Symposium: conference on the science and policy of performance-enhancing products

The Conference on the Science and Policy of Performance-Enhancing Products, held January 8–9, 2002, examined the available scientific evidence that addresses the safety and efficacy of performance-enhancing dietary supplement products. The conference also provided an initial step in broadening a partnership to identify gaps in knowledge, frame research questions, and address major societal challenges in the responsible use of sports nutrition products. The conference was organized by the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) and the dietary supplement trade association Council for Responsible Nutrition (CRN), with additional support from the National Institute of Child Health and Human Development, the NIH Office of Research on Women’s Health and Office of Behavioral and Social Science Research, Phoenix Laboratories, Rexall Sundown, and EAS. As noted in the keynote address by the Olympic gold medal swimmer Donna de Varona, sports supplements are widely used by all types of athletes: male and female, young and old, professional and amateur. Hydration drinks, energy bars, protein powders, and multivitamins are used safely by millions of people. Other sports supplements, however, contain ingredients such as steroid hormone precursors and stimulants, which raise concern. The conference focused on the latter group because there is much confusion about which products are safe, effective, legal, and ethical. Conflicting rules and practices fuel the confusion surrounding performance-enhancing products. For example, androstenedione is allowed in major league baseball, but its use is prohibited by the International Olympic Committee (IOC), National Collegiate Athletic Association (NCAA), and most sports federations. The IOC and NCAA have banned the stimulant ephedrine for many years, but the National Football League just recently prohibited its use and was among the first professional sports league to do so. REGULATION OF PERFORMANCE-ENHANCING PRODUCTS On a federal level, the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC) regulate dietary supplements. Christine Taylor, Ph.D., director of the FDA Office of Nutritional Products, Labeling, and Dietary Supplements, explained that the FDA is authorized to regulate dietary supplements through the Food, Drug and Cosmetic Act and the 1994 Dietary Supplement Health and Education Act (DSHEA). A product’s regulatory status, as a food, drug, or dietary supplement, depends on its intended use. For example, caffeine is considered a food ingredient in coffee and soft drinks, a dietary supplement if there is a claim for alertness, and a drug ingredient in over-the-counter (OTC) migraine products. Consumer safety is protected through regulations for grandfathering, notification procedures, and adulteration. Grandfathered ingredients were those on the market before October 1994 (when DSHEA was signed into law), and they are presumed safe. Postmarketing surveillance tracks their safety. For new ingredients, those introduced to the market after October 1994, the manufacturer must file notification with FDA and submit data supporting the safety of the new ingredient. A dietary supplement is considered adulterated and subject to removal from the market if it presents a significant or unreasonable risk of illness or injury when used according to label directions. Laura Sullivan, J.D., from the FTC Bureau of Consumer Protections explained that section 5 of the FTC Act prohibits deceptive and unfair acts and practices in commerce. Claims made in advertising, express or implied, must be truthful, not misleading, and substantiated by competent and reliable scientific evidence. The studies must relate to the product, and claims must reflect the strength of the science. Consumer anecdotes are never a substitute for scientific evidence. Advertising must also include any material information that qualifies a claim, such as significant side effects or safety risks, conditions of use, or limits on efficacy. In regards to performance-enhancing products, the FTC has focused its activities on unproven safety claims in advertising. PATTERNS OF USE Several speakers addressed the pattern of use of performance-enhancing products, which can vary by age, gender, level of athletic training, and type of sport. Harrison Pope, M.D., chief of the Biological Psychiatry Laboratory at McLean Hospital in Massachusetts, reported results from a study of performance-enhancing supplement use in which a single-page questionnaire was distributed to 511 clients as they entered five Boston-area gyms (14). Among 334 male respondents, more than half (61%) used some type of protein product, 47% used creatine, and 4% consumed androstenedione for 6 months or longer. Protein and ephedrine products were the most frequently consumed by women, 34% and 13%, respectively. Creatine was used by 7% of women, whereas androstenedione supplementation was reported by 3% of women, but none used it longer than 6 months. Extrapolated to a national level, rough estimates indicate that 4.3 million men and 2.7 million women use protein products, 3.3 million men and 0.5 million women use creatine, 1.8 million men and 1 million women use ephedrine supplements, and 1.3 