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Institute of Medicine (US) Committee on Dietary Supplement Use by Military Personnel; Greenwood MRC, Oria M, editors. Use of Dietary Supplements by Military Personnel. Washington (DC): National Academies Press (US); 2008.

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Use of Dietary Supplements by Military Personnel.

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4Other 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 its effects on performance and immune response was partially supported by the Department of Defense (DoD), indicating the level of military interest in this dietary supplement. Likewise, although the frequency of use of tyrosine was not apparent, this amino acid has been of interest to the military 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 wakefulness 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 recommended 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 medications 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), mission environments (e.g., high altitude, extreme temperatures), or the impact of adverse events associated with the supplement (e.g., bleeding, gastrointestinal 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 medications 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 supplement 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 developed 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 efficacy, 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 supplement 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 management 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 similar 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 because 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 concentrations 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) theophylline, 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 cardiovascular, 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- 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 activity 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 supplements 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 products 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 product 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 −116 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 majority 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 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.”

TABLE 4-1 Summary of Average Daily Consumption (ADC) of Caffeine in the United States.

Table

TABLE 4-1 Summary of Average Daily Consumption (ADC) of Caffeine in the United States.

Caffeine in Energy Drinks

Energy drinks have acquired a considerable market in recent years, substantially 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 consumption 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 Association (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 “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 physical 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 endurance performance in a variety of activities (i.e., running, cross-country skiing, 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 caffeine 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., grogginess 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 evaluated several times (IOM, 2001). In 1987, the U.S. Food and Drug Administration (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 consumption 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 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 operations, 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 advantageous low-risk scenarios that were learned prior to sleep deprivation (Killgore et al., 2007).

Additional effects of caffeine may be undesirable in certain environmental 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 temperature (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 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. Numerous 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, corresponding 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 dosage. 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 demonstrated 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.

Caffeine Withdrawal

The most commonly reported symptoms following withdrawal of caffeine, even at doses as low as 100 mg, are headache, irritability, increased fatigue and drowsiness, decreased alertness, difficulty concentrating, nervousness, 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 proximity 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 personnel does not interfere with sleep when the latter is desirable.

Considerations Specific to the Military

Military engagements often involve extended periods of sleep restriction 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 effective 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, regarding 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 environments (e.g., hot climates).

A summary of average daily consumption (ADC) of caffeine in the United States is shown in Table 4-1.

References

  1. Andrews KW, Schweitzer A, Zhao C, Holden JM, Roseland JM, Brandt M, Dwyer JT, Picciano MF, Saldanha LG, Fisher KD, Yetley E, Betz JM, Douglass L. The caffeine contents of dietary supplements commonly purchased in the U.S.: Analysis of 53 products with caffeine-containing ingredients. Annal Bioanal Chem. 2007;389(1):231–239. [PubMed: 17676317]
  2. APA (American Psychiatric Association). Diagnostic and statistical manual of mental disorders (DSM-IV). Arlington, VA: APA; 1994.
  3. Armstrong LE, Casa DJ, Maresh CM, Ganio MS. Caffeine, fluid-electrolyte balance, temperature regulation, and exercise-heat tolerance. Exerc Sport Sci Rev. 2007;35(3):135–140. [PubMed: 17620932]
  4. Barone JJ, Roberts HR. Caffeine consumption. Food Chem Toxicol. 1996;34(1):119–129. [PubMed: 8603790]
  5. Bell DG, Jacobs I, McLellan TM, Miyazaki M, Sabiston CM. Thermal regulation in the heat during exercise after caffeine and ephedrine ingestion. Aviat Space Environ Med. 1999;70(6):583–588. [PubMed: 10373050]
  6. Bonnet MH, Balkin TJ, Dinges DF, Roehrs T, Rogers NL, Wesensten NJ. Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. 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. 2005;28(9):1163–1187. [PubMed: 16268386]
  7. Dodd SL, Herb RA, Powers SK. Caffeine and exercise performance: An update. Sports Med. 1993;15(1):14–23. [PubMed: 8426941]
  8. Doubt TJ, Hsieh SS. Additive effects of caffeine and cold water during submaximal leg exercise. Med Sci Sports Exerc. 1991;23(4):435–442. [PubMed: 2056901]
  9. Energy drinks: Behind the buzz. Consum Rep. 2007;72(9):6. [PubMed: 17907359]
  10. Frary CD, Johnson RK, Wang MQ. Food sources and intakes of caffeine in the diets of persons in the United States. J Am Diet Assoc. 2005;105(1):110–113. [PubMed: 15635355]
  11. Graham DM. Caffeine—It’s identity, dietary sources, intake and biological effects. Nutr Rev. 1978;36(4):97–102. [PubMed: 353595]
  12. Graham TE, Rush JW, van Soeren MH. Caffeine and exercise: Metabolism and performance. Can J Appl Physiol. 1994;19(2):111–138. [PubMed: 8081318]
  13. IOM (Institute of Medicine). Caffeine for the sustainment of mental task performance: Formulations for military operations. Washington, DC: National Academy Press; 2001. [PubMed: 11984428]
  14. Killgore DS, Lipizzi EL, Kamimori GH, Balkin TJ. Caffeine effects on risky decision making after 75 hours of sleep deprivation. Aviat Space Environ Med. 2007;78(10):957–962. [PubMed: 17955944]
  15. Knight CA, Knight I, Mitchell DC, Zepp JE. Beverage caffeine intake in U.S. consumers and subpopulations of interest: Estimates from the Share of Intake Panel Survey. Food Chem Toxicol. 2004;42(12):1923–1930. [PubMed: 15500929]
  16. McLellan TM, Kamimori GH, Voss DM, Charmaine T, Smith SJR. Caffeine effects on physical and cognitive performance during sustained operations. Aviat Space Environ Med. 2007;78(9):871–877. [PubMed: 17891897]
  17. Jordan S, Eastwood J, Rotstein J, Hugenholtz A, Feeley M. Effects of caffeine on human health. Food Addit Contam. 2003;20(1):1–30. [PubMed: 12519715]
  18. Nehlig A. Are we dependent upon coffee and caffeine? A review on human and animal data. Neurosci Biobehav Rev. 1999;23(4):563–576. [PubMed: 10073894]
  19. Neuhäuser-Berthold M, Beine S, Lührmann PML, Verwied SC. Coffee consumption and total body water homeostasis as measured by fluid balance and bioelectrical impedance analysis. Ann Nutr Metab. 1997;41(1):29–36. [PubMed: 9194998]
  20. Nielsen SJ, Popkin BM. Changes in beverage intake between 1977 and 2001. Am J Prev Med. 2004;27(3):205–210. [PubMed: 15450632]
  21. Pao EM, Fleming K, Guenther PM, Mickel SJ. Foods commonly eaten by individuals: Amount per day and per eating occasion. 1982. USDA Home Economics Research Report No. 44.
  22. Pardo LR, Alvarez GY, Barral TD, Farré AM. Caffeine: A nutrient, a drug, or a drug of abuse. Adicciones. 2007;19(2):225–238. [PubMed: 17724925]
  23. Poka-Heiskanen T. Adenosine in sleep and wakefulness. Ann Med. 1999;31(2):125–129. [PubMed: 10344585]
  24. Price NJ, Mullington JM, Kapoor S, Samuel S, Szuba MP, Dinges DF. Plasma norepinephrine during 66 hr of sustained low-dose caffeine intake and 88 hr of sleep deprivation. Sleep. 2000;23(Suppl 1):A119.
  25. Reid TR, Sacha B. Caffeine. National Geographic. 2005;207(1):2–33.
  26. Roache JD, Griffiths RR. Interactions of diazepam and caffeine: Behavioral and subjective dose effects in humans. Pharmacol Biochem Behav. 1987;26(4):801–812. [PubMed: 3602037]
  27. Rogers NL, Dinges DF. Caffeine: Implications for alertness in athletes. Clin Sports Med. 2005;24(2):e1–e13. [PubMed: 15892913]
  28. Rogers NL, Price NJ, Szuba MP, Van Dongen HP, Dinges DF. Effect of sustained caffeine on core body temperature during 88 hours of sustained wakefulness. Sleep. 2001;24 Abstract Suppl:A172–A173.
  29. Spriet LL. Caffeine and performace. Int J Sport Nutr. 1995;5(Suppl):S84–S99. [PubMed: 7550260]
  30. Tarnopolsky MA. Caffeine and endurance performance. Sports Med. 1994;18(2):109–125. [PubMed: 9132918]
  31. Vallerand AL, Jacobs I, Kavanagh MF. Mechanism of enhanced cold tolerance by an ephedrine-caffeine mixture in humans. J Appl Physiol. 1989;67(1):438–444. [PubMed: 2759973]
  32. Van Dongen HP, Price NJ, Mullington JM, Szuba MP, Kapoor SC, Dinges DF. Caffeine eliminates psychomotor vigilance deficits from sleep inertia. Sleep. 2001;24(7):813–819. [PubMed: 11683484]

CHROMIUM

Background

Chromium,2 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 concentrations 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).

Absorption of dietary chromium in the intestines ranges from 0.5 percent 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 absorption. 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 intravenous 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 chromium 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 absorbability; 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 histidine 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 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 significant (Lefavi et al., 1992).

Although chromium picolinate continues to be vigorously marketed and used, the supplement’s ability to alter body composition is questionable (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 examination 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 genotoxic 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 preceding 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).

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, research 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.

TABLE 4-2 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Chromium.

Table

TABLE 4-2 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Chromium.

