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Appendix D Case Studies THE CASE OF DEHYDROEPIANDROSTERONE: DECISIONS FOR ACTION Dehydroepiandrosterone (DHEA) was selected for a review of safety and efficacy because, as the committee compiled data about the use of dietary supplements by military personnel, anabolic supplements or body- building supplements were highlighted as one of the categories of dietary supplements that were most popular. DHEA is a steroid compound that is also popular in the civilian population because of its alleged effect in in- creasing muscle mass and enhancing physical performance. It is no surprise then that, performance enhancement being one of the main reasons military personnel cite for taking dietary supplements, DHEA has become popular among military members. DHEA was among the top 10 dietary supple- ments used at least once a week by Rangers (7 percent) and Special Forces (6 percent) in surveys conducted in 1999 and 2000, respectively (Lieberman et al., 2007). In another survey comparing civilian and military use of dietary supplements among members of health clubs, as many as 13 per- cent of military personnel were using DHEA (Sheppard et al., 2000). When asked by health care providers about “bodybuilder supplement use,” 6.6 percent of military members reported using them (Jaghab, 2007); DHEA may have been among them. In addition, the most recent U.S. Department of Defense (DoD) Survey of Health Related Behaviors Among Military Personnel (Marriott, 2007) found that as many as 20.5 percent of military personnel used bodybuilder supplements within the last 12 months. As a variety of sources suggested a high level of use, the committee initiated a 0

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 APPENDIX D review of DHEA safety and efficacy. The committee searched for literature reviews (Figures 4-1 and 4-2) conducted over the previous 10 years as well as more recent original studies not included in reviews. In addition, a search was conducted for articles specifically designed to signal safety or performance effects of critical importance to the military. Surprisingly, the popular view that DHEA increases muscle mass and therefore might improve performance appears to be based largely on the findings of a 1998 paper that had significant methodological limitations (Morales et al., 1998). The various reviews of the literature addressing effi- cacy indicate that there is little substantiation for such a performance claim. There is a gender-specific effect on blood testosterone that perhaps merits further research to determine effects of DHEA on lean tissue and bone density gain in women during resistance training. Some reviews found that the use of DHEA by women increases testosterone concentration. Other reviews evaluated suspected benefits on cognition, mood, and bone strength from consuming DHEA. A search for original articles on studies that in- clude situations or conditions of particular relevance for the military yielded no result. Based on Table 4-2 and the findings from literature reviews, the committee agrees that there is a low level of benefit to be gained by military personnel from using DHEA. Reviews highlighted adverse androgenizing effects experienced by women, and other minor effects such as facial acne or increased sebum production; there was no adverse effect identified that would decrease the readiness of military personnel. There was some theo- retical increased risk of cardiovascular disease in women due to the reduc- tion in high-density lipoprotein noted in some studies. Although some drugs are known to either increase or decrease blood DHEA, there were no reports that supplementary DHEA affected the action of most drugs. Other prescription steroid hormones (e.g., testosterone ana- logs, estrogen) may be exceptions; it is possible that DHEA consumption could affect the metabolism of those drugs. One long-term theoretical but critical adverse effect uncovered during the safety reviews is the potential association of DHEA levels in blood with a higher risk of breast cancer seen in various epidemiological studies. The potential for hepatic neoplasia was also suggested by results from a review of animal studies. This potential adverse effect is serious enough that, al- though a cause and effect could not be established from those studies, a high level of concern was determined for DHEA (Box 4-1). The military should decide on the course of action based on the high level of concern and low benefit derived from its use. A course of action might be to do the following: • Follow up with the research community to determine whether the equivocal animal data related to neoplasia are translated to humans and to

