Beyond Muscle Energetics: Creatine in Brain Function, Mental Health, and Exercise Performance
DOI:
https://doi.org/10.12775/QS.2026.59.72819Keywords
creatine, supplementation, brain, health, muscle, strenght, endurance, performance, brain fatigueAbstract
Background. Creatine is widely recognized for its role in cellular energy metabolism, particularly in skeletal muscle. Increasing evidence indicates that its function extends to the central nervous system, where it may influence cognitive processes, neural stability, and resistance to fatigue.
Aim. The aim of this review is to examine the effects of creatine on brain function, cognitive performance, and exercise-related outcomes, with a focus on mechanisms linking neural and physical performance.
Material and methods. A narrative review of current literature was conducted, including experimental and clinical studies investigating the role of creatine in brain energetics, cognitive function, mental fatigue, and exercise performance.
Results. Available evidence indicates that creatine contributes to the maintenance of stable neural activity under sustained demand. Effects are most evident under conditions of increased cognitive load, sleep deprivation, or prolonged physical effort. While improvements in strength and power performance are consistently reported, effects in endurance and cognitive domains appear more context-dependent and are related to the preservation of signal stability and reduced variability in performance.
Conclusions. Creatine influences both cognitive and physical performance through mechanisms related to the consistency of neural function rather than isolated enhancement of capacity. Its effects are most pronounced in conditions requiring sustained or repeated effort, supporting a unified perspective linking brain function and exercise performance.
References
1. Sahlin K, Tonkonogi M, Söderlund K. Energy supply and muscle fatigue in humans. Acta Physiologica Scandinavica. 1998 Feb;162(3):261–6. doi:10.1046/j.1365-201X.1998.0298f.x
2. Braissant O, Henry H, Loup M, Eilers B, Bachmann C. Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Molecular Brain Research. 2001 Jan;86(1–2):193–201. doi:10.1016/S0169-328X(00)00269-2
3. Ellington WR. Evolution and Physiological Roles of Phosphagen Systems. Annu Rev Physiol. 2001 Mar;63(1):289–325. doi:10.1146/annurev.physiol.63.1.289
4. Dolan E, Gualano B, Rawson ES. Beyond muscle: the effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury. European Journal of Sport Science. 2019 Feb;19(1):1–14. doi:10.1080/17461391.2018.1500644
5. Da Silva RP, Nissim I, Brosnan ME, Brosnan JT. Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. American Journal of Physiology-Endocrinology and Metabolism. 2009 Feb;296(2):E256–61. doi:10.1152/ajpendo.90547.2008
6. Da Silva RP, Clow K, Brosnan JT, Brosnan ME. Synthesis of guanidinoacetate and creatine from amino acids by rat pancreas. Br J Nutr. 2014 Feb 28;111(4):571–7. doi:10.1017/S0007114513003012
7. Sarter M, Givens B, Bruno JP. The cognitive neuroscience of sustained attention: where top-down meets bottom-up. Brain Research Reviews. 2001 Apr;35(2):146–60. doi:10.1016/S0165-0173(01)00044-3
8. Demant T, Rhodes E. Effects of Creatine Supplementation on Exercise Performance: Sports Medicine. 1999;28(1):49–60. doi:10.2165/00007256-199928010-00005
9. Balsom PD, Söderlund K, Ekblom B. Creatine in Humans with Special Reference to Creatine Supplementation: Sports Medicine. 1994 Oct;18(4):268–80. doi:10.2165/00007256-199418040-00005
