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 ? Therapeutic Usage
 ? Diseases Affecting
 ? Mitochondrial disease
 ? Parkinson’s disease
 ? Huntington’s disease
 ? Muscular disease
 ? Heart Disease
 ? Pathologies
 ? Brain effects



Clinical Pharmacology of the Dietary Supplement
Creatine Monohydrate

Therapeutic Usage

    Although the majority of studies on Cr have been on exercise performance in healthy subjects, recent evidence indicates Cr may be useful in the treatment of certain diseases. Patients with diseases that result in atrophy or muscle fatigue secondary to impaired energy production may benefit from Cr supplementation. The true mechanisms by which Cr can be effective in these diseases are unclear but the theorized mechanisms of increased energy in the form of PCr, increased muscle accretion, and stabilization of membranes may be influential as discussed previously.

    Research has recently focused on the clinical application of Cr in rodents and humans, and therefore there is a limited amount of information available on the relationship between the rodent studies and human studies. Although studies involving rodents offer credence in the therapeutic use of Cr, the results may not fully explain the usefulness in humans. Rodents typically have a higher blood Cr level than humans (Marescau et al., 1986) and do not respond to supplementation in the same manner that humans respond. For example, rats fed a 3% Cr diet for 40 days showed little increase in skeletal muscle tCr levels with large increases in tCr in liver and kidney (Horn et al., 1998). Therefore, the distribution processes in the rodent may differ from humans and may cause some differences in Cr application.

Diseases Affecting Mitochondria

    Because Cr is involved in energy production and acts as a shuttle of ATP from the inner mitochondria to the cytosol, Cr was theorized to be useful in diseases of mitochondria where energy production is altered. Cr supplementation has been shown to be beneficial in diseases in which there is mitochondrial dysfunction such as Parkinson’s, Huntington’s, and myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).

1. Parkinson’s Disease.

a. Animal Studies. Parkinson’s disease is an idiopathic neurodegenerative disease characterized by depletion of dopamine levels in the brain. The loss of dopaminergic neurons may be caused by energy impairment resulting in cell death. MPTP neurotoxicity is used as a model for Parkinson’s. MPTP is converted to MPP+, which inhibits complex I of the electron transport chain and impairs oxidative phosphorylation and subsequent ATP production. The administration of MPTP alone results in 70% depletion in brain dopamine levels in rodents (Matthews et al., 1999). Matthews et al. (1999) used this model and found that rats fed a 1% Cr diet (w/w diet) for 2 weeks showed less than a 10% brain dopamine loss when compared with nonsupplemented animals after exposure to MPTP/MPP+. here was a dose dependence from 0.25 to 1% Cr diet; however, this protection disappeared at 2 and 3% Cr diet. Interestingly, the Cr analog cyclocreatine was also neuroprotective at concentrations of 0.25 to 1% w/w diet. Histologically, there was no significant loss of nigral neurons in the Cr treated group. There was no explanation for the inverted U-shaped response curve in dopamine protection or whether higher doses elicited additional beneficial or toxicological effects. Reasons for the inverted U shape may be the result of changes in CreaT density, changes in intracellular osmotic pressure, or dysfunction in energy metabolism. Additionally, no intracellular Cr, tCr, PCr, or ATP levels were measured in this study.

2. Huntington’s Disease.

a. Animal Studies. Huntington’s disease results in the formation of lesions in the brain from an alteration in energy production. Matthews et al. (1998) used 3-nitropropionic acid (3-NP) to mimic changes in energy metabolism seen in Huntington’s. 3-NP irreversibly inhibits complex II of the electron transport system and produces lesions caused by energy depletion. They reported that 1% Cr (w/w diet) after 2 weeks showed an 83% reduction in lesion volume as compared with untreated animals. Animals treated with the Cr analog cyclocreatine showed no protection and appeared to have exacerbated toxicity. Malonate can also be used to induce Huntington’s-like lesions. In the same study, Matthews et al. found similar protection against malonate induced toxicity with a U-shaped dose-response curve using a 1 and 2% Cr w/w diet demonstrating the most protection. In these studies, Cr fed animals had higher striatal levels of PCr than control animals and Cr treated animals exposed to 3-NP had higher levels of Cr, PCr, AMP, GDP, NAD, ATP, and lower levels of lactate than control animals treated with 3-NP. These changes would correlate with improved energy production. Cr fed animals also showed reduced markers of oxidative damage caused by malonate or 3-NP. Again, no reason was given for the U-shaped response curve of Cr against lesion size.

