National Academies Press: OpenBook

Use of Dietary Supplements by Military Personnel (2008)

Chapter: 4 Other Dietary Supplements for Military Personnel

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Suggested Citation:"4 Other Dietary Supplements for Military Personnel." Institute of Medicine. 2008. Use of Dietary Supplements by Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/12095.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

4 Other Dietary Supplements for Military Personnel INTRODUCTION The committee was asked to select a limited number of dietary supple- ments from those identified as commonly used and, on the basis of pub- lished reports, to identify those that may be of benefit or might pose serious hazards. The committee used the information provided at the February 12–13, 2007, workshop to select dietary supplements to review based on their frequency of use, potential for adverse events, and interest for the mili- tary. This chapter includes a review of the following dietary supplements: caffeine, chromium, creatine, dehydroepiandrosterone (DHEA), Ephedra, garlic, Ginkgo biloba, ginseng, β-hydroxy-β-methylbutyrate (HMB), mela- tonin, quercetin, sports bars, sports drinks, tyrosine, and valerian. HMB, creatine, sports drinks and bars, garlic, Ginkgo biloba, and ginseng were reviewed owing to their high frequency of use (see Appendix C). A review of DHEA was conducted because the use of anabolic supplements was shown as high, it is legally considered a dietary supplement, and because DHEA is popular among athletes. The committee also considered other factors in their selection, such as severity and number of adverse events reported for a supplement or inter- est of the military in a particular dietary supplement. Ephedra was selected for review by the committee owing to its high frequency of use by military personnel in the past, mainly to achieve weight loss and enhancement of performance, and its adverse event profile. Ginkgo biloba extracts were selected based on their potential to enhance mental performance. Although quercetin is not frequently used by military personnel, research evaluating 84

OTHER DIETARY SUPPLEMENTS 85 its effects on performance and immune response was partially supported by the Department of Defense (DoD), indicating the level of military inter- est in this dietary supplement. Likewise, although the frequency of use of tyrosine was not apparent, this amino acid has been of interest to the mili- tary and the object of research investigations to counteract the decrements in cognition that are associated with stress. Because of the reported use of weight-loss products, chromium was chosen as an example of a dietary supplement ingredient that is often found in such products. The known chronobiotic effects of melatonin may justify its use to ease the effects of jet lag as well as of long or night shifts, and therefore it was included for review. Similarly, valerian could be used for its alleged sedative properties and potential to alleviate sleep disorders, common in military life especially during demanding military operations that require long periods of wakeful- ness or unusual working shifts. Details about the strategies used in conducting literature searches are described in Chapter 5. In general, the committee evaluated reviews that concentrated on safety and efficacy. For some dietary supplements (e.g., Gingko biloba), research on use is so broad and encompasses so many areas that the committee decided to focus the review on effects that would be of interest to the military (e.g., effects on cognition). This is especially recom- mended for those supplements that have already been extensively studied. Reviews of safety emphasized two areas: bioactivity and interactions with other dietary supplements or medications. For the latter, a list of the medi- cations most frequently dispensed to active duty U.S. Army personnel was obtained from the DoD Pharmacy Operations Center, as a representation of typical medications used by military personnel. Although the committee was also asked to provide information on potential withdrawal effects, and the committee recognizes their importance, caffeine is the only supplement for which such information was found. The committee did not perform an evidence-based classification of original research on each supplement. As requested in the statement of task for this study and in accordance with the primary intent to identify supplements that pose serious concerns, the committee relied, as much as possible, on existing reviews by other authors to produce the summaries for each dietary supplement. If a review was not available for the last 10 years, original research was included. In those cases, limitations were noted where appropriate (see tables in Chapter 4). Although the committee emphasized review of safety, the management of dietary supplements for the military needs to follow an evaluation of both risks and benefits, as the recommended framework notes. The reviews therefore also include information about benefits. When reviewing safety, effects judged to be especially pertinent to specific military subpopulations because of performance demands (e.g., cognitive or physical fitness), mis- sion environments (e.g., high altitude, extreme temperatures), or the impact

86 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL of adverse events associated with the supplement (e.g., bleeding, gastroin- testinal disturbances, infectious diseases) received particular attention. The committee recognizes that when trying to identify safety concerns, the fact that dietary supplements are taken in combination and also with medica- tions is a challenge. The committee emphasizes that it is very important that interactions between dietary supplements, medications, nutrients, and other dietary supplements be considered in all elements of this framework: when conducting surveys, when applying the framework and conducting reviews, and when examining and associating adverse events with dietary supple- ment use. However, when conducting the reviews, it would not be feasible for this committee to address all the potential combination scenarios for dietary supplements, and only a few known and potential interactions with medications have been noted. Because new dietary supplements are being rapidly introduced into the market, information about their quantity and purity would quickly become obsolete and, therefore, it was not included in this chapter. Although many other dietary supplements could have been reviewed, this chapter provides a selected subset as examples of monographs devel- oped for each dietary supplement. For example, although there are risks from the misuse of growth hormones and anabolic steroids, a review of those substances is beyond the scope of this report because they are illegal, and/or there is also no evidence of use among the military. The monographs in this chapter were developed in order to evaluate the review process outlined in Chapter 5. They present scientific reviews of safety and effi- cacy, but do not attempt to provide a final assessment of safety or efficacy. Monographs are intended to serve as one key tool for making decisions about how to manage each dietary supplement. Other factors affecting the decision-making process on managing use of a specific dietary supple- ment relate to the characteristics of the targeted population (see Box 1-3 in Chapter 1); that is, decisions about weighing benefits and risks as well as the level of concern will have to consider the tasks (i.e., mission risks and environments) of the subpopulation. The committee recognizes that the military leadership (e.g., local commanders, or leadership at the service or DoD level) is best informed to make such assessments. Examples of how conclusions from the panel of experts could be synthesized are shown in Chapter 5, Table 5-3. This table includes summary conclusions about the level of concern and the putative benefits that will be useful in making man- agement decisions and for developing outreach materials. Also, Appendix D shows examples of how these monographs could serve as a scientific basis for decision making and includes suggestions for management actions for DHEA, melatonin, and Ephedra. A barrier to the application of the committee’s framework was the lack of data from studies designed with subpopulations or circumstances simi-

OTHER DIETARY SUPPLEMENTS 87 lar to those of the military. Also, data from interactions with medications were infrequently found. It should be noted that the monographs are not exhaustive and present mainly data from reviews. The committee did not provide a list of research recommendations for each dietary supplement be- cause research priorities need to be outlined within the scope of an overall research agenda for dietary supplements; such priorities are delineated in Chapter 7. CAFFEINE Background Caffeine [1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione] is arguably the most widely consumed psychoactive substance in the world. It is an alkaloid that occurs naturally in the leaves, seeds, and fruit of tea, coffee, cacao, kola trees, and more than 60 other plants (Reid and Sacha, 2005). It is rapidly absorbed from the gastrointestinal tract into the bloodstream. Within 1–1.5 hours following ingestion, maximum caffeine concentra- tions are reached in blood, and it is readily distributed throughout the body (Nawrot et al., 2003). Natural sources of caffeine generally also contain varying mixtures of other xanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances such as polyphenols that can form insoluble complexes with caffeine. Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (1A2 isozyme) into three metabolic dimethylxanthines: (1) paraxanthine, which increases lipolysis, leading to elevated levels of glycerol and free fatty acids; (2) theobromine, the principal alkaloid in cocoa and chocolate, which dilates blood vessels and increases urine volume; and (3) theophyl- line, which relaxes smooth muscles of the bronchi, and is therefore used to treat asthma (but at therapeutic doses much higher than those achieved from caffeine metabolism). Caffeine is a central nervous system (CNS) stimulant that can also have physiological effects on the autonomic nervous system as well as the car- diovascular, respiratory, and renal systems. The actions of caffeine and its metabolites on these systems are mediated by way of several mechanisms, including antagonism of adenosine receptors (caffeine and paraxanthine are nonselective antagonists for A1 and A2a receptors, but the effect of caffeine on A3 receptors is unknown). A1 receptors have been identified in many brain regions, including the hippocampus, cerebral cortex, cerebel-   The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

88 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL lar cortex, and thalamus (Porkka-Heiskanen, 1999). Other mechanistic pathways for the effects of caffeine and its metabolites include inhibition of phosphodiesterase activity, increased calcium mobilization, and antagonism of benzodiazepine receptors. Caffeine’s inhibition of phosphodiesterase ac- tivity may account for its effects on both the cardiovascular and respiratory systems in that nonxanthine phosphodiesterases are cardiac stimulants as well as effective bronchiolar and tracheal relaxants (IOM, 2001). Caffeine in Dietary Supplements A recent review of caffeine content in common U.S. dietary supple- ments evaluated 53 products with caffeine-containing ingredients as part of a study initiating the development of an analytically validated Dietary Supplement Ingredient Database (Andrews et al., 2007). Selection of prod- ucts for analysis was based on market share information and included those sold as tablets, caplets, or capsules and listing at least one caffeine- containing ingredient, including botanicals such as guarana, yerba mate, kola nut, and green tea extract on the label. Products were analyzed using high-pressure liquid chromatography. Caffeine intake per serving and per day was calculated using the maximum recommendations on each prod- uct label. Laboratory analyses revealed product means ranging from 1 to 829 mg caffeine per day. “For products with a label amount for comparison (n=28), 89 percent (n=25) of the products had analytically based caffeine levels per day of between −16 percent and +16 percent of the claimed levels. Lot-to-lot variability (n=2 or 3) for caffeine in most products (72 percent) was less than 10 percent” (Andrews et al., 2007). This review article also noted that caffeine can be present in supplements as a proprietary blend, but not be listed as an ingredient on the label. Less than one-third (11 of 36) of the products whose caffeine content was more than that of one cup of brewed coffee per day listed caffeine as an ingredient, although a major- ity of these products (27 of 36) did voluntarily list a caffeine level on the label (Andrews et al., 2007). Changes in Caffeine Consumption Over the Past Several Decades It appears that coffee remains the primary source of caffeine in the diets of persons in the United States. However, the Continuing Survey of Food Intakes by Individuals (CSFII) found the consumption of caffeine from soft drinks now exceeds the consumption of caffeine from tea (Frary et al., 2005). Frary et al. compared mean values of caffeine consumption as reported by the 1989 Market Research Corporation of America (MRCA) study and the CSFII study. MRCA reported a daily mean consumption value for tea of 0.54 mg/kg, and for soft drinks, 0.27 mg/kg. In contrast, the

OTHER DIETARY SUPPLEMENTS 89 more recent CSFII study showed that soft drink consumption exceeded tea consumption, reporting mean values of 30.6 mg (16 percent of sample size) and 23.4 mg (12 percent of sample size) respectively (Frary et al., 2005). Table 4-1 (see pages 94–95) summarizes what is known about changes in caffeine consumption over the past several decades. Most ­ studies do not find an increase in caffeine consumption, although in 2005, Frary et al. concluded that “During the past 20 years it appears the percentage of persons consuming caffeine has increased while mean caffeine intakes may have decreased” (Frary et al., 2005). With regard to overall changes in beverage consumption, Nielsen and Popkin (2004) concluded that “Within every age group for all other beverages—including coffee and tea, alcohol, fruit drinks, and fruit juices—the changes have been minor between 1977 and 2001.” Caffeine in Energy Drinks Energy drinks have acquired a considerable market in recent years, sub- stantially contributing to caffeine consumption. Consumers Union recently tested 12 carbonated energy drinks and found caffeine levels ranging from 50 mg to 145 mg per 8-ounce serving (Energy drinks, 2007). Most of the drinks tested were sold in packages containing more than 8 ounces, so con- sumption of the entire contents could amount to intake of over 200 mg of caffeine. Furthermore, most of the energy drinks tested contained multiple stimulants, and because caffeine content is not required by law to be listed, the amount of caffeine in an energy drink (or any food for that matter) is often unknown (Energy drinks, 2007). Although caffeine is not classified as addictive in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Associa- tion (APA, 1994), it has been asserted in a comprehensive review of caffeine that habitual daily use of over 500 mg of caffeine (i.e., four to seven cups of coffee or seven to nine cups of tea) represents a significant health risk and may therefore be regarded as abuse (Nawrot et al., 2003). Other mental disorders such as dependence, withdrawal syndrome, and intoxication can be caused by caffeine (Pardo et al., 2007). Therefore, “depending on its use, caffeine can be considered a nutrient, a drug, or a drug of abuse” (Pardo et al., 2007, p. 225). Update on Institute of Medicine Caffeine Report (2001)—Putative Benefits The Institute of Medicine (IOM) Committee on Military Nutrition Research (IOM, 2001) concluded in its report on the use of caffeine for the sustainment of mental task performance for military operations that

90 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL “Research shows that caffeine in the range of 100–600 mg is effective in increasing the speed of reaction time without affecting accuracy and in improving performance on visual and audio vigilance tasks” (IOM, 2001, p. 7). The report indicated that caffeine in doses of 100–600 mg can be used to maintain cognitive performance—particularly in situations of sleep deprivation—and doses of 200–600 mg can be effective in enhancing physi- cal endurance. Moreover, caffeine ingestion has been often associated with a increase in endurance time in physical activities of moderate intensity and long duration (IOM, 2001). Caffeine improves aerobic endurance by increasing fat oxidation and sparing muscle glycogen (IOM, 2001). Four separate reviews (Dodd et al., 1993; Graham et al., 1994; Spriet, 1995; T ­ arnopolsky, 1994) concluded that caffeine consistently “enhances endur- ance performance in a variety of activities (i.e., running, cross-country ski- ing, cycling), with doses from 2 to 9 mg/kg, in naïve and habituated, trained and untrained test subjects” (IOM, 2001). Similar conclusions and recommendations regarding the effects of caf- feine on cognitive performance during sleep deprivation were reached in a 2005 review of stimulants by the Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. Their review concluded that Caffeine is a readily available, short-acting stimulant that has been shown to reduce some of the deficits associated with sleep loss. Studies suggest that caffeine can provide improved alertness and performance at doses of 75 to 150 mg after acute restriction of sleep and at doses of 200 to 600 mg after a night or more of total sleep loss. Caffeine is unlikely to have major disruptive effects on the sleep that follows 8 hours or longer after administration. However, frequent use of caffeine can lead to tolerance and negative withdrawal effects. (Bonnet et al., 2005, p. 1168) While caffeine consumed too close to sleep time can interfere with sleep, caffeine appears to help reverse the effects of sleep inertia (i.e., grog- giness and psychomotor lethargy immediately upon awakening from deep sleep) (Van Dongen et al., 2001). Update on IOM Caffeine Report (2001)—Safety Concerns The safety of caffeine as a food and beverage additive has been evalu- ated several times (IOM, 2001). In 1987, the U.S. Food and Drug Admin- istration (FDA) concluded that caffeine added to beverages at a level of 0.02 percent (200 mg/L) or less did not present a health risk. Another FDA review in 1992 concluded that there was no evidence that the consump- tion of 100 mg per day or less of caffeine in cola beverages posed a hazard to human health (but this does not imply safety at higher doses) (Bonnet

OTHER DIETARY SUPPLEMENTS 91 et al., 2005). It was also noted in the 2001 IOM report that caffeine might be associated with a small increase of spontaneous abortion in the first trimester of pregnancy and that it can significantly increase 24-hour urine output. These effects were not seen as limitations on the military use of caffeine, although increased urine output could provide practical problems under some operational conditions. It was recommended that daily doses should not exceed 600 mg due to possible negative effects on mood and performance at higher doses. Nawrot et al. (2003) concluded that there is ample evidence indicating that for healthy adults, there is no association between caffeine intakes of 400 mg per day and general toxicity, increase in incidence of cancer, adverse effects in the cardiovascular system, behavior, or male fertility. However, recent data from studies at the Walter Reed Army Institute of Research (WRAIR) show that caffeine may not benefit all aspects of neurobehavioral function in sleep-deprived subjects. During military op- erations, the ability to make advantageous and safe decisions is vital. A 2007 WRAIR study demonstrated that after 51 continuous hours of sleep deprivation, the decision-making process was impaired under conditions of uncertainty on the Iowa Gambling Task (Killgore et al., 2007). Caffeine was reported to have no significant beneficial effects that compensated for the detriments of sleep deprivation on the performance of this risk-taking task. Even when administered caffeine, sleep-deprived study participants frequented disadvantageous high-risk scenarios as opposed to the advan- tageous low-risk scenarios that were learned prior to sleep deprivation (Killgore et al., 2007). Additional effects of caffeine may be undesirable in certain environ- mental conditions. Among the other physiological effects of caffeine that are relevant to the military are its effects on thermoregulation. While these effects are advantageous to tolerance of cold temperatures, in a heat stress situation, the effects would be undesirable. A review of the literature found no conclusive evidence of caffeine’s effect on body temperature (Armstrong et al., 2007). However, a carefully controlled study of sustained low- dose (0.3 mg/kg/hour) caffeine intake (in tablet form) by healthy adults undergoing sleep deprivation found a reliable increase in core body tem- perature (measured with a continuous rectal probe) (Rogers et al., 2001). It was also found that caffeine markedly increased circulating levels of noradrenaline relative to a placebo (Price et al., 2000). Research on effects of an ephedrine–caffeine mixture showed that this mixture might also have beneficial thermoregulatory effects for cold tolerance. This effect might be in part due to an 18.6 percent increase in energy expenditure compared to placebo (Vallerand et al., 1989). In a different experiment the additive effects of caffeine and cold water exposure on energy production during submaximal exercise were observed (Doubt and Hsieh, 1991). In another

92 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL placebo-controlled experiment where individuals were subjected to heat stress through physical activity, Bell et al. (1999) reported that although caffeine and ephedrine treatment increased metabolic rate during moderate exercise in a hot, dry environment, there was no increase in internal body temperature; this was possibly due to heat-loss mechanisms that offset the increase in metabolic rate. At higher dosages and/or sustained intake, caffeine can have unwanted physiological and neurobehavioral effects. In addition to the elevated core body temperature and increased plasma noradrenaline levels described by Rogers and Dinges (2005), the adverse effects of caffeine can include locomotor agitation, tachycardia, diuresis, and increased anxiety. Numer- ous studies of the effect of caffeine on fluid homeostasis (diuresis) have generally found a positive correlation between caffeine consumption and increased urine output (IOM, 2001). For example, Neuhäuser-Berthold et al. (1997) administered coffee containing 642 mg of caffeine to healthy volunteers over a single day and monitored fluid homeostasis in comparison with a control group given an equal amount of mineral water. The caffeine group had a highly significant increase in 24-hour urine output, corre- sponding to negative fluid balance and a decrease in body weight (IOM, 2001). Decreased electrolyte (sodium and potassium) levels have also been documented as a result of diuresis; however, a normal diet will restore the homeostatic balance (Armstrong et al., 2007; IOM, 2001). Moreover, fluid and food intake should be monitored under conditions of sustained military operations in hot and cold environments or at high altitudes, as these may present potential for augmented risk of dehydration (IOM, 2001). Interactions with Other Dietary Supplements or Medications Research has shown that caffeine interacts with other drugs in many different ways, although the magnitude of interaction is dependent on dos- age. For example, diazepam (i.e., Valium) is an anxiolytic that is prescribed as a muscle relaxant, sedative-hypnotic, and anticonvulsant (Roache and Griffiths, 1987). Caffeine and diazepam produce disparate effects on the CNS through functionally opposing mechanisms. Caffeine has been dem- onstrated to antagonize subjects’ ratings of sedation and impairment of psychomotor vigilance caused by diazepam, while diazepam countered the restlessness and subject ratings of tension, alertness, and arousal caused by caffeine (Roache and Griffiths, 1987). Less is known about the extent to which caffeine has synergistic effects with other stimulants.

OTHER DIETARY SUPPLEMENTS 93 Caffeine Withdrawal The most commonly reported symptoms following withdrawal of caf- feine, even at doses as low as 100 mg, are headache, irritability, increased fatigue and drowsiness, decreased alertness, difficulty concentrating, ner- vousness, confusion, depressed mood, and decreased energy and activity levels (Nehlig, 1999). These symptoms are typically short-lived and mild to moderate in severity. Despite the long history of use of caffeine, there have been few studies that systematically examined the nature of caffeine withdrawal (Rogers and Dinges, 2005). Depending on dosage and proxim- ity to sleep time, caffeine can disturb sleep by lengthening sleep latency and reducing total sleep time and sleep efficiency (Rogers and Dinges, 2005). Care should therefore be taken to ensure that caffeine use by military per- sonnel does not interfere with sleep when the latter is desirable. Considerations Specific to the Military Military engagements often involve extended periods of sleep restric- tion that are accompanied by well-documented physical and cognitive impairment (Killgore et al., 2007). Consistent with the 2001 IOM report on the military use of caffeine, studies continue to find that caffeine is an ef- fective countermeasure to the detriments of sleep deprivation. These studies support “the recommendation for the use of caffeine to extend the period of operational effectiveness during the conduct of military operations that involve unavoidable periods of sleep loss over a three to four day period” (McLellan et al., 2007). In this 2007 study, the use of 800 mg of caffeine throughout three overnight periods maintained alertness and vigilance in comparison to a placebo group (without caffeine) (McLellan et al., 2007). However, it must also be noted that chronic frequent use of caffeine can lead to tolerance and reduce the benefits of caffeine as a countermeasure for sleep deprivation during military operations. To the extent that caffeine is being consumed in ever-larger doses via coffee, soft drinks, energy drinks, and dietary supplements or medications, the military benefits of caffeine as a cognitive and physical performance enhancer may be reduced by tolerance from such widespread consumption of caffeine (see also Chapter 2, regard- ing the need for obtaining ingredient identification in dietary supplement products and total dosage consumed). In addition, caffeine may not benefit all aspects of cognitive and neurobehavioral functions (e.g., risk-taking decisions), and it may produce physiological effects (e.g., heat retention, diuresis) that may compromise physical performance in certain environ- ments (e.g., hot climates). A summary of average daily consumption (ADC) of caffeine in the United States is shown in Table 4-1.

94 TABLE 4-1  Summary of Average Daily Consumption (ADC) of Caffeine in the United States Reference Source Data Mean ADC Graham, 1978 NASa: Generally Recognized as Adults: 227 mg/day Safe (GRAS) survey, 1977 Children: 101 mg/day Pao et al., 1982 USDAb: Nationwide Food Coffee drinkers: 3.3 Consumption Survey (NFCS), mg/kg 1977–1978 Tea drinkers: 1.1 mg/kg Cola drinkers: 0.4 mg/kg Barone and Roberts, 1996 MRCA: National Household Adults: 2.4 mg/kg Menu Census Survey, 1989 Children: <1 mg/kg Knight et al., 2004 NFO WorldGroup: Share of Adults: 1.5–2.3 mg/kg Intake Panel Survey, 1999 Frary et al., 2005 USDA: CSFII, 1994, 1996, and ADC calculations in this 1998 paper are unreliable NOTE: Average consumption numbers are based on responses from “caffeine consumers,” not the entire population. The most recent paper attempting to determine average caffeine intake was published in 2004, using data from a survey taken in 1999. Thus, none of the data takes into consideration the recent surge in sales of energy drinks. In addition, the results of different References Andrews, K. W., A. Schweitzer, C. Zhao, J. M. Holden, J. M. Roseland, M. Brandt, J. T. Dwyer, M. F. Picciano, L. G. Saldanha, K. D. Fisher, E. Yetley, J. M. Betz, and L. ­ Douglass. 2007. The caffeine contents of dietary supplements commonly purchased in the U.S.: Analysis of 53 products with caffeine-containing ingredients. Annal Bioanal Chem 389(1):231-239. APA (American Psychiatric Association). 1994. Diagnostic and statistical manual of mental disorders (DSM-IV). Arlington, VA: APA. Armstrong, L. E., D. J. Casa, C. M. Maresh, and M. S. Ganio. 2007. Caffeine, fluid-electrolyte balance, temperature regulation, and exercise-heat tolerance. Exerc Sport Sci Rev 35(3): 135-140. Barone, J. J., and H. R. Roberts. 1996. Caffeine consumption. Food Chem Toxicol 34(1): 119-129. Bell, D. G., I. Jacobs, T. M. McLellan, M. Miyazaki, and C. M. Sabiston. 1999. Thermal regulation in the heat during exercise after caffeine and ephedrine ingestion. Aviat Space Environ Med 70(6):583-588. Bonnet, M. H., T. J. Balkin, D. F. Dinges, T. Roehrs, N. L. Rogers, N. J. Wesensten, and Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. 2005. The use of stimulants to modify performance during sleep loss: A review by the Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. Sleep 28(9):1163-1187. Dodd, S. L., R. A. Herb, and S. K. Powers. 1993. Caffeine and exercise performance: An update. Sports Med 15(1):14-23.

OTHER DIETARY SUPPLEMENTS 95 90th Percentile ADC Conclusions Adults: 5.2 mg/kg The authors report slight declines in ADC when comparing the Children: <2 mg/kg MRCA surveys of 1975 and 1989, but slight increases when comparing the USDA NFCS surveys of 1977 and 1987. Adults: 3.2–5.2 mg/kg Men and nonpregnant women in the same age groups consumed similar amounts of caffeine. The authors conclude that the percentage of American adults who consume caffeine is increasing when comparing the 1977 GRAS surveys and 1998 CSFII (82% and 87%). papers cannot be validly and reliably compared when trying to quantify a change in average caffeine consumption in recent years because the methodology is poorly defined. Finally, no paper includes caffeine obtained through dietary supplements. aNational Academy of Sciences. bU.S. Department of Agriculture. Doubt, T. J., and S. S. Hsieh. 1991. Additive effects of caffeine and cold water during sub- maximal leg exercise. Med Sci Sports Exerc 23(4):435-442. Energy drinks: Behind the buzz. 2007. Consum Rep 72(9):6. Frary, C. D., R. K. Johnson, and M. Q. Wang. 2005. Food sources and intakes of caffeine in the diets of persons in the United States. J Am Diet Assoc 105(1):110-113. Graham, D. M. 1978. Caffeine—It’s identity, dietary sources, intake and biological effects. Nutr Rev 36(4):97-102. Graham, T. E., J. W. Rush, and M. H. van Soeren. 1994. Caffeine and exercise: Metabolism and performance. Can J Appl Physiol 19(2):111-138. IOM (Institute of Medicine). 2001. Caffeine for the sustainment of mental task performance: Formulations for military operations. Washington, DC: National Academy Press. Killgore, D. S., E. L. Lipizzi, G. H. Kamimori, and T. J. Balkin. 2007. Caffeine effects on risky decision making after 75 hours of sleep deprivation. Aviat Space Environ Med 78(10):957-962. Knight, C. A., I. Knight, D. C. Mitchell, and J. E. Zepp. 2004. Beverage caffeine intake in U.S. consumers and subpopulations of interest: Estimates from the Share of Intake Panel Survey. Food Chem Toxicol 42(12):1923-1930. McLellan, T. M., G. H. Kamimori, D. M. Voss, T. Charmaine, and S. J. R. Smith. 2007. Caf- feine effects on physical and cognitive performance during sustained operations. Aviat Space Environ Med 78(9):871-877. Nawrot P., S. Jordan, J. Eastwood, J. Rotstein, A. Hugenholtz, and M. Feeley. 2003. Effects of caffeine on human health. Food Addit Contam 20(1):1-30. Nehlig, A. 1999. Are we dependent upon coffee and caffeine? A review on human and animal data. Neurosci Biobehav Rev 23(4):563-576.

96 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Neuhäuser-Berthold, M., S. Beine, S. C. Verwied, and P. M. Lührmann. 1997. Coffee consump- tion and total body water homeostasis as measured by fluid balance and bioelectrical impedance analysis. Ann Nutr Metab 41(1):29-36. Nielsen, S. J., and B. M. Popkin. 2004. Changes in beverage intake between 1977 and 2001. Am J Prev Med 27(3):205-210. Pao, E. M., K. Fleming, P. M. Guenther, and S. J. Mickel. 1982. Foods commonly eaten by individuals: Amount per day and per eating occasion. USDA Home Economics Research Report No. 44. Pardo, L. R., G. Y. Alvarez, T. D. Barral, and A. M. Farré. 2007. Caffeine: A nutrient, a drug, or a drug of abuse. Adicciones 19(2):225-238. Porkka-Heiskanen, T. 1999. Adenosine in sleep and wakefulness. Ann Med 31(2):125-129. Price, N. J., J. M. Mullington, S. Kapoor, S. Samuel, M. P. Szuba, and D. F. Dinges. 2000. Plasma norepinephrine during 66 hr of sustained low-dose caffeine intake and 88 hr of sleep deprivation. Sleep 23(Suppl 1):A119. Reid, T. R., and B. Sacha. 2005. Caffeine. National Geographic 207(1):2-33. Roache, J. D., and R. R. Griffiths. 1987. Interactions of diazepam and caffeine: Behavioral and subjective dose effects in humans. Pharmacol Biochem Behav 26(4):801-812. Rogers, N. L., and D. F. Dinges. 2005. Caffeine: Implications for alertness in athletes. Clin Sports Med 24(2):e1-e13. Rogers, N. L., N. J. Price, M. P. Szuba, H. P. Van Dongen, and D. F. Dinges. 2001. Effect of sustained caffeine on core body temperature during 88 hours of sustained wakefulness. Sleep 24(Abstract Suppl):A172-A173. Spriet, L. L. 1995. Caffeine and performace. Int J Sport Nutr 5(Suppl):S84-S99. Tarnopolsky, M. A. 1994. Caffeine and endurance performance. Sports Med 18(2):109-125. Vallerand, A. L., I. Jacobs, M. F. Kavanagh. 1989. Mechanism of enhanced cold tolerance by an ephedrine-caffeine mixture in humans. J Appl Physiol 67(1):438-444. Van Dongen, H. P., N. J. Price, J. M. Mullington, M. P. Szuba, S. C. Kapoor, and D. F. Dinges. 2001. Caffeine eliminates psychomotor vigilance deficits from sleep inertia. Sleep 24(7):813-819. CHROMIUM Background Chromium, an essential trace mineral, is important for the metabolism of carbohydrate, fat, and protein. Chromium enhances the action of insulin and is associated with improved glucose tolerance and lipid-­lipoprotein profiles. In 2001, the Food and Nutrition Board of the Institute of Medicine (IOM) determined the Recommended Dietary Allowance for chromium to be 35 µg for adult males and 25 µg for adult females. Relatively high con- centrations of chromium are found in processed meats, ready-to-eat bran cereals, whole-grain products, green beans, and ­broccoli, and relatively low concentrations in foods high in simple sugars ­(Lukaski, 1999). Estimates of nutrient intakes indicate that the diets of most Americans provide sufficient amounts of chromium (ODS, 2005; Vincent, 2003a).   The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

OTHER DIETARY SUPPLEMENTS 97 Absorption of dietary chromium in the intestines ranges from 0.5 per- cent to 2.0 percent. This variation is related to intake of the mineral: As dietary intake of chromium increases, absorption of the mineral decreases. Moreover, both dietary and nondietary factors can moderate chromium ab- sorption. For example, foods containing ascorbic acid promote chromium absorption, while foods containing phytates, which bind to chromium, inhibit transport of the mineral across the intestinal tract (Lukaski, 1999). Chromium absorption is also reduced by medicines that alter stomach acidity, such as antacids, corticosteroids, and proton pump inhibitors, and by other medicines including beta-blockers, insulin, nonsteroidal anti- inflammatory drugs, and prostaglandin inhibitors (ODS, 2005). Although chromium deficiency is rare, patients maintained on intrave- nous solutions that do not contain the mineral can suffer from impaired control of blood glucose levels, elevated triglyceride and cholesterol levels, and peripheral neuropathy. Treatment with chromium rapidly reversed these symptoms (Lukaski, 1999; ODS, 2005; Stoecker, 2001; Vincent, 2003a). Marginal intake of chromium coupled with physiological stressors such as physical trauma and acute exercise that might occur in a military setting increases the possibility of chromium deficiency (Lukaski, 1999). Chromium in the form of chromium picolinate, which is the salt of chromium with three molecules of the intermediary metabolite picolinic acid, has been widely promoted as a dietary supplement for stimulating weight loss, increasing lean body mass, promoting longevity, and enhancing fitness (Evans, 1989; IOM, 2000; Pittler et al., 2003). Chromium picolinate is found both as a single-ingredient dietary supplement and as a component of multivitamin and multimineral products including pills, energy drinks, energy bars, and chewing gums (Andersson et al., 2007). Although chro- mium picolinate is the most widely used form of the mineral, chromium nicotinate, chromium chloride, and chromium histidine are also found in dietary supplements. The various forms of the mineral differ in absorb- ability; data indicating that the picolinate form was absorbed more readily than the nicotinate or chloride form contributed to the popularity of the picolinate form of the mineral in dietary supplements (DiSilvestro and Dy, 2007). However, more recent research demonstrating that chromium histi- dine is absorbed almost twice as well as chromium picolinate could lead to an increase in the use of supplements containing this form of the mineral (Anderson et al., 2004). Putative Benefits Initial support for a beneficial role of chromium picolinate supplements in the management of body composition came from a 1989 study. College- age athletes participating in a strength-training program who were given 200 mg of chromium picolinate for 6 weeks lost more weight and gained

98 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL more lean body mass than athletes not taking the supplement ­(Evans, 1989). This report was followed by a spectacular rise in the sales of ­ chromium picolinate, making it one of the most widely used nutrient supplements for weight loss and/or muscle development (Sharpe et al., 2006; Vincent, 2003b). The study by Evans, however, presents methodological problems; for instance, there was no control over prior training, and differences found in anthropomorphic measurements appeared to be functionally not signifi- cant (Lefavi et al., 1992). Although chromium picolinate continues to be vigorously marketed and used, the supplement’s ability to alter body composition is question- able (Hallmark et al., 1996; Lukaski et al., 2007; Nissen and Sharp, 2003; Pittler et al., 2003; Stallings and Vincent, 2006; Vincent, 2003a,b). A 2003 meta-analysis of 10 double-blind, randomized control trials concluded that individuals taking 200 to 400 µg of chromium picolinate on a daily basis for 6 to 14 weeks lost approximately 1.1 kg more (i.e., 0.08–0.2 kg/week) during the intervention and increased lean body mass to a slightly greater degree than those taking a placebo (Pittler et al., 2003). More detailed ex- amination revealed that data from only two of the trials accounted for most of the observed differences in body composition between individuals taking chromium picolinate and those taking a placebo. These findings suggest that the effects of chromium picolinate on weight loss and body composition are small and of marginal clinical significance (Pittler et al., 2003). More recent studies have confirmed this suggestion (Lukaski et al., 2007). Taken together, the results of studies evaluating the effects of chromium picolinate on body weight and composition indicate that the supplement is not a useful adjunct to either weight reduction or body building programs. Safety Concerns No frequent, consistent adverse events have been reported in studies assessing the use of chromium picolinate for periods of up to 3 months. However, a few isolated reports of detrimental effects of taking chromium picolinate, including weight loss, changes in cognitive behavior, allergic skin disorders, renal failure, and liver dysfunction have appeared in the literature (Jeejeebhoy, 1999; Lamson and Plaza, 2002; Lukaski, 1999; Vincent, 2003b; Wani et al., 2006). Additional studies addressing the geno- toxic and cytotoxic effects of trivalent chromium complexes have led to the conclusion that these toxic effects of chromium are not a concern for individuals taking supplements containing the mineral (Andersson et al., 2007; Hininger et al., 2007; Lamson and Plaza, 2002). Taking the preced- ing findings together, there is insufficient evidence to indicate concern about the safety of chromium-containing supplements as presently used, and therefore, a Tolerable Upper Intake Level has not been established by the IOM (IOM, 2005; Lukaski, 1999; ODS, 2005).

OTHER DIETARY SUPPLEMENTS 99 Considerations Specific to the Military Studies on the effects of chromium picolinate on body weight and composition have not been conducted in military settings. However, re- search involving individuals engaged in strength-training programs similar to those that might be used in a military setting (e.g., weight lifters, varsity wrestlers) indicates that the benefits of chromium picolinate for decreasing body weight while increasing lean body mass are limited at best. Relevant data and conclusions on efficacy and safety reviews and publications identified for chromium are shown in Table 4-2 on pages 156–159. References Anderson, R. A., M. M. Polansky, and N. A. Bryden. 2004. Stability and absorption of chro- mium and absorption of chromium and absorption of chromium histidinate complexes by humans. Biol Trace Elem Res 101(3):211-218. Andersson, M. A., K. V. P. Grawe, O. M. Karlsson, L. A. Abramsson-Zetterberg, and B. E. Hellman. 2007. Evaluation of the potential genotoxicity of chromium picolinate in mam- malian cells in vivo and in vitro. Food Chem Toxicol 45(7):1097-1106. Campbell, W. W., L. J. Joseph, S. L. Davey, D. Cyr-Campbell, R. A. Anderson, and W. J. Evans. 1999. Effects of resistance training and chromium picolinate on body composition and skeletal muscle in older men. J Appl Physiol 86(1):29-39. Diaz, M. L., B. A. Watkins, Y. Li, R. A. Anderson, and W. W. Campbell. 2008. Chromium picolinate and conjugated linoleic acid do not synergistically influence diet- and exercise- induced changes in body composition and health indexes in overweight women. J Nutr Biochem 19(1):61-68. DiSilvestro, R. A., and E. Dy. 2007. Comparison of acute absorption of commercially available chromium supplements. J Trace Elem Med Biol 21(2):120-124. Evans, G. W. 1989. The effect of chromium picolinate on insulin controlled parameters in humans. Int J Biosoc Med Res 11(2):163-180. Hallmark, M. A., T. H. Reynolds, C. A. DeSouza, C. O. Dotson, R. A. Anderson, and M. A. Rogers. 1996. Effects of chromium and resistive training on muscle strength and body composition. Med Sci Sports Exerc 28(1):139-144. Hininger, I., R. Benaraba, M. Osman, H. Faure, A. M. Roussel, and R. A. Anderson. 2007. Safety of trivalent chromium complexes: No evidence for DNA damage in human H ­ ACaT keratinocytes. Free Radic Biol Med 42(12):1759-1765. IOM (Institute of Medicine). 2000. Dietary reference intakes for vitamin A, vitamin K, ar- senic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press. IOM. 2005. Nutrient composition of rations for short-term, high-intensity combat operations. Washington, DC: The National Academies Press. Jeejeebhoy, K. N. 1999. The role of chromium in nutrition and therapeutics and as a potential toxin. Nutr Rev 57(11):329-335. Lamson, D. W., and S. M. Plaza. 2002. The safety and efficacy of high-dose chromium. Altern Med Rev 7(3):218-235. Lefavi, R., R. A. Anderson, R. E. Keith, G. D. Wilson, J. L. McMillan, and M. H. Stone. 1992. Efficacy of chromium supplementation in athletes: Emphasis on anabolism. Int J Sport Nutr 2(2):111-122.