References

  1. Anderson RA, Polansky MM, Bryden NA. Stability and absorption of chromium and absorption of chromium and absorption of chromium histidinate complexes by humans. Biol Trace Elem Res. 2004;101(3):211–218. [PubMed: 15564651]
  2. Andersson-Zetterberg MA, Grawe KVP, Karlsson OM, Abramsson LA, Hellman BE. Evaluation of the potential genotoxicity of chromium picolinate in mammalian cells in vivo and in vitro. Food Chem Toxicol. 2007;45(7):1097–1106. [PubMed: 17418471]
  3. Cyr-Campbell WW, Joseph LJ, Davey SL, Cyr D, Anderson RA, Evans WJ. Effects of resistance training and chromium picolinate on body composition and skeletal muscle in older men. J Appl Physiol. 1999;86(1):29–39. [PubMed: 9887110]
  4. Diaz ML, Watkins BA, Li Y, Anderson RA, Campbell WW. 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. 2008;19(1):61–68. [PubMed: 17531459]
  5. DiSilvestro RA, Dy E. Comparison of acute absorption of commercially available chromium supplements. J Trace Elem Med Biol. 2007;21(2):120–124. [PubMed: 17499152]
  6. Evans GW. The effect of chromium picolinate on insulin controlled parameters in humans. Int J Biosoc Med Res. 1989;11(2):163–180.
  7. Hallmark MA, Reynolds TH, DeSouza CA, Dotson CO, Anderson RA, Rogers MA. Effects of chromium and resistive training on muscle strength and body composition. Med Sci Sports Exerc. 1996;28(1):139–144. [PubMed: 8775366]
  8. Hininger I, Benaraba R, Osman M, Faure H, Roussel AM, Anderson RA. Safety of trivalent chromium complexes: No evidence for DNA damage in human HACaT keratinocytes. Free Radic Biol Med. 2007;42(12):1759–1765. [PubMed: 17512455]
  9. IOM (Institute of Medicine). Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2000. [PubMed: 11269606]
  10. IOM. Nutrient composition of rations for short-term, high-intensity combat operations. Washington, DC: The National Academies Press; 2005.
  11. Jeejeebhoy KN. The role of chromium in nutrition and therapeutics and as a potential toxin. Nutr Rev. 1999;57(11):329–335. [PubMed: 10628183]
  12. Lamson DW, Plaza SM. The safety and efficacy of high-dose chromium. Altern Med Rev. 2002;7(3):218–235. [PubMed: 12126463]
  13. Lefavi R, Anderson RA, Keith RE, Wilson GD, McMillan JL, Stone MH. Efficacy of chromium supplementation in athletes: Emphasis on anabolism. Int J Sport Nutr. 1992;2(2):111–122. [PubMed: 1299487]
  14. Livolsi JM, Adams GM, Laguna PL. The effect of chromium picolinate on muscular strength and body composition in women athletes. J Strength Cond Res. 2001;15(2):161–166. [PubMed: 11710399]
  15. Lukaski HC. Chromium as a supplement. Annu Rev Nutr. 1999;19:279–302. [PubMed: 10448525]
  16. Lukaski HC, Siders WA, Penland JG. Chromium picolinate supplementation in women: Effects on body weight, composition, and iron status. Nutrition. 2007;23(3):187–195. [PubMed: 17291720]
  17. Martin J, Wang ZQ, Zhang XH, Watchel D, Volaufova J, Matthews DE, Cefalu WT. Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. Diabetes Care. 2006;29(8):1826–1832. [PubMed: 16873787]
  18. Nissen SL, Sharp RL. Effect of dietary supplements on lean mass and strength gains with resistance exercise: A meta-analysis. J Appl Physiol. 2003;94(2):651–659. [PubMed: 12433852]
  19. ODS (Office of Dietary Supplements). Dietary supplement fact sheet: Chromium. 2005. [accessed September 5, 2007]. http://ods​.od.nih.gov​/factsheets/chromium.asp
  20. Pittler MH, Stevinson C, Ernst E. Chromium picolinate for reducing body weight: Meta-analysis of randomized trials. Int J Obes Relat Metab Disord. 2003;27(4):522–529. [PubMed: 12664086]
  21. Sharpe PA, Granner ML, Conway JM, Ainsworth BE, Dobre M. Availability of weight-loss supplements: Results of an audit of retail outlets in a southeastern city. J Am Diet Assoc. 2006;106(12):2045–2051. [PubMed: 17126636]
  22. Stallings D, Vincent JB. Chromium: A case study in how not to perform nutritional research. Curr Topics Nutraceut Res. 2006;4(2):89–112.
  23. Stoecker BJ. Chromium. In: Bowman BA, Russell RM, editors. Present knowledge in nutrition. 8th ed. Washington, DC: ILSI Press; 2001. pp. 366–372.
  24. Trumbo PR, Ellwood KC. Chromium picolinate intake and risk of type 2 diabetes: An evidence-based review by the United States Food and Drug Administration. Nutr Rev. 2006;64(8):357–363. [PubMed: 16958312]
  25. Vincent JB. Recent advances in the biochemistry of chromium (III). J Trace Elem Exp Med. 2003a;16(4):227–236.
  26. Vincent JB. The potential value and toxicity of chromium picolinate as a nutritional supplement, weight loss agent and muscle development agent. Sports Med. 2003b;33(3):213–230. [PubMed: 12656641]
  27. Wani S, Weskamp C, Marple J, Spry L. Acute tubular necrosis associated with chromium picolinate-containing dietary supplement. Ann Pharmacother. 2006;40(3):563–566. [PubMed: 16492795]

CREATINE

Background

Creatine3 is a natural component of the body that is synthesized principally 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 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 administration 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 significant 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). Despite 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 submaximal aerobic training in young men and women (Reardon et al., 2006), for tennis-specific training (Pluim et al., 2006), multiple sprint running performance (Glaister et al., 2006), and sprint skating in hockey players (Cornish et al., 2006). Thus, creatine can be a relatively safe and effective ergogenic 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 obstacle 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., 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 inhibitors 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 common among those who take creatine supplements, data about significant interactions 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 available studies suggest either no impact or improvement in tolerance of thermal 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 intracellular location, there have been concerns about dehydration or local fluid retention 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 edematous limbs presumed secondary to fluid retention were seen more commonly in those taking creatine than those in the placebo group (Groeneveld et al., 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, responsive 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 reported 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 publications identified for creatine are shown in Table 4-3 on pages 160–181.

TABLE 4-3 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Creatine.

Table

TABLE 4-3 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Creatine.

References

  1. Bailes JE, Cantu RC, Day AL. The neurosurgeon in sport: Awareness of the risks of heatstroke and dietary supplements. Neurosurgery. 2002;51(2):283–286. [PubMed: 12182766]
  2. Bemben M, Lamont H. Creatine supplementation and exercise performance: Recent findings. Sports Med. 2005;35(2):107–125. [PubMed: 15707376]
  3. Calfee R, Fadale P. Popular ergogenic drugs and supplements in young athletes. Pediatrics. 2006;117(3):e577–e589. [PubMed: 16510635]
  4. Cornish S, Chilibeck P, Burke D. The effect of creatine monohydrate supplementation on sprint skating in ice-hockey players. J Sports Med Phys Fitness. 2006;46:90–98. [PubMed: 16596105]
  5. Dechent P, Pouwels P, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol Regul Integr Comp Physiol. 1999;277(3):R698–R704. [PubMed: 10484486]
  6. Derave W, Eijnde BO, Verbessem P, Ramaekers M, Van M, Richter EA, Hespel P. Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT-4 content and glucose tolerance in humans. J Appl Physiol. 2003;94(5):1910–1916. [PubMed: 12524381]
  7. Doherty M, Smith PM, Davison RC, Hughes MG. Caffeine is ergogenic after supplementation of oral creatine monohydrate. Med Sci Sports Exerc. 2002;34(11):1785–1792. [PubMed: 12439084]
  8. Glaister M, Lockey R, Abraham C, Staerck A, Goodwin J, McInnnes G. Creatine supplementation and multiple sprint running performance. J Strength Cond Res. 2006;20(2):273–277. [PubMed: 16686553]
  9. Graham AS, Hatton RC. Creatine: A review of efficacy and safety. J Am Pharm Assoc (Wash). 1999;39(6):803–810. [PubMed: 10609446]
  10. Greenwood M, Kreider RB, Melton C, Rasmussen C, Lancaster S, Cantler E, Milnor P. Creatine supplementation during college football training does not increase the incidence of cramping or injury. Mol Cell Biochem. 2003;244(1-2):83–88. [PubMed: 12701814]
  11. Groeneveld GJ, Beijer C, Veldink JH, Kalmijn S, Wokke JH, van den Berg LH. Few adverse effects of long-term creatine supplementation in a placebo-controlled trial. Int J Sports Med. 2005;26(4):307–313. [PubMed: 15795816]
  12. Gualano B, Novaes RB, Artioli GG, Freire TO, Coelho DF, Scagliusi FB, Rogeri PS, Roschel H, Ugrinowitsch C, Lancha AH Jr. Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training. Amino Acids. 2008;34(2):245–250. [PubMed: 17396216]
  13. Hespel P, Op’t Eijnde B, Van M. Opposite actions of caffeine and creatine on muscle relaxation time in humans. J Appl Physiol. 2002;92(2):513–518. [PubMed: 11796658]
  14. Hoffman J, Ratamess N, Kang J, Mangine G, Faigenbaum A, Stout J. Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes. Int J Sport Nutr Exerc Metab. 2006;16(4):430–446. [PubMed: 17136944]
  15. Kilduff LP, Georgiades E, James N, Minnion RH, Mitchell M, Kingsmore D, Hadjicharlambous M, Pitsiladis YP. 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. 2004;14(4):443–460. [PubMed: 15467102]
  16. Klivenyi P, Kiaei M, Gardian G, Calingasan NY, Beal MF. Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem. 2004;88(3):576–582. [PubMed: 14720207]
  17. Korzun WJ. Oral creatine supplements lower plasma homocysteine concentrations in humans. Clin Lab Sci. 2004;17(2):102–106. [PubMed: 15168891]
  18. Law M, Rudnicka AR. Statin safety: A systematic review. Am J Cardiol. 2006;97(8):S52–S60. [PubMed: 16581329]
  19. McMorris T, Harris R, Swain J, Corbett J, Collard K, Dyson R, Dye L, Hodgson C, Draper N. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology (Berl). 2006;185(1):93–103. [PubMed: 16416332]
  20. Mendel RW, Blegen M, Cheatham C, Antonio J, Ziegenfuss T. Effects of creatine on thermoregulatory responses while exercising in the heat. Nutrition. 2005;21(3):301–307. [PubMed: 15797670]
  21. Op’at Eijnde B, Jijakli H, Hespel P, Malaisse WJ. 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. 2006;17(6):1077–1084. [PubMed: 16685419]
  22. Parise G, Mihic S, MacLennan D, Yarasheski KE, Tarnopolsky MA. Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J Appl Physiol. 2001;91(3):1041–1047. [PubMed: 11509496]
  23. Persky AM, Brazeau GA, Hochhaus G. Pharmacokinetics of the dietary supplement creatine. Clin Pharmacokinet. 2003;42(6):557–574. [PubMed: 12793840]
  24. Pline KA, Smith CL. The effect of creatine intake on renal function. Ann Pharmacother. 2005;39(6):1093–1096. [PubMed: 15886291]
  25. Pluim B, Ferrauti A, Broekhof F, Deutekom M, Gotzmann A, Kuipers H, Weber K. The effects of creatine supplementation on selected factors of tennis specific training. Br J Sports Med. 2006;40(6):507–511. [PMC free article: PMC2465117] [PubMed: 16720886]
  26. Pritchard NR, Kalra PA. Renal dysfunction accompanying oral creatine supplements. Lancet. 1998;351(9111):1252–1253. [PubMed: 9643752]
  27. Reardon T, Ruell P, Fiatarone S, Thompson C, Rooney K. Creatine supplementation does not enhance submaximal aerobic training adaptations in healthy young men and women. Eur J Appl Physiol. 2006;98(3):234–241. [PubMed: 16896727]
  28. Santos RV, Bassit RA, Caperuto EC, Costa Rosa LF. The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30 km race. Life Sci. 2004;75(16):1917–1924. [PubMed: 15306159]
  29. Scheff SW, Dhillon HS. Creatine-enhanced diet alters levels of lactate and free fatty acids after experimental brain injury. Neurochem Res. 2004;29(2):469–479. [PubMed: 15002746]
  30. Shao A, Hathcock J. Risk assessment for creatine monohydrate. Regul Toxicol Pharmacol. 2006;45(3):242–251. [PubMed: 16814437]
  31. Smith J, Dahm DL. Creatine use among a select population of high school athletes. Mayo Clin Proc. 2000;75(12):1257–1263. [PubMed: 11126833]
  32. Sullivan PG, Geiger JD, Mattson MP, Scheff SW. Dietary supplement creatine protects against traumatic brain injury. Ann Neurol. 2000;48(5):723–729. [PubMed: 11079535]
  33. Thorsteinsdottir B, Grande J, Garovic V. Acute renal failure in a young weight lifter taking multiple food supplements, including creatine monohydrate. J Ren Nutr. 2006;16(4):341–345. [PubMed: 17046619]
  34. Volek JS, Mazzetti SA, Farquhar WB, Barnes BR, Gomez AL, Kraemer WJ. Physiological responses to short-term exercise in the heat after creatine loading. Med Sci Sports Exerc. 2001;33(7):1101–1108. [PubMed: 11445756]
  35. Volek J, Forsythe C, Kraemer W. Nutritional aspects of women strength athletes. Br J Sports Med. 2006;40(9):742–748. [PMC free article: PMC2564387] [PubMed: 16855068]
  36. Warber J, Thorian W, Patton J, Champagne C, Mitotti P, Lieberman H. The effect of creatine monohydrate supplementation on obstacle course and multiple bench press performance. J Strength Cond Res. 2002;16:500–509. [PubMed: 12423177]
  37. Watsford ML, Murphy AJ, Spinks WL, Walshe AD. Creatine supplementation and its effect on musculotendinous stiffness and performance. J Strength Cond Res. 2003;17(1):26–33. [PubMed: 12580652]
  38. Weiss BA, Powers ME. Creatine supplementation does not impair the thermoregulatory response during a bout of exercise in the heat. J Sports Med Phys Fitness. 2006;46(4):555–563. [PubMed: 17119520]

