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NOTE: In the US, nutraceuticals are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA). Consequently, scientific data supporting claimed benefit(s) are not always available for nutraceuticals as they are for traditional pharmaceuticals since nutraceuticals are not regulated as drugs. Consumers should also note that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products. Monographs on nutraceuticals are included in CP when reliable clinical data are available. The information presented below is condensed from the best clinical data we could find.
Creatine monophosphate is a dietary supplement similar to the natural compound creatine phosphate, which is an essential component of the energy-building system in muscle cells. Phosphocreatine is a nitrogen-containing compound found naturally in meats and fish. Creatine is also synthesized endogenously by the kidney, liver, and pancreas from arginine, glycine, and methionine. Normal dietary needs of creatine are suggested to be approximately 2 g/day to replace catabolized creatine.[2205] Many sports nutrition experts believe that the majority of world-class athletes use creatine. It is also widely used at the collegiate level. Quality scientific studies have been conducted to evaluate the exercise response to creatine loading in various forms of sport (e.g., jump squats, sprinting, weight lifting), and in many of these studies, creatine exhibited ergogenic properties.[2206] The most beneficial effects of creatine appear to be seen in events requiring extremely high-intensity effort for very brief periods (e.g., less than 60 seconds). High intensity exercise increases the demands on the anaerobic energy system and creatine loading helps supplement this. Overall, creatine supplementation along with resistance exercise may enhance exercise performance and increase lean body mass. Creatine supplementation is not considered doping and is not banned by NCAA or USOC. Creatine has been available over-the-counter (OTC) as a dietary supplement since 1993; it is currently not classified as a drug by the FDA. However, in March 2002, the FDA granted orphan drug status to The Avicena Group for creatine in patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). The Avicena Group (www.avicenagroup.com) has been studying creatine (Neotine®) for use in ALS patients. Safety and efficacy has been demonstrated in these patients. Creatine appears to slow progression of ALS and improve patients' quality of life. Neotine® is currently in Phase III trials for this indication. A new formulation of creatine, PD-02, has been developed by Avicena for evaluation in the treatment of Parkinson's disease. A large scale Phase III trial is currently underway through the NIH National Institute of Neurological Disorders and Stroke (NINDS) to assess the efficacy of creatine in slowing progression of the disease. A previously completed Phase II futility clinical trial showed potential benefit of the drug.[10021]
Mechanism of Action: Creatine acts as an "energy buffer". Adenosine triphosphate is the free energy source used to drive many biological processes including muscle contractions. Adenosine triphosphate provides energy through hydrolysis of its high-energy phosphoanhydride bonds. During high intensity exercise, muscle stores of ATP are depleted in approximately 10 seconds. Therefore, ATP must be continuosly regenerated. The ability to replenish ATP in muscle is directly related to the amount of creatine which is present in muscle as either free creatine or phosphocreatine. Free creatine can undergo rapid phosphorylation to form phosphocreatine. Resynthesis of ATP is catalyzed by creatine kinase which transfers the phosphate group from phosphocreatine to adenosine diphosphate (ADP) to form ATP. Creatine supplementation acts to raise muscle stores of creatine phosphate thereby increasing the amount of ATP available during intense physical activity.
Oral administration
•Creatine is given orally as a powder or as a "fruit chew" candy. The powder must be mixed with a beverage before consuming. Beverages that contain simple sugars (e.g., apple, grape, and orange juices) may provide added benefits when used as the vehicle for administration of creatine powder.[2207; Green AL, Hultman E, MacDonald IA, et al. Carbohydrate feeding augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol 1996;271:821?6.
] The beverage may be hot or cold, however, the creatine powder should not be cooked or microwaved. Use immediately after mixing. If the mixture cannot be used immediately, use within 8 hours. Some manufacturers recommend that there be a period of at least 4 hours between doses to avoid stomach discomfort.
†non-FDA approved
Adverse reactions: In general, manufacturers of creatine report that commonly used doses of oral creatine supplements are well tolerated. Weight gain is the most frequently reported adverse event. During short-term creatine supplementation, weight gain may result from fluid retention.[2208] Weight gain during long-term creatine supplementation (combined with resistance training) may be due to increases in lean body mass, however, more data are needed for confirmation.[2206]
Anecdotal reports of adverse reactions have included anxiety, atrial fibrillation, diarrhea, dyspnea, fatigue, migraine headache, myopathy, nausea/vomiting, nervousness, polymyositis, rash (unspecified), and seizures. It has also been suggested that creatine may cause an increased incidence of dehydration, muscle cramps, and muscle strains/pulls when exercising in heat, however, studies have not supported this.[2212] Data are scarce to support an association of the use of creatine with renal side effects.[3664]
Creatine was administered orally in doses of 10 grams/day for up to 12 months in a Phase II placebo-controlled trial of a clinically formulated creatine product (PD-02) in Parkinson's disease patients. Adverse events occurring more frequently with creatine than placebo included joint pain (19%), nausea (16%), dizziness (13%), headache (10%), tremor aggravated (7%), depression (7%), constipation (9%), diarrhea (6%), xerostomia (3%), influenza-like symptoms (3%), and hypercholesterolemia (1%).[10021] Unspecified upper respiratory symptoms were the most frequently reported adverse events in the creatine group (25%); however, these symptoms occurred in 31% of placebo patients as well. Eight patients receiving creatine required dose reductions versus 11 patients in the placebo group. Six patients (9%) in the creatine group experienced an elevated serum creatinine, with some being assessed by the investigators as clinically significant.
