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Creatine in Health and Disease

Human Clinical Research Facility, Exercise & Sport Nutrition Lab, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA
Physiology of Work and Exercise Response (POWER) Laboratory, Institute of Exercise Physiology and Rehabilitation Science, School of Kinesiology and Physical Therapy, University of Central Florida, 12494 University Blvd., Orlando, FL 32816, USA
Author to whom correspondence should be addressed.
Nutrients 2021, 13(2), 447;
Submission received: 8 December 2020 / Revised: 22 January 2021 / Accepted: 27 January 2021 / Published: 29 January 2021
(This article belongs to the Special Issue Creatine Supplementation for Health and Clinical Diseases)


Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because creatine plays a critical role in cellular metabolism, particularly during metabolically stressed states, and limitations in the ability to transport and/or store creatine can impair metabolism. Moreover, increasing availability of creatine in tissue may enhance cellular metabolism and thereby lessen the severity of injury and/or disease conditions, particularly when oxygen availability is compromised. This systematic review assesses the peer-reviewed scientific and medical evidence related to creatine’s role in promoting general health as we age and how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it provides reasonable conclusions about the role of creatine on health and disease based on current scientific evidence. Based on this analysis, it can be concluded that creatine supplementation has several health and therapeutic benefits throughout the lifespan.

1. Introduction

Creatine supplementation is one of the most studied and effective ergogenic aids for athletes [1]. The multifaceted mechanisms by which creatine exerts its beneficial effect include increasing anaerobic energy capacity, decreasing protein breakdown, leading to increased muscle mass and physical performance [1]. While these well-recognized creatine effects benefit the athlete, creatine may also serve as a potential clinical and therapeutic supplementary treatment to conventional medical interventions [2,3,4,5,6,7,8,9,10]. In this regard, over recent years, researchers have been investigating the potential therapeutic role of creatine supplementation on health-related conditions such as diabetes [11], sarcopenia [4,6,12,13], osteoporosis [2,14], cancer [10,15,16,17,18], rehabilitation [4,19,20,21,22,23,24,25,26], cognition [3,27,28,29], and cardiovascular health [5,6,8,30,31,32], among others. This work has increased interest in creatine use as a nutritional strategy to help maintain functional and mental capacity and, as we age, reduce risk to chronic disease, and/or serve as an adjunctive intervention to help manage disease and/or promote recovery. This special issue aims to provide comprehensive reviews of the role of creatine in health and clinical disease. To do so, we have invited a number of top creatine scholars to contribute comprehensive reviews as well as encouraged colleagues to submit meta-analyses and original research to this special issue.
As an introduction about creatine’s potential role in health and disease, the following provides a general overview of creatine’s metabolic role, purported benefits throughout the lifespan, and potential therapeutic applications. Additionally, we provide reasonable conclusions about the state of the science on creatine supplementation. This overview will be accompanied by separate, more comprehensive, literature reviews on the metabolic basis of creatine in health and disease as well as the potential role of creatine in pregnancy; children and adolescents; exercise and performance; physical therapy and rehabilitation; women’s health; aging, sarcopenia, and osteoporosis; brain neuroprotection and function; immunity, cancer protection and management; heart and muscle health; and, chronic and post-viral fatigue. We hope that this review and special issue will help readers and medical practitioners better understand the safety and efficacy of creatine supplementation in a variety of populations and provide recommendations about future research needs.

2. Methods

A systematic review of the scientific and medical literature was conducted to assess the state of the science related to creatine supplementation on metabolism, performance, health, and disease management. This was accomplished by doing keyword searches related to creatine supplementation on each topic summarized using the National Institutes for Health National Library of Medicine search engine. A total of 1322 articles were reviewed with relevant research highlighted in this systematic review.

3. Metabolic Role

Creatine (N-aminoiminomethyl-N-methyl glycine) is a naturally occurring and nitrogen-containing compound comprised from amino acids that is classified within the family of guanidine phosphagens [1,33]. Creatine is synthesized endogenously from arginine and glycine by arginine glycine amidinotransferase (AGAT) to guanidinoacetate (GAA). The GAA is then methylated by the enzyme guanidinoacetate N-methyltransferase (GAMT) with S-adenosyl methionine (SAMe) to form creatine [34]. The kidney, pancreas, liver, and some regions in the brain contain AGAT with most GAA formed in the kidney and converted by GMAT to creatine in the liver [35,36,37]. Endogenous creatine synthesis provides about half of the daily need for creatine [35]. The remaining amount of creatine needed to maintain normal tissue levels of creatine is obtained in the diet primarily from red meat and fish [38,39,40,41] or dietary supplements [1,42,43]. About 95% of creatine is stored in muscle with the remaining amount found in other tissues, like the heart, brain, and testes [44,45]. Of this, about 2/3 of creatine is bound with inorganic phosphate (Pi) and stored as phosphocreatine (PCr) with the remainder stored as free creatine (Cr). The total creatine pool (Cr + PCr) is about 120 mmol/kg of dry muscle mass for a 70 kg individual who maintains a diet that includes red meat and fish. Vegetarians have been reported to have muscle creatine and PCr stores about 20–30% lower than non-vegetarians [46,47]. The body breaks down about 1–2% of creatine in the muscle per day into creatinine which is excreted in the urine [46,48,49]. Degradation of creatine to creatinine is greater in individuals with larger muscle mass and individuals with higher physical activity levels. Therefore, a normal-sized individual may need to consume 2–3 g/day of creatine to maintain normal creatine stores depending on diet, muscle mass, and physical activity levels. In fact, Wallimann and colleagues [50] noted that since creatine stores are not fully saturated on vegan or normal omnivore diets that generally provide 0 or 0.75–1.5 g/day of creatine, daily dietary creatine needs may be in the order of 2–4 g/person/day to promote general health [1,50]. The most effective and rapid way to increase muscle creatine stores is to ingest 5 g of creatine monohydrate four times daily for 5–7 days (i.e., 0.3 g/kg/day) [46,49]. However, some studies have shown that consuming 2–3 g/day of creatine for 30 days can also effectively increase muscle creatine stores [46,49]. Dietary supplementation of 20–30 g/day of creatine monohydrate for up to 5 years has also been studied in some clinical populations who need higher levels to increase brain concentrations of creatine, offset creatine synthesis deficiencies, or influence disease states [51,52,53].
Creatine and phosphagens play a critical role in providing energy through the creatine kinase (CK) and PCr system [50,54,55]. In this regard, the free energy yielded from the enzymatic degradation of adenosine triphosphate (ATP) into adenosine diphosphate (ADP) and Pi by CK serves as a primary fuel to replenish ATP for cellular metabolism. Breaking down PCr into Pi and Cr with the enzyme CK yields about 10.3 kcals of free energy that can be used to resynthesize ADP -+ Pi into ATP [38,39,56,57]. The ability to replenish depleted ATP levels during high-energy demand states like intense exercise or in conditions where energy production is either impaired (e.g., ischemia, hypoxia) or insufficient due to increased demand (e.g., mental fatigue, some disease states) is important in maintaining ATP availability.
Creatine enters the cytosol through creatine transporters (CRTR) [58,59,60,61]. In the cytosol, creatine and associated cytosolic and glycolytic CK isoforms help maintain glycolytic ATP levels, the cytosolic ATP/ADP ratio, and cytosolic ATP-consumption [50]. Additionally, creatine diffuses into the mitochondria and couples with ATP produced from oxidative phosphorylation and the adenine nucleotide translocator (ANT) via mitochondrial CK. PCr then diffuse back into the cytosol and help meet energy needs. This coupling reduces the formation of reactive oxygen species (ROS) and therefore creatine acts as a direct and/or indirect antioxidant [18,21,62,63]. The creatine phosphate shuttle is important in translocating ATP produced from oxidative phosphorylation in the mitochondrial to the cytosol and areas within the cell needing ATP for energy metabolism [50,56,57]. The creatine phosphate shuttle thereby serves as an important regulator of cellular metabolism. The role of creatine in energy metabolism and impact that creatine has on maintaining energy availability in diseases that depend on the CK/PCr system provides the metabolic basis on how creatine can affect health, disease, and provide therapeutic benefit [6,9,21,41,50,64,65,66,67,68,69,70,71]. The role of creatine in energy metabolism will be discussed in greater detail in another paper in this special issue.

4. General Health Benefits

Most creatine research initially focused on creatine’s role in exercise performance, training adaptations, and safety in untrained and trained healthy individuals [1]. Creatine supplementation has been reported to increase muscle creatine and PCr levels, enhance acute exercise capacity, and improve training adaptations [44,66,69,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96]. The improvement in performance has generally been 10–20% on various high-intensity exercise tasks [97] that include lifetime fitness activities like fitness/weight training [77,84,91,98,99,100,101,102,103,104,105,106,107,108], golf [109], volleyball [110], soccer [82,111,112], softball [113], ice hockey [114], running [115,116,117,118,119], and swimming [73,74,120,121,122,123], among others. Ergogenic benefits have been reported in men and women from children to elderly populations, although the majority of studies have been conducted on men [74,111,113,124,125,126,127,128]. After comprehensively reviewing the literature, the International Society of Sports Nutrition (ISSN) concluded that creatine is “the most effective ergogenic nutritional supplement currently available to athletes in terms of increasing high-intensity exercise capacity and lean body mass during training” [1,42,44,89]. The American Dietetic Association, Dietitians of Canada, and the American College of Sports Medicine have come to similar conclusions in their position stands [129,130]. Thus, there is a strong scientific consensus that creatine supplementation is an effective ergogenic nutrient for athletes as well as individuals starting a health and fitness program.
As performance-related studies assessed health and safety markers, evidence began to accumulate that creatine supplementation may also offer some health and/or therapeutic benefits as we age [4,12,14,67,69,70,71,131]. In this regard, creatine supplementation has been reported to help lower cholesterol, triglycerides and/or manage blood lipid levels [77,132,133]; reduce the accumulation of fat on the liver [133,134]; decrease homocysteine thereby reducing risk of heart disease [30,135]; serve as an antioxidant [30,136,137,138,139]; enhance glycemic control [1,11,140,141,142,143]; reduce the progress of some forms of cancer [8,17,18,135,144,145,146,147]; increase strength and muscle mass [2,9,13,67,70,71,93,99,101,148,149,150,151,152,153,154]; minimize bone loss in some studies [2,4,14,16,99,150,155,156,157,158,159,160]; improve functional capacity in osteoarthritic and fibromyalgia patients [22,161,162]; enhance cognitive function particularly in older populations [3,27,28,69,94,127,131,159,163,164,165,166,167,168]; and, in some instances, improve the efficacy of some anti-depressant medications [5,29,169,170,171,172]. These findings support contentions that it is prudent for individuals to consume at least 3 g/day of creatine to support general health as one ages [1,50]. Therefore, although more research is needed, it can be reasonably concluded based on current evidence that creatine supplementation can increase cellular energy availability and support general health, fitness, and well-being throughout the lifespan.

5. Role of Creatine in Aging Populations

Several studies have evaluated the effects of creatine supplementation in older populations in an attempt to prevent sarcopenia, maintain strength, and/or reduce the risk of chronic disease. The following discusses some of these potential applications.

5.1. Muscle Mass, Strength, Bone and Body Composition

Sarcopenia is an age-related muscle condition characterized by a reduction in muscle quantity, muscle strength, and functional capacity. Although multifactorial, sarcopenia may be caused by changes in muscle protein kinetics (synthesis and breakdown), neuromuscular function, inflammation, physical activity, and nutrition [12,14]. We also generally lose strength, muscle mass, bone mass, balance while increasing body fat as we age, whether clinically diagnosed with sarcopenia or not [3,69,131]. A number of nutritional and exercise interventions have been suggested to counteract sarcopenia in older individuals, including creatine supplementation during resistance training [12,14]. For example, Brose and colleagues [173] were among the first to report that creatine supplementation (5 g/day for 14 weeks) during heavy resistance training promoted greater gains in muscle mass and isometric muscle strength in older adults (>65 years). Chrusch and coworkers [106] reported that older participants (60–84 years) who supplemented their diet with creatine (0.3 g/kg/day for 5 days and 0.07 g/kg/day for 79 days) during supervised resistance training (3 days/week for 12 weeks) experienced greater gains in lean tissue mass, lower-body maximal strength, and endurance, and isokinetic knee flexion/extension power compared to controls. Candow and colleagues [99] reported that creatine (0.1 g/kg/day) and protein (0.3 g/kg/day) supplementation increased muscle mass and strength while decreasing protein degradation and bone resorption markers in older men. Chilibeck and associates [150] found that creatine supplementation (0.1 g/kg/day) during 12 months of resistance training increased strength and bone density in postmenopausal women. Gualano and coworkers [98] reported that creatine supplementation (20 g/day for 5 days; 5 g/day for 161 days) during resistance training improved appendicular lean mass and muscle function in older vulnerable women and that creatine supplementation alone resulted in similar gains in muscle mass compared to those engaged in resistance training alone. Aguiar and coworkers [96] also found that creatine supplementation (5 g/day for 12 weeks) combined with resistance training improved muscle endurance, ability to perform functional tasks, maximal strength, and muscle mass in older women.
Additionally, McMorris et al. [174] reported that creatine supplementation (20 g/day for 7 days) after sleep deprivation improved balance measures. Bernat and colleagues [175] reported that creatine supplementation (0.1 g/kg/day) during 8 weeks of high-velocity resistance training in untrained healthy aging men promoted significantly greater gains in leg press and total lower-body strength, muscle thickness, and some measures of peak torque and physical performance. Moreover, a meta-analysis revealed that older individuals participating in resistance training experienced greater gains in muscle mass, strength, and functional capacity when supplementing their diet with creatine [91]. A similar meta-analysis conducted by Candow and colleagues [9] found that older individuals who took creatine during resistance training experienced significantly greater gains in muscle mass and upper body. While not all studies report statistically significant effects, the preponderance of available research supports contentions that creatine supplementation, when combined with resistance exercise, can help maintain or increase muscle mass, strength, and balance in older individuals and therefore serve as an effective countermeasure to attenuate sarcopenia. The role of creatine supplementation during resistance training in sarcopenic populations will be discussed in more detail in this paper series on aging, sarcopenia, and bone health.
In addition, people often experience adult-onset obesity as they age, prompting them to diet to promote weight loss. Unfortunately, this often leads to loss of muscle mass and strength, which would be counterproductive in older individuals. Creatine supplementation while following an energy-restricted diet may be an effective strategy to maintain muscle mass, promote fat loss, and help manage adult-onset obesity. In support of this contention, Forbes and colleagues [176] recently conducted a meta-analysis on the effects of creatine on body composition and found that creatine supplementation may not only help maintain muscle mass but also promote fat mass loss. This strategy could be helpful in preventing or managing adult-onset obesity. Thus, although more research is needed, it can be reasonably concluded based on available literature that creatine supplementation, particularly when combined with resistance training, can promote gains in strength and help maintain or increase muscle mass and bone density in older individuals. Further, creatine supplementation during energy-restriction-induced weight loss interventions may be an effective way to preserve muscle mass, promote fat loss, and thereby help manage adult-onset obesity.

5.2. Cognitive Function

Creatine supplementation has been reported to increase brain PCr content by 5–15% and thereby enhance brain bioenergetics [21,53,69,131,171]. Consequently, research has examined whether creatine supplementation affects cognition, memory, and/or executive function in older individuals as well as patients with mild cognitive impairment [94,168,174,177,178]. Several studies have found that creatine supplementation attenuates mental fatigue [27,28,127] and/or can improve cognition, executive function, and/or memory [28,94,127,168,177,179]. For example, Watanabe and associates [180] found that creatine supplementation (8 g/day for 5 days) increased oxygen utilization in the brain and reduced mental fatigue in participants performing repetitive mathematical calculations. Rae et al. [177] found that working memory and processing speed increased with creatine supplementation (5 g/day for 6 weeks). McMorris and colleagues [174] reported that sleep-deprived participants better maintained random movement generation, time to react to choices, mood state, and balance when supplemented with creatine (20 g/day for 7 days). These researchers also reported that random number generation, forward spatial recall, and long-term memory tasks were significantly improved in elderly participants when supplemented with creatine. Ling et al. [178] also reported that cognition on some tasks was improved with creatine ethyl ester supplementation (5 g/day for 15 days). More recently, VAN Cutsem and coworkers [27] reported that creatine supplementation (20 g/day for 7 days) prior to performing a simulated soccer match improved muscular endurance and prolonged cognitive performance. While more research is needed and not all studies show benefit [127,167], it can be reasonably concluded based on current scientific evidence that creatine supplementation may increase brain creatine content and/or support cognitive function, particularly as one ages.

5.3. Glucose Management and Diabetes

Creatine uptake into tissue is influenced by glucose and insulin [142,181,182]. Creatine supplementation has also been reported to prevent declines in the GLUT-4 transporter during immobilization while increasing GLUT-4 by 40% during rehabilitation after atrophy [140]. Moreover, co-ingestion of creatine with carbohydrate [47,183] or creatine with carbohydrate and protein [184] has been reported to increase creatine uptake and/or muscle glycogen levels [47,184,185]. Consequently, research has evaluated whether creatine supplementation may influence glucose management [10,11,140,141,142,143]. For example, Gualano et al. [141] evaluated the effects of creatine supplementation (5 g/day for 12 weeks) during training in participants with type 2 diabetes. The researchers found that creatine supplementation improved glucose tolerance to ingesting a standard meal, increased GLUT-4 translocation, and promoted a significant reduction in HbA1c levels. Moreover, the AMPK-alpha protein content tended to be higher after Cr supplementation and was significantly related to the changes in GLUT-4 translocation and Hb1Ac levels, suggesting that AMPK signaling may be implicated in the effects of supplementation on glucose uptake in type 2 diabetes [143]. Thus, there is evidence to suggest that creatine supplementation enhances glucose uptake and insulin sensitivity and, therefore, can help individuals manage glucose and HbA1c levels, particularly when initiating an exercise program [10,11,186]. Based on this literature, it can be reasonably concluded that creatine supplementation may support healthy glucose management.

