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7 Response to Military Questions, Conclusions, and Recommendations This chapter presents the committee's responses to the specific questions posed by the military by briefly reviewing the pertinent information provided in the earlier chapters. It then presents the comm~ttee's conclusions and recommendations. 1. Efficacy: Does the Committee on Military Nutrition Research stand by its earlier recommendation that there are sufficient data to rec- ommend a caffeine product to enhance performance? What are the specific indications for use and contraindications for use? Caffeine has been shown to induce a variety of positive effects that have contributed to its extensive use worldwide. Caffeine use has been associated with enhanced physical performance and increased alertness, and as a counter- measure to the effects of sleep deprivation. Extensive research has been done on each of these caffeine effects. Caffeine use is associated with a reproducible increase in endurance time in physical activities of moderate intensity and long duration. Caffeine enhances endurance performance in a variety of activities (i.e., running, cross-country skiing, cycling), with doses in the range of 2 to 9 mg/kg (approximately 150- 650 mg in a 70-72 kg individual), in both naive and habituated, trained and un- trained, test subjects. High-altitude exposure may augment the positive effects of caffeine on endurance performance. Exercise performance is dramatically re- duced by altitude exposure, and maximal effort may be diminished by as much as 25 percent. Ingestion of caffeine (4 mg/kg) increased the time to exhaustion 79

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80 CAFFEINE FOR MENTAL TASK PERFORMANCE in eight trained men riding a cycle ergometer at 4,300 m, but not at sea level. This positive effect was present after 1 hour of altitude exposure and tended to remain even after 2 weeks of acclimatization. There is some debate about whether caffeine enhances cognitive perform- ance or simply restores degraded psychomotor performance in rested individu- als. The majority of studies that have examined the effects of caffeine in rested subjects studied moderate caffeine consumers (20~300 mg of caffeine per day) who were required to abstain from caffeine for some period of time prior to cognitive testing. Some researchers have speculated that for regular caffeine users, this abstinence could have resulted in some degree of withdrawal. Thus, beneficial effects on cognitive behavior may represent remediation of deterio- rated performance during caffeine withdrawal back to baseline performance in the presence of caffeine rather than a net enhancement of performance. A number of studies have demonstrated that caffeine enhances cognitive performance independent of its ability to reverse symptoms of withdrawal (see Chapter 3~. Caffeine can enhance performance on some types of cognitive tasks and some aspects of mood in nonsleep-deprived individuals. Caffeine enhanced accuracy and reduced reaction time on auditory and visual vigilance tasks in a dose-related manner. Moreover, caffeine significantly increased self-reports of vigor and decreased reports of fatigue, depression, and hostility on the Profile of Moods Scale. Self-assessments of energy levels were also improved by caffeine. In a simulated military situation involving a tedious task that required sustained attention for proficient performance (i.e., sentry duty), caffeine eliminated the vigilance decrement that occurred with increasing time on duty, reduced subjec- tive reports of tiredness, and did not impair rifle firing accuracy. Additionally, in this situation, caffeine increased the number of correct target identifications in both males and females. Military personnel face many situations in which extended wakefulness may be required including sentry duty, deployment-related activities, air trans- portation during emergencies, radar and sonar monitoring, submarine duty, and combat. As part of their duties in these situations, individuals are required to perform complex cognitive tasks. The performance of these tasks is compro- mised during periods of extended wakefulness. A variety of instruments have been used to quantify the effects of sleep dep- rivation on behavior. Alertness has been assessed using objective measures such as ambulatory vigilance monitors, visual and auditory vigilance tasks, and sub- jective measures such as self-reports and questionnaires. Studies using these measures have found that sleep deprivation impairs performance on vigilance tasks and decreases self-reports of alertness. A number of mental tasks, includ- ing mental arithmetic tasks, such as a serial add-subtract test, logical reasoning, mental rotation, perceptual cueing, and memory tests have been used to assess the effects of sleep deprivation on higher cognitive processes. Using these tests, mental performance deteriorates as a function of length of sleep deprivation.

