The following research* study was compiled and edited by Dr. Richard Kreider, Pd.D. In addition to serving as the Chairman of our Scientific Advisory Board, Dr. Kreider serves as Professor, Executive Director of the Human Clinical Research Facility, and Director of the Exercise & Sport Nutrition Lab at Texas A&M University. Dr. Richard Kreider states, “We all agree that the best source of creatine for dietary supplements is the same active ingredient found in Encour - pure creatine monohydrate from Germany.”
Pure German Creatine from Germany is the primary active ingredient in Encour.
*THIS STUDY IS SHARED WITH PERMISSION FROM THE AUTHOR.
CREATINE IN HEALTH
December 1, 2020
Richard B. Kreider, PhD, FACSM, FISSN, FACN, FNAK
Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport; several health and potential therapeutic benefits have been reported. The reason for this is that 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 the role of creatine in promoting general health as we age as well as how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it suggests reasonable structure and function claims that can be made based on the scientific literature. Based on this analysis, it can be concluded that the creatine supplementation has a number of health and therapeutic benefits throughout the lifespan.
A systematic review of the scientific and medical literature was conducted to assess the state of science related to creatine supplementation on metabolism, performance, health, and disease management. This was accomplished by doing key word searches related to creatine supplementation on each topic summarized using the National Institutes for Health National Library of Medicine PubMed.gov search engine. A total of 1,322 articles were reviewed with relevant research highlighted in this systematic review.
Creatine (N-aminoiminomethyl-N-methyl glycine) is a member of the guanidine phosphagen family [1, 2] and is a naturally occurring nitrogen containing compound found primarily in red meat and fish [3-6]. It is also processed and manufactured as a dietary supplement and used by a variety of populations [2, 7, 8]. The majority of creatine is found in skeletal muscle (~95%) with about 5% found in the brain and testes [9, 10]. About two thirds of intramuscular creatine is stored as phosphocreatine (PCr) with the remaining is free creatine. The total creatine pool (PCr + Cr) in the muscle averages about 120 mmol/kg of dry muscle mass for a 70 kg individual on a normal diet while vegetarians have been reported to have muscle creatine and PCr stores about 20-30% lower than non-vegetarians [11, 12]. About 1–2% of intramuscular creatine is degraded each day into creatinine and excreted in the urine [11, 13, 14]. Degradation of creatine to creatinine is greater in individuals with larger muscle mass and individuals with higher physical activity levels.
About half of the daily need for creatine is obtained from the diet primarily from meat and fish . The remaining amount of daily creatine needed to maintain tissue creatine concentrations is synthesized primarily in the liver and kidneys from arginine and glycine by the enzyme arginine:glycine amidinotransferase (AGAT) to guanidinoacetate (GAA), which is then methylated by guanidinoacetate N-methyltransferase (GAMT) using S-adenosyl methionine to form creatine . Therefore, normal sized individuals need to consume about 2-3 grams/day of creatine to maintain normal creatine stores depending on diet, muscle mass, and physical activity levels. Consequently, it has been recommended that people ingest 3 grams/day of creatine in their diet to promote general health [2, 17]. The most effective way to increase muscle creatine stores is to ingest five grams of creatine monohydrate four times daily (or 0.3 grams/kg body weight) for 5 – 7 days [11, 14]. However, higher levels of creatine supplementation (e.g., 20 – 30 grams/day) for longer periods of time may be needed to increase brain concentrations of creatine, offset creatine synthesis deficiencies, or influence disease states [18-20].