5.4. Heart Disease

Coronary artery disease limits blood supply to the heart, thereby increasing susceptibility to ischemic events, arrhythmias, and/or heart failure. Creatine and PCr play an important role in maintaining myocardial bioenergetics during ischemic events [21]. For this reason, there has been interest in assessing the role of creatine or PCr administration in reducing arrhythmias, ischemia-related damage, and/or heart function in individuals with chronic heart failure [187,188,189,190,191,192,193,194,195,196,197]. For example, Anyukhovsky et al. [195] reported that intravenous administration of PCr and phosphocreatinine (300 mg/kg) in canines prevented the accumulation of lysophosphoglycerides in the ischemic zone of the heart, which is associated with an increased prevalence of arrhythmias. The researchers concluded that this might explain the antiarrhythmic action of PCr and phosphocreatinine in acute myocardial ischemia. Sharov and coworkers [194] reported that exogenous PCr administration protected against ischemia in the heart. Likewise, Balestrino and coworkers [21] evaluated the effects of adding PCr to cardioplegic solutions on energy availability during myocardial ischemia. The researchers found that PCr administration improved energy availability to the heart, reduced the incidence of arrhythmias, and improved myocardial function. As noted below, there is also evidence that creatine supplementation may maintain energy availability during brain ischemia and reduce stroke-related damage. Moreover, several studies have reported some benefit of oral creatine supplementation in heart failure patients participating in rehabilitation programs [198,199,200,201]. While not all studies report benefit from oral creatine supplementation [23,202] and more research is needed, current evidence suggests that phosphocreatine administration and possibly creatine supplementation support heart metabolism and health, particularly during ischemic challenges.

6. Potential Therapeutic Role of Creatine Supplementation

Given the metabolic role of creatine and the PCR/CK system, particularly during ischemia and in some disease states, there has been interest in examining the potential therapeutic role of creatine in a number of clinical populations. The following provides a brief overview of some of this work as an introduction to topics that will be reviewed in greater detail in other papers in this special issue.

6.1. Creatine Synthesis Deficiencies

Some individuals are born with rare deficiencies in creatine-related enzymes or transporters (e.g., AGAT, GAMT, and CRTR) that reduce the ability to transport creatine into the cell or synthesize creatine endogenously [203]. There is also recent evidence that the human genome encodes 19 genes of the solute carrier 6 (SLC6) family and that non-synonymous changes in the coding sequence give rise to mutated or misfolded transporters that cause diseases in affected individuals [204]. This includes the creatine transporter (CT1, SLC6A8) in which deficiencies have been reported to account for about 2% of intellectual disabilities in boys [205]. Individuals with creatine synthesis deficiencies and creatine transporter mutations typically present with low brain Cr and PCr levels [53,61,204,206,207,208,209,210]. Low brain creatine content has been associated with muscle myopathies (e.g., weakness), voluntary or involuntary movement disorders that can affect muscle function and coordination, speech development, epilepsy, cognitive and motor development delays, and/or autism [53,61,203,204,206,207,208,209,210]. Individuals with these conditions have a greater dependence on dietary creatine. For this reason, high-dose, long-term creatine supplementation (e.g., 0.3–0.8 g/kg/day) throughout the lifespan is a nutritional strategy of increasing brain creatine content in these populations [53,61,203,204,206,207,208,209,210,211,212,213,214]. This research has generally found that long-term creatine supplementation can improve clinical outcomes, particularly in patients with AGAT and GAMT deficiencies [207].
For example, Bianchi et al. [215] found that creatine supplementation (200–800 mg/kg/day divided into 5 servings per day) significantly increased brain creatine and PCr levels in patients with GAMT-d and AGAT-d creatine synthesis deficiencies. Battini et al. [216] reported that a patient diagnosed at birth with AGAT deficiency who was treated with creatine supplementation beginning at four months of age experienced normal psychomotor development at eighteen months compared to siblings who did not have the deficiency. Stockler-Ipsiroglu and coworkers [217] evaluated the effects of creatine monohydrate supplementation (0.3–0.8 g/kg/day) in 48 children with GMAT deficiency with clinical manifestations of global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems (n = 44), epilepsy (n = 35), or movement disorder (n = 13). The median age at treatment was 25.5 months, 39 months, and 11 years in patients with mild, moderate, and severe DD/ID, respectively. The researchers found that creatine supplementation increased brain creatine levels and improved or stabilized clinical symptoms. Moreover, four patients treated younger than nine months had normal or almost normal developmental outcomes. Long-term creatine supplementation has also been used to treat patients with ornithine aminotransferase (OAT) deficiency that causes gyrate atrophy of the choroid and retina due to secondary creatine depletion that is characterized by progressive vision loss [218,219,220,221,222]. These findings and others provide promise that high-dose creatine monohydrate supplementation is well tolerated and may be an effective adjunctive therapy for infants, children, and adults, particularly with AGAT deficiency [207,223,224,225,226]. Thus, it can be reasonably concluded that long-term, high-dose creatine supplementation in individuals with creatine synthesis can increase brain creatine and PCr levels and reduce the severity of deficits associated with these disorders.

6.2. Neurodegenerative Diseases and Muscular Dystrophy

Several studies have investigated the short- and long-term therapeutic benefit of creatine supplementation in animals, children, and adults with various neuromuscular diseases like Huntington’s disease (HD) [51,227,228,229,230,231,232]; Parkinson’s disease (PD) [51,66,100,227,233,234,235]; mitochondria-related diseases [58,235,236,237,238,239]; amyotrophic lateral sclerosis (ALS) [227,240,241,242,243,244,245,246]; spinal and bulbar muscular atrophy [247]; and, muscular dystrophies (MD) [248,249,250,251,252,253]. Several of these investigations, particularly in animal models, reported improved exercise tolerance and/or clinical outcomes. However, a large multi-site clinical trial conducted by Bender and coworkers [51] on PD, HD, and ALS patients did not find promising results. In this regard, they monitored 1687 participants who supplemented their diet with creatine (9.5 g/day for up to 5 years). The researchers did not observe statistically significant improvement in PD or ALS patient outcomes. However, in patients with HD, there was some evidence that creatine supplementation attenuated brain atrophy, suggesting some potential clinical benefit in this population. The reason animal studies may have yielded more promising results may be due to the fact that people typically do not present with symptoms of neurodegenerative disorders (e.g., ALS, HD, PD, etc.) until they have lost 70% or more of their alpha neurons. On the other hand, results in muscular dystrophy populations have been more promising because the muscle is the primary target. To support this contention, Kley and coworkers [254] conducted a Cochrane systemic review of the literature and found that high-quality evidence from randomized clinical trials (RCTs) demonstrated that short- and medium-term creatine supplementation increases muscle strength in muscular dystrophies and functional performance in muscular dystrophy and idiopathic inflammatory myopathy. However, assessment of high quality RCTs found no significant improvement in muscle strength in metabolic myopathies [254]. Thus, while creatine supplementation has been shown to have neuroprotective properties and improve muscle strength and endurance in patient populations, the efficacy of long-term, high-dose creatine supplementation in individuals with neurodegenerative diseases is currently equivocal, while promising, in patients with muscular dystrophy.

6.3. Brain and Spinal Cord Neuroprotection

It is well known that creatine supplementation increases brain bioenergetics [21,166,215,235,255,256] and has neuroprotective benefits, particularly in response to injury and/or ischemic conditions [58,64,66,257]. Consequently, there has been interest in determining the effects of creatine supplementation on cerebral ischemia, stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). For example, Adcock and associates [258] prophylactically administered neonatal rats creatine (3 g/kg for 3 days) and assessed brain bioenergetics in response to a cerebral ischemic event. The researchers found that creatine feeding significantly increased the ratio of brain PCr to Pi and promoted a 25% reduction in the volume of brain damage. Prass and coworkers [259] found that creatine administration decreased ischemia-induced brain infarction size by 40%. Zhu and colleagues [260] reported that oral creatine feeding in mice decreased the size of ischemia-induced brain damage and attenuated neuronal cell death, thereby providing neuroprotection. Allah and colleagues [261] found that neonatal mice fed creatine monohydrate for 10 weeks experience less ischemia-induced brain damage, as well as had better learning/memory during recovery. Finally, Turner and coworkers [166] reported that 7 days of creatine supplementation increased brain creatine content by 9.2%, increased corticomotor excitability, and prevented the decline in attention during hypoxia in healthy adults. Collectively, these findings suggest that prophylactic creatine supplementation may reduce the severity of brain ischemia and therefore may have some therapeutic benefits in individuals at risk to stroke [8,21,197].
Several studies have also evaluated the impact of creatine supplementation on mild traumatic brain injury (TBI) and spinal cord injury (SCI) outcomes in animals [3,6,171,262,263,264,265,266]. For example, Sullivan and coworkers [264] found that provision of creatine in the diet for 5 days prior to TBI decreased the amount of cortical brain damage by 36% in rats and 50% in mice. The researchers attributed the reduction in cortical damage to an improved energy availability. Hausmann and associates [265] reported that rats fed creatine (5 g/100 g dry food) prior to and following moderate SCI experienced less scar tissue and improved locomotor function test performance compared to controls. Moreover, Rabchevsky et al. [267] reported that rats fed a diet with 2% creatine for 4–5 weeks prior to and following SCI experienced less loss of gray matter. While these types of studies could not be performed in humans, they support contentions that creatine supplementation may reduce the severity of TBI and/or SCI. In humans, creatine supplementation has also been reported to enhance training adaptations in patients recovering from SCI. For example, Jacobs et al. [268] reported that creatine supplementation (20 g/day for 7 days) enhanced aerobic exercise capacity and ventilatory anaerobic threshold in patients with cervical SCI. Moreover, Amorim et al. [266] reported that individuals with SCI who consumed creatine (3 g/day for 8 weeks) with vitamin D (25,000 IU/day) while participating in a resistance-training program experienced significantly greater improvements in arm muscle area, strength, and functional capacity. While some studies report no benefit of creatine supplementation in patients with SCI [269,270], there is compelling evidence that creatine supplementation may reduce the severity of mild concussions, TBI, and/or SCI in animal models [21,263]. In fact, this evidence was so strong that the International Society of Sports Nutrition recommended that all athletes who are involved in sports with risk to TBI and/or SCI should take creatine to reduce the severity of these types of injury [1]. Based on this literature, it can be reasonably concluded that creatine supplementation can enhance energy availability during ischemic events and provide neuroprotection from TBI and/or SCI.

6.4. Enhanced Rehabilitation Outcomes

Since creatine supplementation has been reported to increase resistance-training adaptations, a number of studies have examined whether creatine supplementation may enhance physical therapy outcomes from musculoskeletal injury [25,159,171,247]. For example, Hespel and associates [26] reported that creatine supplementation (20 g/day and reduced to 5 g/day during immobilization, 15 g/day during the first 3 weeks of rehabilitation, and 5 g/day for the remaining 7 weeks) promoted increases in myogenic regulating factor 4 (MRF4) and myogenic protein expression, which was associated with greater muscle fiber area (+10%) and peak strength (+25%) during rehabilitation. Jacobs et al. [268] reported that creatine supplementation (20 g/d for 7 days) increased peak oxygen uptake and ventilatory anaerobic threshold in patients with cervical-level spinal cord injury (SCI). Moreover, several studies reported that creatine supplementation in chronic heart failure and chronic obstructive pulmonary disease (COPD) patients enhanced rehabilitative outcomes [23,198,199,200,202,271,272,273]. For example, Andrews and colleagues [199] found that creatine supplementation (20 g/day for 5 days) in chronic heart failure patients augmented skeletal muscle endurance and attenuated the abnormal skeletal muscle metabolic response to exercise. Fuld et al. [271] reported that creatine supplementation (17.1 g/day for 2 weeks prior to rehabilitation and 5.7 g/day for 16 weeks during rehabilitation) increased fat-free mass, peripheral muscle strength, and endurance, and health status in patients with COPD. Hass and colleagues [100] reported that creatine supplementation (20 g/day for 5 days and 5 g/day for 12 weeks) during resistance training in PD patients promoted greater muscle strength and ability to perform the functional chair sit-to-rise test. Cooke and assistants [274] reported that creatine supplementation prior to (0.3 g/kg/day for 5 days) and following (0.1 g/kg/day for 14 days) performing an eccentric-resistance-only exercise bout designed to promote muscle injury significantly reduced markers of muscle damage and hastened recovery of muscle function. Finally, Neves et al. [22] reported that creatine supplementation (20 g/day for 5 days and 5 g/day for 79 days) improved physical function, lower-limb lean mass, and quality of life in postmenopausal women with knee osteoarthritis undergoing strengthening exercises. Conversely, some studies have found no statistically significant effects of creatine supplementation during recovery from orthopedic injury. For example, Roy et al. [275] reported that creatine supplementation (10 g/day for 10 days before surgery and 5 g/day for 30 days after surgery) did not improve body composition, muscle strength, or enhance recovery in osteoarthritic patients who underwent total knee arthroplasty. Likewise, Tyler et al. [276] reported that creatine supplementation (20 g/day for 1 week and 5 g/day for 11 weeks) after anterior cruciate ligament (ACL) reconstruction had no significant effects on isokinetic strength measures during or following rehabilitation. Although more research is needed, there is evidence that creatine supplementation prior to and following injury may reduce immobilization-related atrophy and/or enhance rehabilitative outcomes in a number of populations.

6.5. Pregnancy

Since creatine supplementation has been shown to improve cellular bioenergetics during ischemic conditions and possess neuroprotective properties, there has been interest in creatine use during pregnancy to promote neural development and reduce complications resulting from birth asphyxia [7,277,278,279,280,281,282,283,284,285]. The rationale for creatine supplementation during pregnancy is that the fetus relies upon placental transfer of maternal creatine until late in pregnancy, and significant changes in creatine synthesis and excretion occur as pregnancy progresses [7,280]. Consequently, there is an increased demand for and utilization of creatine during pregnancy. Maternal creatine supplementation has been reported to improve neonatal survival and organ function following birth asphyxia in animals [277,278,279,281,282,283,285]. In humans, there is evidence that the creatine needs of the mother increase during pregnancy [7,280]. Consequently, there has been interest in determining the role of creatine during pregnancy on fetal growth, development, and health of the mother and child [7,280,286,287,288]. Available literature suggests that creatine metabolism may play an essential role in the bioenergetics of successful reproduction and that creatine supplementation may improve reproductive and/or perinatal outcomes [7,277,278,279,280,283,284,286,288]. However, it should be noted that research on the role of creatine supplementation in pregnant women is limited. While creatine supplementation has been reported to be safe in a number of populations [10,42,171,289,290] and there is no evidence that creatine supplementation poses a risk for women of reproductive age or preterm infants [287,288,291], additional safety and tolerability studies in pregnant women and those trying to conceive are needed. Consequently, although there is emerging evidence that creatine supplementation may help support the mother and child’s nutritional needs and health, due to the limited studies in pregnant humans, caution should be exercised when recommending use during human pregnancy.

6.6. Immune Support

One of the more novel potential uses of creatine is its influence on the immune system. A number of in vitro and animal studies indicate that creatine has immunomodulatory effects [6]. In this regard, several studies have reported that creatine supplementation may alter production and/or the expression of molecules involved in recognizing infections like toll-like receptors (TLR) [6]. For example, Leland and colleagues [292] reported that creatine down-regulated expression of TLR-2, TLR-3, TLR-4, and TLR-7 in a mouse macrophage cell line (RAW 254.7). While this could reduce the ability to sense some infections in immunocompromised individuals, TLR-4 downregulation may also alter Parkinson’s disease pathology and inhibit neuronal death as the disease progresses [293,294]. There is also evidence that creatine influences cytokines possibly via the NF-κB signaling pathway, thereby affecting cytokines, receptors, and/or growth factors that can positively or negatively influence immune response [6,292]. A creatine-induced reduction of pro-inflammatory cytokines (e.g., IL-6) and other markers of inflammation (e.g., TNFα, PGE2) may help explain some of the neuroprotective benefits observed in patients with central nervous system-related diseases [6]. It may also explain reports that creatine supplementation attenuates inflammatory and/or muscle damage in response to intense exercise [274,295,296,297]. On the other hand, there have been several studies in mice suggesting that creatine supplementation may impair airway inflammation, thereby exacerbating exercise-induced asthma [298,299]. However, other studies suggest that creatine attenuates the pulmonary and systemic effects of lung ischemia in reperfusion injury in rats [300]; improves rehabilitative outcomes in patients with cystic fibrosis [301] and COPD [271]; or, has no statistically significant effects on pulmonary rehabilitation outcomes [24,273] and youth soccer players with allergies [302]. Additional research is needed to understand creatine’s anti-inflammatory and immunomodulating effects, but it is clear that creatine can affect these pathways. Thus, there is evidence to suggest that supplementation may have anti-inflammatory and immunomodulating effects.

6.7. Anticancer Properties

Another emerging area is related to the potential anticarcinogenic effects of creatine supplementation. As noted above, creatine and phosphagens play an important role in maintaining energy availability [38,39,56,57], particularly related to the role of the CK/PRr system and shuttling of ATP, ADP, and Pi in and out of the mitochondria for cellular metabolism [50,54,55]. Prior studies have shown that creatine content and energy availability are low in several types of malignant cells and T cells that mediate the immune responses against cancer [17,18,144,145,147]. Additionally, the creatine transport SLC6A8 gene expression encodes a surface transporter controlling the uptake of creatine into a cell, markedly increases in tumor-infiltrating immune cells [17]. It has been well established that creatine and its related compound cyclocreatine have anticancer properties [144,303,304]. For example, Patra et al. [144] also noted that the efficacy of the anticancer medication methylglyoxal (MG) is significantly augmented in the presence of creatine and that administration of creatine, methylglyoxal, and ascorbic acid provided greater efficacy and eliminated visible signs of tumor growth. Moreover, creatine and CK, which were very low in sarcoma tissue, were significantly elevated with the concomitant regression of tumor cells. Similarly, Pal and colleagues [147] reported that MG efficacy was improved with co-administration of creatine and ascorbic acid in muscle cells in vitro and in sarcoma animal model in vivo, suggesting that creatine supplementation may serve as an adjunctive anticancer therapeutic intervention with MG. Di Biase and coworkers [17] also reported that creatine uptake deficiency severely impaired CD8 T cell responses to tumor challenge in vivo and to antigen stimulation in vitro, while supplementation of creatine through either direct administration or dietary supplementation significantly suppressed tumor growth in multiple mouse tumor models. Moreover, the energy-shuttling function of creatine goes beyond regulating CD8 T cells, in that reduced energy capacity has also been reported in multiple immune cells in various mouse tumor models in creatine transporter knockout mice [17]. The researchers concluded that creatine is an important metabolic regulator controlling antitumor T cell immunity and that creatine supplementation may improve T cell–based cancer immunotherapies [17]. Collectively, these findings indicate that creatine supplementation may have anticancer properties. Thus, it can be reasonably concluded based on available evidence that creatine is an important energy source for immune cells, can help support a healthy immune system, and may have some anticancer properties.

