Creatine: More Than a Performance Booster

by Alazar Menbere Haile, MD

Creatine is a widely used sports performance supplement best known for its role in strength training and remains one of the most extensively studied supplements on the market. It is synthesized from the amino acids arginine and glycine by the kidneys, liver, and pancreas, with a smaller contribution from the brain (1). This natural production by the body accounts for roughly half of daily requirements, while the remainder is obtained from dietary sources such as red meat and seafood (1). Most of the body’s creatine is stored in skeletal muscle, where it functions as a rapid, short-term energy source (1). Despite its popularity among exercise enthusiasts, its broader clinical applications and safety profile are less well recognized. This article summarizes these aspects in a concise and structured manner, drawing on the highest available levels of evidence.

Figure: Creatine powder

Creatine Supplementation in Sarcopenia

Beyond optimizing exercise performance, creatine supplementation has been investigated for its potential to mitigate sarcopenia, the age-related loss of muscle mass and function. A recent systematic review and meta-analysis of 33 studies in older adults and individuals with chronic disease found that creatine improved physical function, as measured by the sit-to-stand (STS) test, a reliable indicator of functional performance (2). Improvements were also observed in upper body strength, handgrip strength, and lean tissue mass (2). However, the overall quality of evidence ranged from low to very low, and no significant improvements were observed in measures of endurance, including timed up-and-go, walking time, and aerobic capacity (2). These findings are consistent with earlier meta-analyses demonstrating that creatine, particularly when combined with resistance training, enhances lean tissue mass and upper body strength in older adults (3, 4).

Creatine Supplementation and Memory

Creatine serves as a cellular energy reserve and a rapid fuel source for the brain (5, 6). A systematic review and meta-analysis by Prokopidis et al. (2023) demonstrated improvements in memory performance, particularly in adults older than 65 years (5). Similarly, a broader systematic review and meta-analysis by Xu et al. (2024), which examined higher-order cognitive functions (attention, memory, executive function, language, and processing speed), also reported a beneficial effect on memory (6). However, in contrast to the former review, the latter suggested greater benefit in individuals under 60 years of age (6). The latter review also reported a reduction in processing speed in women, suggesting a possible sex-based difference (6).

Several mechanisms have been proposed to explain these effects. Creatine improves brain energy availability by maintaining ATP (the main energy currency of cells) levels, enhances neuronal signaling through modulation of neurotransmitters such as acetylcholine, and supports both neuroplasticity and neuroprotection (6). However, both studies found no clear difference by duration of supplementation, suggesting a possible early time plateau beyond which additional benefit may be limited (5, 6). Additionally, no significant difference was observed between doses above and below five grams per day (5).

In summary, current evidence supports a modest beneficial effect of creatine supplementation on memory. However, results vary by age group, and the overall quality of evidence remains moderate due to differences in study design and outcome measures (5, 6).

Creatine Supplementation and Depression

The pooled results from a recent systematic review and meta-analysis suggest that creatine supplementation is associated with a modest reduction in depressive symptoms (7). However, the certainty of this evidence is very low, primarily due to small sample sizes and substantial variability across trials (7). As such, no strong recommendation can be made at present, and further high-quality studies are needed to clarify its role.

Creatine Supplementation and Glycemic Control

An emerging area of interest is the effect of creatine supplementation on glycemic control in both healthy individuals and those with type 2 diabetes. A systematic review and meta-analysis by Pinto et al. (2016) demonstrated that exercise is a strong effect modifier, as studies that did not include exercise alongside creatine failed to show improvements in glucose tolerance and insulin sensitivity, despite increased muscle creatine content (8). In contrast, when combined with exercise, creatine supplementation was associated with increased glucose uptake, mediated by increasing the number of glucose transporters (8). Additionally, the glucose response during an oral glucose tolerance test (OGTT), measured as the area under the curve, was reduced compared to controls, indicating improved glucose handling (8). These findings have been linked to increased muscle glycogen content and improved after-meal glucose profiles (8).