10. Wallimann T, Tokarska-Schlattner M, Schlattner U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids. 2011 May;40(5):1271–96. doi:10.1007/s00726-011-0877-3
11. Meyer RA, Sweeney HL, Kushmerick MJ. A simple analysis of the ‘phosphocreatine shuttle’. American Journal of Physiology-Cell Physiology. 1984 May 1;246(5):C365–77. doi:10.1152/ajpcell.1984.246.5.C365
12. Balsom PD, Söderlund K, Sjödin B, Ekblom B. Skeletal muscle metabolism during short duration high‐intensity exercise: influence of creatine supplementation. Acta Physiologica Scandinavica. 1995 Jul;154(3):303–10. doi:10.1111/j.1748-1716.1995.tb09914.x
13. Kushmerick MJ, Moerland TS, Wiseman RW. Mammalian skeletal muscle fibers distinguished by contents of phosphocreatine, ATP, and Pi. Proc Natl Acad Sci USA. 1992 Aug 15;89(16):7521–5. doi:10.1073/pnas.89.16.7521
14. Jacobus WE, Lehninger AL. Creatine Kinase of Rat Heart Mitochondria. Journal of Biological Chemistry. 1973 Jul;248(13):4803–10. doi:10.1016/S0021-9258(19)43737-X
15. Peral MJ, García‐Delgado M, Calonge ML, Durán JM, De La Horra MC, Wallimann T, et al. Human, rat and chicken small intestinal Na+ ‐Cl− ‐creatine transporter: functional, molecular characterization and localization. The Journal of Physiology. 2002 Nov;545(1):133–44. doi:10.1113/jphysiol.2002.026377
16. Saltarelli MD, Bauman AL, Moore KR, Bradley CC, Blakely RD. Expression of the Rat Brain Creatine Transporter in situ and in Transfected HeLa Cells. Dev Neurosci. 2009 Aug 24;524–34. doi:10.1159/000111450
17. Spencer K. Analytical Reviews in Clinical Biochemistry: The Estimation of Creatinine. Ann Clin Biochem. 1986 Jan;23(1):1–25. doi:10.1177/000456328602300101
18. Shulman RG, Rothman DL, Behar KL, Hyder F. Energetic basis of brain activity: implications for neuroimaging. Trends in Neurosciences. 2004 Aug;27(8):489–95. doi:10.1016/j.tins.2004.06.005
19. Ivanov AI, Malkov AE, Waseem T, Mukhtarov M, Buldakova S, Gubkina O, et al. Glycolysis and Oxidative Phosphorylation in Neurons and Astrocytes during Network Activity in Hippocampal Slices. J Cereb Blood Flow Metab. 2014 Mar;34(3):397–407. doi:10.1038/jcbfm.2013.222
20. Hall CN, Klein-Flugge MC, Howarth C, Attwell D. Oxidative Phosphorylation, Not Glycolysis, Powers Presynaptic and Postsynaptic Mechanisms Underlying Brain Information Processing. Journal of Neuroscience. 2012 Jun 27;32(26):8940–51. doi:10.1523/JNEUROSCI.0026-12.2012
21. Erecińska M, Dagani F. Relationships between the neuronal sodium/potassium pump and energy metabolism. Effects of K+, Na+, and adenosine triphosphate in isolated brain synaptosomes. The Journal of general physiology. 1990 Apr 1;95(4):591–616. doi:10.1085/jgp.95.4.591
22. Bertorello AM, Hopfield JF, Aperia A, Greengard P. Inhibition by dopamine of (Na+ + K+)ATPase activity in neostriatal neurons through D1 and D2 dopamine receptor synergism. Nature. 1990 Sep 27;347(6291):386–8. doi:10.1038/347386a0
23. Tachikawa M, Fukaya M, Terasaki T, Ohtsuki S, Watanabe M. Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK‐Mi and CK‐B suggest a novel neuron–glial relationship for brain energy homeostasis. Eur J of Neuroscience. 2004 Jul;20(1):144–60. doi:10.1111/j.1460-9568.2004.03478.x
24. Rangaraju V, Calloway N, Ryan TA. Activity-Driven Local ATP Synthesis Is Required for Synaptic Function. Cell. 2014 Feb;156(4):825–35. doi:10.1016/j.cell.2013.12.042
25. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR. Functions and effects of creatine in the central nervous system. Brain Research Bulletin. 2008 Jul;76(4):329–43. doi:10.1016/j.brainresbull.2008.02.035