    Ferrante et al. (2000) used the transgenic R6/2 mouse model for Huntington’s disease to examine the effect of Cr. There was a U-shaped dose dependent increase of 9.4%, 17.4% for survival in mice fed a 1 and 2%, respectively. However, only a 4.4% increase in survival was found for a 3% w/w diet of Cr. Mice supplemented with Cr also showed increased rotarod performance when fed 1 and 2% Cr but not a 3% diet. Additionally, Cr maintained brain weight, reduced striatal atrophy, reduced striatal aggregates, and delayed the onset of diabetes. A recent study by Shear et al. (2000) supports the previous studies that Cr can attenuate anatomical abnormalities induced by 3-NP as well as improve motor performance variables.

3. Other Mitochondrial Pathologies.

a. Animal Studies. Other mitochondrial-related diseases can be affected by Cr supplementation. In a model for amyotrophic lateral sclerosis, GP3A transgenic mice (SOD1 mutation) had a life-span increased by 13 and 26 days when fed 1% or 2% Cr (w/w diet), respectively (Klivenyi et al., 1999). These animals also had no increase in 3-nitrotyrosine and other indicators of oxidative damage and showed increased motor performance, and Cr protected against loss of motor neurons and substantia nigra neurons. However, no levels of cellular tCr, Cr, PCr, ATP, or ADP were assessed in this study.

b. Human Studies. In a large study of 81 patients, Tarnopolsky and Martin (1999) investigated Cr supplementation in various neuromuscular diseases including mitochondrial cytopathies, neuropathic disorders, dystrophies, congenital myopathies, and inflammatory myopathies. They found increases in high-intensity strength measurements such as iso-metric dorsiflexion, handgrip strength, and isokinetic and isometric knee strength in these patients following supplementation of 10 g/day for 5 days with 5 g/day for 5 to 7 days of maintenance. These patients also showed small but significant increases in body weight with supplementation. In the same investigation, 21 patients were supplemented in a single-blind placebo-controlled study and found results similar to that of the 81-patient study. Tarnopolsky’s group also performed a short-term, randomized, crossover trial of Cr supplementation in patients with mitochondrial cytopathies (MELAS) (Tarnopolsky et al., 1997). Patients treated with Cr (2x3 5 g/day for 2 weeks with 2x2 g/day for 1 week of maintenance) showed a 19% increase in hand-grip strength and a reduction in post-exercise cycle ergometry blood lactate. There were no differences in body composition, maximal voluntary contraction, resting energy expenditure, oxygen consumption, or rating of perceived exertion. It was concluded that Cr increased strength and high-intensity anaerobic and aerobic activities with no effect in lower intensity aerobic activity. Most of the patients in this study were already taking vitamin E and C and coenzyme Q10 for treatment of their mitochondrial cytopathy.

