Creatine Uncovered: A Scientific Review of Its Role in Fitness and Health

Introduction

Creatine is a naturally occurring compound involved in cellular energy metabolism, commonly used as a dietary supplement in sports and medicine. While widely researched, its effectiveness and safety continue to be evaluated. This article examines creatine’s history, mechanism of action, clinical evidence, and areas of ongoing research.

Background and History of Creatine Use

Creatine is synthesized primarily in the liver, kidneys, and pancreas from amino acids—arginine, glycine, and methionine¹. It is stored in skeletal muscles and utilized as a rapid energy source during high-intensity activities. Discovered in the 19th century, creatine became widely used in the 1990s for athletic performance. Ongoing research has expanded its potential applications beyond sports, though findings remain mixed depending on the population studied.

Mechanism of Action

Creatine plays a role in cellular energy homeostasis primarily through the phosphocreatine (PCr) system²:

1. ATP Regeneration – During high-energy demands, adenosine triphosphate (ATP) is rapidly broken down to adenosine diphosphate (ADP), depleting energy stores. Phosphocreatine donates a phosphate group to ADP, restoring ATP levels, particularly in tissues with high energy demands such as skeletal muscle and the brain.
2. Buffering Intracellular pH – Creatine may help buffer acidosis in muscles, delaying fatigue by reducing hydrogen ion accumulation during anaerobic activity.
3. Mitochondrial and Cellular Bioenergetics – Some studies suggest that creatine supplementation can support mitochondrial function, though the extent of these effects in different populations is still being evaluated.
4. Neuroprotective and Systemic Roles – Emerging hypotheses suggest creatine may play a role in protecting against oxidative stress and maintaining cellular energy balance in non-muscle tissues, including the brain and heart.

Creatine and Fitness Performance: Current Findings

Studies have examined the efficacy of creatine supplementation in athletic performance:

• A 2024 systematic review published in Nutrients assessed multiple randomized controlled trials (RCTs) and found that creatine supplementation can improve maximal strength and power in resistance-trained individuals³. However, effects on endurance performance were inconsistent, and the intensity, volume, and types of resistance training protocols varied across the studies. 
• Another 2023 review in Nutrients concluded that creatine supplementation may enhance lean mass and recovery when combined with resistance training, though inter-individual response variability was noted⁴.

While evidence suggests benefits in anaerobic performance, systematic reviews highlight the variability in response depending on training status, baseline creatine levels, and other dietary factors.

Creatine Beyond Sports: Other Potential Applications

Beyond fitness, studies have investigated creatine’s role in neurological health, aging, and disease management.

1. Neurological and Cognitive Function
   1. A 2024 systematic review in Frontiers in Aging Neuroscience assessed creatine’s effects on cognitive function in adults, suggesting that creatine monohydrate supplementation may confer beneficial effects in memory, attention time, and information processing speed⁵. Larger robust clinical trials are warranted to further validate these findings, and future research should investigate the influence of different populations and intervention durations on the effects of creatine monohydrate supplementation.
   2. A 2023 meta-analysis in Nutrition Reviews examined creatine’s role on memory performance in healthy humans⁶. Overall, creatine supplementation improved measures of memory compared with placebo (standard mean difference [SMD] = 0.29; P = 0.02). Subgroup analyses revealed a significant improvement in memory in older adults (66–76 years) (SMD = 0.88; P = 0.009) compared with their younger counterparts (11–31 years) (SMD = 0.03; P = 0.72). Creatine dose (≈ 2.2–20 g/d), duration of intervention (5 days to 24 weeks), sex, or geographical origin did not influence the findings.
2. Mental Health and Depression
   1. A 2024 review article published in Cureus analyzed the effects of creatine supplementation on depression, finding reduced symptoms when combined with selective serotonin reuptake inhibitors, with potential improvement in brain energy metabolism and neuroplasticity⁷. It was generally well tolerated, though caution was warranted due to potential side effects, such as manic episodes in bipolar disorder and renal function impairment in patients with kidney dysfunction. Further research is needed to establish optimal dosing, long-term efficacy, and safety across diverse patient populations.
3. Aging and Sarcopenia
   1. A 2022 systematic review in Bone found that creatine, when combined with resistance training, is a viable lifestyle intervention to improve aging muscle mass, strength and measures of functionality, which may decrease the risk of falls and fractures in older adults⁸. The combination of creatine and resistance training has some beneficial effects on aging bone. However, these benefits disappear when no exercise intervention is used. Despite having some musculoskeletal benefits, the effects of creatine supplementation in individuals diagnosed with sarcopenia, osteoporosis, frailty and cachexia is relatively unknown.
4. Cardiometabolic Health
   1. A 2022 randomized clinical trial in Clinical Nutrition ESPEN evaluated creatine’s role in cardiovascular health in older men, concluding positive vascular effects of arterial stiffness and atherosclerosis, having the potential to serve as a potent adjuvant in the management of cardiovascular disease for older adults⁹. However, more research is recommended before any recommendations can be made.