26. Bonvento G, Bolaños JP. Astrocyte-neuron metabolic cooperation shapes brain activity. Cell Metabolism. 2021 Aug;33(8):1546–64. doi:10.1016/j.cmet.2021.07.006
27. Jang S, Nelson JC, Bend EG, Rodríguez-Laureano L, Tueros FG, Cartagenova L, et al. Glycolytic enzymes localize to synapses under energy stress to support synaptic function [Internet]. Cell Biology; 2016 [cited 2026 Apr 26]. Available from: http://biorxiv.org/lookup/doi/10.1101/042002 doi:10.1101/042002
28. Braissant O, Henry H. AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: A review. J of Inher Metab Disea. 2008 Apr;31(2):230–9. doi:10.1007/s10545-008-0826-9
29. Miller K, Sharer K, Suhan J, Koretsky AP. Expression of functional mitochondrial creatine kinase in liver of transgenic mice. American Journal of Physiology-Cell Physiology. 1997 Apr 1;272(4):C1193–202. doi:10.1152/ajpcell.1997.272.4.C1193
30. Dolder M, Wendt S, Wallimann T. Mitochondrial Creatine Kinase in Contact Sites: Interaction with Porin and Adenine Nucleotide Translocase, Role in Permeability Transition and Sensitivity to Oxidative Damage. Biol Signals Recept. 2001;10(1–2):93–111. doi:10.1159/000046878
31. Wallimann T, Dolder M, Schlattner U, Eder M, Hornemann T, O’Gorman E, et al. Some new aspects of creatine kinase (CK): compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology. BioFactors. 1998 Jan;8(3–4):229–34. doi:10.1002/biof.5520080310
32. Ricci JE, Gottlieb RA, Green DR. Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis. The Journal of Cell Biology. 2003 Jan 6;160(1):65–75. doi:10.1083/jcb.200208089
33. Kowaltowski AJ, Vercesi AE. Mitochondrial damage induced by conditions of oxidative stress. Free Radical Biology and Medicine. 1999 Feb;26(3–4):463–71. doi:10.1016/S0891-5849(98)00216-0
34. Nicholls DG, Budd SL, Castilho RF, Ward MW. Glutamate Excitotoxicity and Neuronal Energy Metabolism. Annals of the New York Academy of Sciences. 1999 Nov;893(1):1–12. doi:10.1111/j.1749-6632.1999.tb07813.x
35. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. American Journal of Physiology-Cell Physiology. 2004 Oct;287(4):C817–33. doi:10.1152/ajpcell.00139.2004
36. Balestrino M, Rebaudo R, Lunardi G. Exogenous creatine delays anoxic depolarization and protects from hypoxic damage: dose–effect relationship. Brain Research. 1999 Jan;816(1):124–30. doi:10.1016/S0006-8993(98)01131-7
37. Beal MF. Neuroprotective effects of creatine. Amino Acids. 2011 May;40(5):1305–13. doi:10.1007/s00726-011-0851-0
38. Attia A, Ahmed H, Gadelkarim M, Morsi M, Awad K, Elnenny M, et al. Meta-Analysis of Creatine for Neuroprotection Against Parkinson’s Disease. CNSNDDT. 2017 Feb 15;16(2):169–75. doi:10.2174/1871527315666161104161855
39. McTeague LM, Rosenberg BM, Lopez JW, Carreon DM, Huemer J, Jiang Y, et al. Identification of Common Neural Circuit Disruptions in Emotional Processing Across Psychiatric Disorders. AJP. 2020 May 1;177(5):411–21. doi:10.1176/appi.ajp.2019.18111271
40. Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. The Lancet Neurology. 2011 Feb;10(2):187–98. doi:10.1016/S1474-4422(10)70277-5
41. Harper DG, Jensen JE, Ravichandran C, Perlis RH, Fava M, Renshaw PF, et al. Tissue Type-Specific Bioenergetic Abnormalities in Adults with Major Depression. Neuropsychopharmacol. 2017 Mar;42(4):876–85. doi:10.1038/npp.2016.180
42. Kato T, Takahashi S, Shioiri T, Inubushi T. Brain phosphorous metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy. Journal of Affective Disorders. 1992 Dec;26(4):223–30. doi:10.1016/0165-0327(92)90099-R
