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August 02, 2022 6 min read

The ergogenic effects of creatine supplementation are well documented, with evidence supporting its efficacy in increasing muscle strength, lean mass, and exercise performance/muscle function, particularly when combined with exercise in different populations, from athletes to a wide spectrum of patient populations [1].

Although most of the total body’s creatine is found in skeletal muscle, the brain is also a very metabolically active tissue, accounting for up to 20% of the body’s energy consumption [2].  

Creatine seems to be relevant for energy provision to the central nervous system.

In fact, creatine-deficient syndromes which comprise depletion of brain creatine levels are characterized by major mental and developmental disorders (e.g., mental retardation, learning delays, autism, and seizures), which may be partially reversed by creatine supplementation [3].

Creatine Supplementation and Brain Creatine Levels

While muscle exclusively relies on dietary ingestion and endogenous synthesis from the liver, kidneys, and pancreas, the brain can synthesize creatine. Brain creatine doesn’t seem to be influenced by habitual dietary intake from food, because similar brain phosphocreatine levels are seen between vegetarians and omnivores [4]. 

The figure below illustrates endogenous creatine synthesis in the brain and its transport across the blood–brain barrier.

Fig: Dietary creatine is transported through the blood–brain barrier via a creatine transporter. Astrocytes cells can also endogenously produce creatine, which is taken up by the neurons expressing the creatine transporter. Cr: creatine; PCr: phosphocreatine; Gly: glycine; Arg: arginine; AGAT: L-ariginine: glycine amidinotransferase; GAA: guanidinoacetate; GAMT: guanidinoacetate methyltransferase, SAM: S-adenosylmethionine; CreaT: Cr transporter. [5]

 

Aging has been proposed to affect brain creatine content, however, comparable levels of brain phosphocreatine have also been found between apparently healthy elderly and young individuals [6].

Other factors related to aging that may influence brain creatine concentrations include reduced brain and/or physical activity, depression, schizophrenia, and panic disorder.

While reliable information is available on supplementation protocols aimed at increasing muscle creatine content [7], much less is known regarding the optimal supplementation strategy to increase brain creatine levels.  

There is a lot of discrepancy in the few studies done in respect to brain creatine assessment. 

Nevertheless, the available literature indicates possible elevations in both creatine and phosphocreatine in the brain following supplementation, though smaller than that seen in muscle (approximately half the increase) [8].

The explanation for these differences in creatine uptake between muscle and brain remains speculative.

Brain creatine content may rely less on exogenous creatine than muscle, which could theoretically involve a down-regulated response in brain creatine synthesis upon supplementation.

The brain also lacks the expression of creatine transporter in the astrocytes involved in the blood–brain barrier, thus implying a limited permeability of the brain to the circulating creatine [9], which is in agreement with the lack of increase in brain creatine following supplementation reported by some studies [6].

It's also reasonable to speculate that if the brain is, in fact, resistant to exogenous creatine, a high-dose, long duration protocol would be needed (i.e., 20 g/day for 4 weeks) [10].

The need for a higher supplementation dose in order to increase brain creatine level, as compared to the supplementation dose required for muscle, is substantiated by data from the only study assessing both muscle and brain creatine levels in response to supplementation, with increases found in muscle, but not the brain [6].

Creatine’s Effects On Cognition

Creatine supplementation may positively influence some aspects of cognition in different experimental paradigms [2].

It’s important to note that creatine’s effects seem more pronounced in stressful conditions like hypoxia and sleep deprivation combined with exercise [2].



Creatine’s ability to improve cognitive processing is of high interest to the athletic population.

There are many sports that include motor control, decision making, coordination, reaction time, and other cognitive tasks as key aspects of performance, which potentially can be affected by mental fatigue.

In reference to this, creatine may exert an ergogenic role, as it may mitigate mental fatigue and enhance performance. This has been shown under conditions of sleep deprivation and improvement in throwing accuracy in creatine supplemented individuals [11] whereas other studies showed no improvement in non-stressed individuals.

Creatine’s Effects On Brain Injury, Concussion & Hypoxia

One of the key problems with traumatic brain injury is the alteration of ATP demand due to reduced blood flow and hypoxia, which is low oxygen in the blood.