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RESPONSE TO QUESTIONS, CONCLUSIONS, RECOMMENDATIONS 81 All of the above-listed decrements in cognitive behavior can best be reversed by sleep. Any amount of sleep from as little as a 15-minute nap can restore some degree of function, although the longer the sleep episode, the greater the amount of cognitive function restored. Naps are effective both prior to (prophylactic naps) and during (restorative naps) a period of sleep deprivation. The only nega- tive side effect of sleep in this context is sleep inertia, a period of mental confu- sion upon awakening from such naps that may last up to 30 minutes. In sleep-deprived subjects, judicious use of caffeine can restore alertness, performance on mental tasks, and positive mood states. Caffeine reversed the sleep deprivation-induced increased response time, and increased alertness and performance on a visual vigilance task, mental arithmetic tests, and logical rea- soning in sleep-deprived subjects. Caffeine is also effective in delaying sleep onset in sleep-deprived subjects. Using visual analog scales, caffeine intake led to reports of decreased sleepiness and increased alertness, ability to concentrate, confidence, talkativeness, energy levels, anxiety, jitteriness, and nervousness. Conclusions Caffeine at levels ranging from 200 to 600 mg/d enhances endurance per- formance in a variety of activities. Limited research has shown caffeine to be especially useful in restoring decrements in physical performance that occur at high altitudes. Food and fluid intake have to be monitored carefully when caffeine is used for this purpose, particularly at high altitudes and in hot environments. The documented declines in food intake during special operations would be of par- ticular concern if food is the delivery vehicle chosen for administering caffeine. Although there is considerable variation in doses tested and subject re- sponses to the effects of caffeine on cognitive function, overall research shows that caffeine in the range of 100 to 600 mg is effective in increasing speed of reaction time without affecting accuracy and in improving performance on visual and audio vigilance tasks. A number of studies have also reported improved performance on long-term memory recall, but not short-te~m word recall. These enhancing effects of caffeine on cognitive performance are most pronounced when functions are impaired or suboptimal (e.g., as a result of sleep deprivation). Recommendations Caffeine in doses of 100 to 600 mg may be used to maintain cognitive per- formance, particularly in situations of sleep deprivation. Specifically, it can be used in maintaining speed of reactions and visual and auditory vigilance, which in military operations could be a life or death situation. A similar dose range (200-600 ma) is also effective in enhancing physical endurance and may be especially useful in returning some of the physical func- tion lost at high altitude. However, if caffeine is used either at high altitudes or

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82 CAFFEINE FOR MENTAL TASK PE~O~NCE in extremely hot environments, fluid and food intake of personnel should be monitored to ensure adequate intake. 2. Safety: What are the medical risks to individuals associated with ready availability of caffeine, including acute health risks, long-term health risks, potential interaction with other drugs or factors specific to military operations, and potential problems of habituation of use? The effect of caffeine on various aspects of health has been and continues to be an active area of scientific research, in spite of the fact that caffeine has been used for more than 1,000 years without apparent ill effects. Over the past 100 years, the list of diseases in which caffeine has been implicated has changed. Con- vincing research evidence has removed several diseases from consideration, in- cluding various cancers, hypercholesteremia, and benign breast disease. Extensive research also has evaluated the impact of caffeine consumption on the incidence of hypertension, cardiovascular disease, reproduction and pregnancy outcome, osteo- porosis, and fluid homeostasis. It has been shown that ingestion of very high doses of caffeine can produce undesirable effects on mental function. Additionally, caffeine use has been associated with physical dependence, which may be re- flected in performance decrements during withdrawal under some circumstances. Hypertension Results summarized in recent reviews by Myers (in press) and Green and Suls (1996) suggest that caffeine-naive individuals may experience a small in- crease in blood pressure after acute dosing with caffeine. During chronic ad- ministration of caffeine, tolerance appears to develop, and chronic, long-lasting changes in blood pressure are usually not seen in individuals who consume caffeine routinely. A recent critical review of 30 years of controlled clinical and epidemiological studies on the blood pressure effects of coffee and caffeine (Nurminen et al., 1999) concluded that the acute presser effects of caffeine are well documented, but that at present there is no clear epidemiological evidence that caffeine consumption is causally related to hypertension. They also con- cluded, however, that high caffeine intake may be an additional risk factor for hypertension at the individual level due to long-lasting stress or to a genetic susceptibility to hypertension. Caffeine consumption has also been demonstrated to potentiate the effects of acute exercise and mental stress in increasing blood pressure. This effect of caffeine is more pronounced in those with high stress reactivity (i.e., high levels of anxiety) and those who are borderline hypertensive or are hypertensive.