43. Lener MS, Niciu MJ, Ballard ED, Park M, Park LT, Nugent AC, et al. Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine. Biological Psychiatry. 2017 May;81(10):886–97. doi:10.1016/j.biopsych.2016.05.005
44. Lyoo IK, Yoon S, Kim TS, Hwang J, Kim JE, Won W, et al. A Randomized, Double-Blind Placebo-Controlled Trial of Oral Creatine Monohydrate Augmentation for Enhanced Response to a Selective Serotonin Reuptake Inhibitor in Women With Major Depressive Disorder. AJP. 2012 Sep;169(9):937–45. doi:10.1176/appi.ajp.2012.12010009
45. Kondo DG, Sung YH, Hellem TL, Fiedler KK, Shi X, Jeong EK, et al. Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: A 31-phosphorus magnetic resonance spectroscopy study. Journal of Affective Disorders. 2011 Dec;135(1–3):354–61. doi:10.1016/j.jad.2011.07.010
46. Hultman R, Mague SD, Li Q, Katz BM, Michel N, Lin L, et al. Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology. Neuron. 2016 Jul;91(2):439–52. doi:10.1016/j.neuron.2016.05.038
47. Monk CS, Telzer EH, Mogg K, Bradley BP, Mai X, Louro HMC, et al. Amygdala and Ventrolateral Prefrontal Cortex Activation to Masked Angry Faces in Children and Adolescents With Generalized Anxiety Disorder. Arch Gen Psychiatry. 2008 May 1;65(5):568. doi:10.1001/archpsyc.65.5.568
48. Kenwood MM, Kalin NH, Barbas H. The prefrontal cortex, pathological anxiety, and anxiety disorders. Neuropsychopharmacol. 2022 Jan;47(1):260–75. doi:10.1038/s41386-021-01109-z
49. Davis GW, Müller M. Homeostatic Control of Presynaptic Neurotransmitter Release. Annu Rev Physiol. 2015 Feb 10;77(1):251–70. doi:10.1146/annurev-physiol-021014-071740
50. Contreras SA, Schleimer JH, Gulledge AT, Schreiber S. Activity-mediated accumulation of potassium induces a switch in firing pattern and neuronal excitability type. Rubin J, editor. PLoS Comput Biol. 2021 May 27;17(5):e1008510. doi:10.1371/journal.pcbi.1008510
51. Mamah D, Barch DM, Repovš G. Resting state functional connectivity of five neural networks in bipolar disorder and schizophrenia. Journal of Affective Disorders. 2013 Sep;150(2):601–9. doi:10.1016/j.jad.2013.01.051
52. Calhoun VD, Sui J, Kiehl K, Turner J, Allen E, Pearlson G. Exploring the Psychosis Functional Connectome: Aberrant Intrinsic Networks in Schizophrenia and Bipolar Disorder. Front Psychiatry. 2012;2. doi:10.3389/fpsyt.2011.00075
53. Heinz A, Schlagenhauf F. Dopaminergic Dysfunction in Schizophrenia: Salience Attribution Revisited. Schizophrenia Bulletin. 2010 May 1;36(3):472–85. doi:10.1093/schbul/sbq031
54. Schloesser RJ, Huang J, Klein PS, Manji HK. Cellular Plasticity Cascades in the Pathophysiology and Treatment of Bipolar Disorder. Neuropsychopharmacol. 2008 Jan;33(1):110–33. doi:10.1038/sj.npp.1301575
55. Kraguljac NV, Reid M, White D, Jones R, Den Hollander J, Lowman D, et al. Neurometabolites in schizophrenia and bipolar disorder — A systematic review and meta-analysis. Psychiatry Research: Neuroimaging. 2012 Aug;203(2–3):111–25. doi:10.1016/j.pscychresns.2012.02.003
56. Toniolo RA, Fernandes FDBF, Silva M, Dias RDS, Lafer B. Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial. Journal of Affective Disorders. 2017 Dec;224:69–75. doi:10.1016/j.jad.2016.11.029
57. Ohtsuki S, Tachikawa M, Takanaga H, Shimizu H, Watanabe M, Hosoya K ichi, et al. The Blood–Brain Barrier Creatine Transporter is a Major Pathway for Supplying Creatine to the Brain. J Cereb Blood Flow Metab. 2002 Nov;22(11):1327–35. doi:10.1097/01.WCB.0000033966.83623.7D
58. Braissant O. Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers. J of Inher Metab Disea. 2012 Jul;35(4):655–64. doi:10.1007/s10545-011-9433-2