Creatine and phosphagens are prevalent in all species and play an important role in maintaining cellular energy
availability [3, 4, 21, 22]. The primary metabolic role of creatine is to combine with a phosphoryl group (Pi) to form PCr through the enzymatic reaction of creatine kinase (CK). Wallimann and colleagues [17, 23, 24] suggested that the physiological and biochemical effects of Cr are mostly related to the functions of CK and PCr (i.e., CK/PCr system). As adenosine triphosphate (ATP) is degraded into adenosine diphosphate (ADP) and Pi to provide free energy for metabolic activity, the free energy released from the hydrolysis of PCr into Cr + Pi can be used as a buffer to resynthesize ATP [21, 22]. This helps maintain ATP availability particularly during maximal effort anaerobic sprint-type exercise. The CK/PCr system also plays an important role in shuttling intracellular energy from the mitochondria into the cytosol. This creatine phosphate shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases) [17, 21, 22]. In this regard, creatine enters the cytosol through a creatine transporters (CRTR) [25-28]. 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 . Additionally, creatine diffuses into the mitochondria and couples with ATP produced from oxidative phosphorylation and the adenine nucleotide translocator (ANT) via mitochondrial CK. ATP and PCr can then diffuse back into the cytosol and help buffer energy needs. This coupling also reduces the formation of reactive oxygen species (ROS) and can therefore act as a direct and/or indirect antioxidant [29-32]. The creatine phosphate shuttle thereby connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases) in order to fuel energy metabolism [17, 21, 22]. In this way, the CK/PCr system serves as an important regulator of metabolism. The role of CK/PCr system in normal metabolism as well as disease states help explain the ergogenic, health, and potential therapeutic benefits of creatine supplementation [6, 17, 30, 33-42].
General Health Benefits
Most research on creatine initially focused on the role of creatine on exercise performance, training adaptations, and safety in untrained and trained healthy individuals . Creatine supplementation has been reported to increase muscle creatine and PCr levels, enhance acute exercise capacity, and improve training adaptations in adolescents [43-47], younger adults [48-59], and older individuals [9, 37, 40, 60-67]. These adaptations allow an athlete to do more work over a series of sets or sprints leading to greater gains in strength, muscle mass, and/or performance due to an improvement in the quality of training. After creatine loading, performance of high intensity and/or repetitive exercise is generally increased by 10-20% depending on the magnitude of increase in muscle PCr . This includes many lifetime fitness activities like fitness/weight training [48, 55, 62, 69-79], golf , volleyball , soccer [53, 82, 83], softball , ice hockey , running [86-90], and swimming [44, 45, 91-94] among others. Benefits have been reported in men and women from children to elderly populations although the majority of studies have been conducted on men and some studies suggest that women may not see as much gain in strength and/or muscle mass during training in response to creatine supplementation [45, 82, 84, 95-99]. In terms of performance, the International Society of Sports Nutrition (ISSN) has concluded that creatine monohydrate 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 [2, 7, 9, 60]. Position stands by the American Dietetic Association, Dietitians of Canada, and the American College of Sports Medicine on nutrition for athletic performance have drawn similar conclusions [100, 101]. Thus, there is wide-spread consensus creatine supplementation can serve as an effective nutritional ergogenic aid that may benefit athletes involved in numerous sports as well as individuals initiating exercise training to promote health and fitness.
As performance-related studies assessed markers of health and safety, evidence began to that creatine supplementation may improve health status and/or reduce risk to chronic disease as individuals age [38, 40-42, 102-105]. In this regard, creatine supplementation has been reported to help lower cholesterol, triglycerides and/or manage blood lipid levels [48, 106, 107]; reduce fat accumulation in the liver [107, 108]; reduce homocysteine levels and thereby risk to heart disease [109, 110]; serve as an antioxidant [110-114]; enhance glycemic control [2, 115-119]; slow tumor growth in some types of cancers [29, 109, 120-125]; increase strength and/or muscle mass [34, 38, 41, 42, 64, 70, 72, 126-134]; minimize bone loss in some studies [70, 103, 104, 128, 129, 135-141]; improve functional capacity in patients with knee osteoarthritis [142, 143] and fibromyalgia  in some studies; enhance cognitive function particularly in older populations [40, 65, 98, 102, 140, 145-153]; and, in some instances improve the efficacy of some anti-depressant medications [154-160]. These findings support contentions that it is prudent for individuals to consume at least 3 g/day of creatine in their diet to support general health as one ages [2, 17].
