Docket Management
Docket: 95N-0304 - Dietary Supplements Containing Ephedrine Alkaloids
Comment Number: EC -26

Accepted - Volume 298

Comment Record
Commentor Dr. Richard Kreider Date/Time 2003-03-04 13:26:23
Organization CENPHR, Baylor University
Category Academic

Comments for FDA General
Questions
1. General Comments We thank the FDA for the opportunity to provide public comment regarding Docket: 95N-0304 - Dietary Supplements Containing Ephedrine Alkaloids. Our lab has a long history of conducting research on the role of exercise and nutrition on health, performance, disease and rehabilitation. Much of this work involves assessing the safety and efficacy of nutritional supplements. In so doing, we have received national and international distinction as a leading lab in this area. As such, we feel it is important to provide our input on the proposed regulations by the FDA to further regulate the labeling and claims made about dietary supplements containing ephedra alkaloids. It has been our position that claims and public policy regarding dietary supplements should be based on a thorough analysis of the scientific literature. Before I begin this analysis, it is important to understand our general view regarding the use of dietary supplements in the general population and among athletes. 1. It is our view that the best way to enhance performance and/or improve body composition profiles is through prudent exercise and dietary modification. Most people can reach their fitness, health, and/or body composition goals through proper diet and exercise. However, we also know that that some nutrients have been shown in clinical studies to enhance exercise and/or training adaptations. Further, that in obese populations, exercise and diet interventions alone may not be enough to promote as much weight loss as needed to reduce the medical risk related to obesity. Therefore, we understand that there may be medical interest in determining additive and/or alternative means of helping people gain and/or lose weight. 2. It is our view that recommendations about exercise, training, supervision of athletes, and dietary supplementation should be based on science not speculation or political pressure. A decision whether or not to use nutritional supplements should be based on analysis of available clinical studies that have evaluated the safety and efficacy of the nutrient as well as whether use of a supplement is legal or not in a particular sport. It is our view that athletes should only consider use of supplements that have been shown to be effective and safe in clinical trials and that are legal for use in their sport. Individuals that are not regulated by sport governing bodies should also only consider use of supplements that have been shown to be safe and effective. 3. We recommend that anyone starting an exercise program, diet, and/or considering use of a dietary supplement consult with a knowledgeable physician that is familiar with the scientific literature in order to determine if any underlying medical condition may be contraindicated for the exercise, diet, and/or a supplementation program. We also recommend that athletes report all nutritional supplements they are taking or plan to take to their athletic trainer so they may be counseled as to the safety, efficacy and legality of taking a nutritional supplement. 4. Most studies conducted on nutritional supplements in athletes and medical populations show little to no ergogenic value. However, research over the last 20 years has also revealed that some nutrients may play a role in reducing risk to certain diseases. Additionally, that dietary modification, timing of food intake, and a limited number of nutritional supplements may provide some value to athletes, the general population, and various diseased populations. 5. Most nutritional supplements available for athletes provide a convenient way to add carbohydrate and/or protein to their diet (e.g., energy bars, carbohydrate/protein powders/drinks/gels, sports drinks, etc). It is our view that these types of energy related supplements may be helpful for athletes as pre-workout snacks, to refuel and maintain hydration during exercise, and/or as post-workout supplements. Additionally, that they may provide a nutrient dense food choice for people trying to manage their weight. 6. Our goal is to help educated individuals about the safety and efficacy of nutritional supplements so they can make an informed decision about whether or not to use them. Further, to serve as a resource to media and government agencies regarding the science behind various exercise and nutritional strategies. While we do not endorse the use of specific dietary supplements, we feel that people should have the right to take dietary supplements as long as they are aware of the potential risks and benefits and the supplement does not pose a significantly greater health risk than other over-the-counter medications and common lifestyle practices. 