6.8. Improve Functional Capacity in Patients with Chronic Fatigue?

Chronic fatigue syndrome (CFS), also known as post-viral fatigue syndrome (PFS) or myalgic encephalomyelitis (ME), is characterized by fatigue and associated symptoms (e.g., muscle and joint pains, anxiety, cognitive and sleep disorders, intolerance to physical exertion) persisting more than six months in duration [305]. Although the etiology of these conditions are unknown, there has been some recent interest in whether creatine may help improve functional capacity and thereby help people with CFS conditions better manage this condition. Although controversial, there is some evidence that a lack of creatine availability and/or impaired creatine metabolism may play a role in CFS-related diseases. For example, Malatji et al. [306] reported a significant relationship between urinary creatine levels and symptoms of pain, fatigue, and energy levels in patients with CFS-related chronic pain syndrome, fibromyalgia. Mueller and associates [307] reported that creatine levels in the left parietal cortex was significantly lower in patients with ME/CFS, while higher in the left putamen and not affected in 45 other areas examined. Moreover, when using creatine as the denominator to normalize values, significant differences were observed in the ratio of N-acetylasparte/creatine, choline/creatine, lactate/creatine, and myo-inositol/creatine ratios between CFS and controls. In a similar study, van der Schaaf et al. [308] reported that greater pain levels inversely related to the N-acetylaspartylglutamate/creatine ratio in the dorsolateral prefrontal cortex of a group of 89 women with CF compared to controls. While it is unclear how changes in brain metabolites, including creatine, are involved in the pathology or symptomology of CFS, creatine and GAA supplementation have been reported to increase brain creatine content and might thereby help normalize some of these ratios. Although this is highly speculative and needs additional research, it is interesting to note that alterations in the ratio of brain metabolites to creatine have been implicated in CFS.
With that said, several studies have investigated the role of creatine or creatine-related compounds on patient outcomes in CFS patients. For example, Amital and coworkers [309] reported that creatine supplementation (3 g/day for 7 days and 5 g/day for 21 days) in a patient presenting with post-traumatic stress disorder, depression, and fibromyalgia showed improvement in symptoms of depression, pain measures, and quality of life. The patient continued supplementation for another 4 weeks and retained these benefits. Leader et al. [310] conducted an open-label study to assess the effects of creatine supplementation (3 g/day for 3 weeks and 5 g/day for 5 weeks) as an adjunctive nutritional therapy in 16 patients with Fibromyalgia Syndrome. The researchers found that creatine supplementation significantly improves markers related to the severity of fibromyalgia, disability, pain, sleep quality, and quality of life. The improvements observed returned toward baseline after 4 weeks after stopping creatine therapy. Alves and colleagues [162] reported that creatine supplementation (20 g/day for 5 days; 5 g/day for 107 days) increased intramuscular phosphorylcreatine content and improved lower- and upper-body muscle function, with minor changes in other fibromyalgia features. The authors concluded that creatine supplementation may serve as a useful dietary intervention to improve fibromyalgia patients’ muscle function. Finally, Ostojic and colleagues [311] reported that GAA supplementation (2.4 g/day for 3 months) positively affected creatine metabolism and work capacity in women with CFS but did not affect general fatigue symptoms musculoskeletal soreness. While all studies do not report benefits, these findings provide some support that creatine and/or GAA may have some therapeutic benefit for patients with CFS, PFS, ME, and/or fibromyalgia. However, it should be noted that the improvements in functional capacity observed in these studies are similar to those observed in healthy individuals who take creatine and that pain indices were not significantly affected in all of these studies. Nevertheless, although more research is needed, it can be reasonably concluded that creatine and/or GAA may improve functional capacity in patients with chronic fatigue-related syndromes such as post-viral fatigue syndrome (PFS) and myalgic encephalomyelitis (ME).

6.9. Antidepressive Effects

Reports since the early 1980s have suggested that creatine metabolism and/or availability may have antidepressive effects [312,313,314,315,316,317,318]. These studies and others have provided the basis for assessing the effects of creatine and/or creatine precursors like S-adenosyl-L-methionine (SAMe) and GAA affect brain phosphagen levels, markers of depression, and/or the therapeutic efficacy of antidepressant medications [8,169,170]. For example, the creatine precursor SAMe has been reported to be an effective treatment for clinical depression. Silveri et al. [316] reported that SAMe supplementation (1600 mg/day) increased brain creatine and PCr levels and lowered transverse relaxation time (T2RT) using magnetic resonance spectroscopy (31P MRS) in nondepressed subjects; this effect was larger in women compared to men. Allen and colleagues [319] reported that rats fed creatine diets (4%) for 5 weeks altered depression-like behavior in response to forced swim training in a sex-dependent manner, with female rats displaying an antidepressant-like response. Ahn and coworkers [320] reported that a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression and that combining creatine and exercise promoted greater benefits. Pazini et al. [321] reported that creatine administration (21 days, 10 mg/kg, p.o.) abolished corticosterone-induced depressive-like behaviors in mice. Similarly, Leem and colleagues [322] reported that mice exposed to mild chronic stress for 4 weeks had a greater effect on hippocampal neurogenesis via the Wnt/GSK3beta/beta-catenin pathway activation when creatine and exercise were combined compared with each treatment in chronic mild stress-induced behavioral depression. There is some support in human trials that creatine supplementation may affect depression [171,323]. For example, Bakian et al. [324] recently assessed the dietary patterns from the National Health and Nutrition Examination Survey (NHANES) database and found a significant negative relationship between dietary creatine intake and depression among adults in the United States. Roitman et al. [169] reported in an open-label study that creatine monohydrate supplementation (3–5 g/day for 4 weeks) improved outcomes in a small sample of patients with unipolar depression. Toniolo et al. [29] evaluated the effects of creatine supplementation (6 g/day for 6 weeks) in bipolar patients and reported on Montgomery–Asberg Depression Rating Scale (MADRS) remission rates (i.e., 66.7% remission in the creatine group vs. 18.2% in the placebo group). In a similar study [29], this group reported that adjunctive creatine therapy (6 g/day for 6 weeks) in patients with bipolar depression improved verbal fluency tests. Moreover, in a proof-of-concept study [172], these researchers reported that creatine supplementation (6 g/day for 6 weeks) in patients with bipolar disorder type I or II enhanced remission MADRS scores in participants who completed the study. Although more research is needed, there is some evidence suggesting that creatine may help individuals manage some types of depression and/or anxiety disorders, particularly when combined with choline [325,326]. Thus, there is evidence that creatine supplementation may support mental health.

6.10. Fertility

Since sperm motility is dependent on ATP availability and CK activity has been associated with greater sperm quality and function [50,327,328,329], there has been some interest in whether creatine supplementation and/or administration might improve fertility. For example, creatine has been added to medium during intrauterine insemination to increase the viability of sperm and the success of fertility treatments [327,328,329,330,331,332]. Although more research is needed, these findings suggest that creatine may play an important role in fertility and support reproductive health.

6.11. Skin Health

Since creatine availability has been reported to affect energy status in the dermis and is an antioxidant, several studies have evaluated whether creatine’s topical application influences skin health and/or may serve as an effective anti-wrinkle intervention [333]. For example, Lenz et al. [333] reported that stress decreases CK activity in cutaneous cells and that topical creatine application improved cellular energy availability and markedly protected against a variety of cellular stress conditions, like oxidative and UV damage, which are involved in premature skin aging and skin damage. Peirano and coworkers [334] found that topically applied creatine rapidly penetrates the dermis, stimulates collagen synthesis, and influences gene expression and protein. Additionally, the topical application of a creatine-containing formulation for 6 weeks significantly reduced the sagging cheek intensity in the jowl area, crow’s feet wrinkles, and wrinkles under the eyes. The researchers concluded that creatine represents a beneficial active ingredient for topical use in the prevention and treatment of human skin aging. Thus, there is evidence that creatine supports skin health.

7. Conclusions

The benefits of creatine monohydrate supplementation go well beyond increasing muscle Cr and PCr levels and thereby enhancing high-intensity exercise and training adaptations. Research has clearly shown several health and/or potential therapeutic benefits as we age and in clinical populations that may benefit by enhancing Cr and PCr levels. Although additional research is needed to explore further the health and potential therapeutic benefits of creatine supplementation, many of these topics will be described in more detail in other papers within this special issue. Based on the available evidence, the following can be reasonably concluded based.
  • Creatine supplementation can increase cellular energy availability and support general health, fitness, and well-being throughout the lifespan.
  • Creatine supplementation, particularly with resistance training, can promote gains in strength and help maintain or increase muscle mass in older individuals. Additionally, creatine supplementation during energy-restriction-induced weight loss may be an effective way to preserve muscle while dieting and thereby help manage adult-onset obesity.
  • Creatine supplementation may support cognitive function, particularly as one ages.
  • Creatine supplementation may support healthy glucose management.
  • Phosphocreatine administration and possibly creatine supplementation may support heart metabolism and health, particularly during ischemic challenges.
  • Long-term, high-dose creatine supplementation in individuals with creatine synthesis deficiencies can increase brain creatine and PCr levels and may reduce the severity of deficits associated with these disorders.
  • Although creatine supplementation has been shown to have neuroprotective properties and improve strength and endurance, the efficacy of long-term, high-dose creatine supplementation in individuals with neurodegenerative diseases is equivocal, while promising, in patients with muscular dystrophy.
  • Creatine supplementation may increase brain creatine content, enhance energy availability during ischemic events, and provide neuroprotection from TBI and/or SCI.
  • Creatine supplementation prior to and following injury may reduce immobilization-related atrophy and/or enhance rehabilitative outcomes in a number of populations.
  • Creatine supplementation during pregnancy may help support the mother and child’s nutritional needs and health; however, due to the limited studies in pregnant humans, caution should be exercised when recommending use during human pregnancy.
  • Creatine supplementation may have anti-inflammatory and immunomodulating effects.
  • Creatine is an important energy source for immune cells, can help support a healthy immune system, and may have some anticancer properties.
  • Creatine and/or GAA may improve functional capacity in patients with chronic fatigue-related syndromes such as post-viral fatigue syndrome (PFS) and myalgic encephalomyelitis (ME).
  • Creatine may support mental health.
  • Creatine may support reproductive health.
  • Creatine may support skin health.

Author Contributions

Conceptualization, R.B.K. and J.R.S.; writing—original draft preparation, R.B.K.; writing—review and editing, R.B.K. and J.R.S.; funding acquisition, R.B.K. All authors have read and agreed to the published version of the manuscript.


The APC of selected papers of this special issue are being funded by AlzChem, LLC. (Trostberg, Germany), which manufactures creatine monohydrate. The funders had no role in the writing of the manuscript, interpretation of the literature, or in the decision to publish the results.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.


The authors would like to thank all of the research participants, scholars, and funding agencies who have contributed to the research cited in this manuscript.

Conflicts of Interest

R.B.K. has conducted industry sponsored research on creatine, received financial support for presenting on creatine at industry sponsored scientific conferences, and has served as an expert witness on cases related to creatine. Additionally, he serves as Chair of the Scientific Advisory Board for AlzChem who sponsored this special issue. J.R.S. has conducted industry-sponsored research on creatine and other nutraceuticals over the past 25 years. Further, J.R.S. has also received financial support for presenting on the science of various nutraceuticals, except creatine, at industry-sponsored scientific conferences.


