A review recently published in Sports Medicine has discussed a considerable number of research papers that describe the effects of the muscle-building supplement creatine on the brain.
Broadening the studies of a well-known supplement
Creatine is a natural compound that is naturally formed in the human body from other amino acids and is found in meat and fish [1]. Most of the research around creatine has been on its use as a bodybuilding supplement that is predominantly consumed by, and tested on, young male athletes [2]. It appears to have effects on women [3], including older women [4], although those effects may be blunted [5].
While this team has previously reviewed the effects of creatine supplementation on the brain [6], that review did not take sex- and age-related differences into account. Therefore, these authors have revisited the topic, including aging and its associated disorders.
Uptake is vital for functioning
The human brain requires creatine to function properly, and children who cannot properly process creatine suffer from a wide range of crippling developmental disorders [7]. Previous research suggests that both natively produced and consumed creatine are important for function, and creatine has its own specialized transporter, CT1, to cross the blood-brain barrier [6].
The specific biochemistry of creatine in the brain is highly complex, as not all brain cells process creatine in the same way [8]. Some disorders associated with low brain creatine are unaffected by creatine supplements [9], and a lack of CT1 seems to be to blame for that [10]. Other compounds that lead to creatine have been suggested in these cases [11].
Cognitive results
Creatine supplementation does not seem to benefit the standard cognitive performance of young people [12]. However, 68- to 85-year-olds showed improvements in memory after taking a much larger dose for a week [13].
Creatine has also been shown to reduce mental fatigue in a way that suggests better handling of oxygen [14], and one clinical trial suggests that it might aid in recovery from traumatic brain injuries in children and adolescents [15]. Other research leads these authors to conclude that creatine aids the brain in responding to stressors, such as sleep and oxygen deprivation.
Neurodegenerative disorders
The researchers lament the lack of creatine studies in human beings with Alzheimer’s. One rat study suggested that creatine supplementation may be negative in this case [16], with this disease causing creatine to become toxic.
There was a randomized clinical trial conducted on people with Parkinson’s disease. While creatine was well-tolerated, that trial found no benefit [17]. A different trial used creatine along with coenzyme Q10, another well-known supplement, and found that this combination maintained cognitive performance after a year [18].
The effects on creatine on multiple sclerosis were little studied. Here, the studies focused on the muscles rather than the brain, but there was no benefit found in creatine uptake [19]. While mouse studies suggested that creatine might have benefits for amyotrophic lateral sclerosis, most human studies have found no benefit [20].
Mood disorders
Because of creatine reuptake, some researchers consider creatine to be a neurotransmitter itself [21]. Lower brain creatine is associated with mood disorders, including social anxiety disorder [22]. Research into the effects of creatine on these disorders has been mixed, with some research finding that it has a statistically significant effect in combination with an antidepressant drug [23] while a different study shows no effect [24].
The lesson learned
While the research included in this review suggests that creatine supplements appear to have limited effects against brain stress, possibly including age-related brain stress, these broadly mixed and inconclusive results showcase an important lesson. Simply because a disorder is linked to a decrease in a vital compound does not mean that supplementing that compound is going to be an effective treatment, particularly when there are significant hurdles to getting the compound to its proper place.
Additionally, the depletion of creatine, in many cases, appears to be an effect rather than a cause, and finding and ameliorating the upstream causes of these disorders is likely to be considerably more effective than creatine supplementation. However, human research is extremely limited in most cases, and it may be that creatine has a significant effect on a specific disease.
Literature
[1] Wyss, M., & Kaddurah-Daouk, R. (2000). Creatine and creatinine metabolism. Physiological reviews, 80(3), 1107-1213.
[2] Kreider, R. B., & Stout, J. R. (2021). Creatine in health and disease. Nutrients, 13(2), 447.
[3] Smith-Ryan, A. E., Cabre, H. E., Eckerson, J. M., & Candow, D. G. (2021). Creatine supplementation in women’s health: a lifespan perspective. Nutrients, 13(3), 877.
[4] Candow, D. G., Forbes, S. C., Chilibeck, P. D., Cornish, S. M., Antonio, J., & Kreider, R. B. (2019). Effectiveness of creatine supplementation on aging muscle and bone: focus on falls prevention and inflammation. Journal of clinical medicine, 8(4), 488.
[5] Syrotuik, D. G., & Bell, G. J. (2004). Acute creatine monohydrate supplementation: a descriptive physiological profile of responders vs. nonresponders. The Journal of Strength & Conditioning Research, 18(3), 610-617.