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL monitor future research on either safety or benefits to determine if it needs to be reclassified in the future, which would likely lead to different manage- ment actions. Research on DHEA should be monitored to determine if it should be reclassified as future research unfolds. • Develop an outreach strategy to educate military members about the high risks and low benefits of using DHEA by – including DHEA in a list of dietary supplements to avoid. Recommend the use of alternative products (e.g., creatine, beta-hydroxy- beta-methylbutyrate [HMB]) or strategies (modification of resistance train- ing regime, increase of energy intake) that might provide similar desired effects; – informing military health care providers, fitness trainers and ther- apists, registered dietitians, nutritionists, commanders, and other educators about the risks and benefits of using DHEA and recommend alternative products or foods; and – monitoring use and potential adverse effects among military personnel. THE CASE OF EPHEDRA: DECISIONS FOR ACTION Ephedra (Ephedra sinica Stapf and other ephedrine-containing Ephedra species) was selected for a review of safety by the committee for various reasons. First, due to the severe adverse effects reported, the sale of ephedra in dietary supplements has been banned in the United States since 2004 (Rados, 2004); it is therefore the first and only dietary supplement that has been banned since the Dietary Supplement Health and Education Act was implemented (the ephedra alkaloids ephedrine and pseudoephedrine, however, are allowed to be sold as over-the-counter medications in the United States). A study by Deuster et al. (2003) reported that 13 percent of the U.S. Army Rangers surveyed used ephedrine. Simi- larly, a high percentage (21 percent) of ephedra users were calculated from a self-reporting questionnaire distributed among U.S. Army active duty personnel (Brasfield, 2004). These surveys, however, were conducted prior to the ephedra ban in the United States; the impact of the ban on the use of ephedra and its alkaloids is not known. A survey focusing on supplement use that was distributed among Army health care providers revealed that 5.2 and 7.7 percent of soldiers reported use of ephedra to their physicians or other health care personnel, respectively (Jaghab, 2007). Although these numbers might not be representative of the military population, they do raise safety concerns about the use of ephedra. The odds of adverse events from misuse of over-the-counter medications containing ephedra alkaloids might be small but continue to be of concern. Also, botanicals that are chemically similar to ephedra and might mimic its effects are still available in the market.

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 APPENDIX D Although initially the military had considered ephedra among the dietary supplements likely to be efficacious and of interest, defense ap- plications for use of ephedra were never developed by The Technical Co- operation Program (TTCP) panel1 because of safety concerns (Lieberman et al., 2007). These safety concerns and its use among military personnel prompted a safety evaluation of ephedra. The committee initiated a safety review by applying Figures 5-1 and 5-2 (see Chapter 5). An initial search for reviews of ephedra was carried out in appropriate databases such as PubMed, Napralert, Toxline, SciFinder, UIC, and Company Digital Libraries. Among the terms used in the search were ephedra and Latin binomials, healthy, performance, ergogenic, memory, interactions, aderse, toxicity, and infection. The review only focused on perceived benefits such as increased weight loss and performance enhance- ment as relevant benefits for military personnel. A few studies demonstrate a statistically significant weight loss using ephedra versus placebo. Most studies, however, showed a weight loss of only 0.6–0.8 kg per month using ephedra, or 1.0 kg with ephedra-caffeine combinations. The committee con- cluded that these effects are not clinically relevant. Moreover, there are no clinical studies with long-term data. Likewise, clinical studies with ephedra alkaloids have not been shown to result in significant improvements in performance for the specific modalities tested. However, combinations of ephedrine HCl (synthetic ephedrine) and caffeine seem to enhance various measurements of performance. During clinical trials it was noted that the risk of adverse events in- creased two- to fourfold and that the adverse effect profile of ephedra was primarily related to serious cardiovascular effects, from palpitations to tachycardias and strokes. Although most adverse effects are relevant to the general population, some of them, such as psychosis, vision impairment, dehydration, or muscle failure, would specifically present heightened risks for military personnel. Interaction with sympathomimetic drugs as well as the occurrence of palpitations should be of concern. Some of the adverse events (e.g., psychosis, increased heart rate and blood pressure, myocardial infarction, arrhythmias) were also seen in studies when ephedra and caf- feine were provided in combination. The committee concluded that the use of ephedra (and related alka- loids) presents a high level of concern. With only moderate potential for benefits and the high level of concern, this committee supports the current ban on ephedra use. Military leadership might decide to take the following actions on ephedra and its alkaloids, particularly directed toward popula- 1 The TTCP panel is an international panel of military scientists whose mission is to con- duct research, share information, and write papers on performance-enhancing treatments for potential operational use.