D. Other Brain Pathologies.

1. Animal Studies. Hypoxia and energy-related brain pathologies (e.g., stroke) might benefit from Cr supplementation. Cr has been shown to protect the brainstem and hippocampus from hypoxia and that this protection may be attributable to the prevention of ATP depletion (Balestrino et al., 1999; Dechent et al., 1999; Wilken et al., 2000). Rodents supplemented with Cr (~2g/ kg of body weight per day) showed increased brain Cr:choline levels with a slight decrease in apparent diffusion coefficient (ADC) during an acute ischemic challenge (Wick et al., 1999). ADC is associated with cyto-toxic cellular swelling, and therefore a reduction in ADC may offer protection. Michaelis et al. (1999) found that Cr supplementation (~2 g/kg of body weight per day) showed no differences in metabolic responses after global cerebral ischemia despite increased brain tCr. Due to increases in glucose and slight reductions in lactate found in the Cr-fed group, the authors concluded that neuroprotection may occur with more focal ischemia rather than global ischemia. Cr has been found to be neuroprotective against N-methyl- D-aspartate and malonate excitotoxicity following a 1% (w/w) diet for 1 week in rats (Malcon et al., 2000). These investigators did not find protection against a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainic toxicity. In either case, no dose response relationship was established. Cr has been shown to protect hippocampal neurons from glutamate toxicity and partially protect embryonic neurons from b-amyloid toxicity (Brewer and Wallimann, 2000). This protection against b-amyloid was also seen in adult and aged neurons and therefore may attenuate the formation of senile plaques seen in Alzheimer’s disease. In both cases, intracellular Cr and PCr were elevated when compared with toxin-treated neurons not supplemented with Cr.

2. Human Studies. There are few clinical data on the effect of Cr in the human brain. Stockler et al. (1994, 1996) report a treatable inborn error in Cr metabolism that causes tCr depletion in the brain and results in extrapyramidal movement disorders. Treatment with Cr in these patients restores Cr levels and improves neurologic symptoms. Other studies have found supplementation (4x5 g/day) for 4 weeks in human volunteers caused an 8.7% increase in brain tCr. The largest increases were seen in gray matter (4.7%), white matter (11.5%), cerebellum (5.4%), and thalamus (14.6%). Although no human studies have been done on Cr supplementation and resistance to brain injury, the increase in brain Cr may be relevant in ischemic injury similar to that seen in the rodent models.

E. Muscular Disease.

1. Animal Studies. Since 95% of Cr in the body is found in skeletal muscle, supplementation may be useful in treating myopathies. Duchenne’s muscular dystrophy is a degenerative disease that causes mechanical instability of the sarcolemma leading to increased calcium leakage during periods of stress. Using mdx mice as a model for Duchenne’s muscular dystrophy, Pulido et al. (1998) prepared a primary cell culture from hind-limb muscles. During myotube formation, cells were incu-bated with 20 mM Cr. After 12 to 14 days, cells were exposed to hypo-osmotic shock. Cells treated with Cr showed significantly lower intracellular calcium levels that were nearly equivalent to baseline calcium levels of control myotubes. This effect of Cr could be due to decreased sarcolemmal leakage or enhanced uptake by the sarcoplasmic reticulum. Further evidence from the Pulido study supported more of an effect on calcium uptake by sarcoplasmic reticulum Ca 2+ ATPase. Intracellular PCr increased in both mdx and control myotubes with the former having a more pronounced increase.

2. Human Studies. In a double-blind crossover clinical study, Felber et al. (2000) examined Cr supplementation (10 g/day for adults and 5 g/day for children) for 8 weeks in 32 patients with various muscular dystrophies. At the end of the treatment period, the Cr group had a 3% increase in strength and a 10% increase in neuro-muscular symptom score. There were no differences in clinical chemistries between groups. The authors concluded that long-term Cr supplementation in this population is needed.

    In other studies related to muscle, patients with rheumatoid arthritis had strength improvements after supplementation with 20 g of Cr/day for 5 days and then 2 g/day for the remaining 16 days but no change in physical functional ability or disease activity (Willer et al., 2000). This was an open study examining arthritis pre-and post-supplementation, but after supplementation there was a small increase in muscle Cr (;7%) and a decrease in both PCr (;24%) and tCr (;14.3%). The lack of change in muscle tCr may reflect the lack of change in functional ability and raises a more important question of why these patients did show the more typical increase of 20% seen in young healthy males. Patients with myo-phosphorylase deficiency (McArdle’s disease) showed mild improvements from supplementation of 150 mg/kg for 1 week with maintenance doses of 60 mg/kg/day n a placebo-controlled crossover trial (Vorgerd et al., 2000). These improvements consisted of lower self-reported severity and lower frequency of muscle pain and increased exercise performance including increased strength. Cr-treated patients showed increase in muscle PCr and increases in exercise performance during ischemia. This was the first study to examine the effects of Cr supplementation in McArdle’s disease.