100 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Livolsi, J. M., G. M. Adams, and P. L. Laguna. 2001. The effect of chromium picolinate on muscular strength and body composition in women athletes. J Strength Cond Res 15(2):161-166. Lukaski, H. C. 1999. Chromium as a supplement. Annu Rev Nutr 19:279-302. Lukaski, H. C., W. A. Siders, and J. G. Penland. 2007. Chromium picolinate supplementa- tion in women: Effects on body weight, composition, and iron status. Nutrition 23(3): 187-195. Martin, J., Z. Q. Wang, X. H. Zhang, D. Watchel, J. Volaufova, D. E. Matthews, and W. T. Cefalu. 2006. Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. Diabetes Care 29(8):1826-1832. Nissen, S. L., and R. L. Sharp. 2003. Effect of dietary supplements on lean mass and strength gains with resistance exercise: A meta-analysis. J Appl Physiol 94(2):651-659. ODS (Office of Dietary Supplements). 2005. Dietary supplement fact sheet: Chromium. http:// ods.od.nih.gov/factsheets/chromium.asp (accessed September 5, 2007). Pittler, M. H., C. Stevinson, and E. Ernst. 2003. Chromium picolinate for reducing body weight: Meta-analysis of randomized trials. Int J Obes Relat Metab Disord 27(4): 522-529. Sharpe, P. A., M. L. Granner, J. M. Conway, B. E. Ainsworth, and M. Dobre. 2006. Avail- ability of weight-loss supplements: Results of an audit of retail outlets in a southeastern city. J Am Diet Assoc 106(12):2045-2051. Stallings, D., and J. B. Vincent. 2006. Chromium: A case study in how not to perform nutri- tional research. Curr Topics Nutraceut Res 4(2):89-112. Stoecker, B. J. 2001. Chromium. In Present knowledge in nutrition, 8th ed., edited by B. A. Bowman and R. M. Russell. Washington, DC: ILSI Press. Pp. 366-372. Trumbo, P. R., and K. C. Ellwood. 2006. Chromium picolinate intake and risk of type 2 diabetes: An evidence-based review by the United States Food and Drug Administration. Nutr Rev 64(8):357-363. Vincent, J. B. 2003a. Recent advances in the biochemistry of chromium (III). J Trace Elem Exp Med 16(4):227-236. Vincent, J. B. 2003b. The potential value and toxicity of chromium picolinate as a nu- tritional supplement, weight loss agent and muscle development agent. Sports Med 33(3):213-230. Wani, S., C. Weskamp, J. Marple, and L. Spry. 2006. Acute tubular necrosis associated with chromium picolinate-containing dietary supplement. Ann Pharmacother 40(3): 563-566. CREATINE Background Creatine is a natural component of the body that is synthesized prin- cipally in the liver and composed of the essential amino acids methionine, arginine, and glycine. The daily turnover of creatine is about 2 g/day (Shao and Hathcock, 2006), with about half coming from the diet and half from  The monographs were developed in order to evaluate the review process outlined in Chap-   ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

OTHER DIETARY SUPPLEMENTS 101 endogenous synthesis with catabolism through nonenzymatic production of creatinine. The principal dietary sources are protein foods such as meat, fish, and poultry, since most creatine (approximately 95 percent) is found in skeletal muscle. Creatine’s primary role in human metabolism is as an intracellular storage form of high-energy phosphate bonds that can serve as a source of energy without the requirement for oxidative metabolism when the minute storage amount of adenosine-5′-triphosphate is consumed during brief periods of high energy consumption, as during high-intensity muscular activity. Thus, as might be expected, short-term creatine admin- istration primarily benefits anaerobic performance, while longer-term use increases the development of strength and fosters lean tissue accretion with resistance exercise (Volek et al., 2006); there is evidence suggesting that this increase is primarily caused by an anticatabolic effect in skeletal muscle (Parise et al., 2001). Creatine supplementation is thought to increase the size of the creatine phosphate pool in muscle, and a pattern of nonresponsiveness in a signifi- cant minority of subjects may be attributable to an already optimal pool of creatine phosphate (Calfee and Fadale, 2006). Although creatine was initially provided with up to a week of loading with 20–30 g/day followed by 5 g/day, the current mode of use is to provide the smaller dose daily in relation to the beginning or end of exercise (Bemben and Lamont, 2005; Shao and Hathcock, 2006). Putative Benefits Nearly 100 randomized trials of creatine supplementation have been conducted in the past decade, generally with beneficial results on short, repeated bouts of high-intensity exercise (Bemben and Lamont, 2005). De- spite considerable variability in results, there is an average greater gain of 2–5 pounds of muscle mass and 5–15 percent of muscle power and strength with creatine compared to placebo (Bemben and Lamont, 2005; Shao and Hathcock, 2006). Although studies have been conducted mostly in men, similar results for improvement of performance in high-intensity activity or exercise or increased strength and improved body composition (lean body mass gains) with resistance training have been found in women (Volek et al., 2006). As might be anticipated from the mode of action, there is little or no evidence for improvement in endurance or aerobic performance (Bemben and Lamont, 2005). A recent review of the literature confirms the lack of effect for submaxi- mal aerobic training in young men and women (Reardon et al., 2006), for tennis-specific training (Pluim et al., 2006), multiple sprint running perfor- mance (Glaister et al., 2006), and sprint skating in hockey players (Cornish et al., 2006). Thus, creatine can be a relatively safe and effective ergogenic

102 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL aid, but its value for any specific activity does need to be examined. For the military, an additional cogent application is suggested by the recent preliminary report that creatine supplementation showed a positive effect on cognitive and psychomotor performance and mood state following 24 hours of sleep deprivation (McMorris et al., 2006). This is in agreement with the fact that creatine is found in the brain, and creatine monohydrate supplementation increases brain creatine content (Dechent et al., 1999). A study by Warber et al. (2002) confirmed the ability of creatine to increase muscle strength and lean tissue but showed no benefit for the military ob- stacle course. There is also substantial evidence from animal studies that creatine intake may be useful in protecting against traumatic brain injury, perhaps through improvement of mitochondrial bioenergetics (Scheff and Dhillon, 2004; Sullivan et al., 2000). Safety Concerns The Tolerable Upper Intake Level (UL) for creatine was not derived from a recent risk assessment based on cumulative studies in animals and humans. Rather, a newer assessment method, the Observed Safe Level, was utilized. It suggests that the evidence for safety is strong for chronic intakes of 5 g/day (Shao and Hathcock, 2006). Although there was some concern about gastrointestinal side effects (Calfee and Fadale, 2006), these were either mild or not found in randomized trials (Shao and Hathcock, 2006). There is also concern about two noted cases of renal function compromise (Calfee and Fadale, 2006; Shao and Hathcock, 2006), one of whom had underlying renal disease, and a third case of reversible renal failure in a healthy 24-year-old taking creatine as well as multiple other supplements used for bodybuilding (Thorsteinsdottir et al., 2006). Interactions with Other Dietary Supplements or Medications Research on the pharmacokinetics of creatine is limited, but effects of caffeine and carbohydrate intake on creatine transporters have been noted (Persky et al., 2003). The limited data and studies available do suggest important interactions with caffeine that are relevant particularly because caffeine, widely used in the military, is so often employed as an ergogenic aid. One study reported an ergogenic effect of the combination (Doherty et al., 2002); another reported opposing effects on muscle relaxation time that were nullified when creatine and caffeine were combined (Hespel et al., 2002). Several studies in human subjects have demonstrated improvements in glucose tolerance with creatine taken alone (Derave et al., 2003; Gualano et al., 2007) or combined with protein supplementation (Op’t Eijnde et al.,

OTHER DIETARY SUPPLEMENTS 103 2006), a popular combination for users of creatine. Although statin drugs interact with numerous other drugs, low levels of toxicity were found with use in combination with other drugs (Law and Rudnicka, 2006). The absence of reported interactions of creatine with the common statin drugs presumably implies a very low level of concern; most likely the absence of reported interactions is because populations that take statins are different from those who consume creatine. There is also a paucity of data on the interaction of creatine with analgesics and nonsteroidal anti-inflammatory drugs, an instance in which the two patient populations should overlap in a significant manner. However, there is one interesting report of a significant positive interaction—the combination of creatine with cyclooxygenase-2 in- hibitors produced additive neuroprotective effects and extended survival by 30 percent—in an animal model of amyotrophic lateral sclerosis (Klivenyi et al., 2004). Finally, although vitamin supplementation is probably com- mon among those who take creatine supplements, data about significant in- teractions are sparse. There is one report that creatine lowers homocysteine concentration (Korzun, 2004), which might be of some interest, given the effect of vitamins B12, pyridoxine, and folic acid on homocysteine. Considerations Specific to the Military Although studies are not definitive, some trials with creatine in subjects involved in high-intensity activities and sports with a high likelihood of injury have shown very little evidence for concern (Greenwood et al., 2003; Hoffman et al., 2006; Santos et al., 2004). Performance is often enhanced or injury lessened. This suggests that there is, if anything, improvement in conditions where injury is common (e.g., sports), and no evidence for bleeding complications. There are no data on creatine intake and tolerance of cold. The avail- able studies suggest either no impact or improvement in tolerance of ther- mal stress (Kilduff et al., 2004; Mendel et al., 2005; Volek et al., 2001; Weiss and Powers, 2006). There are no data available on the effect of creatine use at high altitudes. Given the large amount of creatine usually provided and its intracel- lular location, there have been concerns about dehydration or local fluid re- tention and even risk of heatstroke (Bailes et al., 2002). However, in clinical trials and experience in sports usage, there is little evidence for cramping, diarrhea, or dehydration (Graham and Hatton, 1999; Greenwood et al., 2003; Santos et al., 2004; Smith and Dahm, 2000). There was an increase noted in all fluid volumes in one study of creatine use (Weiss and Powers, 2006). A trial of 175 subjects showed few adverse effects, although edema- tous limbs presumed secondary to fluid retention were seen more commonly in those taking creatine than those in the placebo group (Groeneveld et al.,

104 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL 2005). However, a single randomized study of musculotendinous injury, which might be considered a consequence of overhydrated tissues, did not demonstrate this effect (Watsford et al., 2003). Although fluid retention may be related to the intracellular location of creatine, this does not seem to present a major concern in terms of effects on body weight. Diarrhea was generally not a problem associated with creatine use (Graham and Hatton, 1999; Greenwood et al., 2003; Santos et al., 2004; Smith and Dahm, 2000). In the trial of 175 subjects, severe diarrhea, respon- sive to discontinuation of creatine, was seen in two subjects (Groeneveld et al., 2005). No data are available on infectious disease and creatine intake. There has been concern about renal dysfunction as well as two re- ported cases of renal failure and three deaths in American wrestlers, but minimal impact of creatine intake on renal function was seen in short- and intermediate-term trials (Pline and Smith, 2005; Pritchard and Kalra, 1998; Watsford et al., 2003). Thus, renal function compromise may represent an idiosyncratic reaction, perhaps related to dose or related by association only. It does, however, remain a concern. Relevant data and conclusions on efficacy and safety reviews and pub- lications identified for creatine are shown in Table 4-3 on pages 160–181. References Bailes, J. E., R. C. Cantu, and A. L. Day. 2002. The neurosurgeon in sport: Awareness of the risks of heatstroke and dietary supplements. Neurosurgery 51(2):283-286. Bemben, M., and H. Lamont. 2005. Creatine supplementation and exercise performance: Recent findings. Sports Med 35(2):107-125. Calfee, R., and P. Fadale. 2006. Popular ergogenic drugs and supplements in young athletes. Pediatrics 117(3):e577-e589. Cornish, S., P. Chilibeck, and D. Burke. 2006. The effect of creatine monohydrate supplemen- tation on sprint skating in ice-hockey players. J Sports Med Phys Fitness 46:90-98. Dechent, P., P. Pouwels, B. Wilken, F. Hanefeld, and J. Frahm. 1999. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol Regul Integr Comp Physiol 277(3):R698-R704. Derave, W., B. O. Eijnde, P. Verbessem, M. Ramaekers, M. Van Leemputte, E. A. Richter, and P. Hespel. 2003. Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT-4 content and glucose tolerance in humans. J Appl Physiol 94(5):1910-1916. Doherty, M., P. M. Smith, R. C. Davison, and M. G. Hughes. 2002. Caffeine is ergogenic after supplementation of oral creatine monohydrate. Med Sci Sports Exerc 34(11): 1785-1792. Glaister, M., R. Lockey, C. Abraham, A. Staerck, J. Goodwin, and G. McInnnes. 2006. Cre- atine supplementation and multiple sprint running performance. J Strength Cond Res 20(2):273-277. Graham, A. S., and R. C. Hatton. 1999. Creatine: A review of efficacy and safety. J Am Pharm Assoc (Wash) 39(6):803-810.

OTHER DIETARY SUPPLEMENTS 105 Greenwood, M., R. B. Kreider, C. Melton, C. Rasmussen, S. Lancaster, E. Cantler, and P. Milnor. 2003. Creatine supplementation during college football training does not increase the incidence of cramping or injury. Mol Cell Biochem 244(1-2):83-88. Groeneveld, G. J., C. Beijer, J. H. Veldink, S. Kalmijn, J. H. Wokke, and L. H. van den Berg. 2005. Few adverse effects of long-term creatine supplementation in a placebo-controlled trial. Int J Sports Med 26(4):307-313. Gualano, B., R. B. Novaes, G. G. Artioli, T. O. Freire, D. F. Coelho, F. B. Scagliusi, P. S. Rogeri, H. Roschel, C. Ugrinowitsch, and A. H. Lancha, Jr. 2008. Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training. Amino Acids 34(2):245-250. Hespel, P., B. Op’t Eijnde, and M. Van Leemputte. 2002. Opposite actions of caffeine and creatine on muscle relaxation time in humans. J Appl Physiol 92(2):513-518. Hoffman, J., N. Ratamess, J. Kang, G. Mangine, A. Faigenbaum, and J. Stout. 2006. Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes. Int J Sport Nutr Exerc Metab 16(4):430-446. Kilduff, L. P., E. Georgiades, N. James, R. H. Minnion, M. Mitchell, D. Kingsmore, M. Hadjicharlambous, and Y. P. Pitsiladis. 2004. The effects of creatine supplementation on cardiovascular, metabolic, and thermoregulatory responses during exercise in the heat in endurance-trained humans. Int J Sport Nutr Exerc Metab 14(4):443-460. Klivenyi, P., M. Kiaei, G. Gardian, N. Y. Calingasan, and M. F. Beal. 2004. Additive neuropro- tective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem 88(3):576-582. Korzun, W. J. 2004. Oral creatine supplements lower plasma homocysteine concentrations in humans. Clin Lab Sci 17(2):102-106. Law, M., and A. R. Rudnicka. 2006. Statin safety: A systematic review. Am J Cardiol 97(8): S52-S60. McMorris, T., R. Harris, J. Swain, J. Corbett, K. Collard, R. Dyson, L. Dye, C. Hodgson, and N. Draper. 2006. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentra- tions of catecholamines and cortisol. Psychopharmacology (Berl) 185(1):93-103. Mendel, R. W., M. Blegen, C. Cheatham, J. Antonio, and T. Ziegenfuss. 2005. Effects of creatine on thermoregulatory responses while exercising in the heat. Nutrition 21(3): 301-307. Op’t Eijnde, B., H. Jijakli, P. Hespel, and W. J. Malaisse. 2006. Creatine supplementation increases soleus muscle creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes. Int J Mol Med 17(6):1077-1084. Parise, G., S. Mihic, D. MacLennan, K. E. Yarasheski, and M. A. Tarnopolsky. 2001. Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J Appl Physiol 91(3):1041-1047. Persky, A. M., G. A. Brazeau, and G. Hochhaus. 2003. Pharmacokinetics of the dietary supple- ment creatine. Clin Pharmacokinet 42(6):557-574. Pline, K. A., and C. L. Smith. 2005. The effect of creatine intake on renal function. Ann Pharmacother 39(6):1093-1096. Pluim, B., A. Ferrauti, F. Broekhof, M. Deutekom, A. Gotzmann, H. Kuipers, and K. Weber. 2006. The effects of creatine supplementation on selected factors of tennis specific train- ing. Br J Sports Med 40(6):507-511. Pritchard, N. R., and P. A. Kalra. 1998. Renal dysfunction accompanying oral creatine supple- ments. Lancet 351(9111):1252-1253. Reardon, T., P. Ruell, S. Fiatarone, C. Thompson, and K. Rooney. 2006. Creatine supplemen- tation does not enhance submaximal aerobic training adaptations in healthy young men and women. Eur J Appl Physiol 98(3):234-241.

106 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Santos, R. V., R. A. Bassit, E. C. Caperuto, and L. F. Costa Rosa. 2004. The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30 km race. Life Sci 75(16):1917-1924. Scheff, S. W., and H. S. Dhillon. 2004. Creatine-enhanced diet alters levels of lactate and free fatty acids after experimental brain injury. Neurochem Res 29(2):469-479. Shao, A., and J. Hathcock. 2006. Risk assessment for creatine monohydrate. Regul Toxicol Pharmacol 45(3):242-251. Smith, J., and D. L. Dahm. 2000. Creatine use among a select population of high school athletes. Mayo Clin Proc 75(12):1257-1263. Sullivan, P. G., J. D. Geiger, M. P. Mattson, and S. W. Scheff. 2000. Dietary supplement cre- atine protects against traumatic brain injury. Ann Neurol 48(5):723-729. Thorsteinsdottir, B., J. Grande, and V. Garovic. 2006. Acute renal failure in a young weight lifter taking multiple food supplements, including creatine monohydrate. J Ren Nutr 16(4):341-345. Volek, J. S., S. A. Mazzetti, W. B. Farquhar, B. R. Barnes, A. L. Gomez, and W. J. Kraemer. 2001. Physiological responses to short-term exercise in the heat after creatine loading. Med Sci Sports Exerc 33(7):1101-1108. Volek, J., C. Forsythe, and W. Kraemer. 2006. Nutritional aspects of women strength athletes. Br J Sports Med 40(9):742-748. Warber, J., W. Thorian, J. Patton, C. Champagne, P. Mitotti, and H. Lieberman. 2002. The effect of creatine monohydrate supplementation on obstacle course and multiple bench press performance. J Strength Cond Res 16:500-509. Watsford, M. L., A. J. Murphy, W. L. Spinks, and A. D. Walshe. 2003. Creatine supplementa- tion and its effect on musculotendinous stiffness and performance. J Strength Cond Res 17(1):26-33. Weiss, B. A., and M. E. Powers. 2006. Creatine supplementation does not impair the ther- moregulatory response during a bout of exercise in the heat. J Sports Med Phys Fitness 46(4):555-563. DEHYDROEPIANDROSTERONE (DHEA) Background Dehydroepiandrosterone (DHEA), a steroid compound considered a prohormone, is secreted by the adrenal glands and produced in the brain. It can be converted to a variety of steroid hormones, including estrogen and testosterone. Most of the circulating DHEA in the body is in the sulfated form, DHEA-S. Blood concentrations peak in early adulthood and decline with age; at 70+ years old, they are approximately at 10–20 percent of peak levels (Allolio and Arlt, 2002). Some epidemiological ­studies demon- strate a correlation between lower blood DHEA and increased mortality in men (Allolio and Arlt, 2002). This fact, as well as the loss of lean body mass and muscle function with age, has prompted some to explore the use of DHEA as a supplement for aging individuals. There is some evi- 4  The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

OTHER DIETARY SUPPLEMENTS 107 dence linking DHEA to cognitive function including mood and sexuality (Allolio and Arlt, 2002). DHEA may exert its actions via conversion to estrogens or androgens or via direct action as a neurosteroid on receptors in the brain ­ (Allolio and Arlt, 2002). Blood DHEA is reduced in some clinical conditions, including anorexia nervosa, cancer, lupus, HIV, kid- ney disease, and diabetes. Some drugs are known to reduce blood DHEA (e.g., ­dexamethasone, insulin, ­carbamazepine, phenytoin) while others (e.g., b ­ enfluorex, diltiazem) ­increase concentration of this prohormone (Kroboth et al., 1999; Salek et al., 2002). Although many other prohormones came under tighter regulation by the U.S. Food and Drug Administration in 2004 (the Anabolic Steroid Control Act), DHEA was exempt from this act and thus can still be sold as a dietary supplement (Handelsman, 2005). Putative Benefits Because the primary indication for use has been to restore reduced blood DHEA concentration to values typical of young adults, most studies have been performed on older individuals (60+ years of age). Most of these studies show that ingestion of DHEA can increase the blood DHEA concen- tration of elderly individuals to that of young adults (Morales et al., 1998; Percheron et al., 2003). There is a gender difference in DHEA’s effect on other steroid hormones in that women usually also have an increase in tes- tosterone while men have an increase in estrogen (Allolio and Arlt, 2002). Although one of the earlier clinical trials reported a reduction in body fat, increase in lean body mass, and increase in muscle strength in men taking 100 mg/d DHEA for 6 months, this study had a small subject number (9 men and 10 women, ages 50–65 years) and no placebo group (Morales et al., 1998). Most subsequent studies using larger groups of subjects for up to 2 years report similar effects on blood hormone concentration but no effects on body composition or muscle function (e.g., Baulieu et al., 2000; Nair et al., 2006). One exception is a study reporting improved in- sulin sensitivity and reduced visceral and subcutaneous fat in subjects over 65 years of age subsequent to ingestion of 50 mg/d DHEA for 6 months (Villareal and Holloszy, 2004). Another study reported a modest but sig- nificant increase in bone mineral density in 87 elderly men (>60 years old), but as this change was much less than that reported for other therapeutic interventions, the authors concluded that this was of limited value (Nair et al., 2006). The few studies performed on younger individuals involved in resistance training did not report a benefit on lean tissue or strength gain (Bahrke and Yesalis, 2004; Brown et al., 2006). A Cochrane review of several randomized, placebo-controlled trials that investigated the effects of DHEA on individuals over 50 years of age concluded that DHEA did not improve cognitive function in older individuals (Evans et al., 2007).

108 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Although there is limited data, a few studies suggest potential benefit on mood and sexuality, especially in older women (Allolio and Arlt, 2002; Baulieu et al., 2000). In conclusion, while DHEA may be of medical value for people with certain clinical problems, including adrenal insufficiency, or for those under chronic glucocorticoid treatment, the largest, longest, and best-designed studies do not identify benefits of DHEA on body composi- tion, muscle function, or cognitive function. Safety Concerns Negative effects of DHEA ingestion were primarily observed in women (and were likely secondary to an increase in endogenously synthesized testosterone) and included acne, hirsutism, and reduction in serum high- density lipoprotein (HDL) cholesterol (Allolio and Arlt, 2002). Because of the effects of DHEA on steroid hormones, there has been concern about its potential effects on development of hormone-sensitive cancers such as breast and prostate. One study observed no effect on prostate size or serum prostate-specific antigen (PSA) in men who consumed 75 mg/d of DHEA for 2 years (Nair et al., 2006). However, this may not be long enough to detect an effect on neoplasia. Epidemiological and case-control studies of pre- and postmenopausal women who later developed breast cancer have identified an increase in breast cancer risk for those with the highest blood DHEA levels (Kaaks et al., 2005a,b; Missmer et al., 2004; Raven and Hinson, 2007). This suggests, but does not prove, an association between DHEA supplementation and risk of breast cancer. Caution is appropriate, at least in women already at higher risk of breast cancer, and for long-term users. Studies measuring typical health-related blood panels, including liver function, do not report a change attributable to DHEA taken in typical doses (50–100 mg/d) (Morales et al., 1998; Nair et al., 2006). However, because rodent studies have identified hepatic carcinogenic properties of DHEA (Mayer and Forstner, 2004) in rats fed 0.45–1 percent of their diet as DHEA for 52–100 weeks, safety cannot be assured. Although there is modest evidence for enhancement of neoplasia— mostly from large epidemiological studies in women, with some evidence for hepatic cancer in animal models—performance of additional research (i.e., clinical trials) is not warranted because of DHEA’s potential health risk combined with little evidence of benefit. Considerations Specific to the Military There are no reports of studies evaluating DHEA in conditions that would be specific to the military. However, there is no reason to suspect that effects would be different in different environmental or working condi-

OTHER DIETARY SUPPLEMENTS 109 tions. In addition, study subjects were generally older than active duty mili- tary personnel. Most studies with participants who were demographically similar to the military population did not reveal benefits, so the research conducted does not support the value of DHEA as a performance enhancer for military personnel. Relevant data and conclusions on efficacy and safety reviews and pub- lications identified for DHEA are shown in Table 4-4 on pages 182–191. References Allolio, B., and W. Arlt. 2002. DHEA treatment: Myth or reality? Trends Endo Metab 13(7):288-294. Bahrke, M. S., and C. E. Yesalis. 2004. Abuse of anabolic androgenic steroids and related substances in sport and exercise. Curr Opin Pharmacol 4:614-620. Baulieu, E. E., G. Thomas, S. Legrain, N. Lahlou, M. Roger, B. Debuire, V. Faucounau, L. Girard, M. P. Hervy, F. Latour, M. C. Leaud, A. Mokrane, H. Pitti-Ferrandi, C. Trivalle, O. de Acharriere, S. Nouveau, B. Rakoto-Arison, J. C. Souberbielle, J. Raison, Y. Le Bouc, A. Raynaud, X. Girerd, and F. Forette. 2000. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge study to a sociobiomedical issue. Proc Natl Acad Sci 97(8):4279-4284. Brown, G. A., M. Vukovich, and D. S. King. 2006. Testosterone prohormone supplements. Med Sci Sports Exerc 38(8):1451-1461. Evans, G. J., R. Malouf, F. Huppert, and J. K. van Niekerk. 2007. Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people (review). Co- chrane Database Syst Rev 4:CD006221. Handelsman, D. J. 2005. Editorial: Andro and the prosteroids: Bolting the stable door. J Clin Endocrinol Metab 90(2):1249-1251. Kaaks, R., F. Berrino, T. Key, S. Rinaldi, L. Dossus, C. Biessy, G. Secreto, P. Amiano, S. Bingham, H. Boeing, H. B. Bueno de Mesquita, J. Chang-Claude, F. Clavel-Chapelon, A. Fournier, C. H. van Gils, C. A. Gonzalez, A. B. Gurrea, E. Critselis, K. T. Khaw, V. Krogh, P. H. Lahmann, G. Nagel, A. Olsen, N. C. Onland-Moret, K. Overvad, D. Palli, S. Panico, P. Peeters, J. R. Quirós, A. Roddam, A. Thiebaut, A. Tjønneland, M. D. ­Chirlaque, A. Trichopoulou, D. Trichopoulos, R. Tumino, P. Vineis, T. Norat, P. Ferrari, N. Slimani, and E. Riboli. 2005a. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 97(10):755-765. Kaaks, R., S. Rinaldi, T. J. Key, F. Berrino, P. H. M. Peeters, C. Biessy, L. Dossus, A. Lukanova, S. Bingham, K.-T. Khaw, N. E. Allen, H. B. Bueno de Mesquita, C. H. van Gils, D. Grobbee, H. Boeing, P. H. Lahmann, G. Nagel, J. Chang-Claude, F. Clavel-Chapelon, A. Fournier, A. Thiébaut, C. A. González, J. R. Quirós, M.-J. Tormo, E. Ardanaz, P. ­Amiano, V. Krogh, V. Palli, S. Panico, R. Tumino, P. Vineis, A. Trichopoulou, V. ­Kalapothaki, D. Trichopoulos, P. Ferrari, T. Norat, R. Saracci, and E. Riboli. 2005b. Postmenopausal serum androgens, oestrogens and breast cancer risk: The European Prospective Investiga- tion into Cancer and Nutrition. Endocr Relat Cancer 12(4):1071-1082. Kroboth, P. D., F. S. Salek, A. L. Pittenger, T. J. Fabian, and R. F. Frye. 1999. DHEA and DHEA-S: A review. J Clin Pharmacol 39(4):327-348. Mayer, D., and K. Forstner. 2004. Impact of dehydroepiandrosterone on hapatocarcinogenesis in the rat (review). Int J Oncol 25:1021-1030.

110 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Missmer, S. A., A. H. Eliassen, R. L. Barbieri, and S. E. Hankinson. 2004. Endogenous estro- gen, androgen, and progesterone concentrations and breast cancer risk among postmeno- pausal women. J Natl Cancer Inst 96(24):1856-1865. Morales, A. J., R. H. Haubricht, J. Y. Hwang, H. Asakura, and S. S. Yen. 1998. The effect of six months with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and woman. Clin Endo 49(4):421-432. Muller, M., A. W. van den Beld, Y. T. van der Schouw, D. E. Grobbee, and S. W. J. Lamberts. 2006. Effects of dehydroepiandrosterone and atamestane supplementation on frailty in elderly men. J Clin Endocrinol Metab 91(10):3988-3991. Nair, K. S., R. A. Rizza, P. O’Brien, K. Dhatariya, K. R. Short, A. Nehra, J. L. Vittone, G. G. Klee, A. Basu, R. Basu, C. Cobelli, G. Toffolo, C. Dalla Man, D. J. Tindall, L. J. III, G. E. Smith, S. Khosla, and M. D. Jensen. 2006. DHEA in elderly women and DHEA or testosterone in elderly men. New Eng J Med 355(16):1647-1659. Percheron, G., J. Hogrel, S. Denot-Ledunois, G. Fayet, F. Forette, E. Baulieu, M. Fardeau, and J. Marini. 2003. Effect of 1-year oral administration of dehydroepiandrosterone to 60- to 80-year-old individuals on muscle function and cross-sectional area. Arch Intern Med 163(6):720-727. Raven, P. W., and J. P. Hinson. 2007. Dehydroepiandrosterone (DHEA) and the menopause: An update. Menopause Int 13(2):75-78. Salek, F. S., K. L. Bigos, and P. D. Broboth. 2002. The influence of hormones and pharmaceu- tical agents on DHEA and DHEA-S concentrations: A review of clinical studies. J Clin Pharmacol 42(3):247-266. Villareal, D. T., and J. O. Holloszy. 2004. Effect of DHEA on abdominal fat and insulin action in elderly women and men: A randomized controlled trial. JAMA 292(18):2243-2248. EPHEDRA Background The genus Ephedra is composed of 40 different species all belonging to the family Ephedraceae (Andraws et al., 2005; Mahady et al., 1999). The correct scientific name for the most commonly used form of Ephedra is Ephedra sinica Stapf; however, other ephedrine-containing species of the same genus are also used. While there are no botanical synonyms used for this plant, there are numerous vernacular (common) names used worldwide for Ephedra (for a listing, see Mahady et al., 1999). Ephedra sinica is a small, green, almost leafless shrub native to many parts of the world. Ephedra species are found in China, India, Mongolia, and Afghanistan, as well as regions of the Mediterranean and North and Central America (Mahady et al., 1999). Ephedra herb has a pinelike odor and an astringent taste, often having a numbing action on the tongue (Blumenthal and King, 1995). The traditional Chinese name by which it is  The monographs were developed in order to evaluate the review process outlined in Chap-   ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

OTHER DIETARY SUPPLEMENTS 111 commonly known, ma huang, is thought to refer to the astringent action (ma) and the yellow color (huang) of the twigs (Tyler et al., 1988). In traditional Chinese medicine, Ephedra-containing preparations have been used for 5,000 years for the treatment of colds, influenzas, f ­ ever, headache, bronchial asthma, nasal congestion, coughs, and wheezing ( ­ Blumenthal and King, 1995; Mahady et al., 2001). In Western medicine, some of the alkaloids in Ephedra, such as ephedrine and pseudoephedrine, are employed as drug therapy for the treatment of bronchial asthma, nasal congestion, acute bronchospasm, and idiopathic orthostatic hypertension ( ­ Mahady et al., 2001). In the United States, the Food and Drug Adminis- tration (FDA) has approved several alkaloids in Ephedra as ingredients in over-the-counter nasal decongestants and bronchodilator drugs. Pseudo- ephedrine is approved as an oral decongestant for the symptomatic treat- ment of the common cold, hay fever, allergic rhinitis, upper respiratory allergies, and sinusitis. Ephedrine has been approved as topical therapy only for the treatment of nasal congestion and asthma (Blumenthal and King, 1995). The plant and its alkaloids are also used for modern purposes that include weight loss and enhancement of athletic performance; however, the usefulness of Ephedra for these indications remains to be proven. Standardized extracts and other commercial products of Ephedra are prepared from the dried stem or aerial part of Ephedra sinica Stapf and other ephedrine-containing species of the same genus. The chemical constit- uents of Ephedra include (-)-ephedrine in concentrations of 40–90 percent of the total alkaloid fraction, accompanied by (+)-pseudoephedrine. Other compounds in the alkaloid complex include trace amounts of (–)-nor- ephedrine, (+)-norpseudoephedrine, (-)-methylephedrine and (+)-methyl­ pseudoephedrine. Although the total alkaloid content can exceed 2 percent depending on the species, not all Ephedra species contain ephedrine or alkaloids (Mahady et al., 1999). The daily dose of Ephedra-containing products varies depending on the concentration of ephedrine in the preparation: for crude plant mate- rial, 1–6 g daily, generally given as a decoction; for liquid extract (1:1 in 45 percent alcohol), 1–3 mL daily; for tincture (1:4 in 45 percent alcohol), 6–8 mL daily (Mahady et al., 1999). Putative Benefits Ephedrine acts as a stimulant in the central nervous system (ODS, 2007). Of the Ephedra alkaloids, ephedrine is the most potent thermogenic agent. It may function as an anorectic by acting on the satiety center in the hypothalamus. A review of all of the clinical trials for Ephedra is beyond the scope of this work, and only clinical trials or case reports involving weight loss and athletic performance were assessed.

112 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Limited data from a meta-analysis of the clinical trials for Ephedra- containing supplements showed an increase in weight loss of 0.6–0.8 kg per month as compared with placebo. Ephedra taken in combination with caffeine resulted in a weight loss of 1.0 kg/month when compared with placebo, observed for only a 6-month period (Keisler and Hosey, 2005). No long-term data exist. The majority of the studies published in the literature show no effect on athletic performance (Keisler and Hosey, 2005). Clinical trials have assessed the effects of ephedrine hydrochloride (HCl) (the synthetic drug form of ephedrine) and other Ephedra alkaloids such as pseudoephedrine in combination with caffeine. In various exercise modalities, ephedrine and related alkaloids have not been shown to result in any significant perfor- mance improvements (Magkos and Kavouras, 2004). The committee identified and reviewed various studies in which the ef- fects of use of Ephedra–caffeine combinations on either performance (Bell et al., 2001; Jacobs et al., 2003), weight loss (Boozer et al., 2002; Coffey et al., 2004; Hackman et al., 2006), or adverse events (Haller et al., 2005; Kalman et al., 2002; Vukovich et al., 2005) were investigated (see Table 4-5 on pages 192–229). Caffeine–ephedrine mixtures have been reported to provide a greater ergogenic benefit than either drug alone. However, the published scientific data are too heterogeneous to allow conclusions to be drawn. An increase in athletic performance is a uniform finding observed during submaximal steady-state aerobic exercise, short- and long-distance running, and maximal and supramaximal anaerobic cycling, as well as weight lifting. The ingestion of ephedrine in combination with caffeine in- creases blood glucose and lactate concentrations during exercise, whereas similar qualitative effects on lipid fuels (free fatty acids and glycerol) are less pronounced. In parallel, epinephrine and dopamine concentrations are significantly increased, while the effects on norepinephrine are not sig- nificant. No physiologically significant effects on pulmonary gas exchange were observed during short-term intense exercise following the ingestion of caffeine, ephedrine, or a combination of the two. However, tests during longer and/or more demanding efforts have shown some sporadic enhance- ments. An increase in heart rate, exceeding that caused by exercise alone, is a relatively consistent concomitant effect of the caffeine-ephedrine mixture. Finally, evidence to date strongly suggests that the combination of caffeine and synthetic ephedrine HCl may be effective in decreasing the rating of perceived exertion; this appears to be independent of the type of activity being performed (Magkos and Kavouras, 2004).