Ongoing Research and Future Directions

Despite extensive research, several areas remain under investigation:

• Creatine and Long COVID – Preliminary studies are assessing creatine’s potential to support muscle function in post-viral fatigue syndromes.
• Creatine and Metabolic Disorders – Studies are evaluating whether creatine influences insulin sensitivity and glucose metabolism in individuals with type 2 diabetes.
• Personalized Supplementation – Future research may focus on genetic factors affecting creatine uptake and response to supplementation.

Safety and Dosage Considerations

Creatine has been extensively studied for safety, concluding that long-term supplementation at recommended doses most likely will not cause adverse effects in healthy individuals. The standard dosing regimen includes 3-5g per day. 

Individuals with pre-existing kidney conditions should consult a healthcare provider before use, as creatine metabolism can affect renal function markers. 

Conclusion

Creatine remains one of the most researched supplements in sports science. Systematic reviews and other research indicate potential benefits for muscle performance, particularly in combination with resistance training. However, evidence for its effects in cognitive function, aging, and disease prevention is still developing, with many studies showing promise. More large-scale, high-quality randomized controlled trials are needed to clarify creatine’s role beyond fitness.

References

1. LeWine HE. What is creatine? Potential benefits and risks of this popular supplement. Harvard Health. Published March 20, 2024. https://www.health.harvard.edu/exercise-and-fitness/what-is-creatine-potential-benefits-and-risks-of-this-popular-supplement. 
2. Bonilla DA, Kreider RB, Stout JR, et al. Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review. Nutrients. 2021;13(4):1238. Published 2021 Apr 9. doi:10.3390/nu13041238. 
3. Wang Z, Qiu B, Li R, Han Y, Petersen C, Liu S, Zhang Y, Liu C, Candow DG, Del Coso J. Effects of Creatine Supplementation and Resistance Training on Muscle Strength Gains in Adults <50 Years of Age: A Systematic Review and Meta-Analysis. Nutrients. 2024; 16(21):3665. https://doi.org/10.3390/nu16213665. 
4. Burke R, Piñero A, Coleman M, et al. The Effects of Creatine Supplementation Combined with Resistance Training on Regional Measures of Muscle Hypertrophy: A Systematic Review with Meta-Analysis. Nutrients. 2023;15(9):2116. Published 2023 Apr 28. doi:10.3390/nu15092116. 
5. Xu C, Bi S, Zhang W, Luo L. The effects of creatine supplementation on cognitive function in adults: a systematic review and meta-analysis. Frontiers in Nutrition. 2024;11. doi:https://doi.org/10.3389/fnut.2024.1424972. 
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):416-427. doi:10.1093/nutrit/nuac064. 
7. Juneja K, Bhuchakra HP, Sadhukhan S, et al. Creatine Supplementation in Depression: A Review of Mechanisms, Efficacy, Clinical Outcomes, and Future Directions. Cureus. 2024;16(10):e71638. Published 2024 Oct 16. doi:10.7759/cureus.71638. 
8. Darren G. Candow, Philip D. Chilibeck, Scott C. Forbes, et al. Creatine supplementation for older adults: Focus on sarcopenia, osteoporosis, frailty and Cachexia, Bone, Volume 162, 2022, 116467, ISSN 8756-3282, https://doi.org/10.1016/j.bone.2022.116467. 
9. Adrian Aron, Eryn J. Landrum, Adam D. Schneider, et al. Effects of acute creatine supplementation on cardiac and vascular responses in older men; a randomized controlled trial, Clinical Nutrition ESPEN, Volume 63, 2024, Pages 557-563, ISSN 2405-4577, https://doi.org/10.1016/j.clnesp.2024.07.008. 

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