F. Heart Disease.

1. Animal Studies. The effects of Cr on cardiac tissue have been investigated. A study by Sharov et al. (1987) showed a protective effect of PCr on cardiac tissue following ischemia. Using rabbit hearts, PCr was administered intravenously either before and during cardiac artery ligation or 30 min post-ligation. These investiga-tors found a reduction in necrotic zone under both PCr treatments compared with controls (Fig. 4). Ruda et al. (1988) found that PCr administration reduced ventricular arrhythmia after acute myocardial infarctions, but the effects of Cr on cardiac tissue are still unclear. Other studies have also shown PCr to possess anti-arrhythmic activities (Rosenshtraukh et al., 1988). Feeding Cr to healthy rats or rats after a myocardial infarction failed to increase intramuscular Cr (Horn et al., 1998). The b-blocker bispropolol has been shown to increase total cardiac Cr up to 40% (Laser et al., 1996). The ability to increase Cr and related energetics in heart tissue may be one beneficial mechanism of the action of b-blocker therapy (Laser et al., 1996). Ingwall et al. (1985) have also shown that diseased myocardium has lower Cr content. Supplementation with Cr has also provided protection to cardiac tissue from metabolic stress (Constantin-Teodosiu et al., 1995)

2. Human Studies. Gordon et al. (1995) investigated the effect on ingestion of Cr in patients with congestive heart failure in a double-blind, placebo-controlled study (20 g/day for 10 days). Ejection fraction at rest and at work did not change but increased exercise performance in regard to both strength and endurance. Another study in patients with congestive heart failure showed that Cr supplementation improved skeletal muscle metabolism with reductions in ammonia and lactate accumulation (Andrews et al., 1998). Recently, Neubauer et al. (1999) showed that hearts with dilated cardiomyopathy had 50% less tCr compared with healthy hearts as well as 30% less CreaT. Cr supplementation also has been shown to lower total plasma cholesterol and triglycerides (Earnest et al., 1996). These results were similar in humans and rodents and may suggest a therapeutic benefit of Cr supplementation.

G. Use of Creatine Analogs

     Analogs of Cr were used initially to study Cr metabolism and uptake. These analogs are currently being investigated as a treatment for Huntington’s disease, anti-tumor agents, and as antiviral agents. The most commonly used analogs are b-guanidinopropionic acid and cyclocreatine. This class of compounds has been shown to inhibit replication of several viruses including human and simian cytomegaloviruses and varicella zoster virus (Lillie et al., 1994), to protect neurons from 3-NP toxicity disease (Matthews et al., 1998), and reduce tumor size (Bergnes et al., 1996). A recent article by Wyss and Kaddurah-Daouk (2000) reviews the use and potential use of Cr analogs.