DEHYDROEPIANDROSTERONE (DHEA)

Background

Dehydroepiandrosterone4 (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 demonstrate 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 evidence 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, kidney disease, and diabetes. Some drugs are known to reduce blood DHEA (e.g., dexamethasone, insulin, carbamazepine, phenytoin) while others (e.g., benfluorex, 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 concentration 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 testosterone 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 insulin 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 significant 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). 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 composition, 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 conditions. In addition, study subjects were generally older than active duty military 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 publications identified for DHEA are shown in Table 4-4 on pages 182–191.

TABLE 4-4 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for DHEA.

Table

TABLE 4-4 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for DHEA.

References

  1. Allolio B, Arlt W. DHEA treatment: Myth or reality? Trends Endo Metab. 2002;13(7):288–294. [PubMed: 12163230]
  2. Bahrke MS, Yesalis CE. Abuse of anabolic androgenic steroids and related substances in sport and exercise. Curr Opin Pharmacol. 2004;4:614–620. [PubMed: 15525553]
  3. Baulieu EE, Thomas G, Legrain S, Lahlou N, Roger M, Debuire B, Faucounau V, Girard L, Hervy MP, Latour F, Leaud MC, Mokrane A, Pitti-Ferandi H, Trivalle C, Nouveau S, Rakoto-Arison B, Souberbielle JC, Raison J, Le Y, Raynaud A, Girerd X, Forette F. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge study to a sociobiomedical issue. Proc Natl Acad Sci. 2000;97(8):4279–4284. [PMC free article: PMC18228] [PubMed: 10760294]
  4. Brown GA, Vukovich M, King DS. Testosterone prohormone supplements. Med Sci Sports Exerc. 2006;38(8):1451–1461. [PubMed: 16888459]
  5. Evans GJ, Malouf R, van Niekerk JK, Huppert F. Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people (review). Cochrane Database Syst Rev. 2007;4:CD006221. [PubMed: 17054283]
  6. Handelsman DJ. Editorial: Andro and the prosteroids: Bolting the stable door. J Clin Endocrinol Metab. 2005;90(2):1249–1251. [PubMed: 15699545]
  7. Kaaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C, Secreto G, Amiano P, Bingham S, Khaw KT, Boeing H, Bueno de Mesquita HB, Chang-Claude J, Clavel-Chapelon F, Fournier A, Gonzalez CA, Gurrea AB, Critselis E, Khaw KT, Krogh V, Lahmann PH, Nagel G, Olsen A, Onland-Moret NC, Overvad K, Palli D, Panico S, Peeters P, Quirós JR, Roddam A, Thiébaut A, Tjønneland A, Chirlaque MD, Trichopoulou A, Trichopoulos D, Tumino R, Vineis P, Norat T, Ferrari P, Slimani N, Riboli E. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst. 2005a;97(10):755–765. [PubMed: 15900045]
  8. Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PHM, Biessy C, Dossus L, Lukanova A, Bingham S, Khaw KT, Allen NE, Bueno de Mesquita HB, Grobbee D, Boeing H, Lahmann PH, Nagel G, Chang-Claude J, Clavel-Chapelon F, Fournier A, Thiébaut A, Gonzáles CA, Quirós JR, Tormo MJ, Ardanaz E, Amiano P, Krogh V, Palli V, Panico S, Tumino R, Vineis P, Trichopoulou A, Kalapothaki V, Trichopoulos D, Ferrari P, Norat T, Saracci R, Riboli E. Postmenopausal serum androgens, oestrogens and breast cancer risk: The European Prospective Investigation into Cancer and Nutrition. Endocr Relat Cancer. 2005b;12(4):1071–1082. [PubMed: 16322344]
  9. Kroboth PD, Salek FS, Pittenger AL, Fabian TJ, Frye RF. DHEA and DHEA-S: A review. J Clin Pharmacol. 1999;39(4):327–348. [PubMed: 10197292]
  10. Mayer D, Forstner K. Impact of dehydroepiandrosterone on hapatocarcinogenesis in the rat (review). Int J Oncol. 2004;25:1021–1030. [PubMed: 15375552]
  11. Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst. 2004;96(24):1856–1865. [PubMed: 15601642]
  12. Morales AJ, Haubricht RH, Hwang JY, Asakura H, Yen SS. 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. 1998;49(4):421–432. [PubMed: 9876338]
  13. Muller M, van den Beld AW, van der Schouw YT, Grobbee DE, Lamberts SWJ. Effects of dehydroepiandrosterone and atamestane supplementation on frailty in elderly men. J Clin Endocrinol Metab. 2006;91(10):3988–3991. [PubMed: 16804050]
  14. Nair KS, Rizza RA, O’Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla C, Tindall DJ, Smith GE, Khosla S, Jensen MD. DHEA in elderly women and DHEA or testosterone in elderly men. New Eng J Med. 2006;355(16):1647–1659. [PubMed: 17050889]
  15. Percheron G, Hogrel J, Denot-Ledunois S, Fayet G, Forette F, Baulieu E, Fardeau M, Marini J. 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. 2003;163(6):720–727. [PubMed: 12639206]
  16. Raven PW, Hinson JP. Dehydroepiandrosterone (DHEA) and the menopause: An update. Menopause Int. 2007;13(2):75–78. [PubMed: 17540138]
  17. Salek FS, Bigos KL, Broboth PD. The influence of hormones and pharmaceutical agents on DHEA and DHEA-S concentrations: A review of clinical studies. J Clin Pharmacol. 2002;42(3):247–266. [PubMed: 11865961]
  18. Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: A randomized controlled trial. JAMA. 2004;292(18):2243–2248. [PubMed: 15536111]

EPHEDRA

Background

The genus Ephedra5 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 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, fever, 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 Administration (FDA) has approved several alkaloids in Ephedra as ingredients in over-the-counter nasal decongestants and bronchodilator drugs. Pseudoephedrine is approved as an oral decongestant for the symptomatic treatment 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 constituents 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 (−)-norephedrine, (+)-norpseudoephedrine, (−)-methylephedrine and (+)-methylpseudoephedrine. 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 material, 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.

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 performance improvements (Magkos and Kavouras, 2004).

The committee identified and reviewed various studies in which the effects 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 increases 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 significant. 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 enhancements. 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).

TABLE 4-5 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ephedra.

Table

TABLE 4-5 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ephedra.

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 considered 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 palpitations, tachycardia, or both (13 reports); stroke (10 reports); and seizures (7 reports). There were 10 events resulting in death, and 13 resulted in permanent disability. Sixty-three percent of ephedra users were under the age of 45 years (Haller and Benowitz, 2000). Use of ephedra-containing supplements 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 contraindicated 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 increased 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 of norepinephrine from sympathetic neurons. Indirect sympathomimetic agents given in combination with monoamine oxidase inhibitors may induce severe hypertension, hyperpyrexia, seizures, arrhythmias, and possibly death (Hansten and Horn, 2000).

Ephedra in combination with cardiac glycosides or halothane (anesthesia) 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 cardiovascular health.

Relevant data and conclusions on efficacy and safety reviews and publications identified for ephedra are shown in Table 4-5 on pages 192–229.

