10
Creatine

Creatine (N-[aminoiminomethyl]-N-methyl glycine) is an amino acid–like compound that is produced endogenously in the liver, kidney, pancreas, and possibly the brain from the biosynthesis of the essential amino acids methionine, glycine, and arginine, or obtained from dietary sources. The primary dietary sources are high-protein foods including meat, fish, and poultry. Once synthesized or ingested, creatine is transferred from the plasma through the intestinal wall into other tissues by specific creatine transporters located in skeletal muscles, the kidney, heart, liver, and brain.

Creatine and the creatine kinase/phosphocreatine system play an important role as reserved sources of energy in tissues with high and fluctuating energy requirements (e.g., muscle and brain). Creatine’s role in energy metabolism involves the transfer of N-phosphoryl groups from phosphorylcreatine to adenosine diphosphate (ADP) to regenerate adenosine triphosphate (ATP) through a reversible reaction catalyzed by phosphorylcreatine kinase (Andres et al., 2008; Brosnan and Brosnan, 2007).

Both creatine and phosphocreatine are broken down spontaneously to creatinine, which is removed from the body in urine. The rate of loss is approximately 1.7 percent of the total body pool of creatine per day. Because more than 90 percent of creatine and phosphocreatine is located in skeletal muscle, creatine losses and creatine excretion vary as a function of differences in muscle mass resulting from age, gender, and levels of daily activity. Creatinine excretion is greatest in young men between 18 and 29 years of age—the typical age of most military personnel in combat (Brosnan and Brosnan, 2007).

CREATINE AND THE BRAIN

Although the brain represents only 2 percent of total body weight, it uses approximately 20 percent of the body’s energy. As the brain requires significant ATP turnover to maintain membrane potentials and signaling capacity, creatine metabolism and the creatine kinase/phosphocreatine system are important for normal brain function, and may be compromised



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10 Creatine Creatine (N-[aminoiminomethyl]-N-methyl glycine) is an amino acid–like compound that is produced endogenously in the liver, kidney, pancreas, and possibly the brain from the biosynthesis of the essential amino acids methionine, glycine, and arginine, or obtained from dietary sources. The primary dietary sources are high-protein foods including meat, fish, and poultry. Once synthesized or ingested, creatine is transferred from the plasma through the intestinal wall into other tissues by specific creatine transporters located in skeletal muscles, the kidney, heart, liver, and brain. Creatine and the creatine kinase/phosphocreatine system play an important role as re- served sources of energy in tissues with high and fluctuating energy requirements (e.g., mus- cle and brain). Creatine’s role in energy metabolism involves the transfer of N-phosphoryl groups from phosphorylcreatine to adenosine diphosphate (ADP) to regenerate adenosine triphosphate (ATP) through a reversible reaction catalyzed by phosphorylcreatine kinase (Andres et al., 2008; Brosnan and Brosnan, 2007). Both creatine and phosphocreatine are broken down spontaneously to creatinine, which is removed from the body in urine. The rate of loss is approximately 1.7 percent of the total body pool of creatine per day. Because more than 90 percent of creatine and phosphocre- atine is located in skeletal muscle, creatine losses and creatine excretion vary as a function of differences in muscle mass resulting from age, gender, and levels of daily activity. Creatinine excretion is greatest in young men between 18 and 29 years of age—the typical age of most military personnel in combat (Brosnan and Brosnan, 2007). CREATINE AND THE BRAIN Although the brain represents only 2 percent of total body weight, it uses approximately 20 percent of the body’s energy. As the brain requires significant ATP turnover to maintain membrane potentials and signaling capacity, creatine metabolism and the creatine kinase/ phosphocreatine system are important for normal brain function, and may be compromised 130

