4
Other Dietary Supplements for Military Personnel

INTRODUCTION

The committee was asked to select a limited number of dietary supplements from those identified as commonly used and, on the basis of published 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 military. 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), melatonin, 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 interest 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



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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 

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 OTHER DIETARY SUPPLEMENTS 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

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 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-

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 OTHER DIETARY SUPPLEMENTS 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 Caffeine1 [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- 1 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.

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 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 Oer the Past Seeral 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

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 OTHER DIETARY SUPPLEMENTS 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

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0 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; Tarnopolsky, 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

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 OTHER DIETARY SUPPLEMENTS 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

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 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.

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 OTHER DIETARY SUPPLEMENTS 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.

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 TABLE 4-1 Summary of Average Daily Consumption (ADC) of Caffeine in the United States Reference Source Data Mean ADC NASa: Generally Recognized as Graham, 1978 Adults: 227 mg/day Safe (GRAS) survey, 1977 Children: 101 mg/day USDAb: Nationwide Food Pao et al., 1982 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 Children: <1 mg/kg Menu Census Survey, 1989 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 Re 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. Aiat Space Eniron 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.

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 OTHER DIETARY SUPPLEMENTS Interactions with Pharmaceuticals, Outcomes Adverse Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Body mass, Mean body mass change of approximately Gastrointestinal None reported performance 2.4%. discomfort on 2 half marathons Three runners reported gastrointestinal discomfort after consuming gel, which impaired marathon performance. The effect of gel on performance was insignificant (time was improved by 0.3% or 14 sec compared with placebo). No benefits of carbohydrate gel intake on half marathon performance. Maximal No differences in bicycle treadmill speed, None reported None reported aerobic blood glucose, blood lactose, hydration status, power, perceived exertion, thermal sensation, or hydration stomach fullness. status, body mass Significantly lower absolute power output in changes, water plus gel group to maintain same speed sweat rate, as carbohydrate-electrolyte drink group during blood treadmill test. glucose, blood Time to exhaustion was significantly shorter in lactose, water plus gel group. rating of exertion, Ingestion of water and a sport gel reduced the thermal exercise capacity of trained cyclists during sensation, laboratory cycling hill-climbing. and stomach fullness Maximal Fat oxidation rates were greater in subjects None reported None reported oxygen who ingested energy bar compared to those consumption, ingesting carbohydrate gel. respiratory exchange Ingestion of a sports bar significantly enhanced ratio, heart fat metabolism during prolonged submaximal rate, fat exercise. oxidation, perceived Ingestion of sports bar containing exertion carbohydrate, fat, and protein during exercise, led to impaired performance on subsequent high-intensity exercise.

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-13 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Sports Drinks Review/Clinical Type of Study Product Trial Reference and Subjects Indication Control Dose Specification Gibala, 2007 Review Protein Various Various None metabolism reported Jeukendrup, Review Exercise Various Various None 2004 performance reported Maughan and Review Exercise Various Various None Murray, 2001 performance reported Nieman, 2007 Review Immune None None reported None function reported reported Winnick et al., Double-blind, Peripheral Placebo 6% carbohydrate solution: Gatorade 1995 randomized, and central 5 mL/kg before exercise, Sports counter-balanced nervous 3 mL/kg after exercise, Science n=20 active system 8 mL/kg during exercise Institute, adults (10 men, function Barrington, 10 women), IL mean age 23.9 y

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 OTHER DIETARY SUPPLEMENTS Interactions with Adverse Pharmaceuticals, Outcomes Events Foods, or Other Measured Conclusions/Results Profile Dietary Supplements Endurance One study found that ingestion of a sports drink None None reported performance, with added protein provided no additional benefit reported repair and on athletic performance. There is no established synthesis of mechanism by which protein intake during muscle proteins, exercise should improve acute endurance synthesis of performance. muscle glycogen Ingestion of protein with carbohydrate improves net protein balance during exercise and recovery compared with carbohydrate alone, but it remains to be determined whether this practice facilitates the adaptive response to chronic training. Endurance Ingestion of small amounts of carbohydrate (16 g/ None None reported capacity and h) during exercise has positive ergogenic effects on reported performance performance. Larger amounts do not show any further benefits. Various Rehydration with sports drinks can restore the negative fluid balance caused by exercise. Sports drinks can also restore muscle glycogen after exercise. Ingestion of a sports drink at regular intervals during physical activity may enhance performance. Immune Ingestion of carbohydrate beverages during None None reported dysfunction exercise is an effective countermeasure to exercise- reported induced immune suppression in marathon athletes. Carbohydrate supplementation decreases exercise- induced increases in plasma cytokines and stress hormones, but is largely ineffective against other immune components including natural killer cell function and salivary IgA, with an undetermined influence on incidence of upper respiratory tract infections. Tests of peripheral Carbohydrate intake during exercise resulted in None None reported and central significantly faster 20-m sprint times and higher reported nervous system average jump height at the end of the exercise function (sprints, period. Carbohydrate intake also reduced force jumping, mood sensation, enhanced motor skills, and improved evaluation, mood late in exercise. cognitive function, force sensation, Carbohydrate intake during intermittent high- motor skills tests, intensity exercise similar to that of team sports and target improved peripheral and central nervous system jumping accuracy) function late in exercise.