[6] Forbes, S. C., Cordingley, D. M., Cornish, S. M., Gualano, B., Roschel, H., Ostojic, S. M., … & Candow, D. G. (2022). Effects of creatine supplementation on brain function and health. Nutrients, 14(5), 921.
[7] Fons, C., & Campistol, J. (2016, November). Creatine defects and central nervous system. In Seminars in pediatric neurology (Vol. 23, No. 4, pp. 285-289). WB Saunders.
[8] Braissant, O., & Henry, H. (2008). AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: a review. Journal of inherited metabolic disease, 31, 230-239.
[9] Bender, A., & Klopstock, T. (2016). Creatine for neuroprotection in neurodegenerative disease: end of story?. Amino Acids, 48, 1929-1940.
[10] Christie, D. L. (2007). Functional insights into the creatine transporter. Subcellular Biochemistry, 46, 99.
[11] Ostojic, S. M., Stojanovic, M., Drid, P., Hoffman, J. R., Sekulic, D., & Zenic, N. (2016). Supplementation with guanidinoacetic acid in women with chronic fatigue syndrome. Nutrients, 8(2), 72.
[12] Rawson, E. S., Lieberman, H. R., Walsh, T. M., Zuber, S. M., Harhart, J. M., & Matthews, T. C. (2008). Creatine supplementation does not improve cognitive function in young adults. Physiology & behavior, 95(1-2), 130-134.
[13] McMorris, T., Mielcarz, G., Harris, R. C., Swain, J. P., & Howard, A. (2007). Creatine supplementation and cognitive performance in elderly individuals. Aging, Neuropsychology, and Cognition, 14(5), 517-528.
[14] Watanabe, A., Kato, N., & Kato, T. (2002). Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neuroscience research, 42(4), 279-285.
[15] Sakellaris, G., Kotsiou, M., Tamiolaki, M., Kalostos, G., Tsapaki, E., Spanaki, M., … & Evangeliou, A. (2006). Prevention of complications related to traumatic brain injury in children and adolescents with creatine administration: an open label randomized pilot study. Journal of Trauma and Acute Care Surgery, 61(2), 322-329.
[16] Alimohammadi-Kamalabadi, M., Eshraghian, M., Zarindast, M. R., Aliaghaei, A., & Pishva, H. (2016). Effect of creatine supplementation on cognitive performance and apoptosis in a rat model of amyloid-beta-induced Alzheimer’s disease. Iranian Journal of Basic Medical Sciences, 19(11), 1159.
[17] Kieburtz, K., Tilley, B. C., Elm, J. J., Babcock, D., Hauser, R., Ross, G. W., … & Wills, A. M. (2015). Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial. Jama, 313(6), 584-593.
[18] Li, Z., Wang, P., Yu, Z., Cong, Y., Sun, H., Zhang, J., … & Ju, X. (2015). The effect of creatine and coenzyme q10 combination therapy on mild cognitive impairment in Parkinson’s disease. European neurology, 73(3-4), 205-211.
[19] Lambert, C. P., Archer, R. L., Carrithers, J. A., Fink, W. J., Evans, W. J., & Trappe, T. A. (2003). Influence of creatine monohydrate ingestion on muscle metabolites and intense exercise capacity in individuals with multiple sclerosis. Archives of physical medicine and rehabilitation, 84(8), 1206-1210.
[20] Groeneveld, G. J., Veldink, J. H., & van der Tweel, J. (2002). A randomized placebo-controlled trial of creatine in amyotrophic lateral sclerosis. Amyot Lat Scler, 3, 23.
[21] van de Kamp, J. M., Pouwels, P. J., Aarsen, F. K., ten Hoopen, L. W., Knol, D. L., de Klerk, J. B., … & Mancini, G. M. (2012). Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect. Journal of inherited metabolic disease, 35, 141-149.
[22] Yue, Q., Liu, M., Nie, X., Wu, Q., Li, J., Zhang, W., … & Gong, Q. (2012). Quantitative 3.0 T MR spectroscopy reveals decreased creatine concentration in the dorsolateral prefrontal cortex of patients with social anxiety disorder.
[23] Lyoo, I. K., Yoon, S., Kim, T. S., Hwang, J., Kim, J. E., Won, W., … & Renshaw, P. F. (2012). 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. American Journal of Psychiatry, 169(9), 937-945.
[24] Nemets, B., & Levine, J. (2013). A pilot dose-finding clinical trial of creatine monohydrate augmentation to SSRIs/SNRIs/NASA antidepressant treatment in major depression. International clinical psychopharmacology, 28(3), 127-133.
