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1 Basic Concepts MILITARY INTEREST IN CAFFEINE Optimal job performance without compromising the health and well-being of the worker is the goal of employers regardless of the field of endeavor. Inter- mittent or prolonged physiological and psychological stressors that employees bring to the workplace have an impact not only on their own performance but also on those with whom they work and interact. The internal stressors an indi- vidual brings to his or her job are compounded by the day-to-day physical and mental stressors of the job itself. Military personnel in combat settings endure highly unpredictable timing and types of stressors as well as situations that re- quire continuing vigilance for long periods of time. The U.S. military's concerns about the individual war fighter's ability to avoid performance degradation and the need to enhance mental capabilities in highly stressful situations have led to an interest in devising military ration com- ponents that could enhance physical and cognitive performance. Previous Committee on Military Nutrition Research Recommendations In 1992 the Committee on Military Nutrition Research (CMNR) was asked by the U.S. Army Medical Research and Materiel Command to evaluate the potential of selected amino acids, carbohydrates, structured lipids, choline, car- nitine, and caffeine to enhance performance. The committee was asked to ad- dress two questions: first, whether the use of diet components or supplements to enhance physical and mental performance in "normal" healthy, young adult 17

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18 CAFFEINE FOR MENTAL TASK PERFORMANCE soldiers was a fruitful approach and, second, which food components, if any, would be the best candidates for enhancing military mental and physical per- formance. In response to this request the committee held a workshop, reviewed the scientific literature, and published the report, Food Components to Enhance Performance (IOM, 1994), in which it recommended continued research on the mechanisms of the effects of caffeine on cognitive performance, mood, and alertness. It was noted that particular attention should be paid to maximizing positive effects when performance is already degraded. Specifically, the corurnittee recornrnended: Caffeine definitely should be considered in developing perform- ance-enhancing rations or ration components. Caffeine is safe as a component of food at doses required to overcome sleep deprivation and has already been included in diets of military personnel via coffee and many soft drinks. Since many soldiers may not normally drink coffee, a mechanism for including caffeine in another ration component that can be selectively used when the situation requires should be evaluated. It appears that doses of 300-600 mg/70 kg person will achieve the desired stimulus in those nonhabituated to caffeine; additional research needs to be conducted to determine the effects of this level of caffeine in those with higher habitual intakes. (IOM, 1994, p. 50) The Current Situation Changes in military operations over the last 50 years have forced continued assessment and adoption of technologies that will sustain or enhance physical and cognitive performance of the individual service member. This urgency in main- taining and enhancing performance is fostered by increased reliance on the indi- vidual's cognitive skills in the operation and maintenance of complex military equipment in an ever-increasing variety of environmental conditions. Today's military relies heavily on the use of computer-controlled systems that require highly trained and alert operators. In addition, there is greater reliance on rapid mobility to enable deployment at any time to achieve the nation's military objec- tives. The urgency of maintaining and enhancing performance is also driven by constant pressure, due to personnel reductions, to have the individual perform for longer periods of time with less sleep, shorter transition times, less recovery time between missions, and less reliance on traditional logistical support. These scenarios can have severe impacts on the individual's level of fatigue, alertness, response time, mood, judgment, reliability in decision making, and other cognitive skills. Increased likelihood of decrements in cognitive function is coupled with greater dependence on each individual in accomplishment of the mission. Both of these factors have a profound impact on the success or failure of a military operation.