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-14 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Tyrosine Review/ Clinical Trial Type of Study and Product Reference Subjects Indication Control Dose Specification Banderet Double-blind, Mood, Placebo 2 gelatin None reported and crossover physical capsules Lieberman, n=23 male U.S. condition, and adjusted to 1989 soldiers, ages 18– cognitive contain 50 mg/ 20 y performance kg tyrosine under environmental stress Wiegmann Controlled Cognitive Placebo 2 doses of Ajinomoto et al., 1993 n=20 male U.S. performance 75 mg/kg Company, Inc. Marines, ages 21– after sleep loss tyrosine 27 y and sustained work Deijen and Double-blind, Cognitive Placebo 100 mg/kg Country Life, Orlebeke, randomized performance L-tyrosine Hauppauge, NY 1994 n=9 male and 7 female healthy subjects, ages 25– 35 y Shurtleff Controlled Cognitive Placebo Applesauce Tysons & Assoc., et al., 1994 n=8 men performance adjusted to Santa Monica, contain CA (crystalline 150 mg/kg tyrosine) tyrosine Neri et al., Double-blind Cognitive Placebo 150 mg/kg None reported 1995 n=20 male U.S. performance tyrosine Marines, ages 21– after sleep loss 27 y

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 OTHER DIETARY SUPPLEMENTS Interactions with Adverse Pharmaceuticals, Clinical Details and Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Mood states, sustained Individuals were exposed to environmental None None reported attention, vigilance, stressors: Two levels of decreased reported processing spatial and temperature and reduced atmospheric verbal information, math pressure versus normal temperature and skills, number coding, pressure. Relative to placebo, tyrosine pattern recognition significantly reduced symptoms of headache, coldness, distress, fatigue, muscular discomfort, and sleepiness in subjects who responded adversely to environmental stress. Tyrosine also reduced dizziness, feelings of confusion, unhappiness, hostility, and tension, and reversed the adverse effects of environmental stressors on cognitive performance on tasks measuring math skills, pattern recognition, vigilance, and coding. Eye-hand coordination, Participants tested under conditions with None None reported short-term memory, noise stressor. Across night performance on reported dichotic listening, mood, cognitive tasks decreased. However, sleepiness, blood pressure, tyrosine administration led to smaller heart rate decrements in performance in eye-hand coordination, and short-term memory than placebo. Additionally, participants reported being less sleepy after tyrosine than placebo. Perceptual motor tasks, Relative to placebo, tyrosine improved None None reported vigilance task, short-term performance on short-term memory and reported memory test, Stroop task, Stroop task. and adjective checklist of mood Performance on delayed Tested at ambient temperatures of 4°C and None None reported matching to sample test of 22°C. Relative to placebo, tyrosine reported working memory prevented cold-induced memory deficit. Performance on Tyrosine prevented performance decline on None None reported psychomotor tasks and a psychomotor task and exhibited reported mood scales reduction on lapse responses on a vigilance task in sleep-deprived participants. continued

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0 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-14 Continued Review/ Clinical Trial Type of Study and Product Reference Subjects Indication Control Dose Specification Deijen Double-blind, Cognitive Carbohydrate- 2 g tyrosine in PROTIFAR et al., 1999 randomized performance rich drink a protein-rich powder n=20 male and 1 drink female military cadets, ages 18–27 y Thomas Double-blind, Cognitive Placebo Applesauce None reported et al., 1999 crossover performance adjusted to n=10 male and 10 under stress contain female active duty condition 150 mg/kg personnel and tyrosine civilians, ages 20– 38 y Chinevere Double-blind, Endurance Polydextrose 25 mg/kg None reported et al., 2002 randomized, exercise solution or tyrosine counter-balanced performance aspartame dissolved in a n=9 male solution polydextrose competitive cyclists solution or water Magill Double-blind, Cognitive Placebo 150 mg/kg None reported et al., 2003 randomized performance n=76 men, ages 18– when sleep 35 y deprived O’Brien Double-blind Cognitive and Placebo 2 energy bars None reported et al., 2007 n=15 soldiers (14 psychomotor adjusted to men, 1 women) performance each contain after cold 150 mg/kg water tyrosine immersion

