Creatine: what survives replication

What survives replication, in creatine's case, fits into a single sentence: a gain in fatigue resistance during very intense, repeated efforts, measured from 2.3 g per day in young adults. The rest of the promise (cognition, bone density, mitochondrial metabolism) narrowed as the trials grew larger. It remains the most studied bioactive in the history of human supplementation: the official position stand of the International Society of Sports Nutrition counts over 1,000 studies conducted since the early 1990s (PubMed).

That mass of data has a rarely stated consequence. It made it possible to test the promises one by one, and to withdraw several of them.

The phosphocreatine/ATP system: a universal energy buffer

To understand why creatine interests longevity research, we need to return to the fundamental mechanism. Creatine is an endogenous nitrogen-containing molecule, synthesized primarily in the liver and kidneys from three amino acids: arginine, glycine, and methionine. Once inside the cell, it is phosphorylated by the enzyme creatine kinase (CK) to form phosphocreatine (PCr).

Phosphocreatine acts as a molecular battery. When energy demand spikes (intense muscle contraction, sustained neuronal activity, cellular stress), PCr donates its phosphate group to ADP (the "spent" form of the energy molecule) to regenerate ATP (adenosine triphosphate, the universal energy currency of our cells) within milliseconds. This is faster than glycolysis (the breakdown of glucose to produce energy). Vastly faster than mitochondrial oxidative phosphorylation (the process by which mitochondria produce ATP using oxygen).

This system is not limited to skeletal muscle. Creatine kinase and phosphocreatine are present in the brain, heart, retina, bone cells, and immune cells (PubMed). Every tissue with high energy demand depends on this buffer.

This universality is a solid mechanistic fact, and it is what fed the promise of a molecule good for everything. On its own it says nothing about what a daily 3 g intake produces in each of these tissues. That distance is exactly what the past ten years have measured.

2024: two regulators close the cognitive avenue

The brain represents 2% of body mass but consumes 20% of total energy. It is extremely dependent on the phosphocreatine/ATP system to maintain membrane potentials (the electrical signals that allow neurons to communicate), neurotransmission, and synaptic plasticity (the brain's ability to form and strengthen its connections). On paper, no tissue seemed better placed to benefit from an additional energy buffer.

The hypothesis was born from a randomized crossover trial published in the Proceedings of the Royal Society B. Six weeks of creatine monohydrate at 5 g per day improved working memory and processing speed in 45 young vegetarian adults (PubMed). The choice of population was no accident: dietary creatine comes exclusively from animal products, and vegetarian reserves are lower.

Benton and Donohoe extended that logic in 2011, in 128 young women split between vegetarians and omnivores. Supplementation improved memory in the vegetarians alone (PubMed). The dose used deserves reading: 20 g per day for five days, close to seven times what a food supplement may deliver in France.

The most cited synthesis in the field is a 2018 systematic review bringing together six randomized trials and 281 participants. It concludes that short-term memory and reasoning may improve, with a clearer signal in older and stressed individuals. It also carries a sentence that later accounts often omit: performance on cognitive tasks stayed unchanged in young individuals (PubMed). It is regularly presented as a meta-analysis; its authors did not pool the results.

In March 2024, Alzchem Trostberg GmbH, the leading European creatine producer, filed a health claim application: daily creatine supplementation can contribute to improved cognitive function. Proposed conditions of use: 3 g per day, for the general population, meaning healthy individuals of both sexes over 18 years of age. The dossier was assessed separately on both sides of the Channel, and refused twice in the same year.

The UK nutrition and health claims committee published its opinion on 14 August 2024. Of the ten randomized trials submitted, eight were set aside because they used a dose above 3 g per day, including the one by Benton and Donohoe. A ninth was set aside because it involved Muay Thai fighters taken to exhaustion. One relevant trial remained, conducted at 2.2 g per day in healthy non-vegetarian participants: it reported no difference between creatine and placebo, on any cognitive measure, at any time point. The committee's conclusion: no cause-and-effect relationship is established between the consumption of 3 g per day of creatine and improved cognitive function.

The European Food Safety Authority concluded in the same direction in November 2024. Its scientific panel notes that the acute effect on working memory, observed in two studies at 20 g per day for five to seven days, is found neither at lower doses (2.2 to 14 g per day), nor with continuous consumption at 5 g per day for six weeks (PubMed). The cause-and-effect relationship is not established.

The trial that could have settled the question had been published a year earlier. It is the largest ever conducted on cognition in healthy individuals: 123 participants, half of them vegetarians, 5 g per day for six weeks, crossover and double-blind (PubMed). Neither primary outcome reached the significance threshold (p = 0.064 and p = 0.327). Above all, the vegetarian hypothesis the trial had been specifically designed to test is not recovered: vegetarians did not benefit more from creatine than omnivores.

