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Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?
Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine: glycine amidinotransferase (AGAT), S-adenosyl-L-methionine: N-guanidinoacetate methyltransferase (GAMT) and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity. Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency. In addition, creatine supplementation displayed neuroprotective effects in several animal models of neurological disease, such as Huntingtons disease, Parkinsons disease or amyotrophic lateral sclerosis. All these findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphorylcreatine/creatine system and proper brain function. They also offer a starting-point for novel means of delaying neurodegenerative disease, and/or for strengthening memory function and intellectual capabilities. Finally, creatine biosynthesis has been postulated as a major effector of homocysteine concentration in the plasma, which has been identified as an independent graded risk factor for atherosclerotic disease. By decreasing homocysteine production, oral creatine supplementation may, thus, also lower the risk for developing, e.g., coronary heart disease or cerebrovascular disease. Although compelling, these results require further confirmation in clinical studies in humans, together with a thorough evaluation of the safety of oral creatine supplementation.
Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results.
Creatine supplementation in humans has been reported to enhance power and strength both in normal subjects and in patients with various neuromuscular diseases. The purpose of this study was to examine the effects of supplementation on exercise performance and maximal voluntary isometric muscular contraction (MVIC) in amyotrophic lateral sclerosis (ALS) patients. We report the results obtained in 28 patients with probable/definite ALS. In each patient we acquired the dynamometric measurement of MVIC in 10 muscle groups of upper and lower limbs and a measure of fatigue by means of a high-intensity intermittent protocol in elbow flexors and knee extensors muscles. All patients completed the protocols at the baseline and after supplementation of 20 g per day for seven days and after supplementation of 3 g per day for three and six months. MVIC increased after seven days of supplementation in 20 patients (70%) in knee extensors and in 15 (53%) of them also in elbow flexors. A statistically significant difference between pre and post-treatment mean values of MVIC was found both in elbow flexors (P<0.05) and knee extensors (p<0.04). The analysis of the slopes of fatigue test showed a statistically significant improvement after seven days of supplementation in 11 patients (39%) in elbow flexors and in nine patients (32%) also in knee extensors muscles. During the six month follow-up period all the examined parameters showed a linear progressive decline. In conclusion, our preliminary results have demonstrated that supplementation temporarily increases maximal isometric power in ALS patients so it may be of potential benefit in situations such as high intensity activity and it can be proposed as a symptomatic treatment.
J Neurol Sci 2001 Oct 15;191(1-2):139-44
DHEA treatment reduces fat accumulation and protects against insulin resistance in male rats.
The purpose of this study was to determine whether administration of dehydroepiandrosterone (DHEA) protects male rats against the accumulation of body fat and the development of insulin resistance with advancing age. We found that supplementation of the diet with 0.3% DHEA between the ages of five months and approximately 25 months resulted in a significantly lower final body weight (DHEA, 593 +/- 18 g vs control, 668 +/- 12 g, p < 0.02), despite no decrease in food intake. Lean body mass was unaffected by the DHEA, and the lower body weight was due to a approximately 25% reduction in body fat. The rate of glucose disposal during a euglycemic, hyperinsulinemic clamp was 30% higher in the DHEA group than in the sedentary controls due to a greater insulin responsiveness. The DHEA administration was as effective in reducing body fat content and maintaining insulin responsiveness as exercise in the form of voluntary wheel running. The DHEA had no significant effect on muscle GLUT4 content. A preliminary experiment provided evidence suggesting that muscle insulin signaling, as reflected in binding of phosphatidylinositol 3-kinase to the insulin receptor substrate-1, was enhanced in the DHEA-treated and wheel running groups as compared to controls. These results provide evidence that DHEA, like exercise, protects against excess fat accumulation and development of insulin resistance in rats.
J Gerontol A Biol Sci Med Sci 1998 Jan;53(1):B19-24
Herbal ephedra/caffeine for weight loss: a six month randomized safety and efficacy trial.
OBJECTIVE: To examine long-term safety and efficacy for weight loss of an herbal Ma Huang and Kola nut supplement (90/192 mg/day ephedrine alkaloids/caffeine). DESIGN: Six month randomized, double-blind placebo controlled trial. SUBJECTS: A total of 167 subjects (body mass index (BMI) 31.8+/-4.1 kg/m(2)) randomized to placebo (n=84) or herbal treatment (n=83) at two outpatient weight control research units. MEASUREMENTS: Primary outcome measurements were changes in blood pressure, heart function and body weight. Secondary variables included body composition and metabolic changes. RESULTS: By last observation carried forward analysis, herbal vs placebo treatment decreased body weight (-5.3+/-5.0 vs -2.6+/-3.2 kg, P<0.001), body fat (-4.3+/-3.3 vs -2.7+/-2.8 kg, P=0.020) and LDL-cholesterol (-8+/-20 vs 0+/-17 mg/dl, P=0.013), and increased HDL-cholesterol (+2.7+/-5.7 vs -0.3+/-6.7 mg/dl, P=0.004). Herbal treatment produced small changes in blood pressure variables (+3 to -5 mmHg, P</=0.05), and increased heart rate (4+/-9 vs -3+/-9 bpm, P<0.001), but cardiac arrhythmias were not increased (P>0.05). By self-report, dry mouth (P<0.01), heartburn (P<0.05), and insomnia (P<0.01) were increased and diarrhea decreased (P<0.05). Irritability, nausea, chest pain and palpitations did not differ, nor did numbers of subjects who withdrew. CONCLUSIONS: In this six month placebo-controlled trial, herbal ephedra/caffeine (90/192 mg/day) promoted body weight and body fat reduction and improved blood lipids without significant adverse events.