OTHER DIETARY SUPPLEMENTS 113 Safety Concerns Haller and Benowitz (2000) reviewed 140 case reports of adverse events associated with the use of dietary supplements that were reported to the FDA from 1997 to 1999. Of these reports, 43 cases (31 percent) were con- sidered definitely or probably associated with the use of ­Ephedra alkaloids (for simplicity, products containing ephedrine alkaloids will be ­ referred to as “ephedra”), and another 44 cases (31 percent) possibly related. Of events related to ephedra, 47 percent involved cardiovascular symptoms and 18 percent were central nervous system events. Hyper­tension was the adverse effect most frequently reported (17 reports), followed by palpita- tions, tachycardia, or both (13 reports); stroke (10 reports); and seizures (7 reports). There were 10 events resulting in death, and 13 resulted in perma- nent disability. Sixty-three percent of ephedra users were under the age of 45 years (Haller and Benowitz, 2000). Use of ephedra-containing supple- ments is associated with both ischemic and hemorrhagic stroke, cardiac arrhythmias including ventricular tachycardia, coronary vasospasm, acute myocardial infarction, tachycardia-induced cardiomyopathy, and sudden death (Dhar et al., 2005). Increased coronary vasoconstriction, tachycardia, and hypertension reported associated with use of ephedra may be due to induction of myocardial ischemia and infarction. Hemorrhagic stroke is likely secondary to hypertension or cerebral vasculitis (Dhar et al., 2005). Other adverse events such as hearing loss (Schweinfurth and Pribitkin, 2003), ­ psychosis (Jacobs and Hirsch, 2000), rhabdomyolysis (Moawad et al., 2006; Stahl et al., 2006), seizures (Haller et al., 2005), and visual disturbances (Moawad et al., 2006; Simsek et al., 2006) have also been reported. Products containing Ephedra and ephedra alkaloids are contraindi- cated in patients with coronory thrombosis, diabetes, glaucoma, coronary heart disease, hypertension, thyroid disease, impaired circulation to the cerebrum, pheochromocytoma, or enlargement of the prostate (Mahady et al., 1999). In 2004, because of concerns over cardiovascular effects including in- creased blood pressure and irregular heart rhythm, the FDA banned the sale of dietary supplements containing ephedra. The final FDA rule, published February 6, 2004, became effective on April 12, 2004, and has remained unchanged in spite of attempts by industry to have this ruling overturned (Rados, 2004). Interactions with Other Dietary Supplements or Medications Ephedrine (ephedrine sulfate) is both an α- and a β-adrenergic agonist, and also acts as an indirect sympathomimetic drug by enhancing the release

114 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL of norepinephrine from sympathetic neurons. Indirect sympathomimetic agents given in combination with monoamine oxidase inhibitors may in- duce severe hypertension, hyperpyrexia, seizures, arrhythmias, and possibly death (Hansten and Horn, 2000). Ephedra in combination with cardiac glycosides or halothane (anes- thesia) may cause heart rhythm disturbances; with guanethidine, it may enhance the sympathomimetic effect; with ergot alkaloid derivatives or oxytocin, it may increase the risk of high blood pressure (Mahady et al., 1999). Considerations Specific to the Military Owing to the strong impetus in the military to maintain prescribed weight and enhance physical performance, past studies reported that the use of ephedra-containing products was high (Brasfield, 2004; Deuster et al., 2003). Although the use of ephedra is currently banned in the United States, the availability of botanicals that are chemically similar to ephedra and might mimic its effects raises safety concerns. The likelihood of adverse events resulting from the misuse of over-the-counter medications containing ephedra might be small, but continues to be of concern. While the effects of ephedra on alertness, physical activity, and caloric intake may be beneficial, the ingestion of products containing ephedra alkaloids is more likely to have negative effects on hydration, thermal regulation, gastrointestinal tract function, kidney stone development, liver function, mood, and recovery from injury, and be dangerous to cardiovas- cular health. Relevant data and conclusions on efficacy and safety reviews and pub- lications identified for ephedra are shown in Table 4-5 on pages 192–229. References Abourashed, E. A., A. T. El-Alfy, I. A. Khan, and L. Walker. 2003. Ephedra in perspective: A current review. Phytother Res 17(7):703-712. Andraws, R., P. Chawla, and D. L. Brown. 2005. Cardiovascular effects of ephedra alkaloids: A comprehensive review. Prog Cardiovasc Dis 47(4):217-225. Bell, D. G., I. Jacobs, and K. Ellerington. 2001. Effect of caffeine and ephedrine ingestion on anaerobic exercise performance. Med Sci Sports Exerc 33(8):1399-1403. Bell, D. G., T. M. McLellan, and C. M. Sabiston. 2002. Effect of ingesting caffeine and ephed- rine on 10-km run performance. Med Sci Sports Exerc 34(2):344-349. Bent, S., T. N. Tiedt, M. C. Odden, and M. G. Shlipak. 2003. The relative safety of ephedra compared with other herbal products. Ann Intern Med 138(6):468-471. Blumenthal, M., and P. King. 1995. A review of the botany, chemistry, medicinal uses, safety concerns and legal status of Ephedra and its alkaloids. Herbalgram 34:22-57. Boerth, J. M., and C. F. Caley. 2003. Possible case of mania associated with ma-huang. Phar- macotherapy 23(3):380-383.

OTHER DIETARY SUPPLEMENTS 115 Boozer, C. N., P. A. Daly, P. Homel, J. L. Solomon, D. Blanchard, J. A. Nasser, R. Strauss, and T. Meredith. 2002. Herbal ephedra/caffeine for weight loss: A 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Disord 26(5):593-604. Brasfield, K. 2004. Dietary supplement intake in the active duty enlisted population. US Army Med Dep J (Oct-Dec):44-56. Charatan, F. 2003. Ephedra supplement may have contributed to sportsman’s death. Br Med J 326(7387):464. Chen, C., J. Biller, S. J. Willing, and A. M. Lopez. 2004. Ischemic stroke after using over the counter products containing ephedra. J Neurol Sci 217(1):55-60. Chen-Scarabelli, C., S. E. Hughes, G. Landon, P. Rowley, Z. Allebban, N. Lawson, L. S ­ aravolatz, J. Gardin, D. Latchman, and T. M. Scarabelli. 2005. A case of fatal ephedra intake associated with lipofuscin accumulation, caspase activation and cleavage of myo- fibrillary proteins. Eur J Heart Fail 7(5):927-930. Coffey, C. S., D. Steiner, B. A. Baker, and D. B. Allison. 2004. A randomized double-blind placebo-controlled clinical trial of a product containing ephedrine, caffeine, and other ingredients from herbal sources for treatment of overweight and obesity in the absence of lifestyle treatment. Int J Obes Relat Metab Disord 28(11):1411-1419. 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. Dhar, R., C. W. Stout, M. S. Link, M. K. Homoud, J. Weinstock, and N. A. Estes III. 2005. Cardiovascular toxicities of performance-enhancing substances in sports. Mayo Clin Proc 80(10):1307-1315. Goldberg, L. D., D. Elliot, and K. Kuehl. 2002. Effect of caffeine and ephedrine ingestion on anaerobic exercise performance (Letter). Med Sci Sports Exerc 34(1):181-182. Hackman, R. M., P. J. Havel, H. J. Schwartz, J. C. Rutledge, M. R. Watnik, E. M. Noceti, S. J. Stohs, J. S. Stern, and C. L. Keen. 2006. Multinutrient supplement containing e ­ phedra and caffeine causes weight loss and improves metabolic risk factors in obese women: A randomized controlled trial. Int J Obes (Lond) 30(10):1545-1556. Haller, C., and N. L. Benowitz. 2000. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 343(25):1833-1838. Haller, C., K. H. Meier, and K. R. Olson. 2005. Seizures reported in association with use of dietary supplements. Clin Toxicol 1:23-30. Hansten, P. D., and J. R. Horn. 2000. The top 100 drug interactions: A guide to patient man- agement. Edmonds, WA: H & H Publications. Jacobs, I., H. Pasternak, and D. G. Bell. 2003. Effects of ephedrine, caffeine, and their com- bination on muscular endurance. Med Sci Sports Exerc 35(6):987-994. Jacobs, K. M., and K. A. Hirsch. 2000. Psychiatric complications of Ma-huang. Psychosomat- ics 41:58-62. Jordan, J., J. R. Shannon, A. Diedrich, B. Black, D. Robertson, and I. Biaggioni. 2004. Water potentiates the pressor effect of ephedra alkaloids. Circulation 109(15):1823-1825. Kalman, D., T. Incledon, I. Gaunaurd, H. Schwartz, and D. Krieger. 2002. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss prod- uct in healthy overweight adults. Int J Obes Relat Metab Disord 26(10):1363-1366. Keisler, B. D., and R. G. Hosey. 2005. Ergogenic aids: An update on ephedra. Curr Sports Med Rep 4(4):231-235. Libman, R. B., B. L. Menna, and S. Gulati. 2005. Case report: Consequences of ephedra use in an athlete. Lancet 366(Suppl 1):S22. LoVecchio, F., B. Sawyers, and P. A. Eckholdt. 2005. Transient ischemic attack associated with Metabolife 356 use. Am J Emerg Med 23(2):199-200.

116 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Magkos, F., and S. A. Kavouras. 2004. Caffeine and ephedrine: Physiological, metabolic and performance-enhancing effects. Sports Med 34(13):871-889. Maglione, M., K. Miotto, M. Iguchi, L. Hilton, and P. Shekelle. 2005. Psychiatric symptoms associated with ephedra use. Expert Opin Drug Saf 4(5):879-884. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 1999. Herba Ephedrae. WHO monographs on selected medicinal plants. Vol. I. Geneva, Switzerland: World Health Organization. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 2001. Botanical dietary supplements: Quality, safety and efficacy. Lisse, The Netherlands: Swets and Zeilinger. Miller, S. C. 2004. Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements. Mil Med 169(2):87-93. Moawad, F. J., J. D. Hartzell, T. J. Biega, and C. J. Lettieri. 2006. Transient blindness due to posterior reversible encephalopathy syndrome following ephedra overdose. South Med J 99(5):511-514. Morgenstern, L. B., C. M. Viscoli, W. N. Kernan, L. M. Brass, J. P. Broderick, E. Feldmann, J. L. Wilterdink, T. Brott, and R. I. Horwitz. 2003. Use of ephedra-containing products and risk for hemorrhagic stroke. Neurology 60(1):132-135. Naik, S. D., and R. S. Freudenberger. 2004. Ephedra-associated cardiomyopathy. Ann Phar- macother 38(3):400-403. ODS (Office of Dietary Supplements). 2003. Ephedra and ephedrine alkaloids for weight loss and athletic performance. http://ods.od.nih.gov/factsheets/ephedraandephedrine.asp (ac- cessed April 17, 2008). Peters, C. M., J. O. O’Neill, J. B. Young, and C. Bott-Silverman. 2005. Is there an association between ephedra and heart failure? A case series. J Card Fail 11(1):9-11. Rados, C. 2004. Ephedra ban: No shortage of reasons. FDA Consum 38(2):6-7. Rakovec, P., M. Kozak, and M. Sebestjen. 2006. Ventricular tachycardia induced by abuse of ephedrine in a young healthy woman. Wien Klin Wochenschr 118(17-18):558-561. Schweinfurth, J., and E. Pribitkin. 2003. Sudden hearing loss associated with ephedra use. Am J Health Syst Pharm 60(4):375-377. Shekelle, P. G., M. L. Hardy, S. C. Morton, M. Maglione, W. A. Mojica, M. J. Suttorp, S. L. Rhodes, L. Jungvig, and J. Gagne. 2003. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: A meta-analysis. JAMA 289(12):1537-1545. Simsek, S., A. Khazen, and P. J. Lansink. 2006. Visual impairment and ephedra. Eur J Intern Med 17(2):147. Stahl, C. E., C. V. Borlongan, M. Szerlip, and H. Szerlip. 2006. No pain, no gain—Exercise- induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra. Med Sci Monit 12(9):CS81-CS84. Tyler, V. E., L. R. Brady, and J. E. Robbers. 1988. Pharmacognosy, 9th ed. Philadelphia, PA: Lea and Febiger. Verduin, M. L., and L. A. Labbate. 2002. Psychosis and delirium following Metabolife use. Psychopharmacol Bull 36(3):42-45. Vukovich, M. D., R. Schoorman, C. Heilman, P. Jacob III, and N. L. Benowitz. 2005. Caffeine- herbal ephedra combination increases resting energy expenditure, heart rate and blood pressure. Clin Exp Pharmacol Physiol 32(1-2):47-53. Walton, R., and G. H. Manos. 2003. Psychosis related to ephedra-containing herbal supple- ment use. South Med J 96(7):718-720.

OTHER DIETARY SUPPLEMENTS 117 GARLIC Background Garlic is a perennial, erect, bulbous herb, with the bulb giving rise to a number of narrow, keeled, grasslike leaves above the ground (Mahady et al., 1999). Botanical researchers believe that garlic originated in central Asia (Koch and Lawson, 1996; Mahady et al., 1999), but its botanical name, Allium sativum, may have been derived from the Celtic word áll, meaning warm or pungent (Mahady et al., 2001; Srivastava et al., 1995). Botanical synonyms that may appear in the scientific literature include Porvium sativum Rehb. (Mahady et al., 1999). Due to its widespread use throughout the world, there are numerous vernacular (common) names for garlic (for a listing, see Mahady et al., 1999). Currently, garlic is com- mercially cultivated in Argentina, China, Egypt, France, Hungary, India, Italy, Japan, Mexico, Spain, the United States, and the Czech Republic and Slovakia (Koch and Lawson, 1996; Scientific Technical & Research Com- mission, 1985). Garlic is one of the earliest documented examples of a food plant that was also used for the prevention and treatment of disease (Mahady et al., 1999; Srivastava et al., 1995). The medical history of garlic dates back approximately 4,000 years, when its medicinal uses were described in Chi- nese, Indian, and Sumerian literature (Mahady et al., 2001; Srivastava et al., 1995). In 1550 BCE, the importance of garlic in Egyptian medical practice was illustrated in the Codex Ebers, a famous Egyptian papyrus recording over 800 medical formulas. Garlic is contained in 22 of them, for treatment of various ailments including body weakness, headaches, and throat tumors (Srivastava et al., 1995). Cloves of garlic were often found among the ruins of the tombs of Egyptian pharaohs, including Tutankhamen (Mahady et al., 2001). During the first century CE, the Roman naturalist Pliny the Elder advocated garlic for the treatment of epilepsy, hoarseness, hemorrhoids, and tuberculosis. The Greek physician Dioscorides recommended garlic to clean the arteries, and Hippocrates (460–370 BCE) prescribed garlic for a wide variety of ailments including infections (Mahady et al., 2001). The therapeutic properties of garlic are also mentioned in the Bible and the Talmud. In medieval Europe, garlic was purported to confer immunity from the bubonic plague, and individual resistance to the plague was often at- tributed to its consumption (Mahady et al., 2001; Srivastava et al., 1995). Standardized extracts and other commercial products of garlic are prepared from the fresh or dried bulbs of Allium sativum L. (Liliaceae)   The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

118 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL (European pharmacopoeia, 1996; Mahady et al., 1999; Sendl, 1995). The important chemical constituents of garlic bulbs are organosulfur com- pounds (Mahady et al., 1999). Approximately 82 percent of the total sulfur content of a garlic bulb is composed of the cysteine sulfoxides (e.g., alliin) and the nonvolatile γ-glutamylcysteine peptides. The thiosulfinates (e.g., allicin), ajoenes (e.g., E-ajoene, Z-ajoene), vinyldithiins (e.g., 2-vinyl-(4H)- 1,3-dithiin, 3-vinyl-(4H)-1,2-dithiin), and sulfides (e.g., diallyl disulfide, diallyl trisulfide), however, are not naturally occurring compounds. These compounds are degradation products that are produced from the naturally occurring cysteine sulfoxide, alliin. When a garlic bulb is crushed, minced, or otherwise processed, the compartmentalized alliin comes in contact with the enzyme alliinase from the adjacent vacuoles, resulting in hydrolysis and immediate condensation of the reactive intermediate (allylsulfenic acid) to form allicin. Allicin is an unstable compound, and will undergo additional reactions to form other derivatives, depending on environmental or pro- cessing conditions (Mahady et al., 1999; Reuter and Sendl, 1994; Sendl, 1995). Analysis of various commercial garlic products shows the variation in sulfur chemical profiles that are reflective of the processing procedure. For example, processed bulb or dried garlic bulb powder products contain mainly alliin and allicin, while the volatile oil contains almost entirely diallyl sulfide, diallyl disulfide, diallyl trisulfide, and diallyl tetrasulfide. Oil macerates, on the other hand, contain mainly 2-vinyl-[4H]-1,3-dithiin; 3-vinyl-[4H]-1,3-dithiin; cis-ajoene; and trans-ajoene (Lawson, 1991; Sendl, 1995; Ziegler and Sticher, 1989). Putative Benefits Modern therapeutic applications for products containing garlic include its use as an adjunct to dietetic management of hyperlipidemia and the prevention of atherosclerotic (age-associated) vascular changes (Mahady et al., 1999). However, results from recent clinical trials that included a low-cholesterol diet for 2 to 4 weeks prior to garlic treatments failed to show any benefits of garlic supplementation when used in conjunction with a cholesterol-lowering diet (Mahady et al., 2001; Pittler and Ernst, 2007). Other reviews of the scientific literature assessing the effectiveness of garlic in reductions in serum cholesterol, low-density lipoproteins, oxidation, platelet aggregation, and hypertension show that 44 percent of clinical t ­ rials demonstrated a reduction in total cholesterol, with the most profound e ­ ffect observed in garlic’s ability to reduce platelet aggregation. Mixed re- sults have been obtained in the area of blood pressure and oxidative-stress reduction (Ackermann et al., 2001; Rahman and Lowe, 2006).

OTHER DIETARY SUPPLEMENTS 119 Garlic has been reported to reduce the growth of various antibiotic- resistant microorganisms and reduce the minimum inhibitory concentra- tions of specific antibiotics in vitro (Cai et al., 2007; Cutler and Wilson, 2004; Tsao and Yin, 2001). Pure compounds from garlic, such as ajoene and allicin, have both antibacterial and antifungal activities in vitro, in vivo, and in human studies; however, these results need to be repeated in controlled clinical trials. One 12-week double-blind clinical trial involving 146 subjects treated daily with garlic or placebo showed a reduction in the symptoms of the common cold and a reduction in the duration of illness in those receiving garlic compared to those receiving placebo (Pittler and Ernst, 2007). Other medical uses claimed for garlic include treatment of asthma, bronchitis, dyspepsia, fever, lower urinary tract infections, ringworm, and rheumatism; however, there are no clinical data to support these claims (Mahady et al., 1999). Safety Concerns Garlic has been reported to reduce the activity of the cytochrome P450 enzyme isomer CYP2E1, thus affecting liver function and health (Hu et al., 2005). Consumption of large doses of garlic-containing dietary supplements may increase the risk of postoperative bleeding (Mahady et al., 1999). Use of supplements containing garlic is contraindicated in patients with a known allergy to garlic, and there is often a cross-sensitivity to onions and tulips (Mahady et al., 1999). Interactions with Other Dietary Supplements or Medications The level of safety for garlic is reflected by its worldwide use as a seasoning in food. However, in therapeutic doses, garlic may cause post- operative bleeding, especially when used in combination with anticoagu- lants such as warfarin. Two case reports suggest that the combination of warfarin and garlic products may increase clotting time and potentially cause postoperative bleeding (Mahady et al., 1999). Therefore, daily use of garlic-containing dietary supplements with concurrent administration of anticoagulants and antiplatelet drugs is not recommended. The possible interaction of garlic with chlorpropamide resulting in hypoglycemia has been reported. Daily administration of garlic-containing supplements has been reported to reduce the plasma concentrations of protease inhibitors, reducing their efficacy and increasing the potential for serious gastrointestinal adverse events.

120 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Considerations Specific to the Military The use of supplements containing garlic would likely have no impact on high-intensity physical activity, caloric restriction, hydration, mood, alertness, or ability to function at high altitude or in extreme tempera- tures. However, garlic supplementation has been reported to cause gastric upset including heartburn, nausea, vomiting, and diarrhea (Mahady et al., 1999). Because of the increased risk of bleeding, especially when taken concurrently with anticoagulants, the use of garlic as a dietary supplement might expose military subpopulations to unnecessary risks when they are in combat situations. Garlic-containing supplements should be discontinued 2 weeks prior to any surgical procedures or combat deployment. Relevant data and conclusions on efficacy and safety reviews and pub- lications identified for garlic are shown in Table 4-6 on pages 230–237. References Ackermann, R. T., C. D. Mulrow, G. Ramirez, C. D. Gardner, L. Morbidoni, and V. A. L ­ awrence. 2001. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med 161(6):813-824. Ankri, S., and D. Mirelman. 1999. Antimicrobial properties of allicin from garlic. Microbes Infect 1(2):125-129. Cai, Y., R. Wang, F. Pei, and B. B. Liang. 2007. Antibacterial activity of allicin alone and in combination with beta-lactams against Staphylococcus spp. and Pseudomonas aerugi- nosa. J Antibiot (Tokyo) 60(5):335-338. Cutler, R. R., and P. Wilson. 2004. Antibacterial activity of a new, stable, aqueous extract of al- licin against methicillin-resistant Staphylococcus aureus. Br J Biomed Sci 61(2):71-74. European pharmacopoeia. 1996. 3rd ed. Strasbourg: Council of Europe. Hu, Z., X. X. Yang, P. C. L. Ho, S. Y. Chan, P. W. S. Heng, E. Chan, W. Duan, H. L. Koh, and S. F. Zhou. 2005. Herb-drug interactions. Drugs 65(9):1239-1282. Koch, H. P., and L. D. Lawson. 1996. Garlic, the science and therapeutic application of Allium sativum L. and related species, 2nd ed. Baltimore: Williams & Wilkins. Lawson, L. 1991. HPLC analysis of allicin and other thiosulfinates in garlic clove homog- enates. Planta Medica 57:263-270. Ledezma, E., and R. Apitz-Castro. 2006. Ajoene the main active compound of garlic (Allium sativum): A new antifungal agent. Rev Iberoam Micol 23(2):75-80. Mahady, G. B., H. H. S. Fong, and N. F. Farnsworth. 1999. Bulbus Allii sativi. WHO monographs on selected medicinal plants. Vol. 1. Geneva, Switzerland: World Health Organization. Mahady, G. B., H. H. S. Fong, and N. F. Farnsworth. 2001. Botanical dietary supplements: Quality, safety and efficacy. Lisse, the Netherlands: Swets & Zeilinger. Martin, K. W., and E. Ernst. 2003. Herbal medicines for treatment of bacterial infections: A review of controlled clinical trials. J Antimicrob Chemother 51(2):241-246. Milner, J. 2006. Preclinical perspectives on garlic and cancer. J Nutr 136(3):827S-831S. Pittler, M. H., and E. Ernst. 2007. Clinical effectiveness of garlic (Allium sativum). Mol Nutr Food Res 51:1382-1385. Rahman, K., and G. M. Lowe. 2006. Garlic and cardiovascular disease: A critical review. J Nutr 136(3):736S-740S.

OTHER DIETARY SUPPLEMENTS 121 Reuter, H. D., and A. Sendl. 1994. Allium sativum and Allium ursinum: Chemistry, pharma- cology, and medicinal applications. In Economic and medicinal plants research, Vol. 6, edited by H. Wagner and N. R. Farnsworth. London: Academic Press. Pp. 55-113. Scientific Technical and Research Commission. 1985. African pharmacopoeia, 1st ed., Vol. 1. Lagos, Nigeria: Organization of African Unity. Sendl, A. 1995. Allium sativum and Allium ursinum: Part 1. Chemistry, analysis, history, botany. Phytomedicine 4:323-339. Sengupta, A., S. Ghosh, and S. Bhattacharjee. 2004. Allium vegetables in cancer prevention. Asian Pac J Cancer Prev 5(3):237-245. Srivastava, K. C., A. Bordia, and S. K. Verma. 1995. Garlic (Allium sativum) for disease pre- vention. South African Journal of Science 91:68-77. Tsao, S., and M. Yin. 2001. In vitro activity of garlic oil and four diallyl sulphides against antibiotic-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae. J Antimicrob Chemother 47(5):665-670. Ziegler, S. J., and O. Sticher. 1989. HPLC of S-alk(en)yl-l-cysteine derivatives in garlic includ- ing quantitative determination of (+)-S-allyl-l-cysteine sulfoxide (alliin). Planta Medica 55:372-378. GINKGO BILOBA Background Ginkgo biloba is a tall, deciduous tree, known to be extremely resis- tant to insects, bacterial and viral infections, and air pollution (Mahady, 2001, 2002; Major, 1967; Van Beek et al., 1998). The tree is native to China, and the earliest documentation describes the tree as originating in a region south of the Yangtze River (Huh and Staba, 1992). Many specimens of Ginkgo biloba are thought to be over 1,000 years old. Ginkgo biloba was not introduced into Europe and North America until the middle and latter part of the 18th century; it is currently grown as an ornamental shade tree in Europe, Japan, Australia, Southeast Asia, and the United States (Huh and Staba, 1992; Mahady, 2002). It is commercially cultivated in China, France, Korea, and the United States (Mahady, 2002). Medical therapy with ginkgo dates back approximately 5,000 years to the origins of traditional Chinese medicine, when ginkgo was described in ancient Chinese medical texts such as Chen Noung Pen T’sao, Shi Wu Ben Cao, and Ri Yong Ben Cao (Mahady, 2001, 2002). In China, the seeds (nuts) of the ginkgo tree are considered a tonic, and the medicinal uses of ginkgo seeds were reported in the Pen Ts’ao Kang Mu (Great Herbal of 1596) written by Li Shih-Chen (Van Beek et al., 1998). Ginkgo seeds were used for the treatment of alcohol abuse, asthma, bladder inflammation, coughs, and leukorrhoea; in the modern Chinese pharmacopoeia, prepara-   The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

122 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL tions of the leaves of Ginkgo biloba are the official treatment of heart and lung diseases (Mahady, 2002; Van Beek et al., 1998). In 1965, the German physician and pharmacist Dr. Willmar Schwabe introduced a standardized Ginkgo biloba leaf extract into Western medical practice (Mahady, 2001). Only a few ginkgo extracts have ever been tested in randomized con- trolled clinical trials. The most widely investigated ginkgo standardized leaf extract, EGb 761, is manufactured by Dr. Willmar Schwabe BmbH & ­ Company in Karlsruhe, Germany. EGb 761 contains 22–27 percent fl ­ avonoid glycosides; 5–7 percent terpene lactones, of which approximately 2.8–3.4 percent consists of ginkgolides A, B, and C and 2.6–3.2 percent bilobalide; and <5 ppm of ginkgolic acids (Mahady et al., 1999; Van Beek et al., 1998). Today, EGb 761 is used worldwide for the treatment of m ­ emory-related disorders and peripheral arterial occlusive diseases and shows some promise for the treatment and prevention of cardiovascular disease and stroke (Mahady, 2001, 2002). Putative Benefits Results from meta-analysis and reviews of the clinical trials indicate that standardized leaf extracts of Ginkgo biloba may reduce the symptoms of age-associated memory impairment and dementia, including Alzheimer’s disease, and may be of some benefit for the treatment of intermittent clau- dication (Birks et al., 2002; Mahady, 2001, 2002; Mahady et al., 1999). However, many of the early trials used poor methodology and small sample size, and publication bias could not be excluded. The evidence that ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent; the studies would require adequately designed randomized control trials (Birks and Grimley Evans, 2007). The usefulness of ginkgo for the treatment of tinnitus (i.e., ringing in the ears) is limited and thus far unconvincing (Hilton and Stuart, 2004). Its effectiveness in improving cognitive function in healthy subjects has not been well investigated and is also controversial. Ten randomized, placebo-controlled studies involving approximately 1,077 healthy volun- teers have measured the effects of various doses of specific Ginkgo biloba extracts on attention, cognition, executive function, reaction times, and quality of life (Burns et al., 2006; Cieza et al., 2003; Elsabagh et al., 2005; Kennedy et al., 2000; Mattes and Pawlik, 2004; Mix and Crews, 2002; Solomon et al., 2002; Stough et al., 2001; Subhan and Hindmarch, 1984; Warot et al., 1991). The dose of ginkgo extract used ranged from 120 mg/d to 720 mg/d and the length of treatment from a single dose to 4 months. In the most recent study by Burns et al. (2006), no statistically significant dif- ference was found between the group receiving a low dose of ginkgo (120 to 180 mg/d) and that receiving placebo for any of the cognition tests per-

OTHER DIETARY SUPPLEMENTS 123 formed in either young (18–43 years old) or older (55–79 years old) healthy volunteers. In the acute dosing studies, administration of a single dose of ginkgo extract (120 to 600 mg/d) improved performance on sustained at- tention tasks and pattern recognition memory task, while administration of chronic doses to healthy individuals showed no effect (Elsabagh et al., 2005; Kennedy et al., 2000; Subhan and Hindmarch, 1984; Warot et al., 1991). These studies presented limitations such as small subject numbers, lack of dose–response, and lack of standardized tests. Two larger randomized, placebo-controlled studies assessed the effects of ginkgo in healthy adults over 60 years of age (Mix and Crews, 2002; Solomon et al., 2002). Mix and Crews used a standardized Ginkgo biloba extract at a higher dose, 180 mg/d versus 120 mg/d used in the Solomon et al. (2002) study. Salomon et al. (2002) analyzed a modified intent-to- treat population and indicated that there were no significant differences between treatment groups on any outcome measure after chronic adminis- tration of ginkgo to healthy subjects. In this study, ginkgo did not enhance performance on standard neuropsychological tests of learning, memory, attention, and concentration or naming and verbal fluency ­(Solomon et al., 2002). Conversely, the results of the study by Mix and Crews (2002) demonstrated that healthy older participants who received 180 mg of the extract EGb 761 daily for 6 weeks exhibited significant improvement on standard recognition test tasks involving 30 minutes of free recall and recognition (P < .01) of noncontextual, auditory–verbal material, as com- pared with the placebo controls. By treatment end, the follow-up self-report questionnaire showed that significantly more older adults in the ginkgo group rated their overall abilities to remember as “improved” as compared with the placebo controls. The results of this study, from both objective, standardized, neuropsychological tests and a subjective, follow-up self- report questionnaire, suggest that extract EGb 761 is effective in enhanc- ing certain neuro­psychological or memory processes of cognitively intact adults 60 years of age and older (Mix and Crews, 2002). Thus, the results of these two studies are conflicting. These two studies measured different outcomes, supporting the need for further studies with larger populations and standardized methodologies and products. In summary, for younger healthy subjects, high acute dosing of ginkgo may enhance mental performance for short periods of time, while chronic dosing does not appear to be effective. In older healthy subjects with no cognitive deficits, the data about beneficial effects on mental performance are still conflicting, with one study showing benefits with the chronic use of a higher dose of ginkgo (180 mg/d) and one study showing that a lower dose (120 mg/d) was not effective. The Chinese Pharmacopoeia includes an official monograph on use of Ginkgo biloba for the treatment of cardiovascular disease (Mahady, 2002).

124 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL In pilot studies, ginkgo is reported to reduce nanoplaque formation in high-risk cardiovascular patients (Rodriguez et al., 2007) and is used in the treatment of acute ischemic stroke (Liu, 2006; Zeng et al., 2005); however, the data are poor, and large-scale randomized controlled clinical trials are needed before any therapeutic recommendations can be made. Ginkgo has been reported to have a protective effect on liver function in various animal models due to its strong antioxidant and anti-inflammatory effects (Harputluoglu et al., 2006; Naik and Panda, 2007; Yuan et al., 2007; Zhou et al., 2007). Ginkgo biloba extracts inhibit the activities of cytochrome P450 (CYP) enzymes CYP1A2, CYP2D6, CYP2E1, or CYP3A4 in elderly subjects (Gurley et al., 2005). Ginkgo extracts have been shown to reduce nephrotoxicity due to hypoxia, cisplatin, adriamycin, and diabetic-induced neuropathy in ani- mal models (Abd-Ellah and Mariee, 2007; Gulec et al., 2006; Welt et al., 2007). In one small Chinese clinical study, ginkgo extract was reported to improve the renal function of patients with nephritic syndrome (Zhong et al., 2007). Safety Concerns A recent review of the clinical data has concluded that use of Ginkgo biloba appears to be safe, with no excess side effects compared with pla- cebo (Birks and Grimley Evans, 2007). However, 15 published case reports described a temporal association between the use of ginkgo and bleeding events (Bent et al., 2005). Most cases involved serious medical conditions, including eight episodes of intracranial bleeding. However, 13 of the case reports identified other risk factors for the increased bleeding, and only six reports clearly stated that when subjects stopped using ginkgo, bleeding did not recur. In three reports, bleeding times were increased when patients were taking ginkgo. The review concluded that a structured assessment of published case reports suggests a possible causal association between the use of ginkgo and bleeding events (Bent et al., 2005). Given these data, it is recommended that products containing Ginkgo biloba not be taken with other prescription medications that may also cause bleeding, such as anticoagulants. Interactions with Other Dietary Supplements or Medications Ginkgo biloba extract has been reported to interact with trazodone, warfarin, acetylsalicyclic acid, ibuprofen, ticlopidine, tolbutamide, and chlorpropamide (see Table 4-7 on pages 238–259). In addition, Ginkgo biloba extract (120 mg/d) decreased plasma insulin by 26 percent in hyper­ insulinemic patients with type 2 diabetes mellitus who were taking anti­

OTHER DIETARY SUPPLEMENTS 125 hyperglycemic drugs. Ginkgo may increase the hepatic clearance of insulin and antihyperglycemic drugs. Ginkgo biloba extracts inhibit cytochrome P450 (CYP) enzymes CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activities in elderly subjects (Gurley et al., 2005). Because many medications, including antiarrhythmics, antibiotics, calcium channel blockers, corticosteroids, immunosuppressants, HMG-CoA reductase inhibitors, anxiolytics, and some neuropsychiatric medications are metabolized in the liver by the cytochrome P450 enzyme complex, Ginkgo biloba has the potential to negatively affect drug metabo- lism and produce an adverse reaction. Considerations Specific to the Military High acute dosing of ginkgo may enhance mental performance for short periods of time, while chronic dosing does not appear to be effec- tive. Ginkgo extracts have the potential to relieve symptoms of altitude sickness that might result with high-altitude military activities. The clinical trial methodologies from published studies are poor, however, and data are conflicting. The largest clinical study showed no effect on altitude sickness (Gertsch et al., 2004). The ingestion of ginkgo-containing products has been reported to cause bleeding, particularly when used in combination with aspirin or warfarin. Postoperative bleeding has also been reported. Although a recent review of the clinical data has concluded that Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo (Birks and Grimley Evans, 2007), chronic daily use of Ginkgo biloba extracts, in therapeutic doses, may have the potential to cause serious bleeding events postsurgery and in combat situations. Ginkgo extracts have been reported to cause gastrointestinal tract dis- turbances such as nausea, vomiting, and diarrhea. Upon initiation of ginkgo therapy, transient headaches have also been reported. These headaches are associated with increased blood circulation to the brain and usually resolve over a week of daily administration of the product. Allergic skin reactions have been reported (Mahady et al., 1999). There is no apparent reason to believe that the physiological effects of Ginkgo biloba will be altered by physical activity, diets with caloric re- striction, or inadequate hydration. There is also no scientific evidence that Ginkgo biloba would improve other outcomes that are vital to military performance, such as alertness, immune function, or mood. Relevant data and conclusions on efficacy and safety reviews and pub- lications identified for ginkgo are shown in Table 4-7 on pages 238–259.

126 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL References Abd-Ellah, M. F., and A. D. Mariee. 2007. Ginkgo biloba leaf extract (EGb 761) diminishes adriamycin-induced hyperlipidaemic nephrotoxicity in rats: Association with nitric oxide production. Biotechnol Appl Biochem 46(Pt 1):35-40. Bent, S., H. Goldberg, A. Padula, and A. L. Avins. 2005. Spontaneous bleeding associated with Ginkgo biloba: A case report and systematic review of the literature. J Gen Intern Med 20(7):657-661. Betz, J., and R. Costello. 2006. Studies on natural products. Arch Intern Med 166(3): 370-371. Birks, J., and J. Grimley Evans. 2007. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev (2):CD003120. Birks, J., E. V. Grimley, and M. Van Dongen. 2002. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2(4):CD003120. Burns, N. R., J. Bryan, and T. Nettelbeck. 2006. Ginkgo biloba: No robust effect on cogni- tive abilities or mood in healthy young or older adults. Hum Psychopharmacol 21(1): 27-37. Carlson, J. J., J. W. Farquhar, E. DiNucci, L. Ausserer, J. Zehnder, D. Miller, K. Berra, L. Hagerty, and W. L. Haskell. 2007. Safety and efficacy of a Ginkgo biloba-containing dietary supplement on cognitive function, quality of life, and platelet function in healthy, cognitively intact older adults. J Am Diet Assoc 107(3):422-432. Chow, T., V. Browne, H. L. Heileson, D. Wallace, J. Anholm, and S. M. Green. 2005. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: A randomized, placebo-controlled trial. Arch Intern Med 165(3):296-301. Cieza, A., P. Maier, and E. Poppel. 2003. Effects of Ginkgo biloba on mental functioning in healthy volunteers. Arch Med Res 34(5):373-381. Elsabagh, S., D. E. Hartley, O. Ali, E. M. Williamson, and S. E. File. 2005. Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers. Psychopharmacology (Berl) 179(2):437-446. Gertsch, J. H., T. B. Seto, J. Mor, and J. Onopa. 2002. Ginkgo biloba for the prevention of severe acute mountain sickness (AMS) starting one day before rapid ascent. High Alt Med Biol 3(1):29-37. Gertsch, J. H., B. Basnyat, E. W. Johnson, J. Onopa, and P. S. Holck. 2004. Randomised, double blind, placebo controlled comparison of Ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: The prevention of high altitude illness trial (PHAIT). Br Med J 328(7443):797-802. Gulec, M., M. Iraz, H. R. Yilmaz, H. Ozyurt, and I. Temel. 2006. The effects of Ginkgo biloba extract on tissue adenosine deaminase, xanthine oxidase, myeloperoxidase, malon­ dialdehyde, and nitric oxide in cisplatin-induced nephrotoxicity. Toxicol Ind Health 22(3):125-130. Gurley, B. J., S. F. Gardner, M. A. Hubbard, D. K. Williams, W. B. Gentry, Y. Cui, and C. Y. Ang. 2005. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St. John’s wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging 22(6):525-539. Harputluoglu, M. M., U. Demirel, H. Ciralik, I. Temel, S. Firat, C. Ara, M. Aladag, M. K ­ arincaoglu, and F. Hilmioglu. 2006. Protective effects of Ginkgo biloba on ­thioacetamide- induced fulminant hepatic failure in rats. Hum Exp Toxicol 25(12):705-713. Hilton, M., and E. Stuart. 2004. Ginkgo biloba for tinnitus. Cochrane Database Syst Rev (2):CD003852. Hu, Z. P., X. X. Yang, P. C. Lui, S. Y. Chan, P. W. Heng, E. Chan, W. Duan, H. L. Koh, and S. F. Zhou. 2005. Herb-drug interactions: A literature review. Drugs 65(9):1239-1282. Huh, H., and E. J. Staba. 1992. The botany and chemistry of Ginkgo biloba L. J Herbs, Spices Med Plants 1:91-124.