Benefits of Creatine in Aging Populations
Since creatine has been reported to increase muscle mass and strength, a number of studies have evaluated the effects of creatine supplementation in older populations in an attempt to prevent sarcopenia, maintain strength, and/or reduce risk to chronic disease. The following discusses some of these potential applications.
Reduce Muscle Loss and Sarcopenia
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, neuromuscular function, inflammation, physical activity and nutrition [104, 105]. A number of nutritional and exercise interventions have been suggested to counteract sarcopenia in older individuals including creatine supplementation during resistance-training [104, 105]. For example, Chrusch et al.  reported that older participants ( 60 – 84 years) who supplemented their diet with creatine (0.3 g/kg/day for 5 days,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 average power compared to controls.
Candow and colleagues  reported that low-dose creatine (0.1 g/kg/day) combined with protein supplementation (0.3 g/kg/day) increased lean tissue mass and upper body strength while decreasing markers of muscle protein degradation and bone resorption in older men (59-77 yr). Chilibeck et al.  reported that 12 months of creatine supplementation (0.1 g/kg/day) during resistance training increased strength and preserved femoral neck bone mineral density and increased femoral shaft subperiosteal width in postmenopausal women. Gualano and coworkers  reported that creatine supplementation (20 g/day for 5 days and 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 et al  reported that 12-weeks of creatine supplementation (5 g/day) combined with resistance training improved muscle endurance, ability to perform functional tasks, maximal strength, and muscle mass in older women. McMorris et al  reported that creatine supplementation (20 g/day for 7-days) after sleep deprivation improved balance measures.
Bernat and colleagues  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  of 357 elderly individuals (64 years) participating in an average of 12.6 weeks of resistance training found that participants supplementing their diet with creatine experienced greater gains in muscle mass, strength, and functional capacity. These findings were corroborated in a meta-analysis of 405 elderly participants (64 years) who experienced greater gains in muscle mass and upper body strength with creatine supplementation during resistance-training compared to training alone . While not all studies report statistically significant effects, the preponderance of available research supports contentions that creatine supplementation, particularly 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 prevent sarcopenia.
Additionally, given that creatine supplementation has been reported to increase muscle mass and older adults often diet to lose weight, 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 has been reported to increase brain PCr content by 5% - 15% and thereby enhance brain bioenergetics [163-165]. For this reason, there has been interest in assessing the effects of creatine supplementation on cognition, memory, and executive function in older individuals as well as patients with mild cognitive impairment [140, 146, 148, 149]\. A number of studies have shown that creatine supplementation can reduce mental fatigue [145, 149, 166] and/or improve cognitive function [65, 140, 145, 146, 148, 149, 153, 161, 167, 168].
For example, Watanabe et al.  reported that creatine supplementation (8 g/day for 5-days) reduced mental fatigue when subjects repeatedly performed a simple mathematical calculation as well as increased oxygen utilization in the brain. Rae and colleagues  reported that creatine supplementation (5 g/day for 6-weeks) significantly improved working memory and intelligence tests requiring speed of processing. McMorris and coworkers  found that creatine supplementation (20 g/day for 7-days) after sleep deprivation resulted in significantly less decrement in performance in random movement generation, choice reaction time, balance, and mood state. This group also examined the effects of creatine supplementation (20 g/day for 7-days) on cognitive function in elderly participants and found that creatine supplementation significantly improved performance on random number generation, forward spatial recall, and long-term memory tasks. Ling and associates  reported that creatine supplementation (5 g/day for 15-days) improved cognition on some tasks.