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131 CREATINE in diseases of the central nervous system (Andres et al., 2008) (see also papers by Sullivan and by Hall in Appendix C). Evidence of the importance of the creatine system for brain function comes from animal studies using creatine kinase knockout mice, which display significant reductions in hippocampal functioning and impairments in both learning and memory compared to non-genetically modified mice. Learning is further compromised in mice given a drug that competitively inhibits the creatine transporter and results in reductions of creatine pools in muscle and brain (Andres et al., 2008). In contrast, mice fed a diet supplemented with 1 percent creatine live longer, have less reactive oxygen species in their brains, and show better memory function than nonsupplemented littermates (Bender et al., 2008). In humans, individuals born with errors in creatine synthesis or x-linked creatine trans- porter defects suffer from mental retardation, autistic behavior, severe language and speech impairments, epilepsy, and brain atrophy. In some individuals, the cognitive deficits result- ing from these congenital errors can be improved, though not totally reversed, with chronic administration of large doses of creatine (Andres et al., 2008; Gualano et al., 2010). Studies using nuclear magnetic resonance spectroscopy have shown that creatine supple- mentation increases brain levels of both creatine and phosphocreatine (Dechent et al., 1999; Pan and Takahashi, 2007). These increases in brain creatine may translate into improve- ments in cognitive behavior, particularly under stressful or compromised conditions. For example, young men given creatine supplements prior to experiencing 36 hours of sleep deprivation did better on a test of executive functioning than nonsupplemented individuals (McMorris et al., 2006). Creatine supplements have additionally been shown to enhance working memory in vegetarians, who typically have lower levels of creatine than omnivores (Rae et al., 2003), and to improve performance on tests of verbal and spatial memory in elderly individuals (McMorris et al., 2007). There is growing evidence that creatine may be of value in the treatment of a number of neurological conditions, including congenital creatine deficiency syndromes, age-related cognitive decline (e.g., Alzheimer’s disease), and neurodegenerative diseases (e.g., Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis), all of which are linked to dys- functional energy metabolism (Andres et al., 2008; Gualano et al., 2010). Creatine supple- mentation is also beginning to attract attention as a complementary strategy in the treatment of psychiatric disorders (e.g., depression, posttraumatic stress disorder, and schizophrenia) (Allen et al., 2010; Amital et al., 2006b; Roitman et al., 2007). As described in Chapter 3, damage following traumatic brain injury (TBI) can be cat- egorized as primary, secondary, and long-term. Although understanding of the mechanisms underlying secondary injury is yet in its early stage, data indicate that impairments of mitochondrial function play a role in mediating the delayed consequences of TBI (Andres et al., 2008; Scheff and Dhillon, 2004; Sullivan et al., 2000; Zhu et al., 2004). It has been hypothesized that creatine’s neuroprotective effects following TBI may involve creatine- induced maintenance of mitochondrial bioenergetics (Sullivan et al., 2000). Supporting this hypothesis is the finding by Sullivan and colleagues (2000) that rats fed a diet containing one percent creatine for four weeks displayed significantly higher mitochondrial membrane po- tentials and maintained levels of ATP better than nonsupplemented rats following controlled cortical contusion. Other indications of improved mitochondrial function in creatine-treated rats included decreased levels of reactive oxidative intermediaries and intramitochondrial calcium. Brain levels of both lactate and free fatty acids increase following focal brain injury. These increases are believed to be a consequence of secondary brain damage resulting from the accumulation of excitotoxic levels of the neurotransmitter glutamate. Scheff and Dhillon