VI. Side Effects

    Side effects from Cr supplementation have been reported both anecdotally and in the scientific literature. Possible side effects of Cr supplementation have been previously reviewed by Juhn and Tarnopolsky (1998b). Briefly, Cr supplementation has been documented as being associated with weight gain, gastrointestinal distress, and renal dysfunction and anecdotally reported to cause muscle cramps and hepatic dysfunction. Typically weight gain is between 1 and 2 kg and is initially brought on by water retention, but may be maintained by changes in amount of lean body mass. Athletes generally desire this effect. Gastrointestinal distress has been reported anecdotally but little to no studies have documented nausea, vomiting, or diarrhea. This may be a function of single large doses of Cr or subsequent ingestion of large amounts of carbohydrates. Muscle cramps have been reported anecdotally, but published studies have yet to find muscle cramps associated with supplementation. In a double-blind, crossover study, subjects were supplemented with Cr at 20 g/day (4x5 g/day) for 5 days with a 28-day washout between treatments (Kamber et al., 1999). Supplementation had no effect on hepatic function as indicated by no changes in blood liver enzymes (i.e., creatine kinase, urea, aspartate aminotransferase, alanine aminotransferase, g-glutamyl transferase, lactate dehydrogenase). This study indicates that short-term supplementation may be safe, but the effect of long term supplementation is still unknown. Cardio-vascular function as assessed by changes in systolic and diastolic blood pressure was unaffected by Cr (Mihic et al., 2000). Finally, Cr has been implicated in renal dysunction. In two isolated cases, one patient presented with interstitial nephritis that improved upon termination of Cr use (Koshy et al., 1999), and another patient with focal glomerular sclerosis showed a reduction in GFR with Cr supplementation that returned upon termination of supplementation (Pritchard and Kalra, 1998). Before the diagnosis of focal glomerular sclerosis, the patient had relapsing steroid-responsive nephrotic syndrome and was currently on cyclosporin. It was recently found that cyclosporin inhibits Cr uptake in vitro and may explain the nephropathy brought on by Cr (Tran et al., 2000). Although these pathologies are serious, these were isolated incidences including one patient that had a history of kidney disease. Studies have shown that renal function and glomerular filtration are not effected by supplementation despite slight increases in plasma creatinine (Poortmans et al., 1997; Poortmans and Francaux, 1999). In one of these studies (Poortmans et al., 1997), subjects were self-supplementing with 2 to 30 g of Cr for 10 months to 5 years, and no changes in renal responses to creatinine, urea, or albumin were observed. It was recently hypothesized that Cr supplementation could be cytotoxic (Yu and Deng, 2000). Cr can be ultimately converted to formaldehyde and hydrogen peroxide by the reaction illustrated in Fig. 1. Formaldehyde has the potential to cross-link proteins and DNA leading to cytotoxicity. The investigators did find increased urine formaldehyde after Cr administration; however, they did not measure markers of protein or DNA cross-linking or indicators of oxidative stress.

VII. Products

    Cr products may be purchased from supermarkets, nutrition stores, and via the Internet. Because Cr falls under the Dietary Supplement Health Education Act of 1994, the Food and Drug Administration does not regulate the quality of dietary supplements but does regulate structure/function claims. Therefore, there is some concern of the quality of products available. A recent review by Benzi (2000) discusses some product quality issues, some of which are discussed briefly here. Commercial Cr is produced from the reaction of sarcosine and cyanamide. This process can yield several possible contaminants such as creatinine, dicyandamide, dihydrotrianzines, and ions such as arsenic. The ion contaminants as well as dicyandamide could be a potential health hazard. Therefore, good manufacturing practices need to be employed to protect the consumer. The ultimate goal for product quality research is to establish a monograph for the United States Pharmacopoeia (USP).

VIII. Conclusion

    It has been nearly 170 years since the discovery of Cr, but it was not until the 1990s that athletes began to supplement themselves to enhance exercise performance and muscle mass. Research has corroborated the reports from athletes that Cr can increase exercise performance and muscle mass especially in conjunction with resistance training. Since then, the use of Cr has been extended to the medical field for the treatment of energy related and neuromuscular related diseases. Recent advances in molecular biology has allowed the location and cloning of the creatine transporter, which can further our understanding of Cr physiology and possibly allow a target for pharmacological intervention. As research explores further applications for the therapeutic use of Cr or Cr analogs, it will be necessary to establish pharmacokinetic information for purposes of dosing and the possible prediction of physiological effects via pharmacokinetic/ pharmaco-dynamic modeling. It will also be necessary to establish good manufacturing practices to ensure product quality to the users. Other concerns need to be addressed regarding long term Cr use, the identification of side effects, and populations to exclude from supplementation.


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