More recently, VAN Cutsem and colleagues , reported that creatine supplementation (20 g/day for 7-days) prior to performing a simulated soccer match improved muscular endurance and prolonged cognitive performance. Although not all studies show benefits, there is clear evidence that creatine supplementation can increase brain creatine and/or improve cognitive function [40, 140, 146].
Glucose Management and Diabetes
It is well-known that creatine uptake into tissue is influenced by glucose and insulin [117, 169, 170]. Additionally, that creatine supplementation prevents declines in the GLUT-4 transporter during immobilization while increasing GLUT-4 by 40% during rehabilitation after atrophy . Moreover, that co-ingestion of creatine with carbohydrate [12, 171] or creatine with carbohydrate and protein  enhanced creatine uptake and/or muscle glycogen levels [12, 172, 173]. For this reason, there has been interest in determining whether creatine supplementation may help diabetics manage blood glucose levels [115-119, 174].
For example, Gualano and associates  supplemented patients with type 2 diabetes with a placebo or creatine (5 g/day) for 12-weeks during training. Creatine supplementation significantly decreased HbA1c and glycemic response to standardized meal as well as increased GLUT-4 translocation. These researchers also reported  that the AMPK-alpha protein content tended to be higher after Creatine supplementation and were 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.
These findings suggest that creatine supplementation combined with an exercise program improves glycemic control and glucose disposal in type 2 diabetic patients. Thus, there is evidence indicating that creatine supplementation enhances glucose uptake and insulin sensitivity and therefore can help individuals manage glucose and HbA1c levels particularly when initiating and exercise program [119, 174, 175].
Ischemic Heart Disease
Coronary heart 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 . 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 [176-186]. For example, Anyukhovsky et al.  reported that intravenous administration of PCr and PCr-nine (300 mg/kg) in canines prevented accumulation of lysophosphoglycerides in the ischemic zone of the heart which is associated with increase prevalence of arrhythmias.
The researchers concluded that this may explain the antiarrhythmic action of PCr and PCr-nine in acute myocardial ischemia. Sharov and coworkers  reported that exogenous PCr administration provided protection against ischemia in the heart. Likewise, Balestrino and colleagues  concluded that
phosphocreatine administration, primarily as an addition to cardioplegic solutions, may improve energy availability during myocardial ischemia, prevent ischemia-induced arrhythmias, and improve cardiac function.
As noted below, there is also evidence that creatine supplementation may maintain energy availability during brain ischemia and thereby reduce stroke related damage. Thus, prophylactic creatine supplementation may be beneficial for patients at risk for myocardial and/or cerebral ischemia.
Potential Therapeutic Uses of Creatine
Given the role of creatine in metabolism, a number of researchers have been investigating the potential therapeutic benefits of creatine supplementation in various clinical populations. The following highlights some of these applications.
Creatine Synthesis Deficiencies
Creatine deficiency syndromes are a group of inborn errors (e.g., AGAT deficiency, GAMT deficiency, and CRTR deficiency) that reduce or eliminate the ability to synthesize creatine or effectively transport creatine into the cell . There is also recent evidence  that 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. This includes transporters for creatine (CT1, SLC6A8).
Individuals with creatine synthesis deficiencies and creatine transporter mutations have low levels of creatine and PCr in the muscle and the brain [20, 28, 188-193]. As a result, they often have clinical manifestations of muscle myopathies, gyrate atrophy, movement disorders, speech delay, autism, mental retardation, epilepsy, and/or developmental problems [20, 28, 187-193]. For this reason, a number of studies have investigated the use of relatively high doses of creatine monohydrate supplementation (e.g., 0.3 – 0.8 g/kg/day equivalent to 21 – 56 g/day of creatine for a 70 kg person) throughout the lifespan as a nutritional strategy of increasing muscle and brain in children and adults with creatine synthesis deficiencies [20, 28, 187-197]. These studies generally show some improvement in clinical outcomes particularly for AGAT and GAMT with less consistent effects on CRTR deficiencies .