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132 NUTRITION AND TRAUMATIC BRAIN INJURY (2004) demonstrated that cortical and hippocampal levels of lactate and free fatty acids are lower in rats fed creatine than in nonsupplemented rats (Scheff and Dhillon, 2004). These results provide support for the hypothesis that creatine’s neuroprotective effects are at least partly due to a reduction in the processes associated with secondary brain damage. It also has been proposed that the neuroprotective effects of creatine may reflect its ability to improve cerebrovascular function (Prass et al., 2007). Support for this proposal comes from a recent study demonstrating that feeding creatine to mice subjected to middle artery occlusion resulted in reductions in infarct volumes. Although there were no changes in brain creatine, phosphocreatine, ATP, ADP, or adenosine monophosphate (AMP), such supplementation did improve cerebral blood flow in these animals, suggesting that creatine may have beneficial effects on cerebrovascular functioning. A list of human studies (years 1990 and beyond) evaluating the effectiveness of creatine in providing resilience or treating TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy) in humans is presented in Table 10-1. This also includes supporting evidence from animal models of TBI. Although this report does not generally include studies on the effectiveness of nutrition interventions on long-term effects of TBI effects, depression as an effect of TBI has been included in this chapter. The occurrence or absence of adverse effects in human studies is included if reported by the authors. USES AND SAFETY Creatine is one of the most widely used dietary supplements. Athletes, body builders, and military personnel use creatine to enhance muscle mass and increase strength. Creatine is also used as an ergogenic aid to improve performance of high-intensity exercise of short duration (Bemben and Lamont, 2005; Branch, 2003; IOM, 2008). Creatine’s popularity as a dietary supplement was further increased by a 2006 study demonstrating its positive effect on cognitive and psychomotor performance (McMorris et al., 2006). Because it can be synthesized in the body, there is no Recommended Dietary Allowance for creatine; however, as a result of daily losses, creatine stores need to be maintained either by diet or synthesis. Research indicates that creatine supplementation increases the creatine and phosphocreatine pools in muscle, particularly in younger individuals who are engaging in vigorous physical activity, and in vegetarians, who may have a less than optimal pool of phosphocreatine (Brosnan and Brosnan, 2007; Burke et al., 2003; Rawson et al., 2002). Experiments among athletes and military personnel indicate that creatine taken at levels commonly available in supplements produces minimal, if any, side effects (IOM, 2008; Shao and Hathcock, 2006). Using evidence from well-designed, randomized controlled human clinical trials of creatine, Shao and Hathcock (2006) concluded that chronic intake of 5 g/ day of creatine was safe and posed no significant health risks. EVIDENCE INDICATING EFFECT ON RESILIENCE Human Studies As with other nutrients or food components, the committee found no human studies testing the potential benefits of creatine in TBI or other related diseases or conditions in- cluded in the reviewed of the literature (subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy).

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133 CREATINE TABLE 10-1 Relevant Data Identified for Creatine Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Tier 1: Clinical trials Sakellaris TBI Prospective, Postinjury, In short-term assessments, patients treated with et al., randomized, creatine creatine were less likely to experience post-traumatic 2008 comparative, (0.4 g/kg) oral amnesia (p=0.019). At 6 months, creatine-treated patients were less likely to experience headaches (χ2b= open-labeled suspension 23.139; dfc=1; p < 0.001), dizziness (χ2=7.886, df=1; pilot study form daily p=0.005), and fatigue (χ2=17.881, df=1; p < 0.001). for 6 months na=39 TBI or nothing; patients ages No side effects due to creatine administration were follow-up at 1–18 years, observed. 6 months Glasgow Coma Scale (GCS) score between 3 and 9 Sakellaris TBI Prospective, Postinjury, Short-term assessment showed that patients et al., randomized, creatine (0.4 treated with creatine were less likely to experience 2006 comparative, g/kg) oral posttraumatic amnesia (p=0.019). open-labeled suspension Long-term analysis at 3 months showed that pilot study form daily patients in the creatine group had better overall for 6 months, outcomes than the control group (χ2=21.099, df=7; n=39 TBI or nothing; patients ages p=0.004). Specifically, creatine group performed follow-up better in neurophysical parameters (χ2=14.269, 1–18 years, at 3 and 6 df=4; p=0.006), cognitive parameters (χ2=18.453, GCS between months 3 and 9 df=4; p=0.001), personality/behavioral outcomes (χ2=19.595, df=4; p=0.001), and sociability measures (χ2 = 20.562, df=4; p < 0.001). However, no significant differences were observed regarding locomotion, self care, and communication. At 6 months, creatine patients were more likely to achieve “good recovery” as measured using GOS (Glasgow Outcome Scores)-8 than control group (χ2=29.231; df=5; p < 0.001). Creatine group showed greater improvement on cognitive (χ2=29.262, df=4; p < 0.001) and personality/behavioral measures (χ2=29.262, df=4; p < 0.001), as well as self care (χ2=9.050, df=3; p=0.029) and communication (χ2=8.011, df=2; p=0.029). No significant difference was observed on neurophysical, social, and locomotion measures after 6 months. No side effects due to creatine administration were observed. Tier 2: Observational studies None found continued