In individuals with type 2 diabetes, creatine supplementation has also been associated with reductions in HbA1c, a test that measures average blood sugar levels over three months, suggesting a potential benefit for long-term glycemic control (8). Overall, the available evidence indicates a net benefit when creatine is combined with exercise.

Creatine Supplementation and Renal Safety

A small proportion of total body creatine is converted to creatinine, which is freely filtered by the kidneys. Because creatinine is commonly used as a marker of renal function, concerns have been raised regarding the potential nephrotoxic effects of creatine supplementation. However, current evidence does not support this association. A recent systematic review and meta-analysis demonstrated an increase in serum creatinine levels following creatine supplementation, without a corresponding change in glomerular filtration rate (GFR), a more reliable indicator of renal function (9). This suggests that the observed rise in creatinine reflects increased production rather than impaired renal clearance.

It is important to note that isolated case reports have described adverse renal outcomes. For example, Taner et al. reported acute renal failure in a bodybuilder following a loading dose of 20 g/day for five days, followed by maintenance dosing (10). Similarly, Thorsteinsdottir et al. described acute kidney injury in a bodybuilder taking multiple supplements, including creatine (11). However, these reports contrast with the broader body of evidence, which has not demonstrated consistent harm (9). A key limitation of the literature remains the relative lack of long-term data beyond that of a year, as noted by Naeini et al. (2025) (9).

Final Takeaway

The current body of evidence is limited by the diversity of participants and small sample sizes, precluding definitive conclusions. Nevertheless, available data suggest that creatine supplementation may improve muscle mass and physical function in older adults, provide modest benefits for memory, and enhance glycemic control when combined with exercise. Importantly, it appears to have a generally favorable renal safety profile in healthy individuals.

References

1. Photo by Alex Saks on Unsplash (Source for cover art)

2. Kreider RB, Stout JR. Creatine in Health and Disease. Nutrients. 2021;13(2):447.

3. Davies TW, Watson N, Pilkington JJ, McClelland TJ, Azzopardi G, Pearse RM, et al. Creatine supplementation for optimization of physical function in the patient at risk of functional disability: A systematic review and meta-analysis. JPEN J Parenter Enteral Nutr. 2024;48(4):389-405.

4. Chilibeck PD, Kaviani M, Candow DG, Zello GA. Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: a meta-analysis. Open Access J Sports Med. 2017;8:213-26.

5. Forbes SC, Candow DG, Ostojic SM, Roberts MD, Chilibeck PD. Meta-Analysis Examining the Importance of Creatine Ingestion Strategies on Lean Tissue Mass and Strength in Older Adults. Nutrients. 2021;13(6):1912.

6. Prokopidis K, Giannos P, Triantafyllidis KK, Kechagias KS, Forbes SC, Candow DG. Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2023;81(4):416-27.

7. Xu C, Bi S, Zhang W, Luo L. The effects of creatine supplementation on cognitive function in adults: a systematic review and meta-analysis. Front Nutr. 2024;11:1424972.

8. Eckert I, Lima J, Dariva AA. Creatine supplementation for treating symptoms of depression: a systematic review and meta-analysis. Br J Nutr. 2025;134(11):947-59.

9. Pinto CL, Botelho PB, Pimentel GD, Campos-Ferraz PL, Mota JF. Creatine supplementation and glycemic control: a systematic review. Amino Acids. 2016;48(9):2103-29.

10. Naeini EK, Eskandari M, Mortazavi M, Gholaminejad A, Karevan N. Effect of creatine supplementation on kidney function: a systematic review and meta-analysis. BMC Nephrol. 2025;26(1):622.

11. Taner B, Aysim O, Abdulkadir U. The effects of the recommended dose of creatine monohydrate on kidney function. NDT Plus. 2011;4(1):23-4.

12. Thorsteinsdottir B, Grande JP, Garovic VD. Acute renal failure in a young weight lifter taking multiple food supplements, including creatine monohydrate. J Ren Nutr. 2006;16(4):341-5.

Assessed and Endorsed by the MedReport Medical Review Board