OTHER DIETARY SUPPLEMENTS 127 Kennedy, D. O., A. B. Scholey, and K. A. Wesnes. 2000. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacol- ogy (Berl) 151(4):416-423. Liu, J. 2006. The use of Ginkgo biloba extract in acute ischemic stroke. Explore (NY) 2(3):262-263. Mahady, G. B. 2001. Ginkgo biloba: A review of quality, safety and efficacy. Nutr Clin Care 4(3):140-147. Mahady, G. B. 2002. Ginkgo biloba for the prevention and treatment of cardiovascular dis- ease: A review of the literature. J Cardiovasc Nurs 16(4):21-32. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 1999. Folium Ginkgo. WHO Monographs on selected medicinal plants. Vol 1. Geneva, Switzerland: World Health Organization. Major, R. T. 1967. The Ginkgo, the most ancient living tree. Science 157(3794):1270-1273. Mattes, R. D., and M. K. Pawlik. 2004. Effects of Ginkgo biloba on alertness and chemosen- sory function in healthy adults. Hum Psychopharmacol 19(2):81-90. Mix, J. A., and W. D. Crews, Jr. 2002. A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: Neuro- psychological findings. Hum Psychopharmacol 17(6):267-277. Naik, S. R., and V. S. Panda. 2007. Antioxidant and hepatoprotective effects of Ginkgo biloba phytosomes in carbon tetrachloride-induced liver injury in rodents. Liver Int 27(3):393-399. Rodriguez, M., L. Ringstad, P. Schafer, S. Just, H. W. Hofer, M. Malmsten, and G. Siegel. 2007. Reduction of atherosclerotic nanoplaque formation and size by Ginkgo biloba (EGb 761) in cardiovascular high-risk patients. Atherosclerosis 192(2):438-444. Roncin, J. P., F. Schwartz, and P. D’Arbigny. 1996. EGb 761 in control of acute mountain sick- ness and vascular reactivity to cold exposure. Aviat Space Environ Med 67(5):445-452. Solomon, P. R., F. Adams, A. Silver, J. Zimmer, and R. DeVeaux. 2002. Ginkgo for memory enhancement: A randomized controlled trial. JAMA 288(7):835-840. Stough, C., J. Clarke, J. Lloyd, and P. J. Nathan. 2001. Neuropsychological changes after 30- day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol 4(2):131-134. Subhan, Z., and I. Hindmarch. 1984. The psychopharmacological effects of Ginkgo biloba extract in normal healthy volunteers. Int J Clin Pharmacol Res 4(2):89-93. Van Beek, T. A., E. Bombardelli, P. Morazzoni, and F. Peterlongo. 1998. Ginkgo biloba L. Fitoterapia 69(3):195-244. Warot, D., L. Lacomblez, P. Danjou, E. Weiller, C. Payan, and A. J. Puech. 1991. Comparative effects of Ginkgo biloba extracts on psychomotor performances and memory in healthy subjects. Therapie 46(1):33-36. Welt, K., J. Weiss, R. Martin, T. Hermsdorf, S. Drews, and G. Fitzl. 2007. Ginkgo bi- loba extract protects rat kidney from diabetic and hypoxic damage. Phytomedicine 14(2-3):196-203. Wolf, H. R. 2006. Does Ginkgo biloba special extract EGb 761 provide additional effects on coagulation and bleeding when added to acetylsalicylic acid 500 mg daily? Drugs R D 7(3):163-172. Yuan, G., Z. Gong, J. Li, and X. Li. 2007. Ginkgo biloba extract protects against alcohol- induced liver injury in rats. Phytother Res 21(3):234-238. Zeng, X., M. Liu, Y. Yang, Y. Li, and K. Asplund. 2005. Ginkgo biloba for acute ischaemic stroke. Cochrane Database Syst Rev (4):CD003691. Zhong, Z. M., L. Yu, Z. Y. Weng, Z. H. Hao, L. Zhang, Y. X. Zhang, and W. Q. Dong. 2007. Therapeutic effect of Ginkgo biloba leaf extract on hypercholestrolemia in children with nephrotic syndrome. Nan Fang Yi Ke Da Xue Xue Bao 27(5):682-684.

128 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Zhou, J. B., X. K. Yang, Q. F. Ye, Y. Z. Ming, and Z. J. Xia. 2007. Effect of extract of Ginkgo biloba leaves on the precondition of liver graft in rat liver transplantation. Zhong Nan Da Xue Xue Bao Yi Xue Ban 32(1):54-58. GINSENG Background Some of the most popular and well-known dietary supplements come from a group of plants known generically as ginseng. The primary com- mercial species (scientific name, Panax ginseng C.A. Meyer), is commonly referred to as Korean or Asian ginseng. The plant is indigenous to the mountainous regions of Korea, Japan, China (Manchuria), and Russia (eastern Siberia) (Hu, 1976; Mahady et al., 1999). However, most com- mercial ginseng is now cultivated, as wild Panax ginseng is a protected species in both Russia and China (Carlson, 1986). Commercial products are prepared from cultivated ginseng imported from China and Korea (Hu, 1976; Mahady et al., 1999). In China, the root or rhizome (underground stem) and other parts of the plant have been used medicinally (Hu, 1976). However, the root is cer- tainly the most prominent part and sales of root-derived products dominate the commercial market. The plant is a slow-growing perennial herb, and the roots are usually not harvested until the fifth or sixth year of growth, when the ginsenosides (the active constituents) are at their highest concentration (Hu, 1976; Mahady et al., 2001). After harvesting, Panax ginseng roots are prepared for commercial use by one of two methods to prevent rotting and microbial contamination. Ginseng root prepared by drying and bleaching the roots using sulfur dioxide is called “white ginseng.” The root is also sometimes peeled to remove the outer coating (skin). “Red ginseng” is pre- pared by steaming the root for 3 hours and then air-drying it. The steamed root turns a caramel color and is resistant to invasion by fungi and pests (Hu, 1976; Mahady et al., 2001; Shibata et al., 1985). The main active chemical constituents of Panax ginseng include the triterpene saponins, known as the ginsenosides (Mahady et al., 1999). More than 30 are based on the dammarane structure, with one, ginsenoside Ro, being an oleanolic acid derivative (Cui, 1995; Mahady et al., 1999; Shibata et al., 1985). The ginsenosides are derivatives of either protopanaxadiol or protopanaxatriol. The most important constituents are the ginsenosides Rb–1, Rb–2, Rc, Rd, Rf, Rg–1, and Rg–2 (Mahady et al., 1999, 2001).   The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

OTHER DIETARY SUPPLEMENTS 129 Putative Benefits While the genus name Panax derives from the Greek word panacea, meaning “cure-all,” its application according to traditional Chinese medi- cine is actually very specific (Hu, 1976; Mahady et al., 2001; Sonnenborn and Proppert, 1991). Panax ginseng is used to treat older patients with chronic illnesses, especially given during periods of convalescence, to re- store the person to a normal state of good health (Hu, 1976; Mahady et al., 2001). Up until 1937, Panax ginseng was an official compendial drug in the United States, listed in the The Dispensatory of the United States of ­ merica. The U.S. Food and Drug Administration currently regards ginseng A as a food and ginseng-containing products as dietary supplements (Mahady et al., 2001). According to the World Health Organization’s (WHO’s) WHO Monographs on Selected Medicinal Plants, Panax ginseng is used as a tonic or immune stimulant for enhancement of mental and physical capacity during fatigue, chronic illness, and convalescence (Mahady et al., 1999). The hypothesis that Panax ginseng might be used as an ergogenic agent in healthy subjects is a more modern idea; in 2001 and 2003, two small controlled clinical trials investigated the ergogenic effects of standardized Panax ginseng extract G115 in healthy subjects (Engels et al., 2001, 2003). Both studies failed to find ergogenic benefits in the recovery from short, supra­ maximal exercise or in the Wingate Anaerobic test (an all-out-effort, 30- second leg cycle test). These studies confirm the lack of ergogenic effects for Panax ginseng in healthy subjects seen in previous studies ­(Lieberman, 2001). Thus, to date, there are no compelling data that suggest that Panax ginseng has any positive effects on physical performance in healthy individuals. One randomized placebo-controlled clinical trial assessed the effects of Panax ginseng extract G115 at a dose of 200 to 400 mg/day on mood and other psychological parameters in 83 young healthy subjects (Cardinal and Engels, 2001). After 8 weeks of treatment, no improvements were observed in any measured parameter, indicating that ginseng has no beneficial ef- fects on mood or memory in young healthy subjects (Cardinal and Engels, 2001). Two smaller clinical studies assessed the cognitive effects of Panax ginseng extract G115 at a dose of 200 mg or 400 mg in 30 or 27 healthy young adults respectively (Reay et al., 2005, 2006). The 2006 study showed that both Panax ginseng or glucose enhanced the performance of a mental arithmetic task and ameliorated the increase in subjective feelings of mental fatigue experienced by participants during the later stages of the sustained, cognitively demanding task performance. No evidence of synergistic effects was observed when glucose and Panax ginseng G115 were administered together (Reay et al., 2006). The 2005 trial showed that improvements in

130 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL behavioral effects were associated with the oral administration of 200 mg of Panax ginseng G115 extract, and included significant improvements (P < .05) in the Serial Sevens subtraction task performance and a significant reduction in the subjective mental fatigue test throughout all of the post- dose completions of the 10-minute battery (with the exception of one time point in each case) (Reay et al., 2005). The study concluded that Panax ginseng may improve performance and subjective feelings of mental fatigue during sustained mental activity and that these effects may be related to the acute glucoregulatory properties of the extract (Reay et al., 2005). Some of the problems with these investigations include the small sample sizes, lack of dose–response, poor methodology, and the short delay between intake and testing, all making the studies difficult to interpret. The effects of a combination of Panax ginseng extract G115 and Ginkgo biloba extracts look more promising in terms of improving mood and memory in healthy subjects. In four randomized placebo-controlled t ­ rials, the combination of ginkgo plus Panax ginseng was investigated in one large (n=256) and three small (n=20) clinical studies (Kennedy et al., 2001, 2002; Scholey and Kennedy, 2002; Wesnes et al., 2000). Results from the smaller studies suggest an enhancement in quality of memory and im- provements in secondary memory and accuracy as well as improvements in mood in healthy subjects (Kennedy et al., 2001, 2002; Scholey and ­Kennedy, 2002). However, the quality of these studies is low due to the small number of subjects and poor methods. In the larger study, treatment of healthy volunteers with a combination of ginseng and ginkgo significantly im- proved the Index of Memory Quality (Wesnes et al., 2000). Improvements averaging 7.5 percent were seen in a number of aspects of memory, includ- ing working and long-term memory. These memory enhancements were observed throughout the 12-week dosing period as well as after a 2-week washout (Wesnes et al., 2000). Panax ginseng extracts, particularly the water-soluble polysaccharides from these extracts, are reported in animals to have immune-stimulating effects against infections (Lee and Han, 2006; Quan et al., 2007; Song et al., 2003) and radiation damage (Han et al., 2005; Kim et al., 2007). Five clinical trials assessed the effects of ginseng on immune function (reviewed in Kaneko and Nakanishi, 2004; Mahady et al., 2001). The studies in general used poor methods and had few subjects, but showed an increase in immune function via an increase in natural killer cell activity, T-cell ratios, phagocytosis by macrophages, and antibody titers when administered in addition to an anti-influenza ­polyvalent vaccination (Kaneko and Nakanishi, 2004; Mahady et al., 2001). Safety Concerns With few exceptions, Panax ginseng appears to be safe if administered in recommended therapeutic doses (Mahady et al., 1999).

OTHER DIETARY SUPPLEMENTS 131 In a 2-year uncontrolled study involving 133 patients who were taking large doses of ginseng (up to 15 g/d compared to a normal dose of 2 g/d), 14 patients presented with symptoms of hypertension, nervousness, irritability, diarrhea, skin eruptions, and insomnia, which were collectively called gin- seng abuse syndrome (GAS) (Coon and Ernst, 2002; Mahady et al., 2001). Critical analysis of this report has shown that there were no controls, nor was there analysis to determine the type of ginseng being ingested or the constituents of the preparation taken. Additionally, the authors of this improperly designed study did not take into account the concomitant inges- tion of prescription drugs and/or alcohol by the subjects. In a follow-up study, when the ginseng dose was decreased to 1.7 g/d, the symptoms of GAS were rare, indicating that excessive and uncon- trolled intake of ginseng products should be avoided. One case of ginseng- associated cerebral arteritis has been reported in a patient consuming a high dose of a rice-wine extract of ginseng root (approximately 6 g in one dose). Two cases of mydriasis and disturbance in accommodation as well as dizziness have been reported after ingestion of large doses (3–9 g) of an unspecified type of ginseng preparation (Coon and Ernst, 2002; Mahady et al., 2001). Mahady et al. (2001) indicated that ginseng supplementation has also been reported to cause estrogenic-like adverse effects in both pre- and postmenopausal women, including seven cases of mastalgia and one case of vaginal bleeding in a postmenopausal woman. These effects have not been confirmed. Ginseng supplementation was associated with the development of Stevens-Johnson syndrome (SJS) in one patient, but the type of the gin- seng was not identified, and the patient had been taking both acetylsalicylic acid and unspecified antibiotics 6 days prior to the development of SJS (Mahady et al., 2001). In one human study, administration of Panax ginseng to elderly sub- jects was followed by a statistically significant inhibition of cytochrome 2D6; however, the magnitude of the effect (approximately 7 percent) was not clinically relevant (Gurley et al., 2005). Interactions with Other Dietary Supplements or Medications Panax ginseng reduces the blood concentrations of alcohol and warfa- rin, induces mania when used concomitantly with phenelzine (a monoamine oxidase inhbitor), and may increase the efficacy of influenza vaccination (Hu et al., 2005). While co-administration of ginseng with warfarin did not appear to alter the international normalized ratio (INR) or platelet ag- gregation in one clinical trial (Jiang et al., 2004), alterations were observed in another study (Yuan et al., 2004). Considering the potential seriousness of this interaction, co-administration of warfarin with products containing Panax ginseng is not recommended.

132 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL With few exceptions, Panax ginseng appears to be safe if administered in recommended therapeutic doses (Mahady et al., 1999). Considerations Specific to the Military Although there is no evidence to believe that Panax ginseng would have different effects under the extreme conditions of military operations (e.g., high physical activity, caloric restriction, or high altitude), there are no data available from which to draw conclusions. According to Coon and Ernst (2002), the most commonly experienced adverse events are headache, sleep disorders, and gastrointestinal disorders. Although the consumption of Panax ginseng might not cause dehydration per se, some adverse gastrointestinal effects (e.g., vomiting, diarrhea) might result in dehydration. Panax ginseng has been shown to have vasodilating effects in animal models and in one human study. Administration of Panax ginseng to volun- teers subjected to cold stress increased tolerability in the ice water tolerance test (Kaneko and Nakanishi, 2004). This effect was thought to be due to dilation of the blood vessels, increased blood flow under cold stress, de- creased pain from ischemia, and protection from local tissue damage. Relevant data and conclusions on efficacy and safety reviews and pub- lications identified for ginseng are shown in Table 4-8 on pages 260–269. References Cardinal, B. J., and H. J. Engels. 2001. Ginseng does not enhance psychological well-being in healthy, young adults: Results of a double-blind, placebo-controlled, randomized clinical trial. J Am Diet Assoc 101(6):655-660. Carlson, A. W. 1986. Ginseng: America’s botanical drug connection to the Orient. Econ Bot 40(2):233-249. Cheng, T. O. 2005. Ginseng and other herbal medicines that interact with warfarin. Int J Cardiol 104(2):227. Coon, J. T., and E. Ernst. 2002. Panax ginseng: A systematic review of adverse effects and drug interactions. Drug Saf 25(5):323-344. Cui, J. F. 1995. Identification and quantification of ginsenosides in various commercial ginseng preparations. Eur J Pharm Sci 3(2):77-85. Engels, H. J., I. Kolokouri, T. J. Cieslak II, and J. C. Wirth. 2001. Effects of ginseng supple- mentation on supramaximal exercise performance and short-term recovery. J Strength Cond Res 15(3):290-295. Engels, H. J., M. M. Fahlman, and J. C. Wirth. 2003. Effects of ginseng on secretory IgA, per- formance, and recovery from interval exercise. Med Sci Sports Exerc 35(4):690-696. Gurley, B. J., S. F. Gardner, M. A. Hubbard, D. K. Williams, W. B. Gentry, Y. Cui, and C. Y. Ang. 2005. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St. John’s wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging 22(6):525-539. Han, S. K., J. Y. Song, Y. S. Yun, and S. Y. Yi. 2005. Ginsan improved Th1 immune response inhibited by gamma radiation. Arch Pharm Res 28(3):343-350.

OTHER DIETARY SUPPLEMENTS 133 Hu, S. Y. 1976. The genus Panax (ginseng) in Chinese medicine. Econ Bot 30(1):11-28. Hu, Z., X. Yang, P. C. Ho, S. Y. Chan, P. W. Heng, E. Chan, W. Duan, H. L. Koh, and S. Zhou. 2005. Herb-drug interactions: A literature review. Drugs 65(9):1239-1282. Jiang, X., K. M. Williams, W. S. Liauw, A. J. Ammit, B. D. Roufogalis, C. C. Duke, R. O. Day, and A. J. McLachlan. 2004. Effect of St. John’s wort and ginseng on the pharmaco­ kinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 57(5):592-599. Kaneko, H., and K. Nakanishi. 2004. Proof of the mysterious efficacy of ginseng: Basic and clinical trials: Clinical effects of medical ginseng, korean red ginseng: Specifically, its anti- stress action for prevention of disease. J Pharmacol Sci 95(2):158-162. Kennedy, D. O., A. B. Scholey, and K. A. Wesnes. 2001. Differential, dose dependent changes in cognitive performance following acute administration of a Ginkgo biloba/Panax gin- seng combination to healthy young volunteers. Nutr Neurosci 4(5):399-412. Kennedy, D. O., A. B. Scholey, and K. A. Wesnes. 2002. Modulation of cognition and mood following administration of single doses of Ginkgo biloba, ginseng, and a ginkgo/ginseng combination to healthy young adults. Physiol Behav 75(5):739-751. Kim, H. J., M. H. Kim, Y. Y. Byon, J. W. Park, Y. Jee, and H. G. Joo. 2007. Radioprotective effects of an acidic polysaccharide of Panax ginseng on bone marrow cells. J Vet Sci 8(1):39-44. Lee, J. H., and Y. Han. 2006. Ginsenoside Rg1 helps mice resist to disseminated candidiasis by Th1 type differentiation of CD4+ T cell. Int Immunopharmacol 6(9):1424-1430. Lieberman, H. R. 2001. The effects of ginseng, ephedrine, and caffeine on cognitive perfor- mance, mood and energy. Nutr Rev 59(4):91-102. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 1999. WHO monographs of selected medicinal plants. Vol. 1. Geneva, Switzerland: World Health Organization. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 2001. Botanical dietary supplements: Quality, safety and efficacy. Lisse, the Netherlands: Swets and Zeilinger. Quan, F. S., R. W. Compans, Y. K. Cho, and S. M. Kang. 2007. Ginseng and salviae herbs play a role as immune activators and modulate immune responses during influenza virus infection. Vaccine 25(2):272-282. Reay, J. L., D. O. Kennedy, and A. B. Scholey. 2005. Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. J Psychopharmacol 19(4):357-365. Reay, J. L., D. O. Kennedy, and A. B. Scholey. 2006. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained “mentally demanding” tasks. J Psychopharmacol 20(6):771-781. Rosado, M. F. 2003. Thrombosis of a prosthetic aortic valve disclosing a hazardous interaction between warfarin and a commercial ginseng product. Cardiology 99(2):111. Scholey, A. B., and D. O. Kennedy. 2002. Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: Differential interactions with cognitive demand. Hum Psychopharmacol 17(1):35-44. Shibata, S., O. Tanaka, J. Shoji, and H. Saito. 1985. Chemistry and pharmacology of panax. In Economic and medicinal plants research. Vol. 1, edited by H. Wagner and N. R. F ­ arnsworth. London-San Diego-New York: Academic Press. Pp. 217-284. Song, Z., C. Moser, H. Wu, V. Faber, A. Kharazmi, and N. Hoiby. 2003. Cytokine modulating effect of ginseng treatment in a mouse model of Pseudomonas aeruginosa lung infection. J Cyst Fibros 2(3):112-119. Sonnenborn, U., and Proppert, Y. 1991. Ginseng (Panax ginseng C. A. Meyer). Brit J Phyto- therapy 2:3-14. Wesnes, K. A., T. Ward, A. McGinty, and O. Petrini. 2000. The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers. Psycho- pharm (Berl) 152(4):353-361.

134 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Yuan, C. S., G. Wei, L. Dey, T. Karrison, L. Nahlik, S. Maleckar, K. Kasza, M. Ang-Lee, and J. Moss. 2004. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: A randomized, controlled trial. Ann Intern Med 141(1):23-27. β-HYDROXY-β-METHYLBUTYRATE (HMB) Background β-Hydroxy-β-methylbutyrate (HMB) is a metabolic derivative of the amino acid leucine. The first step of catabolism of leucine is transami- nation to α-ketoisocaproate, followed by production of HMB via KIC- kioxygenase. Under normal conditions, approximately 5 percent of leucine is converted to HMB (Baxter et al., 2005). There have been over 20 human clinical trials investigating the effects of HMB on body composition, muscle function, and safety factors concerning HMB intake (Alon et al., 2002; Bohn et al., 2002; Nissen and Sharp, 2003; Nissen et al., 2000; Palisin and Stacy, 2005; Slater and Jenkins, 2000; van Someren et al., 2005). The mechanism of action appears to be primarily via reduction in muscle protein catabolism. Specifically, HMB has been shown in vitro to attenuate the protein degradation induced by proteolysis-inducing factor (PIF) through the ubiquitin-proteasome proteolytic pathway by inhibition of protein kinase C and resulting stabilization of the IκB/NFκB complex (Smith et al., 2004). This is compatible with the finding that HMB is most effective in individuals undergoing substantial muscle catabolism (e.g., elderly people, AIDS and cancer patients, untrained individuals beginning a resistance exercise program). HMB’s role as precursor for cholesterol synthesis in muscle cells has been suggested as a mechanism for an effect of HMB of decreasing muscle damage following strenuous exercise (Baxter et al., 2005). Putative Benefits Altogether, the literature supports the value of HMB to increase fat-free mass gain in untrained subjects undergoing resistance training (Alon et al., 2002; Bohn et al., 2002; Nissen and Sharp, 2003; Palisin and Stacy, 2005; Slater and Jenkins, 2000) and in elderly or clinically catabolic subjects (e.g., patients with cancer or AIDS) without resistance training (Alon et al., 2002; Palisin and Stacy, 2005). One meta-analysis of nine studies determined that the net increase in lean mass gain in untrained men consuming 3 g/d of   The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

OTHER DIETARY SUPPLEMENTS 135 HMB during resistance training was 0.28 percent per week greater than in those consuming a placebo (Nissen and Sharp, 2003). Some studies sup- port an increase in muscle function (e.g., strength) as well as mass (Slater and Jenkins, 2000). One meta-analysis calculated a net increase in strength gain of 1.40 percent per week for subjects consuming HMB compared to placebo (Nissen and Sharp, 2003). The value of HMB for well-trained ath- letes is less often observed than for individuals initiating a resistance train- ing program (Palisin and Stacy, 2005). Several studies reported reduction in markers of muscle damage and/or soreness following strenuous exercise associated with the use of HMB (Bohn et al., 2002; van Someren et al., 2005). However, the majority of studies do not support a unique value of this supplement for reduction of markers (e.g., serum creatine kinase) or functional impairment (e.g., strength, soreness, range of motion) associated with skeletal muscle injury following resistance exercise (Bloomer, 2007). Almost all human clinical trials that supported a benefit of HMB used a dose of 3 g/d for 4 to 24 weeks. None of the studies involving shorter pe- riods of supplementation (e.g., 6 to 10 days) reported any benefits (Palisin and Stacy, 2005). Most studies used between 28 and 35 subjects, with 9 to 18 subjects per group. Some of the studies used HMB in combination with arginine and lysine in elderly or clinically catabolic subjects (Palisin and Stacy, 2005). Those studies reported anabolic effects of the combination supplement compared to placebo, but as the isoenergetic placebo was not isonitrogenous, it is not possible to attribute the benefits to HMB per se. Safety Concerns for HMB Toxicological studies in rats show no negative effects for HMB given at up to 5 percent of the diet for 91 days (Baxter et al., 2005). Many of the human studies of HMB ingestion measured health-related blood factors, psychological function, and frequency of adverse events. There was virtu- ally no indication of negative side effects of the supplement, with several suggestions of improvement in some measures of blood cholesterol and blood pressure, especially in those who began with elevated levels. How- ever, the long-term effects of chronic ingestion are not known, as most of the studies were performed for relatively brief periods (up to 12 weeks). A minority of studies used doses greater than 3 g/d (i.e., 6 g/d). There were no clear benefits or side effects associated with this higher dose compared to 3 g/d. No interactions with food components or drugs were noted, and none would be expected based on the theoretical metabolism of the compound. There is no evidence to support a safety concern for this supplement taken in doses of 3 g/d for up to 24 weeks.

136 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Considerations Specific to the Military HMB may help to slightly increase lean tissue gains for new military recruits undergoing vigorous resistance training but is less likely to be of value for well-trained individuals, and its high cost relative to other poten- tially anabolic supplements (e.g., creatine) may reduce the practicality of HMB use. Although negative effects on liver or kidney function have not been reported in any study, individuals with compromised function of either of these organs are advised not to use these supplements. Relevant data and conclusions on efficacy and safety reviews and pub- lications identified for HMB are shown in Table 4-9 on pages 270–277. References Alon, T., D. Bagchi, and H. G. Preuss. 2002. Supplementing with beta-hydroxy-beta- methylbutyrate (HMB) to build and maintain muscle mass: A review. Res Comm Mol Path Pharma 111(1-4):139-152. Baxter, J. H., J. L. Carlos, J. Thurmond, R. N. Rehani, J. Bultman, and D. Frost. 2005. Dietary toxicity of calcium β-hydroxy-β-methyl butyrate (CaHMB). Food Chem Toxic 43(12):1731-1741. Bloomer, R. J. 2007. The role of nutritional supplements in the prevention and treatment of resistance exercise-induced skeletal muscle injury. Sports Med 37(6):519-532. Bohn, A. M., S. Betts, and T. L. Schwenk. 2002. Creatine and other nonsteroidal strength- enhancing aids. Curr Sports Med Rep 1(4):239-245. Crowe, M. J., D. M. O’Connor, and J. E. Lukins. 2003. The effects of beta-hydroxy-beta- methylbutyrate (HMB) and HMB/creatine supplementation on indices of health in highly trained athletes. Int J Sport Nutr Exerc Metab 13(2):184-197. Flakoll, P., R. Sharp, S. Baier, D. Levenhagen, C. Carr, and S. Nissen. 2004. Effect of beta- hydroxy-beta-methylbutyrate, arginine, and lysine supplementation on strength, func- tionality, body composition, and protein metabolism in elderly women. Nutrition 20(5): 445-451. Hoffman, J. R., J. Cooper, M. Wendell, J. Im, and J. Kang. 2004. Effects of beta-hydroxy-beta- methylbutyrate on power performance and indices of muscle damage and stress during high-intensity training. J Strength Cond Res 18(4):747-752. May, P. E., A. Barber, J. T. D’Olimpio, A. Hourihane, and N. N. Abumrad. 2002. Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy- beta-methylbutyrate, arginine, and glutamine. Am J Surg 183(4):471-479. Nissen, S., and R. L. Sharp. 2003. Effect of dietary supplements on lean mass and strength gains with resistance exercise: A meta-analysis. J Appl Physiol 94(2):651-659. Nissen, S., R. L. Sharp, L. Panton, M. Vukovich, S. Trappe, and J. C. Fuller. 2000. β-Hydroxy- β-Methylbutyrate (HMB) supplementation in humans is safe and may decrease cardio- vascular risk factors. J Nutr 130(8):1937-1945. Palisin, T., and J. J. Stacy. 2005. β-Hydroxy-β-Methylbutyrate and its use in athletics. Curr Sports Med Rep 4(4):220-223. Ransone, J., K. Neighbors, R. Lefavi, and J. Chromiak. 2003. The effect of beta-hydroxy beta-methylbutyrate on muscular strength and body composition in collegiate football players. J Strength Cond Res 17(1):34-39.

OTHER DIETARY SUPPLEMENTS 137 Rathmacher, J. A., S. Nissen, L. Panton, R. H. Clark, P. E. May, A. E. Barber, J. D’Olimpio, and N. N. Abumrad. 2004. Supplementation with a combination of beta-hydroxy-beta- methylbutyrate (HMB), arginine, and glutamine is safe and could improve hematological parameters. J Parenter Enteral Nutr 28(2):65-75. Slater, G. J., and D. Jenkins. 2000. β-Hydroxy-β-Methylbutyrate (HMB) supplementation and the promotion of muscle growth and strength. Sports Med 30(2):105-116. Smith, H. J., S. M. Wyke, and M. J. Trisdale. 2004. Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by β-Hydroxy-β- Methylbutyrate. Cancer Res 64(23):8731-8735. van Someren, K. A., A. J. Edwards, and G. Howatson. 2005. Supplementation with β- Hydroxy-β-Methylbutyrate (HMB) and α-ketoisocaproic acid (KIC) reduces signs and symptoms of exercise-induced muscle damage in man. Int J Sport Nutr Exerc Metab 15(4):413-424. MELATONIN Background Melatonin10 is a light-sensitive hormone synthesized from tryptophan (i.e., it is a metabolite of 5-hydroxytryptamine). It is secreted by the pineal gland, and is a mediator in circadian processes. Because the pineal gland is neurobiologically part of the endogenous circadian system in humans and many other complex animals, the secretory profile of melatonin is circadian (i.e., about a day in length). Plasma levels of melatonin peak during the period of darkness (nighttime) in all mammal species (Arendt and Skene, 2005). A 10- to 50-fold increase in blood melatonin concentration occurs 1 to 2 hours after dusk (Lewy et al., 1992), suggesting that endogenous mela- tonin has a role in facilitating sleep (e.g., it lowers core body temperature by increasing heat loss prior to sleep). Similarly, exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during “biologi- cal daytime.” The half-life of endogenous melatonin in the bloodstream is less than 1 hour, making hangover effects in the morning relatively rare (Morin et al., 2007). Due to widespread belief that endogenous melatonin has a key role in the “natural” promotion or regulation of sleep, exogenous melatonin has become one of the most frequently requested over-the-counter sleep aids (Wagner et al., 1998). Among 31,044 people who completed the 2002 Alternative Health/Complementary and Alternative Medicine supple- ment to the National Health Interview Survey, 5.2 percent reported using m ­ elatonin. Of those users, 27.5 percent reported insomnia as a reason for taking the supplement (Bliwise and Ansari, 2007). Women were five times 10  The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

138 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL as likely to report melatonin use as men, and 13.9 percent of them described taking melatonin for anxiety and/or depression. Putative Benefits Laboratory studies of melatonin in treating sleep disorders have shown mixed results in various measures of sleep quality. Melatonin is typically administered orally, with dosages ranging from 0.3 to 5 mg in both regular and time-release capsules. In one placebo-controlled study of patients with primary insomnia, melatonin treatment reduced sleep onset latency by an average of 4.0 minutes, increased sleep efficiency by 2.2 percent, and increased total sleep duration by 12.8 minutes (Brzezinski et al., 2005). Another meta-analysis found that melatonin decreased sleep-onset latency by an average of 7.2 minutes in insomniacs and by an average of 38.8 minutes in patients with delayed sleep phase syndrome (Buscemi et al., 2005). However, there was no significant difference between melatonin and placebo. Most reviews of the effects of exogenous melatonin on insomnia conclude that the consensus is that the majority of studies find no benefits of melatonin for insomnia, and/or that the studies are inadequate, and that larger, long-term studies are needed to determine efficacy (Buscemi et al., 2005; Turek and Gillette, 2004). In contrast to the absence of evidence that exogenous melatonin administration can improve physiological signs and subjective symptoms of insomnia, an extensive scientific literature shows that exogenous melatonin can be an effective chronobiotic (Arendt and Skene, 2005). That is, when its ingestion is timed appropriately (i.e., most effective around dusk and dawn), it will shift the phase of the human circa- dian clock (i.e., recalibrate sleep, core body temperature, and endogenous production of melatonin and cortisol) to earlier or later times. Thus, the literature reveals that ingestion of melatonin 1 hour before the desired sleep time can be effective for insomnia associated with jet lag (Morin et al., 2007). Exogenous melatonin has also been tested in several different ways to facilitate adjustment to night-shift work. Although ex- ogenous melatonin has been shown to have some benefit in adjustment to jet lag when used prior to the desired sleep time, there is considerably less scientific evidence for its efficacy in promoting adjustment to night-shift work, perhaps because circadian synchronizers such as bright light also promote phase adjustment to jet lag, while they promote no adjustment to night-shift work. The authors of the leading scientific review on the effects of exogenous melatonin concluded that due to the large number of poorly controlled studies, use of melatonin for adaptation to night-shift work is unproven but promising (Arendt and Skene, 2005).