What holds: short, repeated effort

A single family of effects has cleared European regulatory scrutiny, and it is an old one. The regulation authorizes the statement that creatine increases physical performance in successive bursts of short-term, high-intensity exercise. The condition of use is twofold: the effect is obtained with 3 g of creatine per day, and the claim may accompany only foods targeting adults performing high-intensity exercise. Outside that context of effort, it does not apply.

A 2011 trial brought this family below the authorized dose. Twenty healthy adults averaging 21 years received, double-blind against placebo, 0.03 g per kilogram per day, roughly 2.3 g, for six weeks. Across five sets of thirty concentric knee extensions, fatigue resistance improved by 7, 9, 9, and 11% on sets 2 through 5, while the placebo group did not move (PubMed). No difference in body mass, fat-free mass, fat mass, or total body water was recorded. The sample is small and the analysis compares each group with its own baseline, without a reported interaction test: a robust signal that stops short of a definitive demonstration.

That leaves the question of timing. Sports literature popularized the loading phase: 20 g per day for five to seven days, then a maintenance dose. Muscle biopsies performed in 31 men in 1996 show that 20 g per day raise total muscle creatine by about 20% in six days, and that 3 g per day produce the same rise, more gradually, over 28 days (PubMed). The authors write it plainly: in the long term, 3 g per day are likely to raise tissue levels as effectively as the higher dose.

The second claim authorized in Europe concerns strength. It states that daily creatine consumption can enhance the effect of resistance training on muscle strength in adults over the age of 55. Its conditions are demanding: 3 g per day, in conjunction with progressive-load resistance training, at least three times per week for several weeks, at an intensity of at least 65 to 75% of one repetition maximum load. It rests on a meta-analysis of 357 older adults (64 years on average) followed across roughly twelve weeks of training, where adding creatine produced greater gains in fat-free mass and in chest press and leg press strength (PubMed).

The two longest trials in the field temper that picture. Two years of creatine in 237 postmenopausal women, at 0.14 g per kilogram per day and with training, produced no strength gain on bench press or hack squat (PubMed). Two years at 3 g per day in 200 postmenopausal women did not alter lean mass or muscle function either (PubMed). The claim rests on the regulatory assessment of a body of evidence more than on a consensus of trials, and that deserves to be known.

Lean mass follows the same dose logic. A 2024 meta-analysis of twelve trials puts a figure on the gain: about 1.1 kg more fat-free mass than training alone, at 7 g per day, or 0.3 g per kilogram (PubMed). That is more than double what a food supplement may deliver in France.

Bone, mitochondria, longevity: what the large trials did not find

Creatine's effect on bone tissue is biologically coherent. Osteoblasts (the cells that build bone) are high-energy-demand cells. They express creatine kinase and use the phosphocreatine/ATP system to fuel bone matrix synthesis. Preclinical data point that way: in vitro, creatine stimulates osteoblast differentiation and increases mineralization (PubMed).

The human result that launched this avenue dates from 2015: twelve months of resistance training in postmenopausal women, with 0.1 g of creatine per kilogram per day, roughly 7 g for a 70 kg person (PubMed). The femoral neck was better preserved in the creatine group.

The same team repeated the experiment on a larger scale, and did not recover its result. Two years, 237 postmenopausal women, an even higher dose of 0.14 g per kilogram per day: no effect on bone mineral density at the femoral neck, the total hip, or the lumbar spine (PubMed). What subsists concerns bone geometry, section modulus and buckling ratio, better maintained under creatine. The dedicated meta-analysis carries its conclusion in its title: creatine supplementation during resistance training does not lead to greater bone mineral density in older humans (PubMed). Its second signatory is the very author of the 2015 trial. And at 3 g per day for two years, bone markers, microarchitecture, falls, and fractures remained unchanged (PubMed).

The mitochondrial side has stayed in the laboratory. Mitochondrial creatine kinase forms functional complexes with porins (protein channels) on the outer mitochondrial membrane, which allows direct energy transfer between the mitochondrial matrix (the interior of the mitochondrion, where ATP is manufactured) and the cytoplasm. That description is mechanistic, and it remains so. The only human trial that has actually measured mitochondrial function under creatine is negative: in 15 patients carrying a single large-scale mitochondrial DNA deletion, six weeks at 150 mg per kilogram per day improved neither the resting phosphocreatine/ATP ratio, nor phosphocreatine recovery after exercise, which is the reference index of oxidative capacity measured in humans (PubMed).