References

  1. Abourashed EA, El-Alfy AT, Khan IA, Walker L. Ephedra in perspective: A current review. Phytother Res. 2003;17(7):703–712. [PubMed: 12916063]
  2. Andraws R, Chawla P, Brown DL. Cardiovascular effects of ephedra alkaloids: A comprehensive review. Prog Cardiovasc Dis. 2005;47(4):217–225. [PubMed: 15991150]
  3. Bell DG, Jacobs I, Ellerington K. Effect of caffeine and ephedrine ingestion on anaerobic exercise performance. Med Sci Sports Exerc. 2001;33(8):1399–1403. [PubMed: 11474345]
  4. Bell DG, McLellan TM, Sabiston CM. Effect of ingesting caffeine and ephedrine on 10-km run performance. Med Sci Sports Exerc. 2002;34(2):344–349. [PubMed: 11828246]
  5. Bent S, Tiedt TN, Odden MC, Shlipak MG. The relative safety of ephedra compared with other herbal products. Ann Intern Med. 2003;138(6):468–471. [PubMed: 12639079]
  6. Blumenthal M, King P. A review of the botany, chemistry, medicinal uses, safety concerns and legal status of Ephedra and its alkaloids. Herbalgram. 1995;34:22–57.
  7. Boerth JM, Caley CF. Possible case of mania associated with ma-huang. Pharmacotherapy. 2003;23(3):380–383. [PubMed: 12627938]
  8. Boozer CN, Daly PA, Homel P, Solomon JL, Blanchard D, Nasser JA, Strauss R, Meredith T. Herbal ephedra/caffeine for weight loss: A 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Disord. 2002;26(5):593–604. [PubMed: 12032741]
  9. Brasfield K. Dietary supplement intake in the active duty enlisted population. US Army Med Dep J. 2004;(Oct-Dec):44–56.
  10. Charatan F. Ephedra supplement may have contributed to sportsman’s death. Br Med J. 2003;326(7387):464. [PMC free article: PMC1125365] [PubMed: 12609922]
  11. Chen C, Biller J, Willing SJ, Lopez AM. Ischemic stroke after using over the counter products containing ephedra. J Neurol Sci. 2004;217(1):55–60. [PubMed: 14675610]
  12. Chen-Scarabelli C, Hughes SE, Landon G, Rowley P, Allebban Z, Lawson N, Saravolatz L, Gardin J, Latchman D, Scarabelli TM. A case of fatal ephedra intake associated with lipofuscin accumulation, caspase activation and cleavage of myofibrillary proteins. Eur J Heart Fail. 2005;7(5):927–930. [PubMed: 16054866]
  13. Coffey CS, Steiner D, Baker BA, Allison DB. 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. 2004;28(11):1411–1419. [PubMed: 15356670]
  14. Deuster PA, Sridhar A, Becker WJ, Coll R, O’Brien KK, Bathalon G. Health assessment of U.S. Army Rangers. Mil Med. 2003;168(1):57–62. [PubMed: 12546248]
  15. Dhar R, Stout CW, Link MS, Homoud MK, Weinstock J, Estes NA III. Cardiovascular toxicities of performance-enhancing substances in sports. Mayo Clin Proc. 2005;80(10):1307–1315. [PubMed: 16212144]
  16. Goldberg LD, Elliot D, Kuehl K. Effect of caffeine and ephedrine ingestion on anaerobic exercise performance (Letter). Med Sci Sports Exerc. 2002;34(1):181–182. [PubMed: 11782665]
  17. Hackman RM, Havel PJ, Schwartz HJ, Rutledge JC, Watnik MR, Noceti EM, Stohs SJ, Stern JS, Keen CL. Multinutrient supplement containing ephedra and caffeine causes weight loss and improves metabolic risk factors in obese women: A randomized controlled trial. Int J Obes (Lond). 2006;30(10):1545–1556. [PubMed: 16552410]
  18. Haller C, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343(25):1833–1838. [PubMed: 11117974]
  19. Haller C, Meier KH, Olson KR. Seizures reported in association with use of dietary supplements. Clin Toxicol. 2005;1:23–30. [PubMed: 15732443]
  20. Hansten PD, Horn JR. The top 100 drug interactions: A guide to patient management. Edmonds, WA: H & H Publications; 2000.
  21. Jacobs I, Pasternak H, Bell DG. Effects of ephedrine, caffeine, and their combination on muscular endurance. Med Sci Sports Exerc. 2003;35(6):987–994. [PubMed: 12783047]
  22. Jacobs KM, Hirsch KA. Psychiatric complications of Ma-huang. Psychosomatics. 2000;41:58–62. [PubMed: 10665269]
  23. Jordan J, Shannon JR, Diedrich A, Black B, Robertson D, Biaggioni I. Water potentiates the pressor effect of ephedra alkaloids. Circulation. 2004;109(15):1823–1825. [PubMed: 15066944]
  24. Kalman D, Incledon T, Gaunaurd I, Schwartz H, Krieger D. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int J Obes Relat Metab Disord. 2002;26(10):1363–1366. [PubMed: 12355332]
  25. Keisler BD, Hosey RG. Ergogenic aids: An update on ephedra. Curr Sports Med Rep. 2005;4(4):231–235. [PubMed: 16004835]
  26. Libman RB, Menna BL, Gulati S. Case report: Consequences of ephedra use in an athlete. Lancet. 2005;366(Suppl 1):S22. [PubMed: 16360736]
  27. LoVecchio F, Sawyers B, Eckholdt PA. Transient ischemic attack associated with Metabolife 356 use. Am J Emerg Med. 2005;23(2):199–200. [PubMed: 15765346]
  28. Magkos F, Kavouras SA. Caffeine and ephedrine: Physiological, metabolic and performance-enhancing effects. Sports Med. 2004;34(13):871–889. [PubMed: 15487903]
  29. Maglione M, Miotto K, Iguchi M, Hilton L, Shekelle P. Psychiatric symptoms associated with ephedra use. Expert Opin Drug Saf. 2005;4(5):879–884. [PubMed: 16111450]
  30. Mahady GB, Fong HHS, Farnsworth NR. WHO monographs on selected medicinal plants. Vol. I. Geneva, Switzerland: World Health Organization; 1999. Herba Ephedrae.
  31. Mahady GB, Fong HHS, Farnsworth NR. Botanical dietary supplements: Quality, safety and efficacy. Lisse, The Netherlands: Swets and Zeilinger; 2001.
  32. Miller SC. Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements. Mil Med. 2004;169(2):87–93. [PubMed: 15040625]
  33. Moawad FJ, Hartzell JD, Biega TJ, Lettieri CJ. Transient blindness due to posterior reversible encephalopathy syndrome following ephedra overdose. South Med J. 2006;99(5):511–514. [PubMed: 16711314]
  34. Morgenstern LB, Viscoli CM, Kernan WN, Brass LM, Broderick JP, Feldmann E, Wilterdink JL, Brott T, Horwitz RI. Use of ephedra-containing products and risk for hemorrhagic stroke. Neurology. 2003;60(1):132–135. [PubMed: 12525737]
  35. Naik SD, Freudenberger RS. Ephedra-associated cardiomyopathy. Ann Pharmacother. 2004;38(3):400–403. [PubMed: 14742827]
  36. ODS (Office of Dietary Supplements). Ephedra and ephedrine alkaloids for weight loss and athletic performance. 2003. [accessed April 17, 2008]. http://ods​.od.nih.gov​/factsheets/ephedraandephedrine.asp
  37. Peters CM, O’Neil JO, Young JB, Bott-Silverman C. Is there an association between ephedra and heart failure? A case series. J Card Fail. 2005;11(1):9–11. [PubMed: 15704057]
  38. Rados C. Ephedra ban: No shortage of reasons. FDA Consum. 2004;38(2):6–7. [PubMed: 15101356]
  39. Rakovec P, Kozak M, Sebestjen M. Ventricular tachycardia induced by abuse of ephedrine in a young healthy woman. Wien Klin Wochenschr. 2006;118(17-18):558–561. [PubMed: 17009070]
  40. Schweinfurth J, Pribitkin E. Sudden hearing loss associated with ephedra use. Am J Health Syst Pharm. 2003;60(4):375–377. [PubMed: 12625221]
  41. Shekelle PG, Hardy ML, Morton SC, Maglione M, Mojica WA, Suttorp MJ, Rhodes SL, Jungvig L, Gagne J. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: A meta-analysis. JAMA. 2003;289(12):1537–1545. [PubMed: 12672771]
  42. Simsek S, Khazen A, Lansink PJ. Visual impairment and ephedra. Eur J Intern Med. 2006;17(2):147. [PubMed: 16490699]
  43. Stahl CE, Borlongan CV, Szerlip M, Szerlip H. No pain, no gain—Exercise-induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra. Med Sci Monit. 2006;12(9):CS81–CS84. [PubMed: 16940935]
  44. Tyler VE, Brady LR, Robbers JE. Pharmacognosy. Philadelphia, PA: Lea and Febiger; 1988.
  45. Verduin ML, Labbate LA. Psychosis and delirium following Metabolife use. Psychopharmacol Bull. 2002;36(3):42–45. [PubMed: 12473963]
  46. Vukovich MD, Schoorman R, Heilman C, Jacob P, Benowitz NL. Caffeine-herbal ephedra combination increases resting energy expenditure, heart rate and blood pressure. Clin Exp Pharmacol Physiol. 2005;32(1-2):47–53. [PubMed: 15730434]
  47. Walton R, Manos GH. Psychosis related to ephedra-containing herbal supplement use. South Med J. 2003;96(7):718–720. [PubMed: 12940331]

GARLIC

Background

Garlic6 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 commercially 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 Commission, 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 Chinese, 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 attributed 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) (European pharmacopoeia, 1996; Mahady et al., 1999; Sendl, 1995). The important chemical constituents of garlic bulbs are organosulfur compounds (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 processing 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 trials demonstrated a reduction in total cholesterol, with the most profound effect observed in garlic’s ability to reduce platelet aggregation. Mixed results have been obtained in the area of blood pressure and oxidative-stress reduction (Ackermann et al., 2001; Rahman and Lowe, 2006).

Garlic has been reported to reduce the growth of various antibiotic-resistant microorganisms and reduce the minimum inhibitory concentrations 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 postoperative bleeding, especially when used in combination with anticoagulants 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.

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 temperatures. 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 publications identified for garlic are shown in Table 4-6 on pages 230–237.

TABLE 4-6 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Garlic.

Table

TABLE 4-6 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Garlic.