7. We encourage nutritional supplement companies to conduct research with appropriate research design on their products and to base claims about their products on scientific findings. Further, given the public interest in nutritional supplementation, we encourage the Federal government to increase funding to examine the safety and efficacy of nutrition products. Products found in research to be unsafe and/or ineffective should be banned from sale and/or include sufficient warning labels to properly inform the public about the associated risk of taking nutritional supplements. We feel, however, it is important to place risks of taking nutritional supplements, if any, in proper perspective of many common products that are available on the market and widely used by Americans. Comments Regarding Proposed FDA Regulations We understand that the issue of availability of dietary supplements containing ephedra alkaloids is controversial. The easy and politically correct position would simply be to concur with the FDA’s proposed warning and limitations on marketing claims regarding dietary supplements containing ephedra. Nevertheless, we feel it is important for the FDA to consider the following points regarding the proposed FDA regulations regarding use of dietary supplements containing ephedra. 1. As the Rand report concurs, numerous studies indicate that dietary supplementation of ephedrine/caffeine or herbal ephedra can safely promote weight loss in healthy but overweight populations [1-21]. Ephedrine/caffeine supplementation typically allows for about a 1-2 pound per month greater weight loss than individuals taking placebos with or without exercise and dietary modification. The Rand report indicated that studies have only been conducted for up to 6 months. However, it should be noted that a recent study was presented at the IX International Congress on Obesity in Sao Paolo, Brazil found that supplementation of ephedrine/caffeine (20 mg/day of ephedrine and 200 mg/day of caffeine) for 11 months after a 4-week dietary weight loss program allowed subjects to maintain weight loss while subjects taking a placebo regained the weight [22]. No side effects were reported. Generally, when side effects were reported in these studies, they have been minor and consistent with the incidence of side effects reported in placebo groups. 2. The primary mechanisms of weight loss appears to be due to synergistic effect of ephedrine/caffeine on modestly increasing resting energy expenditure (typically 5 – 10 kcal/hour or 120 – 240 kcals/day), an increase in fat metabolism, and suppression of appetite. While this increased energy expenditure may help promote a slow loss in body fat (i.e., 1-2 pounds per month), such an increase in caloric expenditure in response to ephedrine/caffeine supplementation would have minimal, if any, measurable effects on core temperature. In comparison, exercise typically increases energy expenditure by 600 – 1,200 kcals/hour depending on intensity. It is our view that claims suggesting that ephedrine/caffeine supplementation significantly increases thermal load is not supported by available literature. 3. Studies have shown that ephedrine or ephedra supplementation either mildly increases heart rate (an average of less than 5 beats/min) or blood pressure (an average less than 4 mmHg) [18] or has no impact on resting cardiovascular dynamics [20]. There is no evidence from clinical studies that ephedrine supplementation increases peak heart rate, peak blood pressure, or increases the prevalence of cardiac arrhythmias in comparison to subjects taking placebos [18]. Further, there is no evidence that short-term ephedra supplementation causes a marked increase in resting heart rate, blood pressure, or cardiovascular function as is commonly describe in media reports [20]. The changes in heart rate and blood pressure are small in consideration that cardiac reserve is typically 100 – 140 beats/min above resting heart rate and systolic reserve is typically 60 – 80 mmHg above resting during maximal exercise in normal individuals. 4. Studies comparing the safety of ephedrine/caffeine supplementation to other weight loss medications and/or over-the-counter drugs have revealed similar or greater efficacy and/or safety [23-25]. It is our view that any warnings about ephedra must be placed in proper context to the risks of common behaviors like taking aspirin, ibuprofen, other weight loss medications, and/or consuming alcohol and smoking cigarettes. Further, that if the FDA places warning labels on dietary supplements containing ephedra alkaloids, it should also do so on over-the-counter medications that contain ephedrine and common products that have been reported to have similar or greater risk profiles (e.g., aspirin, ibuprofen, alcohol, etc). 