That leaves the result that circulates most. In mice, creatine supplementation reduces lipofuscin accumulation (a marker of cellular aging) and increases median lifespan (PubMed). Extrapolating directly to humans would be premature. The mechanism remains consistent with what we know about the role of cellular energy in aging, and that is all that can be said about it today.

Form, dose, and safety

The supplement industry has multiplied creatine forms over the years: ethyl ester, hydrochloride, buffered kre-alkalyn, nitrate, pyruvate, magnesium chelate. Each claims superior absorption or reduced side effects. The position of the International Society of Sports Nutrition is explicit: monohydrate is the most extensively studied and clinically effective form, in terms of muscle uptake and capacity to increase performance during high-intensity exercise (PubMed). The same text describes as unfounded the claims that other forms degrade less in vivo or are better taken up by muscle. None has demonstrated superiority in head-to-head trials.

Monohydrate needs none of those devices. The conversion of creatine into creatinine in the digestive tract is minimal, whatever the transit time, and blood absorption is close to 100% (PubMed). Ingesting creatine with carbohydrates, or with carbohydrates and protein, more consistently favours its muscle retention. As for micronization, the European Commission has formally established that it changes neither the composition nor the structure of the food, nor its nutritional value: what it changes is physical, a micronized powder disperses and dissolves faster.

The practical protocol fits into one line. Three grams of creatine per day, without a loading phase, every day. Cycling in periods of stopping and restarting is supported by no data, and muscle stores return to their baseline level about thirty days after intake ceases (PubMed). Consistency outweighs intensity.

Three persistent myths

Creatine damages the kidneys. This is the most persistent myth, and the most unfounded. It rests on a confusion between creatine and creatinine. Creatinine is a kidney filtration marker whose levels rise naturally with supplementation, since creatine degrades into creatinine. A creatinine elevated for that reason does not reflect kidney dysfunction, a point developed in our article on creatinine. The longest controlled trial available followed 1,741 adults on 10 g per day for at least five years, in a Parkinson's disease cohort where creatine was being tested as a neuroprotective candidate: no detectable difference in adverse events, organ system by organ system (PubMed).

Creatine causes water retention. The weight gain described in the literature follows loading phases at 20 g per day. At 2.3 g per day for six weeks, the trial closest to the doses actually sold records no difference in body mass, fat-free mass, fat mass, or total body water (PubMed). The Spanish food safety agency concluded in 2024 that there is now more evidence to support that creatine does not cause the fluid retention attributed to it.

Creatine is a steroid or a stimulant. It belongs to neither of those two families. It does not by itself increase muscle protein synthesis: its mechanism runs through energy availability during effort, which improves the quality of the work performed and therefore the adaptation stimulus. It does not appear on the World Anti-Doping Agency prohibited list, verified against the 2026 edition.

One signal deserves to be placed alongside those three. In the largest trial available in healthy individuals, at 5 g per day, side effects were reported significantly more often under creatine than under placebo (p = 0.002, relative risk of 4.25) (PubMed). That is the tolerance datum closest to common doses, and it belongs in the picture.

What this story says about creatine goes beyond creatine. A molecule can be the most studied in its field and watch several of its promises shrink within ten years, simply because the trials grew larger and the doses were read closely. What remains is narrow, old, and solid: short, repeated, very intense efforts, at a dose the muscle saturates in a month.

The next frontier is identifiable. In healthy individuals, the largest cognitive trial counts 123 people and the longest window ever explored is six weeks; the single trial of 1,741 participants over five years was conducted in a neurodegenerative population. What is missing is a trial that is long, large, and run at a dose a food supplement is allowed to deliver. Until it exists, rigour consists in carrying the authorized dose and describing exactly what it produces.

Frequently asked questions

Does creatine act beyond muscle?#[ + ]

The phosphocreatine/ATP system it fuels is universal: it is found in muscle, but also in the brain, heart, bones, and immune cells. The benefits demonstrated in humans nonetheless remain centred on effort. The authorized European claim covers successive bursts of short-term, high-intensity exercise, with 3 g per day, in adults performing high-intensity exercise. The bone and mitochondrial avenues belong to the laboratory or to higher doses.

Is creatine dangerous for the kidneys?#[ + ]

The available data show no kidney damage in healthy individuals. The myth rests on a confusion between creatine and creatinine: supplementation mechanically raises this marker, which is a degradation product of creatine. The longest controlled trial available followed 1,741 adults on 10 g per day for at least five years, with no detectable difference in adverse events by organ system. Creatine remains inadvisable in cases of renal insufficiency.

Does creatine improve cognitive function?#[ + ]

At 3 g per day, the data do not establish it. In 2024, the European authority and the UK claims committee separately assessed a dossier filed at that dose for healthy adults, and both concluded that no cause-and-effect relationship had been established. Acute effects on working memory were observed at 20 g per day for five to seven days, and are not found at lower doses. The largest trial in healthy individuals, 123 participants at 5 g per day for six weeks, finds no particular advantage in vegetarians.