References

  1. Ackermann RT, Mulrow CD, Ramirez G, Gardner CD, Morbidoni L, Lawrence VA. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med. 2001;161(6):813–824. [PubMed: 11268223]
  2. Ankri S, Mirelman D. Antimicrobial properties of allicin from garlic. Microbes Infect. 1999;1(2):125–129. [PubMed: 10594976]
  3. Cai Y, Wang R, Pei F, Liang BB. Antibacterial activity of allicin alone and in combination with beta-lactams against Staphylococcus spp. and Pseudomonas aerugi-nosa. J Antibiot (Tokyo). 2007;60(5):335–338. [PubMed: 17551215]
  4. Cutler RR, Wilson P. Antibacterial activity of a new, stable, aqueous extract of allicin against methicillin-resistant Staphylococcus aureus. Br J Biomed Sci. 2004;61(2):71–74. [PubMed: 15250668]
  5. European pharmacopoeia. 3rd ed. Strasbourg: Council of Europe; 1996.
  6. Hu Z, Yang XX, Ho PCL, Chan SY, Heng PWS, Chan E, Duan W, Koh HL, Zhou SF. Herb-drug interactions. Drugs. 2005;65(9):1239–1282. [PubMed: 15916450]
  7. Koch HP, Lawson LD. Garlic, the science and therapeutic application of Allium sativum L. and related species. Baltimore: Williams & Wilkins; 1996.
  8. Lawson L. HPLC analysis of allicin and other thiosulfinates in garlic clove homogenates. Planta Medica. 1991;57:263–270. [PubMed: 17226157]
  9. Ledezma E, Apitz-Castro R. Ajoene the main active compound of garlic (Allium sativum): A new antifungal agent. Rev Iberoam Micol. 2006;23(2):75–80. [PubMed: 16854181]
  10. Mahady GB, Fong HHS, Farnsworth NF. WHO monographs on selected medicinal plants. Vol. 1. Geneva, Switzerland: World Health Organization; 1999. Bulbus Allii sativi.
  11. Mahady GB, Fong HHS, Farnsworth NF. Botanical dietary supplements: Quality, safety and efficacy. Lisse, the Netherlands: Swets & Zeilinger; 2001.
  12. Martin KW, Ernst E. Herbal medicines for treatment of bacterial infections: A review of controlled clinical trials. J Antimicrob Chemother. 2003;51(2):241–246. [PubMed: 12562687]
  13. Milner J. Preclinical perspectives on garlic and cancer. J Nutr. 2006;136(3):827S–831S. [PubMed: 16484574]
  14. Pittler MH, Ernst E. Clinical effectiveness of garlic (Allium sativum). Mol Nutr Food Res. 2007;51:1382–1385. [PubMed: 17918163]
  15. Rahman K, Lowe GM. Garlic and cardiovascular disease: A critical review. J Nutr. 2006;136(3):736S–740S. [PubMed: 16484553]
  16. Reuter HD, Sendl A. Allium sativum and Allium ursinum: Chemistry, pharmacology, and medicinal applications. In: Wagner H, Farnsworth NR, editors. Economic and medicinal plants research. Vol. 6. London: Academic Press; 1994. pp. 55–113.
  17. Scientific Technical and Research Commission. African pharmacopoeia. Vol. 1. Lagos, Nigeria: Organization of African Unity; 1985.
  18. Sendl A. Allium sativum and Allium ursinum: Part 1. Chemistry, analysis, history, botany. Phytomedicine. 1995;4:323–339. [PubMed: 23196023]
  19. Sengupta A, Ghosh S, Bhattacharjee S. Allium vegetables in cancer prevention. Asian Pac J Cancer Prev. 2004;5(3):237–245. [PubMed: 15373701]
  20. Srivastava KC, Bordia A, Verma SK. Garlic (Allium sativum) for disease prevention. South African Journal of Science. 1995;91:68–77.
  21. Tsao S, Yin M. In vitro activity of garlic oil and four diallyl sulphides against antibiotic-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae. J Antimicrob Chemother. 2001;47(5):665–670. [PubMed: 11328781]
  22. Ziegler SJ, Sticher O. HPLC of S-alk(en)yl-l-cysteine derivatives in garlic including quantitative determination of (+)-S-allyl-l-cysteine sulfoxide (alliin. Planta Medica. 1989;55:372–378. [PubMed: 17262437]

GINKGO BILOBA

Background

Ginkgo biloba7 is a tall, deciduous tree, known to be extremely resistant 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, preparations 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 controlled 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 flavonoid 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 memory-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 claudication (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 volunteers 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 difference 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 performed 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 attention 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 administration 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 compared 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 enhancing 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). 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 animal 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 placebo (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 hyperinsulinemic patients with type 2 diabetes mellitus who were taking anti-hyperglycemic drugs. Ginkgo may increase the hepatic clearance of insulin and antihyperglycemic drugs.

TABLE 4-7 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ginkgo Biloba.

Table

TABLE 4-7 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ginkgo Biloba.

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 metabolism 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 effective. 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 disturbances 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 restriction, 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 publications identified for ginkgo are shown in Table 4-7 on pages 238–259.

References

  1. Abd-Ellah MF, Mariee AD. Ginkgo biloba leaf extract (EGb 761) diminishes adriamycin-induced hyperlipidaemic nephrotoxicity in rats: Association with nitric oxide production. Biotechnol Appl Biochem. 2007;46(Pt 1):35–40. [PubMed: 16848766]
  2. Bent S, Goldberg H, Padula A, Avins AL. Spontaneous bleeding associated with Ginkgo biloba: A case report and systematic review of the literature. J Gen Intern Med. 2005;20(7):657–661. [PMC free article: PMC1490168] [PubMed: 16050865]
  3. Betz J, Costello R. Studies on natural products. Arch Intern Med. 2006;166(3):370–371. [PubMed: 16476883]
  4. Birks J, Grimley J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2007;(2):CD003120. [PubMed: 17443523]
  5. Birks J, Grimley EV, Van M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2002;2(4):CD003120. [PubMed: 12519586]
  6. Burns NR, Bryan J, Nettelbeck T. Ginkgo biloba: No robust effect on cognitive abilities or mood in healthy young or older adults. Hum Psychopharmacol. 2006;21(1):27–37. [PubMed: 16329161]
  7. Carlson JJ, Farquhar JW, DiNucci E, Ausserer L, Zehnder J, Miller D, Berra K, Hagerty L, Haskell WL. 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. 2007;107(3):422–432. [PubMed: 17324660]
  8. Chow T, Browne V, Heileson HL, Wallace D, Anholm J, Green SM. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: A randomized, placebo-controlled trial. Arch Intern Med. 2005;165(3):296–301. [PubMed: 15710792]
  9. Cieza A, Maier P, Poppel E. Effects of Ginkgo biloba on mental functioning in healthy volunteers. Arch Med Res. 2003;34(5):373–381. [PubMed: 14602503]
  10. Elsabagh S, Hartley DE, Ali O, Williamson EM, File SE. Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers. Psychopharmacology (Berl). 2005;179(2):437–446. [PubMed: 15739076]
  11. Gertsch JH, Seto TB, Mor J, Onopa J. Ginkgo biloba for the prevention of severe acute mountain sickness (AMS) starting one day before rapid ascent. High Alt Med Biol. 2002;3(1):29–37. [PubMed: 12006162]
  12. Gertsch JH, Basnyat B, Johnson EW, Onopa J, Holck PS. 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. 2004;328(7443):797–802. [PMC free article: PMC383373] [PubMed: 15070635]
  13. Gulec M, Iraz M, Yilmaz HR, Ozyurt H, Temel I. The effects of Ginkgo biloba extract on tissue adenosine deaminase, xanthine oxidase, myeloperoxidase, malondialdehyde, and nitric oxide in cisplatin-induced nephrotoxicity. Toxicol Ind Health. 2006;22(3):125–130. [PubMed: 16716042]
  14. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. 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. 2005;22(6):525–539. [PMC free article: PMC1858666] [PubMed: 15974642]
  15. Harputluoglu MM, Demirel U, Ciralik H, Temel I, Firat S, Ara C, Aladag M, Karincaoglu M, Hilmioglu F. Protective effects of Ginkgo biloba on thioacetamide-induced fulminant hepatic failure in rats. Hum Exp Toxicol. 2006;25(12):705–713. [PubMed: 17286148]
  16. Hilton M, Stuart E. Ginkgo biloba for tinnitus. Cochrane Database Syst Rev. 2004;(2):CD003852. [PubMed: 15106224]
  17. Hu ZP, Yang XX, Lui PC, Chan SY, Heng PW, Chan E, Duan W, Koh HL, Zhou SF. Herb-drug interactions: A literature review. Drugs. 2005;65(9):1239–1282. [PubMed: 15916450]
  18. Huh H, Staba EJ. The botany and chemistry of Ginkgo biloba L. J Herbs, Spices Med Plants. 1992;1:91–124.
  19. Kennedy DO, Scholey AB, Wesnes KA. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology (Berl). 2000;151(4):416–423. [PubMed: 11026748]
  20. Liu J. The use of Ginkgo biloba extract in acute ischemic stroke. Explore (NY). 2006;2(3):262–263. [PubMed: 16781654]
  21. Mahady GB. Ginkgo biloba: A review of quality, safety and efficacy. Nutr Clin Care. 2001;4(3):140–147.
  22. Mahady GB. Ginkgo biloba for the prevention and treatment of cardiovascular disease: A review of the literature. J Cardiovasc Nurs. 2002;16(4):21–32. [PubMed: 12597260]
  23. Mahady GB, Fong HHS, Farnsworth NR. WHO Monographs on selected medicinal plants. Vol 1. Geneva, Switzerland: World Health Organization; 1999. Folium Ginkgo.
  24. Major RT. The Ginkgo, the most ancient living tree. Science. 1967;157(3794):1270–1273. [PubMed: 5341600]
  25. Mattes RD, Pawlik MK. Effects of Ginkgo biloba on alertness and chemosensory function in healthy adults. Hum Psychopharmacol. 2004;19(2):81–90. [PubMed: 14994317]
  26. Mix JA Jr, Crews WD. A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: Neuropsychological findings. Hum Psychopharmacol. 2002;17(6):267–277. [PubMed: 12404671]
  27. Naik SR, Panda VS. Antioxidant and hepatoprotective effects of Ginkgo biloba phytosomes in carbon tetrachloride-induced liver injury in rodents. Liver Int. 2007;27(3):393–399. [PubMed: 17355462]
  28. Rodriguez M, Ringstad L, Schafer P, Just S, Hofer HW, Malmsten M, Siegel G. Reduction of atherosclerotic nanoplaque formation and size by Ginkgo biloba (EGb 761) in cardiovascular high-risk patients. Atherosclerosis. 2007;192(2):438–444. [PubMed: 17397850]
  29. Roncin JP, Schwartz F, D’Arbigny P. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure. Aviat Space Environ Med. 1996;67(5):445–452. [PubMed: 8725471]
  30. Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: A randomized controlled trial. JAMA. 2002;288(7):835–840. [PubMed: 12186600]
  31. Stough C, Clarke J, Lloyd J, Nathan PJ. Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol. 2001;4(2):131–134. [PubMed: 11466162]
  32. Subhan Z, Hindmarch I. The psychopharmacological effects of Ginkgo biloba extract in normal healthy volunteers. Int J Clin Pharmacol Res. 1984;4(2):89–93. [PubMed: 6469442]
  33. Van Beek TA, Bombardelli E, Morazzoni P, Peterlongo F. Ginkgo biloba L. Fitoterapia. 1998;69(3):195–244.
  34. Warot D, Lacomblez L, Danjou P, Weiller E, Payan C, Puech AJ. Comparative effects of Ginkgo biloba extracts on psychomotor performances and memory in healthy subjects. Therapie. 1991;46(1):33–36. [PubMed: 2020921]
  35. Welt K, Weiss J, Martin R, Hermsdorf T, Drews S, Fitzl G. Ginkgo biloba extract protects rat kidney from diabetic and hypoxic damage. Phytomedicine. 2007;14(2-3):196–203. [PubMed: 16781853]
  36. Wolf HR. 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. 2006;7(3):163–172. [PubMed: 16752942]
  37. Yuan G, Gong Z, Li J, Li X. Ginkgo biloba extract protects against alcohol-induced liver injury in rats. Phytother Res. 2007;21(3):234–238. [PubMed: 17154234]
  38. Zeng X, Liu M, Yang Y, Li Y, Asplund K. Ginkgo biloba for acute ischaemic stroke. Cochrane Database Syst Rev. 2005;(4):CD003691. [PubMed: 16235335]
  39. Zhong ZM, Yu L, Weng ZY, Hao ZH, Zhang L, Zhang YX, Dong WQ. Therapeutic effect of Ginkgo biloba leaf extract on hypercholestrolemia in children with nephrotic syndrome. Nan Fang Yi Ke Da Xue Xue Bao. 2007;27(5):682–684. [PubMed: 17545089]
  40. Zhou JB, Yang XK, Ye QF, Ming YZ, Xia ZJ. 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. 2007;32(1):54–58. [PubMed: 17344587]