5. Concerns over the safety of ephedra containing supplements have been voiced for a number of years. The basis of this concern has primarily come from case reports submitted to the FDA’s Adverse Event Monitoring System (AEMS). The AEMS was a voluntary system of reporting perceived side effects related to taking nutritional supplements. Approximately 1,500 reports to the AEMS since 1993 have indicated that individuals who were taking ephedra containing supplements (with or without other supplements) experienced some type of symptom, side effect, and/or adverse event including approximately 88 suspected deaths. In context, according to the Nutrition Business Journal, approximately 12 million people purchased dietary supplements containing ephedra alkaloids last year alone with an estimated 3 billion doses taken. Based on these types of reports, the FDA issued a warning about ingesting ephedra containing dietary supplements in 1995 and attempted to ban sale of ephedra containing supplements in 1997. The attempt to ban sale of ephedra supplements was rescinded by Congress who found that there was insufficient data to support FDA claims that ephedra was not a safe nutritional supplement. 6. A paper that was published in the New England Journal of Medicine in the fall of 2000 renewed warnings about ephedra supplements [26]. This study evaluated 141 cases reported to the AEMS from 1997-1999 that involved ephedra supplements. The researchers reported that it was their view that 31% of cases were considered definitely or probably related to the use of supplements containing ephedra alkaloids and 31 percent were deemed possibly related. Of these, 47 percent involved cardiovascular symptoms and 18 percent involved the central nervous system. Hypertension was the single most frequent adverse effect (17 reports), followed by palpitations and/or tachycardia (13); stroke (10); and seizures (7). According to these reviewers, 10 events resulted in death and 13 events produced permanent disability. In some instances, excessive amounts of ephedra or ephedrine were apparently consumed (i.e., more than the apparent upper limit of safety of 90 mg/d) often with other supplements and/or medications. The authors concluded that use of dietary supplements that contain ephedra alkaloids may pose a health risk to some persons. Critics of this report suggested that since findings were based on incomplete, unsubstantiated, and/or uncorroborated reports to the FDA’s Special Nutritional AEMS, it was unclear whether any of these purported adverse events were or were not related to ephedra supplementation. It should be noted that the FDA removed the SNAEMS effective August 29, 2002 stating the following: “Data from the Special Nutritional Adverse Event Monitoring System website for dietary supplements has not been added to or updated since 1999, and the website has now been removed. The information previously available on dietary supplement adverse event reports on this website was very limited and was provided in a manner that made it difficult for users to appropriately interpret the adverse events.” Since the publication of this report, a number of case reports and/or review papers have questioned the safety of ephedra supplementation [19,27-41]. We concur with the findings in the Rand report that although these reports and concerns deserve careful well-controlled clinical study to examine a possible relationship to ephedra supplementation, these reports are too incomplete to make any definitive clinical judgment as to the safety of ephedra supplementation. In this regard, if the FDA considers reports to their Special Nutritional AEMS as “difficult for users to appropriately interpret the adverse events” then there is little merit in analyzing these reports in an attempt to make any conclusions about the safety of ephedra supplementation from these reports. The same holds true for reports to the U.S. Poison Control Center that have been recently described in the literature [27]. There is simply no way of verifying whether the adverse events reported were related in any way to ephedra supplementation or not. Further, I am aware of several letters to the editor that have been submitted questioning the methods and conclusions of recent studies described as by the FDA as “new medical information” justifying in part actions against ephedra. When reviewing these reports, it is important to note that the significant media attention regarding the possible side effects of ephedra supplements may have influenced the reporting of side effects and/or association of non-related side effects to ephedra. In our view, the best evidence as to the possible side effects of ephedra supplementation come from available clinical studies that compared reported side effects in ephedrine/ephedra users to those on placebos. The most thorough study conducted to date on the safety of herbal ephedra and caffeine supplements