Effects of Creatine Supplementation on Brain Function: History
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Panagiotis Giannos

Creatine, a nitrogenous organic compound derived from reactions involving the amino acids arginine, glycine, and methionine, is important for resynthesizing ATP, particularly during times of increased metabolic demand (e.g., sleep deprivation, mental health conditions, or neurological diseases). Creatine supplementation (and guanidinoacetic acid; GAA) has the ability to increase brain creatine content in humans. Furthermore, creatine has shown some promise for attenuating symptoms of concussion, mild traumatic brain injury and depression but its effect on neurodegenerative diseases appears to be lacking. 

  • supplementation
  • mental health

1. Creatine and Guanidinoacetic Acid (GAA) Supplementation on Brain Creatine and Phophorylcreatine (PCr)

1.1. Creatine Monohdyrate Supplementation

Pioneering work in the 1990s by Harris et al. [1] and Hultman et al. [2] demonstrated increased muscle creatine levels following oral creatine monohydrate supplementation. Since the publication of these studies, it has been repeatedly shown that creatine supplementation increases muscle creatine and PCr levels using both nuclear magnetic resonance (NMR) spectroscopy and muscle biopsies (Kreider et al. [3]). It appears that the average increase in muscle creatine from creatine supplementation is about 20% with responses that could be characterized as low, medium, or high (≈40%). Intramuscular creatine levels can be further increased when creatine monohydrate ingestion is combined with exercise [1][4], insulin [5], carbohydrate [6], carbohydrate and protein [7], or lipoic acid [8].

Overall, it appears that brain creatine content can be increased with creatine supplementation. However, it is difficult to compare individual studies where brain creatine was assessed pre- and post-supplementation because the supplementation protocols are heterogeneous (2 to 20 g/d), the populations are different (e.g., patient vs. healthy), the regions of the brain assessed were dissimilar, and while some labs measure brain PCr using P31-NMR other research teams measured total creatine using H1-NMR. One factor that must be investigated in the future is the optimal dosage of creatine needed to elicit the largest increase in brain uptake in response to supplementation. Similarly, few data assessing simultaneous changes in creatine in multiple tissues (e.g., muscle and brain) are available. It is unlikely that the addition of nutrients such as carbohydrate or protein, or endocrine factors such as insulin will have any effect on brain creatine uptake. Currently, research indicates that brain creatine increases in response to creatine monohydrate supplementation. This increase is smaller than the skeletal muscle response to a similar supplementation protocol.

1.2. GAA Supplementation

Being a direct natural precursor of creatine, GAA (also known as glycocyamine; chemical formula: C3H7N3O2) has been used to treat neurological diseases for almost 70 years. In 1952, Henry Borsook from Caltech was arguably the first to investigate the effects of supplemental GAA (co-administered with betaine) in poliomyelitis-related disability [9]. The scholars reported beneficial effects of glycocyamine therapy in patients affected by acute anterior poliomyelitis, with the presumed therapeutic mechanism entailing enhanced creatine synthesis in target organs, including the brain and skeletal muscle. Succeeding neurological studies from the 1950s derived equivocal results in terms of GAA therapeutic potential, with some showing no clinical improvement in patients with various neurological dysfunctions (e.g., multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease) [10][11], while others demonstrated favorable effects of GAA on specific surrogate indicators of tissue metabolism in poliomyelitis [12], or mild patient-reported benefits from the treatment in motor-neuron disease [13]. However, these pioneering studies did not assess the effects of GAA on tissue creatine levels nor did they evaluate more brain-specific outcomes following GAA administration.