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134 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 10-1 Continued Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Tier 3: Animal studies Scheff Moderate Adult, male Preinjury, Lactate level: In the ipsilateral cortex, levels of lactate and TBI Sprague- 0.5% or 1% were higher 6 hours postinjury than 30 minutes after injury (p < 0.002). TBI rats had higher levels than Dhillon, Dawley rats creatine- sham-injured rats at both times (p < 0.05). At 30 2004 supplemented n=85 diet (0.5% minutes, rats on regular diet had higher lactate levels than rats on 1% creatine diet (p < 0.05). At 6 hours, or 1%) or regular lactate levels of regular diet group was higher than both creatine groups (p < 0.05). rodent diet fed for 2 In the penumbra of the ipsilateral cortex, all injured weeks before groups had higher lactate levels than sham-injured TBI; some rats at 30 minutes (p < 0.05), with regular diet group rats were at higher levels than 1% creatine rats (p < 0.05). At killed 30 6 hours, regular diet-fed rats had higher lactate levels minutes or 6 than sham-injured rats and both creatine groups (p hours after < 0.05), but creatine groups were not different from injury, while sham-injured rats. others were killed 7 days In the ipsilateral hippocampus, regular diet group after injury and 0.5% creatine group had higher levels than sham injury rats (p < 0.05) at 30 minutes. Levels in 1% creatine rats were not different from sham group. Lactate levels at 6 hours were greater than at 30 minutes (p < 0.02), with all TBI groups at higher levels than sham group (p < 0.05), and regular diet group at higher levels than 1% creatine group. Free fatty acid (FFA) level: In the ipsilateral cortex, at 30 minutes, TBI rats had higher FFA levels than sham-injured rats (p < 0.05) and creatine-fed rats had lower levels of all FFAs than regular diet rats (p < 0.05). At 6 hours, only regular diet group and 0.5% creatine group had higher levels than sham controls (p < 0.05). Compared to regular diet rats, palmitic and stearic acids were lower in both creatine groups, and arachidonic was lower in 1% creatine group (p < 0.05). In the penumbra, at 30 minutes, both creatine groups were lower than regular diet group (p < 0.05) but were not different from sham group. However, at 6 hours, all injured rats had higher levels than sham group (p < 0.05). Creatine-fed rats had lower FFA levels than regular diet rats, specifically in the levels of palmitic and stearic acids (p < 0.05). In the ipsilateral hippocampus, at 30 minutes, regular diet group and 0.5% creatine group had higher levels than sham group (p < 0.05), while 1% creatine group was not significantly different from sham group. 1% creatine group had lower levels of palmitic, stearic, and arachidonic acids than regular diet group (p < 0.05). No significant FFA differences were observed among any group at 6 hours.