was an NIH funded 6-month study reported last year by Boozer and colleagues [18] which concluded that “herbal ephedra/caffeine supplementation, when used as directed by healthy overweight men and women in combination with healthy diet and exercise habits, may be beneficial for weight reduction without significantly increased risk of adverse events.” This study involved a comprehensive analysis of side effects including 24-hour Holter monitoring for arrhythmias, ambulatory blood pressure readings, and comprehensive medical examinations to assess side effects. At worst, the researchers reported that a greater frequency of participant dropouts occurred in subjects taking herbal ephedra/caffeine supplements. This study did not support contentions that herbal ephedra/caffeine supplementation produces untoward side effects. 7. We concur with findings in the Rand report that there is too little data to conclude that herbal ephedra provides ergogenic benefit for athletes. If there is any ergogenic benefit, it most likely is associated with the caffeine often found in herbal ephedrine/caffeine supplements rather than the ephedra. Therefore, we support the FDA’s action against supplement companies who market these supplements as an ergogenic aid to athletes. 8. We do not concur with the FDA’s position that ephedra supplementation is dangerous “especially under conditions of strenuous exercise and in combination with other stimulants, including caffeine”. While this may be a prudent recommendation, we are aware of no data supporting the view that ephedra supplementation affects maximal heart, myocardial function, promotes dehydration, or significantly increases core temperature during exercise. We assume that this warning has been issued in response to several high profile deaths among athletes suspected of taking dietary supplements containing ephedra while training in hot/humid environments. However, it is currently unclear whether ephedra supplementation played a role in the deaths of these athletes. As trained exercise and conditioning specialists, we have significant concerns regarding the appropriate screening, training, supervision, and medical condition of these athletes and feel that these factors may have played more of a role in the death of these athletes than the purported use of a dietary supplement containing ephedra. In several instances, whether the athletes actually took ephedra is in dispute. 9. We concur with the FDA recommendation that warnings should indicate that anyone under 18 should not take ephedra containing supplements. There is simply too little evidence as to efficacy and/or safety in younger populations. However, since the Molnar and associate [15] paper showed efficacy and safety in obese adolescent patients participating in a medically supervised weight loss program, it is our view that a qualifier should include “unless directed by their physician”. 10. We believe that the new warnings should highlight possible side effects attributed to ephedra supplementation as described in the Rand report including “mild to moderate side effects such as heart palpitations, psychiatric and upper gastrointestinal effects, and symptoms of autonomic hyperactivity such as tremor and insomnia, especially when it is taken with other stimulants”. We do not believe there is sufficient evidence to conclude at this time that ephedra supplementation increases “risks of serious adverse events, including heart attack, seizure, stroke, and death”. We recommend that this statement be modified to indicate that these side effects have been reported to occur in rare instances among people claiming to have taken ephedra containing dietary supplements but that this relationship has yet to be medically proven. 11. While we support appropriate warning labels of possible side effects associated with taking dietary supplements containing ephedra, we do not believe that available data shows that ephedra supplements “present a significant and unreasonable risk of illness and injury”. Dietary supplements containing ephedra are clearly not for everyone. However, research shows they can be safely used by healthy populations to promote a modest amount of weight loss. While some Americans may feel that the possible risk of taking ephedra containing dietary supplements outweigh the potential benefits, millions of people have safely used ephedra containing dietary supplements without any apparent side effects. We feel that as long as the public is made aware of the possible risks and benefits, then it should be up to the consumer, in consultation with their physician, as to whether they should or should not take dietary supplements containing ephedra. Further, when one compares the safety record of ephedra to such common practices as taking aspirin, pain medications, cold medications, weight loss medications, and alcohol, ephedra supplementation appears to be