OTHER DIETARY SUPPLEMENTS 139 Safety Concerns Although available as an over-the-counter product in the United States, melatonin is classified as a drug in Canada and is available only by prescrip- tion in the United Kingdom. One recent review concluded that there is no long-term safety data on the use of exogenous melatonin or on the optimal dose and formulation for any application (Arendt and Skene, 2005). Another review concluded that melatonin is generally regarded as safe in recom- mended doses for short-term use, and is likely safe when taken orally for up to 2 years at a maximum dose of 5 mg/d (Morin et al., 2007). A placebo- controlled study showed that the occurrence of adverse events was similar for melatonin and placebo. The most commonly reported adverse effects were headaches, dizziness, nausea, and drowsiness (Buscemi et al., 2006). Exogenous melatonin is a vasodilator—it lowers core body tempera- ture, and it can affect skin blood flow, which suggests it is not advisable in cold environments, where it may accelerate heat loss (Weekley, 1993). While one study reported a case of exogenous melatonin being linked to psychosis, other case reports suggest it helps prevent psychotic symptoms from severe reactions to jet lag (Katz et al., 2001). Interactions with Other Dietary Supplements or Medications To the extent that melatonin is sedating, it has the potential for un- wanted synergy with other sedating agents. Therefore, in people engaged in safety-sensitive activities that require alertness and quick responses, this supplement should not be taken in conjunction with other sedating or hyp- notic substances. Of the 109 medications most frequently prescribed for military personnel, 13 have sedating side effects (e.g., hypnotics, anxiolyt- ics, antidepressants, opioids). Considerations Specific to the Military Although there is evidence that exogenous melatonin has chronobiotic effects—helping to phase shift circadian rhythms in jet lag and night-shift work—the timing of intake in relation to the effect (i.e., phase response curve) is essential. The decrease in core body temperature seen as a common effect of melatonin poses a risk to military personnel in cold environments, and drowsiness can adversely effect both physical and mental performance. However, melatonin could counteract disruptions in sleep and the thermo- regulatory and central nervous systems, which would be of benefit for active duty military personnel. Therefore, consideration should be given to the tasks performed and circumstances; for instance, its use might be limited to

140 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL the needed adjustment to jet lag and/or night-shift work and in a thermal environment that is above freezing. Relevant data and conclusions on efficacy and safety reviews and publica- tions identified for melatonin are shown in Table 4-10 on pages 278–281. References Arendt, J., and D. J. Skene. 2005. Melatonin as a chronobiotic. Sleep Med Rev 9(1):25-39. Bliwise, D. L., and F. P. Ansari. 2007. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. Sleep 30(7):881-884. 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 Rev 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. BMJ 332(7538):385-393. Katz, G., R. Durst, and H. Y. Knobler. 2001. Exogeneous melatonin, jet lag, and psychosis: Preliminary case results. J Clin Psychopharmacol 21(3):349-351. Lewy, A. J., S. Ahmed, J. M. Jackson, and R. L. Sack. 1992. Melatonin shifts human circadian rhythms according to a phase–response curve. Chronobiol Int 9(5):380-392. 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. Turek, F. W., and M. U. Gillette. 2004. Melatonin, sleep and circadian rhythms: Rationale for development of specific melatonin agonists. Sleep Med 5(6):523-532. 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. Weekley, L. B. 1993. Effects of melatonin on pulmonary and coronary vessels are exerted through perivascular nerves. Clin Auton Res 3(1):45-47. QUERCETIN Background There are more than 5,000 different flavonoid compounds in plants that can be subdivided into six major subclasses. One subclass is the flavo- nols, which include quercetin,11 myricetin, and kaempferol. Flavonols are three-ring compounds chemically characterized as flavan-3,4-diols. These compounds are especially prevalent in onions, kale, broccoli, apples, and 11  The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

OTHER DIETARY SUPPLEMENTS 141 berries (Ross and Kasum, 2002). Quercetin is the most frequently studied of all flavonoids (Formica and Regelson, 1995). The absorption and bioavailability of quercetin has been extensively studied. Recent reviews point to evidence that quercetin is readily absorbed from foods or supplements, although there is some variability depending on the specific food matrix in which it is consumed and whether the molecule has a glycoside linkage (Erdman et al., 2007; Ross and Kasum, 2002). The maximal blood concentration of quercetin is reached within a few hours of ingestion with reported half-lives of between 11 and 28 hours. Results from several studies suggest that repeated consumption of foods contain- ing ­ quercetin will maintain blood concentrations of this flavonol (Ross and Kasum, 2002). In persons consuming their habitual diets, blood con- centrations ranging between about 15 and 24 µg/L (50–80 nmole/L) were noted compared to about 42 µg/L (140 nmole/L) after a diet high in veg- etables, fruits, and berries, respectively (Erlund, 2004). Long-term feeding of ­quercetin to rats leads to accumulation in many tissues including lungs, testes, kidney, heart, liver, thymus, and muscle (de Boer et al., 2005). Putative Benefits A variety of in vitro trials have provided support for antioxidant ac- tivity of quercetin and other flavonoids. It is quite difficult, however, to demonstrate that specific food components in isolation such as flavonoids have biologically important antioxidant effects in vivo. These flavonols have also been reported to have utility as antibiotic, antiallergenic, an- tidiarrheal, antiulcer, and anti-inflammatory agents. Other studies of these compounds have shown inhibition of cellular proliferation in a variety of cancer cell models, although some studies have used concentrations of the flavonoids that are 100 times or higher than achieved by eating diets high in flavonoid-containing foods. Epidemiological evaluations of diets high in flavonoids provide some support of the theory that flavonoid intake is related to reduction in risk factors of cardiovascular disease. Most recently, an ILSI-North America (International Life Sciences Institute-North America) workshop group con- cluded that “[d]ata presented support the concept that certain flavonoids in the diet can be associated with significant health benefits, including heart health” (Erdman et al., 2007). For example, Lotito and Frei (2006) demonstrated that quercetin and some other flavonols were able to inhibit endothelial adhesion molecule expression in human aortic endothelial cells. There is also a great deal of interest in the role of flavonoids in the reduc- tion of inflammation and inflammatory states that are thought to be related to a variety of diseases such as cardiovascular disease. The effects of quercetin on immunological responses have been studied

142 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL in several testing systems. For example, Formica and Regelson (1995) stated that flavonoids appear to inhibit enzyme pathways involved in lymphocyte activation via their ability to scavenge free radicals. In a double-blind, randomized, crossover study, MacRae and Mefferd (2006) investigated whether 6 weeks of supplementation with an anti­ oxidant would enhance the performance of elite male cyclists in 30-km time trials. The supplement contained a variety of nutrient and nonnutrient anti­ oxidants, and included a total of 600 mg of quercetin. The results showed that the supplement improved the time trial performance and enhanced power output. These findings could not be attributed to quercetin, however, as there was no quercetin-only supplement. Nieman et al. (2007) tested whether 1,000 mg/d of quercetin would have an effect on upper respiratory tract infections (URTI) and exercise-induced changes in immune function in trained male cyclists (n=40). Participants were randomized to receive quercetin or placebo supplements twice daily under double-blind condi- tions for 3 weeks prior to, during, and 2 weeks following a 3-day period in which subjects cycled at high output for 3 hours per day. The results of this trial showed no effects on natural killer cell activity, PHA-stimulated lymphocyte proliferation, polymorphonuclear oxidative burst activity, or salivary immunoglobulin A (IgA) output. However, the incidence of URTI during the 2-week postexercise period differed significantly between groups (P = .004), with quercetin resulting in only one versus nine episodes of URTI in the placebo group. Interestingly, plasma quercetin was increased from 113 µg/L in the placebo group to 1,158 µg/L in supplemented groups. The authors concluded that even in the absence of demonstrated effects of the supplement on multiple measures of immune function, quercetin may have a direct antiviral mechanism. Davis et al. (2007) evaluated the effects of 7 days of an oral gavage of quercetin (either 12.5 or 25 mg/kg body weight) on tissue mitochondrial enzymes and performance on a treadmill in previously sedentary mice. Both dose levels of quercetin were associated with significant increases in mitochondrial content in skeletal muscle and brain cells as well as increased endurance capacity in the mice. Safety Concerns The safety of quercetin was extensively reviewed by Okamoto (2005). He notes that although the National Toxicology Program had reported some studies showing carcinogenic effects in rats, most in vivo studies indicated that quercetin is not carcinogenic. Moreover, in 1999, the Inter- national Agency for Research on Cancer concluded that quercetin is not classifiable as to its carcinogenicity to humans (IARC, 1999). One phase I clinical trial of the effects of quercetin on the inhibition of tyrosine kinase

OTHER DIETARY SUPPLEMENTS 143 activity has been completed, and antitumor activity was shown (Ferry et al., 1996). Numerous published in vitro trials have reported the effects of querctin on a variety of cell culture types and a wide range of outcomes. Many have focused on cell proliferation in cancer cell lines. There is a clear, though not consistent, effect of dose level on whether quercetin inhibits cancer cell growth or causes cellular damage. For example, van der Woude et al. (2005) showed a biphasic effect of quercetin in several breast cancer cell lines in which, at a low dose level (10–20 µmol/L), quercetin increases cell proliferation, while at higher doses (40–80 µmol/L), there is decreased proliferation. In contrast, Watjen et al. (2005) showed in a rat hepatoma cell line that lower concentrations of quercetin (as low as 10–25 µmol/L) and other flavonoids protected against DNA strand breaks and induced apoptosis, but at higher concentrations (between 50–250 µmol/L) caused DNA damage. Thus, dose level may play a critical role in whether quercetin supplementation has helpful or adverse outcomes. To put the concentrations used in typical cell culture studies into per- spective, it was estimated that blood concentrations of quercetin ranging between about 50 nmol/L and about 140 nmol/L are reached for persons consuming their habitual diets and diets high in vegetables, fruits, and ber- ries, respectively (Erlund, 2004). Nieman et al. (2007) reported achieving levels of 1,158 µg/L, or about 3.8 µmol/L, in test subjects receiving 1,000 mg of quercetin daily for several weeks. These blood levels are substantially be- low those of most in vitro trials. It is not known whether concentrations of quercetin higher than plasma levels might be achieved in other tissues after consuming quercetin. However, it appears that the majority of in vitro stud- ies have involved quercetin levels that are not achieved even with high-dose dietary supplements. The applicability of the findings of these high-dose in vitro studies to human health and safety is questionable. Overall, Okamoto (2005) concluded that it is unlikely that administra- tion of quercetin at a typical dosage could cause any adverse effect. There do not appear to be any safety concerns about quercetin supplements at doses of 1,000 mg daily or less. However, most dietary supplements cur- rently on the market contain mixtures of compounds, not just quercetin in isolation. There are no clear interactions of quercetin with other dietary supplements or medications. Considerations Specific to the Military There are no clear indications that quercetin supplements have adverse effects upon issues of military concern (e.g., high-intensity physical activity, injury/bleeding, temperature extremes, high altitude, dehydration, diarrhea, infectious disease, risk of kidney stones, weight considerations).

144 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Relevant data and conclusions on efficacy and safety reviews and publications identified for quercetin are shown in Table 4-11 on pages 282–283. References Davis, J. M., E. A. Murphy, M. D. Carmichael, J. B. Davis, J. D. Gangemi, and E. P. Mayer. 2007. Effect of quercetin feedings on tissue mitochondrial enzymes and performance in mice. Am Coll Sports Med Abstract. de Boer, V. C. J., A. A. Dihal, H. van der Woude, I. C. W. Arts, S. Wolffram, G. M. Alink, I. M. C. M. Rietjens, J. Kiejer, and P. C. H. Hollman. 2005. Tissue distribution of q ­ uercetin in rats and pigs. J Nutr 135(7):1718-1725. Erdman, J. W., Jr., D. Balentine, L. Arab, G. Beecher, J. T. Dwyer, J. Folts, J. Harnly, P. ­Hollman, C. L. Keen, G. Mazza, M. Messina, A. Scalbert, J. Vita, G. Williamson, and J. Burrowes. 2007. Flavonoids and heart health: Proceedings of the ILSI North America ­ flavonoids workshop, May 31–June 1, 2005. Washington, DC. J Nutr 137(3):718S-737S. Erlund, I. 2004. Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutr Res 24(10):851-874. Ferry, D. R., A. Smith, J. Malkhandi, D. W. Fyfe, P. G. de Takats, D. Anderson, J. Baker, and D. J. Kerr. 1996. Phase I clinical trial of the flavonoid quercetin: Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2(4):659-668. Formica, J. V., and W. Regelson. 1995. Review of the biology of quercetin and related biofla- vonoids. Food Chem Toxicol 33(12):1061-1080. IARC (International Agency for Research on Cancer). 1999. IARC monographs on the evalu- ation of carcinogenic risks to humans. IARC 73:497-515. Lotito, S. B., and B. Frei. 2006. Dietary flavonoids attenuate tumor necrosis factor α-induced adhesion molecule expression in human aortic endothelial cells. J Biol Chem 281(48): 37102-37110. MacRae, H. S. H., and K. M. Mefferd. 2006. Dietary antioxidant supplementation combined with quercetin improves cycling time trial performance. Int J Sport Nutr Exerc Metab 16(4):405-419. Nieman, D. C., D. A. Henson, S. J. Gross, D. P. Jenkins, J. M. Davis, E. A. Murphy, M. D. Carmichael, C. L. Dumke, A. C. Utter, S. R. Mcanulty, L. S. Mcanulty, and E. P. Mayer. 2007. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc 39(9):1561-1569. Okamoto, T. 2005. Safety of quercetin for clinical application (review). Int J Molec Med 16(2):275-278. Ross, J. A., and C. M. Kasum. 2002. Dietary flavonoids: Bioavailability, metabolic effects and safety. Annu Rev Nutr 22:19-34. van der Woude, H., G. M. Alink, and I. M. C. M. Rietjens. 2005. The definition of hormesis and its implications for in vitro to in vivo extrapolation and risk assessment. Crit Rev Toxicol 35(6):603-607. Watjen, W., G. Michels, B. Steffan, P. Niering, Y. Chovolou, A. Kampkooter, Q-H. Tran-Thi, P. Proksch, and R. Kahl. 2005. Low concentrations of flavonoids are protective in rat H411E cells whereas high concentrations cause DNA damage and apoptosis. J Nutr 135(3):525-531.

OTHER DIETARY SUPPLEMENTS 145 SPORTS BARS Background Sports bars12 are a vehicle for provision of calories, macronutrients, and micronutrients for active individuals. Although more concentrated and thus a lighter-weight form of energy than sports drinks, they do not contribute to hydration. This category cannot be easily summarized—there is a very broad range of sports bars commercially available. Most bars contain substantial amounts of carbohydrate and protein, moderate to low amounts of fat, and a total of 100–300 kcal/bar. Most companies fortify these products with vitamins or minerals, and some add herbs or other compounds purported to improve health or performance (e.g., creatine, antioxidants). Sports bars can serve as a snack contributing to the overall carbohydrate and protein needs of service members, especially those with higher energy demands. For example, the Military Dietary Reference Intake for protein is 91 g/d for an 80-kg male. For sustained operations, the car- bohydrate and protein needs for an 80-kg male have been estimated at 450 g/d and 100–120 g/d, respectively (IOM, 2005). A more detailed review of the value of protein and carbohydrate for military personnel is presented in the previous IOM report, Nutrient Composition of Rations for Short-Term, High-Intensity Combat Operations (2005). Energy supplements in the form of gels are another vehicle for ingestion of carbohydrate during activity. The energy in these products (approxi- mately 100 kcal) typically comes only from carbohydrate, but they may be fortified with electrolytes or other micronutrients. They are intended to serve as a concentrated source of carbohydrate (one or two packages per hour is the suggested rate of ingestion) during prolonged periods of exertion. Putative Benefits Very few published studies have examined the effect of sports bars on physical performance. One study observed that consumption of a bar con- taining a mix of macronutrients (7 g fat, 14 g protein, 19 g carbohydrate) increased use of fat during exercise of 330 minutes in duration, but reduced ability to complete a high-intensity time trial following the submaximal exercise bout compared to ingestion of an equal amount of energy as carbo- hydrate (glucose polymer) alone (Rauch et al., 1999). Thus, if carbohydrate and fluids are the limiting factor for physical performance, consumption of 12  The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

146 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL a sports drink would likely be a better choice during exercise than a sports bar. However, sports bars may be especially valuable after exercise when a concentrated source of energy and carbohydrate is beneficial, and adequate fluids are available and ingested. These products can also serve to boost energy (and nutrient) intake between meals in individuals with high energy demand. Safety Concerns Sports bars, like sports gels, need to be ingested with copious amounts of water since they do not provide sufficient fluid to prevent dehydration. Research shows that ingestion of gels with a small amount of water im- paired endurance exercise performance in a hot environment relative to ingestion of the same amount of carbohydrate in a sports drink (Ebert et al., 2007). Some individuals may experience gastrointestinal distress when us- ing gels during exercise (Burke et al., 2005). A minor safety concern is the potential for excess energy intake from the additional calories provided to those whose activity level or environ- ment does not require additional energy. Many bars are highly fortified, so there is potential for overconsumption of micronutrients, including the potential to exceed the upper limit for some minerals. It is valuable to train personnel to read the labels of the bars so users are aware of the unique composition, energy, and nutrient value of the product and how it fits into their daily diet. The safety of added ingredients other than macronutrients and required micronutrients cannot be summarized but needs to be assessed individually. Considerations Specific to the Military Sports bars are a convenient vehicle to carry fuel for active individuals. These bars typically have long shelf lives and so can be transported and stored without refrigeration until needed. This may be important for vari- ous military environments and circumstances. If consumed during exercise, they should be consumed with sufficient water to maintain hydration. Relevant data and conclusions on efficacy and safety reviews and publications identified for sports bars are shown in Table 4-12 on pages 284–285. References Burke, L. M., C. Wood, D. B. Pyne, D. R. Telford, and P. U. Saunders. 2005. Effect of carbo- hydrate intake on half-marathon performance of well-trained runners. Int J Sport Nutr Exerc Metab 15(6):573-589.

OTHER DIETARY SUPPLEMENTS 147 Ebert, T. R., D. T. Martin, N. Bullock, I. Mujika, M. J. Quod, L. A. Farthing, L. M. Burke, and R. T. Withers. 2007. Influence of hydration status on thermoregulation and cycling hill climbing. Med Sci Sports Exerc 39(2):323-329. IOM (Institute of Medicine). 2005. Nutrient composition of rations for short-term, high- ­ntensity combat operations. Washington, DC: The National Academies Press. i Rauch, H. G., J. A. Hawley, M. Woodey, T. D. Noakes, and S. C. Dennis. 1999. Effects of ingesting a sports bar versus glucose polymer on substrate utilisation and ultra-endurance performance. Int J Sports Med 20(4):252-257. SPORTS DRINKS Background Sports drinks13 were developed to supply carbohydrate as a fuel and maintain hydration or enhance rehydration in response to the stresses of exercise. Most sports drinks contain 6–8 percent carbohydrate (as combi- nations of various forms including glucose, fructose, sucrose, high-fructose corn syrup, multidextrans) and electrolytes (10–25 mmol/L sodium and 3–5 mmol/L potassium) (Maughan and Murray, 2001). They are typically used prior to exercise to ensure fluid balance and to top off carbohydrate stores; during exercise to maintain hydration and provide carbohydrate fuel; and after exercise to replace body fluids, electrolytes, and carbohydrate. Some newer sports drinks have protein added, with the claim that this will en- hance hydration and muscle protein balance. Some newer beverages marketed to active individuals also include additional compounds such as vitamins, minerals, herbs, and stimulants. These products contributed to a recent broad market for “energy drinks” or “functional beverages.” Some of these products are claimed to improve mood, athletic performance, or health. These products blur the line between foods and supplements. Some manufacturers may attempt to sell functional beverages as supplements because of the differences in regulation between supplements and foods. Very little research has been done to validate the effects of these beverages on health or performance. Putative Benefits Much research has been performed using traditional sports drinks with virtually no evidence of harm. On the contrary, there is much research that demonstrates evidence of benefit of carbohydrate ingestion for prolonged, moderately intense endurance exercise (especially in a hot environment). 13  The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

148 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Most studies demonstrate that consumption of sports drinks (at up to 1 g/min carbohydrate) can improve endurance performance of exercise at 70 percent of aerobic capacity for 60 min or more (Jeukendrup, 2004; Maughan and Murray, 2001). Some studies support a benefit for exercise bouts of approximately an hour, but this finding is not consistent. More recent studies that performed simulating sport activities such as soccer or basketball report improved performance and/or perception of effort ( ­ Winnick et al., 2005). The fluids and electrolytes provided by sports drinks can maintain plasma volume during exercise better than plain water and more rapidly rehydrate the body following dehydration. The electrolytes in these drinks help maintain the drive to drink such that more total fluid volume is typi- cally ingested than if water alone is provided. There is some evidence that consumption of carbohydrate during exer- cise reduces the immune suppression that can occur with strenuous exercise (Nieman, 2007). As reviewed by Gibala (2007), addition of protein to a carbohydrate beverage ingested during endurance exercise improves protein balance but does not consistently affect performance. Additional well-designed research is necessary to confirm the effects of protein on health and performance during exercise. Several studies suggest that sports beverages contain- ing protein may improve muscle protein balance after strenuous exercise (Gibala, 2007), which also requires additional validation. Enhancement of muscle protein balance by protein ingestion following resistance exercise has been repeatedly observed, but most hydration-type sports beverages that do contain protein would not provide the amount observed to have a substantial effect. Protein-carbohydrate products marketed specifically for recovery following resistance exercise typically have the recommended 6 g or more of protein per serving that may improve acute muscle balance. Very limited research suggests that consumption of these products or foods containing carbohydrate and protein shortly after every resistance workout will enhance lean tissue gains (Koopman et al., 2007). Safety Concerns There is little reason to be concerned about harm from the various “traditional” sports drinks containing electrolytes and 6–8 percent car- bohydrate, other than provision of extra calories to those whose physi- cal activities and environment do not warrant the additional hydration and energy. Substantial overconsumption of any hypotonic fluid, including sports drinks, could cause hyponatremia (blood sodium <135 mmol/L), a very rare but potentially fatal condition caused by retention of fluids in vascular space in spite of efflux of blood sodium (Gardner, 2002; Montain

OTHER DIETARY SUPPLEMENTS 149 et al., 2001). Data from the military estimated this risk to be very low, at 0.10 per 1,000 soldier-years (Craig, 1999). The risk may be higher for those whose sweat is very salty and for those drinking extreme amounts of fluid. Evaluation of cases of hyponatremia among military personnel showed that all had consumed more than 5 L (usually 10–20 L) of water during a period of a few hours (Gardner, 2002). The incidence of hyponatremia is higher in female marathon runners than in male marathon runners, but the reported incidence in the military is similar to the gender distribution of the Army (15 percent female and 85 percent male) (Montain et al., 2001). Weight gain during prolonged exercise suggests evidence of possible hyponatremia. The risk of hyponatremia can be reduced by consuming an appropriate amount (not to exceed 150 percent of losses during exercise, typically not greater than 1.5 L/h) of sodium-containing fluid. The value of ingestion of an electrolyte-containing beverage compared to water for superior maintenance of blood sodium during exertion has been shown in experimental studies (Barr et al., 1991) and with theoretical models ( ­ Montain et al., 2006). Considerations Specific to the Military Sports drinks are most likely to be of benefit for military personnel working in hot, humid environments where sweat loss is substantial. In addition, those personnel who are doing considerable amounts of exercise (>1 h/d) as part of their duties may perform better, feel better, and become less dehydrated if they consume a sports drink at regular intervals. The amount consumed should attempt to match the loss of body weight (i.e., sweat loss) and/or provide aproximately 1 g/min carbohydrate. Relevant data and conclusions on efficacy and safety reviews and pub- lications identified for sports drinks are shown in Table 4-13 on pages 286–287. References Barr, S. I., D. L. Costill, and W. Fink. 1991. Fluid replacement during prolonged exercise: Ef- fects of water, saline, or no fluid. Med Sci Sports Exerc 23:811-817. Craig, S. C. 1999. Hyponatremia associated with heat stress and excessive water consumption: The impact of education and a new Army fluid replacement policy. MSMR 5:1-9. Gardner, J. W. 2002. Death by water intoxication. Military Med 5:432-434. Gibala, M. 2007. Protein metabolism and endurance exercise. Sports Med 37(4-5):337-340. Jeukendrup, A. 2004. Carbohydrate intake during exercise and performance. Nutrition 20(7-8):669-677. Koopman, R., W. H. Saris, A. J. Wagenmakers, and L. J. van Loon. 2007. Nutritional interven- tions to promote post-exercise muscle protein synthesis. Sports Med 37(10):895-906. Maughan, R., and R. Murray. 2001. Sports drinks: Basic science and practical aspects. Boca Raton, FL: CRC Press.

150 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Montain, S. J., M. N. Sawka, and C. B. Wenger. 2001. Hyponatremia associated with exercise: Risk factors and pathogenesis. Exerc Sports Sci Rev 29(3):113-117. Montain, S. J., S. N. Cheuvront, and M. N. Sawka. 2006. Exercise associated hyponatremia: Quantitative analysis to understand the etiology. Brit J Sports Med 40:98-105. Nieman, D. C. 2007. Marathon training and immune function. Sports Med 37(4-5): 412-415. Winnick, J. J., J. M. Davis, R. S. Welsh, M. D. Carmichael, E. A. Murphy, and J. A. Blackmon. 2005. Carbohydrate feedings during team sport exercise preserve physical and CNS func- tion. Med Sci Sports Exerc 37(2):306-315. TYROSINE Background Tyrosine,14 a large neutral amino acid found in most protein-containing foods, is the metabolic precursor for the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. These neurotransmitters play a significant role in mediating neural functions such as attention, arousal, and mood. Under normal conditions, the brain receives sufficient quantities of tyrosine from the diet to provide adequate amounts of these neurotrans- mitters. However, in stressful situations in which there are increases in the activity of catecholaminergic neurons and subsequent depletion of these neurotransmitters, tyrosine supplementation may prove useful. Both norepinephrine and dopamine play an important role in the per- formance of cognitive tasks involving psychomotor skills, decision making, vigilance, and memory. Decrements in these tasks are often observed in stressful situations resulting from conditions such as extremes in envi- ronmental temperature, sleep deprivation, and high altitudes. It has been hypothesized that these stress-induced decrements in cognitive performance are the result of increased activity within catecholaminergic neurons, and the consequent reduction of norepinephrine and dopamine within the cen- tral nervous system. It has been further suggested that increasing the syn- thesis of these neurotransmitters could ameliorate stress-induced deficits in mental functioning. Putative Benefits One way to increase levels of dopamine, epinephrine, and norepi- nephrine is to provide more of their metabolic precursor, tyrosine. Indeed, research using young military and nonmilitary personnel of normal weight 14  The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

OTHER DIETARY SUPPLEMENTS 151 has shown that tyrosine supplements can reverse a portion of the deficits in cognitive performance observed in cold environments (Ahlers et al., 1994; Mahoney et al., 2007; O’Brien et al., 2007; Shurtleff et al., 1994), at high altitudes (Bandertet and Lieberman, 1989), as a function of sleep depriva- tion (Magill et al., 2003; Wiegmann et al., 1993), after extensive combat training (Deijen et al., 1999), and in a multitasking environment (Thomas et al., 1999). Tasks involving memory and attention particularly benefited by tyrosine supplementation. Additionally, relative to placebo, tyrosine may alleviate stress-induced decrements in performance of psychomotor skills such as marksmanship (O’Brien et al., 2007). Tyrosine might also reduce negative mood states including fatigue, confusion, and tension that accom- pany environmental stressors (Banderet and Lieberman, 1989). Safety Concerns Studies investigating the effects of tyrosine on cognitive behavior and psychomotor performance have examined doses of the amino acid rang- ing between 50 and 300 mg/kg body weight. The majority of these studies have used healthy, young military personnel of normal weight as partici- pants. The number of participants in these studies ranges from 8 to 75. Participants reported no adverse consequences of tyrosine supplementation. However, it is important to note that in all of these studies, only a single trial of tyrosine supplementation was examined. There are no data on the effects of chronic tyrosine supplementation on cognitive function, or on the actions of tyrosine in individuals over the age of 35. A review of the literature on the use of tyrosine supplements did not find any studies indicating significant interactions between tyrosine and medications. Considerations Specific to the Military There is no indication that tyrosine will impart benefits to military per- sonnel under normal garrison situations. However, tyrosine could benefit military personnel experiencing stressful environmental conditions that are typically associated with decrements in cognitive behavior, such as intense combat, exposure to extreme heat or cold, high altitudes, and sleep depriva- tion. Additionally, tyrosine could potentially improve mental performance when military personnel are required to respond to multiple demanding cognitive and psychomotor tasks. The scientific evidence for these putative effects, however, is still preliminary and lacks confimation. Relevant data and conclusions on efficacy and safety reviews and publi- cations identified for tyrosine are shown in Table 4-14 on pages 288–293.

152 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL References Ahlers, S. T., J. R. Thomas, J. Schrot, and D. Shurtleff. 1994. Tyrosine and glucose modula- tion of cognitive deficits resulting from cold stress. In Food components to enhance performance, edited by B. M. Marriott. Washington, DC: National Academy Press. Pp. 301-320. Banderet, L. E., and H. R. Lieberman. 1989. Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans. Brain Res Bull 22(4):759-762. Chinevere, T. D., R. D. Sawyer, A. R. Creer, R. K. Conlee, and A. C. Parcell. 2002. Effects of L-tyrosine and carbohydrate ingestion on endurance exercise performance. J Appl Physiol 93(5):1590-1597. Deijen, J. B., and J. F. Orlebeke. 1994. Effect of tyrosine on cognitive function and blood pressure under stress. Brain Res Bull 33(3):319-323. Deijen, J. B., C. J. E. Wientjes, H. F. M. Vullinghs, P. A. Cloin, and J. J. Langefeld. 1999. Tyrosine improves cognitive performance and reduces blood pressure in cadets after one week of a combat training course. Brain Res Bull 48(2):203-209. Magill, R. A., W. F. Waters, G. A. Bray, J. Volaufova, S. R. Smith, H. R. Lieberman, N. ­McNevin, and D. H. Ryan. 2003. Effects of tyrosine, phentermine, caffeine, D-amphetamine, and placebo on cognitive and motor performance deficits during sleep deprivation. Nutr Neurosci 6(4):237-246. Mahoney, C. R., J. Castellani, F. M. Kramer, A. Young, and H. R. Lieberman. 2007. Tyrosine supplementation mitigates working memory decrements during cold exposure. Physiol Behav 92(4):575-582. Neri, D. F., D. Wiegmann, R. R. Stanny, S. A. Shappell, A. McCardie, and D. L. McKay. 1995. The effects of tyrosine on cognitive performance during extended wakefulness. Aviat Space Environ Med 66(4):313-319. O’Brien, C., C. Mahoney, W. J. Tharion, I. V. Sils, and J. W. Castellani. 2007. Dietary tyrosine benefits cognitive and psychomotor performance during body cooling. Physiol Behav 90(2-3):301-307. Shurtleff, D., J. R. Thomas, J. Schrot, K. Kowalski, and R. Hardford. 1994. Tyrosine re- verses a cold-induced working memory deficit in humans. Pharmacol Biochem Behav 47(4):935-942. Thomas, J. R., P. A. Lockwood, A. Sing, and P. A. Deuster. 1999. Tyrosine improves working memory in a multitasking environment. Pharmacol Biochem Behav 64(3):495-500. Wiegmann, D. L., D. F. Neri, R. R. Stanny, S. A. Shappell, A. H. McCardie, and D. L. McKay. 1993. Behavioral effects of tyrosine during sustained wakefulness. Pensacola, FL: Naval Aerospace Medical Research Laboratory. VALERIAN Background Valerian15 is an herbal product made from the roots of the plant ­ aleriana officinalis that has been used for hundreds of years as a mild V hypnotic. Over 150 individual compounds can be found in valerian, and 15  The monographs were developed in order to evaluate the review process outlined in Chap- ter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

OTHER DIETARY SUPPLEMENTS 153 although the exact mechanism by which it works is unknown, valepotriates and valerenic acid have been proposed as active ingredients (Houghton, 1999). One study found that valerian extracts bind to benzodiazepine receptors in vitro (Holzl and Godau, 1989). It was subsequently reported that valerian extract increased gamma-aminobutyric acid (GABA) con- centrations in the synaptic cleft, but this was complicated by the pres- ence of endogenous GABA in the aqueous extract used (Gyllenhaal et al., 2000; Santos et al., 1994). Among the 31,044 people who completed the 2002 ­Alternative Health/Complementary and Alternative Medicine supple- ment to the ­National Healthy Interview Survey, 5.9 percent reported using v ­ alerian. Of those users, 29.9 percent reported insomnia as a reason for taking the supplement (Bliwise and Ansari, 2007). Women reported using it more than men (2.6:1 ratio), and 23.4 percent reported using it to treat anxiety and/or depression. Putative Benefits Despite published literature and widespread belief that valerian has positive effects on sleep, the lack of scientifically sound clinical trials and longer-term studies investigating valerian makes it inappropriate to attribute any sleep-promoting efficacy to valerian. The available evidence suggests, but does not clearly demonstrate, the possibility that valerian may improve sleep quality (Bent et al., 2006), but this is not an outcome recognized by the U.S. Food and Drug Administration (FDA). Recent reviews suggest that valerian generally produced decreased sleep latency, fewer nocturnal awak- enings, and improved subjective sleep quality. However, in some studies the placebo effect was large, and in others the beneficial effects of valerian were not seen until after 2 to 4 weeks of therapy (Beaubrun and Gray, 2000). Five studies of valerian for sleep that included polysomnographic (PSG) re- cordings revealed no consistent, statistically significant changes in any PSG outcome measures (i.e., in sleep-onset latency, sleep efficiency index, sleep period time, time in each sleep stage, and number of arousals). Six random- ized trials showed no difference between valerian and placebo groups in terms of sleepiness the next morning (Bent et al., 2006). Safety Concerns Despite recommended dosages for valerian, there may be significant dif- ferences in effective dose among the many commercially available products. First, the number and amount of active chemicals can vary greatly within individual species and between different species of plants used to produce a valerian dietary supplement (Hobbs, 1989), though most reputable dis- tributors use the level of valerenic acid in their product for standardization

154 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL (Gyllenhaal et al., 2000). Second, since valerian is considered an over-the- counter supplement by the FDA, its contents and manufacturing process are not strictly regulated. Third, valerian products come in a variety of forms and dosages. Adult dosages for insomnia range from 1.5 to 3 g of actual herb or root, which roughly corresponds to 400–900 mg of an aqueous extract, taken 30–60 minutes before bedtime (Morin et al., 2007). Owing to the lack of comprehensive randomized, double-blind, placebo-controlled t ­ rials (Stevinson and Ernst, 2000), valerian is not recommended for subjects u ­ nder the age of 18 years. The FDA generally regards valerian as safe, but some studies have reported concerns about toxicity. One study reported hepatoxicity in four women using a combination of valerian and another herbal product called skullcap (Scutellaria spp.) (MacGregor et al., 1989). Concern has also been expressed about the cytotoxicity of valepotriates, constituents found in negligible amounts in most valerian preparations. Valepotriates contain an epoxide group and were found to act as alkylating agents in vitro. However, this property was not found in vivo, presumably because of the poor absorption and distribution of valepotriates (Tortarolo et al., 1982; Wagner et al., 1998). Most studies reporting on the side effects of valerian found them to be mild and generally not more common than the placebo condition. In a placebo-controlled study of 128 subjects, one person experienced nausea and withdrew from the study. However, it was not possible to attribute the nausea definitively to valerian (Leathwood et al., 1982). Another placebo- controlled study found more adverse events with placebo than with valerian (Donath et al., 2000). Some evidence suggests that valerian does not have measurable hangover effects (Leathwood et al., 1982) or adverse effects on cognitive or psychomotor performance (Hallam et al., 2003), but further studies are needed to confirm these claims. Considerations Specific to the Military Valerian has the potential for unwanted synergy with other sedating agents that may be ingested. Therefore, people engaged in safety-sensitive activities that require alertness and quick responses should not take valerian in conjunction with other sedating substances, especially not in conjunction with prescription medications having sedating effects. Thirteen (12 percent) of the 109 medications most frequently prescribed for military personnel (e.g., hypnotics, anxiolytics, antidepressants, opioids) have sedating side effects. Relevant data and conclusions on efficacy and safety reviews and publi- cations identified for valerian are shown in Table 4-15 on pages 294–295.

OTHER DIETARY SUPPLEMENTS 155 References Beaubrun, G., and G. E. Gray. 2000. A review of herbal medicines for psychiatric disorders. Psychiatr Serv 51(9):1130-1134. Bent, S., A. Padula, D. Moore, M. Patterson, and W. Mehling. 2006. Valerian for sleep: A systematic review and meta-analysis. Am J Med 119(12):1005-1012. Bliwise, D. L., and F. P. Ansari. 2007. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. Sleep 30(7):881-884. Diaper, A., and I. Hindmarch. 2004. A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytother Res 18(10):831-836. Donath, F., S. Quispe, K. Diefenbach, A. Maurer, I. Fietze, and I. Roots. 2000. Critical evalu- ation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsy- chiatry 33(2):47-53. Gyllenhaal, C., S. L. Merritt, S. D. Peterson, K. I. Block, and T. Gochenour. 2000. Effi- cacy and safety of herbal stimulants and sedatives in sleep disorders. Sleep Med Rev 4(3):229-251. Hallam, K. T., J. S. Olver, C. McGrath, and T. R. Norman. 2003. Comparative cognitive and psychomotor effects of single doses of Valeriana officianalis and triazolam in healthy volunteers. Hum Psychopharmacol 18(8):619-625. Hobbs, C. 1989. Valerian: A literature review. HerbalGram 21:19-34. Holzl, J., and P. Godau. 1989. Receptor binding studies with Valeriana officinalis on the benzodiazepine receptor. Planta Medica 55:642. Houghton, P. J. 1999. The scientific basis for the reputed activity of valerian. J Pharm Phar- macol 51(5):505-512. Leathwood, P. D., F. Chauffard, E. Heck, and R. Munoz-Box. 1982. Aqueous extract of va- lerian root (Valeriana officinalis L) improves sleep quality in man. Pharmacol Biochem Behav 17(1):65-71. MacGregor, F. B., V. E. Abernathy, S. Dahabra, I. Cobden, and P. C. Hayes. 1989. Hepato- toxicity of herbal remedies. Br Med J 299(6708):1156-1157. 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. Santos, M., F. Ferreira, A. T. Cunha, A. P. Carvalho, and T. Macedo. 1994. An aqueous extract of valerian influences the transport of GABA in synaptosomes. Planta Medica 60(3):278-279. Stevinson, C., and E. Ernst. 2000. Valerian for insomnia: A systematic review of randomized clinical trials. Sleep Med 1(2):91-99. Tortarolo, M., R. Braun, G. E. Hübner, and H. R. Maurer. 1982. In vitro effects of epoxide- bearing valepotriates on mouse early hematopoietic progenitor cells and human T- lymphocytes. Arch Toxicol 51(1):37-42. 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.

156 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-2  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Chromium Review/ Clinical Trial Product Reference Type of Study and Subjects Indication Control Dose Specification Campbell Double-blind, randomized Increasing lean Placebo 500 µg, 2×/d Nutrition et al., n=18 men, 56–69 y body mass and for 12 wk 21, San 1999 strength Diego, CA Diaz Randomized Reducing body Placebo 133 µg None et al., n=35 overweight women weight, chromium reported 2008 increasing lean picolinate body mass, and 0.59 g and improving conjugated aerobic fitness linoleic acid 3×/d for 3 mo in conjunction with dietary energy restriction and exercise program Livolsi Randomized Increasing lean Placebo 500 µg/d Nutrition et al., n=15 female softball players body mass and chromium 21, San 2001 strength picolinate for Diego, CA 6 wk Lukaski Double-blind, randomized Reducing body Placebo 187 µg Nutrition et al., n=83 females, age 19–50 y weight and chromium 21, San 2007 altering body for 12 wk Diego, CA composition Martin Double-blind, randomized Reducing body Placebo 1,000 µg/d None et al., n=37, age 25–75 y, with type 2 weight and chromium reported 2006 diabetes adipose tissue, picolinate for glycemic 6 mo control, insulin sensitivity Nissen Meta-analysis of 12 studies Increasing lean Placebo 200 to 1,000 None and involving chromium body mass and µg reported Sharp, supplementation with weight strength 2003 training in healthy men and women

OTHER DIETARY SUPPLEMENTS 157 Interactions with Adverse Pharmaceuticals, Clinical Details and Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Body composition, High-dose chromium picolinate None None reported metabolic rate, muscle supplements did not influence body reported strength composition, strength, or power development. Body composition measured No differences in heart rate, VO2 None None reported by DEXA; aerobic fitness maximum, or body composition between reported measured by heart rate and participants receiving chromium or VO2b maximum during placebo. exercise Body weight, percent body No differences in muscle strength or None None reported fat, lean body mass, body composition. reported strength Body weight; skin fold Participants given chromium and placebo None None reported thickness; bone mineral lost similar amounts of weight and body reported content; fat mass; lean body fat; no differences in bone mineral mass; hematocrit content, fat-free or hematocrit as a function of supplementation or time. DEXA measurement of Improved glycemic control, increased None None reported body composition; glucose insulin sensitivity, attenuated body reported tolerance following a 75-g weight gain, changes in body fat challenge; urinary distribution with chromium picolinate. chromium excretion; blood levels of triglycerides; free fatty acids, insulin, adiponectin, and C-peptide Body composition measured Chromium supplementation associated None None reported by skin folds, hydrostatic with small, nonsignificant increases in reported weighing, and DEXAa lean body mass and strength. continued

158 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-2  Continued Review/ Clinical Trial Product Reference Type of Study and Subjects Indication Control Dose Specification Pittler Meta-analysis of 10 trials that Reducing body Placebo 200 to 400 Various et al., met all inclusion criteria and 7 weight µg/d for 6 to 2003 studies that were not suitable for 26 wk statistical pooling Normal-weight and obese males and females engaged or not engaged in weight training Trumbo Review of five studies assessing Improving Placebo 400 to 1,000 Various and effect of chromium picolinate on insulin µg/d for 12 Ellwood, the risk of type 2 diabetes in sensitivity and to 32 wk 2006 obese and normal-weight men glucose and women. Studies included tolerance from 13 to 44 participants a  ual-energy X-ray absorptiometry (DEXA) is an enhanced form of X-ray technology that is used to D measure bone loss. DEXA is the established standard for measuring bone mineral density. b  xygen uptake. O

OTHER DIETARY SUPPLEMENTS 159 Interactions with Adverse Pharmaceuticals, Clinical Details and Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Body weight, body fat, lean Small effect of chromium picolinate None None reported body weight compared with placebo for reducing reported body weight; however, difference due primarily to results of two trials. Insulin resistance and oral One intervention study showed a None None reported glucose tolerance test beneficial effect of chromium picolinate reported (OGTT) on insulin sensitivity; no studies showed a beneficial effect of chromium picolinate on OGTT.