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BASIC CONCEPTS 19 In its effort to sustain and enhance the performance of personnel, the mili- tary's emphasis should be placed on providing adequate levels of nutrients, water, life support equipment, clothing, and, to the extent possible, sleeping regimens, appropriate rest areas, and work patterns. After these efforts have been put in place, the potential use of dietary supplements and selected pharma- ceuticals is an appropriate consideration. HISTORY OF CAFFEINE USE In addition to its natural occurrence in some foods, caffeine is used as a food additive and as a drug or a component of many pharmaceutical prepara- tions. It is the most widely consumed psychoactive or central nervous system (CNS) stimulant in the world (Curatolo and Robertson, 1983~. When adminis- tered in the doses commonly found in beverages and drugs, it has measurable effects on certain types of human performance. It is readily available to both the civilian and the military populations as a beverage (coffee, tea, mate), food (co- coa products), food additive (soft drinks, bottled water), and pharmaceutical (over-the-counter pain and weight-loss medications, numerous prescription drugs). No other substance has this combination of uses. As a food additive caffeine is generally considered safe based on its long history of use and on extensive research conducted throughout the world for more than a century. However, despite this long history of use, modern epide- miological techniques have raised concerns about associations between contin- ued use of high levels of caffeine and long-term health. Caffeine (1,3,7-tnmethylxanthine) and the related methylxanthines, theo- bromine (3,7-dimethylxanthine) and theophylline (1,3-dimethylxanthine), are widely distributed in plants throughout the world. More than 60 different plant species containing caffeine have been identified, and history suggests that it may have been consumed, in one form or another, as far back as the Paleolithic pe- riod (Barone and Roberts, 1996~. The primary sources of these compounds are coffee (Canada arabica), Lola nuts (Cola acuminata), tea (Thea sinensis), and chocolate (Cocoa bean). Although the actual discoverer of caffeine as a stimu- lant is unknown, legend has it that it was first discovered in Ethiopia in the third century AD when a shepherd noticed that his goats became very frisky and agitated after eating coffee berries or "beans". The shepherd tried chewing some of the berries and noted their stimulant properties. An abbot at a nearby monas- tery brewed the beans in hot water and found that the beverage helped him to stay awake during long nights of prayer. Cultivation of the coffee plant may have begun as early as the sixth century AD, probably in Ethiopia. Elsewhere in Africa, coffee berries were crushed and mixed with fat to serve as a food to stimulate warriors in battle. By approximately 1000 AD, coffee reached Yemen, where the beverage became very popular and drinking it a social ritual among Muslims. From there it spread to Europe and the Americas. All stable indige-

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20 CAFFEINE FOR MENTAL TASK PERFORMANCE nous cultures having access to caffeine-containing plants have developed drinks or foods containing these stimulant products. The earliest recorded use of caf- feine-containing beverages dates back to the Tang Dynasty of China (618-907 AD) where tea was a popular drink believed to prolong life. Caffeine Content of Common Food Sources The amount of caffeine in commonly consumed beverages and other prod- ucts varies a great deal (Table 1-1), from as little as 5 mg/8 oz of chocolate milk, to as much as 300 mg/6 oz of strong espresso coffee. Since early times the ad- verse effects of very large doses of caffeine, especially in those who are not used to the product, have been noted. The reported signs and symptoms include nerv- ousness, anxiety, insomnia, irregular heartbeats, excess stomach acid, and heart- burn(Duke,1988~. Caffeine Intake of Adults Based on the available product usage data and food consumption data, Bar- one and Roberts (1996) estimated caffeine intakes in the United States, United Kingdom, Denmark, and Australia. The per capita daily caffeine intake for all U.S. adults was approximately 3 mg/kg body weight (BOO) (for a 6~70-kg person). For adults who actually consumed caffeine products, mean daily intake was 4 mg/kg BW, and for the ninetieth percentile of caffeine users, intakes ap- proximated 5-7 mg/kg BW. Caffeine intake was higher in the United Kingdom, with per capita daily consumption being 4 mg/kg BW and 7.5 mg/kg BW for the ninetieth percentile of caffeine users. Consumption was highest in Denmark: 7.0 mg/kg BW for all adults and 14.9 mg/kg BW for the ninetieth percentile of caffeine users. THE COMMITTEE'S TASK Surveys indicate that more than 90 percent of the military population con- sumes caffeine at some level on a daily basis. A small-sample survey reported by Lieberman (1999) indicated that mean caffeine intake among military per- sonnel was 340 mg/d. The majority of those sampled consumed 200 mg/d or less; however, consumption levels were highly variable and thus physiological effects cannot be generalized. Typically, older personnel consumed more caf- feine than younger ones, and males consumed slightly more than females. The majority of caffeine (about 70 percent) was consumed as coffee, 23 percent as soda, 5 percent as tea, and slightly less than 2 percent as chocolate, with the remainder coming from medications. These factors make it difficult to deter- rnine risk and to make risk management decisions on the use of caffeine for maintenance and enhancement of cognitive performance in military operations.