59. Bemben MG, Lamont HS. Creatine Supplementation and Exercise Performance: Recent Findings. Sports Medicine. 2005;35(2):107–25. doi:10.2165/00007256-200535020-00002
60. Benton D, Donohoe R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br J Nutr. 2011 Apr 14;105(7):1100–5. doi:10.1017/S0007114510004733
61. Groeneveld GJ, Beijer C, Veldink JH, Kalmijn S, Wokke JHJ, Van Den Berg LH. Few Adverse Effects of Long-Term Creatine Supplementation in a Placebo-Controlled Trial. Int J Sports Med. 2005 May;26(4):307–13. doi:10.1055/s-2004-817917
62. Yoshizumi WM, Tsourounis C. Effects of Creatine Supplementation on Renal Function. Journal of Herbal Pharmacotherapy. 2004 Jan;4(1):1–7. doi:10.1080/J157v04n01_01
63. Kim HJ, Kim CK, Carpentier A, Poortmans JR. Studies on the safety of creatine supplementation. Amino Acids. 2011 May;40(5):1409–18. doi:10.1007/s00726-011-0878-2
64. Amann M. Central and Peripheral Fatigue: Interaction during Cycling Exercise in Humans. Medicine & Science in Sports & Exercise. 2011 Nov;43(11):2039–45. doi:10.1249/MSS.0b013e31821f59ab
65. Mujika I, Padilla S. Creatine Supplementation as an Ergogenic Aid for Sports Performance in Highly Trained Athletes: A Critical Review. Int J Sports Med. 1997 Oct;18(07):491–6. doi:10.1055/s-2007-972670
66. Gandevia SC, Allen GM, Butler JE, Taylor JL. Supraspinal factors in human muscle fatigue: evidence for suboptimal output from the motor cortex. The Journal of Physiology. 1996 Jan 15;490(2):529–36. doi:10.1113/jphysiol.1996.sp021164
67. Taylor JL, Gandevia SC. A comparison of central aspects of fatigue in submaximal and maximal voluntary contractions. Journal of Applied Physiology. 2008 Feb;104(2):542–50. doi:10.1152/japplphysiol.01053.2007
68. Churchland MM, Afshar A, Shenoy KV. A Central Source of Movement Variability. Neuron. 2006 Dec;52(6):1085–96. doi:10.1016/j.neuron.2006.10.034
69. Féry YA, Ferry A, Hofe AV, Rieu M. Effect of Physical Exhaustion on Cognitive Functioning. Percept Mot Skills. 1997 Feb;84(1):291–8. doi:10.2466/pms.1997.84.1.291
70. Brisswalter J, Collardeau M, Ren?? A. Effects of Acute Physical Exercise Characteristics on Cognitive Performance: Sports Medicine. 2002;32(9):555–66. doi:10.2165/00007256-200232090-00002
71. Wax B, Kerksick CM, Jagim AR, Mayo JJ, Lyons BC, Kreider RB. Creatine for Exercise and Sports Performance, with Recovery Considerations for Healthy Populations. Nutrients. 2021 Jun 2;13(6):1915. doi:10.3390/nu13061915
72. Strauss E, Macdonald SWS, Hunter M, Moll A, Hultsch DF. Intraindividual variability in cognitive performance in three groups of older adults: Cross-domain links to physical status and self-perceived affect and beliefs. J Int Neuropsychol Soc. 2002 Nov;8(7):893–906. doi:10.1017/S1355617702870035
73. Waschke L, Kloosterman NA, Obleser J, Garrett DD. Behavior needs neural variability. Neuron. 2021 Mar;109(5):751–66. doi:10.1016/j.neuron.2021.01.023
74. Vanden Noven ML, Pereira HM, Yoon T, Stevens AA, Nielson KA, Hunter SK. Motor Variability during Sustained Contractions Increases with Cognitive Demand in Older Adults. Front Aging Neurosci. 2014 May 22;6. doi:10.3389/fnagi.2014.00097
75. McMorris T, Harris RC, Howard AN, Langridge G, Hall B, Corbett J, et al. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiology & Behavior. 2007 Jan;90(1):21–8. doi:10.1016/j.physbeh.2006.08.024
76. 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. Experimental Gerontology. 2018 Jul;108:166–73. doi:10.1016/j.exger.2018.04.013
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