160 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Creatine Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Bemben Review Sport and exercise Various Various None reported and performance Lamont, 2005 Calfee and Review Effects of creatine None reported None reported None reported Fadale, use 2006 Cornish Double-blind, Athletic Placebo 0.3g/kg body Muscle Tech et al., 2006 randomized, performance mass/d creatine Research and repeated (sprint skating) monohydrate Development measures for 5 d Inc., n=17 men, Bramptom, competitive ON, Canada college ice hockey players

OTHER DIETARY SUPPLEMENTS 161 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Ergogenic effects related Beneficial effects of creatine No strong None reported to sports and exercise supplementation for repeated, scientific performance (isotonic/ short bouts of high-intensity evidence to dynamic peak force, exercises, particularly isotonic/ support any isokinetic peak torque, dynamic peak force parameters. reported isometric force adverse effects; production, muscle Benefits seen for males and females however, no soreness and damage, of all ages. well-controlled jumping/sprinting, sprint long-term power cycling, continuous studies and intermittent available endurance) Athletic performance Some beneficial effects on athletic Weight gain None reported performance: increasing strength in (1.6–2.4 kg) outcomes of short-duration anaerobic activities. Minor gastrointestinal No improvement in endurance discomfort and performance. muscle cramps Possible adverse renal effects Sprint skating No differences between placebo None reported None reported performance (skating and treatment group for skating treadmill test, lactate treadmill test, blood lactate, analysis, isokinetic testing, isokinetic testing, dietary intake, or and dietary analysis) changes in body mass. Creatine monohydrate supplementation had no effects on sprint skating performance. continued

162 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Derave Double-blind, Glucose tolerance Placebo 2 wk None reported et al., 2003 randomized (maltodextrin) immobilization n=33 healthy phase: 3 daily adults (26 doses of 5 g men, 7 creatine women, age 18–30 y) 6 wk retraining phase: 2.5 g/d creatine or 2.5 g/d creatine, 40 g/d protein, and 6.7 g/d amino acids Doherty Double-blind, Exercise Placebo (200 0.3 g/kg creatine Isotar et al., 2002 randomized, performance mL artificially monohydrate Creatine crossover (treadmill sweetened water for 6 d (given as Direct, n=14 men, running) drink) 4 doses/d); Westcott and mean age caffeine Westcott Ltd., (± SD) 22.7 abstinence Clevedon, UK ± 3.5 y 5 mg/kg caffeine in 200 mL artificially sweetened water drink taken 1 h prior to testing Glaister Double-blind, Exercise Placebo (6 g 5 g creatine Starmax et al., 2006 randomized performance maltodextrin for monohydrate Nutrition, n=42 (sprint running) 4 d) and 1 g Hereford, UK physically maltodextrin for active male 4d students

OTHER DIETARY SUPPLEMENTS 163 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Muscle GLUT-4a muscle Changes in muscle GLUT-4 were None reported None reported glycogen, muscle creatine not significantly different between content, muscle fiber type groups during immobilization composition, muscle phase; significant increases in force, and body weight GLUT-4 and muscle glycogen after retraining for creatine and creatine plus protein groups; no treatment effects observed for body weight. Creatine supplementation stimulates GLUT-4 and glycogen content in human muscle only when combined with changes in habitual activity level. Plasma caffeine Body mass increased during None reported None reported concentration, body mass, creatine supplementation and was MAOD,b treadmill run maintained during placebo and time to exhaustion, total caffeine trials; no increase in VO2 rating of exhaustion, MAOD between trials. and metabolic data Acute caffeine intake was ergogenic after creatine supplementation period and caffeine abstinence. Body mass, mean sprint Increase in body mass relative to None reported None reported time, blood lactate placebo (0.7 kg increase) and reduction in body fat (0.4% reduction). No significant between-group differences in fast sprint time, mean sprint time, fatigue, or posttest blood lactate concentration. Creatine supplementation has no benefit on multiple sprint running performance. continued

164 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Graham Review of Safety and Various Various None reported and literature on efficacy Hatton, creatine 1999 published from 1966 to 1999 Greenwood Observational Muscle cramping Noncreatine- 15.75 g/d Experimental et al., 2003 n=approxi­ and injury containing creatine and Applied mately 100 supplement monohydrate Sciences, college for 5 d and an Degussa football average of 5 g/d Bioactives/ players, age thereafter Traco Labs, 18–23 y (5- to 10-g Champaign, doses) over a IL, and 3-y period MetaResponse Modifiers, San Clemente, CA Groeneveld Double-blind, Neuro­­pro­tective Placebo 5 g creatine DSM Fine et al., 2005 randomized and adverse (Polycose) for monohydrate Chemicals n=175 effects 310 d 2×/d for 310 d Inc., Heerlen, patients with the ALS,c ages Netherlands 18–75 y Patients taking 50 mg riluzole twice daily

OTHER DIETARY SUPPLEMENTS 165 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Various As of 1999, no high-quality May be related Studies on drug research on the effects of creatine to renal interactions are exists. Little data on short-term dysfunction needed and long-term safety of creatine. Limited evidence of benefits. May enhance the performance of high- intensity, short-duration exercise. Injury rates, number of Incidence of cramping, heat/ No evidence of None reported missed practices dehydration, muscle tightness, significant noncontact joint injuries, contact adverse effects injuries, illness, number of missed practices due to injury, players lost for the season, and total injuries/ missed practices were generally proportional or lower than the creatine use rate among players. Creatine supplementation does not appear to increase the incidence of injury or cramping in college football players. Supplement intake was not blinded or randomized and compliance was self-reported. Reported adverse effects, Creatine supplementation was Severe diarrhea None reported renal function, urinary stopped in 3 patients due to (n=2) and creatine complaints of diarrhea and nausea. nausea (n=1) No significant differences in Water occurrence of adverse effects retention between groups. continued

166 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Gualano Double-blind, Glucose tolerance Placebo 0.3 g/kg body None reported et al., 2007 randomized and insulin (dextrose) weight per d n=22 sensitivity; non- creatine for sedentary insulin-dependent 1st wk healthy men, diabetes mellitus mean age 24 y 0.15 g/kg body weight per d creatine for next 11 wk Hespel Double-blind, Muscle Placebo 4 × 5 g/d Creatine Fuel, et al., 2002 randomized, relaxation; (maltodextrin) creatine Twin crossover exercise monohydrate Laboratories, n=10 students performace for 4 d New York, (9 men, 1 NY woman), age 4 × 5 g/d 21–24 y creatine monohydrate and 5 mg/kg body weight per d caffeine 2 other protocols with just caffeine

OTHER DIETARY SUPPLEMENTS 167 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements VO2 max test, aerobic Significant decrease in oral glucose No adverse None reported exercise training, plasma tolerance test compared to placebo. effects were glucose, and plasma No differences in fasting insulin. reported in insulin either Creatine supplementation in treatment combination with moderate group aerobic training over 3 mo improved glucose tolerance in healthy sedentary males but did not alter insulin sensitivity. Maximal knee extension No significant differences in muscle None reported Caffeine and torque, contraction time, contraction time. creatine have relaxation time opposing effect on Caffeine intake increased muscle relaxation relaxation time; creatine intake time shortened relaxation time, compared to placebo. Combined intake of caffeine and creatine have opposing effects. Short-term caffeine intake inhibits muscle relaxation and conteracts the benefits of creatine supplementation in muscle relaxation. continued

168 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Hoffman Randomized Endocrine Placebo 10.5 g/d None reported et al., 2006 n=33 men changes, strength (10.5 g/d creatine college training dextrose) monohydrate football performance or 10.5 g/d players creatine monohydrate and 3.2 g/d β- alanine 10-wk program Kilduff Double-blind, Cardiovascular, Placebo (160 g/d 22.8 g/d None reported et al., 2004 randomized metabolic, and glucose polymer creatine n=21 thermoregulatory in warm/hot monohydrate endurance- responses and water for 7 d) and 35 g trained men, exercise glucose polymer mean age 27 y performance in in warm/hot hot conditions water for 7 d Klivenyi Animal study ALS Unsupplemented Diet Avicena, Inc., et al., 2004 n=11–13 diet supplemented Cambridge, transgenic with 2% MA mice in each creatine, or treatment 0.05% group rofecoxib, or 0.012% celecoxib or combinations of all these

OTHER DIETARY SUPPLEMENTS 169 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Body composition, No significant differences in change None reported Additive benefit of strength measures, in body mass. β-alanine in strength biochemical and and power training hormonal analyses, Greater changes in lean body mass anaerobic power and percent body fat with combination β-alanine and creatine, than creatine alone. Increased strength improvement with creatine alone or with β- alanine. Resting testosterone was elevated with creatine intake, but no other significant endocrine changes. No significant changes seen in power performance for any group. Addition of β-alanine to creatine supplements enhanced strength performance more than creatine supplementation alone. ICW,d TBW,e Creatine supplementation increased No reports of None reported thermoregulatory ICW and TBW and reduced heart gastrointestinal responses (heart rate, rate, temperature, sweat rate. No distress or temperature), significant decrease in time to muscle cardiovascular responses, exhaustion. cramping time to exhaustion Creatine is beneficial for prolonged exercise in hot conditions. Survival, PGE2f tissue Significant improvement of survival None reported Creatine used in content, motor rates in all mice except those with combination with performance, body weight unsupplemented diet. An additive celecoxib and/or neuroprotective effect was seen in rofecoxib (COX-2 mice fed combination diets, inhibitors) had an compared to single supplements. additive effect on Improved motor performance in motor performance supplemented mice, with additive and survival rate effect for combination diets. Creatine used in combination with rofecoxib and/or celecoxib can be a useful strategy in the treatment of ALS. continued

170 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Korzun, Randomized Hyperhomo­ Daily Daily Experimental 2004 n=16 healthy cysteinemia multivitamin for multivitamin for and Applied adults, age 8 wk 4 wk Sciences, ≥19 y Golden, CO Then, creatine monohydrate Centrum One- (equal to twice a-Day their daily multivitamin creatinine excretion on a molar basis) and a daily multivitamin for 4 wk McMorris Double-blind Cognitive and Placebo 5 g creatine Creapure, et al., 2006 n=20 students psychomotor monohydrate, Deguss AG, (17 men, 3 performance and 4×/d for 7 d Dusseldorf, women), mean mood state due to Germany age 21.1 y sleep deprivation Mendel Double-blind Thermoregulatory Placebo (10 g 20 g creatine in None reported et al., 2005 n=16 (15 response to Solka-flok in 60 60 g Gatorade male, 1 exercising in the g Gatorade) for for 5 d female), age heat (cycling) 5d 22–33 y

OTHER DIETARY SUPPLEMENTS 171 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Serum folate, erythrocyte Significantly greater reduction in None reported None reported folate, serum vitamin B12, tHcy seen in creatine plus tHcyg multivitamin group than multivitamin group. Modest doses of creatine supplements may lower tHcy in humans. Cognitive tests (RMG,h At 24 h of sleep deprivation, the None reported None reported verbal and spatial short- creatine group had significantly less term memory tests), change in performance from 0 h in psychomotor tests, mood RMG, choice reaction time, state, plasma balance, and mood state. No catecholamines and significant differences between cortisol groups in plasma concentrations of catecholamines and cortisol. Creatine supplementation has a positive effect on cognitive and psychomotor performance and mood state after 24 h sleep deprivation. Body weight, temperature Significant increase in body weight None reported None reported response to exercise in the for creatine group. heat Core temperature was lower after supplementation in both groups. No differences in mean body and mean skin temperatures. No significant effect of short-term creatine supplementation. Did not have a negative effect on thermoregulation during exercise in heat. continued

172 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Op’t Eijnde Animal study Type 2 diabetes Unsupplemented Diet Creapure, et al., 2006 n=24 male diet supplemented Degussa, Goto-Kakizaki with 2% Freising, rats with creatine Germany inherited type monohydrate 2 diabetes Pline and Review Renal function Various Various None reported Smith, 2005 Pluim Double-blind, Tennis Placebo Loading phase: Podium, et al., 2006 randomized performance (maltodextrose 0.3 g/kg body Synergen, n=36 men, and dextrose) weight/d for 6 d Switzerland, competitive and creatine tennis players, Maintenance monohydrate, mean age 22 y phase: 0.03 g/kg MSD, the body weight/d Netherlands for 28 d Pritchard Case report Renal dysfunction 15 g/d for 1 wk, None reported and Kalra, n=1 man, age then 2 g/d for 1998 25 y with 7 wk nephrotic syndrome taking cyclosporin

OTHER DIETARY SUPPLEMENTS 173 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Body weight, food intake, Creatine supplementation None reported None reported blood D-glucose, blood significantly increased muscle insulin, insulinogenic creatine content and lowered the index, muscle insulinogenic index; this was biochemistry mainly attributable to a lowering of plasma insulin concentration. Creatine supplementation may improve the sensitivity to insulin in extrapancreatic sites of young male rats. Measures of renal In healthy, young adults, creatine Two cases of None reported function supplementation does not have a renal negative effect on renal function. dysfunction Speed of serve, ground No differences in performance or No None reported stroke speed and change in body weight during the gastrointestinal precision, sprint test, loading phase. complaints or strength measurements muscle cramps During maintenance phase, significant increase in body weight in creatine group. No differences in performance between groups. Creatine supplementation does not improve tennis performance and should not be recommended for tennis players. Serum creatinine, Serum creatinine levels increased Renal None reported creatinine clearance (103 μmol/L to 180 μmol/L). One dysfunction month after stopping supplementation, levels dropped to 128 μmol/L. In this case, there is strong circumstantial evidence that creatine is responsible for deterioration in renal function. continued

174 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Reardon Controlled Endurance Placebo (24 g/d Load: 20 g/d Musashi Pty et al., 2006 n=17 healthy, training and maltodextrin for creatine Ltd, Australia active adults performance 7 d, then 6 g/d monohydrate (11 men, 6 (cycling) for 3 wk) and 4 g/d women), ages maltodextrin for 18–27 y 7d Maintenance: 5 g/d creatine monohydrate and 1 g/d maltodextrine for 3 wk Santos Double-blind Inflammation and Placebo (60 g 20 g/d creatine None reported et al., 2004 n=34 male muscle soreness maltodextrine monohydrate athletes, ages associated with for 5 d) and 60 g 21–30 y, long-distance carbohydrate training for a running (maltodextrine) marathon for 5 d Scheff and Animal study, Neuroprotection Unsupplemented Diet Sigma Dhillon, randomized following diet supplemented Chemical Co., 2004 n=85 adult traumatic brain with 0.5% or St. Louis, MO male Sprague- injury 1.0% creatine Dawley rats monohydrate subjected to for 2 wk moderate controlled cortical contusions

OTHER DIETARY SUPPLEMENTS 175 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Muscle total creatine and Muscle total creatine and glycogen None reported None reported glycogen content, body contents were elevated in both weight, body fat, groups. No significant oxidative capacity, anthropometric changes in either endurance performance group, or changes in oxidative capacity. Both groups had significant reductions in carbohydrate oxidation; significant increases in lipid oxidation, total work, and average power output. No treatment effect of creatine supplementation on any parameter of endurance performance. Cell death, inflammation After running a 30 km race, None reported None reported markers, muscle soreness increase of cell death and markers (CK,i lactate inflammation markers in placebo dehydrogenase, PGE2,j group. Increase of CK, PGE2, and TNFαk) TNFα in creatine group. No significant difference between groups in time to finish the race. Supplementation with creatine reduced cell damage and inflammation after an exhaustive 30-km running race. Lactate and free fatty acid Both lactate and free fatty acid None reported None reported levels in cortex and levels were significantly increased hippocampus in all tissues ipsilateral to the injury. Animals supplemented with creatine had significantly lower levels. Greater neuroprotection was seen in animals fed a 1% creatine diet than those fed a 0.5% creatine diet. In adult male rats, a diet supplemented with creatine can provide substantial neuroprotection in part by suppressing secondary brain injury. continued

176 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Shao and Review of Various Various None reported Hathcock, randomized, 2006 controlled human studies that address safety of creatine or risk assessment Smith and Survey of Dahm, creatine use 2000 n=328 student athletes (182 men, 146 women), age 14–18 y Sullivan Animal study, Neuroprotection Daily injections Daily injections Sigma et al., 2000 randomized following of 3 mg/g body of 0.1 mL/10 g Chemical Co., n=40 adult traumatic brain weight olive oil body weight of St. Louis, MO ICR mice and injury for 1, 3, or 5 d creatine 24 adult before injury monohydrate Sprague- suspended in Dawley rats olive oil for 1, subjected to 3, or 5 d before moderate, injury controlled cortical contusions Thor­steins­ Case report 15 g/wk creatine dot­tir n=1 healthy monophosphate, et al., 2006 man, age 24 y multiple herbs, with acute nonherbal renal failure supplements, and and vitamins for proteinuria 6 mo

OTHER DIETARY SUPPLEMENTS 177 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements The Observed Safe Level risk None reported assessment method indicates that the evidence of safety of creatine intake is strong at intakes up to 5 g/d for chronic supplementation. Although much higher levels have been tested under acute conditions without adverse effects and may be safe, the data for intakes above 5 g/d are not sufficient for a confident conclusion of long-term safety. Adverse effects 8.2% of students surveyed reported Diarrhea, None reported creatine use. cramps, and loss of appetite were reported Tissue damage, synaptic Less cortical damage found in mice None reported None reported homeostasis (up to 36%) and rats (up to 50%) that were given creatine. Significant increases in mitochondrial membrane potential; significant decreases in intramitochondrial oxygen levels of reactive oxygen species and calcium. Based on this animal model, creatine may have effective use as a neuroprotective agent against acute and delayed neurodegenerative processes. Adverse effects Previously healthy male presented Renal Patient was also with acute abdominal pain, dysfunction taking a large polydipsia, and polyuria. He was number of other diagnosed with acute renal failure. herbs, supplements, Biopsy showed acute interstitial and vitamins nephritis. Kidney function returned to normal after cessation of supplement intake. continued

178 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Volek Double-blind, Exercise Placebo 0.3 g/kg body Creatine Fuel, et al., 2001 randomized performance in (powdered weight creatine Twin n=20 healthy the heat (sprint cellulose— monohydrate Laboratories, men, mean cycling) equivalent daily for 7 d Inc., age 23 y amount to Hauppauge, creatine intake) NY Volek Review of the Efficacy of Various et al., 2006 nutritional creatine needs of supplementation female for female strength athletes athletes Warber Double-blind, Performance of Placebo (sports 4 sports bars/d M&M Mars, et al., 2002 randomized military training bar without containing 6 g Inc., NJ n=26 male tasks (obstacle creatine) creatine soldiers, mean course, mood monohydrate age 32 y state, and per bar for 5 d marksmanship) Watsford Double-blind, Musculotendinous Placebo 20 g/d creatine None reported et al., 2003 randomized stiffness and for 7 d, then n=22 healthy exercise 10 g/d for 21 d men, mean performance age 23.4 y

OTHER DIETARY SUPPLEMENTS 179 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Body mass, body water, Significant increase in body mass in No adverse None reported cardiovascular responses, creatine group. No differences effects were temperature responses, between groups for heart rate, found kidney function, and peak blood pressure, and sweat rate and mean power responses. Greater increase in peak power found in the creatine group after sprints. Creatine supplementation had a positive effect on repeated sprint cycle performance in the heat without changes in thermoregulatory responses. High-intensity exercise Like men, women may also benefit None reported None reported performance; leucine rate from creatine supplementation for of appearance improving exercise performance. Anthropometric data, No difference between groups on No reports of None reported body composition, obstacle test performance, rifle gastrointestinal maximal oxygen uptake, marksmanship, or mood. Creatine distress or any obstacle test performance, group had significant increase in other medical bench press performance, bench press repetitions. Creatine problems or rifle marksmanship usage resulted in 1.4 kg increase in symptoms performance, and mood body mass and a 0.5% decrease in body fat, both significantly different than placebo. Short-term supplementation with creatine improved performance on strength tests, but did not significantly improve performance on a military obstacle course in male soldiers. Body mass, isometric Significant gain in body mass, None reported None reported force, rate of force countermovement jump height, and development, and drop jump height. No increase in musculotendinous musculotendinous stiffness. stiffness Creatine supplementation did not cause muscle strain injuries. Performance enhancement was found. continued

180 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-3  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Weiss and Double-blind, Exercise Placebo 25 g/d creatine Creatine Fuel, Powers, randomized, performance in monohydrate Twin 2006 counter­ the heat (cycling) for 5 d Laboratories, balanced Inc., n=24 athletic, Ronkonkoma, healthy men, NY mean age 22.9 y a  GLUT-4 is a factor in the regulation of blood glucose and the primary glucose transporter in skeletal muscle. b Maximal accumulated oxygen deficit. c  Amyotrophic lateral sclerosis. d Intracellular water. e  Total body water.

OTHER DIETARY SUPPLEMENTS 181 Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Heart rate, blood No differences in changes in heart None reported None reported pressure, core rate, blood pressure, temperature, temperature, body water sweat loss, or relative humidity volumes and sweat loss, between groups. relative humidity, side effects Creatine group had significant increase in body water volumes. Short-term creatine supplementation does not impair the thermoregulatory response during exercise in the heat. f  Prostaglandin E2. g  Total plasma homocysteine. h  random movement generation test. A i  Creatinase kinase. j  Prostaglandin E2. k  Tumor necrosis factor-alpha.

182 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-4  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for DHEA Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Kroboth Review of changes in DHEA in Oral doses Various et al., aging, disease, and with drug from 50 to 1999 or vitamin use. Individual 1,600 mg/d studies had 5–36 subjects Salek Review of effects of disease et al., and drugs on DHEA 2002

OTHER DIETARY SUPPLEMENTS 183 Interactions with Clinical Details Pharmaceuticals, and Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Effects of various Blood DHEA is lower in variety of The majority of Some drugs reduced drugs and disease clinical conditions including anorexia studies showed an (e.g., states on DHEA; nervosa, renal disease, diabetes, and inverse dexamethasone, effects of DHEA lupus. relationship insulin) while others supplementation on between DHEA/ increased (e.g., blood DHEA, Acute, strenuous exercise increased DHEA-S benfluorex, behavior (mood, DHEA in two studies. One study on concentrations and diltiazem) blood depression, U.S. Army Rangers during training cardiovascular DHEA cognition), body observed an increase in morning disease composition DHEA that was interpreted as response to exercise, sleep, and Minimal serious energy balance stress. side effects; some include changes in Blood DHEA increased from 1.7- to hormone 14-fold depending on oral dose and concentrations, gender. increased facial hair, nasal Inconsistent effects were reported on congestion, body composition. headache, fatigue, and mild insomnia Some drugs decrease DHEA by inhibiting ACTH (dexamethasone), including P450 (central nervous system agents). Some drugs increase DHEA by inhibiting sulfatase (danazol) or measure clearance rate (insulin) One epidemiological study showed that blood DHEA-S was inversely associated with multivitamin use and positively with retinol supplementation continued

184 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-4  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Allolio Review of epidemiological and Reduce Various 25, 50, Various and Arlt, clinical trial research in those consequences of 100 mg/d used 2002 with adrenal insufficiency as aging in various well as normal older adults studies Bahrke Review of anabolic androgenic Performance, and steroids and related substances body Yesalis, composition, 2004 and health Mayer Review of rodent studies Liver cancer 0.45–1% of and the diet for Forstner, 52–100 wk 2004 depending on study

OTHER DIETARY SUPPLEMENTS 185 Interactions with Clinical Details Pharmaceuticals, and Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Hormone Increase in testosterone and decreased Mild and transient None reported concentration, blood HDL in women, increase in estrogen side effects: facial lipids, well-being and in men. Neuronal growth and acne, increased mood, body development affected. Low DHEA in sebum production; composition, and men (no association in women) effect on performance associated with reduced longevity promoting sex and higher incidence of hormone- cardiovascular disease (unclear dependent cancer whether marker of illness or is still “unsettled” predictor/contributor). and requires more research Improved overall well-being, sexual satisfaction, and mood following months of treatment but no effect on cognitive performance. Some studies report increased lean body mass and muscle strength but none of the double-blind trials observed these effects. Use in clinical populations with adrenal insufficiency and chronic glucocorticoid treatment may be warranted as well as in individuals with impaired well-being, mood, or sexuality. Not enough evidence to recommend use for reducing normal effects of aging. Increase in testosterone or enhance adaptations to resistance training in young men; increases in testosterone and virilizing effects are noted in women. Not of benefit for male athletes and has masculinizing effects in women. Liver metabolism, Hepatic tumor promotion and hepatocarcinogenesis, inhibition effects depending on dose, modulation of rat strain, and duration of ingestion. chemically induced Liver metabolism increases and hepatocarcinogenesis becomes catabolic (e.g., reduction of glycogen). continued

186 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-4  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Brown Review of several prohormone Performance Doses up to Various et al., supplements for athletes and body 1,600 mg/d 2006 composition Evans Cochrane Collaboration Effect on Placebo 50 mg/d Various et al., review of randomized, cognitive 2007 placebo-controlled trials in function in people age >50 y without elderly dementia who received DHEA of any dose for more than 1 d Raven Update on review previously Chronic disease and performed in 2001, Hinson, postmenopausal women 2007

OTHER DIETARY SUPPLEMENTS 187 Interactions with Clinical Details Pharmaceuticals, and Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Serum hormone Acute ingestion: DHEA may have None reported concentration, health Men—Increases serum DHEA, some similar and performance androstenedione, estrogen, but not effects on effects testosterone. androstenedione Women—Increases DHEA, reduction in HDL. androstenedione, testosterone. Speculation on possible effects on Chronic ingestion: premature closure Men—Dose-dependent increases in of epiphyseal DHEA, androstenedione with no plates during change in testosterone. Studies in growth, young novice or older experienced hypertrophy of weight lifters report no benefit on fat areas of the brain loss, muscle gain, or muscle function. related to Women—Increases serum aggression, and testosterone, acne, facial hair, insulin prostate resistance. Few studies evaluated hypertrophy. No effects on muscle size and strength evidence of change concurrent with resistance training. in liver function markers Conclusion: No benefit of DHEA supplements for athletes. No evidence of improvement in One trial reported None reported memory or other aspects of cognitive reduced function in nondemented older performance in the people. visual memory recall test with DHEA. No consistent adverse effects, none longer than 3 mo Supplementation is not recommended for majority of postmenopausal women. Only exceptions could be those with the lowest endogenous DHEA or those with low bone mineral density. continued

188 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-4  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Morales Double-blind, randomized, Aging-related Placebo 100 mg/d for Diosynth et al., crossover reduction in for 6 6 mo Corporation, 1998 n=9 men, 10 women muscle strength mo Chicago, IL. and hormones Purity confirmed with HPLC Baulieu Double-blind, randomized Reduce Placebo 50 mg/d for Prasterone et al., n=280 healthy men and consequences of for 12 12 mo 2000 women, ages 60–79 y aging mo Percheron Double-blind, randomized Muscle Placebo 50 mg/d for Akzo et al., n=280 healthy men and function change for 12 12 mo Laboratories, 2003 women, ages 60–80 y during aging mo Diosynth, France Missmer Case-control nested within None None None et al., Nurses’ Health Study reported reported reported 2004 n=322 women who developed breast cancer Villareal Double-blind, randomized Abdominal fat Placebo 50 mg/d for Schering- and n=52 elderly men and women, and insulin 6 mo Plough, Holloszy, age 65–78 y action Munich, 2004 Germany

OTHER DIETARY SUPPLEMENTS 189 Interactions with Clinical Details Pharmaceuticals, and Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Body composition Both genders: Increased serum DHEA None reported None reported (DEXA), serum to young adult range hormones, muscle Women—Increase in body weight by strength 1.4 kg, increased testosterone to concentrations greater than normal range Men—Elevation of serum IGF-1,a reduction in body fat mass of 1.0 kg, increase in muscle strength. DHEA improved body composition. Blood hormones, Small increase in estrogen and None reported None reported bone mineral density testosterone (particularly in women), and turnover reduced bone turnover and increased markers, libido libido, improved skin integrity in parameters, skin women over 70 y, reduced some integrity effects of aging on bone, skin, and libido. Muscle strength and Serum DHEA restored to ranges for None reported None reported cross-sectional area young adults (increase of >200%) but and serum DHEA no effect on muscle strength or cross- sectional area. No benefits found. Blood samples High DHEA was associated with Risk of breast collected 8–9 y prior higher risk of developing hormone- cancer to development of sensitive breast cancer. breast cancer. Measured for Relative risk for those in highest concentration of DHEA quartile was 2.3 compared to endogenous sex those in lowest quartile. hormones and stratified into quartiles Magnetic resonance More reduction in visceral and None reported None reported imaging for visceral subcutaneous fat area, and insulin and subcutaneous area under the curve compared with abdominal fat, placebo. Glucose area under the glucose and insulin curve was unchanged. response to oral Could play a role in reducing glucose tolerance test abdominal fat and improving insulin sensitivity in aged individuals. continued

190 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-4  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Kaaks Case-control nested within the Endogenous 726 None reported None et al., European Prospective hormones and cancer- reported 2005a Investigation into Cancer and breast cancer free Nutrition cohort risk in matched n=370 premenopausal women premenopausal controls who developed breast cancer women Kaaks Case-control study nested Endogenous 1,309 None reported None et al., within the European hormones and cancer- reported 2005b Prospective Investigation into breast cancer free Cancer and Nutrition cohort risk in matched n=677 postmenopausal women postmenopausal controls who developed breast cancer women Nair Double-blind, randomized Prevention of Placebo Men: 75 mg/d Confirmed et al., n=87 men, 57 women, age age-related Women: to be 95.5% 2006 ≥60 y disabilities 50 mg/d, pure upon placebo or analysis testosterone patch 2-y treatment Muller Double-blind, randomized Prevention of Placebo 50 mg/d Schering AG et al., n=100 men, age ≥70 y frailty in elderly DHEA (other provided the 2006 men arms included tablets atamestane, atamestane and DHEA, or placebo) aInsulin-like growth factor.

OTHER DIETARY SUPPLEMENTS 191 Interactions with Clinical Details Pharmaceuticals, and Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Blood concentrations Highest quartile of blood DHEA had Risk of breast of endogenous sex relative risk of 1.48 for breast cancer cancer hormones compared to those at lowest quartile. Blood concentrations Highest quintile of blood DHEA had Risk of breast None reported of endogenous sex relative risk of 1.69 for breast cancer cancer hormones compared to those at lowest quintile. Physical DHEA: No effect on None reported performance, body Men—Increase in plasma DHEA and prostate size or composition, bone slight but significant increase in bone blood PSA, liver mineral density, mineral density (femoral neck), but function markers, glucose tolerance, no effect on body composition, peak electrolytes, or quality of life oxygen consumption (aerobic fitness), hemoglobin (Health Status muscle strength, insulin sensitivity, or Questionnaire), adverse events. It was noted that prostate imaging for Women—Modest increase in plasma 2 years of testing size and PSA test testosterone and increase in DHEA, may not be slight increase in bone mineral sufficient to detect density at ultradistal radius. No effects on prostate improvement in muscle strength, aerobic fitness, quality-of-life indicators, or major adverse events. Testosterone and DHEA: Reduction in HDL, slight (<0.5 kg) but significant increase in fat-free mass. No evidence of benefit for physical performance. The modest effect on bone mineral density in one location for each gender is less than that for other pharmacological interventions, so is of limited value. Grip strength, leg No effects of any treatment on any None reported None reported extensor power variable. No support for use of DHEA to reduce frailty in elderly men.

192 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ephedra Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Andraws Review of Weight loss Placebo Doses of Various et al., 2005 clinical trials and athletic ephedrine and performance related and compounds cardiovascular ranged from 60– risk 150 mg/d Boozer et al., Randomized, Weight loss Placebo Ephedra None reported 2002 double-blind 90 mg/d, n=167 caffeine BMIa= 192 mg/d, for 31.8±4.1 kg/m2 6 mo

OTHER DIETARY SUPPLEMENTS 193 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Efficacy and safety Studies to date have examined small Modest incidence of None reported of ephedra and cohorts for relatively short periods of cardiovascular side ephedrine for the time (usually ≤6 mo), and have high effects, including treatment of attrition rates, and most studies have mild and transient obesity looked at ephedrine in combination increases in systolic with caffeine and, in several cases, and diastolic blood aspirin. pressure, heart rate, and palpitations Weight loss due to these products, while statistically significant, may not No major adverse be clinically relevant (1 kg) with cardiovascular anywhere from a 2- to 4-fold events (i.e., stroke, increase in side effects compared to myocardial placebo. infarction, or malignant arrhythmias) Adverse event profiles may be different in cohorts with preexisting cardiovascular disease Changes in blood Body weight, body fat, and low- Reports of None reported pressure, heart density lipoprotein cholesterol irritability, nausea, function, body decreased significantly. Increased chest pain, and weight, body high-density lipoprotein cholesterol. palpitations did not composition, and Small changes in blood pressure differ, nor did metabolic changes variables (+3 to –5 mm Hg), and numbers of subjects increased heart rate (4±9 who withdrew vs. –3±9 bpm). No increase in cardiac arrhythmias. By self-report, dry mouth, heartburn, and insomnia were increased in the treatment group; the placebo group reported more diarrhea. Herbal ephedra/caffeine supplements promoted reduction in body weight and body fat and improved blood lipids without significant adverse events. continued

194 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Coffey et al., Double-blind, Weight loss Placebo Ephedra product None reported 2004 randomized, containing multicenter 125 mg ma n=102, huang (10 mg ages 18–65 y, ephedra at 8%), with 250 mg kola nut 30<BMI≤39.9 (60 mg caffeine kg/m2 at 25%), 100 mg white willow bark (15 mg salicin at 15%), 12 wk Hackman Double-blind, Weight loss Placebo Ephedra/caffeine Mixture providing et al., 2006 randomized 9 mo study 40 mg/d ephedra n=61 healthy alkaloids, 100 mg/d premenopausal caffeine, high- women, BMI potency mixture of 27–39 kg/m2 vitamins, minerals, omega-3 fatty acids

OTHER DIETARY SUPPLEMENTS 195 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Weight, percent Additional None reported None reported body fat, fat mass, weight loss (average=1.5 kg) and waist greater reductions in BMI and waist circumference, circumference in treatment group but BMI, blood may not be clinically significant. pressure, and pulse measured at 2 d, No differences observed in percent 1 wk, 2 wk, 4 wk, body fat, fat mass, diastolic or 8 wk, and 12 wk systolic blood pressure, pulse, the postrandomization occurrence of any adverse event. Testing of the study product by two independent laboratories indicated that it only had approximately half the amount of ephedrine alkaloids and caffeine indicated on the label. Changes in body The treatment group lost significantly Dry mouth, None reported weight, body more body weight (–7.18 kg) and insomnia, composition, lipids, body fat (–5.33 kg) than the control nervousness, and insulin, leptin, group (–2.25 and –0.99 kg, palpitations adiponectin, respectively), and showed significant ghrelin, and self- declines in serum cholesterol, reports of physical triglycerides, cholesterol to high- activity, diet, and density lipoprotein ratio, glucose, quality-of-life fasting insulin, and leptin. indexes as well as well blood Blood pressure, electrocardiograms, pressure, heart other clinical chemistry measures, rate, blood histology, urinalysis, and self- electrocardiograms, reported physical activity were urinalysis, blood similar in both groups. histology, serum chemistry The treatment group reported more measures, and self- energy and decreased appetite reported symptoms compared with placebo and scored higher on a quality-of-life domain assessing vitality. Low dose (40 mg/d) of ephedra alkaloids plus caffeine appeared safe and effective in causing loss of weight and body fat and improving several metabolic parameters, including insulin sensitivity and lipid profiles, when tested under physician supervision. continued

196 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Keisler and Review Weight loss Placebo Various Various Hosey, 2005 and athletic performance Shekelle et al., Meta-analysis Weight loss Placebo/ 10–20 mg/d low Various 2003 and athletic none dose, 52 randomized performance 40–90 mg/d clinical trials and safety middle dose, analysis 100–150 mg/d 65 case reports high dose, up to 6 mo

OTHER DIETARY SUPPLEMENTS 197 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Athletic Ephedra use showed a 0.6–0.8 kg/mo Myocardial None reported performance weight loss compared to placebo. infarction reported in two male athletes Caffeine plus ephedra resulted in a ages 16–19 y 1.0 kg/mo weight loss compared to placebo, reported only over a 6-mo Cardiac period. No long-term data exist. arrhythmias, hemorrhagic stroke, The majority of the studies published and seizures have in the literature show no effect on been reported in athletic performance. young athletes Development of psychotic symptoms including decreased sleep, increased agitation, hostility, paranoid delusions, and auditory hallucinations in men ages 19–33 y. Kidney stones have also been reported Weight loss, heart Pooled results for trials with Psychiatric None reported palpitations, and ephedrine (n=5), ephedrine and disturbances, psychiatric, caffeine (n=12), ephedra (n=1), and autonomic and autonomic, or ephedra and herbs containing gastrointestinal gastrointestinal caffeine (n=4) yielded estimates of symptoms, and symptoms weight loss of 0.6, 1.0, 0.8, and heart palpitations 1.0 kg/mo, respectively, greater than placebo. Data are insufficient to draw conclusions No trials of ephedra and athletic about adverse performance were found; seven trials events occurring at of ephedrine were too heterogeneous a rate less than 1.0 to analyze. per thousand Ephedrine and ephedra promote modest short-term weight loss (approximately 0.9 kg/mo more than placebo) in clinical trials. No data regarding long-term weight loss and insufficient evidence to support use of ephedra for athletic performance. continued