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 OTHER DIETARY SUPPLEMENTS Interactions with Adverse Pharmaceuticals, Clinical Details and Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Memory, perceptual, Tyrosine supplementation reduced None None reported motor, vigilance tasks, cognitive deficits associated with reported and mood scales psychosocial stress and fatigue associated with combat training. Tyrosine did not affect mood. Study design does not eliminate the possibility that other amino acids contributed to the observed results. Simple task battery Tyrosine improved performance on None None reported measuring working multiple task battery, but not on simple reported memory and multiple task task battery. battery consisting of four simultaneously occurring Tyrosine might be beneficial to memory tasks measuring memory, under conditions of increased cognitive math skills, visual stress (e.g., multiple cognitive demands monitoring, auditory placed on military personnel). monitoring Time trial performance Tyrosine, either alone or with None None reported test on a stationary carbohydrates did not improve cycling reported bicycle time trial performance. Visual scanning, memory, Tyrosine showed positive effects for None None reported logical reasoning, overcoming performance deficits due to reported mathematical processing, prolonged sleep deprivation. Effects most reaction time, vigilance, pronounced for deficits in tasks measuring pursuit tracking memory and mathematical processing. Skin folds, U.S. Special Tyrosine mitigated cold-induced None None reported Operations Command decrements in performance on tasks reported standardized tests of measuring short-term memory, pattern cognitive and physical recognition, and marksmanship. performance evaluating short-term spatial memory and pattern recognition, complex reaction time, visual vigilance, mathematical reasoning, logical reasoning, psychomotor performance, marksmanship, grip strength, pull-ups, cycle ergometer, step ups continued

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-14 Continued Review/ Clinical Trial Type of Study and Product Reference Subjects Indication Control Dose Specification Mahoney Double-blind Cognitive Placebo 2 energy bars None reported et al., 2007 n=19 military performance adjusted to members and mood each contain after acute 150 mg/kg cold stress tyrosine

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 OTHER DIETARY SUPPLEMENTS Interactions with Adverse Pharmaceuticals, Clinical Details and Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Visual vigilance, reaction Tyrosine reduced cold-induced decrements None None reported time, short-term memory, in working memory and mitigated cold- reported mood state, muscle induced increased score on tension subscale discomfort, alertness of mood test.

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 4-15 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Valerian Review/ Clinical Trial Product Reference Type of Study and Subjects Indication Control Dose Specification Leathwood Randomized, controlled Improvement Placebo 400 mg Valerian et al., 1982 n=128 of sleep aqueous extract quality and latency Donath Randomized, double-blind, Sleep quality Placebo 600 mg/d Valerian extract et al., 2000 crossover and structure for 8 d (300 mg) pills n=16 (4 men, 12 women), ages as Sedonium 22–55 y, with psychophysiological insomnia Beaubrun Review Sleep latency, Placebo 400 mg to Valerian extract and Gray, nocturnal 900 mg 2000 awakenings, and subjective sleep quality Bent et al., Review Improving Placebo Variable Variable 2006 n=16 studies sleep quality Diaper and Double-blind, crossover Insomnia and Placebo 300 mg and Valerian extract Hindmarch, n=16 (5 men, 11 women) improving 600 mg for (300 mg) 2004 sleep-disturbed patients sleep quality 1d Sedonium Hallam Randomized, double-blind, Cognitive and Placebo 500 mg and Valerian extract et al., 2003 crossover psychomotor 1,000 mg (500 mg) Herb n=9 (5 men, 4 women) healthy effects of for 1 d Valley subjects valerian aElectroencephalography is the technique of using electrodes placed on the scalp to measure electrical activity of the brain. bElectro-oculography is a technique for measuring the resting potential of the retina.

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 OTHER DIETARY SUPPLEMENTS Interactions with Pharmaceuticals, Adverse Events Foods, or Other Outcomes Measured Conclusions/Results Profile Dietary Supplements Subjective ratings of The aqueous extract of valerian One person None reported sleep quality, sleep produced a significant withdrew from latency, night improvement in sleep quality in the study because awakenings, dream young, poor sleepers as well as a they experienced recall, next morning significant improvement in sleep nausea. However, sleepiness quality in women who were poor it was not sleepers. There were no possible to differences between placebo and attribute the valerian in dream recall, night nausea definitively awakenings, or next morning to valerian sleepiness. Sleep structure changes In insomnia patients, valerian had More adverse None reported as measured by EEG,a positive effects on sleep structure events were seen EOG,b EMG,c and ECGd and sleep perception. It can be under the placebo Subjective sleep quality recommended for the treatment condition of patients with mild (18 vs. 3) psychophysiological insomnia. Sleep latency, nocturnal Valerian generally produced Rare, but may Potential interaction awakening, subjective decreased sleep latency and include headache, with other sedative sleep quality nocturnal awakenings and restless sleep, hypnotics improved subjective sleep quality. allergies, However, in some studies the gastrointestinal placebo effect was large and in problems, and others the beneficial effects of mydriasis valerian were not seen until after 2 to 4 wk of therapy. Sleep quality Valerian may be an effective treatment for insomnia; larger studies needed. Time in bed, total sleep No significant difference was None reported None reported time, sleep latency, found between either dose of number of awakenings, valerian and placebo. Valerian is total slow-wave sleep ineffective as an acute treatment for sleeping problems at these doses. Critical flicker fusion, Valerian was without effect on None reported None reported choice reaction time, either cognitive or psychomotor digit symbol substitution performance at the doses used in test, symbol search test, this study. digit span test, and visual analogue scales of mood cElectromyography is a technique for evaluating physiologic properties of muscles. dElectrocardiogram is a recording of the electrical activity of the heart over time.