For example, Bianchi et al.  reported 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.  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  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 creatine deficiency-related gyrate atrophy [201-205].
These findings and others provide promise that high-dose creatine monohydrate supplementation may be an effective adjunctive therapy for children and adults with creatine synthesis and/or transporter deficiencies [190, 206-209]. Additionally, these reports provide strong evidence regarding the long-term safety and tolerability of high-dose creatine supplementation in pediatric populations with creatine synthesis deficiencies, including infants less than one year of age .
A number of studies have investigated the short and long-term therapeutic benefit of creatine supplementation in children and adults with various neuromuscular diseases like muscular dystrophies [210-215], Huntington's disease [18, 216-221]; Parkinson disease [18, 37, 71, 216, 222-224]; mitochondria-related diseases [25, 224-228]; amyotrophic lateral sclerosis or Lou Gehrig’s Disease [216, 229-235]; and, spinal and bulbar muscular atrophy . These studies have provided some evidence that creatine supplementation may improve exercise capacity and/or clinical outcomes in these patient populations. However, Bender and colleagues  reported results of several large clinical trials evaluating the effects of creatine supplementation in patients with Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). A total of 1,687 patients took an average of 9.5 g/day of creatine for a total of 5,480 patient years. Results revealed no clinical benefit on patient outcomes in patients with PD or ALS.
However, there was some evidence that creatine supplementation slowed down progression of brain atrophy in patients with HD (although clinical markers were unaffected). Whether creatine supplementation may have a role in mediating other clinical markers in these patient populations and/or whether individual patients may respond more positively to creatine supplementation than others remains to be determined. Nevertheless, these studies show that creatine supplementation has been used to treat children and adults with neurodegenerative conditions and is apparently safe and well-tolerated when taking up to 30 g/day for five years in these populations.
Brain and Spinal Cord Neuroprotection
It is well-known that creatine supplementation increases brain bioenergetics [30, 151, 165, 198, 224, 237] and has neuroprotective benefits particularly in response to injury and/or ischemic conditions [25, 35, 37, 238]. For this reason, a number of studies have examined the effects of creatine supplementation on cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI).
For example, Adcock et al.  reported that neonatal rats fed 3 g/kg of creatine for three days observed a significant increase in the ratio of brain PCr to Pi and a 25% reduction in the volume of edemic brain tissue following cerebral hypoxic ischemia. The authors concluded that creatine supplementation appears to improve brain bioenergetics thereby helping minimize the amount of brain damage in response to brain ischemia.
Prass and colleagues  reported that creatine administration reduced the brain infarct size following an ischemic event by 40%. Zhu and colleagues  reported that oral creatine administration resulted in a marked reduction in ischemic brain infarction size, neuronal cell death, and provided neuroprotection after cerebral ischemia in mice.
Allah et al.  reported that creatine monohydrate supplementation for ten weeks reduced infarction size and improved learning/memory following neonatal hypoxia ischemia encephalopathy in female mice.
Finally, Turner and coworkers  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 creatine supplementation may reduce the severity of brain ischemia and therefore may have some therapeutic benefits in individuals at risk to stroke [30, 120, 186].
In terms of injury, several studies have evaluated the effects of creatine supplementation on response to mild TBI and SCI in animal models [33, 146, 157, 243-247]. For example, Sullivan et al.  reported that five days of creatine administration prior to a controlled TBI in rats and mice reduced the amount of cortical damage by 36% to 50%, respectively. The researchers attributed the reduction in cortical damage to a creatine-induced maintenance of neuronal mitochondrial bioenergetics. Hausmann and associates  reported that rats fed creatine (5 g/100 g dry food) before and after a moderate SCI reduced the size of scar tissue and improved locomotor function test performance. The authors suggested that pretreatment of patients with creatine may provide neuroprotection in patients undergoing spinal surgery who are at risk to SCI. Rabchevsky and associates  examined the efficacy of creatine-supplemented diets on hind limb functional recovery and tissue sparing in adult rats. Rats were fed a control diet or 2% creatine-supplemented chow for 4-5 weeks prior to and following SCI. Results revealed that creatine feeding significantly reduced loss of gray matter after SCI. Creatine supplementation has also been reported to enhance training adaptations in patients recovering from spinal cord injury.