million men and 240,000 women use products from the androstenedione family. Dr. Pope questioned the long-term effects of supplements such as ephedrine, androstenedione, and creatine, which are used continuously for years by certain subpopulations (e.g., body builders). Studies by Harris Lieberman, Ph.D., U.S. Army Research Institute of Environmental Medicine, with elite military populations demonstrated that use varies by age or maturity. Dr. Lieberman assessed dietary supplement use among 768 Army Rangers, 152 members of the Special Forces, and 315 officers at the Army War College. Ranger units consist of young enlisted volunteers (aged 23.6 ± 4.3 yr), and the participants’ average time in the Army was 2 yr. The Special Forces are more mature than Rangers (aged 31.3 ± 6.1 yr), and the participants had about 10 yr military experience. Officers at the Army War College represent the middle to upper management level and are typically 40 yr of age or older. All three military groups reported high levels of supplement use (65–80%), but the type of supplements consumed varied by group. Rangers and Special Forces reported using supplements for muscle or performance enhancement or to increase energy. Among the Rangers, the most frequently used products were carbohydrate-electrolyte drinks (70%), multivitamins (28%), and creatine (23%). Similarly, the most popular supplements among Special Forces were sports drinks (36%), multivitamins (32%), and creatine and protein powders (each 16%). War College officers, however, tended to take supplements for general health. Vitamins and minerals were the most frequently consumed products, for example, 53% of female officers and 42% of male officers used multivitamins. Considering the popular use of dietary supplements among these elite military populations, Dr. Lieberman recommended research to assess the benefits and risks of these products. Determining whether supplementation is physiologically required or beneficial among soldiers consuming calorie-dense foods is of particular interest. Every 4 yr, the NCAA surveys college-student athletes to evaluate the use of drugs, nutritional supplements, cigarettes, and alcohol. Gary Green, M.D., chair of the NCAA Subcommittee on Drug Testing/Drug Evaluation, reported the 2001 survey results (11). Nutritional supplements were used by 29% of respondents in the previous 12 months. Creatine was the most popular supplement (26%), followed by amino acids (10%), androstenedione, chromium, and ephedra (each about 4%). Improving athletic performance and physical appearance were the primary reasons cited for the use of nutritional supplements (27%), followed by weight loss–weight gain and general health (20%), preventing injury (9%), and recovery from illness or injury (6%). Supplement use typically began before college: 57% of respondents began use in high school and 6% in junior high or earlier. Ann Grandjean, Ed.D., executive director of the Center for Human Nutrition in Omaha, described the use of supplements by elite athletes (18a). Data were collected from 592 American athletes who participated in the 2000 Olympic summer games. Preventing illness is the most frequent reason stated by Olympic athletes who use supplements. Getting sick before Olympic competition is a real threat to ending careers, hopes, and dreams. It follows that multivitamin–multimineral supplements were the most commonly consumed product. Further analysis of the data is ongoing. Dr. Grandjean noted the need to research the benefits of sports supplements among fitness center clientele and their reasons for use. STIMULANT AND THERMOGENIC INGREDIENTS Ira Jacobs, Dr. Med. Sc., chief scientist for the Defense and Civil Institute of Environmental Medicine in Toronto, described investigations that assessed the effects of pharmaceutical grade anhydrous caffeine and ephedrine hydrochloride on physical performance across a range of exercise intensities among military personnel. A randomized controlled trial evaluating performance on a cycle ergometer test (2) showed that supplementation with caffeine (5 mg·kg−1 bodyweight) or ephedrine (1 mg·kg−1 bodyweight) extended time to exhaustion by approximately 1.5 min compared with placebo. A combination of caffeine and ephedrine, however, extended time to exhaustion by 5 min, a magnitude of improvement normally achieved after several weeks if not months of physical training. The effect of caffeine and ephedrine on muscle endurance during weight lifting exercise also was assessed. Thirteen males each ingested the following treatments: 4 mg·kg−1 caffeine, 0.8 mg·kg−1 ephedrine, caffeine plus ephedrine, or placebo. The mean number of repetitions for leg press was significantly higher after using caffeine plus ephedrine (19.8) or ephedrine alone (17.4) compared with placebo (14.0). It would take several weeks of training to accomplish this magnitude of improvement without supplementation. Because ephedrine and caffeine elevate metabolic heat production, there is concern that this combination could impair body temperature regulation during exercise in the heat. To explore this possibility, 10 subjects exercised at 40°C and 30% relative humidity for 3 h or until rectal temperature reached 39.3°C or heart rate was 95% of maximal heart rate for 3 min (1). The