  1. Kreider, R.B.; Kalman, D.S.; Antonio, J.; Ziegenfuss, T.N.; Wildman, R.; Collins, R.; Candow, D.G.; Kleiner, S.M.; Almada, A.L.; Lopez, H.L. 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, 18. [Google Scholar] [CrossRef] [PubMed]
  2. Stares, A.; Bains, M. The Additive Effects of Creatine Supplementation and Exercise Training in an Aging Population: A Systematic Review of Randomized Controlled Trials. J. Geriatr. Phys. Ther. 2020, 43, 99–112. [Google Scholar] [CrossRef] [PubMed]
  3. Dolan, E.; Gualano, B.; Rawson, E.S. Beyond muscle: The effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury. Eur. J. Sport Sci. 2019, 19, 1–14. [Google Scholar] [CrossRef] [PubMed]
  4. Dolan, E.; Artioli, G.G.; Pereira, R.M.R.; Gualano, B. Muscular Atrophy and Sarcopenia in the Elderly: Is There a Role for Creatine Supplementation? Biomolecules 2019, 9, 642. [Google Scholar] [CrossRef] [Green Version]
  5. Wallimann, T.; Riek, U.; Moddel, M. Intradialytic creatine supplementation: A scientific rationale for improving the health and quality of life of dialysis patients. Med. Hypotheses 2017, 99, 1–14. [Google Scholar] [CrossRef]
  6. Riesberg, L.A.; Weed, S.A.; McDonald, T.L.; Eckerson, J.M.; Drescher, K.M. Beyond muscles: The untapped potential of creatine. Int. Immunopharmacol. 2016, 37, 31–42. [Google Scholar] [CrossRef] [Green Version]
  7. Ellery, S.J.; Walker, D.W.; Dickinson, H. Creatine for women: A review of the relationship between creatine and the reproductive cycle and female-specific benefits of creatine therapy. Amino Acids 2016, 48, 1807–1817. [Google Scholar] [CrossRef]
  8. Smith, R.N.; Agharkar, A.S.; Gonzales, E.B. A review of creatine supplementation in age-related diseases: More than a supplement for athletes. F1000Research 2014, 3, 222. [Google Scholar] [CrossRef] [Green Version]
  9. Candow, D.G.; Chilibeck, P.D.; Forbes, S.C. Creatine supplementation and aging musculoskeletal health. Endocrine 2014, 45, 354–361. [Google Scholar] [CrossRef]
  10. Gualano, B.; Roschel, H.; Lancha, A.H., Jr.; Brightbill, C.E.; Rawson, E.S. In sickness and in health: The widespread application of creatine supplementation. Amino Acids 2012, 43, 519–529. [Google Scholar] [CrossRef]
  11. Pinto, C.L.; Botelho, P.B.; Pimentel, G.D.; Campos-Ferraz, P.L.; Mota, J.F. Creatine supplementation and glycemic control: A systematic review. Amino Acids 2016, 48, 2103–2129. [Google Scholar] [CrossRef] [PubMed]
  12. Candow, D.G.; Forbes, S.C.; Chilibeck, P.D.; Cornish, S.M.; Antonio, J.; Kreider, R.B. Variables Influencing the Effectiveness of Creatine Supplementation as a Therapeutic Intervention for Sarcopenia. Front. Nutr. 2019, 6, 124. [Google Scholar] [CrossRef] [PubMed]
  13. Chilibeck, P.D.; Kaviani, M.; Candow, D.G.; Zello, G.A. Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: A meta-analysis. Open Access J. Sports Med. 2017, 8, 213–226. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Candow, D.G.; Forbes, S.C.; Chilibeck, P.D.; Cornish, S.M.; Antonio, J.; Kreider, R.B. Effectiveness of Creatine Supplementation on Aging Muscle and Bone: Focus on Falls Prevention and Inflammation. J. Clin. Med. 2019, 8, 488. [Google Scholar] [CrossRef] [Green Version]
  15. Fairman, C.M.; Kendall, K.L.; Newton, R.U.; Hart, N.H.; Taaffe, D.R.; Chee, R.; Tang, C.I.; Galvao, D.A. Examining the effects of creatine supplementation in augmenting adaptations to resistance training in patients with prostate cancer undergoing androgen deprivation therapy: A randomised, double-blind, placebo-controlled trial. BMJ Open 2019, 9, e030080. [Google Scholar] [CrossRef]
  16. Fairman, C.M.; Kendall, K.L.; Hart, N.H.; Taaffe, D.R.; Galvao, D.A.; Newton, R.U. The potential therapeutic effects of creatine supplementation on body composition and muscle function in cancer. Crit. Rev. Oncol Hematol 2019, 133, 46–57. [Google Scholar] [CrossRef]
  17. Di Biase, S.; Ma, X.; Wang, X.; Yu, J.; Wang, Y.C.; Smith, D.J.; Zhou, Y.; Li, Z.; Kim, Y.J.; Clarke, N.; et al. Creatine uptake regulates CD8 T cell antitumor immunity. J. Exp. Med. 2019, 216, 2869–2882. [Google Scholar] [CrossRef] [Green Version]
  18. Campos-Ferraz, P.L.; Gualano, B.; das Neves, W.; Andrade, I.T.; Hangai, I.; Pereira, R.T.; Bezerra, R.N.; Deminice, R.; Seelaender, M.; Lancha, A.H. Exploratory studies of the potential anti-cancer effects of creatine. Amino Acids 2016, 48, 1993–2001. [Google Scholar] [CrossRef]
  19. Dover, S.; Stephens, S.; Schneiderman, J.E.; Pullenayegum, E.; Wells, G.D.; Levy, D.M.; Marcuz, J.A.; Whitney, K.; Schulze, A.; Tein, I.; et al. The effect of creatine supplementation on muscle function in childhood myositis: A randomized, double-blind, placebo-controlled feasibility study. J. Rheumatol. 2020. [Google Scholar] [CrossRef]
  20. Balestrino, M.; Adriano, E. Creatine as a Candidate to Prevent Statin Myopathy. Biomolecules 2019, 9, 496. [Google Scholar] [CrossRef] [Green Version]
  21. Balestrino, M.; Sarocchi, M.; Adriano, E.; Spallarossa, P. Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease. Amino Acids 2016, 48, 1955–1967. [Google Scholar] [CrossRef] [PubMed]
  22. Neves, M., Jr.; Gualano, B.; Roschel, H.; Fuller, R.; Benatti, F.B.; Pinto, A.L.; Lima, F.R.; Pereira, R.M.; Lancha, A.H., Jr.; Bonfa, E. Beneficial effect of creatine supplementation in knee osteoarthritis. Med. Sci. Sports Exerc. 2011, 43, 1538–1543. [Google Scholar] [CrossRef] [PubMed]
  23. Cornelissen, V.A.; Defoor, J.G.; Stevens, A.; Schepers, D.; Hespel, P.; Decramer, M.; Mortelmans, L.; Dobbels, F.; Vanhaecke, J.; Fagard, R.H.; et al. Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: A randomized controlled trial. Clin. Rehabil. 2010, 24, 988–999. [Google Scholar] [CrossRef] [PubMed]
  24. Al-Ghimlas, F.; Todd, D.C. Creatine supplementation for patients with COPD receiving pulmonary rehabilitation: A systematic review and meta-analysis. Respirology 2010, 15, 785–795. [Google Scholar] [CrossRef] [PubMed]
  25. Hespel, P.; Derave, W. Ergogenic effects of creatine in sports and rehabilitation. Subcell Biochem. 2007, 46, 245–259. [Google Scholar] [PubMed]
  26. Hespel, P.; Op’t Eijnde, B.; Van Leemputte, M.; Urso, B.; Greenhaff, P.L.; Labarque, V.; Dymarkowski, S.; Van Hecke, P.; Richter, E.A. Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. J. Physiol. 2001, 536, 625–633. [Google Scholar] [CrossRef]
  27. Van Cutsem, J.; Roelands, B.; Pluym, B.; Tassignon, B.; Verschueren, J.O.; De Pauw, K.; Meeusen, R. Can Creatine Combat the Mental Fatigue-associated Decrease in Visuomotor Skills? Med. Sci. Sports Exerc. 2020, 52, 120–130. [Google Scholar] [CrossRef]
  28. Avgerinos, K.I.; Spyrou, N.; Bougioukas, K.I.; Kapogiannis, D. Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. Exp. Gerontol. 2018, 108, 166–173. [Google Scholar] [CrossRef]
  29. Toniolo, R.A.; Fernandes, F.B.F.; Silva, M.; Dias, R.D.S.; Lafer, B. Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial. J. Affect. Disord. 2017, 224, 69–75. [Google Scholar] [CrossRef]
  30. Van Bavel, D.; de Moraes, R.; Tibirica, E. Effects of dietary supplementation with creatine on homocysteinemia and systemic microvascular endothelial function in individuals adhering to vegan diets. Fundam. Clin. Pharmacol. 2019, 33, 428–440. [Google Scholar] [CrossRef]
  31. Zervou, S.; Whittington, H.J.; Russell, A.J.; Lygate, C.A. Augmentation of Creatine in the Heart. Mini Rev. Med. Chem. 2016, 16, 19–28. [Google Scholar] [CrossRef] [PubMed]
  32. Clarke, H.; Kim, D.H.; Meza, C.A.; Ormsbee, M.J.; Hickner, R.C. The Evolving Applications of Creatine Supplementation: Could Creatine Improve Vascular Health? Nutrients 2020, 12, 2834. [Google Scholar] [CrossRef] [PubMed]
  33. Jager, R.; Purpura, M.; Shao, A.; Inoue, T.; Kreider, R.B. Analysis of the efficacy, safety, and regulatory status of novel forms of creatine. Amino Acids 2011, 40, 1369–1383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Paddon-Jones, D.; Borsheim, E.; Wolfe, R.R. Potential ergogenic effects of arginine and creatine supplementation. J. Nutr. 2004, 134, 2888S–2894S. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Brosnan, M.E.; Brosnan, J.T. The role of dietary creatine. Amino Acids 2016, 48, 1785–1791. [Google Scholar] [CrossRef]
  36. da Silva, R.P.; Clow, K.; Brosnan, J.T.; Brosnan, M.E. Synthesis of guanidinoacetate and creatine from amino acids by rat pancreas. Br. J. Nutr. 2014, 111, 571–577. [Google Scholar] [CrossRef] [Green Version]
  37. da Silva, R.P.; Nissim, I.; Brosnan, M.E.; Brosnan, J.T. Creatine synthesis: Hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. Am. J. Physiol. Endocrinol. Metab. 2009, 296, E256–E261. [Google Scholar] [CrossRef]
  38. Bertin, M.; Pomponi, S.M.; Kokuhuta, C.; Iwasaki, N.; Suzuki, T.; Ellington, W.R. Origin of the genes for the isoforms of creatine kinase. Gene 2007, 392, 273–282. [Google Scholar] [CrossRef]
  39. Suzuki, T.; Mizuta, C.; Uda, K.; Ishida, K.; Mizuta, K.; Sona, S.; Compaan, D.M.; Ellington, W.R. Evolution and divergence of the genes for cytoplasmic, mitochondrial, and flagellar creatine kinases. J. Mol. Evol. 2004, 59, 218–226. [Google Scholar] [CrossRef]
  40. Sahlin, K.; Harris, R.C. The creatine kinase reaction: A simple reaction with functional complexity. Amino Acids 2011, 40, 1363–1367. [Google Scholar] [CrossRef]
  41. Harris, R. Creatine in health, medicine and sport: An introduction to a meeting held at Downing College, University of Cambridge, July 2010. Amino Acids 2011, 40, 1267–1270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Kerksick, C.M.; Wilborn, C.D.; Roberts, M.D.; Smith-Ryan, A.; Kleiner, S.M.; Jager, R.; Collins, R.; Cooke, M.; Davis, J.N.; Galvan, E.; et al. ISSN exercise & sports nutrition review update: Research & recommendations. J. Int. Soc. Sports Nutr. 2018, 15, 38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Meyers, S. Sports nutrition market growth watch. In Natural Products Insider; Informa Exhibitions: Irving, TX, USA, 2016. [Google Scholar]
  44. Buford, T.W.; Kreider, R.B.; Stout, J.R.; Greenwood, M.; Campbell, B.; Spano, M.; Ziegenfuss, T.; Lopez, H.; Landis, J.; Antonio, J. International Society of Sports Nutrition position stand: Creatine supplementation and exercise. J. Int. Soc. Sports Nutr. 2007, 4, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Kreider, R.B.; Jung, Y.P. Creatine supplementation in exercise, sport, and medicine. J. Exerc. Nutr. Biochem. 2011, 15, 53–69. [Google Scholar] [CrossRef]
  46. Hultman, E.; Soderlund, K.; Timmons, J.A.; Cederblad, G.; Greenhaff, P.L. Muscle creatine loading in men. J. Appl. Physiol. 1996, 81, 232–237. [Google Scholar] [CrossRef]
  47. Green, A.L.; Hultman, E.; Macdonald, I.A.; Sewell, D.A.; Greenhaff, P.L. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am. J. Physiol. 1996, 271, E821–E826. [Google Scholar] [CrossRef]
  48. Balsom, P.D.; Soderlund, K.; Ekblom, B. Creatine in humans with special reference to creatine supplementation. Sports Med. 1994, 18, 268–280. [Google Scholar] [CrossRef]
  49. Harris, R.C.; Soderlund, K.; Hultman, E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin. Sci. 1992, 83, 367–374. [Google Scholar] [CrossRef] [Green Version]
  50. Wallimann, T.; Tokarska-Schlattner, M.; Schlattner, U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids 2011, 40, 1271–1296. [Google Scholar] [CrossRef] [Green Version]
  51. Bender, A.; Klopstock, T. Creatine for neuroprotection in neurodegenerative disease: End of story? Amino Acids 2016, 48, 1929–1940. [Google Scholar] [CrossRef]
  52. Hanna-El-Daher, L.; Braissant, O. Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models? Amino Acids 2016, 48, 1877–1895. [Google Scholar] [CrossRef] [PubMed]
  53. Braissant, O.; Henry, H.; Beard, E.; Uldry, J. Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids 2011, 40, 1315–1324. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Wallimann, T.; Schlosser, T.; Eppenberger, H.M. Function of M-line-bound creatine kinase as intramyofibrillar ATP regenerator at the receiving end of the phosphorylcreatine shuttle in muscle. J. Biol. Chem. 1984, 259, 5238–5246. [Google Scholar] [CrossRef]
  55. Wallimann, T.; Dolder, M.; Schlattner, U.; Eder, M.; Hornemann, T.; O’Gorman, E.; Ruck, A.; Brdiczka, D. Some new aspects of creatine kinase (CK): Compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology. Biofactors 1998, 8, 229–234. [Google Scholar] [CrossRef] [PubMed]
  56. Schlattner, U.; Klaus, A.; Rios, S.R.; Guzun, R.; Kay, L.; Tokarska-Schlattner, M. Cellular compartmentation of energy metabolism: Creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites. Amino Acids 2016, 48, 1751–1774. [Google Scholar] [CrossRef]
  57. Ydfors, M.; Hughes, M.C.; Laham, R.; Schlattner, U.; Norrbom, J.; Perry, C.G. Modelling in vivo creatine/phosphocreatine in vitro reveals divergent adaptations in human muscle mitochondrial respiratory control by ADP after acute and chronic exercise. J. Physiol. 2016, 594, 3127–3140. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Tarnopolsky, M.A.; Parshad, A.; Walzel, B.; Schlattner, U.; Wallimann, T. Creatine transporter and mitochondrial creatine kinase protein content in myopathies. Muscle Nerve 2001, 24, 682–688. [Google Scholar] [CrossRef]
  59. Santacruz, L.; Jacobs, D.O. Structural correlates of the creatine transporter function regulation: The undiscovered country. Amino Acids 2016, 48, 2049–2055. [Google Scholar] [CrossRef]
  60. Braissant, O. Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers. J. Inherit. Metab. Dis. 2012, 35, 655–664. [Google Scholar] [CrossRef] [Green Version]
  61. Beard, E.; Braissant, O. Synthesis and transport of creatine in the CNS: Importance for cerebral functions. J. Neurochem. 2010, 115, 297–313. [Google Scholar] [CrossRef] [Green Version]
  62. Saraiva, A.L.; Ferreira, A.P.; Silva, L.F.; Hoffmann, M.S.; Dutra, F.D.; Furian, A.F.; Oliveira, M.S.; Fighera, M.R.; Royes, L.F. Creatine reduces oxidative stress markers but does not protect against seizure susceptibility after severe traumatic brain injury. Brain Res. Bull. 2012, 87, 180–186. [Google Scholar] [CrossRef] [PubMed]
  63. Rahimi, R. Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise. J. Strength Cond. Res. 2011, 25, 3448–3455. [Google Scholar] [CrossRef] [PubMed]
  64. Tarnopolsky, M.A. Clinical use of creatine in neuromuscular and neurometabolic disorders. Subcell Biochem. 2007, 46, 183–204. [Google Scholar] [PubMed]
  65. Kley, R.A.; Tarnopolsky, M.A.; Vorgerd, M. Creatine for treating muscle disorders. Cochrane Database Syst. Rev. 2011. [Google Scholar] [CrossRef]
  66. Tarnopolsky, M.A. Potential benefits of creatine monohydrate supplementation in the elderly. Curr. Opin. Clin. Nutr. Metab. Care 2000, 3, 497–502. [Google Scholar] [CrossRef]
  67. Candow, D.G.; Vogt, E.; Johannsmeyer, S.; Forbes, S.C.; Farthing, J.P. Strategic creatine supplementation and resistance training in healthy older adults. Appl. Physiol. Nutr. Metab. 2015, 40, 689–694. [Google Scholar] [CrossRef] [Green Version]
  68. Moon, A.; Heywood, L.; Rutherford, S.; Cobbold, C. Creatine supplementation: Can it improve quality of life in the elderly without associated resistance training? Curr. Aging Sci. 2013, 6, 251–257. [Google Scholar] [CrossRef]
  69. Rawson, E.S.; Venezia, A.C. Use of creatine in the elderly and evidence for effects on cognitive function in young and old. Amino Acids 2011, 40, 1349–1362. [Google Scholar] [CrossRef]
  70. Candow, D.G. Sarcopenia: Current theories and the potential beneficial effect of creatine application strategies. Biogerontology 2011, 12, 273–281. [Google Scholar] [CrossRef]
  71. Candow, D.G.; Chilibeck, P.D. Potential of creatine supplementation for improving aging bone health. J. Nutr. Health Aging 2010, 14, 149–153. [Google Scholar] [CrossRef]
  72. Cornish, S.M.; Chilibeck, P.D.; Burke, D.G. The effect of creatine monohydrate supplementation on sprint skating in ice-hockey players. J. Sports Med. Phys. Fit. 2006, 46, 90–98. [Google Scholar]
  73. Dawson, B.; Vladich, T.; Blanksby, B.A. Effects of 4 weeks of creatine supplementation in junior swimmers on freestyle sprint and swim bench performance. J. Strength Cond. Res. 2002, 16, 485–490. [Google Scholar] [PubMed]
  74. Grindstaff, P.D.; Kreider, R.; Bishop, R.; Wilson, M.; Wood, L.; Alexander, C.; Almada, A. Effects of creatine supplementation on repetitive sprint performance and body composition in competitive swimmers. Int. J. Sport Nutr. 1997, 7, 330–346. [Google Scholar] [CrossRef] [PubMed]
  75. Juhasz, I.; Gyore, I.; Csende, Z.; Racz, L.; Tihanyi, J. Creatine supplementation improves the anaerobic performance of elite junior fin swimmers. Acta Physiol. Hung. 2009, 96, 325–336. [Google Scholar] [CrossRef]