For example, Jacobs et al.  reported that creatine supplementation (20 g/day for 7-days) enhanced aerobic exercise capacity and ventilator anaerobic threshold in individuals with complete cervical-level SCI. Moreover, Amorim et al.  reported that individuals with SCI who consumed creatine (3 g/day) with vitamin D (25,000 IU/day) while participating in a resistance-training program for 8-weeks experienced significantly greater improvements in arm muscle area, strength, and function capacity. While some studies report no benefit of creatine supplementation on maximal voluntary contractions  or 800-m wheel chair performance  in individuals with SCI, collective findings provide strong evidence that creatine supplementation may limit damage from concussions, TBI, and/or SCI [30, 244]. In fact, this evidence is so strong the International Society of Sports Nutrition has recommended that all athletes who are involved in sports with risk to TBI and/or SCI should take creatine to reduce the severity of TBI and/or SCI.
Enhanced Rehabilitation Outcomes
Since creatine supplementation has been reported to promote gains in muscle mass and improved strength, there has been interest in examining the effects of creatine supplementation on preserving muscle mass during limb immobilization and/or enhancing rehabilitation outcomes in a variety of populations [140, 157, 236, 252]. For example, Hespel and coworkers  examined the effects of creatine supplementation (20 g/day, then 5 g/day) on atrophy rates and 10-week rehabilitation outcomes in individuals who had their right leg casted for two weeks.
The researchers reported that individuals in the creatine group experienced greater changes in the crosssectional area of muscle fiber (+10%) and peak strength (+25%) during the rehabilitation period. These changes were associated with greater changes in myogenic regulating factor 4 (MRF4) and myogenic protein expression. Jacobs and associates  examined the effects of creatine supplementation (20 g/d for seven days) on upper extremity work capacity in individuals with cervical-level spinal cord injury (SCI). Results revealed that peak oxygen uptake and ventilatory anaerobic threshold were increased following creatine supplementation.
Although findings are mixed, several studies reported that creatine supplementation in chronic heart failure patient’s enhanced rehabilitative outcomes [254- 258]. Fuld et al.  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 chronic obstructive pulmonary disease (COPD).
Hass and colleagues  reported that creatine supplementation (20 g/day for 5-days; 5 g/day for 12-weeks) during resistance training in Parkinson’s patients promoted greater gains in muscle strength and ability to perform the functional chair sit to rise test. Cooke and assistants  reported that creatine supplementation (0.3 g/kg/day for 5-days prior to performing a eccentric-only resistance exercise bout to promote muscle damage/injury and 0.1 g/kg/day for 14-days following the bout) significantly reduced markers of muscle damage and improved the rate of recovery of knee extension muscle function after creatine supplementation following injury. Finally, Neves et al.  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 OA
undergoing strengthening exercises.
While not all studies show benefit to rehabilitative outcomes, there is evidence that creatine supplementation may help lessen muscle atrophy following immobilization and promote recovery during exercise-related rehabilitation in some populations.
Since creatine supplementation has been shown to improve brain and heart bioenergetics during ischemic conditions and possess neuroprotective properties, there has been recent interest in use of creatine during pregnancy to promote neural development and reduce complications resulting from birth asphyxia [261-270]. 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 [263, 265]. 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 [261, 262, 264, 266-268, 270]. Human studies show changes in the maternal urine and plasma creatine levels across pregnancy and association to maternal diet [263, 265]. Consequently, it has been postulated that there may be benefit to creatine supplementation during pregnancy on fetal growth, development, and health [263, 265]. This area of research may have broad implications for fetal and child development and health.