subjects were supplemented with 5 mg·kg−1 caffeine and 1 mg·kg−1 ephedrine or placebo. Tolerance time and rectal temperature were not affected. The mean skin temperature was lower with supplementation, which explains why rectal temperature did not increase. The subjects were likely to evaporate more sweat to balance the extra metabolic heat production. Although heat tolerance was not impaired in this experiment, the results suggest that predisposition to heat illness may be a concern if exertion occurs in an environment where the ability to remove body heat is impaired (e.g., when protective clothing is worn). Caffeine and ephedrine appear to be effective acute-use ergogenic aids that may be of benefit for certain types of military operations such as those requiring a rapid increased physical work capacity. Dr. Jacobs, however, emphasized the use of pharmaceutical grade caffeine and ephedrine in the studies, and that its bioequivalence to nutritional supplement ingredients should be examined. He also recommended investigation of the health risks and optimal dosing of ephedrine. Luke Bucci, Ph.D., from Weider Nutritional International in Salt Lake City, reviewed studies using other stimulant ingredients such as synephrine, green tea, guarana, and quercetin. Synephrine, from the plant Citrus aurantium, is a direct-acting alpha1-adrenergic agonist and a weak beta-adrenergic agonist. It causes no significant increase in heart rate, blood pressure, or respiratory exchange ratio and is generally recognized as safe (GRAS) based on its use as bitter citrus flavoring. A 20-subject study comparing the effect of a synephrine-caffeine combination with ephedrine-caffeine on resting metabolic rate (RMR) showed that the rate increased significantly with both combinations, although to a greater extent with ephedrine and caffeine. Compared with placebo, both combinations increased body core temperature equivalently, indicating its thermogenic action. The ephedrine-caffeine combination increased heart rate by 12%, whereas the synephrine effect was similar to placebo. Ephedrine-caffeine increased arterial blood pressure by 6–8 mm Hg, but the synephrine-caffeine combination had a smaller effect (3–5 mm Hg). Green tea contains about 250 mg of caffeine per serving. The (−)-epigallocatechin-3-gallate (EGCG) polyphenolic component in green tea works synergistically with caffeine enhancing thermogenesis (7). Green tea also works synergistically with ephedrine by inhibiting the action of phosphodiesterase at the adenosine receptor, preventing the breakdown of epinephrine and norepinephrine, and thus inhibiting the normal feedback mechanism. Guarana is another herbal source of caffeine, containing about 50 mg per serving, and also inhibits phosphodiesterase. Quercetin is a flavonoid antioxidant commonly found in foods such as onions and apples. In vitro evidence suggests that it inhibits prostaglandin A1 for 3–6 h. Potentially, quercetin could inhibit the effect of prostaglandins on the feedback inhibition of epinephrine and norepinephrine. Yohimbe, from the plant Pausinystalia johimbe, contains yohimbine, an indolalkylamine. Yohimbine is an alpha2-adrenergic receptor antagonist and may also inhibit feedback regulation of epinephrine and norepinephrine. Dr. Bucci noted that little is known about stimulant ingredients, particularly those that might serve as substitutes for ephedrine. He encouraged research to characterize alternative thermogenic agents. HORMONE PRODUCTS AND ANALYTICAL CHALLENGES Greg Brown, M.S., from the Department of Health and Human Performance at Iowa State University, reviewed three studies that examined androstenedione’s purported anabolic effects (15,18,23). Each study demonstrated that daily androstenedione supplementation (100 mg, 1 or 3 times·d−1) did not increase serum total or free testosterone and had no effect on muscle strength, muscle fiber area, muscle protein synthesis, or lean body mass. Mr. Brown suggested that the effect of larger single androstenedione doses (e.g., 300 mg) and alternate modes of delivery (e.g., sublingual) are important areas to explore. King et al. (4,15) observed significant negative effects in their studies of androstenedione supplementation. Their research showed that androstenedione caused a significant decrease in high-density lipoprotein (HDL) cholesterol, and they noted that lowered HDL-cholesterol could increase cardiovascular disease risk by 10–15%. In addition, they found significant increases in serum esterone and estradiol concentrations. Elevated estrogen levels have been associated with pancreatic cancer and gynecomastia. In addition, Brown et al. (4) found that the serum dihydrotestosterone (DHT) response to androstenedione supplementation was related to age. Mr. Brown recommended further research to examine age-specific effects. Mr. Brown also noted that androstenedione is combined with herbal in herbal (e.g., purported to inhibit related to or estrogen are to the response to A study of these however, found that the herbal did not the of inhibit production, or increase serum testosterone Ph.D., of at the of Health Science Center in explained that is the most steroid in It is widely distributed in the with the found in the and its are to androstenedione which is to or as the to about of the