  76. Silva, A.J.; Machado Reis, V.; Guidetti, L.; Bessone Alves, F.; Mota, P.; Freitas, J.; Baldari, C. Effect of creatine on swimming velocity, body composition and hydrodynamic variables. J. Sports Med. Phys. Fit. 2007, 47, 58–64. [Google Scholar]
  77. Kreider, R.B.; Ferreira, M.; Wilson, M.; Grindstaff, P.; Plisk, S.; Reinardy, J.; Cantler, E.; Almada, A.L. Effects of creatine supplementation on body composition, strength, and sprint performance. Med. Sci. Sports Exerc. 1998, 30, 73–82. [Google Scholar] [CrossRef]
  78. Stone, M.H.; Sanborn, K.; Smith, L.L.; O’Bryant, H.S.; Hoke, T.; Utter, A.C.; Johnson, R.L.; Boros, R.; Hruby, J.; Pierce, K.C.; et al. Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and body composition in American football players. Int. J. Sport Nutr. 1999, 9, 146–165. [Google Scholar]
  79. Bemben, M.G.; Bemben, D.A.; Loftiss, D.D.; Knehans, A.W. Creatine supplementation during resistance training in college football athletes. Med. Sci. Sports Exerc. 2001, 33, 1667–1673. [Google Scholar]
  80. Hoffman, J.; Ratamess, N.; Kang, J.; Mangine, G.; Faigenbaum, A.; Stout, J. Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes. Int. J. Sport Nutr. Exerc. Metab. 2006, 16, 430–446. [Google Scholar] [CrossRef] [Green Version]
  81. Chilibeck, P.D.; Magnus, C.; Anderson, M. Effect of in-season creatine supplementation on body composition and performance in rugby union football players. Appl. Physiol. Nutr. Metab. 2007, 32, 1052–1057. [Google Scholar] [CrossRef]
  82. Claudino, J.G.; Mezencio, B.; Amaral, S.; Zanetti, V.; Benatti, F.; Roschel, H.; Gualano, B.; Amadio, A.C.; Serrao, J.C. Creatine monohydrate supplementation on lower-limb muscle power in Brazilian elite soccer players. J. Int. Soc. Sports Nutr. 2014, 11, 32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Kerksick, C.M.; Rasmussen, C.; Lancaster, S.; Starks, M.; Smith, P.; Melton, C.; Greenwood, M.; Almada, A.; Kreider, R. Impact of differing protein sources and a creatine containing nutritional formula after 12 weeks of resistance training. Nutrition 2007, 23, 647–656. [Google Scholar] [CrossRef] [PubMed]
  84. Kerksick, C.M.; Wilborn, C.D.; Campbell, W.I.; Harvey, T.M.; Marcello, B.M.; Roberts, M.D.; Parker, A.G.; Byars, A.G.; Greenwood, L.D.; Almada, A.L.; et al. The effects of creatine monohydrate supplementation with and without D-pinitol on resistance training adaptations. J. Strength Cond. Res. 2009, 23, 2673–2682. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Galvan, E.; Walker, D.K.; Simbo, S.Y.; Dalton, R.; Levers, K.; O’Connor, A.; Goodenough, C.; Barringer, N.D.; Greenwood, M.; Rasmussen, C.; et al. Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance. J. Int. Soc. Sports Nutr. 2016, 13, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Volek, J.S.; Kraemer, W.J.; Bush, J.A.; Boetes, M.; Incledon, T.; Clark, K.L.; Lynch, J.M. Creatine supplementation enhances muscular performance during high-intensity resistance exercise. J. Am. Diet. Assoc. 1997, 97, 765–770. [Google Scholar] [CrossRef]
  87. Volek, J.S.; Mazzetti, S.A.; Farquhar, W.B.; Barnes, B.R.; Gomez, A.L.; Kraemer, W.J. Physiological responses to short-term exercise in the heat after creatine loading. Med. Sci. Sports Exerc. 2001, 33, 1101–1108. [Google Scholar] [CrossRef]
  88. Volek, J.S.; Ratamess, N.A.; Rubin, M.R.; Gomez, A.L.; French, D.N.; McGuigan, M.M.; Scheett, T.P.; Sharman, M.J.; Hakkinen, K.; Kraemer, W.J. The effects of creatine supplementation on muscular performance and body composition responses to short-term resistance training overreaching. Eur. J. Appl. Physiol. 2004, 91, 628–637. [Google Scholar] [CrossRef]
  89. Kreider, R.B.; Wilborn, C.D.; Taylor, L.; Campbell, B.; Almada, A.L.; Collins, R.; Cooke, M.; Earnest, C.P.; Greenwood, M.; Kalman, D.S.; et al. ISSN exercise & sport nutrition review: Research & recommendations. J. Int. Soc. Sports Nutr. 2010, 7, 7. [Google Scholar] [CrossRef] [Green Version]
  90. Branch, J.D. Effect of creatine supplementation on body composition and performance: A meta-analysis. Int. J. Sport Nutr. Exerc. Metab. 2003, 13, 198–226. [Google Scholar] [CrossRef]
  91. Devries, M.C.; Phillips, S.M. Creatine supplementation during resistance training in older adults-a meta-analysis. Med. Sci. Sports Exerc. 2014, 46, 1194–1203. [Google Scholar] [CrossRef]
  92. Lanhers, C.; Pereira, B.; Naughton, G.; Trousselard, M.; Lesage, F.X.; Dutheil, F. Creatine Supplementation and Lower Limb Strength Performance: A Systematic Review and Meta-Analyses. Sports Med. 2015, 45, 1285–1294. [Google Scholar] [CrossRef] [PubMed]
  93. Wiroth, J.B.; Bermon, S.; Andrei, S.; Dalloz, E.; Hebuterne, X.; Dolisi, C. Effects of oral creatine supplementation on maximal pedalling performance in older adults. Eur. J. Appl. Physiol. 2001, 84, 533–539. [Google Scholar] [CrossRef] [PubMed]
  94. McMorris, T.; Mielcarz, G.; Harris, R.C.; Swain, J.P.; Howard, A. Creatine supplementation and cognitive performance in elderly individuals. Neuropsychol. Dev. Cogn. B Aging Neuropsychol. Cogn. 2007, 14, 517–528. [Google Scholar] [CrossRef] [PubMed]
  95. Rawson, E.S.; Clarkson, P.M. Acute creatine supplementation in older men. Int. J. Sports Med. 2000, 21, 71–75. [Google Scholar] [CrossRef] [PubMed]
  96. Aguiar, A.F.; Januario, R.S.; Junior, R.P.; Gerage, A.M.; Pina, F.L.; do Nascimento, M.A.; Padovani, C.R.; Cyrino, E.S. Long-term creatine supplementation improves muscular performance during resistance training in older women. Eur. J. Appl. Physiol. 2013, 113, 987–996. [Google Scholar] [CrossRef]
  97. Kreider, R.B. Effects of creatine supplementation on performance and training adaptations. Mol. Cell Biochem. 2003, 244, 89–94. [Google Scholar]
  98. Gualano, B.; Macedo, A.R.; Alves, C.R.; Roschel, H.; Benatti, F.B.; Takayama, L.; de Sa Pinto, A.L.; Lima, F.R.; Pereira, R.M. Creatine supplementation and resistance training in vulnerable older women: A randomized double-blind placebo-controlled clinical trial. Exp. Gerontol. 2014, 53, 7–15. [Google Scholar] [CrossRef]
  99. Candow, D.G.; Little, J.P.; Chilibeck, P.D.; Abeysekara, S.; Zello, G.A.; Kazachkov, M.; Cornish, S.M.; Yu, P.H. Low-dose creatine combined with protein during resistance training in older men. Med. Sci. Sports Exerc. 2008, 40, 1645–1652. [Google Scholar] [CrossRef]
  100. Hass, C.J.; Collins, M.A.; Juncos, J.L. Resistance training with creatine monohydrate improves upper-body strength in patients with Parkinson disease: A randomized trial. Neurorehabilit. Neural Repair 2007, 21, 107–115. [Google Scholar] [CrossRef]
  101. Candow, D.G.; Chilibeck, P.D. Effect of creatine supplementation during resistance training on muscle accretion in the elderly. J. Nutr. Health Aging 2007, 11, 185–188. [Google Scholar]
  102. Chilibeck, P.D.; Chrusch, M.J.; Chad, K.E.; Shawn Davison, K.S.; Burke, D.G. Creatine monohydrate and resistance training increase bone mineral content and density in older men. J. Nutr. Health Aging 2005, 9, 352–353. [Google Scholar] [PubMed]
  103. Burke, D.G.; Chilibeck, P.D.; Parise, G.; Candow, D.G.; Mahoney, D.; Tarnopolsky, M. Effect of creatine and weight training on muscle creatine and performance in vegetarians. Med. Sci. Sports Exerc. 2003, 35, 1946–1955. [Google Scholar] [CrossRef] [PubMed]
  104. Wilder, N.; Gilders, R.; Hagerman, F.; Deivert, R.G. The effects of a 10-week, periodized, off-season resistance-training program and creatine supplementation among collegiate football players. J. Strength Cond. Res. 2002, 16, 343–352. [Google Scholar] [PubMed]
  105. Izquierdo, M.; Ibanez, J.; Gonzalez-Badillo, J.J.; Gorostiaga, E.M. Effects of creatine supplementation on muscle power, endurance, and sprint performance. Med. Sci. Sports Exerc. 2002, 34, 332–343. [Google Scholar] [CrossRef]
  106. Chrusch, M.J.; Chilibeck, P.D.; Chad, K.E.; Davison, K.S.; Burke, D.G. Creatine supplementation combined with resistance training in older men. Med. Sci. Sports Exerc. 2001, 33, 2111–2117. [Google Scholar] [CrossRef]
  107. Becque, M.D.; Lochmann, J.D.; Melrose, D.R. Effects of oral creatine supplementation on muscular strength and body composition. Med. Sci. Sports Exerc. 2000, 32, 654–658. [Google Scholar] [CrossRef] [PubMed]
  108. Volek, J.S.; Duncan, N.D.; Mazzetti, S.A.; Staron, R.S.; Putukian, M.; Gomez, A.L.; Pearson, D.R.; Fink, W.J.; Kraemer, W.J. Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. Med. Sci. Sports Exerc. 1999, 31, 1147–1156. [Google Scholar] [CrossRef]
  109. Ziegenfuss, T.N.; Habowski, S.M.; Lemieux, R.; Sandrock, J.E.; Kedia, A.W.; Kerksick, C.M.; Lopez, H.L. Effects of a dietary supplement on golf drive distance and functional indices of golf performance. J. Int. Soc. Sports Nutr. 2015, 12, 4. [Google Scholar] [CrossRef] [Green Version]
  110. Lamontagne-Lacasse, M.; Nadon, R.; Goulet, E.D. Effect of creatine supplementation on jumping performance in elite volleyball players. Int. J. Sports Physiol. Perform. 2011, 6, 525–533. [Google Scholar] [CrossRef]
  111. Ramirez-Campillo, R.; Gonzalez-Jurado, J.A.; Martinez, C.; Nakamura, F.Y.; Penailillo, L.; Meylan, C.M.; Caniuqueo, A.; Canas-Jamet, R.; Moran, J.; Alonso-Martinez, A.M.; et al. Effects of plyometric training and creatine supplementation on maximal-intensity exercise and endurance in female soccer players. J. Sci. Med. Sport 2016, 19, 682–687. [Google Scholar] [CrossRef] [Green Version]
  112. Yanez-Silva, A.; Buzzachera, C.F.; Picarro, I.D.; Januario, R.S.; Ferreira, L.H.; McAnulty, S.R.; Utter, A.C.; Souza-Junior, T.P. Effect of low dose, short-term creatine supplementation on muscle power output in elite youth soccer players. J. Int. Soc. Sports Nutr. 2017, 14, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Ayoama, R.; Hiruma, E.; Sasaki, H. Effects of creatine loading on muscular strength and endurance of female softball players. J. Sports Med. Phys. Fit. 2003, 43, 481–487. [Google Scholar]
  114. Jones, A.M.; Atter, T.; Georg, K.P. Oral creatine supplementation improves multiple sprint performance in elite ice-hockey players. J. Sports Med. Phys. Fit. 1999, 39, 189–196. [Google Scholar] [CrossRef]
  115. Ahmun, R.P.; Tong, R.J.; Grimshaw, P.N. The effects of acute creatine supplementation on multiple sprint cycling and running performance in rugby players. J. Strength Cond. Res. 2005, 19, 92–97. [Google Scholar] [CrossRef]
  116. Cox, G.; Mujika, I.; Tumilty, D.; Burke, L. Acute creatine supplementation and performance during a field test simulating match play in elite female soccer players. Int. J. Sport Nutr. Exerc. Metab. 2002, 12, 33–46. [Google Scholar] [CrossRef] [PubMed]
  117. Preen, D.; Dawson, B.; Goodman, C.; Lawrence, S.; Beilby, J.; Ching, S. Effect of creatine loading on long-term sprint exercise performance and metabolism. Med. Sci. Sports Exerc. 2001, 33, 814–821. [Google Scholar] [CrossRef] [PubMed]
  118. Aaserud, R.; Gramvik, P.; Olsen, S.R.; Jensen, J. Creatine supplementation delays onset of fatigue during repeated bouts of sprint running. Scand. J. Med. Sci. Sports 1998, 8, 247–251. [Google Scholar] [CrossRef]
  119. Bosco, C.; Tihanyi, J.; Pucspk, J.; Kovacs, I.; Gabossy, A.; Colli, R.; Pulvirenti, G.; Tranquilli, C.; Foti, C.; Viru, M.; et al. Effect of oral creatine supplementation on jumping and running performance. Int. J. Sports Med. 1997, 18, 369–372. [Google Scholar] [CrossRef]
  120. Dabidi Roshan, V.; Babaei, H.; Hosseinzadeh, M.; Arendt-Nielsen, L. The effect of creatine supplementation on muscle fatigue and physiological indices following intermittent swimming bouts. J. Sports Med. Phys. Fit. 2013, 53, 232–239. [Google Scholar]
  121. Selsby, J.T.; Beckett, K.D.; Kern, M.; Devor, S.T. Swim performance following creatine supplementation in Division III athletes. J. Strength Cond. Res. 2003, 17, 421–424. [Google Scholar]
  122. Leenders, N.M.; Lamb, D.R.; Nelson, T.E. Creatine supplementation and swimming performance. Int. J. Sport Nutr. 1999, 9, 251–262. [Google Scholar] [CrossRef] [PubMed]
  123. Peyrebrune, M.C.; Nevill, M.E.; Donaldson, F.J.; Cosford, D.J. The effects of oral creatine supplementation on performance in single and repeated sprint swimming. J. Sports Sci. 1998, 16, 271–279. [Google Scholar] [CrossRef] [PubMed]
  124. Vandenberghe, K.; Goris, M.; Van Hecke, P.; Van Leemputte, M.; Vangerven, L.; Hespel, P. Long-term creatine intake is beneficial to muscle performance during resistance training. J. Appl. Physiol. 1997, 83, 2055–2063. [Google Scholar] [CrossRef] [PubMed]
  125. Tarnopolsky, M.A.; MacLennan, D.P. Creatine monohydrate supplementation enhances high-intensity exercise performance in males and females. Int. J. Sport Nutr. Exerc. Metab. 2000, 10, 452–463. [Google Scholar] [CrossRef] [PubMed]
  126. Ziegenfuss, T.N.; Rogers, M.; Lowery, L.; Mullins, N.; Mendel, R.; Antonio, J.; Lemon, P. Effect of creatine loading on anaerobic performance and skeletal muscle volume in NCAA Division I athletes. Nutrition 2002, 18, 397–402. [Google Scholar] [CrossRef]
  127. Benton, D.; Donohoe, R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br. J. Nutr. 2011, 105, 1100–1105. [Google Scholar] [CrossRef] [Green Version]
  128. Johannsmeyer, S.; Candow, D.G.; Brahms, C.M.; Michel, D.; Zello, G.A. Effect of creatine supplementation and drop-set resistance training in untrained aging adults. Exp. Gerontol. 2016, 83, 112–119. [Google Scholar] [CrossRef]
  129. Rodriguez, N.R.; DiMarco, N.M.; Langley, S.; American Dietetic, A.; Dietitians of, C.; American College of Sports Medicine, N.; Athletic, P. Position of the American Dietetic Association, Dietitians of Canada, and the American College of Sports Medicine: Nutrition and athletic performance. J. Am. Diet. Assoc. 2009, 109, 509–527. [Google Scholar]
  130. Thomas, D.T.; Erdman, K.A.; Burke, L.M. Position of the Academy of Nutrition and Dietetics, Dietitians of Canada, and the American College of Sports Medicine: Nutrition and Athletic Performance. J. Acad. Nutr. Diet. 2016, 116, 501–528. [Google Scholar] [CrossRef]
  131. Gualano, B.; Rawson, E.S.; Candow, D.G.; Chilibeck, P.D. Creatine supplementation in the aging population: Effects on skeletal muscle, bone and brain. Amino Acids 2016, 48, 1793–1805. [Google Scholar] [CrossRef]
  132. Earnest, C.P.; Almada, A.L.; Mitchell, T.L. High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women. Clin. Sci. 1996, 91, 113–118. [Google Scholar] [CrossRef] [PubMed]
  133. da Silva, R.P.; Leonard, K.A.; Jacobs, R.L. Dietary creatine supplementation lowers hepatic triacylglycerol by increasing lipoprotein secretion in rats fed high-fat diet. J. Nutr. Biochem. 2017, 50, 46–53. [Google Scholar] [CrossRef] [PubMed]
  134. Deminice, R.; de Castro, G.S.; Francisco, L.V.; da Silva, L.E.; Cardoso, J.F.; Frajacomo, F.T.; Teodoro, B.G.; Dos Reis Silveira, L.; Jordao, A.A. Creatine supplementation prevents fatty liver in rats fed choline-deficient diet: A burden of one-carbon and fatty acid metabolism. J. Nutr. Biochem. 2015, 26, 391–397. [Google Scholar] [CrossRef] [PubMed]
  135. Deminice, R.; Cella, P.S.; Padilha, C.S.; Borges, F.H.; da Silva, L.E.; Campos-Ferraz, P.L.; Jordao, A.A.; Robinson, J.L.; Bertolo, R.F.; Cecchini, R.; et al. Creatine supplementation prevents hyperhomocysteinemia, oxidative stress and cancer-induced cachexia progression in Walker-256 tumor-bearing rats. Amino Acids 2016, 48, 2015–2024. [Google Scholar] [CrossRef] [PubMed]
  136. Lawler, J.M.; Barnes, W.S.; Wu, G.; Song, W.; Demaree, S. Direct antioxidant properties of creatine. Biochem. Biophys. Res. Commun. 2002, 290, 47–52. [Google Scholar] [CrossRef]
  137. Rakpongsiri, K.; Sawangkoon, S. Protective effect of creatine supplementation and estrogen replacement on cardiac reserve function and antioxidant reservation against oxidative stress in exercise-trained ovariectomized hamsters. Int. Heart J. 2008, 49, 343–354. [Google Scholar] [CrossRef] [Green Version]
  138. Rahimi, R.; Mirzaei, B.; Rahmani-Nia, F.; Salehi, Z. Effects of creatine monohydrate supplementation on exercise-induced apoptosis in athletes: A randomized, double-blind, and placebo-controlled study. J. Res. Med. Sci. 2015, 20, 733–738. [Google Scholar] [CrossRef]
  139. Deminice, R.; Jordao, A.A. Creatine supplementation decreases plasma lipid peroxidation markers and enhances anaerobic performance in rats. Redox Rep. 2015. [Google Scholar] [CrossRef]
  140. Op’t Eijnde, B.; Urso, B.; Richter, E.A.; Greenhaff, P.L.; Hespel, P. Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization. Diabetes 2001, 50, 18–23. [Google Scholar] [CrossRef] [Green Version]