GINSENG

Background

Some of the most popular and well-known dietary supplements come from a group of plants known generically as ginseng.8 The primary commercial 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 commercial 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 certainly 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 prepared 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).

Putative Benefits

While the genus name Panax derives from the Greek word panacea, meaning “cure-all,” its application according to traditional Chinese medicine 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 restore 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 America. The U.S. Food and Drug Administration currently regards ginseng 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, supramaximal 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 effects 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 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 postdose 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 trials, 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 improvements 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 improved the Index of Memory Quality (Wesnes et al., 2000). Improvements averaging 7.5 percent were seen in a number of aspects of memory, including 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).

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 ginseng 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 ingestion 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 uncontrolled 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 ginseng 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 subjects 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 warfarin, 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 aggregation 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.

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 volunteers 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, decreased pain from ischemia, and protection from local tissue damage.

Relevant data and conclusions on efficacy and safety reviews and publications identified for ginseng are shown in Table 4-8 on pages 260–269.

TABLE 4-8 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ginseng.

Table

TABLE 4-8 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ginseng.

References

  1. Cardinal BJ, Engels HJ. 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. 2001;101(6):655–660. [PubMed: 11424544]
  2. Carlson AW. Ginseng: America’s botanical drug connection to the Orient. Econ Bot. 1986;40(2):233–249.
  3. Cheng TO. Ginseng and other herbal medicines that interact with warfarin. Int J Cardiol. 2005;104(2):227. [PubMed: 16168817]
  4. Coon JT, Ernst E. Panax ginseng: A systematic review of adverse effects and drug interactions. Drug Saf. 2002;25(5):323–344. [PubMed: 12020172]
  5. Cui JF. Identification and quantification of ginsenosides in various commercial ginseng preparations. Eur J Pharm Sci. 1995;3(2):77–85.
  6. Engels HJ, Kolokouri I, Cieslak TJ III, Wirth JC. Effects of ginseng supplementation on supramaximal exercise performance and short-term recovery. J Strength Cond Res. 2001;15(3):290–295. [PubMed: 11710653]
  7. Engels HJ, Fahlman MM, Wirth JC. Effects of ginseng on secretory IgA, performance, and recovery from interval exercise. Med Sci Sports Exerc. 2003;35(4):690–696. [PubMed: 12673155]
  8. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. 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. 2005;22(6):525–539. [PMC free article: PMC1858666] [PubMed: 15974642]
  9. Han SK, Song JY, Yun YS, Yi SY. Ginsan improved Th1 immune response inhibited by gamma radiation. Arch Pharm Res. 2005;28(3):343–350. [PubMed: 15832824]
  10. Hu SY. The genus Panax (ginseng) in Chinese medicine. Econ Bot. 1976;30(1):11–28.
  11. Hu Z, Yang X, Ho PC, Chan SY, Heng PW, Chan E, Duan W, Koh HL, Zhou S. Herb-drug interactions: A literature review. Drugs. 2005;65(9):1239–1282. [PubMed: 15916450]
  12. Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. Effect of St. John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2004;57(5):592–599. [PMC free article: PMC1884493] [PubMed: 15089812]
  13. Kaneko H, Nakanishi K. 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. 2004;95(2):158–162. [PubMed: 15215639]
  14. Kennedy DO, Scholey AB, Wesnes KA. Differential, dose dependent changes in cognitive performance following acute administration of a Ginkgo biloba/Panax ginseng combination to healthy young volunteers. Nutr Neurosci. 2001;4(5):399–412. [PubMed: 11842916]
  15. Kennedy DO, Scholey AB, Wesnes KA. 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. 2002;75(5):739–751. [PubMed: 12020739]
  16. Kim HJ, Kim MH, Byon YY, Park JW, Jee Y, Joo HG. Radioprotective effects of an acidic polysaccharide of Panax ginseng on bone marrow cells. J Vet Sci. 2007;8(1):39–44. [PMC free article: PMC2872695] [PubMed: 17322772]
  17. Lee JH, Han Y. Ginsenoside Rg1 helps mice resist to disseminated candidiasis by Th1 type differentiation of CD4+ T cell. Int Immunopharmacol. 2006;6(9):1424–1430. [PubMed: 16846836]
  18. Lieberman HR. The effects of ginseng, ephedrine, and caffeine on cognitive performance, mood and energy. Nutr Rev. 2001;59(4):91–102. [PubMed: 11368507]
  19. Mahady GB, Fong HHS, Farnsworth NR. WHO monographs of selected medicinal plants. Vol. 1. Geneva, Switzerland: World Health Organization; 1999.
  20. Mahady GB, Fong HHS, Farnsworth NR. Botanical dietary supplements: Quality, safety and efficacy. Lisse, the Netherlands: Swets and Zeilinger; 2001.
  21. Quan FS, Compans RW, Cho YK, Kang SM. Ginseng and salviae herbs play a role as immune activators and modulate immune responses during influenza virus infection. Vaccine. 2007;25(2):272–282. [PubMed: 16945454]
  22. Reay JL, Kennedy DO, Scholey AB. Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. J Psychopharmacol. 2005;19(4):357–365. [PubMed: 15982990]
  23. Reay JL, Kennedy DO, Scholey AB. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained “mentally demanding” tasks. J Psychopharmacol. 2006;20(6):771–781. [PubMed: 16401645]
  24. Rosado MF. Thrombosis of a prosthetic aortic valve disclosing a hazardous interaction between warfarin and a commercial ginseng product. Cardiology. 2003;99(2):111. [PubMed: 12711887]
  25. Scholey AB, Kennedy DO. Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: Differential interactions with cognitive demand. Hum Psychopharmacol. 2002;17(1):35–44. [PubMed: 12404705]
  26. Shibata S, Tanaka O, Shoji J, Saito H. Chemistry and pharmacology of panax. In: Wagner H, Farnsworth NR, editors. Economic and medicinal plants research. Vol. 1. London-San Diego-New York: Academic Press; 1985. pp. 217–284.
  27. Song Z, Moser C, Wu H, Faber V, Kharazmi A, Hoiby N. Cytokine modulating effect of ginseng treatment in a mouse model of Pseudomonas aeruginosa lung infection. J Cyst Fibros. 2003;2(3):112–119. [PubMed: 15463859]
  28. Sonnenborn U, Proppert Y. Ginseng (Panax ginseng C. A. Meyer). Brit J Phytotherapy. 1991;2:3–14.
  29. Wesnes KA, Ward T, McGinty A, Petrini O. The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers. Psychopharm (Berl). 2000;152(4):353–361. [PubMed: 11140327]
  30. Yuan CS, Wei G, Dey L, Karrison T, Nahlik L, Maleckar S, Kasza K, Ang-Lee M, Moss J. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: A randomized, controlled trial. Ann Intern Med. 2004;141(1):23–27. [PubMed: 15238367]

β-HYDROXY-β-METHYLBUTYRATE (HMB)

Background

β-Hydroxy-β-methylbutyrate9 (HMB) is a metabolic derivative of the amino acid leucine. The first step of catabolism of leucine is transamination 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 HMB during resistance training was 0.28 percent per week greater than in those consuming a placebo (Nissen and Sharp, 2003). Some studies support 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 athletes is less often observed than for individuals initiating a resistance training 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 periods 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 virtually 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. However, 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.

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 potentially 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 publications identified for HMB are shown in Table 4-9 on pages 270–277.

TABLE 4-9 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for HMB.

Table

TABLE 4-9 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for HMB.