198 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Bell et al., Randomized, Athletic Placebo= Caffeine (5 mg/ None reported 2001 double-blind performance Metamucil kg body weight) n=24 healthy, (bulk- and ephedrine untrained men forming (1.0 mg/kg body laxative) weight)

OTHER DIETARY SUPPLEMENTS 199 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements The trials (3-, 5-, Ephedrine increased power output None reported None reported 10-min exercise) during the early phase of the commenced 1.5 h Wingate test. treatment or placebo Caffeine increased time to exhaustion and O2 deficit during the MAOD Anaerobic power test. and ATP production from Caffeine, ephedrine, and a anaerobic combination increased blood lactate, metabolism glucose, and catecholamine levels. (MAODb) Improvement in anaerobic exercise Measurement of performance may be caused by blood lactate, stimulation of the central nervous glucose, and system by ephedrine and stimulation catecholamines of skeletal muscle by caffeine. (postdrug ingestion just before exercise The outcomes and conclusions of and 3-, 5-, and 10- this study were challenged by min post exercise) Goldberg et al. (2002) in a letter to the Editor-in-Chief, owing to clinical significance and statistical methods used to analyze the data. continued

200 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Bell et al., Controlled Athletic Placebo Caffeine (C) None reported 2002 n=12 performance (P) (4 mg/kg body =300 mg weight) and Metamucil ephedrine (E) (bulk- (0.8 mg/kg body forming weight) laxative)

OTHER DIETARY SUPPLEMENTS 201 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements VO2,c VCO2,d VE,e Run times in minutes were 46.0 for None reported None reported heart rate, and C, 45.5 for E, 45.7 for C&E, and ratings of perceived 46.8 for P. The run times for the E exertion measured trials (E and C&E) were significantly during the run reduced compared with the non-E trials (C and P). Pace was increased Blood lactate, for the E trials compared with the glucose, and non-E trials over the last 5 km of the catecholamines run. The E trials (E and C&E) produced significantly faster run times and rate of perceived effort), a reduction of 1.75% of the non-E trials (C and P). VO2 was not affected by drug ingestion. Heart rate was elevated for the ephedrine trials (E and C&E). Caffeine increased the epinephrine and norepinephrine response associated with exercise and also increased blood lactate, glucose, and glycerol levels. Ephedrine reduced the epinephrine response but increased dopamine and free fatty acid levels. The additive nature of E and C was not evident, with the primary ergogenic effect being attributed to E. continued

202 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Jacobs et al., Double-blind Athletic Placebo= Caffeine (4 mg/ Anhydrous caffeine 2003 n=13 healthy performance 300 mg kg body weight) (Sandoz Canada) men Metamucil and ephedrine and ephedrine HCl (bulk- HCl (0.8 mg/kg (Roberts forming body weight) Pharmaceutical laxative) Canada)

OTHER DIETARY SUPPLEMENTS 203 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Muscular Ephedrine trials (C&E and E), High blood pressure None reported endurance indicated a transient but significant increase in the mean number of repetitions completed for both the leg-press and bench-press exercises compared with the non-ephedrine trials (C and P), but only during the first set of traditional resistance- training exercise. Total weight lifted during all three sets was greater for the trials involving ephedrine ingestion. Systolic blood pressure was significantly increased with both ephedrine treatment trials when compared with the other trials (C&E=156 mm Hg; E=150 mm Hg; C=141 mm Hg; P=138 mm Hg). Acute ingestion of E or C&E increases muscular endurance during the first set of traditional resistance- training exercise. The performance enhancement was attributed primarily to the effects of E; there was no additive effect of caffeine. continued

204 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Magkos and Review Athletic Placebo Various Caffeine plus Kavouras, performance ephedrine 2004 Abourashed Review of Weight loss, Various Various Various et al., 2003 adverse events performance enhancements

OTHER DIETARY SUPPLEMENTS 205 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Performance Mixtures of caffeine and ephedrine Increase in heart None reported enhancement and HCl have been reported to confer a rate metabolic greater ergogenic benefit than either parameters drug used alone. Data on increased performance are limited but consistent during submaximal steady-state aerobic exercise, short- and long-distance running, maximal and supramaximal anaerobic cycling, and weight lifting. Blood glucose and lactate concentrations were increased during exercise with ingestion of caffeine and ephedrine in combination; similar effects on lipid fuels (free fatty acids and glycerol) are less pronounced. Concentrations of epinephrine and dopamine are significantly increased though the effects on norepinephrine are less clear. No physiologically significant effects have been reported on pulmonary gas exchange during short-term intense exercise following ingestion of caffeine, ephedrine or their combination; during longer and/or more demanding efforts, some sporadic enhancements have been shown. Despite the type of activity being performed, caffeine and ephedrine combined are quite effective in decreasing the rating of perceived exertion. Weight loss, Of the 140 adverse events submitted Various None reported performance to the FDA for dietary supplements enhancements, and between 1997 and 1999, 31% were potential health probably related to ephedra and risks 31% were deemed possibly related. continued

206 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Bent et al., Review of case None Various Various 2003 series and case reported reports Dhar et al., Review of Various Various Various 2005 adverse events

OTHER DIETARY SUPPLEMENTS 207 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements The relative risk Although products containing Various None reported and 95% ephedra accounted for only 0.82% confidence interval of sales of herbal products in the for experiencing an United States, they were associated adverse reaction with 64% of all adverse event after ephedra use reports for such products. compared with other herbs. This The relative risks for an adverse risk was defined as reaction in persons using ephedra the ratio of adverse were extremely high compared with reactions to other herbs, ranging from 100 for ephedra versus kava to 720 for Ginkgo biloba. other products, divided by the ratio Use of ephedra is associated with a of their relative use risk for adverse reactions that is in the United States greatly increased compared with other herbal products, and its use should be restricted. Cardiovascular Ephedra use is None reported adverse events associated with related to ephedra ischemic and use hemorrhagic stroke, cardiac arrhythmias including ventricular tachycardia, coronary vasospasm, acute myocardial infarction, tachycardia-induced cardiomyopathy, and sudden death. Increased coronary vasoconstriction, tachycardia, and hypertension due to ephedra may be the mechanism of induced myocardial ischemia and infarction. Hemorrhagic stroke is likely secondary to hypertension or cerebral vasculitis continued

208 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Haller et al., Review of 65 None Various Ephedra/ 2005 cases (4 reported caffeine MedWatch reports from 1993 to 1999) Kalman et al., Double-blind, Placebo Ephedra Xenadrine 2002 randomized 335 mg, guarana n=27 healthy 910 mg, bitter overweight orange 85 mg, adults (ages for 14 d 21–60 y)

OTHER DIETARY SUPPLEMENTS 209 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Probability of Of the 65 cases, 20 seizures were None reported None reported causation based on judged to be probably related, 13 temporal possibly related, and 10 unrelated to relationship, use of dietary supplements; 5 cases biological were not seizures, and 17 cases plausibility, and contained insufficient information. In underlying risk the 20 probably related cases, 19 factors in involved ephedra, 14 involved herbal supplement- caffeine, and in 1 case, the associated seizure supplement contained an array of cases elemental salts but no herbal constituents. Ephedra was also Characterization of associated with 7 of the 13 possibly the patterns of use related cases, and caffeine was and types of contained in 5 of these supplement supplements products. Weight loss (45%) and involved in cases of athletic performance enhancement seizures (30%) were the most often cited reasons for supplement use. Ephedra Identification of was implicated in 27 of 33 dietary trends that may supplementation-associated seizures explain potential reported to the FDA over a 7-year risks factors for period. dietary supplement-related seizures Systolic and No cardiovascular None reported diastolic blood side effects observed pressure, heart rate, serial No significant electrocardiograms, effects observed in and Doppler heart rate, systolic echocardiograms blood pressure, diastolic blood pressure, left ventricular ejection fraction, heart valve function, or in cardiovascular physiology within the parameters measured compared to placebo continued

210 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Maglione Review Various Various et al., 2005 n=1,800 adverse events (from MedWatch reports through September 2001) Miller, 2004 Review Weight loss Various Ma huang, None reported and athletic ephedra, performances ephedrine-type alkaloids, ephedrine, and dietary supplements (doses not reported)

OTHER DIETARY SUPPLEMENTS 211 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Serious psychiatric Of the almost 1,800 adverse events, Psychosis None reported events: psychosis, 57 were classified as serious mania or severe psychiatric events. Patients with agitation, severe preexisting psychological/psychiatric depression, conditions and/or use of other mood- hallucinations, altering medications or illicit delusions, suicide substances were involved in 2/3 of attempts, paranoia, these psychiatric cases. There was or violent behavior insufficient documentation for the majority of case reports to make an informed judgment about a relationship between the specific adverse event and the use of ephedra. No definitive causal link could be drawn between ephedra and psychiatric complications from the case reports evaluated. Weight loss, Few studies support the efficacy or Seizures, None reported athletic safety of these supplements. Weight myocarditis, performance, loss and athletic performance appear myocardial efficacy, safety to be only modestly improved, for infarction short durations, in the setting of large numbers of (sometimes serious) adverse event reports. continued

212 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Vukovich Double-blind, Placebo 20 mg ephedra Ephedra extract et al., 2005 randomized, alkaloids and plus caffeine crossover 150 mg caffeine n=8 healthy subjects (4 men, 4 women), mean age 23.4±0.8 y and 22.5±3.1% body fat Boerth and Case report Two None reported Caley, 2003 n=1 women, supplements age 21 y containing ephedra Charatan, Case report Ephedra (20 mg Xenadrine RFA1 2003 n=1, healthy ephedrine) 3/d overweight male athlete, age 23 y

OTHER DIETARY SUPPLEMENTS 213 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements REEf After 3 h, heart rate was 22.7% Increases in heart None reported higher than baseline for the caffeine/ rate, blood pressure Heart rate and ephedra group compared with 8.9% blood pressure higher for the placebo group. At 3 h, systolic blood pressure was 9.1% Blood glucose, higher than baseline for the caffeine/ caffeine, ephedrine, ephedra trial compared with a and free fatty difference from baseline of only 1.9% for the placebo trial. There was no effect of the caffeine and ephedra combination on diastolic blood pressure. During the last 30 min, REE was 4.5% higher in the placebo trial and 10.7% higher in the caffeine/ephedra trial; REE was 8.5% higher in the caffeine/ephedra trial compared with the placebo trial. Free fatty acids increased over time in both the placebo and caffeine/ ephedra trials (from 0.5 to 0.63 mEq/L and from 0.48 to 0.8 mEq/L, respectively). Conclusion: Caffeine and ephedra, at doses of 150 mg and 20 mg ephedrine, respectively, result in a significant elevation in REE, heart rate, and blood pressure. Although significant, the increase in energy expenditure is negligible in terms of weight loss. Medical history The patient’s medical history was Potential minor role None reported significant for familial bipolar in exacerbating the disease. She remained hospitalized mania for 2 weeks and was treated for acute psychotic disorder; she was discharged with a diagnosis of schizoaffective disorder, bipolar type. Organ failure Patient died suddenly of heatstroke Sudden death due None reported that resulted in multiorgan failure to heatstroke following a training workout after causing multiple taking Xenadrine RFA1 for weight organ failure loss. continued

214 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Chen- Case report Ephedra plus Xenadrin Scarabelli n=1 woman, other herbs et al., 2005 age 45 y Chen et al., Case report Ephedra plus Ripped Fuel, 2004 n=5 (2 men, 3 other herbs Metabolife 356, ma women), ages huang, Hydroxycut 19–45 y Haller and Review Various Various Shape-Fast Plus, Benowitz, n=140 case Ripped Force, 2000 reports Ripped Fuel, (from adverse Herbalife’s events reported Thermojetics, to the FDA Metabolife 356, from 1997 to OmniTrim Extra 1999) Vitamin-Fortified tea, Ultimate Orange, Purple Blast, Diet Fuel, Fit America Natural Weight Control Aid, Per-Form Dieter’s Natural tea, Diet-Phen, Ultimate Nutrition Product ma huang, Magic Herb

OTHER DIETARY SUPPLEMENTS 215 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Tissue analysis Patient died of cardiovascular Cardiovascular Case confounded by collapse after taking Xenadrin in collapse concomitant combination with aspirin, Nicotrol, ingestion of aspirin, and Prozac. Prozac, and Nicotrol, and Tissue analysis revealed nonspecific possible marijuana degenerative alterations in the use myocardium such as lipofuscin accumulation, caspase activation, and cleavage of myofibrillary proteins. Patient-reported MRI scans showed single or multiple Ischemic stroke Multiple herbal and symptoms areas of infarction. caffeine use (dizziness, headache, right- Ephedra-containing products appear or left-side to have predisposed these five weakness, aphasia patients to both ischemic and and/or slurred hemorrhagic strokes. speech), MRIg Use of ephedra alkaloids was Cardiovascular None reported considered definitely or probably events, associated with 31% of cases, and hypertension, another 31% possibly related. Of the seizures events related to ephedra, 47% were cardiovascular and 18% were central nervous system events. Hypertension was the most frequent adverse event (17 reports); followed by palpitations, tachycardia, or both (13); stroke (10); and seizures (7). There were 10 events resulting in death, and 13 resulted in permanent disability; 63% of patients were under the age of 45 y. Serious events occurred in persons taking low doses of ephedra (12–36 mg/d), and 11 events occurred in healthy individuals; most of the cases were in individuals under the age of 45 y. continued

216 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Haller et al., Review Various Formula 1, Amp II 2005 n=65 case Pro Drops, reports Herbalife (adverse events Thermojetics, reported to the Thermochrome FDA from 500, Shape–Fast, 1993 to 1999) Power Trim, Metabolift, Victory Turbo Pump Jacobs and Case report Ephedra plus None reported Hirsch, 2000 n=2 men, ages other herbs, 27 and 20 y creatine, DHEA, ginseng

OTHER DIETARY SUPPLEMENTS 217 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Hypoglycemia, Of the 65 cases, 20 cases of seizures Seizures None reported secondary stroke, were judged as probably related, 13 cardiac arrest, as possibly, and 10 as unrelated; 5 seizure cases were not seizures; and 17 cases did not contain enough information to be analyzed. Of the 20 probable cases, 19 were associated with ephedra, and 14 with herbal forms of caffeine. Of the 13 possible cases, ephedra was associated with 7 and caffeine with 5. Seizures were associated with hypoglycemia in 3 cases, secondary to stroke in 2 cases, and cardiac arrest in 2 cases. Of the 33 cases of probable and possible seizure associated with ephedra use, 18 were in subjects 18–39 y of age. Mood, psychosis, A 27-year-old man presented to the Psychosis None reported agitation emergency room (ER) with suicidal ideation and irritable mood. He had a 2-year history of ephedra use. Once he stopped using ephedra, his mood returned to normal. A 20-year-old man presented with acute psychosis and agitation. He was taking ephedra-containing dietary supplements, ginseng, DHEA, and creatine with caffeine. continued

218 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Jordan et al., Case reports Pseudoephedrine None reported 2004 n=13 subjects or phenylpropa- with impaired nolamine (12.5– baroflex 25 mg) function due to autonomic failure Libman et al., Case report Ephedra MuscleTech 2005 n=1 male Hydroxycut used bodybuilder, daily for 3 y and age 37 y nandrolone and stanazol used weekly for 1 y

OTHER DIETARY SUPPLEMENTS 219 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Systolic blood Phenylpropanolamine increased Increased blood None reported pressure systolic blood pressure by 21 mm Hg pressure when after 90 min. However, when taken with 16 oz of ingested with 16 oz of room- water temperature tap water, phenylpropanolamine increased systolic blood pressure by 82 mm Hg. When taken with 16 oz of water, 30 mg of pseudoephedrine increased systolic blood pressure 52 mm Hg on average and by as much as 88 mm Hg. Ephedra alkaloids increase blood pressure significantly in individuals with impaired baroreflex function. Concomitant ingestion of ephedra alkaloids and water produced a greater increase in blood pressure. Cardiac function, Patient presented with progressive Visual disturbances None reported visual disturbances headaches, blurred vision in left and cardioembolic visual field, decreased exercise stroke. Case tolerance, and palpitations. confounded by use Electrocardiogram (ECG) showed of anabolic steroids right atrial fibrillation, MRI scan confirmed a right middle cerebral artery territorial infarction with minor hemorrhagic transformation. continued

220 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification LoVecchio Case report Ephedra plus Metabolife 356, et al., 2005 n=1 healthy other herbs; Metabolife woman, age Metabolife 356 International Inc., 20 y contains ma San Diego, CA huang (labeled 12 mg ephedrine), guarana extract (labeled 40 mg caffeine), chromium picolinate, and various herbal and vitamin ingredients per tablet Reported ingestion of 4 tablets of Metabolife 356, 30 min prior to episode and 6– 15 tablets/d for 3 d prior Morgenstern Case- None Ephedra and Various et al., 2003 controlled reported various other study of products hemorrhagic stroke between 1994 and 1999 n=702, ages 18–49 y

OTHER DIETARY SUPPLEMENTS 221 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Family history, Patient experiencing symptoms of a Transient ischemic None reported social history, transient ischemic attack (numbness attack review of systems to her left face, arm, and leg that began 1 hr before arrival, mild headache, and nausea). She denied any other similar episodes or prior medical problems. Family history, social history, and review of systems were otherwise negative. The patient’s symptoms resolved within 4 hours and no rechallenge was performed. Risk of No association between the use of None reported None reported hemorrhagic stroke ephedra-containing products and increased risk for hemorrhagic stroke was observed. continued

222 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Naik and Case report Ephedra plus Stacker III, Ripped Freudenberger, n=2 white other herbs, Fuel 2004 male creatine bodybuilders, ages 19 and 21 y Peters et al., Case reports Ephedra Not reported 2005 n=6 (unspecified) (4 men, 2 women, ages 34–51 y)

OTHER DIETARY SUPPLEMENTS 223 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Coronary artery A 19-year-old white man presented Cardiomyopathy, None reported disease, heart to the ER complaining of exertional heart failure, death, failure, adverse shortness of breath and episodic and disability due drug reaction chest pain radiating to the left arm. to long-term (measured by a Left heart catheterization revealed no product use causality significant coronary artery disease, a assessment dilated left ventricle, and global probability scale) hypokinesis. He died 5 weeks later after returning to the hospital with recurring heart failure. A 21-year-old white man presented to the ER with recurrent chest pain and was diagnosed with myopericarditis. An ECG showed global hypokinesis with an ejection fraction of 40–50%. He was treated for myopericarditis with standard therapies for heart failure. An adverse drug reaction was possible between cardiomyopathy and ephedra use in these 2 patients. Clinical and Patients attending an outpatient Ephedra may be None reported echocardiographic department with new onset heart associated with left data, ejection failure were noted to have exposure ventricular systolic fraction, New York to ephedra. All 6 patients had left dysfunction Heart Association ventricular dysfunction at class presentation (mean ejection fraction 20±5%) and were treated with conventional heart-failure pharmacotherapy. All patients discontinued ephedra use as advised. New York Heart Association class improved from class III in 5 patients (class II in 1 patient) to class I, within a median of 6 mo (range 3–96). Ejection fraction improved to a mean of 47±6%. continued

224 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Simsek et al., Case report Ephedra plus Xenadrine RFA1 2006 n=1 man, age other herbs, for 36 y 10 d Schweinfurth Case report Ephedra plus Ripped Fuel, Twin and Pribitkin, n=1 woman, other herbs, Laboratories, 2003 age 38 y, with dose not stated Hauppauge, NY no significant medical or Taken 4–6 h medication prior to onset of history symptoms Moawad Case report Ephedra plus Stacker 3 and et al., 2006 n=1 healthy other herbs, Ripped Fuel man, age 29 y dose not stated Extreme

OTHER DIETARY SUPPLEMENTS 225 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Visual disturbances Patient had loss of lower half of Visual disturbance None reported (measured by visual field of his right eye, and a in patient with fundoscopy) history of dyslipidemia. Fundoscopy dyslipidemia of the right eye showed a branch retinal artery occlusion with cholesterol embolus at the upper nasal margin of the optic disk, diagnosed as ischemic optic neuropathy. Hearing loss Patient had vertigo and sudden Hearing loss None reported hearing loss in her right ear. Corticosteriod treatment failed to improve hearing. The patient was diagnosed with acute cochlear injury due to a drug-mediated vascular injury. Cardiac function, Patient presented with generalized Potential None reported neurologic tonic-clonic seizure that occurred hypertensive crisis, function, visual while playing basketball. He initially posterior reversible disturbances, liver complained of the abrupt onset of a encephalopathy function, renal severe headache associated with syndrome, multiple function, blood confusion and lethargy. Initial organ failure pressure laboratory values and ECG indicated acute myocardial infarction, fulminant liver failure, acute renal failure, rhabdomyolysis, and transient cortical blindness. Radiographic abnormalities and neurologic dysfunction subsequently resolved with correction of his systolic blood pressure. However, a week later he presented again at the ER with hypertensive crisis without an ephedra rechallenge. Hypertensive crisis may not have been related to ephedra. continued

226 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Rakovec Case report Ephedrine None reported et al., 2006 n=1 healthy 50 mg once or woman, age twice a day for 19 y 10 d Stahl et al., Case report Ephedrine Energel 2006 n=1 man, age 20 mg twice 21 y daily for 1 mo Verduin and Case report Ephedra (12 mg Metabolife Labbate, 2002 n=1 man, age and 40 mg of 45 y, with caffeine) plus schizophrenia, other herbs, olanzapine- several ephedra induced tablets per day obesity, and for 2 wk hyperlipidemia

OTHER DIETARY SUPPLEMENTS 227 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Cardiac function ECG revealed a typical pattern of Ventricular None reported idiopathic left ventricular tachycardia tachycardia, with an heart rate of 170 beats per minute, narrow QRS complex, right bundle branch block, and left axis deviation. Ephedrine alone, or in combination with substances that increase its effects on the cardiovascular system, may also trigger paroxysms of nonischemic ventricular tachycardia. The use of ephedrine carries a risk of development of life-threatening arrhythmias. Muscle function, Patient had complete muscle failure Muscle failure None reported renal function after collapsing after a 2-mile run. likely due to Patient had tachycardia (heart rate dehydration 130+) and was hypotensive. Patient drank very little water over a 2-mo period. Psychosis, Patient was confused and agitated, Case confounded None reported cognition actively hallucinating and incoherent. by antipsychotic After a week of treatment he was medications able to go back to work. The temporal relationship between initiation of Metabolife and subsequent development of psychosis and delirium strongly suggests that ephedra was responsible for these symptoms. continued

228 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-5  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Walton and Case reports Ephedra plus Ripped Fuel, Twin Manos, 2003 n=3 men, ages other herbs, Laboratories, 19, 21, and dose not stated Hauppauge, NY; 33 y Hydroxycut, MuscleTech Research and Development, Inc.; Metabolife aBody mass index. bMaximal accumulated oxygen deficit. cOxygen uptake. dRate of elimination of carbon dioxide.

OTHER DIETARY SUPPLEMENTS 229 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Psychosis, A 19-year-old man was referred for Psychosis None reported depressive psychiatric evaluation due to symptoms decreased sleep, increasing aggressive and disorganized behavior, and paranoid delusions. A 21-year-old man experienced a brief psychotic episode after using Hydroxycut for 2 wk. A 33-year-old man presented with depressive symptoms, suicidal ideation, auditory hallucinations, and paranoid and grandiose delusions. The symptoms in all 3 cases were not abated after discontinuation of the source of ephedra, but did resolve after treatment with antipsychotic drugs, suggesting an underlying pathology. ePulmonary ventilation during exercise. fResting energy expenditure. gMagnetic resonance imaging.

230 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-6  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Garlic Review/ Clinical Type of Study Trial and Sample Reference Size Indication Control Dose Product Specification Ankri and Review of in Antimicrobial None None Pure allicin isolated Mirelman, vitro and reported reported from garlic bulbs 1999 animal studies Ledezma Review of in Antifungal and Terbinafine Topical Pure ajoene extracted and Apitz- vitro and anti-inflammatory applications from garlic Castro, human studies of ajoene 2006 for 7–15 d Martin and Review Anti-Helicobacter None Raw garlic Raw garlic cloves Ernst, 1 trial pylori activity reported 2003 Rahman Review Cardiovascular Matching None Raw garlic, garlic and Lowe, n=25 clinical disease placebo for reported powder tablets, garlic 2006 studies some oil, aged garlic studies extract (20% ethanol)

OTHER DIETARY SUPPLEMENTS 231 Interactions with Pharmaceuticals, Outcomes Foods or Other Measured Conclusions/Results Adverse Events Profile Dietary Supplements Antibacterial, The pure compound, allicin, inhibits the None reported One study showed antifungal, growth of a wide range of Gram-negative synergistic effects and and Gram-positive bacteria, including with antibiotics antiparasitic multidrug-resistant enterotoxigenic strains activities of Escherichia coli. Allicin has shown antifungal activity against Candida albicans and antiparasitic activity against some major human intestinal protozoan parasites such as Entamoeba histolytica and Giardia lamblia. It has also has antiviral activity. Reduction in Treatment produced a clinical cure in None reported None reported tinea pedis 79% of patients treated, with no infections recurrence 90 days after treatment. Reduction in A study of garlic to treat Helicobacter None reported None reported Helicobacter pylori infections reported no significant Poor methodology pylori load effect on Helicobacter pylori load. and urease activity Reductions A reduction in total cholesterol was None reported None reported in serum indicated in 44% of clinical trials; the cholesterol, most profound effect was observed in platelet garlic’s ability to reduce platelet aggregation, aggregation. Mixed results have been blood obtained for blood pressure and pressure oxidative-stress reduction. continued

232 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-6  Continued Review/ Clinical Type of Study Trial and Sample Reference Size Indication Control Dose Product Specification Ackermann Review Cardiovascular Placebo Raw garlic, None reported et al., 2001 n=45 disease garlic randomized powder trials and 73 tablets, additional garlic oil, studies aged garlic reporting extract adverse events (20% ethanol) Pittler and Review of three Hypercholesterolemia Placebo None Garlic (unspecified) Ernst, meta-analyses reported 2007 of various effects in double- blind, randomized, controlled clinical trials

OTHER DIETARY SUPPLEMENTS 233 Interactions with Pharmaceuticals, Outcomes Foods or Other Measured Conclusions/Results Adverse Events Profile Dietary Supplements Reductions Small reductions in the total cholesterol Skin adverse effects: None reported in serum level at 1 mo (range of average pooled Dermatitis cholesterol, reductions, low-density 0.03–0.45 mmol/L [1.2–17.3 mg/dL]) and Allergic reactions: lipoprotein at 3 mo (range of average pooled asthma, rhinitis (LDL), reductions platelet 0.32–0.66 mmol/L [12.4–25.4 mg/dL]), Cardiovascular aggregation, but not at 6 mo. dysfunction: blood myocardial infarction pressure, Changes in LDL and triglyceride levels triglyceride paralleled total cholesterol level results. Coagulation levels No statistically significant changes in dysfunction: bleeding, high-density lipoprotein levels. epidural hematoma, increased Significant reductions in platelet international aggregation and mixed effects on blood normalized ratio in pressure outcomes. persons taking warfarin Gastrointestinal tract dysfunction: small- intestine obstruction, esophageal and abdominal pain, and flatulence Reduction in Modest reduction of 15.7 mg/dL None reported None reported cholesterol compared to placebo over a treatment levels period of 8–24 wk. In an updated meta-analysis (n=971), including 3 additional trials, the effect was diminished to 13.6 mg/dL. In four new double-blind randomized clinical trials (n=3,670), no changes were reported in lipid levels for hypercholesterolemic patients. continued

234 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-6  Continued Review/ Clinical Type of Study Trial and Sample Reference Size Indication Control Dose Product Specification Sengupta Review of Reduced cancer risk None None None reported et al., 2004 epidemiological reported reported studies Milner, Review Reduced cancer risk None Various Various 2006 reported

OTHER DIETARY SUPPLEMENTS 235 Interactions with Pharmaceuticals, Outcomes Foods or Other Measured Conclusions/Results Adverse Events Profile Dietary Supplements Cancer risk Higher intake of Allium vegetables is None reported None reported reduction associated with reduced risk of several types of cancers. These epidemiological findings correlate well with laboratory findings. Proposed mechanisms include inhibition of mutagenesis, modulation of enzyme activities, inhibition of DNA adduct formation, free-radical scavenging, and effects on cell proliferation and tumor growth. Cancer risk Evidence indicates the anticancer None reported None reported reduction properties of fresh garlic extracts, aged garlic, garlic oil, and a number of specific organosulfur compounds generated by processing garlic. These anticarcinogenic and antitumorigenic activities arise through both dose- and temporal-related changes in a number of cellular events involved in the cancer process, including those involving drug metabolism, immune competence, cell-cycle regulation, apoptosis, and angiogenesis. The ability of garlic and related allyl sulfur compounds to block growth of tumors in the colon, lung, breast, and liver suggests general mechanisms that are not tissue specific. continued

236 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-6  Continued Review/ Clinical Type of Study Trial and Sample Reference Size Indication Control Dose Product Specification Hu et al., Review of drug Garlic extract 2005 interactions containing 600 μg of allicin per 600 mg extract; garlic oil; aged garlic extract

OTHER DIETARY SUPPLEMENTS 237 Interactions with Pharmaceuticals, Outcomes Foods or Other Measured Conclusions/Results Adverse Events Profile Dietary Supplements Activity drug Dextromethorphan and alprazolam: Severe gastrointestinal Dextromethorphan interactions Administration of 1,800 mg of garlic toxicity developed in Saquinavir with garlic extract twice a day (3 × 600 mg tablets) two HIV-infected Warfarin products for 14 days increased the ratio of patients taking garlic Chlorpropamide dextromethorphan to its metabolite; did supplements for more not alter pharmacokinetics significantly. than 2 wk after beginning ritonavir Chlorzoxazone: (400 or 600 mg twice Oral administration of garlic oil to daily) therapy. The healthy volunteers for 28 days reduced symptoms resolved CYP2E1 activity. No alterations were after discontinuation observed with midazolam. of therapy. The symptoms reappeared Protease inhibitors: after rechallenge with Saquinavir—In 10 healthy volunteers, 3- garlic, even at a low wk administration of caplets containing ritonavir dose of 3.6 mg garlic powder extract twice daily 100 mg twice daily decreased the plasma area under the curve by 51%, plasma concentrations by 49%, and C(max) by 54% of the protease inhibitor. These parameters did not return to baseline values after 10 d of washout. Ritonavir (400 mg single dose)— Administration of two capsules (10 mg Natural Source odorless garlic extract) for 4 days to 10 healthy volunteers did not significantly decrease the area under the curve of the protease inhibitor. Warfarin: Two case reports suggest that the combination of warfarin and garlic products may increase clotting time and potentially cause postoperative bleeding. Chlorpropamide: Possible interaction, causing hypoglycemia. Acetaminophen: Administration of aged garlic extract (~6– 7 cloves of garlic) for 3 mo to 16 healthy volunteers did not alter its metabolism.

238 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ginkgo Biloba Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Burns et al., Double-blind Cognition, Placebo 120 mg/d (40 mg Ginkgoforte, 2006 n=197 (93 adults attention, 3×/d) for 12 wk Blackmores Ltd., ages 55–79 y and executive Australia 104 adults ages function, and 18–43 y) mood Carlson Double-blind, Cognitive Placebo 160 mg/d (1×/d) Ginkgo biloba-based et al., 2007 randomized, function, for 4 mo product containing parallel design quality of 160 mg Ginkgo biloba, n=90 life, and 68 mg gotu kola (with platelet caffeine), and 180 mg function docosahexaenoic acid Cieza et al., Double-blind, Mental Placebo 720 mg/d Ginkgo biloba special 2003 randomized, function and (240 mg, 3×/d) extract EGb 761, parallel group quality of life for 4 wk Schwabe-Germany n=66 healthy adults ages 50– 65 y

OTHER DIETARY SUPPLEMENTS 239 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Cognitive abilities test, Older adult group: significant trend Headaches, sleep None reported chronometric testing for improvement of longer-term disturbances, (speed of information memory with ginkgo (d = 0.52). gastrointestinal processing), subjective No statistically significant symptoms well-being (mood) difference on any other measure. Young adult group: no statistically significant effects with ginkgo. Six standardized One of six cognitive tests indicated No alterations in None reported cognitive function significant protocol differences for platelet function tests, SF-36 Quality of placebo. No significant differences observed Life questionnaire, in quality of life, platelet function, platelet function, or adverse events. High baseline adverse events scores may have contributed to the null findings. Primary: subjects’ Significant improvements of self- None reported None reported judgment of their own estimated mental health, self- mental health, general estimated quality of life with health, and quality of ginkgo extract. No differences of life based on three self-estimated general health. different visual analog scales. Better motor performance and Secondary: motor emotional evaluation with ginkgo performance and extract. emotional evaluation Findings do not support the use of a ginkgo-containing supplement for improving cognitive function or quality of life in cognitively intact, older, healthy adults. continued

240 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Chow et al., Double-blind, High-altitude Placebo 240 mg/d of Ginkgo biloba product 2005 randomized sickness Ginkgo biloba from NOW foods n=57 for 5 d prior to unacclimatized ascent or adults acetazolamide

OTHER DIETARY SUPPLEMENTS 241 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements AMSa symptoms LLS scores: The median score of None reported None reported graded based on the the acetazolamide group was LLSb: Acute Mountain significantly lower than that of the Sickness scoring placebo group (effect size, 2), system. Incidence of unlike that of the Ginkgo biloba AMS was defined as group (effect size, 0). LLS score ≥3 and headache AMS frequency: Less frequently in the acetazolamide group than in the placebo group (effect size, 30%); similar between the ginkgo group and the placebo group (effect size, –5%). The study concluded that prophylactic acetazolamide therapy decreased the symptoms of AMS and trended toward reducing its incidence. No evidence of similar efficacy for Ginkgo biloba NOW product was found. This study was criticized because of small sample size and that ginkgo was not the primary constituent of the product (Betz and Costello, 2006). The products contain two additional plants, 125 mg Eleutherococcus senticosus (Rupr and Maxim) Maxim and 150 mg of Centella asiatica (L) Urb, and only 120 mg of G. biloba L extract. continued

242 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Cochrane Review Benefits for Placebo Various Various review (Birks n=33 dementia or et al., 2002) unconfounded, cognitive double-blind, decline randomized, placebo- controlled studies of patients with dementia or cognitive decline

OTHER DIETARY SUPPLEMENTS 243 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Clinical Global Impression (CGI) Overall, there are None reported scale: Dose less than 200 mg/d no significant showed improvements compared differences between with placebo at less than 12 wk ginkgo and placebo (54/63 showed significant in the proportion improvement compared with of participants 20/63). Dose of 200 mg/d showed experiencing significant improvements at 24 wk adverse events (57/79 compared with 42/77). Cognition shows significant benefit for ginkgo as compared with placebo at 12, 24, and 52 wk, ginkgo (greater than 200 mg/d) at 12 wk, ginkgo (any dose) at 12 wk. Activities of daily living (ADL) shows significant benefit for ginkgo (dose less than 200 mg/d) as compared with placebo at 12 wk, at 24 wk, and at 52 wk. Measures of mood and emotional function show significant benefit for ginkgo (dose less than 200 mg/d) as compared with placebo at less than 12 wk and at 12 wk. The review concludes that Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo, and there is promising evidence of improvement in cognition and function associated with ginkgo. However, the three most recent trials show inconsistent results. continued

244 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Cochrane Review Assessment None Various Various review (Birks n=35 of efficacy on reported and Grimley randomized, cognition Evans, 2007) double-blind studies, subjects with acquired cognitive impairment, including dementia, of any degree of severity Cochrane Review Treatment of None Various Various review n=12 clinical tinnitus reported (Hilton and studies Stuart, 2004)

OTHER DIETARY SUPPLEMENTS 245 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Various Benefits associated with ginkgo No difference None reported (dose greater than 200 mg/d) at 24 above placebo wk (two studies), but not for a lower dose. Cognition shows benefit for ginkgo (any dose) at 12 wk (p=5 studies) but not at 24 wk. Results of five studies assessing ADLs showed benefit for ginkgo (dose less than 200 mg/d) compared with placebo at 12 wk (one study) and at 24 wk (three studies), but there are no differences at the higher dose. There are no data available on quality of life, measures of depression, or dependency. The evidence that ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unconvincing. Limited evidence did not Few side effects None reported demonstrate that Ginkgo biloba was effective for tinnitus. Ten trials were excluded on methodological grounds. No trials reached a satisfactory standard for inclusion in the review. continued

246 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Elsabagh Double-blind, Attention, Placebo 120 mg/d (1x/d) Ginkgo one-a-day et al., 2005 randomized memory, and tested tablets, Lichtwer n=92 students, executive after 4 h Pharma UK, Mere ages 18–26 y function, and (experiment 1) Park, Marlow, Bucks, mood or 6 wk of UK treatment (experiment 2) Gertsch Prospective, HASc Placebo 120 mg ginkgo, Ginkgo biloba extract et al., 2004 double blind, 250 mg GK 501, randomized acetazolamide, Pharmaton SA, n=614 healthy combination of Lugano, Switzerland men and women 250 mg acetoazolamide and 120 mg ginkgo, or placebo, 2×/d