  141. Gualano, B.; V, D.E.S.P.; Roschel, H.; Artioli, G.G.; Neves, M., Jr.; De Sa Pinto, A.L.; Da Silva, M.E.; Cunha, M.R.; Otaduy, M.C.; Leite Cda, C.; et al. Creatine in type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Med. Sci. Sports Exerc. 2011, 43, 770–778. [Google Scholar] [CrossRef]
  142. Op’t Eijnde, B.; Jijakli, H.; Hespel, P.; Malaisse, W.J. Creatine supplementation increases soleus muscle creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes. Int. J. Mol. Med. 2006, 17, 1077–1084. [Google Scholar] [CrossRef] [PubMed]
  143. Alves, C.R.; Ferreira, J.C.; de Siqueira-Filho, M.A.; Carvalho, C.R.; Lancha, A.H., Jr.; Gualano, B. Creatine-induced glucose uptake in type 2 diabetes: A role for AMPK-alpha? Amino Acids 2012, 43, 1803–1807. [Google Scholar] [CrossRef] [PubMed]
  144. Patra, S.; Ghosh, A.; Roy, S.S.; Bera, S.; Das, M.; Talukdar, D.; Ray, S.; Wallimann, T.; Ray, M. A short review on creatine-creatine kinase system in relation to cancer and some experimental results on creatine as adjuvant in cancer therapy. Amino Acids 2012, 42, 2319–2330. [Google Scholar] [CrossRef] [PubMed]
  145. Soares, J.D.P.; Howell, S.L.; Teixeira, F.J.; Pimentel, G.D. Dietary Amino Acids and Immunonutrition Supplementation in Cancer-Induced Skeletal Muscle Mass Depletion: A Mini-Review. Curr. Pharm. Des. 2020, 26, 970–978. [Google Scholar] [CrossRef]
  146. Cella, P.S.; Marinello, P.C.; Borges, F.H.; Ribeiro, D.F.; Chimin, P.; Testa, M.T.J.; Guirro, P.B.; Duarte, J.A.; Cecchini, R.; Guarnier, F.A.; et al. Creatine supplementation in Walker-256 tumor-bearing rats prevents skeletal muscle atrophy by attenuating systemic inflammation and protein degradation signaling. Eur. J. Nutr. 2020, 59, 661–669. [Google Scholar] [CrossRef] [PubMed]
  147. Pal, A.; Roy, A.; Ray, M. Creatine supplementation with methylglyoxal: A potent therapy for cancer in experimental models. Amino Acids 2016, 48, 2003–2013. [Google Scholar] [CrossRef]
  148. Canete, S.; San Juan, A.F.; Perez, M.; Gomez-Gallego, F.; Lopez-Mojares, L.M.; Earnest, C.P.; Fleck, S.J.; Lucia, A. Does creatine supplementation improve functional capacity in elderly women? J. Strength Cond. Res. 2006, 20, 22–28. [Google Scholar] [CrossRef]
  149. Candow, D.G.; Zello, G.A.; Ling, B.; Farthing, J.P.; Chilibeck, P.D.; McLeod, K.; Harris, J.; Johnson, S. Comparison of creatine supplementation before versus after supervised resistance training in healthy older adults. Res. Sports Med. 2014, 22, 61–74. [Google Scholar] [CrossRef]
  150. Chilibeck, P.D.; Candow, D.G.; Landeryou, T.; Kaviani, M.; Paus-Jenssen, L. Effects of Creatine and Resistance Training on Bone Health in Postmenopausal Women. Med. Sci. Sports Exerc. 2015, 47, 1587–1595. [Google Scholar] [CrossRef]
  151. O’Bryan, K.R.; Doering, T.M.; Morton, R.W.; Coffey, V.G.; Phillips, S.M.; Cox, G.R. Do multi-ingredient protein supplements augment resistance training-induced gains in skeletal muscle mass and strength? A systematic review and meta-analysis of 35 trials. Br. J. Sports Med. 2020, 54, 573–581. [Google Scholar] [CrossRef] [Green Version]
  152. Nilsson, M.I.; Mikhail, A.; Lan, L.; Di Carlo, A.; Hamilton, B.; Barnard, K.; Hettinga, B.P.; Hatcher, E.; Tarnopolsky, M.G.; Nederveen, J.P.; et al. A Five-Ingredient Nutritional Supplement and Home-Based Resistance Exercise Improve Lean Mass and Strength in Free-Living Elderly. Nutrients 2020, 12, 2391. [Google Scholar] [CrossRef] [PubMed]
  153. Gielen, E.; Beckwee, D.; Delaere, A.; De Breucker, S.; Vandewoude, M.; Bautmans, I.; Sarcopenia Guidelines Development Group of the Belgian Society of Geriatrics. Nutritional interventions to improve muscle mass, muscle strength, and physical performance in older people: An umbrella review of systematic reviews and meta-analyses. Nutr. Rev. 2020. [Google Scholar] [CrossRef] [PubMed]
  154. Evans, M.; Guthrie, N.; Pezzullo, J.; Sanli, T.; Fielding, R.A.; Bellamine, A. Efficacy of a novel formulation of L-Carnitine, creatine, and leucine on lean body mass and functional muscle strength in healthy older adults: A randomized, double-blind placebo-controlled study. Nutr. Metab. 2017, 14, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Sales, L.P.; Pinto, A.J.; Rodrigues, S.F.; Alvarenga, J.C.; Goncalves, N.; Sampaio-Barros, M.M.; Benatti, F.B.; Gualano, B.; Rodrigues Pereira, R.M. Creatine Supplementation (3 g/d) and Bone Health in Older Women: A 2-Year, Randomized, Placebo-Controlled Trial. J. Gerontol. A Biol. Sci. Med. Sci. 2020, 75, 931–938. [Google Scholar] [CrossRef] [PubMed]
  156. Castoldi, R.C.; Ozaki, G.A.T.; Garcia, T.A.; Giometti, I.C.; Koike, T.E.; Camargo, R.C.T.; Dos Santos Pereira, J.D.A.; Constantino, C.J.L.; Louzada, M.J.Q.; Camargo Filho, J.C.S.; et al. Effects of muscular strength training and growth hormone (GH) supplementation on femoral bone tissue: Analysis by Raman spectroscopy, dual-energy X-ray absorptiometry, and mechanical resistance. Lasers Med. Sci. 2020, 35, 345–354. [Google Scholar] [CrossRef] [PubMed]
  157. Laskou, F.; Dennison, E. Interaction of Nutrition and Exercise on Bone and Muscle. Eur. Endocrinol. 2019, 15, 11–12. [Google Scholar] [CrossRef]
  158. Candow, D.G.; Forbes, S.C.; Vogt, E. Effect of pre-exercise and post-exercise creatine supplementation on bone mineral content and density in healthy aging adults. Exp. Gerontol. 2019, 119, 89–92. [Google Scholar] [CrossRef]
  159. Rawson, E.S.; Miles, M.P.; Larson-Meyer, D.E. Dietary Supplements for Health, Adaptation, and Recovery in Athletes. Int. J. Sport Nutr. Exerc. Metab. 2018, 28, 188–199. [Google Scholar] [CrossRef] [Green Version]
  160. Forbes, S.C.; Chilibeck, P.D.; Candow, D.G. Creatine Supplementation During Resistance Training Does Not Lead to Greater Bone Mineral Density in Older Humans: A Brief Meta-Analysis. Front. Nutr. 2018, 5, 27. [Google Scholar] [CrossRef] [Green Version]
  161. Cornish, S.M.; Peeler, J.D. No effect of creatine monohydrate supplementation on inflammatory and cartilage degradation biomarkers in individuals with knee osteoarthritis. Nutr. Res. 2018, 51, 57–66. [Google Scholar] [CrossRef]
  162. Alves, C.R.; Santiago, B.M.; Lima, F.R.; Otaduy, M.C.; Calich, A.L.; Tritto, A.C.; de Sa Pinto, A.L.; Roschel, H.; Leite, C.C.; Benatti, F.B.; et al. Creatine supplementation in fibromyalgia: A randomized, double-blind, placebo-controlled trial. Arthritis Care Res. 2013, 65, 1449–1459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Bell, K.E.; Fang, H.; Snijders, T.; Allison, D.J.; Zulyniak, M.A.; Chabowski, A.; Parise, G.; Phillips, S.M.; Heisz, J.J. A Multi-Ingredient Nutritional Supplement in Combination With Resistance Exercise and High-Intensity Interval Training Improves Cognitive Function and Increases N-3 Index in Healthy Older Men: A Randomized Controlled Trial. Front. Aging Neurosci. 2019, 11, 107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Scholey, A. Nutrients for neurocognition in health and disease: Measures, methodologies and mechanisms. Proc. Nutr. Soc. 2018, 77, 73–83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Merege-Filho, C.A.; Otaduy, M.C.; de Sa-Pinto, A.L.; de Oliveira, M.O.; de Souza Goncalves, L.; Hayashi, A.P.; Roschel, H.; Pereira, R.M.; Silva, C.A.; Brucki, S.M.; et al. Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study. Appl. Physiol. Nutr. Metab. 2017, 42, 128–134. [Google Scholar] [CrossRef] [PubMed]
  166. Turner, C.E.; Byblow, W.D.; Gant, N. Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation. J. Neurosci. 2015, 35, 1773–1780. [Google Scholar] [CrossRef]
  167. Rawson, E.S.; Lieberman, H.R.; Walsh, T.M.; Zuber, S.M.; Harhart, J.M.; Matthews, T.C. Creatine supplementation does not improve cognitive function in young adults. Physiol. Behav. 2008, 95, 130–134. [Google Scholar] [CrossRef] [PubMed]
  168. McMorris, T.; Harris, R.C.; Howard, A.N.; Langridge, G.; Hall, B.; Corbett, J.; Dicks, M.; Hodgson, C. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiol. Behav. 2007, 90, 21–28. [Google Scholar] [CrossRef]
  169. Roitman, S.; Green, T.; Osher, Y.; Karni, N.; Levine, J. Creatine monohydrate in resistant depression: A preliminary study. Bipolar Disord. 2007, 9, 754–758. [Google Scholar] [CrossRef]
  170. D’Anci, K.E.; Allen, P.J.; Kanarek, R.B. A potential role for creatine in drug abuse? Mol. Neurobiol. 2011, 44, 136–141. [Google Scholar] [CrossRef]
  171. Balestrino, M.; Adriano, E. Beyond sports: Efficacy and safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle. Med. Res. Rev. 2019, 39, 2427–2459. [Google Scholar] [CrossRef]
  172. Toniolo, R.A.; Silva, M.; Fernandes, F.B.F.; Amaral, J.; Dias, R.D.S.; Lafer, B. A randomized, double-blind, placebo-controlled, proof-of-concept trial of creatine monohydrate as adjunctive treatment for bipolar depression. J. Neural Transm. 2018, 125, 247–257. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Brose, A.; Parise, G.; Tarnopolsky, M.A. Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults. J. Gerontol. A Biol. Sci. Med. Sci. 2003, 58, 11–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. McMorris, T.; Harris, R.C.; Swain, J.; Corbett, J.; Collard, K.; Dyson, R.J.; Dye, L.; Hodgson, C.; Draper, N. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology 2006, 185, 93–103. [Google Scholar] [CrossRef] [PubMed]
  175. Bernat, P.; Candow, D.G.; Gryzb, K.; Butchart, S.; Schoenfeld, B.J.; Bruno, P. Effects of high-velocity resistance training and creatine supplementation in untrained healthy aging males. Appl. Physiol. Nutr. Metab. 2019, 44, 1246–1253. [Google Scholar] [CrossRef] [Green Version]
  176. Forbes, S.C.; Candow, D.G.; Krentz, J.R.; oberts, M.D.; Young, K.C. Changes in Fat Mass Following Creatine Supplementation and Resistance Training in Adults ≥50 Years of Age: A Meta-Analysis. J. Funct. Morphol. Kinesio. 2019, 4, 62. [Google Scholar] [CrossRef] [Green Version]
  177. Rae, C.; Digney, A.L.; McEwan, S.R.; Bates, T.C. Oral creatine monohydrate supplementation improves brain performance: A double-blind, placebo-controlled, cross-over trial. Proc. Biol. Sci. 2003, 270, 2147–2150. [Google Scholar] [CrossRef] [Green Version]
  178. Ling, J.; Kritikos, M.; Tiplady, B. Cognitive effects of creatine ethyl ester supplementation. Behav. Pharmacol. 2009, 20, 673–679. [Google Scholar] [CrossRef] [Green Version]
  179. Robinson, J.L.; McBreairty, L.E.; Ryan, R.A.; Randunu, R.; Walsh, C.J.; Martin, G.M.; Brunton, J.A.; Bertolo, R.F. Effects of supplemental creatine and guanidinoacetic acid on spatial memory and the brain of weaned Yucatan miniature pigs. PLoS ONE 2020, 15, e0226806. [Google Scholar] [CrossRef]
  180. Watanabe, A.; Kato, N.; Kato, T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci. Res. 2002, 42, 279–285. [Google Scholar]
  181. Rooney, K.; Bryson, J.; Phuyal, J.; Denyer, G.; Caterson, I.; Thompson, C. Creatine supplementation alters insulin secretion and glucose homeostasis in vivo. Metabolism 2002, 51, 518–522. [Google Scholar] [CrossRef]
  182. Newman, J.E.; Hargreaves, M.; Garnham, A.; Snow, R.J. Effect of creatine ingestion on glucose tolerance and insulin sensitivity in men. Med. Sci. Sports Exerc. 2003, 35, 69–74. [Google Scholar] [CrossRef] [PubMed]
  183. Greenwood, M.; Kreider, R.B.; Earnest, C.P.; Rasmussen, C.; Almada, A. Differences in creatine retention among three nutritional formulations of oral creatine supplements. J. Exerc. Physiol. Online 2003, 6, 37–43. [Google Scholar]
  184. Steenge, G.R.; Simpson, E.J.; Greenhaff, P.L. Protein- and carbohydrate-induced augmentation of whole body creatine retention in humans. J. Appl. Physiol. 2000, 89, 1165–1171. [Google Scholar] [CrossRef] [PubMed]
  185. Nelson, A.G.; Arnall, D.A.; Kokkonen, J.; Day, R.; Evans, J. Muscle glycogen supercompensation is enhanced by prior creatine supplementation. Med. Sci. Sports Exerc. 2001, 33, 1096–1100. [Google Scholar] [CrossRef] [PubMed]
  186. Gualano, B.; Artioli, G.G.; Poortmans, J.R.; Lancha Junior, A.H. Exploring the therapeutic role of creatine supplementation. Amino Acids 2010, 38, 31–44. [Google Scholar] [CrossRef]
  187. Hultman, J.; Ronquist, G.; Forsberg, J.O.; Hansson, H.E. Myocardial energy restoration of ischemic damage by administration of phosphoenolpyruvate during reperfusion. A study in a paracorporeal rat heart model. Eur. Surg. Res. 1983, 15, 200–207. [Google Scholar]
  188. Thelin, S.; Hultman, J.; Ronquist, G.; Hansson, H.E. Metabolic and functional effects of creatine phosphate in cardioplegic solution. Studies on rat hearts during and after normothermic ischemia. Scand. J. Thorac. Cardiovasc. Surg. 1987, 21, 39–45. [Google Scholar]
  189. Osbakken, M.; Ito, K.; Zhang, D.; Ponomarenko, I.; Ivanics, T.; Jahngen, E.G.; Cohn, M. Creatine and cyclocreatine effects on ischemic myocardium: 31P nuclear magnetic resonance evaluation of intact heart. Cardiology 1992, 80, 184–195. [Google Scholar]
  190. Thorelius, J.; Thelin, S.; Ronquist, G.; Halden, E.; Hansson, H.E. Biochemical and functional effects of creatine phosphate in cardioplegic solution during aortic valve surgery–A clinical study. Thorac. Cardiovasc. Surg. 1992, 40, 10–13. [Google Scholar] [CrossRef]
  191. Boudina, S.; Laclau, M.N.; Tariosse, L.; Daret, D.; Gouverneur, G.; Bonoron-Adele, S.; Saks, V.A.; Dos Santos, P. Alteration of mitochondrial function in a model of chronic ischemia in vivo in rat heart. Am. J. Physiol. Heart Circ. Physiol. 2002, 282, H821–H831. [Google Scholar] [CrossRef] [Green Version]
  192. Laclau, M.N.; Boudina, S.; Thambo, J.B.; Tariosse, L.; Gouverneur, G.; Bonoron-Adele, S.; Saks, V.A.; Garlid, K.D.; Dos Santos, P. Cardioprotection by ischemic preconditioning preserves mitochondrial function and functional coupling between adenine nucleotide translocase and creatine kinase. J. Mol. Cell Cardiol. 2001, 33, 947–956. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  193. Conorev, E.A.; Sharov, V.G.; Saks, V.A. Improvement in contractile recovery of isolated rat heart after cardioplegic ischaemic arrest with endogenous phosphocreatine: Involvement of antiperoxidative effect? Cardiovasc. Res. 1991, 25, 164–171. [Google Scholar] [CrossRef] [PubMed]
  194. Sharov, V.G.; Saks, V.A.; Kupriyanov, V.V.; Lakomkin, V.L.; Kapelko, V.I.; Steinschneider, A.; Javadov, S.A. Protection of ischemic myocardium by exogenous phosphocreatine. I. Morphologic and phosphorus 31-nuclear magnetic resonance studies. J. Thorac. Cardiovasc. Surg. 1987, 94, 749–761. [Google Scholar] [CrossRef]
  195. Anyukhovsky, E.P.; Javadov, S.A.; Preobrazhensky, A.N.; Beloshapko, G.G.; Rosenshtraukh, L.V.; Saks, V.A. Effect of phosphocreatine and related compounds on the phospholipid metabolism of ischemic heart. Biochem. Med. Metab. Biol. 1986, 35, 327–334. [Google Scholar]
  196. Sharov, V.G.; Afonskaya, N.I.; Ruda, M.Y.; Cherpachenko, N.M.; Pozin, E.; Markosyan, R.A.; Shepeleva, I.I.; Samarenko, M.B.; Saks, V.A. Protection of ischemic myocardium by exogenous phosphocreatine (neoton): Pharmacokinetics of phosphocreatine, reduction of infarct size, stabilization of sarcolemma of ischemic cardiomyocytes, and antithrombotic action. Biochem. Med. Metab. Biol. 1986, 35, 101–114. [Google Scholar] [CrossRef]
  197. Perasso, L.; Spallarossa, P.; Gandolfo, C.; Ruggeri, P.; Balestrino, M. Therapeutic use of creatine in brain or heart ischemia: Available data and future perspectives. Med. Res. Rev. 2013, 33, 336–363. [Google Scholar] [CrossRef]
  198. Gordon, A.; Hultman, E.; Kaijser, L.; Kristjansson, S.; Rolf, C.J.; Nyquist, O.; Sylven, C. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Cardiovasc. Res. 1995, 30, 413–418. [Google Scholar] [CrossRef]
  199. Andrews, R.; Greenhaff, P.; Curtis, S.; Perry, A.; Cowley, A.J. The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure. Eur. Heart J. 1998, 19, 617–622. [Google Scholar] [CrossRef] [Green Version]
  200. Kuethe, F.; Krack, A.; Richartz, B.M.; Figulla, H.R. Creatine supplementation improves muscle strength in patients with congestive heart failure. Pharmazie 2006, 61, 218–222. [Google Scholar]
  201. Fumagalli, S.; Fattirolli, F.; Guarducci, L.; Cellai, T.; Baldasseroni, S.; Tarantini, F.; Di Bari, M.; Masotti, G.; Marchionni, N. Coenzyme Q10 terclatrate and creatine in chronic heart failure: A randomized, placebo-controlled, double-blind study. Clin. Cardiol. 2011, 34, 211–217. [Google Scholar] [CrossRef]
  202. Carvalho, A.P.; Rassi, S.; Fontana, K.E.; Kde, S.C.; Feitosa, R.H. Influence of creatine supplementation on the functional capacity of patients with heart failure. Arq. Bras. Cardiol. 2012, 99, 623–629. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  203. Sykut-Cegielska, J.; Gradowska, W.; Mercimek-Mahmutoglu, S.; Stockler-Ipsiroglu, S. Biochemical and clinical characteristics of creatine deficiency syndromes. Acta Biochim. Pol. 2004, 51, 875–882. [Google Scholar] [PubMed]