References

  1. Alon T, Bagchi D, Preuss HG. Supplementing with beta-hydroxy-beta-methylbutyrate (HMB) to build and maintain muscle mass: A review. Res Comm Mol Path Pharma. 2002;111(1-4):139–152. [PubMed: 14632320]
  2. Baxter JH, Carlos JL, Thurmond J, Rehani RN, Bultman J, Frost D. Dietary toxicity of calcium β-hydroxy-β-methyl butyrate (CaHMB). Food Chem Toxic. 2005;43(12):1731–1741. [PubMed: 16006030]
  3. Bloomer RJ. The role of nutritional supplements in the prevention and treatment of resistance exercise-induced skeletal muscle injury. Sports Med. 2007;37(6):519–532. [PubMed: 17503877]
  4. Bohn AM, Betts S, Schwenk TL. Creatine and other nonsteroidal strength-enhancing aids. Curr Sports Med Rep. 2002;1(4):239–245. [PubMed: 12831701]
  5. Crowe MJ, O’Connor DM, Lukins JE. 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. 2003;13(2):184–197. [PubMed: 12945829]
  6. Flakoll P, Sharp R, Baier S, Levenhagen D, Carr C, Nissen S. Effect of beta-hydroxy-beta-methylbutyrate, arginine, and lysine supplementation on strength, functionality, body composition, and protein metabolism in elderly women. Nutrition. 2004;20(5):445–451. [PubMed: 15105032]
  7. Hoffman JR, Cooper J, Wendell M, Im J, Kang J. Effects of beta-hydroxy-beta-methylbutyrate on power performance and indices of muscle damage and stress during high-intensity training. J Strength Cond Res. 2004;18(4):747–752. [PubMed: 15574078]
  8. May PE, Barber A, D’Olimpio JT, Hourihane A, Abumrad NN. Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg. 2002;183(4):471–479. [PubMed: 11975938]
  9. Nissen S, Sharp RL. Effect of dietary supplements on lean mass and strength gains with resistance exercise: A meta-analysis. J Appl Physiol. 2003;94(2):651–659. [PubMed: 12433852]
  10. Nissen S, Sharp RL, Panton L, Vukovich M, Trappe S, Fuller JC. β-Hydroxy-β-Methylbutyrate (HMB) supplementation in humans is safe and may decrease cardiovascular risk factors. J Nutr. 2000;130(8):1937–1945. [PubMed: 10917905]
  11. Palisin T, Stacy JJ. β-Hydroxy-β-Methylbutyrate and its use in athletics. Curr Sports Med Rep. 2005;4(4):220–223. [PubMed: 16004832]
  12. Ransone J, Neighbors K, Lefavi R, Chromiak J. The effect of beta-hydroxy beta-methylbutyrate on muscular strength and body composition in collegiate football players. J Strength Cond Res. 2003;17(1):34–39. [PubMed: 12580653]
  13. Rathmacher JA, Nissen S, Panton L, Clark RH, May PE, Barber AE, D’Olimpio JT, Abumrad NN. Supplementation with a combination of beta-hydroxy-beta-methylbutyrate (HMB), arginine, and glutamine is safe and could improve hematological parameters. J Parenter Enteral Nutr. 2004;28(2):65–75. [PubMed: 15080599]
  14. Slater GJ, Jenkins D. β-Hydroxy-β-Methylbutyrate (HMB) supplementation and the promotion of muscle growth and strength. Sports Med. 2000;30(2):105–116. [PubMed: 10966150]
  15. Smith HJ, Wyke SM, Trisdale MJ. Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by β-Hydroxy-β-Methylbutyrate. Cancer Res. 2004;64(23):8731–8735. [PubMed: 15574784]
  16. van Someren KA, Edwards AJ, Howatson G. 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. 2005;15(4):413–424. [PubMed: 16286672]

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 melatonin 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 “biological 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 supplement to the National Health Interview Survey, 5.2 percent reported using melatonin. Of those users, 27.5 percent reported insomnia as a reason for taking the supplement (Bliwise and Ansari, 2007). Women were five times 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 circadian 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 exogenous 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).

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 prescription 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 recommended 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 temperature, 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 unwanted 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 hypnotic substances. Of the 109 medications most frequently prescribed for military personnel, 13 have sedating side effects (e.g., hypnotics, anxiolytics, 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 thermoregulatory 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 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 publications identified for melatonin are shown in Table 4-10 on pages 278–281.

TABLE 4-10 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Melatonin.

Table

TABLE 4-10 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Melatonin.

References

  1. Arendt J, Skene DJ. Melatonin as a chronobiotic. Sleep Med Rev. 2005;9(1):25–39. [PubMed: 15649736]
  2. Bliwise DL, Ansari FP. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. Sleep. 2007;30(7):881–884. [PMC free article: PMC1978376] [PubMed: 17682659]
  3. Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-Shushan A, Ford I. Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev. 2005;9(1):41–50. [PubMed: 15649737]
  4. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S. The efficacy and safety of exogenous melatonin for primary sleep disorders—A meta-analysis. J Gen Intern Med. 2005;20(12):1151–1158. [PMC free article: PMC1490287] [PubMed: 16423108]
  5. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep-restriction: Meta-analysis. BMJ. 2006;332(7538):385–393. [PMC free article: PMC1370968] [PubMed: 16473858]
  6. Katz G, Durst R, Knobler HY. Exogeneous melatonin, jet lag, and psychosis: Preliminary case results. J Clin Psychopharmacol. 2001;21(3):349–351. [PubMed: 11386504]
  7. Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human circadian rhythms according to a phase–response curve. Chronobiol Int. 1992;9(5):380–392. [PubMed: 1394610]
  8. Morin AK, Jarvis CI, Lynch AM. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy. 2007;27(1):89–110. [PubMed: 17192164]
  9. Turek FW, Gillette MU. Melatonin, sleep and circadian rhythms: Rationale for development of specific melatonin agonists. Sleep Med. 2004;5(6):523–532. [PubMed: 15511698]
  10. Wagner J, Wagner ML, Hening WA. Beyond benzodiazepines: Alternative pharmacologic agents for the treatment of insomnia. Ann Pharmacother. 1998;32(6):680–686. [PubMed: 9640488]
  11. Weekley LB. Effects of melatonin on pulmonary and coronary vessels are exerted through perivascular nerves. Clin Auton Res. 1993;3(1):45–47. [PubMed: 7682878]

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 flavonols, 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 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 containing quercetin will maintain blood concentrations of this flavonol (Ross and Kasum, 2002). In persons consuming their habitual diets, blood concentrations 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 vegetables, 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 activity 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, antidiarrheal, 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 concluded 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 reduction 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 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 antioxidant would enhance the performance of elite male cyclists in 30-km time trials. The supplement contained a variety of nutrient and nonnutrient antioxidants, 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 conditions 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 International 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 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 perspective, 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 berries, 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 below 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 studies 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 administration 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 currently 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).

Relevant data and conclusions on efficacy and safety reviews and publications identified for quercetin are shown in Table 4-11 on pages 282–283.

TABLE 4-11 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Quercetin.

Table

TABLE 4-11 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Quercetin.

References

  1. Davis JM, Murphy EA, Carmichael MD, Davis JB, Gangemi JD, Mayer EP. Effect of quercetin feedings on tissue mitochondrial enzymes and performance in mice. Am Coll Sports Med. 2007
  2. de Boer CVJ, van der Woude H, Dihal AA, Arts ICW, Wolffram S, Alink GM, Rietjens IMCM, Kiejer J, Hollman PCH. Tissue distribution of quercetin in rats and pigs. J Nutr. 2005;135(7):1718–1725. [PubMed: 15987855]
  3. Burrowes J, Erdman JW Jr, Arab L, Beecher G, Dwyer JT, Folts J, Harnly J, Hollman P, Keen CL, Mazza G, Messina M, Scalbert A, Vita J, Williamson G, Burrowes J. Flavonoids and heart health: Proceedings of the ILSI North America flavonoids workshop, May 31–June 1, 2005. Washington, DC: J Nutr. 2007;137(3):718S–737S. [PubMed: 17311968]
  4. Erlund I. Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutr Res. 2004;24(10):851–874.
  5. Ferry DR, Smith A, Malkhandi J, Fyfe DW, de Takats PG, Anderson D, Baker J, Kerr DJ. Phase I clinical trial of the flavonoid quercetin: Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. 1996;2(4):659–668. [PubMed: 9816216]
  6. Formica JV, Regelson W. Review of the biology of quercetin and related bioflavonoids. Food Chem Toxicol. 1995;33(12):1061–1080. [PubMed: 8847003]
  7. IARC (International Agency for Research on Cancer). IARC monographs on the evaluation of carcinogenic risks to humans. IARC. 1999;73:497–515. [PubMed: 10804967]
  8. Lotito SB, Frei B. Dietary flavonoids attenuate tumor necrosis factor α-induced adhesion molecule expression in human aortic endothelial cells. J Biol Chem. 2006;281(48):37102–37110. [PubMed: 16987811]
  9. MacRae HSH, Mefferd KM. Dietary antioxidant supplementation combined with quercetin improves cycling time trial performance. Int J Sport Nutr Exerc Metab. 2006;16(4):405–419. [PubMed: 17136942]
  10. Nieman DC, Henson DA, Gross SJ, Jenkins DP, Davis JM, Murphy EA, Carmichael MD, Dumke CL, Utter AC, Mcanulty SR, Mcanulty LS, Mayer EP. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc. 2007;39(9):1561–1569. [PubMed: 17805089]
  11. Okamoto T. Safety of quercetin for clinical application (review). Int J Molec Med. 2005;16(2):275–278. [PubMed: 16012761]
  12. Ross JA, Kasum CM. Dietary flavonoids: Bioavailability, metabolic effects and safety. Annu Rev Nutr. 2002;22:19–34. [PubMed: 12055336]
  13. van der Woude H, Alink GM, Rietjens IMCM. The definition of hormesis and its implications for in vitro to in vivo extrapolation and risk assessment. Crit Rev Toxicol. 2005;35(6):603–607. [PubMed: 16422398]
  14. Watjen W, Michels G, Steffan B, Niering P, Chovolou Y, Kampkooter A, Tran-Thi QH, Proksch P, Kahl R. Low concentrations of flavonoids are protective in rat H411E cells whereas high concentrations cause DNA damage and apoptosis. J Nutr. 2005;135(3):525–531. [PubMed: 15735088]

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 carbohydrate 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 (approximately 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 containing 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 carbohydrate (glucose polymer) alone (Rauch et al., 1999). Thus, if carbohydrate and fluids are the limiting factor for physical performance, consumption of 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 impaired 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 using 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 environment 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 various 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.

TABLE 4-12 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Sports Bars.

Table

TABLE 4-12 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Sports Bars.

References

  1. Burke LM, Wood C, Pyne DB, Telford DR, Saunders PU. Effect of carbohydrate intake on half-marathon performance of well-trained runners. Int J Sport Nutr Exerc Metab. 2005;15(6):573–589. [PubMed: 16521844]
  2. Ebert TR, Martin DT, Bullock N, Mujika I, Quod MJ, Farthing LA, Burke LM, Withers RT. Influence of hydration status on thermoregulation and cycling hill climbing. Med Sci Sports Exerc. 2007;39(2):323–329. [PubMed: 17277597]
  3. IOM (Institute of Medicine). Nutrient composition of rations for short-term, high-intensity combat operations. Washington, DC: The National Academies Press; 2005.
  4. Rauch HG, Hawley JA, Woodey M, Noakes TD, Dennis SC. Effects of ingesting a sports bar versus glucose polymer on substrate utilisation and ultra-endurance performance. Int J Sports Med. 1999;20(4):252–257. [PubMed: 10376482]

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 combinations 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 enhance 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). 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 typically ingested than if water alone is provided.