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 . 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) .
For example, Leland and colleagues  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 [272, 273]. 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 [33, 271]. 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 . It may also explain reports that creatine supplementation attenuates inflammatory and/or muscle damage in response to intense exercise [260, 274-276]. On the other hand, there have been several studies in mice suggesting that creatine supplementation may impair airway inflammation thereby exacerbating exercise-induced asthma [277, 278]. However, other studies suggest creatine attenuates pulmonary and systemic effects of lung ischemia and reperfusion injury in rats ; improves rehabilitative outcomes in patients with cystic fibrosis  and COPD ; or, has no statistically significant effects on pulmonary rehabilitation outcomes [281, 282] and youth soccer players with allergies .
Additional research is needed to understand the anti-inflammatory and immunomodulating effects of creatine but it is clear that creatine can affect these pathways.
Another emerging area related to creatine supplementation is the potential anti-cancer effects. As noted above, creatine and phosphagens play and important role in maintaining energy availability [3, 4, 21, 22] particularly in relation to the role of the CK/PRr system and shuttling of ATP, ADP and Pi in and out of the mitochondria for cellular metabolism [17, 23, 24]. Prior studies have shown that creatine content and energy availability is low in several types of malignant cells as well as T cells that mediate the immune responses against cancer [29, 121, 122, 124, 125]. Additionally, that the expression of the creatine transport Slc6a8 gene, which encodes a surface transporter controlling the uptake of creatine into a cell, markedly increases in tumor-infiltrating immune cells .
It has been known for some time that creatine and its related compound cyclocreatine have anticancer properties [121, 284, 285]. For example, Patra et al.  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  reported that MG efficacy was improved with co-administration of creatine and ascorbic acid in muscle cells in vitro as well as in sarcoma animal model in vivo suggesting that creatine supplementation may serve as an adjunctive anticancer therapeutic intervention with MG. Di Biase and coworkers  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, that the energy-buffering 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 . The researchers concluded creatine is an important metabolic regulator controlling antitumor T cell immunity and that creatine supplementation may improve T cell–based cancer immunotherapies .
Collectively, these findings indicate that creatine supplementation may have anti-cancer properties.
Chronic fatigue syndrome (CFS), also known as postviral 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 . Although the etiology is not completely understood, there is some evidence that a lack creatine availability and/or impaired creatine metabolism may play a role in CFS related diseases.
For example, Malatji et al.  reported a significant relationship between urinary creatine levels and symptoms of pain, fatigue and energy levels in patients with the CFS related chronic pain syndrome, fibromyalgia. Mueller and associates  reported that creatine levels and energy metabolite ratios were lower in several areas of the brain in patients with ME/CFS and that the levels correlated with fatigue severity. Moreover, reduced creatine ratio in the prefrontal region of the brain was associated with greater pain of CFS patients . Puri et al.  reported that mean ratio of choline to creatine in the occipital cortex of the brain was significantly higher in CFS patients most likely due to an increase in choline peak. Additionally, there a loss of the normal spatial variation of the choline peak. Similarly, Chaudhuri and associates [291, 292] reported that the ratio of choline:creatine was also altered in CFS patients.
Given these potential relationships, a couple of studies have examined the effects of creatine related compounds on patient outcomes in CFS patients. Ostojic and colleagues  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 symptoms of general fatigue and musculoskeletal soreness. Finally, Alves and colleagues  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 muscle function in fibromyalgia patients. While more studies are needed, these findings provide some support that creatine and/or GAA may have some therapeutic benefit for patients with CFS, PFS, EM, and/or fibromyalgia.
There are several studies indicating that creatine and/or creatine precursors like S-adenosyl-Lmethionine (SAMe) and GAA affect brain phosphagen levels and may have anti-depressive effects and/or increase the therapeutic efficacy of anti-depressant medications [120, 154, 155].