  204. Freissmuth, M.; Stockner, T.; Sucic, S. SLC6 Transporter Folding Diseases and Pharmacochaperoning. Handb. Exp. Pharmacol. 2018, 245, 249–270. [Google Scholar] [CrossRef] [PubMed]
  205. van de Kamp, J.M.; Mancini, G.M.; Salomons, G.S. X-linked creatine transporter deficiency: Clinical aspects and pathophysiology. J. Inherit. Metab. Dis. 2014, 37, 715–733. [Google Scholar] [CrossRef]
  206. Mercimek-Mahmutoglu, S.; Salomons, G.S. Creatine Deficiency Syndromes. In GeneReviews(R); Pagon, R.A., Adam, M.P., Ardinger, H.H., Wallace, S.E., Amemiya, A., Bean, L.J.H., Bird, T.D., Ledbetter, N., Mefford, H.C., Smith, R.J.H., Eds.; University of Washington: Seattle, WA, USA, 1993. [Google Scholar]
  207. Stockler-Ipsiroglu, S.; van Karnebeek, C.D. Cerebral creatine deficiencies: A group of treatable intellectual developmental disorders. Semin. Neurol. 2014, 34, 350–356. [Google Scholar] [CrossRef]
  208. Joncquel-Chevalier Curt, M.; Voicu, P.M.; Fontaine, M.; Dessein, A.F.; Porchet, N.; Mention-Mulliez, K.; Dobbelaere, D.; Soto-Ares, G.; Cheillan, D.; Vamecq, J. Creatine biosynthesis and transport in health and disease. Biochimie 2015, 119, 146–165. [Google Scholar] [CrossRef]
  209. Cameron, J.M.; Levandovskiy, V.; Roberts, W.; Anagnostou, E.; Scherer, S.; Loh, A.; Schulze, A. Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder. Int. J. Mol. Sci. 2017, 18, 1665. [Google Scholar] [CrossRef] [Green Version]
  210. Salazar, M.D.; Zelt, N.B.; Saldivar, R.; Kuntz, C.P.; Chen, S.; Penn, W.D.; Bonneau, R.; Leman, J.K.; Schlebach, J.P. Classification of the Molecular Defects Associated with Pathogenic Variants of the SLC6A8 Creatine Transporter. Biochemistry 2020, 59, 1367–1377. [Google Scholar] [CrossRef]
  211. Longo, N.; Ardon, O.; Vanzo, R.; Schwartz, E.; Pasquali, M. Disorders of creatine transport and metabolism. Am. J. Med. Genet. C Semin Med. Genet. 2011, 157C, 72–78. [Google Scholar] [CrossRef]
  212. Nasrallah, F.; Feki, M.; Kaabachi, N. Creatine and creatine deficiency syndromes: Biochemical and clinical aspects. Pediatr. Neurol. 2010, 42, 163–171. [Google Scholar] [CrossRef]
  213. Mercimek-Mahmutoglu, S.; Stoeckler-Ipsiroglu, S.; Adami, A.; Appleton, R.; Araujo, H.C.; Duran, M.; Ensenauer, R.; Fernandez-Alvarez, E.; Garcia, P.; Grolik, C.; et al. GAMT deficiency: Features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 2006, 67, 480–484. [Google Scholar] [CrossRef] [PubMed]
  214. Stromberger, C.; Bodamer, O.A.; Stockler-Ipsiroglu, S. Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J. Inherit. Metab. Dis. 2003, 26, 299–308. [Google Scholar] [CrossRef] [PubMed]
  215. Bianchi, M.C.; Tosetti, M.; Battini, R.; Leuzzi, V.; Alessandri, M.G.; Carducci, C.; Antonozzi, I.; Cioni, G. Treatment monitoring of brain creatine deficiency syndromes: A 1H- and 31P-MR spectroscopy study. AJNR Am. J. Neuroradiol. 2007, 28, 548–554. [Google Scholar] [PubMed]
  216. Battini, R.; Alessandri, M.G.; Leuzzi, V.; Moro, F.; Tosetti, M.; Bianchi, M.C.; Cioni, G. Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: Early treatment can prevent phenotypic expression of the disease. J. Pediatr. 2006, 148, 828–830. [Google Scholar] [CrossRef] [PubMed]
  217. Stockler-Ipsiroglu, S.; van Karnebeek, C.; Longo, N.; Korenke, G.C.; Mercimek-Mahmutoglu, S.; Marquart, I.; Barshop, B.; Grolik, C.; Schlune, A.; Angle, B.; et al. Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol. Genet. Metab. 2014, 111, 16–25. [Google Scholar] [CrossRef]
  218. Valtonen, M.; Nanto-Salonen, K.; Jaaskelainen, S.; Heinanen, K.; Alanen, A.; Heinonen, O.J.; Lundbom, N.; Erkintalo, M.; Simell, O. Central nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinaemia. J. Inherit. Metab. Dis. 1999, 22, 855–866. [Google Scholar] [CrossRef]
  219. Nanto-Salonen, K.; Komu, M.; Lundbom, N.; Heinanen, K.; Alanen, A.; Sipila, I.; Simell, O. Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology 1999, 53, 303–307. [Google Scholar] [CrossRef]
  220. Heinanen, K.; Nanto-Salonen, K.; Komu, M.; Erkintalo, M.; Alanen, A.; Heinonen, O.J.; Pulkki, K.; Nikoskelainen, E.; Sipila, I.; Simell, O. Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia. Eur. J. Clin. Investig. 1999, 29, 1060–1065. [Google Scholar] [CrossRef]
  221. Vannas-Sulonen, K.; Sipila, I.; Vannas, A.; Simell, O.; Rapola, J. Gyrate atrophy of the choroid and retina. A five-year follow-up of creatine supplementation. Ophthalmology 1985, 92, 1719–1727. [Google Scholar] [CrossRef]
  222. Sipila, I.; Rapola, J.; Simell, O.; Vannas, A. Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. N. Engl. J. Med. 1981, 304, 867–870. [Google Scholar] [CrossRef]
  223. Evangeliou, A.; Vasilaki, K.; Karagianni, P.; Nikolaidis, N. Clinical applications of creatine supplementation on paediatrics. Curr. Pharm. Biotechnol. 2009, 10, 683–690. [Google Scholar] [CrossRef] [PubMed]
  224. Verbruggen, K.T.; Knijff, W.A.; Soorani-Lunsing, R.J.; Sijens, P.E.; Verhoeven, N.M.; Salomons, G.S.; Goorhuis-Brouwer, S.M.; van Spronsen, F.J. Global developmental delay in guanidionacetate methyltransferase deficiency: Differences in formal testing and clinical observation. Eur. J. Pediatr. 2007, 166, 921–925. [Google Scholar] [CrossRef] [PubMed]
  225. Ganesan, V.; Johnson, A.; Connelly, A.; Eckhardt, S.; Surtees, R.A. Guanidinoacetate methyltransferase deficiency: New clinical features. Pediatr. Neurol. 1997, 17, 155–157. [Google Scholar] [CrossRef]
  226. Ensenauer, R.; Thiel, T.; Schwab, K.O.; Tacke, U.; Stockler-Ipsiroglu, S.; Schulze, A.; Hennig, J.; Lehnert, W. Guanidinoacetate methyltransferase deficiency: Differences of creatine uptake in human brain and muscle. Mol. Genet. Metab. 2004, 82, 208–213. [Google Scholar] [CrossRef] [PubMed]
  227. Adhihetty, P.J.; Beal, M.F. Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromol. Med. 2008, 10, 275–290. [Google Scholar] [CrossRef] [Green Version]
  228. Verbessem, P.; Lemiere, J.; Eijnde, B.O.; Swinnen, S.; Vanhees, L.; Van Leemputte, M.; Hespel, P.; Dom, R. Creatine supplementation in Huntington’s disease: A placebo-controlled pilot trial. Neurology 2003, 61, 925–930. [Google Scholar] [CrossRef]
  229. Dedeoglu, A.; Kubilus, J.K.; Yang, L.; Ferrante, K.L.; Hersch, S.M.; Beal, M.F.; Ferrante, R.J. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J. Neurochem. 2003, 85, 1359–1367. [Google Scholar]
  230. Andreassen, O.A.; Dedeoglu, A.; Ferrante, R.J.; Jenkins, B.G.; Ferrante, K.L.; Thomas, M.; Friedlich, A.; Browne, S.E.; Schilling, G.; Borchelt, D.R.; et al. Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol. Dis. 2001, 8, 479–491. [Google Scholar] [CrossRef] [Green Version]
  231. Ferrante, R.J.; Andreassen, O.A.; Jenkins, B.G.; Dedeoglu, A.; Kuemmerle, S.; Kubilus, J.K.; Kaddurah-Daouk, R.; Hersch, S.M.; Beal, M.F. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J. Neurosci. 2000, 20, 4389–4397. [Google Scholar] [CrossRef] [Green Version]
  232. Matthews, R.T.; Yang, L.; Jenkins, B.G.; Ferrante, R.J.; Rosen, B.R.; Kaddurah-Daouk, R.; Beal, M.F. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J. Neurosci. 1998, 18, 156–163. [Google Scholar]
  233. Bender, A.; Samtleben, W.; Elstner, M.; Klopstock, T. Long-term creatine supplementation is safe in aged patients with Parkinson disease. Nutr. Res. 2008, 28, 172–178. [Google Scholar] [CrossRef] [PubMed]
  234. Bender, A.; Koch, W.; Elstner, M.; Schombacher, Y.; Bender, J.; Moeschl, M.; Gekeler, F.; Muller-Myhsok, B.; Gasser, T.; Tatsch, K.; et al. Creatine supplementation in Parkinson disease: A placebo-controlled randomized pilot trial. Neurology 2006, 67, 1262–1264. [Google Scholar] [CrossRef] [PubMed]
  235. Duarte-Silva, S.; Neves-Carvalho, A.; Soares-Cunha, C.; Silva, J.M.; Teixeira-Castro, A.; Vieira, R.; Silva-Fernandes, A.; Maciel, P. Neuroprotective Effects of Creatine in the CMVMJD135 Mouse Model of Spinocerebellar Ataxia Type 3. Mov. Disord. 2018, 33, 815–826. [Google Scholar] [CrossRef] [PubMed]
  236. Komura, K.; Hobbiebrunken, E.; Wilichowski, E.K.; Hanefeld, F.A. Effectiveness of creatine monohydrate in mitochondrial encephalomyopathies. Pediatr. Neurol. 2003, 28, 53–58. [Google Scholar] [CrossRef]
  237. Tarnopolsky, M.A.; Parise, G. Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease. Muscle Nerve 1999, 22, 1228–1233. [Google Scholar] [CrossRef]
  238. Tarnopolsky, M.A.; Roy, B.D.; MacDonald, J.R. A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve 1997, 20, 1502–1509. [Google Scholar] [CrossRef]
  239. Gowayed, M.A.; Mahmoud, S.A.; El-Sayed, Y.; Abu-Samra, N.; Kamel, M.A. Enhanced mitochondrial biogenesis is associated with the ameliorative action of creatine supplementation in rat soleus and cardiac muscles. Exp. Ther. Med. 2020, 19, 384–392. [Google Scholar] [CrossRef] [Green Version]
  240. Andreassen, O.A.; Jenkins, B.G.; Dedeoglu, A.; Ferrante, K.L.; Bogdanov, M.B.; Kaddurah-Daouk, R.; Beal, M.F. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J. Neurochem. 2001, 77, 383–390. [Google Scholar] [CrossRef] [Green Version]
  241. Choi, J.K.; Kustermann, E.; Dedeoglu, A.; Jenkins, B.G. Magnetic resonance spectroscopy of regional brain metabolite markers in FALS mice and the effects of dietary creatine supplementation. Eur. J. Neurosci. 2009, 30, 2143–2150. [Google Scholar] [CrossRef] [Green Version]
  242. Derave, W.; Van Den Bosch, L.; Lemmens, G.; Eijnde, B.O.; Robberecht, W.; Hespel, P. Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: Effects of creatine treatment. Neurobiol. Dis. 2003, 13, 264–272. [Google Scholar] [CrossRef]
  243. Drory, V.E.; Gross, D. No effect of creatine on respiratory distress in amyotrophic lateral sclerosis. Amyotroph. Lateral. Scler Other Motor. Neuron. Disord. 2002, 3, 43–46. [Google Scholar] [CrossRef] [PubMed]
  244. Ellis, A.C.; Rosenfeld, J. The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders. CNS Drugs 2004, 18, 967–980. [Google Scholar] [PubMed]
  245. Mazzini, L.; Balzarini, C.; Colombo, R.; Mora, G.; Pastore, I.; De Ambrogio, R.; Caligari, M. Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: Preliminary results. J. Neurol. Sci. 2001, 191, 139–144. [Google Scholar] [CrossRef]
  246. Vielhaber, S.; Kaufmann, J.; Kanowski, M.; Sailer, M.; Feistner, H.; Tempelmann, C.; Elger, C.E.; Heinze, H.J.; Kunz, W.S. Effect of creatine supplementation on metabolite levels in ALS motor cortices. Exp. Neurol. 2001, 172, 377–382. [Google Scholar] [CrossRef]
  247. Hijikata, Y.; Katsuno, M.; Suzuki, K.; Hashizume, A.; Araki, A.; Yamada, S.; Inagaki, T.; Ito, D.; Hirakawa, A.; Kinoshita, F.; et al. Treatment with Creatine Monohydrate in Spinal and Bulbar Muscular Atrophy: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial. JMIR Res. Protoc. 2018, 7, e69. [Google Scholar] [CrossRef]
  248. Ogborn, D.I.; Smith, K.J.; Crane, J.D.; Safdar, A.; Hettinga, B.P.; Tupler, R.; Tarnopolsky, M.A. Effects of creatine and exercise on skeletal muscle of FRG1-transgenic mice. Can. J. Neurol Sci. 2012, 39, 225–231. [Google Scholar] [CrossRef] [Green Version]
  249. Louis, M.; Lebacq, J.; Poortmans, J.R.; Belpaire-Dethiou, M.C.; Devogelaer, J.P.; Van Hecke, P.; Goubel, F.; Francaux, M. Beneficial effects of creatine supplementation in dystrophic patients. Muscle Nerve 2003, 27, 604–610. [Google Scholar] [CrossRef]
  250. Banerjee, B.; Sharma, U.; Balasubramanian, K.; Kalaivani, M.; Kalra, V.; Jagannathan, N.R. Effect of creatine monohydrate in improving cellular energetics and muscle strength in ambulatory Duchenne muscular dystrophy patients: A randomized, placebo-controlled 31P MRS study. Magn. Reson. Imaging 2010, 28, 698–707. [Google Scholar] [CrossRef]
  251. Felber, S.; Skladal, D.; Wyss, M.; Kremser, C.; Koller, A.; Sperl, W. Oral creatine supplementation in Duchenne muscular dystrophy: A clinical and 31P magnetic resonance spectroscopy study. Neurol. Res. 2000, 22, 145–150. [Google Scholar] [CrossRef]
  252. Radley, H.G.; De Luca, A.; Lynch, G.S.; Grounds, M.D. Duchenne muscular dystrophy: Focus on pharmaceutical and nutritional interventions. Int. J. Biochem. Cell Biol. 2007, 39, 469–477. [Google Scholar] [CrossRef]
  253. Tarnopolsky, M.A.; Mahoney, D.J.; Vajsar, J.; Rodriguez, C.; Doherty, T.J.; Roy, B.D.; Biggar, D. Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology 2004, 62, 1771–1777. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  254. Kley, R.A.; Tarnopolsky, M.A.; Vorgerd, M. Creatine for treating muscle disorders. Cochrane Database Syst. Rev. 2013. [Google Scholar] [CrossRef] [PubMed]
  255. Pan, J.W.; Takahashi, K. Cerebral energetic effects of creatine supplementation in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 292, R1745–R1750. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  256. Ipsiroglu, O.S.; Stromberger, C.; Ilas, J.; Hoger, H.; Muhl, A.; Stockler-Ipsiroglu, S. Changes of tissue creatine concentrations upon oral supplementation of creatine-monohydrate in various animal species. Life Sci. 2001, 69, 1805–1815. [Google Scholar] [CrossRef]
  257. Kley, R.A.; Vorgerd, M.; Tarnopolsky, M.A. Creatine for treating muscle disorders. Cochrane Database Syst. Rev. 2007. [Google Scholar] [CrossRef]
  258. Adcock, K.H.; Nedelcu, J.; Loenneker, T.; Martin, E.; Wallimann, T.; Wagner, B.P. Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia. Dev. Neurosci. 2002, 24, 382–388. [Google Scholar] [CrossRef]
  259. Prass, K.; Royl, G.; Lindauer, U.; Freyer, D.; Megow, D.; Dirnagl, U.; Stockler-Ipsiroglu, G.; Wallimann, T.; Priller, J. Improved reperfusion and neuroprotection by creatine in a mouse model of stroke. J. Cereb. Blood Flow Metab. 2007, 27, 452–459. [Google Scholar] [CrossRef]
  260. Zhu, S.; Li, M.; Figueroa, B.E.; Liu, A.; Stavrovskaya, I.G.; Pasinelli, P.; Beal, M.F.; Brown, R.H., Jr.; Kristal, B.S.; Ferrante, R.J.; et al. Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J. Neurosci. 2004, 24, 5909–5912. [Google Scholar] [CrossRef]
  261. Allah Yar, R.; Akbar, A.; Iqbal, F. Creatine monohydrate supplementation for 10 weeks mediates neuroprotection and improves learning/memory following neonatal hypoxia ischemia encephalopathy in female albino mice. Brain Res. 2015, 1595, 92–100. [Google Scholar] [CrossRef]
  262. Ainsley Dean, P.J.; Arikan, G.; Opitz, B.; Sterr, A. Potential for use of creatine supplementation following mild traumatic brain injury. Concussion 2017, 2, CNC34. [Google Scholar] [CrossRef] [Green Version]
  263. Freire Royes, L.F.; Cassol, G. The Effects of Creatine Supplementation and Physical Exercise on Traumatic Brain Injury. Mini Rev. Med. Chem. 2016, 16, 29–39. [Google Scholar] [CrossRef] [PubMed]
  264. Sullivan, P.G.; Geiger, J.D.; Mattson, M.P.; Scheff, S.W. Dietary supplement creatine protects against traumatic brain injury. Ann. Neurol. 2000, 48, 723–729. [Google Scholar] [CrossRef]
  265. Hausmann, O.N.; Fouad, K.; Wallimann, T.; Schwab, M.E. Protective effects of oral creatine supplementation on spinal cord injury in rats. Spinal Cord 2002, 40, 449–456. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  266. Amorim, S.; Teixeira, V.H.; Corredeira, R.; Cunha, M.; Maia, B.; Margalho, P.; Pires, J. Creatine or vitamin D supplementation in individuals with a spinal cord injury undergoing resistance training: A double-blinded, randomized pilot trial. J. Spinal Cord Med. 2018, 41, 471–478. [Google Scholar] [CrossRef] [PubMed]
  267. Rabchevsky, A.G.; Sullivan, P.G.; Fugaccia, I.; Scheff, S.W. Creatine diet supplement for spinal cord injury: Influences on functional recovery and tissue sparing in rats. J. Neurotrauma 2003, 20, 659–669. [Google Scholar] [CrossRef]
  268. Jacobs, P.L.; Mahoney, E.T.; Cohn, K.A.; Sheradsky, L.F.; Green, B.A. Oral creatine supplementation enhances upper extremity work capacity in persons with cervical-level spinal cord injury. Arch. Phys. Med. Rehabil. 2002, 83, 19–23. [Google Scholar] [CrossRef]
  269. Kendall, R.W.; Jacquemin, G.; Frost, R.; Burns, S.P. Creatine supplementation for weak muscles in persons with chronic tetraplegia: A randomized double-blind placebo-controlled crossover trial. J. Spinal Cord Med. 2005, 28, 208–213. [Google Scholar]
  270. Perret, C.; Mueller, G.; Knecht, H. Influence of creatine supplementation on 800 m wheelchair performance: A pilot study. Spinal Cord 2006, 44, 275–279. [Google Scholar] [CrossRef] [Green Version]
  271. Fuld, J.P.; Kilduff, L.P.; Neder, J.A.; Pitsiladis, Y.; Lean, M.E.; Ward, S.A.; Cotton, M.M. Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax 2005, 60, 531–537. [Google Scholar] [CrossRef] [Green Version]