Preliminary data from human studies suggest that GAA can raise brain creatine levels and improve brain performance, with GAA (supplemented alone or along with creatine) perhaps put forward as a promising dietary strategy that could alter biomarkers of tissue bioenergetics in the brain. Nevertheless, more well-designed longitudinal studies are warranted to examine the brain-boosting potential of GAA in various clinical environments, including disorders with neurocognitive impairment and white matter diseases. While future efficacy studies with GAA for brain health are eagerly expected, GAA safety trials remain the utmost priority, considering possible neurotoxicity of exogenous amino acids and derivatives [14]. Addressing both the safety and efficacy of supplemental GAA and other open questions of GAA utilization in nutritional neuroscience (Figure 1) might be the next step forward for the creatine research.
/media/item_content/202206/62a18c4dbc722nutrients-14-00921-g001.png
Figure 1. Open questions of guanidinoacetic acid (GAA) supplementation for brain health.

2. Creatine and Cognitive Function

Robust evidence that clearly demonstrates the importance of creatine on cognitive function comes from individuals with creatine deficient syndromes, known to deplete brain creatine stores. Creatine deficiency syndrome is characterized by mental and development disorders such as learning delays and seizures [15][16], and importantly these symptoms are reversed, at least in part, by creatine supplementation [17][18][19].

Sleep deprivation is known to impact brain bioenergetics, and it appears that the effects of creatine supplementation in combination with sleep deprivation may enhance cognitive function compared to placebo. However, presently there are only two studies that have investigated cognitive function following sleep deprivation in humans and both were combined with mild to moderate exercise [20][21].

Overall, there is some evidence that creatine supplementation can augment measures of cognitive function. These cognitive effects appear to be more robust when brain bioenergetics are challenged, such as sleep deprivation.

3. Creatine for Neurodegenerative Diseases

The relevance of the adenosine triphosphate (ATP)/creatine kinase (CK)/PCr system for central nervous system (CNS) homeostasis is widely recognized. Therefore, increasing brain creatine content is thought to be potentially beneficial for different clinical conditions, such as neurodegenerative diseases [22][23]. Neurodegenerative diseases are commonly characterized as conditions involving a progressive and irreversible loss of neuronal function, thus hampering the ability to perform both cognitive and/or motor tasks. In light of the possible effects of creatine on muscle strength, mass and functionality, its consideration as an adjunct therapy to mitigate disease-related physical impairments is warranted [23][24].
Additionally, oxidative stress, energy depletion and mitochondrial damage are common features in neurodegenerative diseases, to which creatine may act by possibly scavenging reactive oxygen species and increasing energy production [25][26].

3.1. Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons, resulting in muscle atrophy, weakness and paralysis, ultimately leading to death [27]. Using creatine in ALS resides in its potential role as a neuroprotective agent, reducing oxidative stress, attenuating mitochondrial damage and dysfunction and generating energy through ATP resynthesis [25][28].

3.2. Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a life-threatening disease caused by mutations in the dystrophin gene that significantly reduces life span, mainly due to either respiratory or cardiac failure [29].
Creatine supplementation has been shown to improve strength and time to exhaustion in DMD and young Becker’s muscular dystrophy patients [30].

3.3. Huntington’s Disease

Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative condition characterized by movement, cognition, and behavioral impairments, that can also be fatal. It also encompasses mitochondrial damage and energy metabolism impairment, that can result in increased brain lactate and reduced ATP and PCr regeneration, owing to creatine as a possible promising therapeutic strategy [25][31].
In fact, creatine supplementation has been shown to attenuate disease progression [32]; however, these results are not consistent [33][34].

3.4. Multiple Sclerosis

Multiple sclerosis (MS) is characterized as an autoimmune neurodegenerative disease that results in impaired nerve transmission, with symptoms varying across muscle weakness, vision and balance impairments and fatigue. Patients with MS also show alterations in brain and cardiac creatine metabolism, further warranting studies on the effects of creatine supplementation in this disease.

3.5. Parkinson’s Disease

Parkinson’s disease (PD) is a one of the most common neurodegenerative diseases, especially in older adults. It is characterized by progressive losses of dopaminergic neurons, resulting in both cognitive and motor impairment, with symptoms ranging from tremor, postural instability, bradykinesia to loss of muscle mass and strength and increased susceptibility to fatigue [35].
Animal studies have shown that creatine supplementation could be potentially neuroprotective by preventing losses of dopaminergic neurons [36]. In humans, creatine has been shown to elicit an improved response to dopaminergic therapy [37] and increased strength and muscle function [38].