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL tions that might use performance enhancers, such as Rangers or Special Operations forces: • Develop an outreach strategy to educate soldiers about the high risks and low benefits of using ephedra and its alkaloids by – including ephedra and its alkaloids in outreach materials listing dietary supplements to avoid. Recommend the use of alternative products (e.g., creatine, HMB) or strategies (modification of resistance training re- gime, increase of energy intake) that might provide similar desired effects; – informing military health care providers, fitness trainers and therapists, registered dietitians, nutritionists, commanders, and other edu- cators about the risks and benefits of using ephedra and its alkaloids and recommend alternative products or foods; and – monitoring use and potential associated adverse effects among military personnel. THE CASE OF MELATONIN: DECISIONS FOR ACTION The committee’s interest in melatonin originated from its potential value for use by military personnel as a sleep enhancer and for reentrain- ment following rapid deployment across time zones (Lieberman et al., 2007). Although melatonin was not reported as being used in any of the military surveys reviewed, melatonin is being used at a high rate as a dietary supplement in the general population. This committee anticipates that in the future, military personnel might be taking melatonin to achieve circa- dian reentrainment or to improve sleep; therefore, the committee selected melatonin as being of interest to the military and supports a review of safety and efficacy before decisions about its value for military personnel are made. Melatonin is a hormone secreted in the brain by the pineal gland and also reportedly found in a number of plants. It has widespread effects in the body, many of them poorly understood. Endogenous secretion of melatonin is believed to help maintain internal circadian synchrony among organ systems throughout the body. Exogenous melatonin is available over the counter in the United States. Literature searches conducted by the committee focused on ingestion of melatonin for inducing diurnal sleep in healthy adults, for improving nocturnal sleep in persons with insomnia, and for circadian reentrainment (e.g., for jet lag or night-shift work). The searches were conducted in Thomson ISI and PubMed. There are numer- ous published clinical studies and experiments. This committee reviewed the findings from three recent reviews (Arendt and Skene, 2005; Morin et al., 2007; Wagner et al., 1998) and three meta-analyses (Brzezinski et al., 2004; Buscemi et al., 2005, 2006). The committee concluded that there is

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 APPENDIX D moderate potential for benefits (very modest evidence of improvement of sleep, but moderate to good evidence of circadian reentrainment under controlled conditions). Mild adverse effects that might affect military performance have been identified, such as drowsiness, core body heat loss, and gastrointestinal distress (e.g., nausea); serious adverse effects were not found. Putative syn- ergistic effects of exogenous melatonin with sedative hypnotics were not found. Given the moderate concern and moderate potential for benefits of exogenous melatonin, the military leadership could initiate the following activities: • Follow up with the scientific community conducting research on the effects of melatonin for sleep and circadian reentrainment during op- erations in environments inconducive to sleep, to determine if melatonin has advantages over sedative-hypnotics that have carryover effects on performance. • Develop an outreach strategy to educate military members, military health care providers, fitness trainers and therapists, registered dietitians, nutritionists, and commanders about the potential interaction of melatonin with sedative-hypnotic medications and the potential for increased heat loss. REFERENCES Arendt, J., and D. J. Skene. 2005. Melatonin as a chronobiotic. Sleep Med Re 9(1):25-39. Brasfield, K. 2004. Dietary supplement intake in the active duty enlisted population. US Army Med Dept J (Oct-Dec):44-56. Brzezinski, A., M. G. Vangel, R. J. Wurtman, G. Norrie, I. Zhdanova, A. Ben-Shushan, and I. Ford. 2005. Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Re 9(1):41-50. Buscemi, N., B. Vandermeer, N. Hooton, R. Pandya, L. Tjosvold, L. Hartling, G. Baker, T. P. Klassen, and S. Vohra. 2005. The efficacy and safety of exogenous melatonin for primary sleep disorders—A meta-analysis. J Gen Intern Med 20(12):1151-1158. Buscemi, N., B. Vandermeer, N. Hooton, R. Pandya, L. Tjosvold, L. Hartling, S. Vohra, T. P. Klassen, and G. Baker. 2006. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep-restriction: Meta-analysis. Br Med J 332(7538):385-393. Deuster, P. A., A. Sridhar, W. J. Becker, R. Coll, K. K. O’Brien, and G. Bathalon. 2003. Health assessment of U.S. Army Rangers. Mil Med 168(1):57-62. Jaghab, D. 2007. Surey of Army health care proiders concerning dietary supplements. Insti- tute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Lieberman, H. R., T. Stavinoha, S. McGraw, and L. Sigrist. 2007. Use of dietary supplements in U.S. Army populations. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13.

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Marriott, B. M. 2007. Dietary supplement use by actie duty military personnel: A worldwide sample. Institute of Medicine Committee on Dietary Supplement Use by Military Person- nel meeting, Washington, DC, February 13. Morales, A. J., R. H. Haubrich, J. Y. Hwang, H. Asakura, and S. S. Yen. 1998. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf) 49(4):421-432. Morin, A. K., C. I. Jarvis, and A. M. Lynch. 2007. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy 27(1):89-110. Rados, C. 2004. Ephedra ban: No shortage of reasons. FDA Consum 38(2):6-7. Sheppard, H. L., S. M. Raichada, K. M. Kouri, L. Stenson Bar Maor, and J. D. Branch. 2000. Use of creatine and other supplements by members of civilian and military health clubs: A cross-sectional survey. Int J Sport Nutr Exerc Metab 10(3):245-259. Wagner, J., M. L. Wagner, and W. A. Hening. 1998. Beyond benzodiazepines: Alternative phar- macologic agents for the treatment of insomnia. Ann Pharmacother 32(6):680-686.