  272. Griffiths, T.L.; Proud, D. Creatine supplementation as an exercise performance enhancer for patients with COPD? An idea to run with. Thorax 2005, 60, 525–526. [Google Scholar] [CrossRef] [Green Version]
  273. Faager, G.; Soderlund, K.; Skold, C.M.; Rundgren, S.; Tollback, A.; Jakobsson, P. Creatine supplementation and physical training in patients with COPD: A double blind, placebo-controlled study. Int. J. Chron. Obs. Pulmon Dis. 2006, 1, 445–453. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  274. Cooke, M.B.; Rybalka, E.; Williams, A.D.; Cribb, P.J.; Hayes, A. Creatine supplementation enhances muscle force recovery after eccentrically-induced muscle damage in healthy individuals. J. Int. Soc. Sports Nutr. 2009, 6, 13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  275. Roy, B.D.; de Beer, J.; Harvey, D.; Tarnopolsky, M.A. Creatine monohydrate supplementation does not improve functional recovery after total knee arthroplasty. Arch. Phys. Med. Rehabil. 2005, 86, 1293–1298. [Google Scholar] [CrossRef] [PubMed]
  276. Tyler, T.F.; Nicholas, S.J.; Hershman, E.B.; Glace, B.W.; Mullaney, M.J.; McHugh, M.P. The effect of creatine supplementation on strength recovery after anterior cruciate ligament (ACL) reconstruction: A randomized, placebo-controlled, double-blind trial. Am. J. Sports Med. 2004, 32, 383–388. [Google Scholar] [CrossRef]
  277. Ellery, S.J.; LaRosa, D.A.; Cullen-McEwen, L.A.; Brown, R.D.; Snow, R.J.; Walker, D.W.; Kett, M.M.; Dickinson, H. Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration by maternal creatine supplementation during pregnancy. Pediatr. Res. 2017. [Google Scholar] [CrossRef]
  278. LaRosa, D.A.; Ellery, S.J.; Snow, R.J.; Walker, D.W.; Dickinson, H. Maternal creatine supplementation during pregnancy prevents acute and long-term deficits in skeletal muscle after birth asphyxia: A study of structure and function of hind limb muscle in the spiny mouse. Pediatr. Res. 2016, 80, 852–860. [Google Scholar] [CrossRef]
  279. Ellery, S.J.; LaRosa, D.A.; Kett, M.M.; Della Gatta, P.A.; Snow, R.J.; Walker, D.W.; Dickinson, H. Dietary creatine supplementation during pregnancy: A study on the effects of creatine supplementation on creatine homeostasis and renal excretory function in spiny mice. Amino Acids 2016, 48, 1819–1830. [Google Scholar] [CrossRef]
  280. Dickinson, H.; Ellery, S.; Ireland, Z.; LaRosa, D.; Snow, R.; Walker, D.W. Creatine supplementation during pregnancy: Summary of experimental studies suggesting a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy. BMC Pregnancy Childbirth 2014, 14, 150. [Google Scholar] [CrossRef] [Green Version]
  281. Bortoluzzi, V.T.; de Franceschi, I.D.; Rieger, E.; Wannmacher, C.M. Co-administration of creatine plus pyruvate prevents the effects of phenylalanine administration to female rats during pregnancy and lactation on enzymes activity of energy metabolism in cerebral cortex and hippocampus of the offspring. Neurochem. Res. 2014, 39, 1594–1602. [Google Scholar] [CrossRef]
  282. Vallet, J.L.; Miles, J.R.; Rempel, L.A. Effect of creatine supplementation during the last week of gestation on birth intervals, stillbirth, and preweaning mortality in pigs. J. Anim Sci. 2013, 91, 2122–2132. [Google Scholar] [CrossRef] [Green Version]
  283. Ellery, S.J.; Ireland, Z.; Kett, M.M.; Snow, R.; Walker, D.W.; Dickinson, H. Creatine pretreatment prevents birth asphyxia-induced injury of the newborn spiny mouse kidney. Pediatr. Res. 2013, 73, 201–208. [Google Scholar] [CrossRef] [PubMed]
  284. Dickinson, H.; Ireland, Z.J.; Larosa, D.A.; O’Connell, B.A.; Ellery, S.; Snow, R.; Walker, D.W. Maternal dietary creatine supplementation does not alter the capacity for creatine synthesis in the newborn spiny mouse. Reprod. Sci. 2013, 20, 1096–1102. [Google Scholar] [CrossRef] [Green Version]
  285. Ireland, Z.; Castillo-Melendez, M.; Dickinson, H.; Snow, R.; Walker, D.W. A maternal diet supplemented with creatine from mid-pregnancy protects the newborn spiny mouse brain from birth hypoxia. Neuroscience 2011, 194, 372–379. [Google Scholar] [CrossRef] [PubMed]
  286. De Guingand, D.L.; Ellery, S.J.; Davies-Tuck, M.L.; Dickinson, H. Creatine and pregnancy outcomes, a prospective cohort study in low-risk pregnant women: Study protocol. BMJ Open 2019, 9, e026756. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  287. de Guingand, D.L.; Palmer, K.R.; Bilardi, J.E.; Ellery, S.J. Acceptability of dietary or nutritional supplementation in pregnancy (ADONS)—Exploring the consumer’s perspective on introducing creatine monohydrate as a pregnancy supplement. Midwifery 2020, 82, 102599. [Google Scholar] [CrossRef]
  288. de Guingand, D.L.; Palmer, K.R.; Snow, R.J.; Davies-Tuck, M.L.; Ellery, S.J. Risk of Adverse Outcomes in Females Taking Oral Creatine Monohydrate: A Systematic Review and Meta-Analysis. Nutrients 2020, 12. [Google Scholar] [CrossRef]
  289. Jagim, A.R.; Stecker, R.A.; Harty, P.S.; Erickson, J.L.; Kerksick, C.M. Safety of Creatine Supplementation in Active Adolescents and Youth: A Brief Review. Front. Nutr. 2018, 5, 115. [Google Scholar] [CrossRef]
  290. Rawson, E.S. The safety and efficacy of creatine monohydrate supplementation. Sport Sci. Exch. 2018, 29, 1–6. [Google Scholar]
  291. Bohnhorst, B.; Geuting, T.; Peter, C.S.; Dordelmann, M.; Wilken, B.; Poets, C.F. Randomized, controlled trial of oral creatine supplementation (not effective) for apnea of prematurity. Pediatrics 2004, 113, e303–e307. [Google Scholar] [CrossRef] [Green Version]
  292. Leland, K.M.; McDonald, T.L.; Drescher, K.M. Effect of creatine, creatinine, and creatine ethyl ester on TLR expression in macrophages. Int. Immunopharmacol. 2011, 11, 1341–1347. [Google Scholar] [CrossRef] [Green Version]
  293. Beraud, D.; Maguire-Zeiss, K.A. Misfolded alpha-synuclein and Toll-like receptors: Therapeutic targets for Parkinson’s disease. Parkinsonism. Relat. Disord. 2012, 18 (Suppl. 1), S17–S20. [Google Scholar] [CrossRef] [Green Version]
  294. De Paola, M.; Sestito, S.E.; Mariani, A.; Memo, C.; Fanelli, R.; Freschi, M.; Bendotti, C.; Calabrese, V.; Peri, F. Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model. Pharmacol. Res. 2016, 103, 180–187. [Google Scholar] [CrossRef] [PubMed]
  295. Bassit, R.A.; Curi, R.; Costa Rosa, L.F. Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a half-ironman competition. Amino Acids 2008, 35, 425–431. [Google Scholar] [CrossRef] [PubMed]
  296. Deminice, R.; Rosa, F.T.; Franco, G.S.; Jordao, A.A.; de Freitas, E.C. Effects of creatine supplementation on oxidative stress and inflammatory markers after repeated-sprint exercise in humans. Nutrition 2013, 29, 1127–1132. [Google Scholar] [CrossRef] [Green Version]
  297. Santos, R.V.; Bassit, R.A.; Caperuto, E.C.; Costa Rosa, L.F. The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race. Life Sci. 2004, 75, 1917–1924. [Google Scholar] [CrossRef]
  298. Garcia, M.; Santos-Dias, A.; Bachi, A.L.L.; Oliveira-Junior, M.C.; Andrade-Souza, A.S.; Ferreira, S.C.; Aquino-Junior, J.C.J.; Almeida, F.M.; Rigonato-Oliveira, N.C.; Oliveira, A.P.L.; et al. Creatine supplementation impairs airway inflammation in an experimental model of asthma involving P2 x 7 receptor. Eur. J. Immunol. 2019, 49, 928–939. [Google Scholar] [CrossRef]
  299. Vieira, R.P.; Duarte, A.C.; Claudino, R.C.; Perini, A.; Santos, A.B.; Moriya, H.T.; Arantes-Costa, F.M.; Martins, M.A.; Carvalho, C.R.; Dolhnikoff, M. Creatine supplementation exacerbates allergic lung inflammation and airway remodeling in mice. Am. J. Respir. Cell Mol. Biol. 2007, 37, 660–667. [Google Scholar] [CrossRef]
  300. Almeida, F.M.; Oliveira-Junior, M.C.; Souza, R.A.; Petroni, R.C.; Soto, S.F.; Soriano, F.G.; Carvalho, P.T.; Albertini, R.; Damaceno-Rodrigues, N.R.; Lopes, F.D.; et al. Creatine supplementation attenuates pulmonary and systemic effects of lung ischemia and reperfusion injury. J. Heart Lung Transplant. 2016, 35, 242–250. [Google Scholar] [CrossRef]
  301. Braegger, C.P.; Schlattner, U.; Wallimann, T.; Utiger, A.; Frank, F.; Schaefer, B.; Heizmann, C.W.; Sennhauser, F.H. Effects of creatine supplementation in cystic fibrosis: Results of a pilot study. J. Cyst. Fibros. 2003, 2, 177–182. [Google Scholar] [CrossRef]
  302. Simpson, A.J.; Horne, S.; Sharp, P.; Sharps, R.; Kippelen, P. Effect of Creatine Supplementation on the Airways of Youth Elite Soccer Players. Med. Sci. Sports Exerc. 2019, 51, 1582–1590. [Google Scholar] [CrossRef]
  303. Miller, E.E.; Evans, A.E.; Cohn, M. Inhibition of rate of tumor growth by creatine and cyclocreatine. Proc. Natl. Acad. Sci. USA 1993, 90, 3304–3308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  304. Wyss, M.; Kaddurah-Daouk, R. Creatine and creatinine metabolism. Physiol. Rev. 2000, 80, 1107–1213. [Google Scholar] [CrossRef] [PubMed]
  305. Ostojic, S.M. Postviral fatigue syndrome and creatine: A piece of the puzzle? Nutr. Neurosci. 2020. [Google Scholar] [CrossRef] [PubMed]
  306. Malatji, B.G.; Meyer, H.; Mason, S.; Engelke, U.F.H.; Wevers, R.A.; van Reenen, M.; Reinecke, C.J. A diagnostic biomarker profile for fibromyalgia syndrome based on an NMR metabolomics study of selected patients and controls. BMC Neurol. 2017, 17, 88. [Google Scholar] [CrossRef] [PubMed]
  307. Mueller, C.; Lin, J.C.; Sheriff, S.; Maudsley, A.A.; Younger, J.W. Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: Assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging Behav. 2020, 14, 562–572. [Google Scholar] [CrossRef] [PubMed]
  308. van der Schaaf, M.E.; De Lange, F.P.; Schmits, I.C.; Geurts, D.E.M.; Roelofs, K.; van der Meer, J.W.M.; Toni, I.; Knoop, H. Prefrontal Structure Varies as a Function of Pain Symptoms in Chronic Fatigue Syndrome. Biol. Psychiatry 2017, 81, 358–365. [Google Scholar] [CrossRef]
  309. Amital, D.; Vishne, T.; Rubinow, A.; Levine, J. Observed effects of creatine monohydrate in a patient with depression and fibromyalgia. Am. J. Psychiatry 2006, 163, 1840–1841. [Google Scholar] [CrossRef]
  310. Leader, A.; Amital, D.; Rubinow, A.; Amital, H. An open-label study adding creatine monohydrate to ongoing medical regimens in patients with the fibromyalgia syndrome. Ann. N. Y. Acad. Sci. 2009, 1173, 829–836. [Google Scholar] [CrossRef]
  311. Ostojic, S.M.; Stojanovic, M.; Drid, P.; Hoffman, J.R.; Sekulic, D.; Zenic, N. Supplementation with Guanidinoacetic Acid in Women with Chronic Fatigue Syndrome. Nutrients 2016, 8, 72. [Google Scholar] [CrossRef]
  312. Agren, H.; Niklasson, F. Creatinine and creatine in CSF: Indices of brain energy metabolism in depression. Short note. J. Neural Transm. 1988, 74, 55–59. [Google Scholar] [CrossRef]
  313. Niklasson, F.; Agren, H. Brain energy metabolism and blood-brain barrier permeability in depressive patients: Analyses of creatine, creatinine, urate, and albumin in CSF and blood. Biol. Psychiatry 1984, 19, 1183–1206. [Google Scholar] [PubMed]
  314. Kato, T.; Takahashi, S.; Shioiri, T.; Inubushi, T. Brain phosphorous metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy. J. Affect. Disord. 1992, 26, 223–230. [Google Scholar] [CrossRef]
  315. Kato, T.; Takahashi, S.; Shioiri, T.; Murashita, J.; Hamakawa, H.; Inubushi, T. Reduction of brain phosphocreatine in bipolar II disorder detected by phosphorus-31 magnetic resonance spectroscopy. J. Affect. Disord. 1994, 31, 125–133. [Google Scholar] [CrossRef]
  316. Silveri, M.M.; Parow, A.M.; Villafuerte, R.A.; Damico, K.E.; Goren, J.; Stoll, A.L.; Cohen, B.M.; Renshaw, P.F. S-adenosyl-L-methionine: Effects on brain bioenergetic status and transverse relaxation time in healthy subjects. Biol. Psychiatry 2003, 54, 833–839. [Google Scholar] [CrossRef]
  317. Kondo, D.G.; Forrest, L.N.; Shi, X.; Sung, Y.H.; Hellem, T.L.; Huber, R.S.; Renshaw, P.F. Creatine target engagement with brain bioenergetics: A dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression. Amino Acids 2016, 48, 1941–1954. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  318. Yoon, S.; Kim, J.E.; Hwang, J.; Kim, T.S.; Kang, H.J.; Namgung, E.; Ban, S.; Oh, S.; Yang, J.; Renshaw, P.F.; et al. Effects of Creatine Monohydrate Augmentation on Brain Metabolic and Network Outcome Measures in Women With Major Depressive Disorder. Biol. Psychiatry 2016, 80, 439–447. [Google Scholar] [CrossRef]
  319. Allen, P.J.; D’Anci, K.E.; Kanarek, R.B.; Renshaw, P.F. Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology 2010, 35, 534–546. [Google Scholar] [CrossRef] [Green Version]
  320. Ahn, N.R.; Leem, Y.H.; Kato, M.; Chang, H.K. Effects of creatine monohydrate supplementation and exercise on depression-like behaviors and raphe 5-HT neurons in mice. J. Exerc. Nutrition Biochem. 2016, 20, 24–31. [Google Scholar] [CrossRef]
  321. Pazini, F.L.; Cunha, M.P.; Azevedo, D.; Rosa, J.M.; Colla, A.; de Oliveira, J.; Ramos-Hryb, A.B.; Brocardo, P.S.; Gil-Mohapel, J.; Rodrigues, A.L.S. Creatine Prevents Corticosterone-Induced Reduction in Hippocampal Proliferation and Differentiation: Possible Implication for Its Antidepressant Effect. Mol. Neurobiol. 2017, 54, 6245–6260. [Google Scholar] [CrossRef]
  322. Leem, Y.H.; Kato, M.; Chang, H. Regular exercise and creatine supplementation prevent chronic mild stress-induced decrease in hippocampal neurogenesis via Wnt/GSK3beta/beta-catenin pathway. J. Exerc. Nutrition Biochem. 2018, 22, 1–6. [Google Scholar] [CrossRef]
  323. Kious, B.M.; Kondo, D.G.; Renshaw, P.F. Creatine for the Treatment of Depression. Biomolecules 2019, 9, 406. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  324. Bakian, A.V.; Huber, R.S.; Scholl, L.; Renshaw, P.F.; Kondo, D. Dietary creatine intake and depression risk among U.S. adults. Transl. Psychiatry 2020, 10, 52. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  325. Lyoo, I.K.; Demopulos, C.M.; Hirashima, F.; Ahn, K.H.; Renshaw, P.F. Oral choline decreases brain purine levels in lithium-treated subjects with rapid-cycling bipolar disorder: A double-blind trial using proton and lithium magnetic resonance spectroscopy. Bipolar Disord. 2003, 5, 300–306. [Google Scholar] [CrossRef] [PubMed]
  326. Lyoo, I.K.; Kong, S.W.; Sung, S.M.; Hirashima, F.; Parow, A.; Hennen, J.; Cohen, B.M.; Renshaw, P.F. Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. Psychiatry Res. 2003, 123, 87–100. [Google Scholar] [CrossRef]
  327. Sbracia, M.; Sayme, N.; Grasso, J.; Vigue, L.; Huszar, G. Sperm function and choice of preparation media: Comparison of Percoll and Accudenz discontinuous density gradients. J. Androl. 1996, 17, 61–67. [Google Scholar]
  328. Huszar, G.; Vigue, L.; Corrales, M. Sperm creatine kinase activity in fertile and infertile oligospermic men. J. Androl. 1990, 11, 40–46. [Google Scholar]
  329. Fakih, H.; MacLusky, N.; DeCherney, A.; Wallimann, T.; Huszar, G. Enhancement of human sperm motility and velocity in vitro: Effects of calcium and creatine phosphate. Fertil. Steril. 1986, 46, 938–944. [Google Scholar] [CrossRef]
  330. Oehninger, S.; Alexander, N.J. Male infertility: The focus shifts to sperm manipulation. Curr. Opin. Obstet. Gynecol. 1991, 3, 182–190. [Google Scholar] [CrossRef]
  331. Gergely, A.; Szollosi, J.; Falkai, G.; Resch, B.; Kovacs, L.; Huszar, G. Sperm creatine kinase activity in normospermic and oligozospermic Hungarian men. J. Assist. Reprod. Genet. 1999, 16, 35–40. [Google Scholar] [CrossRef]
  332. Froman, D.P.; Feltmann, A.J. A new approach to sperm preservation based on bioenergetic theory. J. Anim. Sci. 2010, 88, 1314–1320. [Google Scholar] [CrossRef] [Green Version]
  333. Lenz, H.; Schmidt, M.; Welge, V.; Schlattner, U.; Wallimann, T.; Elsasser, H.P.; Wittern, K.P.; Wenck, H.; Stab, F.; Blatt, T. The creatine kinase system in human skin: Protective effects of creatine against oxidative and UV damage in vitro and in vivo. J. Investig. Dermatol. 2005, 124, 443–452. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  334. Peirano, R.I.; Achterberg, V.; Dusing, H.J.; Akhiani, M.; Koop, U.; Jaspers, S.; Kruger, A.; Schwengler, H.; Hamann, T.; Wenck, H.; et al. Dermal penetration of creatine from a face-care formulation containing creatine, guarana and glycerol is linked to effective antiwrinkle and antisagging efficacy in male subjects. J. Cosmet. Dermatol. 2011, 10, 273–281. [Google Scholar] [CrossRef] [PubMed]
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Kreider, R.B.; Stout, J.R. Creatine in Health and Disease. Nutrients 2021, 13, 447.

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Kreider RB, Stout JR. Creatine in Health and Disease. Nutrients. 2021; 13(2):447.

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Kreider, Richard B., and Jeffery R. Stout. 2021. "Creatine in Health and Disease" Nutrients 13, no. 2: 447.

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