Pharmacokinetics: Creatine monohydrate is administered orally. Creatine is rapidly absorbed with peak plasma concentrations occurring in approximately 1 hour. Single oral doses of 5 g may produce peak creatine plasma concentrations of 690—1000 µmol/L. Creatine is primarily distributed into muscle primarily skeletal. Animal data suggest that creatine distribution into muscle is a saturable process, however, no equivalent data are available for humans.[2205] A 70 kg male has approximately 120 g of creatine, 95% of which is in skeletal muscle. Of the total creatine (TCr) in muscle, 60% exists as phosphocreatine (PCr) and the remainder as free creatine (FCr).[2206] Following creatine supplementation, both TCr and PCr are increased with the greatest increases occurring the first 2 days of supplementation. Persons with low initial creatine concentrations (e.g., vegetarians) tend to have the greatest increases in TCr.[2205] Coadministration of creatine with a simple carbohydrate such as glucose may increase TCr and PCr to a greater extent than with creatine alone, possibly through an insulin-mediated mechanism.[2207] Creatine is metabolized to creatinine, however, the exact steps involved have not been determined. Excretion is via the urine as both creatine and creatinine.
To achieve ergogenesis† by enhancing anaerobic metabolism during strenuous,
short-term exercise:
NOTE: The concept of a 'loading dose' followed by a 'maintenance dose' is generally
employed in dosing creatine.
Oral dosage:
Adults: Based on the available literature, the loading dose has ranged 20—25
g/day PO for the first 5—7 days, followed by maintenance doses of 5—10 g/day
PO. Dosing based on body weight may include 0.3 g creatine/kg/day PO for a period
of 5—6 days, followed by a maintenance dose of 0.03 g/kg/day PO.[2208 - Hultman
E, Soderland K, Timmons JA, et al. Muscle creatine loading in men. J Appl Physiol
1996;81:232?7.]
For improvement of muscular strength in patients with neuromuscular disease
including amyotrophic lateral sclerosis (ALS)† which is also known as Lou Gehrig's
disease:
Oral dosages:
Adults: Creatine was administered to patients with various neuromuscular diseases
(n=81) in a pilot study followed by a single-blinded study (n=21). Subjects
received creatine monohydrate 5—10 g/day PO for 5 days. At the conclusion of
the study, it was reported that subjects had a 10 to 15 percent improvement
in muscle strength.[2209]
For use in slowing progression of early Parkinson's disease†:
Oral dosage:
Adults: The benefit of creatine in slowing progression of Parkinson's disease
has not been established. However, a placebo-controlled Phase II futility trial
of subjects with early Parkinson's disease receiving 10 grams/day PO of a clinically
formulated creatine product [10021] found that the mean change in Unified Parkinson's
Disease Rating Scale (UPDRS) scores were not significantly greater than the
predetermined futility threshold based on data from the Deprenyl and Tocopherol
Antioxidant Therapy of Parkinsonism (DATATOP) trial. Due to the potential usefulness
of this compound, a large scale Phase III trial sponsored through the NIH National
Institute of Neurological Disorders and Stroke (NINDS) is underway to assess
the efficacy of creatine in slowing the progression of the disease. The study
will measure outcomes such as quality of life, ability to walk, cognitive function,
and ability to perform activities of daily living (ADLs).
Patients with hepatic impairment:
Specific guidelines for dosage adjustments in hepatic impairment are not available.
Patients with renal impairment:
Specific guidelines for dosage adjustments in renal impairment are not available.
†non-FDA approved indication
Interactions: Caffeine may interfere with the benefits gained from creatine supplementation. In a study evaluating possible benefits of using caffeine to enhance the effects of creatine, it was shown that caffeine (5 mg/kg/day PO as capsules) completely eliminated the ergogenic effects of creatine on muscle contraction. However, caffeine did not affect the ability of creatine to raise phosphocreatine concentrations in muscle.[2210 - Vandenberghe K, Gillis N, Van Leemputte M, et al. Caffeine counteracts the ergogenic action of muscle creatine loading. J Appl Physiol 1996;80:452?7.] Guarana [4679] and kola nut also contain a high percentage of caffeine, and natural products, foods, beverages (e.g., coffee, green tea [6531], other teas, or cola), or dietary supplements containing these natural sources of caffeine may also interact with creatine.
Creatine loading generates large quantities of the metabolite creatinine, a nitrogenous compound that must be eliminated by the kidney. In diabetics with already-compromised renal function, excessive concentrations of urea accelerates the decline in renal function. It is unclear what the effects of creatine loading are on the renal function of subjects with normal renal function, although at least one case report is noted of renal dysfunction after the addition of creatine in a 25-year old patient taking cyclosporine.[2211] It is difficult to attribute nephrotoxicity to creatine, however, since cyclosporine is a known nephrotoxic agent. Nevertheless, clinicians should caution patients stabilized on cyclosporine to avoid taking large doses of creatine.
The combination of ephedra, Ma huang and creatine in a previously healthy bodybuilder was reported to lead to ischemic stroke. The patient had been consuming roughly 60 mg of ephedra and 6000 mg of creatine monohydrate daily for 6 weeks. Other dietary supplements were also consumed, including caffeine (600 mg), taurine, inosine and coenzyme Q10. The patient's serum creatinine increased slightly, but was in the normal range. The authors concluded that creatine might potentiate the sympathomimetic effect of ephedra, Ma huang, although data are scarce.[3651 - Vahedi K, Doming V, Amerenco P et al. Ischaemic stroke in a sportsman who consumed ma huang extract and creatine monohydrate for body building. J Neurol Neurosurg Psychiatry 2000;68:112?3. ]