in as much as of in women, and all in women levels with age. age to levels may be of which about age yr. A trial the effect of mg for in 10 young men (aged levels but there was no significant increase in free testosterone or The group a increase in lean and a decrease in mass. The decrease in the would an energy or an increase in energy a similar the effect of was examined among with no in body The effect of on training in young men was also men (aged were randomized to daily placebo or mg levels increased but no in total or free testosterone or the estrogen were was a for the group to increase lean body and decrease but an 50 subjects would be to significant in body Dr. several research On a level, of action is not and age-specific to supplementation have not been The effects of supplementation in and athletes and for female athletes with are also research Dr. Green addressed the of and described a study that examined whether 12 of supplements in the to of to a dietary supplement is considered if the label to the and strength of the product’s was by and was The to ingredients (e.g., androstenedione, ingredients that were not or had ingredient higher or lower than on the who examined products the reported similar AND Creatine is a made in the body from amino acids and can also be in the The primary for creatine is related to energy It is an energy and adenosine during high Ph.D., from the Department at the of reported that the of studies ergogenic effect on performance during high types of it a improvement of Several reasons may why some studies do not a effect from creatine supplementation, such as muscle creatine in the normal and or performance For example, it may not be to a improvement with a in a test on the Dr. stated that there is no scientific evidence that creatine causes side effects in claims of He also noted the research on beneficial effect in disease such as and which showed results in Several studies have examined the effect of on training and Ph.D., in the Science Department at Iowa State University, the The studies showed that muscle increased with supplementation. is associated with in blood pressure mm a decrease in lipoprotein cholesterol, no in cholesterol, no in blood and no negative effects on however, are based on of supplementation, and data on long-term use are Ph.D., at the College of and Health in noted the of the effects of performance-enhancing ingredients in may an or For example, the ephedrine, and each with and a of norepinephrine. Compared with a each of these food is combined with such it the of these in food Dr. recommended that ingredients should be in use The of such is by a study of and which both have would have that the combination a or CHALLENGES M.D., of the Center for in noted that the sports has to the and sports The use of supplements among athletes a number of questions, evidence of need and benefit and the for an of research Ph.D., director of the National Center for Research in Medicine, addressed the of dietary supplement products that athletes can use without of an IOC the Center a study of a and product, which contains yr, ingested the for were collected following IOC The were for approximately banned the of stimulants, and anabolic and agents. All subjects were found to have levels of all the did not contain any IOC banned supporting this level of could use the study results to their as a safe and sports several the dietary of athletes and additional research was explained Ph.D., at the of include type of and and recovery of training, exercise environment (e.g., temperature and age, and Several studies support the beneficial effect of supplementation, of source protein or among For example, a study with elite female showed that a or supplement performance as by the 2000 ergometer of supplementation is another important et al. showed that supplementation was most effective when consumed h after In a study of men who participated in a et al. found that a protein supplement had the effect on muscle strength and when consumed after a weight training is information on use to and In the Center for in and Health was through federal to an on use. Ph.D., and of and director of research at Research Center in explained this The of the age or level of The from the following based on the and rules of and based on the rules of of performance-enhancing health side safety for and and of the and if it causes a The not use it the and negative effects of a to an Dr. emphasized the need for additional information on the benefits and safety of sports supplements. AND Among its is to and dietary supplement research at the conference be of an research and support of to this Each of the conference speakers for and additional The following research optimal dosing and health risks of performance-enhancing ingredients, particularly reasons for with drugs, or other and age-specific to hormone long-term health effects of sports and to supplement of and optimal of of Research conference a and a are available from the following and The to the members of the and speakers for their to this The and reported in this represent those of the participants and not those of the National Institutes of for Dr. Office of Dietary Supplements, National Institutes of

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