Int J Obes Relat Metab Disord 2002 May;26(5):593-604
Nutrition and dietary supplements.
Quality and number of subjects in blinded controlled clinical trials about the nutrition and dietary supplements discussed here is variable. Glucosamine sulfate and chondroitin sulfate have sufficient controlled trials to warrant their use in osteoarthritis, having less side effects than currently used nonsteroidal anti-inflammatory drugs, and are the only treatment shown to prevent progression of the disease. Dietary supplements of ephedrine plus caffeine for weight loss (weight loss being the current first line recommendation of physicians for osteoporosis) show some promise, but are not sufficient in number of study subjects. Phenylpropanolamine is proven successful in weight loss. Both ephedrine and phenylpropanolamine have resulted in deaths and hence are worrisome as an over-the-counter dietary supplement. Other commonly used weight loss supplements like Cola acuminata, dwarf elder, yohimbine and garcinia camborgia are either lacking controlled clinical trials, or in the case of the last two supplements, have clinical trials showing lack of effectiveness (although garcinia has been successful in trials as part of a mixture with other substances, it is unclear if it was a necessary part of the mixture). Safety of these weight loss supplements is unknown. Chromium as a body building supplement for athletes appears to have no efficacy. Creatine may help more in weight lifting than sprinting, but insufficient study subjects and safety information make more studies necessary. Carbohydrate loading is used commonly before endurance competitions, but may be underused as it may be beneficial for other sport performances. Supplements for muscle injury or cramps have had too few studies to determine efficacy. Although proper rehydration with fluids and electrolytes is necessary, a paucity of actual studies to maximize prophylactic treatment for exercise induced cramping still exists. Nutritional supplements for cardiovascular disorders are generally geared to prevention. The United States Department of Agriculture has good recommendations to prevent atherosclerosis; a stricter version by Ornish was shown to reverse coronary heart disease, and the low meat, high fruit, and vegetable DASH diet has been found to decrease hypertension. The epidemiologic studies of hyperhomocysteinemia are impressive enough to give folic acid (or vitamin B6 or B12) supplements to those with elevated homocysteine levels and test patients who have a history of atherosclerotic disease, but no controlled clinical trials have been completed. Soluble fiber has several positive studies in reduction of cholesterol levels and generally is accepted. The data on vitamin E are the most confusing. This vitamin was not helpful in cerebrovascular prevention in China and not helpful at relatively small doses (50 mg) in the United States or Finland against major coronary events. Levels of 400 mg appeared to decrease cardiovascular disease in the United States in studies based on reports by patients and in one large clinical trial. Vitamin E also was successful in prevention of restenosis after PTCA in one clinical trial. Both of these clinical trials need to be repeated in other developed country populations. Some nutritional and dietary supplements are justifiably useful at this point in time. Several meet the criteria of a late Phase 3 FDA clinical trial (where it would be released for public use), but many dietary supplements have insufficient numbers of studies. Some deaths also have occurred with some supplements. If these supplements were required to undergo clinical trials necessary for a new drug by the FDA, they would not be released yet to the public. Several nontoxic supplements appear promising, though need further study. Because they have essentially no toxicity (such as folic acid with B12, soluble fiber and vitamin E) and may have efficacy, some of these supplementations may be useful now, without randomized clinical trials.
Phys Med Rehabil Clin N Am 1999 Aug;10(3):673-703
Ephedrine, caffeine and aspirin: safety and efficacy for treatment of human obesity.
The safety and efficacy of a mixture of ephedrine (75 to 150mg), caffeine (150mg) and aspirin (330mg), in divided premeal doses, were investigated in 24 obese humans (mean BMI 37.0) in a randomized double blind placebo-controlled trial. Energy intake was not restricted. Overall weight loss over eight weeks was 2.2kg for ECA vs. 0.7 kg for placebo (p < 0.05). Eight of 13 placebo subjects returned five months later and received ECA in an unblinded crossover. After eight weeks, mean weight loss with ECA (ephedrine, caffeine and aspirin) was 3.2 kg vs 1.3 kg for placebo (p = 0.036). Six subjects continued on ECA for seven to 26 months. After five months on ECA, average weight loss in five of these was 5.2 kg compared to 0.03 kg gained during five months between studies with no intervention (p = 0.03). The sixth subject lost 66 kg over 13 months by self-imposed caloric restriction. In all studies, no significant changes in heart rate, blood pressure, blood glucose, insulin, and cholesterol levels, and no differences in the frequency of side effects were found. ECA in these doses is thus well tolerated in otherwise healthy obese subjects, and supports modest, sustained weight loss even without prescribed caloric restriction, and may be more effective in conjunction with restriction of energy intake.