Brain creatine levels are reduced in the aftermath of a mild traumatic brain injury [12], making creatine supplementation, and the subsequent increase in brain creatine levels, a viable strategy to reduce severity of, or enhance recovery from, mild traumatic brain injury or concussion. It does this by offsetting negative changes in energy status within the brain.

The duration of the dysregulation in brain energy metabolism could potentially remain for weeks if not years.

This indicates that there could be later-life derangements in brain energy metabolism subsequent to mild traumatic brain injury, and corroborates the concept that creatine supplementation could be quite valuable in enhancing recovery from mild traumatic brain injury, even years post-injury.

Despite limited data, creatine supplementation seems potentially beneficial in reducing severity of or enhancing recovery from mild traumatic brain injury.

Further studies are needed on its role not only as a post-injury therapy but also as a neuroprotective agent in populations at high risk of mild traumatic brain injury.

Encouraging supplementation to reduce damage from or enhance recovery from mild traumatic brain injury based primarily on animal data in lieu of clinical trials would traditionally be considered premature.

However, given the devastating effects of mild traumatic brain injury, combined with a vast body of literature showing the safety and efficacy of creatine supplementation, encouraging supplementation for populations at risk of mild traumatic brain injury might be considered more pragmatic.

Summary

It’s quite evident that there is potential for creatine supplementation to enhance cognitive processing, especially in circumstances characterized by brain creatine deficits, which could be induced by acute stressors such as exercise, sleep deprivation or chronic, pathologic conditions such as Alzheimer’s disease, depression, mild traumatic brain injury.

Although there is solid evidence of creatine’s effectiveness on cognitive function, there are a few areas that need more elaborate data/research to gain a better understanding of this important area.

First, it’s crucial to determine the optimal creatine supplementation protocol that can increase brain creatine levels.

Secondly, supplementation studies that simultaneously assess both brain creatine levels and cognitive function are needed and thirdly, the identification of novel conditions in which supplementing creatine may be more effective in improving cognitive function is essential.

For example, creatine supplementation in a rested healthy brain has been shown to have a lessened effect compared to a ‘stressed’ brain.





References:
1.    Gualano, B., et al., In sickness and in health: the widespread application of creatine supplementation. Amino Acids, 2012. 43(2): p. 519-29.
2.    Turner, C.E., W.D. Byblow, and N. Gant, Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation. J Neurosci, 2015. 35(4): p. 1773-80.
3.    Stockler, S., P.W. Schutz, and G.S. Salomons, Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. Subcell Biochem, 2007. 46: p. 149-66.
4.    Solis M.Y., P.V.D.S., Artioli G.G., Roschel H., Otaduy M.C., Gualano B., Brain creatine depletion in vegetarians? A cross-sectional 1H-magnetic resonance spectroscopy (1H-MRS) study. . Br. J. Nutr., 2013. 111: p. 1272–1274.
5.    Roschel, H., et al., Creatine Supplementation and Brain Health. Nutrients, 2021. 13(2).
6.    Solis, M.Y., et al., Effect of age, diet, and tissue type on PCr response to creatine supplementation. J Appl Physiol (1985), 2017. 123(2): p. 407-414.
7.    Kreider, R.B., 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: p. 18.
8.    Dolan, E., B. Gualano, and E.S. Rawson, Beyond muscle: the effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury. Eur J Sport Sci, 2019. 19(1): p. 1-14.
9.    Beard, E. and O. Braissant, Synthesis and transport of creatine in the CNS: importance for cerebral functions. J Neurochem, 2010. 115(2): p. 297-313.
10.    Dechent, P., et al., Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol, 1999. 277(3): p. R698-704.
11.    Cook, C.J., et al., Skill execution and sleep deprivation: effects of acute caffeine or creatine supplementation - a randomized placebo-controlled trial. J Int Soc Sports Nutr, 2011. 8: p. 2.
12.    Vagnozzi, R., et al., Decrease in N-acetylaspartate following concussion may be coupled to decrease in creatine. J Head Trauma Rehabil, 2013. 28(4): p. 284-92.

 

Dr. Paul Henning

About Dr. Paul

I'm currently an Army officer on active duty with over 15 years of experience and also run my own health and wellness business. The majority of my career in the military has focused on enhancing Warfighter health and performance. I am passionate about helping people enhance all aspects of their lives through health and wellness. Learn more about me