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135 CREATINE TABLE 10-1 Continued Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Sullivan TBI Sprague- Mice: Mice: There was a significant difference in cortical et al., (controlled Dawley rats injection damage between creatine and vehicle groups (F[5,34]=4.16; p < 0.01). Although creatine showed 2000 cortical (n=24) and of creatine contusion) ICR mice monohydrate no significant benefit for rats treated for 1 day, (n=40) suspended significant protection was observed in rats treated for 3 days (p < 0.05) and for 5 days (p < 0.01). in olive oil or vehicle 1, Rats: Cortical damage was significantly smaller in 3, or 5 days rats fed with creatine-enriched diet before TBI (p < before injury; 0.01) than in rats fed with normal diet; all 12 rats killed 7 days were killed 7 days after TBI. after injury In rats that were killed 1 hour postinjury, Rats: fed mitochondrial potential was significantly lower in normal rats fed with normal diet (t[4]=4.02; p < 0.05). diet or diet enriched with Creatine-fed rats showed significantly lower reactive oxygen intermediate levels (t[4]=–7.63; p < 0.05) and 1% creatine Ca2+ levels (t[4]=–2.79; p < 0.05), but higher ATP for 4 weeks levels (t[4]=5.54; p < 0.01). 12 rats (6 on creatine diet and 6 on normal diet) were killed 1 hour after injury Remaining 12 rats were fed diets for additional 1 week after injury, then killed preinjury a n: sample size. χ2: chi-square. b c df: degree of freedom. Animal Studies Animal studies provide a way to determine the effects of creatine supplementation on the biochemical and physiological as well as the behavioral consequences of TBI. The major- ity of studies assessing the neuroprotective effects of creatine have used mild cortical contu- sions as a model of TBI. These contusions result in significant reductions in cortical tissue, disruption of the blood-brain barrier, loss of hippocampal neurons, and severe behavioral deficits. Using this model, Sullivan and colleagues (2000) demonstrated dose-related reduc- tions in cortical damage following contusions in mice that had been given intraperitoneal injections of creatine for 1, 3, or 5 days before the induction of brain damage. Similarly, rats fed a standard rodent diet supplemented with 1 percent creatine for four weeks before the induction of TBI demonstrated 50 percent less cortical damage than nonsupplemented rats. Further evidence of the potentially neuroprotective effects of creatine comes from a study

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136 NUTRITION AND TRAUMATIC BRAIN INJURY by Scheff and Dhillon (2004), who found that rats fed a diet containing 1 percent creatine before experiencing controlled cortical contusions had significantly more sparing of cortical tissue than rats not given creatine. These positive findings are supported by studies conducted on other brain injury mod- els. For example, Prass and colleagues (2007) reported that mice fed diets containing 1 or 2 percent creatine for three weeks preceding middle cerebral artery occlusion, a model of ischemia, suffered significantly less brain damage than mice not given creatine. In this study, however, the neuroprotective effects of creatine were not observed when a large dose of creatine was given immediately following the onset of ischemia, or when a smaller dose was fed for 12 months. EVIDENCE INDICATING EFFECT ON TREATMENT Human Studies There have been no studies to examine the effects on TBI of creatine supplementation in adults. Results of preliminary studies by Sakellaris and colleagues (2006; 2008) suggest that creatine supplementation may be useful in the treatment of the secondary and long-term symptoms of TBI that are not the immediate consequences of the trauma, but develop within minutes, hours, or days after the injury. The statement of task for this study did not include a systematic review of the effectiveness of nutrition interventions on long-term effects of TBI. Studies on creatine and long-term effects such as depression are included here as a prelude to a review that the committee believes should be conducted in the future. In the first study, the neuroprotective effects of an oral suspension of 0.4 g/kg of creatine given first within 4 hours from the time of injury and then once a day for 6 months were examined in TBI patients between the ages of 1 and 18. Children and adolescents given creatine spent less time in an intensive care unit and required tube feeding for a shorter period of time than controls not given creatine. When examined three and six months after injury, individuals who had received creatine supplementation displayed greater improvements in cognitive functioning, self-care, sociability, and communication skills than controls (Sakellaris et al., 2006). In a second part of the study with the same patient population and using the same creatine dosage regimen, the proportion of children with headaches, dizziness, and fatigue during a six-month observation period was significantly lower in the creatine-supplemented group than in the control group (Sakellaris et al., 2008). There were no side effects reported from creatine supplementation. Depression is a noted long-term effect of TBI. There is growing evidence that impair- ments in cellular resilience, neural plasticity, and bioenergetic function within the brain are associated with the pathogenesis of depression. It has been hypothesized that by reversing these impairments, creatine could be useful in preventing or treating depression. Results of a number of studies indicate a relationship between depression, a frequent concomitant of TBI (Bombardier et al., 2010; Jorge and Starkstein, 2005; Masel and DeWitt, 2010), and creatine, and suggest that creatine may be of value in the treatment of the depressive symptoms observed in patients with TBI. The first evidence of a role for creatine in depres- sion came from studies demonstrating a significant negative correlation between creatine metabolites and self-reported suicidal ideation in patients suffering from major depressive disorders (Agren and Niklasson, 1988). Studies performed since 2000 also found that levels of brain creatine are inversely related to the severity of a depressive episode (Dager et al., 2004; Segal et al., 2007). Support for the potential usefulness of creatine in the treatment of depression comes from open-labeled studies demonstrating that daily oral intake of three to