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BASIC CONCEPTS TABLE 1-1 Caffeine Content of Some Common U.S. Food Products Item Coffee (5-oz cupja Brewed, drip method Percolated Instant Decaffeinated Espresso (6-oz cup) Teas (loose or bags, 5-oz cupja 1-m~nute brew 3-m~nute brew Average (mg) Range (mg) 120 90 75 3 240 21 33 9~150 6~124 3~120 1-5 18~300 9-33 2~6 Tea products Instant (5-oz cup) 20 12-28 Iced (12-oz glass) 29 22-36 Carbonated beverages 24 2~0 Colas and pepper drinks (12 oz) National brands, packaged 42 36~8 National brands, fountain 39 32~8 Store brands, packaged 18 5-29 Citrus drinks (12 oz) National brands, packaged 52 43-56 Store brands, packaged 38 26-52 Chocolate products Cocoa beverage (8 oz) Chocolate milk beverage (8 oz) Milk chocolate (1 oz) Dark chocolate, semisweet (1 oz) Balcer's chocolate (1 oz) Chocolate-flavored syrup (1 oz) 4 6 s 6 20 35 3-32 2-7 1-15 5-35 35 4 a Note these caffeine amounts are based on a 5-oz cup of beverage, servings today are more likely to be 8 or 12 oz arid caffeine intalce should be calculated accordingly. SOURCE: Adapted from FDA (1980a); Grand and Bell (1997~; IFT (1983~; Lieberman (1992~. 21 The military requested the committee's assistance in this decision-making process. The CMNP was requested to evaluate the relevant caffeine research, including all relevant studies performed since the 1992 workshop, and address in a brief report the following proposal and questions to assist the Department of De- fense in the transition of research to military application. Specifically, the military provided the following information and questions for the committee's response. A specific transition opportunity could take the following form: a "HOOAH" food bar (a nutrient-dense energy bar developed by the Army) containing 600 mg of caffeine, scored in 150-mg increments, with labeling that provides specific guidance for use of up to one food bar (600 ma) to offset deficits in cognitive

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22 CAFFEINE FOR MENTAL TASK PENANCE function and situational awareness produced by inadequate restorative sleep and during military operations at night. The label should also contain warnings, espe- cially for infrequent or noncaffeine users, that no more than one scored segment (150 ma) should be used in the first hour and should be discontinued if undesir- able changes in hand steadiness, pulse, and respiration occur. This performance- enhancing ration component could be provided separately or as part of opera- tional rations. Alternatives to be considered include coffee, caffeinated soft drinks, modifications of the HOOAH bar dose, caffeinated chewing gum, caf- feine pills, amphetamine pills (dexedrine), and sustained-release caffeine. The intent is to provide a pharmacological/dietary supplement strategy to significantly counter performance deficits in special circumstances when doctrinal and behav- ioral solutions (adherence to appropriate work-rest cycles, naps, etc.) are not possible or break down. The key questions to be addressed: 1. Off cacy: Does the committee stand by its earlier recommendation that there are sufficient data to recommend a caffeine product to enhance perform- ance, and what are the specific indications for use (e.g., vigilance activities fol- lowing inadequate sleep) and contraindications for use (e.g., tasks involving fine motor coordination)? 2. Safety: What are the medical risks to individuals associated with ready availability of caffeine, including acute health risks (e.g., cardiac arrhythmia, caffeine psychosis), long-term health risks (e.g., hypertension, hypercholester- olemia), potential interactions with other drugs (e.g., ephedra-containing sup- plements) or factors specific to military operations (e.g., heat stress, stress reac- tions), and potential problems of habituation of use (e.g., tolerance, caffeine dependence)? 3. Dose and warning labels: What dose levelers) should be recommended to (a) habituated caffeine users and (b) nonhabituated users? What warnings should be provided on such a product in the context of ethical, religious, and potential caffeine habituation concerns? 4. Alternatives: Are there practical alternatives to caffeine, which would better serve the intended purpose of enhancing performance in fatigued service members (e.g., amphetamine)? 