For example, the creatine precursor SAMe has been reported to be an effective treatment for clinical depression. Silveri et al  reported that SAMe supplementation (1,600 mg/day) increase brain creatine and PCr levels higher after treatment as well as lowered transverse relaxation time in women compared to men. Allen and colleagues  reported that rats fed creatine diets (4%) for 5-weeks altered depression-like behavior in response to force swim training in a sex-dependent manner with female rats displaying an antidepressant-like response. Ahn and coworkers  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.  reported that creatine administration (21-days, 10 mg/kg, p.o.) abolished corticosterone induced depressive-like behaviors in mice. Similarly, Leem and colleagues  reported that mice exposed to mild chronic stress for 4-weeks had a greater effect on hippocampal neurogenesis via the Wnt/GSK3beta/betacatenin pathway activation when creatine and exercise was 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. For example, Roitman et al.  reported in an open label study that creatine monohydrate supplementation (3-5 g/day for 4-wks) improved outcomes in a small sample of patients with unipolar depression. Toniolo and colleagues  evaluated the effects of creatine supplementation (6 g/day for 6-wks) in bipolar patients and reported that Montgomery-Asberg Depression Rating Scale (MADRS) remission rates (i.e., 66.7% remission in the creatine group vs. 18.2% in the placebo group). Although more research is needed, there is evidence suggesting that creatine may help individuals manage some types of depression and/or anxiety disorders particularly when combined with choline [164, 299].
Creatine has been used to improve fertility in men and women. The rationale in men is that sperm motility is dependent on ATP availability and CK activity has been associated with greater sperm quality and function [17, 300-302]. Additionally, creatine has been added to medium during intrauterinal insemination to increase viability of sperm and success of fertility treatments [300-305]. These findings suggest that creatine plays an important role in fertility.
Since availability of creatine has been reported to affect energy status and in the dermis and is an antioxidant, several studies have evaluated whether topical application of creatine influences skin health and/or may serve as an effective anti-wrinkle intervention . For example, Lenz et al. 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  found that topically applied creatine rapidly penetrates the dermis, stimulates
collagen synthesis, and influences gene expression and at the protein level. Additionally, that topical application of a creatine-containing formulation for 6-wks 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.
The benefits of creatine supplementation go well-beyond serving to increase muscle Cr and PCr levels and thereby enhance high-intensity exercise and training adaptations. Research has clearly shown a number of 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 further explore the clinical benefits of creatine supplementation, the following structure and function claims can be reasonably made:
1. Creatine supplementation can increase cellular energy availability and support general health, fitness, and wellbeing throughout the lifespan.
2. Creatine supplementation, particularly when combined 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.
3. Creatine supplementation supports cognitive function particularly as one ages.
4. Creatine supplementation supports healthy glucose management.
5. Creatine supplementation supports heart metabolism and health particularly during ischemic challenges.
6. Long-term, high-dose creatine supplementation in individuals with creatine synthesis and/or transport deficiencies can increase brain creatine and PCr levels and reduce the severity of deficits associated with these disorders.
7. 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 neurological diseases is equivocal.
8. Creatine supplementation can increase brain creatine content, enhance energy availability during ischemic events, and provide neuroprotection from TBI and/or SCI.
9. Creatine supplementation prior to and following injury may reduce immobilization related atrophy and/or enhance rehabilitative outcomes in a number of populations.
10. Creatine supplementation during the third trimester of pregnancy may help support health of the mother and child.
11. Creatine supplementation may have anti-inflammatory and immunomodulating effects.
12. Creatine is an important energy source for immune cells, can help support a healthy immune system, and may have some anticancer properties.
13. Creatine and/or GAA may increase brain bioenergetics and provide some therapeutic benefit for patients with chronic fatigue related syndromes such as post viral fatigue syndrome (PFS) or myalgic encephalomyelitis (ME).
14. Creatine supports mental health.
15. Creatine supports reproductive health.
16. Creatine supports skin health.
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