle mass and baseline creatine levels. Women, who typically present with lower creatine stores, may derive greater relative benefit. Similarly, older adults may benefit from creatine’s capacity to mitigate age-associated declines in muscle mass, bone density and cognitive performance.

Dietary patterns have also influenced baseline creatine availability. Individuals who follow vegetarian or vegan diets, and therefore consume little or no dietary creatine, have often exhibited lower endogenous levels and have responded more markedly to supplementation compared with omnivores.

“There is a pressing need for well-designed research projects in humans, utilising labelled creatine to generate relevant data and illuminate the grey areas of our knowledge about these compounds,” Boroujerdi said.

Combination strategies have attracted interest, with creatine frequently paired with compounds such as beta-alanine to enhance performance outcomes. However, the review has cautioned that evidence for synergistic effects remains inconsistent and requires further validation.

Despite its extensive evidence base, creatine has limitations. It does not directly stimulate muscle growth, nor does it replace the requirement for structured training and appropriate nutrition. Furthermore, the assumption that higher doses confer greater benefit has been unsupported, as excess creatine beyond tissue saturation has been converted to creatinine and is excreted without physiological gain.

Safety concerns – particularly those relating to renal function – have largely been addressed in healthy populations. Current evidence has indicated that creatine supplementation does not impair kidney function in individuals without pre-existing renal disease. Nevertheless, those with underlying kidney conditions should seek medical advice prior to use.

“Despite its many benefits, creatine is not a magic bullet. It does not directly build muscle or replace the need for proper training and nutrition.

“For now, creatine is best viewed as a supplement with significant potential, but not a panacea. Whether you’re an athlete, a student, or simply someone looking to support your health, understanding the science behind creatine is key to make informed decisions,” Boroujerdi concluded.

For further reading please visit: 10.1201/9781003604662