5. Formulation: (a) Does the inclusion of other components (e.g., glucose) improve beneficial effects of caffeine in sustained operations (SUSOPS), as previously suggested by the committee? (b) Is there a better approach to caffeine delivery than the HOOAH bar (e.g., is it better to have more rapid absorption and action using caffeinated chewing gum, longer duration of action using sus- tained-release caffeine products, or pill or beverage formulations)? A workshop was organized to review the scientific data on the efficacy of caffeine in maintaining physical and cognitive performance in military opera- tions, its safety, and appropriate formulations for administration during military

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24 CAFFEINE FOR MENTAL TASK PERFORMANCE Caffeine and Adenosine Receptors The ability of caffeine to inhibit adenosine receptors appears to be highly important in its effects on behavior and cognitive function. This ability results from the competitive binding of caffeine and paraxanthine to adenosine receptors and is of importance in contributing to CNS effects, especially those involving the neuromodulatory effects of adenosine. Due to the blocking of adenosine inhibitory effects through its receptors, caffeine indirectly affects the release of norepinephrine, dopamine, acety~choline, serotonin, glutamate, gamma-aminobenzoic acid (GABA), and perhaps neuropeptides (Daly et al., ~ 999~. There are two main classes of adenosine receptor Al and A2; caffeine and paraxanthine are nonselective antagonists at both, although they are not especially potent antagonists. The caffeine concentrations attained in viva that cause mild CNS stimulation (5-10 EM) and that are associated with antiasthmatic effects (50 ~M), are in the range associated with adenosine receptor blockade (as quantitated by in vitro receptor binding assays) (Daly, 1993~. Caffeine and Phosphodiesterase Caffeine increases intracellular concentrations of cyclic adenosine monophosphate (cAMP) by inhibiting phosphodiesterase enzymes in skeletal muscle and adipose tissues. These actions promote lipolysis via the activation of hormone-sensitive lipases with the release of free fatty acids and glycerol. The increased availability of these fuels in skeletal muscle acts to spare the consumption of muscle glycogen. Increased cAMP could also lead to an increase in blood catecholamines. However, caffeine is a fairly weak inhibitor of phosphodiesterase enzymes, and the in viva concentrations at which behavioral effects occur are probably too low to be associated with meaningful phosphodiesterase inhibition (Burg and Werner, 1975, Daly, 1993~. In contrast, phosphodiesterase inhibition may account for caffeine's (and theophyIline's) cardiostimulatory and antiasthmatic actions, since nonxanthine phosphodiesterases are cardiac stimulants (Schmitz et al., 1989) and are also effective as bronchiolar and tracheal relaxants. Indeed, in the latter case, the potency correlates with phosphodiesterase inhibition, not with affinity for adenosine receptors (Brackett et al., 1990; Persson et al., 1982, Polson et al., 1985~. Caffeine and Calcium Mobilization The earliest proposed mechanism of action for caffeine involved the mobilization of intracellular calcium. Certain actions of caffeine in skeletal muscle appear to involve ionic calcium (Ca++~. Caffeine in high concentrations (~-10 mM) was found to interfere with the uptake and storage of calcium in the sarcoplasmic reticulum of striated muscle and to increase the transIocation of C a++ through the plasma membrane (Nehlig et al., 1992~. Caffeine may also increase myofilamental sensitivity to C a++ through its binding to ryanodine receptors in calcium channels of muscle and brain (McPherson et al., 1991~. Although caffeine has been shown to release calcium from intracellular storage pools (sarcoplasmic reticulum) in skeletal and cardiac muscle, the threshold concentration required in vitro to observe this effect (250 ~M) is substantially higher that the concentrations required in vivo for cardiac stimulation (50 ~M). Hence, this subcellular action of caffeine is probably physiologically irrelevant (though it conceivably could be relevant at toxic concentrations of caffeine) (Daly, 1993~.