Which form of creatine should I choose?#[ + ]

Monohydrate is the most extensively studied and clinically effective form, in terms of muscle uptake and capacity to support high-intensity exercise. Conversion to creatinine in the digestive tract is minimal and blood absorption is close to 100%. Claims that other forms degrade less or are better taken up by muscle are described as unfounded by the position stand of the International Society of Sports Nutrition. Micronization changes neither composition nor nutritional value: it makes a powder for reconstitution easier to disperse.

What daily dose, and is a loading phase needed?#[ + ]

Three grams per day, without a loading phase. That is the dose conditioning the two authorized European claims, and it is also the regulatory maximum for a food supplement in France and in Switzerland. Muscle biopsies show that at this rate total muscle creatine rises by about 20% in 28 days, against six days at 20 g per day. Cycling is supported by no data; daily consistency is the only variable that counts.

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References

1. Kreider RB, Kalman DS, Antonio J, et al. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr. 2017;14:18 (PubMed).
2. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc Biol Sci. 2003;270(1529):2147-2150 (PubMed).
3. Benton D, Donohoe R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br J Nutr. 2011;105(7):1100-1105 (PubMed).
4. Avgerinos KI, Spyrou N, Bougioukas KI, Kapogiannis D. Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. Exp Gerontol. 2018;108:166-173 (PubMed).
5. Turck D, Bohn T, Cámara M, et al. Creatine and improvement in cognitive function: evaluation of a health claim pursuant to article 13(5) of regulation (EC) No 1924/2006. EFSA J. 2024;22(11):e9100 (PubMed).
6. Sandkühler JF, Kersting X, Faust A, et al. The effects of creatine supplementation on cognitive performance: a randomised controlled study. BMC Med. 2023;21(1):440 (PubMed).
7. Rawson ES, Stec MJ, Frederickson SJ, Miles MP. Low-dose creatine supplementation enhances fatigue resistance in the absence of weight gain. Nutrition. 2011;27(4):451-455 (PubMed).
8. Hultman E, Söderlund K, Timmons JA, Cederblad G, Greenhaff PL. Muscle creatine loading in men. J Appl Physiol. 1996;81(1):232-237 (PubMed).
9. Devries MC, Phillips SM. Creatine supplementation during resistance training in older adults: a meta-analysis. Med Sci Sports Exerc. 2014;46(6):1194-1203 (PubMed).
10. Chilibeck PD, Candow DG, Gordon JJ, et al. A 2-yr randomized controlled trial on creatine supplementation during exercise for postmenopausal bone health. Med Sci Sports Exerc. 2023;55(10):1750-1760 (PubMed).
11. Sales LP, Pinto AJ, Rodrigues SF, et al. Creatine supplementation (3 g/d) and bone health in older women: a 2-year, randomized, placebo-controlled trial. J Gerontol A Biol Sci Med Sci. 2020;75(5):931-938 (PubMed).
12. Desai I, Wewege MA, Jones MD, et al. The effect of creatine supplementation on resistance training-based changes to body composition: a systematic review and meta-analysis. J Strength Cond Res. 2024;38(10):1813-1821 (PubMed).
13. Gerber I, ap Gwynn I, Alini M, Wallimann T. Stimulatory effects of creatine on metabolic activity, differentiation and mineralization of primary osteoblast-like cells in monolayer and micromass cell cultures. Eur Cell Mater. 2005;10:8-22 (PubMed).
14. Chilibeck PD, Candow DG, Landeryou T, Kaviani M, Paus-Jenssen L. Effects of creatine and resistance training on bone health in postmenopausal women. Med Sci Sports Exerc. 2015;47(8):1587-1595 (PubMed).
15. Forbes SC, Chilibeck PD, Candow DG. Creatine supplementation during resistance training does not lead to greater bone mineral density in older humans: a brief meta-analysis. Front Nutr. 2018;5:27 (PubMed).
16. Kornblum C, Schröder R, Müller K, et al. Creatine has no beneficial effect on skeletal muscle energy metabolism in patients with single mitochondrial DNA deletions: a placebo-controlled, double-blind 31P-MRS crossover study. Eur J Neurol. 2005;12(4):300-309 (PubMed).
17. Bender A, Beckers J, Schneider I, et al. Creatine improves health and survival of mice. Neurobiol Aging. 2008;29(9):1404-1411 (PubMed).
18. Writing Group for the NINDS Exploratory Trials in Parkinson Disease (NET-PD) Investigators. Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial. JAMA. 2015;313(6):584-593 (PubMed).