a relatively safe practice. Summary Comments about nutritional supplements should be based on science and not political and media pressure. Research has indicated that ephedrine/ephedra supplementation can safely promote weight in appropriate populations. The adverse events reported deserve study to see if a relationship actually exists to supplementation with dietary supplements containing ephedra. However, as the Rand report concludes, it is difficult to make definitive clinical conclusions based on these reports due to a lack of information and/or presence of potential confounding variables and medical history. We therefore call on the FDA and Federal government to conduct a large-scale, multi-site clinical trial to investigate the safety and efficacy of dietary supplements containing ephedra. This can be accomplished by developing entrance criteria; having physicians perform a comprehensive medical exam; randomly and blindly assigning patients to a placebo (e.g., caffeine) or ephedra group (ephedra + caffeine); and, conducting follow-up medical assessment at 3-month intervals for a year. This would provide sufficient data to document changes in medical status in comparison to a placebo. Until such a study is conducted to show a statistically greater incidence of side effects among ephedra users, we do not support a ban on the sale of ephedra supplements at this time. Rather, we support efforts to better educate consumers as to the potential risks of taking ephedra containing supplements through proper labeling of risk as described in the Rand report. In our view, this should include: 1. recommending that children under 18 not take dietary supplements containing ephedra unless directed by their physician; 2. recommending the individuals with pre-existing medical conditions (e.g., high blood pressure, heart disease, pulmonary disease, liver disease, thyroid disease, etc) and/or or who are pregnant not take dietary supplements containing ephedra; 3. recommending that anyone considering taking dietary supplements containing ephedra should consult a knowledgeable physician to discuss possible risks and benefits; 4. warning people of an increased risk to “mild to moderate side effects such as heart palpitations, psychiatric and upper gastrointestinal effects, and symptoms of autonomic hyperactivity such as tremor and insomnia, especially when it is taken with other stimulants” as described in the Rand report; 5. indicating that in rare instances, people who purportedly have taken dietary supplements containing ephedra have had heart attacks, strokes, seizures, and/or died but that these risks have yet to be confirmed in medical studies; and, 6. indicating that it is not advisable to diet and/or take stimulants such as ephedra and caffeine when engaged in intense training particularly in hot/humid environments; Respectfully, Richard B. Kreider, PhD, EPC, FACSM, FASEP Professor & Chair Mike Greenwood, PhD, CSSC*D Professor and Research Coordinator Lori Greenwood, PhD, ATC, LAT Associate Professor and Director, Graduate Athletic Training and Sports Medicine Exercise & Sport Nutrition Lab Center for Exercise, Nutrition & Preventive Health Department of Health, Human Performance & Recreation Baylor University P.O. Box 97313 Waco, TX 76798-7313 References 1. Dulloo, A. G., D. S. Miller. Ephedrine, caffeine and aspirin: over-the-counter drugs that interact to stimulate thermogenesis in the obese. Nutrition 5:7-9., 1989 2. Dulloo, A. G., D. S. Miller. Reversal of obesity in the genetically obese fa/fa Zucker rat with an ephedrine/methylxanthines thermogenic mixture. J Nutr 117:383-389., 1987 3. Krieger, D. R., P. A. Daly, A. G. Dulloo, B. J. Ransil, J. B. Young, L. Landsberg. Ephedrine, caffeine and aspirin promote weight loss in obese subjects. Trans Assoc Am Physicians 103:307-312, 1990 4. Astrup, A., B. Buemann, N. J. Christensen, S. Toubro, G. Thorbek, O. J. Victor, F. Quaade. The effect of ephedrine/caffeine mixture on energy expenditure and body composition in obese women. Metabolism 41:686-688., 1992 5. Astrup, A., L. Breum, S. Toubro, P. Hein, F. Quaade. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial. Int J Obes Relat Metab Disord 16:269-277., 1992 6. Daly, P. A., D. R. Krieger, A. G. Dulloo, J. B. Young, L. Landsberg. Ephedrine, caffeine and aspirin: safety and efficacy for treatment of human obesity. Int J Obes Relat Metab Disord 17 Suppl 1:S73-78., 1993 7. Toubro, S., A. Astrup, L. Breum, F. Quaade. The acute and chronic effects of ephedrine/caffeine mixtures on energy expenditure and glucose metabolism in humans. Int J Obes Relat Metab Disord 17 Suppl 3:S73-77; discussion S82., 1993 8. Toubro, S., A. V. Astrup, L. Breum, F. Quaade. Safety and efficacy of long-term treatment with ephedrine, caffeine and an ephedrine/caffeine mixture. Int J Obes Relat Metab Disord 17 Suppl 1:S69-72., 1993 9. Breum, L., J. K. Pedersen, F. Ahlstrom, J. Frimodt-Moller. Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice. Int J Obes Relat Metab Disord 18:99-103., 1994 10. Buemann, B., P. Marckmann, N. J. Christensen, A. Astrup. The effect of ephedrine plus caffeine on plasma lipids and lipoproteins during a 4.2 MJ/day diet. Int J Obes Relat Metab Disord 18:329-332., 1994 11. Toubro, S., A. Astrup. Randomised comparison of diets for maintaining obese subjects' weight after major weight loss: ad lib, low fat, high carbohydrate diet v fixed energy intake. Bmj 314:29-34., 1997 12. Toubro, S., A. V. Astrup. [A randomized comparison of two weight-reducing diets. Calorie counting versus low-fat carbohydrate-rich ad libitum diet]. 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A pilot study evaluating the effects of an ephedrine and forskolin-based product on body weight and body composition in overweight, healthy women. J Am Coll Nutri 20:567, 2001 18. Boozer, C. N., P. A. Daly, P. Homel, J. L. Solomon, D. Blanchard, J. A. Nasser, R. Strauss, T. Meredith. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Disord 26:593-604., 2002 19. Dulloo, A. G. Herbal simulation of ephedrine and caffeine in treatment of obesity. Int J Obes Relat Metab Disord 26:590-592., 2002 20. Kalman, D., T. Incledon, I. Gaunaurd, H. Schwarz, D. Krieger. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra - caffeine weight loss product in healthy overweight adults. Int J Obes 26:1363-1366, 2002 21. Vukovich, M., C. Heilman, J. Brink. Caffeine and ephedrine: effect on resting heart rate, blood pressure, and energy expenditure. Med Sci Sport Exerc 34:S73, 2002 22. Filozof, C., C. Gonzalez, E. Hofman. The effect of ephedrine plus caffein after a 4-week portion-controlled diet. Paper presented at the Int Cong Obes, Sao Paolo, Brazil, 2002 23. Greenway, F. L. The safety and efficacy of pharmaceutical and herbal caffeine and ephedrine use as a weight loss agent. Obes Rev 2:199-211., 2001 24. Greenway, F. L., D. H. Ryan, G. A. Bray, J. C. Rood, E. W. Tucker, S. R. Smith. Pharmaceutical cost savings of treating obesity with weight loss medications. Obes Res 7:523-531., 1999 25. Greenway, F. Ephedra and obesity: Diciphering the science. Paper presented at the Nutricon Annual Conference, San Diego, CA, July 10 2001 26. Haller, C. A., N. L. Benowitz. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 343:1833-1838., 2000 27. Bent, S. The relative safety of ephedra compared with other herbal products. Ann Intern Med:, 2003. Available: http://www.acponline.org/journals/annals/ephedra.htm 28. Deuster, P. A., A. Sridhar, W. J. Becker, R. Coll, K. K. O'Brien, G. Bathalon. Health assessment of U.S. Army Rangers. Mil Med 168:57-62., 2003 29. Wooltorton, E., B. Sibbald. Ephedra/ephedrine: cardiovascular and CNS effects. Cmaj 166:633., 2002 30. Wettach, G. E., S. G. Falvey. A mysterious blood pressure increase in a drilling Naval reservist. Mil Med 167:521-523., 2002 31. Stein, C. M. Are herbal products dietary supplements or drugs? An important question for public safety. Clin Pharmacol Ther 71:411-413., 2002 32. Sandhu, R. S., J. J. Como, T. S. Scalea, J. M. Betts. Renal failure and exercise-induced rhabdomyolysis in patients taking performance-enhancing compounds. J Trauma 53:761-763; discussion 763-764., 2002 33. Samenuk, D., M. S. Link, M. K. Homoud, R. Contreras, T. C. Theohardes, P. J. Wang, N. A. Estes, 3rd. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc 77:12-16., 2002 34. Ruth, L. Analysis comes to dietary supplements. Anal Chem 74:19A-20A., 2002 35. Lindsay, B. D. Are serious adverse cardiovascular events an unintended consequence of the Dietary Supplement Health and Education Act of 1994? Mayo Clin Proc 77:7-9., 2002 36. Irby, H. E. Health hazards and abuse with herbal dietary supplements. J Miss State Med Assoc 43:241-243., 2002 37. Traub, S. J., W. Hoyek, R. S. Hoffman. Dietary supplements containing ephedra alkaloids. N Engl J Med 344:1096; author reply 1096-1097., 2001 38. Arditti, J., J. H. Bourdon, M. Spadari, L. de Haro, N. Richard, M. Valli. [Ma Huang, from dietary supplement to abuse]. Acta Clin Belg Suppl 1:34-36, 2002 39. Spake, A. Natural hazards. Tonic or toxic? Americans are gobbling up nature's remedies for everything from obesity to depression. US News World Rep 130:42-49., 2001 40. Ooms, T. G., S. A. Khan, C. Means. Suspected caffeine and ephedrine toxicosis resulting from ingestion of an herbal supplement containing guarana and ma huang in dogs: 47 cases (1997-1999). J Am Vet Med Assoc 218:225-229., 2001 41. Hutchins, G. M. Dietary supplements containing ephedra alkaloids. N Engl J Med 344:1095-1096; author reply 1096-1097., 2001 * The comments provided above represent the scientific opinions of the authors and do not necessarily reflect those of Baylor University and/or professional organizations that the authors may belong.




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