Int J Obes Relat Metab Disord 1993 Feb;17 Suppl 1:S73-8
Detection and determination of anabolic steroids in nutritional supplements.
A method is described for the determination of anabolic steroids including testosterone, 19-nor-4-androstene-3,17-dione, 4-androstene-3,17-dione and nandrolone in food supplements. Initial clean-up is done by HPLC followed by determination with GC/MS. A contaminated food supplement was analyzed and appeared to contain 19-nor-4-androstene-3,17-dione and 4-androstene-3,17-dione. One capsule of this nutritional supplement was ingested by five male volunteers. Urine samples were collected and analyzed by GC/MS and GC/MS-MS. Neither the ratio testosterone/epitestosterone, nor the ratio androstenedione/epitestosterone increased significantly. Concentrations above 2 ng/ml for norandrosterone, the major metabolite of nandrolone, were detected until 48-144 h after ingestion of the food supplement.
J Pharm Biomed Anal 2001 Jul;25(5-6):843-52
Effect of oral androstenedione on serum testosterone and adaptations to resistance training in young men: a randomized controlled trial.
CONTEXT: Androstenedione, a precursor to testosterone, is marketed to increase blood testosterone concentrations as a natural alternative to anabolic steroid use. However, whether androstenedione actually increases blood testosterone levels or produces anabolic androgenic effects is not known. OBJECTIVES: To determine if short- and long-term oral androstenedione supplementation in men increases serum testosterone levels and skeletal muscle fiber size and strength and to examine its effect on blood lipids and markers of liver function. DESIGN AND SETTING: Eight-week randomized controlled trial conducted between February and June 1998. PARTICIPANTS: Thirty healthy, normotestosterogenic men (aged 19 to 29 years) not taking any nutritional supplements or androgenic-anabolic steroids or engaged in resistance training. INTERVENTIONS: Twenty subjects performed eight weeks of whole-body resistance training. During weeks 1, 2, 4, 5, 7 and 8, the men were randomized to either androstenedione, 300 mg/d (n = 10), or placebo (n = 10). The effect of a single 100-mg androstenedione dose on serum testosterone and estrogen concentrations was determined in 10 men. MAIN OUTCOME MEASURES: Changes in serum testosterone and estrogen concentrations, muscle strength, muscle fiber cross-sectional area, body composition, blood lipids, and liver transaminase activities based on assessments before and after short- and long-term androstenedione administration. RESULTS: Serum free and total testosterone concentrations were not affected by short- or long-term androstenedione administration. Serum estradiol concentration (mean [SEM]) was higher (P<.05) in the androstenedione group after two (310  pmol/L), five (300  pmol/L) and eight (280  pmol/L) weeks compared with presupplementation values (220  pmol/L). The serum estrone concentration was significantly higher (P<.05) after two (153  pmol/L) and five (142  pmol/L) weeks of androstenedione supplementation compared with baseline (106  pmol/L). Knee extension strength increased significantly (P<.05) and similarly in the placebo (770  N vs 1095  N) and androstenedione (717  N vs 1024  N) groups. The increase of the mean cross-sectional area of type 2 muscle fibers was also similar in androstenedione (4703  vs 5307  mm2; P<.05) and placebo (5271  vs 5728  mm2; P<.05) groups. The significant (P<.05) increases in lean body mass and decreases in fat mass were also not different in the androstenedione and placebo groups. In the androstenedione group, the serum high-density lipoprotein cholesterol concentration was reduced after two weeks (1.09 [0.08] mmol/L [42 (3) mg/dL] vs 0.96 [0.08] mmol/L [37 (3) mg/dL]; P<.05) and remained low after five and eight weeks of training and supplementation. CONCLUSIONS: Androstenedione supplementation does not increase serum testosterone concentrations or enhance skeletal muscle adaptations to resistance training in normotestosterogenic young men and may result in adverse health consequences.
JAMA 1999 Jun 2;281(21):2020-8
Androgen use by athletes: a reevaluation of the health risks.
It has been estimated that one to three million male and female athletes in the United States have used androgens. Androgen use has been associated with liver dysfunction, altered blood lipids, infertility, musculotendinous injury and psychological abnormalities. Although androgens have been available to athletes for more than 50 years, there is little evidence to show that their use will cause any long-term detriment. Furthermore, the use of moderate doses of androgens results in side effects that are largely benign and reversible. It is our contention that the incidence of serious health problems associated with the use of androgens by athletes has been overstated.
Can J Appl Physiol 1996 Dec;21(6):421-40