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137 CREATINE five grams of creatine elevated mood in depressed patients resistant to antidepressant drugs and in patients with comorbid posttraumatic stress disorder (Amital et al., 2006b; Roitman et al., 2007). Patients with fibromyalgia often suffer from chronic pain, fatigue, difficulty sleeping, and depression, symptoms also common following brain injury; a strong overlap has been reported between fibromyalgia and posttraumatic stress disorder (Amital et al., 2006a). In an eight-week, open-labeled study of creatine, significant improvements were observed in quality of life, sleep patterns, and pain in patients with fibromyalgia. These improvements deteriorated four weeks after stopping creatine therapy. In all of the preceding studies, ad- verse reactions to creatine supplementation, if any, were mild (e.g., nausea) and decreased over time. Although the results of the preceding studies suggest promise for the possible use of creatine in the treatment of TBI, they are limited by their small number of participants and lack of double-blind procedures. Animal Studies Creatine supplementation also can reduce a number of detrimental consequences of cerebral ischemia. Following middle cerebral artery occlusion, mice fed a diet supplemented with two percent creatine for one month displayed significantly better neurologic function and significantly less brain damage than controls not receiving creatine. Creatine also sig- nificantly reduced ischemia-mediated depletion of ATP as well as caspase-3-activation and cytochrome c release, indicators of cell damage (Zhu et al., 2004). As noted above, depression is one of the most common symptoms of TBI. In support of human studies on creatine and depression, chronic intake of diets supplemented with one or two percent creatine decreased depressive-like behavior in a dose-dependent manner in female rats in the forced swim test, an animal model of depression. In male rats, however, intake of the creatine-supplemented diets failed to reduce depressive behavior (Allen et al., 2010). The observation of sex-specific effects of creatine are interesting, given the fact that depression is more commonly diagnosed in women than in men. CONCLUSIONS AND RECOMMENDATIONS Based on results of both animal and human studies, creatine represents a promising nutritional supplement for increasing resilience to and treating TBI. Taken together, the results of the studies presented indicate that the neuroprotection resulting from intake of creatine-supplemented diets is due, at least in part, to a suppression of secondary brain injury. Although more research is needed in both animal and human populations, these find- ings suggest that prophylactic creatine treatment could be useful for people with an elevated potential to incur TBI; however, there are a number of issues that need to be addressed prior to initiating creatine use in military populations. The question of how to experimentally assess the prophylactic effects of creatine on resilience remains unanswered. Researchers could give creatine to a group of high-risk in- dividuals (e.g., individuals with a high risk of stroke, or a higher than normal risk of head injury) and compare brain functioning and behavior in those who ultimately experience brain injury with that of individuals in similar groups who were not given creatine. There are, however, challenges to conducting such a study. First, obtaining a statistically adequate number of participants for a long-term prospective study might be difficult. An additional problem is the current lack of definitive guidelines on how much creatine should be given