There is some evidence that consumption of carbohydrate during exercise 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 containing 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 carbohydrate, other than provision of extra calories to those whose physical 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 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 publications identified for sports drinks are shown in Table 4-13 on pages 286–287.

TABLE 4-13 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Sports Drinks.

Table

TABLE 4-13 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Sports Drinks.

References

  1. Barr SI, Costill DL, Fink W. Fluid replacement during prolonged exercise: Effects of water, saline, or no fluid. Med Sci Sports Exerc. 1991;23:811–817. [PubMed: 1921673]
  2. Craig SC. Hyponatremia associated with heat stress and excessive water consumption: The impact of education and a new Army fluid replacement policy. MSMR. 1999;5:1–9.
  3. Gardner JW. Death by water intoxication. Military Med. 2002;5:432–434. [PubMed: 12053855]
  4. Gibala M. Protein metabolism and endurance exercise. Sports Med. 2007;37(4-5):337–340. [PubMed: 17465602]
  5. Jeukendrup A. Carbohydrate intake during exercise and performance. Nutrition. 2004;20(7-8):669–677. [PubMed: 15212750]
  6. Koopman R, Saris WH, Wagenmakers AJ, van Loon LJ. Nutritional interventions to promote post-exercise muscle protein synthesis. Sports Med. 2007;37(10):895–906. [PubMed: 17887813]
  7. Maughan R, Murray R. Sports drinks: Basic science and practical aspects. Boca Raton, FL: CRC Press; 2001.
  8. Montain SJ, Sawka MN, Wenger CB. Hyponatremia associated with exercise: Risk factors and pathogenesis. Exerc Sports Sci Rev. 2001;29(3):113–117. [PubMed: 11474958]
  9. Montain SJ, Cheuvront SN, Sawka MN. Exercise associated hyponatremia: Quantitative analysis to understand the etiology. Brit J Sports Med. 2006;40:98–105. [PMC free article: PMC2492017] [PubMed: 16431994]
  10. Nieman DC. Marathon training and immune function. Sports Med. 2007;37(4-5):412–415. [PubMed: 17465622]
  11. Winnick JJ, Davis JM, Welsh RS, Carmichael MD, Murphy EA, Blackmon JA. Carbohydrate feedings during team sport exercise preserve physical and CNS function. Med Sci Sports Exerc. 2005;37(2):306–315. [PubMed: 15692328]

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 neurotransmitters. 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 performance 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 environmental 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 central nervous system. It has been further suggested that increasing the synthesis of these neurotransmitters could ameliorate stress-induced deficits in mental functioning.

Putative Benefits

One way to increase levels of dopamine, epinephrine, and norepinephrine is to provide more of their metabolic precursor, tyrosine. Indeed, research using young military and nonmilitary personnel of normal weight 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 deprivation (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 accompany 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 ranging between 50 and 300 mg/kg body weight. The majority of these studies have used healthy, young military personnel of normal weight as participants. 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 personnel 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 deprivation. 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 publications identified for tyrosine are shown in Table 4-14 on pages 288–293.

TABLE 4-14 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Tyrosine.

Table

TABLE 4-14 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Tyrosine.

References

  1. Ahlers ST, Thomas JR, Schrot J, Shurtleff D. Tyrosine and glucose modulation of cognitive deficits resulting from cold stress. In: Marriott BM, editor. Food components to enhance performance. Washington, DC: National Academy Press; 1994. pp. 301–320.
  2. Banderet LE, Lieberman HR. Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans. Brain Res Bull. 1989;22(4):759–762. [PubMed: 2736402]
  3. Chinevere TD, Sawyer RD, Creer AR, Conlee RK, Parcell AC. Effects of L-tyrosine and carbohydrate ingestion on endurance exercise performance. J Appl Physiol. 2002;93(5):1590–1597. [PubMed: 12381742]
  4. Deijen JB, Orlebeke JF. Effect of tyrosine on cognitive function and blood pressure under stress. Brain Res Bull. 1994;33(3):319–323. [PubMed: 8293316]
  5. Deijen JB, Wientjes CJE, Vullinghs HFM, Cloin PA, Langefeld JJ. Tyrosine improves cognitive performance and reduces blood pressure in cadets after one week of a combat training course. Brain Res Bull. 1999;48(2):203–209. [PubMed: 10230711]
  6. Magill RA, Waters WF, Bray GA, Volaufova J, Smith SR, Lieberman HR, McNevin N, Ryan DH. Effects of tyrosine, phentermine, caffeine, D-amphetamine, and placebo on cognitive and motor performance deficits during sleep deprivation. Nutr Neurosci. 2003;6(4):237–246. [PubMed: 12887140]
  7. Mahoney CR, Castellani J, Kramer FM, Young A, Lieberman HR. Tyrosine supplementation mitigates working memory decrements during cold exposure. Physiol Behav. 2007;92(4):575–582. [PubMed: 17585971]
  8. Neri DF, Wiegmann D, Stanny RR, Shappell SA, McCardie A, McKay DL. The effects of tyrosine on cognitive performance during extended wakefulness. Aviat Space Environ Med. 1995;66(4):313–319. [PubMed: 7794222]
  9. O’Brien C, Mahoney C, Tharion WJ, Sils IV, Castellani JW. Dietary tyrosine benefits cognitive and psychomotor performance during body cooling. Physiol Behav. 2007;90(2-3):301–307. [PubMed: 17078981]
  10. Shurtleff D, Thomas JR, Schrot J, Kowalski K, Hardford R. Tyrosine reverses a cold-induced working memory deficit in humans. Pharmacol Biochem Behav. 1994;47(4):935–942. [PubMed: 8029265]
  11. Thomas JR, Lockwood PA, Sing A, Deuster PA. Tyrosine improves working memory in a multitasking environment. Pharmacol Biochem Behav. 1999;64(3):495–500. [PubMed: 10548261]
  12. Wiegmann DL, Neri DF, Stanny RR, Shappell SA, McCardie AH, McKay DL. Behavioral effects of tyrosine during sustained wakefulness. Pensacola, FL: Naval Aerospace Medical Research Laboratory; 1993.

VALERIAN

Background

Valerian15 is an herbal product made from the roots of the plant Valeriana officinalis that has been used for hundreds of years as a mild hypnotic. Over 150 individual compounds can be found in valerian, and 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) concentrations in the synaptic cleft, but this was complicated by the presence 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 supplement to the National Healthy Interview Survey, 5.9 percent reported using valerian. 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 awakenings, 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) recordings 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 randomized 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 differences 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 distributors use the level of valerenic acid in their product for standardization (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 trials (Stevinson and Ernst, 2000), valerian is not recommended for subjects under 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 publications identified for valerian are shown in Table 4-15 on pages 294–295.

TABLE 4-15 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Valerian.

Table

TABLE 4-15 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Valerian.

References

  1. Beaubrun G, Gray GE. A review of herbal medicines for psychiatric disorders. Psychiatr Serv. 2000;51(9):1130–1134. [PubMed: 10970915]
  2. Bent S, Padula A, Moore D, Patterson M, Mehling W. Valerian for sleep: A systematic review and meta-analysis. Am J Med. 2006;119(12):1005–1012. [PMC free article: PMC4394901] [PubMed: 17145239]
  3. Bliwise DL, Ansari FP. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. Sleep. 2007;30(7):881–884. [PMC free article: PMC1978376] [PubMed: 17682659]
  4. Diaper A, Hindmarch I. 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. 2004;18(10):831–836. [PubMed: 15551388]
  5. Donath F, Quispe S, Diefenbach K, Maurer A, Fietze I, Roots I. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry. 2000;33(2):47–53. [PubMed: 10761819]
  6. Gyllenhaal C, Merritt SL, Peterson SD, Block KI, Gochenour T. Efficacy and safety of herbal stimulants and sedatives in sleep disorders. Sleep Med Rev. 2000;4(3):229–251. [PubMed: 12531167]
  7. Hallam KT, Olver JS, McGrath C, Norman TR. Comparative cognitive and psychomotor effects of single doses of Valeriana officianalis and triazolam in healthy volunteers. Hum Psychopharmacol. 2003;18(8):619–625. [PubMed: 14696021]
  8. Hobbs C. Valerian: A literature review. HerbalGram. 1989;21:19–34.
  9. Holzl J, Godau P. Receptor binding studies with Valeriana officinalis on the benzodiazepine receptor. Planta Medica. 1989;55:642.
  10. Houghton PJ. The scientific basis for the reputed activity of valerian. J Pharm Pharmacol. 1999;51(5):505–512. [PubMed: 10411208]
  11. Leathwood PD, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L) improves sleep quality in man. Pharmacol Biochem Behav. 1982;17(1):65–71. [PubMed: 7122669]
  12. MacGregor FB, Abernathy VE, Dahabra S, Cobden I, Hayes PC. Hepato-toxicity of herbal remedies. Br Med J. 1989;299(6708):1156–1157. [PMC free article: PMC1838039] [PubMed: 2513032]
  13. Morin AK, Jarvis CI, Lynch AM. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy. 2007;27(1):89–110. [PubMed: 17192164]
  14. Santos M, Ferreira F, Cunha AT, Carvalho AP, Macedo T. An aqueous extract of valerian influences the transport of GABA in synaptosomes. Planta Medica. 1994;60(3):278–279. [PubMed: 8073095]
  15. Stevinson C, Ernst E. Valerian for insomnia: A systematic review of randomized clinical trials. Sleep Med. 2000;1(2):91–99. [PubMed: 10767649]
  16. Tortarolo M, Braun R, Hübner GE, Maurer HR. In vitro effects of epoxide-bearing valepotriates on mouse early hematopoietic progenitor cells and human T-lymphocytes. Arch Toxicol. 1982;51(1):37–42.
  17. Wagner J, Wagner ML, Hening WA. Beyond benzodiazepines: Alternative pharmacologic agents for the treatment of insomnia. Ann Pharmacother. 1998;32(6):680–686. [PubMed: 9640488]

Footnotes

1

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

2

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

3

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

4

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

5

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

6

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

7

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

8

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

9

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

10

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

11

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

12

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

13

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

14

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

15

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

Copyright © 2008, National Academy of Sciences.
Bookshelf ID: NBK3985

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