OTHER DIETARY SUPPLEMENTS 247 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Mood rating scales, Experiment 1: Acute dose of ginkgo None reported None reported sustained attention, significantly improved performance episodic and working on the sustained-attention task and memory, mental pattern recognition memory task; flexibility and however, there were no effects on planning working memory, planning, mental flexibility, or mood. Experiment 2: No significant effects on mood or any of the cognitive tests. Acute administration improved performance in tests of attention and memory. Tolerance to the effects may develop in young, healthy participants. LLSRd score ≥3 with Ginkgo at a dose of 240 mg/d, 3–4 Potential None reported headache and one doses prior to ascent, was not worsening of other symptom. significantly different from placebo headaches Secondary outcome for any outcome. associated with measures included Acetazolamide group showed HAS. (Headaches blood oxygen content, significant levels of protection. The usually resolve severity of syndrome, incidence of acute mountain within 1 wk of incidence of headache, sickness was 34% for placebo, daily use of the and severity of 12% for acetazolamide, 35% for product.) headache. ginkgo, and 14% for combined Measured at the ginkgo and acetazolamide. The approach to Mount proportion of patients with Everest base camp in increased severity of acute the Nepal Himalayas mountain sickness was 18% for at 4,280 m or 4,358 placebo, 3% for acetazolamide, m and study end point 18% for ginkgo, and 7% for at 4,928 m combined ginkgo and acetazolamide. continued

248 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Gertsch Double-blind, AMSe Placebo 180 mg/d (60 mg Ginkgo biloba extract et al., 2002 randomized 3×/d) for 48 h GK 501, Memfit, n=26 Pharmaton SA, living at sea level Lugano, Switzerland Kennedy Double-blind, Cognitive Placebo 120 mg/d, GK501 standardized et al., 2000 matching enhancement 240 mg/d, and Ginkgo biloba extract, n=20, ages 19– 360 mg/d Pharmaton SA, 24 y Lugano, Switzerland

OTHER DIETARY SUPPLEMENTS 249 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements The subjects received Median LLSR at 4,205 m was None reported None reported ginkgo or placebo significantly lower for ginkgo starting 24 h before versus placebo (4, range 1–8 vs. 5, ascending Mauna Kea, range 2–9). Ginkgo use did not Hawaii. Subjects were reach statistical significance for transported from sea lowering incidence of AMS level to the summit compared with placebo (ginkgo (4,205 m) over a 3-h 7/12, 58.3% vs. placebo 13/14, period, including 1 92.9%). Twenty-one of 26 (81%) hour at 2,835 m. subjects developed AMS overall. LLSR Questionnaire was used as the The results suggest that primary outcome pretreatment with ginkgo 60 mg measure at baseline, three times daily may significantly 2,835 m, and after 4 h reduce the severity of AMS prior to at 4,205 m. AMS was rapid ascent from sea level to defined as a LLSR ≥3 4,205 m. with headache Cognitive performance Ginkgo produced a number of None reported None reported using the CDR significant changes in performance computerized test measures: battery immediately Dose-dependent improvement of prior to dosing and at the speed of attention factor 1, 2.5, 4, and 6 h following both 240 mg and 360 mg thereafter of the extract, which was evident at 2.5 h and still present at 6 h. The primary outcome Other time- and dose-specific measures were: changes (both positive and speed of attention, negative) in performance of the accuracy of attention, other factors. speed of memory, quality of memory The authors concluded that Ginkgo biloba is capable of producing a sustained improvement in attention in healthy young volunteers after acute dosing. continued

250 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Mattes and Double-blind, Assessment Placebo 4 mg/kg/d for Ginkgo biloba extract Pawlik, matched of 13 wk 2004 n=39, ages amelioration 23.6±5.4 y of the postlunch dip Roncin Randomized AMS and Placebo 160 mg/d for 5 d EGb 761 et al., 1996 n=44 vasomotor changes Solomon Double-blind, Improvement Placebo 40 mg, 3×/d for Ginkoba, Boehringer et al., 2002 randomized, of memory 6 wk Ingelheim parallel group Pharmaceuticals n=230 adults, ages >60 y

OTHER DIETARY SUPPLEMENTS 251 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Alertness, Subjects experienced the None reported None reported performance, affective postprandial affective state state, chemosensory decrement (“postlunch dip”) but no tests at wk 1, 5, 9, performance decrement. and 13 Performance on the chemosensory tests improved over the 13-wk study for all subjects. Ginkgo biloba was ineffective at alleviating the symptoms of the postlunch dip or enhancing taste and smell function. The primary outcomes No subject in the EGb 761 group None reported None reported assessment was based developed AMS-cerebral versus above placebo on the Environmental 40.9% of subjects in the placebo Symptom group; this difference was very Questionnaire score significant. Three subjects (13.6%) and vasomotor in the EGb 761 group developed changes measured by AMS-respiratory versus 18 (81.8%) photoplethysmography in the placebo group. Ginkgo also and a specific decreased vasomotor disorders of questionnaire the extremities and improved circulation. Standardized No significant differences between None reported None reported neuropsychological treatment groups on any outcome tests of verbal and measure. Ginkgo did not facilitate nonverbal learning performance on standard and memory, attention neuropsychological tests of and concentration, learning, memory, attention, and naming, and concentration or naming and verbal expressive language fluency in adults ages 60 or older without cognitive impairment. Self-report on a There was also no difference memory questionnaire between groups in self-reported memory function or global rating Caregiver clinical by spouses, friends, and relatives. global impression of change continued

252 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Mix and Double-blind, Assessment Placebo 180 mg/d EGb 761 Crews, 2002 randomized, of memory fixed-dose improvement n=262 adults, in older ages >60 y adults Stough Double-blind, Memory and Placebo 120 mg/d for EGb 761 et al., 2001 randomized executive 30 d n=61, ages 18– processing 40 y

OTHER DIETARY SUPPLEMENTS 253 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Change in Significantly more improvement on None reported None reported performance scores on spatial recognition tasks involving standardized delayed (30 min) free recall and neuropsychological recognition of noncontextual, measures (Selective auditory–verbal material, compared Reminding Test [SRT], with placebo. Wechsler Adult Intelligence Scale-III Significantly greater improvements Block Design [WAIS- in the WMS-III FII subtest assessing III BD] and Digit delayed (30 min) recognition of Symbol-Coding visual material (i.e., human faces), [WAIS-III DS] compared with placebo. However, subtests, and the the significant difference found Wechsler Memory between the two groups’ Scale-III Faces I pretreatment baseline scores on the [WMS-III FI] and WMS-III FII suggest this result Faces II [WMS-III FII] should be interpreted with caution. subtests) from pretreatment baseline Follow-up self-report questionnaire to just prior to also revealed that significantly more termination of adults in the EGb 761 group rated treatment. their overall abilities to remember Follow-up self-report as improved by treatment end questionnaire just compared with placebo. prior to termination of the treatment phase Overall, the results provided complementary evidence of the potential efficacy of Ginkgo biloba EGb 761 in enhancing certain neuropsychological/memory processes of cognitively intact adults 60 y of age and over. A battery of validated Significant improvements in speed None reported None reported neuropsychological of information processing, working tests before and after memory, and executive processing treatment to measure were attributable to the ginkgo changes in memory extract. and executive processing continued

254 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Subhan and Double-blind, Central Placebo 120, 240, and Tebonin Hindmarch, randomized, nervous 600 mg (Germany) 1984 crossover system Tanakan (France) n=8, ages 25– arousal, 40 y psychomotor performance, and short- term memory Warot et al., Double-blind Assessment Placebo 600 mg/d Tanakan (standardized 1991 n=12 of vigilance, ginkgo extract, France) memory, and ginkgo extract reaction times Bent et al., 15 case reports None Various Various 2005 between 1966 reported and 2004

OTHER DIETARY SUPPLEMENTS 255 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Subjects completed a No statistically significant changes None reported None reported battery of from placebo were observed on psychological tests CFF, CRT, or LARS. However, including CFF,e CRT,f memory as assessed using the subjective ratings of Sternberg technique was found to drug effects (LARS), be significantly improved following and a Sternberg treatment with ginkgo at a dose of memory scanning test 600 mg when compared to placebo, 1 h after treatment and results suggested a localized effect of the extract on the serial comparison stage of the reaction process. These results suggest a specific effect of the extract on central cognitive processes. Objective measures of No statistically significant changes None reported None reported vigilance (CFF, CRT), from placebo were observed on memory tasks CFF, CRT, or LARS. No differences (pictures and between treatment were evident on Sternberg scanning Sternberg scanning test and picture tests), and self-rating recognition. Compared to baseline, evaluation (visual free recall score, while decreasing analogue scales). Test under placebo and ginkgo extract, administered pre- and remained the same under Tanakan, 1 h postdosing indicating that the Tanakan product improved free recall. Published case reports A temporal association between use Potential bleeding None reported of bleeding events in of ginkgo and a bleeding event was due to chronic persons using ginkgo described in the 15 published case administration were queried from reports, with most of the cases especially in MEDLINE, EMBASE, involving serious medical combination with IBIDS, and the conditions (with 8 episodes of liver cirrhosis or Cochrane intracranial bleeding). use of nonsteroidal Collaboration anti-inflammatory Database from 1966 Other risk factors for bleeding were drugs or warfarin to October 2004. identified in 13 of the case reports. Two reviewers Six reports clearly described independently cessation of ginkgo followed by abstracted a standard lack of bleeding recurrence. In three set of information to reports, bleeding times were assess whether ginkgo elevated when patients were taking caused the bleeding ginkgo. event The review concluded that a structured assessment of published case reports suggests a possible causal association between using ginkgo and bleeding events. continued

256 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Hu et al., Review of case None Various Various 2005 studies and reported clinical trials

OTHER DIETARY SUPPLEMENTS 257 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements A review of drug One case report of an interaction None reported Trazodone, interactions with with ginkgo and trazodone that warfarin, aspirin, herbal products resulted in coma. However, this ibuprofen, including ginkgo case was confounded due to the ticlopidine, numerous other drugs that were tolbutamide, being taken by the patient. chlorpropamide Interactions with warfarin, ticlopidine, and nonsteroidal anti- inflammatory drugs such as aspirin and ibuprofen have been reported. Changes in international normalized ratio (INR) and prolonged bleeding times have resulted when ginkgo was combined with these drugs. In healthy subjects, doses of ginkgo up to 480 mg/d did not alter bleeding times or INR. A small clinical trial demonstrated that administration of ginkgo (280 mg/d) for 14 d significantly decreased the plasma concentrations of omeprazole. A reduction in the efficacy of thiazide diuretics in one subject was indicated in one case report, and rodent studies have indicated that treatment with ginkgo in combination with diltazem inhibited the metabolism of the drug. Ginkgo did not alter the metabolism of midazolam or donepezil in clinical studies. Ginkgo (120 mg/d) decreased plasma insulin by 26% in hyperinsulinemic patients with type 2 diabetes mellitus taking antihyperglycemic drugs. Ginkgo may increase the hepatic clearance of insulin and antihyperglycemic drugs. continued

258 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-7  Continued Review/ Clinical Trial Type of Study Reference and Subjects Indication Control Dose Product Specification Wolf, 2006 Double-blind Placebo Aspirin (ASA) EGb 761® n=50 in each followed by group, men, ages aspirin + EGb 20–44 y 761 or aspirin + EGb 761 followed by aspirin 2×/d for 7 d Dose/d: 500 mg aspirin or 500 mg aspirin + 240 mg EGb 761® aAcute mountain sickness. bLake Louis Score. cHigh-altitude sickness.

OTHER DIETARY SUPPLEMENTS 259 Interactions with Pharmaceuticals, Clinical Details and Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Bleeding time, ASA given alone prolonged In each group there Bleeding in coagulation bleeding time. was at least one combination with parameters, and ASA and the combination of ASA + adverse effect aspirin, platelet activity in EGb 761® exerted similar effects consisting mainly anticoagulants, response to various on all coagulation parameters of coagulation alcohol agonists were measured: disorders. The determined. In Bleeding time (ASA alone: 4.1 min pattern of adverse addition, adverse before therapy, 6.2 min after effects matched the events, laboratory therapy; ASA + EGb 761®: 4.2 min effects of aspirin variables, and vital before therapy, 6.3 min after on coagulation signs were measured therapy parameters. Agonist-induced platelet Mild to moderate aggregation (collagen-induced gastrointestinal platelet aggregation—ASA: 84.5% adverse effects before therapy, 81.0% after were also reported therapy; ASA + EGb 761®: 86.6% in 12–18% of before therapy, 81.0% after subjects therapy; adenosine diphosphate- induced platelet aggregation—ASA: 72.6% before therapy, 47.2% after therapy; aspirin + EGb 761®: 71.7% before therapy, 44.8% after therapy; ratio of means). Co-administration of aspirin and EGb 761® does not constitute a safety risk. No additive effect was observed. dLake Louise self-report. eCriticalflicker fusion. fChoice reaction time.

260 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-8  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ginseng Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Cardinal Prospective, Enhancement Placebo 200 or 400 mg/d Standardized and Engels, double-blind, of mental (lactose) (2 or 4 capsules/ extract Panax 2001 randomized performance d) for 60 d ginseng G115, n=40 healthy women 100-mg and 43 men, mean capsules age 25.7 y, with relatively normal psychological profiles Engels et al., Double-blind, Exercise Placebo 400 mg/d (4 Standardized 2001 randomized performance capsules/d) for extract Panax n=24 women and short-term 8 wk ginseng G115, recovery 100-mg capsules Engels et al., Double-blind, Exercise Placebo 400 mg/d (4 Standardized 2003 randomized performance capsules/d) for extract Panax n=38 active, healthy and short-term 8 wk ginseng G115, adults recovery 100-mg capsules

OTHER DIETARY SUPPLEMENTS 261 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Positive affect, No psychological benefits observed None reported None reported negative affect, and after 8 wk of chronic ginseng total mood supplementation at its clinically disturbance. recommended dose (200 mg/d) or at Measures were 400 mg/d compared to placebo. obtained pre- and post-intervention Peak anaerobic No significant difference found for A single case None reported power output, mean peak anaerobic power output, mean of stomach anaerobic power anaerobic power output, rate of upset output, rate of fatigue, and immediate postexercise associated with fatigue (as recovery heart rates. Prolonged ginseng measured by a supplementation with ginseng provided Wingate ergonomic no ergogenic benefits during and in the protocol), and recovery from short supramaximal recovery heart rates exercise. Exercise Compared with resting levels, S-SIgA, None reported None reported performance (as SIgA:protein ratio, and saliva flow rate measured by were significantly lower after exercise consecutive Wingate at baseline. Significant decline seen in tests), absolute both peak and mean mechanical power SIgA,a salivary output across consecutive Wingate protein tests. Few changes seen in scores for concentrations, salivary parameters, exercise SIgA secretion rate performance, and exercise recovery (S-SIgA), the heart rate between ginseng- and relation of SIgA to placebo-treated groups. Mucosal total protein, peak immunity was not affected as indicated and mean by changes in SIgA at rest and after an mechanical power exercise-induced state of homeostatic output, and heart disturbance; neither did it improve rate during exercise physical performance or heart rate recovery recovery for individuals undergoing repeated periods of exhausting exercise. continued

262 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-8  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Kennedy Balanced crossover, Mood and Placebo 320 mg (120 mg Ginkgo biloba et al., 2001 double-blind, cognitive ginkgo, 200 mg standardized randomized performance ginseng), 640 mg extract GK n=20 healthy, young (240 mg ginkgo, 501, 60-mg adults 400 mg ginseng), capsules; Panax or 960 mg ginseng (360 mg ginkgo, standardized 600 mg ginseng) extract G115, 100-mg capsules Kennedy Balanced crossover, Mood and Placebo 360 mg of Ginkgo biloba et al., 2002 double-blind, cognitive ginkgo, 400 mg standardized randomized performance of ginseng, extract GK n=20 960 mg of a 501; Panax product ginseng combining the standardized two extracts extract G115 Lieberman, Review of 7 clinical Physical Placebo Various Various 2001 trials performance and well-being

OTHER DIETARY SUPPLEMENTS 263 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Effect on mood and A dose-dependent improvement in None reported None reported aspects of cognitive performance on the “quality of performance memory” factor was observed for the (quality of memory, highest dose (960 mg). This effect was secondary memory, differentially targeted at the secondary working memory, memory rather than the working speed of memory, memory component. Also a dose- quality of attention dependent decrement was seen in and speed of performance of the “speed of attention) attention” factor for both the 320- and 640-mg doses. Cognitive testing All three treatments were associated None reported None reported (using the CDRb with an improvement of secondary computerized memory performance on the CDR assessment battery battery, with ginseng treatment and two serial showing some improvement in the subtraction mental speed of performing memory tasks and arithmetic tasks) in accuracy of attention-related tasks. Ginkgo and the ginkgo/ginseng Mood testing combination improved performance of (Bond-Lader visual the Serial Threes and Serial Sevens analogue scales) subtraction tasks. No modulation of the speed of performing attention tasks Measured 1, 2.5, 4, was evident. Ginkgo improved self- and 6 h rated mood; lesser improvements with posttreatment dose the combination product. Physical No compelling evidence that ginseng None reported None reported performance, had any positive effects on physical or cognitive cognitive performance, immune performance, function, or any specific disease state. immune function, disease state continued

264 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-8  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Reay et al., Balanced crossover, Cognition and Placebo Standardized Panax ginseng 2006 double-blind glucose ginseng extract, standardized n=27 healthy, young tolerance 200 mg/d (2 extract G115, adults capsules/day) 100-mg capsules 200 mg G115/0 mg glucose (ginseng); 0 mg G115/25 g glucose (glucose); or 200 mg G115/25 g glucose (ginseng/ glucose combination) Reay et al., Balanced crossover, Cognition and Placebo Standardized Panax ginseng 2005 double-blind glucose ginseng extract, standardized n=30 tolerance 100-mg capsules, extract G115 2 or 4/d

OTHER DIETARY SUPPLEMENTS 265 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Cognitive function Panax ginseng and glucose enhanced Not reported, Insulin and (as measured by the performance of mental arithmetic poor prescription Serial Threes tasks and ameliorated the increase in methodology medications to treat subtraction task, participants’ subjective feelings of type 2 diabetes Serial Sevens task, mental fatigue during performance of and RVIPc the sustained, cognitively demanding performance task), task performance. Glucose improved mental fatigue accuracy in performance of the RVIP. (visual analogue No evidence in any cognitive outcome scale), blood measure of a synergistic relationship glucose levels was found. A reduction in blood glucose levels was seen 1 hour Measured 60 min following consumption of Panax posttreatment dose ginseng without glucose. Panax ginseng may have glucoregulatory properties and can enhance cognitive performance. Conclusions from this study are limited due to poor methodology. Cognitive function Treatment with both 200-mg and None reported None reported (as measured by 400-mg dosage led to significant Serial Threes reductions in levels of blood glucose subtraction task, levels at all three posttreatment Serial Sevens task, measurements. and RVIP performance task), Administration of 200 mg of ginseng mental fatigue (as significantly improved performance on measured by a the Serial Sevens subtraction task and visual analogue significantly reduced subjective mental scale), blood fatigue throughout all (with the glucose levels exception of one time point in each case) of the postdose completions of Measured 60 min the 10-min battery. Panax ginseng can posttreatment dose, improve performance and subjective 6 times in feelings of mental fatigue during immediate sustained mental activity. This effect succession may be related to the acute glucoregulatory properties of the extract. continued

266 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-8  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Scholey and Balanced crossover, Cognition Placebo 320 mg (120 mg Ginkgo biloba Kennedy, double-blind ginkgo and standardized 2002 n=20 200 mg ginseng) extract GK 501; Panax 640 mg (240 mg ginseng ginkgo and standardized 400 mg ginseng) extract G115 960 mg (360 mg ginkgo and 600 mg ginseng) Given daily Wesnes Multicenter trial, Memory- Placebo 160 mg (60 mg Ginkgo biloba et al., 2000 double-blind enhancement ginkgo and standardized n=256, ages 38–66 y 100 mg ginseng) extract GK 2×/d or 320 mg 501; Panax (120 mg ginkgo ginseng and 200 mg standardized ginseng) 1×/d extract G115 for 14 wk Cheng, Review of interactions None Various Various 2005 with warfarin reported n=3 Hu et al., Review of drug None Various Various 2005 interactions with reported ginseng

OTHER DIETARY SUPPLEMENTS 267 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Cognitive function Ginseng: Dose-dependent improvement None reported None reported (as measured by in speed of response during Serial Serial Threes and Threes, depending on dosage. Serial Sevens Ginkgo-ginseng combination (320 mg): subtraction tasks) Most significant and sustained increase in the number of Serial Sevens Measured before responses at all posttreatment testing treatment and 1, times. 2.5, 4, and 6 h Ginkgo-ginseng combination (640 and thereafter 960 mg): Improved accuracy on performance of the Serial Sevens and Serial Threes tasks with 640 and 960 mg, respectively. Attention and Ginkgo/ginseng combination None reported None reported memory (as significantly improved the Index of measured by the Memory Quality. Average improvement CDR computerized was 7.5%; this reflected improvements cognitive to different aspects of memory assessment system) including working and long-term measured prior to memory. Benefit was seen throughout receiving their first the 12-wk dosing period as well as daily dose and after a 2-wk washout. repeated 1, 3, and 6 h later Mood states, quality of life, and sleep quality (as measured by questionnaire) Anticoagulant In three reports, ginseng reduced the Reduced Ginseng affects the effects of warfarin anticoagulant effects of warfarin. anticoagulant anticoagulant effects when properties of warfarin used in combination with warfarin Blood Panax ginseng was seen to reduce the None reported Ginseng influences the concentrations of blood concentrations of alcohol and effects of alcohol, alcohol and warfarin, induce mania when used warfarin, phenelzine, warfarin, mania, concomitantly with phenelzine, and and influenza vaccine efficacy of the increase the efficacy of the influenza influenza vaccination. vaccination continued

268 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-8  Continued Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Jiang et al., Randomized, St. John’s Extract Golden Glow 2004 crossover wort equivalent to Korean ginseng n=12 healthy men 0.5 g Panax ginseng root and 8.93 mg ginsenosides as ginsenoside Rg1, given as 2 capsules 2×/d for 7 days 25 mg warfarin Rosado, Case report Ginseng 2003 n=1 male, age 58 y product with a thrombosis on obtained a mechanical bileaflet overseas aortic valve prosthesis admitted to hospital with diagnosis of acute anteroseptal myocardial infarction and diabetic ketoacidosis Yuan et al., Double-blind, Placebo For 2 wk Panax 2004 randomized quinquefolius n=20 (American ginseng) aSecretoryimmunoglobulin A. bCognitive Drug Research. cRapid visual information processing.

OTHER DIETARY SUPPLEMENTS 269 Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Platelet aggregation, No effect on INR and platelet None reported Ginseng does not INR of aggregation by St. John’s wort or appear to affect the prothrombin time, ginseng. No effect on the apparent pharmacokinetics of warfarin volumes of distribution or protein warfarin enantiomer protein binding of warfarin enantiomers. St. binding, warfarin John’s wort significantly induced the enantiomer apparent clearance of both S-warfarin concentrations in and R-warfarin, which in turn resulted plasma, and S-7- in a significant reduction in the hydroxywarfarin pharmacological effect of warfarin. Co- concentration in administration of warfarin with ginseng urine did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin. Panax ginseng should not affect bleeding times during injury or in patients treated with warfarin. INR and coronary Thrombosis was thought to be caused Thrombosis Ginseng interaction angiography through an interaction with ginseng with warfarin and warfarin that produced a reduction in his INR. INR and plasma Peak INR significantly decreased None reported Ginseng interaction warfarin compared to placebo (difference with warfarin concentrations as between ginseng and placebo. measures of Significant reduction in the INR area interactions of under the curve (AUC), peak plasma ginseng with warfarin level, and warfarin AUC. Peak warfarin INR and peak plasma warfarin level were positively correlated. Ginseng may reduce the efficacy of warfarin.

270 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-9  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for HMB Review/ Clinical Trial Type of Study and Product Reference Subjects Indication Control Dose Specification Slater and Review, included 84 Muscle growth Placebo Typically 3 g/d, a Various Jenkins, references with at and strength minority 1.5 or 6 2000 least 10 describing g/d human clinical trials with HMB n=20–41 Nissen Nine clinical trial Muscle growth Placebo 3 g/d for 3–8 wk et al., 2000 studies that included and strength safety data

OTHER DIETARY SUPPLEMENTS 271 Interactions with Clinical Details Pharmaceuticals, and Outcomes Conclusions/ Adverse Events Foods, or Other Measured Results Profile Dietary Supplements Total lean mass, Most studies with HMB supplementation of Some studies None reported strength gains, 3 g/d paired with resistance training performed muscle protein observed enhanced lean tissue and strength routine blood breakdown, gains; a minority of studies showed no screens for muscle soreness effect. Evidence was reviewed suggesting hepatic, renal, or and damage that the benefits are primarily observed in immune effects indicators untrained individuals with less response for or had surveys trained subjects. The mechanism was regarding adverse suggested to be reduction in muscle protein effects; none catabolism. reported serious negative clinical effects. Similarly, none of the animal studies (most on lambs, chickens, and steers) have reported adverse effects with doses up to 100 g/d Data provided Emotional profiles: Only significant change No difference None reported on health-related was decrease in “unactivated unpleasant observed between blood measures, affect” (associated with reduced sensation placebo and emotional of sluggish, bored, tired). HMB treatments profiles Blood measures: Significant 3.7% decrease (Circumplex test in serum cholesterol and 5.7% in low- of emotion), and denisty lipoproteins (effect was greater in adverse events subjects who began with elevated lipids). reported via There was also less increase in high-denisty questionnaire lipoproteins in response to exercise for HMB group, but this was eliminated when expressed relative to total cholesterol. Systolic blood pressure fell 3% more for the HMB than placebo group. None of the indicators of liver function or traditional blood chemistries were altered by HMB with the exception of a significant (2%) drop in blood potassium, a significantly greater increase in albumin/globulin ratio, and a significantly lower (0.5%) hematocrit in HMB. continued

272 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-9  Continued Review/ Clinical Trial Type of Study and Product Reference Subjects Indication Control Dose Specification Bohn et al., Review of several Muscle growth Placebo 2–3 g/d 2002 strength-enhancing and strength supplements including HMB; four were not part of Slater and Jenkins (2000) review Alon et al., Review of human Body Placebo 9 cancer patients 2002 studies; only composition received 3 g/d additional clinical HMB+14 g/d trial not included in arginine and 14 reviews above was g/d glutamine one on effect on body composition in cancer patients (May et al., 2002) Nissen and Meta-analysis of nine Placebo 3 g/d (8 studies) Sharp, 2003 HMB studies; two or 38 mg/kg/d + were not included in resistance above reviews exercise

OTHER DIETARY SUPPLEMENTS 273 Interactions with Clinical Details Pharmaceuticals, and Outcomes Conclusions/ Adverse Events Foods, or Other Measured Results Profile Dietary Supplements (See Slater and One study beyond Slater and Jenkins (2000) None reported None reported Jenkins above): studied variety of markers of hematology as Reduction in well as renal, hepatic function. markers of muscle damage following 2-mile run reported in one study; beneficial effects on body composition observed in men and women 70 y of age and older Questionnaire on adverse events indicated None reported None reported no effect of HMB on adverse events in the patients; no effects on serum chemistries with exception of increase in blood urea nitrogen, sodium, phosphorus, and uric acid contrasted to reduction in placebo group. The treated cancer group had a greater increase in fat-free mass compared to placebo group over the 24-wk trial. Body fat was not different. There was no evaluation of HMB alone. Net increase in HMB was one of few supplements reviewed None reported None reported lean mass gain of that had anabolic effects when paired with 0.28%/wk resistance training. during resistance training with effect size of 0.15. Net increase in strength gain of 1.40%/wk and effect size of 0.19 continued

274 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-9  Continued Review/ Clinical Trial Type of Study and Product Reference Subjects Indication Control Dose Specification Palisin and Review with 20 Various Placebo 2 or 3 g HMB/d Stacy, 2005 references; (depending on 6 were not included in the study) alone above reviews or combined with creatine, arginine or lysine, or glutamine or arginine for 10 d to 12 wk

OTHER DIETARY SUPPLEMENTS 275 Interactions with Clinical Details Pharmaceuticals, and Outcomes Conclusions/ Adverse Events Foods, or Other Measured Results Profile Dietary Supplements Consensus of studies shows that HMB alone None reported None reported or in combination with other amino acids: –  educed loss of muscle mass and function r in elderly, – mproved fat-free mass gains in AIDS and i cancer patients, –  ay improve fat-free mass and muscle m strength gains in untrained better than in trained individuals, – s effective if consumed 4–8 wk but not i briefly, and –  oes not cause adverse effects. d The effect to reduce muscle damage is provocative but needs to be confirmed. The effects of longer treatments and higher doses need to be studied. Effect of HMB alone is not possible to determine in those studies that used it in combination with arginine and lysine (and the placebos in those cases were not isonitrogenous). Ransone et al., 2003: 35 football players consumed HMB or placebo for 4 wk; no difference in muscular strength or body composition. Crowe et al., 2003: 6 wk HMB (3 g) or HMB (3 g) + creatine (3 g) or control (received nothing) in 28 trained male rugby players; no effects were observed on health- related blood measures with exception of reduced bicarbonate and higher lymphocyte and monocyte counts in HMB (all still in normal range). Hoffman et al., 2004: No effect of 10 d of HMB in 26 players during preseason 2-a-day football practice on anaerobic power, hormones, or markers of muscle damage. (continues) continued

276 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-9  Continued Review/ Clinical Trial Type of Study and Product Reference Subjects Indication Control Dose Specification Palisin and Stacy, 2005 (continued) Baxter et al., Dietary 0, 1, 2, 5% of CaHMB 2005 toxicity of diet as CaHMB calcium HMB for 91 days (CaHMB) van Someren Effects on Placebo 3 g/d HMB Maximuscle et al., 2005 muscle damage + 0.3 g/d HMB 1000, caused by α-ketoisocaproic Maximuscle exercise acid Ltd., Watford UK

OTHER DIETARY SUPPLEMENTS 277 Interactions with Clinical Details Pharmaceuticals, and Outcomes Conclusions/ Adverse Events Foods, or Other Measured Results Profile Dietary Supplements Flakoll et al., 2004: 57 elderly women given 2 g HMB + 5 g arginine + 1.5 g lysine or placebo for 12 wk; supplement increased fat- free mass, whole-body protein synthesis, limb circumferences, strength, and functionality compared to placebo (not isonitrogenous placebo). Rathmacher et al., 2004: 3 studies, one on 34 healthy males, one on 43 HIV patients, one in 32 cancer patients; combination of 3 g HMB + 14 g arginine + 14 g glutamine; no adverse effects on blood chemistries (with exception that blood urea nitrogen increased), emotional profile, or adverse events; in fact, positive effects on emotional profile, reduced feeling of weakness, and increased red blood cells and lymphocytes. Mortality, No effect on body weight, food intake, no None reported None reported clinical meaningful hematological changes (some observations, inconsistent effects on hematocrit), organ body weight, weights, micro- or macroscopic pathology. food The only clinical chemistry measure changed consumption, was increase in inorganic phosphorus in 5% clinical and group. anatomic pathology HMB was well tolerated up to 5% of the evaluation diet for 91 days. Subjects Combination supplement reduced the None reported None reported consumed either increase in marker of muscle damage, HMB + muscle soreness, percentage decrement in α-ketoisocaproic muscle strength, and increase in limb girth acid or placebo compared to placebo. for 14 days followed by performance of exercise designed to cause muscle damage

278 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-10  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Melatonin Review/ Clinical Trial Type of Study and Product Reference Subjects Indication Control Dose Specification Arendt and Review of 14 studies Jet lag and Various 1.8 mg sustained Skene, 2005 shift work release or 5 mg fast release Brzezinski Meta-analysis Insomnia Placebo Various None reported et al., 2005 of 7 studies n=284 subjects Buscemi Meta-analysis Insomnia and Placebo None reported None reported et al., 2005 of 14 randomized delayed sleep controlled trials phase syndrome Buscemi Meta-analysis Secondary Placebo Various; Various; mostly et al., 2006 sleep disorders 0.5 mg to 7.5 mg oral capsules or sleep and tablets disorders accompanying sleep restriction

OTHER DIETARY SUPPLEMENTS 279 Interactions with Clinical Details and Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Sleep phase shifts 11 of 14 placebo controlled studies on Exogenous None reported the use of melatonin for jet lag found melatonin is a at least some benefit. The benefits vasodilator—it included reduction in subjective jet lag, lowers core and improvements in sleep and body alertness. The evidence for using temperature, melatonin to adapt to night-shift work and it can was inconclusive. affect skin blood flow. Therefore, if taken in a cold environment it may accelerate heat loss Polysomnography Melatonin treatment reduced sleep None reported None reported and actigraphy used onset latency by an average of 4.0 to measure sleep minutes, increased sleep efficiency by onset latency, total 2.2%, and increased total sleep sleep duration, duration by 12.8 minutes. sleep efficiency Sleep onset latency, Melatonin decreased sleep onset latency No significant None reported sleep efficiency, by an average of 7.2 minutes in difference wakefulness after insomniacs and by an average of 38.8 observed sleep onset, total minutes in patients with delayed sleep between sleep time, REM phase syndrome. Some evidence that melatonin and sleep percentage melatonin is not effective in treating placebo primary sleep disorders over the short term (less than 4 wk). Sleep onset latency, Change in sleep onset latency was not The occurrence None reported sleep efficiency, statistically significant. Although the of adverse wakefulness after increase in sleep efficiency in people events was sleep onset, total with secondary sleep disorders was similar for sleep time, REM statistically significant with melatonin, melatonin and sleep percentage the effect was small (1.9%) an increase placebo. The of less than 10 min if the amount of most time spent asleep for 8 h spent in bed. commonly reported adverse events were headaches, dizziness, nausea, and drowsiness continued

280 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-10  Continued Review/ Clinical Trial Type of Study and Product Reference Subjects Indication Control Dose Specification Morin et al., Review Insomnia, Various Various; ranges None reported 2007 delayed sleep from 0.3 mg to phase 5 mg syndrome, jet lag Wagner Review Insomnia and Various 0.3 mg to 10 mg Various et al., 1998 circadian disorders Bliwise and Database evaluation Ansari, 2007 n=31,044 adults (ages 18–61+); representative U.S. sample

OTHER DIETARY SUPPLEMENTS 281 Interactions with Clinical Details and Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Sleep latency, sleep Although there is some evidence Common: Potential synergy with duration, sleep supporting the use of melatonin in fatigue, other sedative quality treating jet lag and sleep disturbance dizziness, hypnotics caused by shift work, more research is headache, needed before melatonin can be irritability, and recommended as a treatment for drowsiness insomnia. Less common: mood changes, hypotension, atherosclerotic plaques, hyperglycemia, mild gastrointestinal distress, increased intraocular pressure, fluctuations in reproductive and thyroid hormones Many, including The evidence may support melatonin Fatigue, None reported sleep quality, sleep use for circadian rhythm disorders and headache, latency, EEG, sleep in patients with low melatonin levels dizziness, duration such as the elderly; more evidence is irritability needed before it can be recommended for insomnia in the general population. Data from 2002 Alternative Health/ None reported None reported Complementary and Alternative Medicine supplement to the National Health Interview Survey: 5.2% of the survey sample used melatonin of which 27.5% (standard error=3.93) endorsed insomnia as one reason for use; 5.8% of the survey sample mentioned insomnia in association with valerian and melatonin use. Women used it more than men (5.5:1). Melatonin showed a 13.9% usage rate in association with anxiety/depression.

282 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-11  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Quercetin Review/ Clinical Trial Type of Study Product Reference and Subjects Indication Control Dose Specification Lotito and Pharmacologic Inflammation and Quercetin Frei, 2006 study atherosclerosis Nieman Double-blind, Upper respiratory Placebo 1,000 mg/day twice Quercetin et al., 2007 randomized, infections and daily for 3 wk prior controlled immune function and 2 wk after the 3-d after exercise period of exercise n=40 males Davis et al., Animal study 12.5 or 25 mg/kg Quercetin 2007 body weight for 7 d Okamoto, Review Quercetin 2005 IARC, 1999 Review Quercetin van der Tissue culture: 10–80 µmol/L Quercetin Woude et al., breast cancer cells 2005 Watjen et al., Tissue culture: Quercetin 2005 hepatoma rat cells

OTHER DIETARY SUPPLEMENTS 283 Interactions with Adverse Pharmaceuticals, Clinical Details and Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Inhibition of Quercetin, among other hydroxyl flavones, None None reported endothelial molecule was able to inhibit endothelial adhesion reported expression molecule expression. Upper respiratory No effects on natural killer cell activity, None None reported tract infections PHA-stimulated lymphocyte proliferation, reported (URTI) and changes polymorphonuclear oxidative burst in immune function activity, or salivary IgA output. after cycling at high Incidence of URTI during the 2-wk output for 3 h/d postexercise period differed significantly between groups. Quercetin might have antiviral effect. Mitochondrial Significant increases in mitochondrial None None reported content in muscle and content in skeletal muscle and brain. reported brain, endurance Increased endurance capacity observed in capacity the mice. Carcinogenicity Quercetin is not carcinogenic. None None reported reported Carcinogenicity Quercetin is not carcinogenic. None None reported reported Cell proliferation Biphasic effect: increase in cell proliferation None None reported at a low dose level (10–20 µmol/L) and reported decrease in proliferation at higher doses (40–80 µmol/L). Effects on DNA Biphasic effect: lower doses of 10–25 None None reported µmol/L protect against DNA strand breaks reported and induced apoptosis, but 50–250 µmol/L caused DNA damage.

284 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-12  Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Sports Bars Review/ Clinical Type of Trial Study and Product Reference Subjects Indication Control Dose Specification Burke Crossover Athletic Placebo Commercial gel providing Powergel, et al., n=18 highly performance (426±227 mL) 1.1±0.2 g/kg body mass Nestle 2005 trained (marathons) or water carbohydrate Australia marathon (386±185 mL) runners Ebert Randomized, Athletic None reported 0.4 L water and a sport gel or Gu Energy et al., crossover, performance 2.4 L of a 7% carbohydrate- Gel, Sports 2007 not blinded (cycling in a electrolyte drink Street n=8 well- warm Marketing, trained male environment) Sports gel had same Berkeley, cyclists carbohydrate content as CA