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138 NUTRITION AND TRAUMATIC BRAIN INJURY or for how long it should be provided. Indeed, animal studies suggest that long-term feeding of creatine may reduce its ability to protect against the consequences of brain injury (Prass et al., 2007). These challenges to the feasibility of prospective studies will be common to any nutrient or food component of interest. To overcome these challenges, the committee recommends in Chapter 5 that a study be conducted on preinjury and postinjury dietary intake status (e.g., dietary supplement use) in individuals with TBI in order to determine any relationship to TBI outcome, including an analysis of the possible synergistic effects between nutrients, food components, and dietary supplements. Creatine should be included as part of that study. With respect to treatment, preliminary studies by Sakellaris and colleagues (2006, 2008) provide evidence of the potentially positive therapeutic effects of creatine on brain function and behavior after brain injury. These positive effects should be confirmed in the adult population. RECOMMENDATION 10-1. Based on the evidence supporting the effects of creatine on brain function and behavior after brain injury in children and adolescents, DoD should initiate studies in adults to assess the value of creatine for treating TBI patients. REFERENCES Agren, H., and F. Niklasson. 1988. Creatinine and creatine in CSF—indexes of brain energy-metabolism in depres- sion. Journal of Neural Transmission 74(1):55–59. Allen, P. J., K. E. D’Anci, R. B. Kanarek, and P. F. Renshaw. 2010. Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology 35(2):534–546. Amital, D., L. Fostick, M. L. Polliack, S. Segev, J. Zohar, A. Rubinow, and H. Amital. 2006a. Posttraumatic stress disorder, tenderness, and fibromyalgia syndrome: Are they different entities? Journal of Psychosomatic Re- search 61(5):663–669. Amital, D., T. Vishne, S. Roitman, M. Kotler, and J. Levine. 2006b. Open study of creatine monohydrate in treatment-resistant posttraumatic stress disorder. Journal of Clinical Psychiatry 67(5):836–837. Andres, R. H., A. D. Ducray, U. Schlattner, T. Wallimann, and H. R. Widmer. 2008. Functions and effects of cre- atine in the central nervous system. Brain Research Bulletin 76(4):329–343. Bemben, M. G., and H. S. Lamont. 2005. Creatine supplementation and exercise performance—recent findings. Sports Medicine 35(2):107–125. Bender, A., J. Beckers, I. Schneider, S. M. Holter, T. Haack, T. Ruthsatz, D. M. Vogt-Weisenhorn, L. Becker, J. Genius, D. Rujescu, M. Irmler, T. Mijalski, M. Mader, L. Quintanilla-Martinez, H. Fuchs, V. Gailus-Dumer, M. H. de Angelis, W. Wurst, J. Schmid, and T. Klopstock. 2008. Creatine improves health and survival of mice. Neurobiology of Aging 29(9):1404–1411. Bombardier, C. H., J. R. Fann, N. R. Temkin, P. C. Esselman, J. Barber, and S. S. Dikmen. 2010. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. Journal of the American Medical Association 303(19):1938–1945. Branch, J. D. 2003. Effect of creatine supplementation on body composition and performance: A meta-analysis. International Journal of Sport Nutrition and Exercise Metabolism 13(2):198–226. Brosnan, J. T., and M. E. Brosnan. 2007. Creatine: Endogenous metabolite, dietary, and therapeutic supplement. Annual Review of Nutrition 27:241–261. Burke, D. G., P. D. Chilibeck, G. Parise, D. G. Candow, D. Mahoney, and M. Tarnopolsky. 2003. Effect of creatine and weight training on muscle creatine and performance in vegetarians. Medicine and Science in Sports and Exercise 35(11):1946–1955. Dager, S. R., S. D. Friedman, A. Parow, C. Demopulos, A. L. Stoll, K. Lyoo, D. L. Dunner, and P. F. Renshaw. 2004. Brain metabolic alterations in medication-free patients with bipolar disorder. Archives of General Psychiatry 61(5):450–458. Dechent, P., P. J. Pouwels, B. Wilken, F. Hanefeld, and J. Frahm. 1999. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. American Journal of Physiology 277(3 Pt 2):R698–704. Gualano, B., G. G. Artioli, J. R. Poortmans, and A. H. Lancha. 2010. Exploring the therapeutic role of creatine supplementation. Amino Acids 38(1):31–44.

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