4. Creatine and Mental Health

The critical role of creatine in the brain is well documented through creatine deficiency syndromes, which are characterized by intellectual disability, language delay, seizure disorders, autism spectrum disorder and various movement disorders, with the primary treatment being creatine monohydrate supplementation in an attempt to increase creatine content in the brain [39]. Many mental health disorders have also been characterized to have abnormalities in brain bioenergetics, with some of the more prevalent disorders, such as depression, being associated with low creatine levels in certain regions of the brain [40]. Based on such observations, there has been growing interest in the possible use of creatine monohydrate in various brain/neurological disorders, including mental/psychiatric disorders.

4.1. Depression

Population-based research has established a link between dietary intake of creatine and depression risk in adults [41]. The scholars used the National Health and Nutrition Examination Survey to demonstrate a significant negative relationship between dietary creatine and depression. Direct interventional studies using 1H-magnetic resonance spectroscopy (1H-MRS) have also demonstrated that lower creatine levels in the prefrontal cortex are associated with low mood/increased depression [40]. Even prior to these observations, many different groups have undertaken trials of creatine supplementation in both animals and humans alone and/or in combination with other pharmaceutical interventions to treat depression.
Collectively, when looking at both the preclinical research and the limited number of small-scale human trials, the research suggests a possible role for creatine supplementation in the treatment of different forms of depression. However, more larger-scale randomized control trials are warranted, and they should include measurements of brain creatine and dietary measures to better understand habitual dietary intake of creatine on the response to such an intervention.

4.2. Anxiety and Post-Traumatic Stress Disorder

Generalized anxiety disorder (GAD) is the second most common mental health disorder in Canada, with a reported prevalence of 2.57% [42], while an estimated 70% of the population has experienced a traumatic event in their lifetime and 33% will experience three or more such events [43], which could lead to post-traumatic stress disorder (PTSD). There has been limited investigation into a possible role of creatine in GAD and PTSD. One study has suggested that creatine levels are lower in white matter of patients with GAD that was related to early trauma [44]. Similarly for PTSD, two studies have described reduced creatine levels in the hippocampal region of the brain [45][46]. Despite these observations, there has been little investigation into the possible use of creatine supplementation in these patient populations.

5. Creatine for Concussion and Traumatic Brain Injury (TBI)

Although the current body of research is limited, the utilization of creatine in the protection and management of concussion and mild traumatic brain injury (mTBI) has been noted as a particular area of interest [3][22][47][48][49][50][51][52]. The current treatment options to address physiological dysfunction following concussion and mTBI is limited to aerobic exercise treatment; however, creatine is postulated to be another option which could address aspects of the neurometabolic cascade associated with a concussion or mTBI [53][54]. Specifically, immediately following a concussion or mTBI a state of hypermetabolism occurs which is then followed by a state of hypometabolism [54][55], however due to limited cerebral energy availability and injury-induced cerebral blood flow anomalies [56], energy supply and demand are uncoupled [53]. Following mTBI, brain creatine content decreases [57][58] and, therefore, creatine supplementation could be beneficial in this scenario.

6. Conclusions and Future Directions

It is well established that creatine supplementation can have favorable effects on measures of skeletal muscle mass and performance (i.e., strength). Beyond muscle, accumulating research shows that creatine supplementation and GAA can increase brain creatine content which may help explain some of the preliminary benefits from creatine supplementation on indices of cognition, depression, concussion, and TBI. Research is lacking or inconsistent regarding the efficacy of creatine for treating symptoms of neurodegenerative diseases, anxiety, or PTSD. Future research is needed to determine the mechanistic and clinical effects of longer-term creatine supplementation dosing strategies on brain function and health. Future multifactorial interventions may also be required where creatine is combined with other strategies to enhance cognition or treat neurodegenerative diseases.

This entry is adapted from the peer-reviewed paper 10.3390/nu14050921

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