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RESPONSE TO QUESTIONS, CONCLUSIONS, RECOMMENDATIONS 83 Cardiovascular Disease In spite of numerous studies (including controlled clinical trials) attempting to show a relationship between caffeine and serum lipoproteins, blood pressure, cardiac arrhythmias, and risk of coronary heart disease, results have failed to show a consistent adverse effect of ingestion of moderate amounts of caffeine. Whereas case-control studies have produced variable results, a meta-analysis of 11 pro- spective, longitudinal cohort studies showed no increased risk of coronary heart disease associated with consumption of up to 6 cups of coffee per day. Thus, in- creased risk of cardiovascular problems resulting from the use of caffeine supple- ments by the military would not appear to be of major concern in most cases. Reproduction Caffeine consumption has also been suggested as the cause of numerous negative reproductive outcomes, from shortened menstrual cycles to reduced conception, delayed implantation, spontaneous abortion, premature birth, low birthweight, and congenital malformations. As with most other aspects of caf- feine consumption, there is a paucity of reliable data concerning the effects of caffeine on reproductive processes. More recent reviews of human studies suggest that some of the initial re- ported associations between caffeine and reduced fertility, teratogenicity, and other fetal and maternal effects in humans may be explained by confounders such as associated cigarette smoking, alcohol consumption, reporting inaccura- cies, and other methodological errors. A recent well-controlled study of 487 women with spontaneous abortions and 2,087 normal controls, in which caffeine exposure was quantitated objectively by serum paraxanthine levels, showed that the mean serum paraxanthine concentra- tion was significantly higher in women who had spontaneous abortions than in controls (752 versus 583 ng/mL). However, the odds ratio for spontaneous abor- tion was not significantly increased except in subjects with extremely high para- xanthine levels (> 1,845 ng/mL). These authors concluded that moderate con- sumption of caffeine was not likely to increase the risk of spontaneous abortion. Osteoporosis Caffeine consumption has been proposed as a risk factor for osteoporosis. The original observations stimulated several epidemiological studies that exam- ined the possible relationship among caffeine consumption, calcium intake, and various indices of bone health. There appears to be no consistent trend linking caffeine consumption and negative effects on bone mineral density or incidence of fracture.

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84 CAFFEINE FOR MENTAL TASK PERFORMANCE Although early experimental studies also indicated a significant effect on acute calcium diuresis, subsequent work indicated that this acute phase of ex- cretion was accompanied by a later decrease in excretion of calcium in the urine. Moreover, later studies found either no significant effect of caffeine on calcium balance or negative balance only in subjects consuming less than about 660 mg of calcium per day, or half of the currently recommended intake of calcium. Fluid Homeostasis Consumption of 2,500 mL of a carbohydrate-electrolyte solution containing approximately 1 mg of caffeine per kg body weight increased 3-hour urine output by over 400 mL as compared to the same amount of solution without caffeine (Wemple et al., 1997~. While this level of caffeine was too low to produce a positive effect on cycling performance, the fact that urine volume was affected could be of significance in military situations where considerably higher caffeine doses may be used. An oral dose of 250 mg of caffeine increased diuresis, so- dium, potassium, and osmol excretion within 1 hour post-treatment (Nussberger et al., 1990), while amounts of coffee sufficient to provide 642 mg of caffeine in a single day caused a highly significant increase in 24-hour urine output of 753 + 532 mL compared to an identical amount of fluid provided as mineral water. Total body water as measured by bioelectrical impedance decreased 2.7 percent, and sodium and potassium excretion increased by 66 and 28 percent, respectively (Neuhauser-Berthold et al., 1997~. The information to date is inconsistent, indi- cating that caffeine may or may not create a total body water deficit. The deficit may depend on the amount of caffeine consumed, the individual's history of caffeine use, and the total solute load of any accompanying food or beverage. However, the risk of water deficit may be increased when caffeine is used in situations already known to put personnel at risk of dehydration, such as in hot or desert environments (IOM, 1993), or in cold environments (IOM, 1996~. Behavioral Effects One potential risk of high doses of caffeine, which needs further substantia- tion, is dose-related decrements in mental functioning. A number of researchers have found that high doses of caffeine can adversely affect mental performance. Although a relatively low dose of caffeine (250 ma) produced favorable subjec- tive effects (e.g., elation, pleasantness) and enhanced performance on cognitive tasks in healthy volunteers, higher doses (500 ma) led to less favorable subjec- tive reports (e.g., tension, nervousness, anxiety, restlessness) and less improve- ment in cognitive performance than placebo. Negative effects may be more pronounced in nonusers than in regular users of caffeine. Caffeine has been shown to produce anxiety or panic attacks in individuals with agoraphobia or panic disorders, but not in healthy controls. However, caffeine has been shown to potentiate ho~onal responses to other stressors.

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RESPONSE TO QUESTIONS, CONCLUSIONS, RECOMMENDATIONS 85 Physical Dependence and Withdrawal The use of caffeine by humans is generally not associated with abuse or ad- diction. Tolerance develops to some of the physiological effects of caffeine when caffeine-containing beverages are consumed regularly; however, there have been no reports of tolerance for caffeine effects on cognitive performance. Withdrawal symptoms can occur with the abrupt removal of caffeine from the diet. The symptoms of cessation, when they do occur, are not long-lasting and are generally mild. These include headaches, drowsiness, irritability, fatigue, low vigor, and flu-like symptoms. Caffeine acts as a vasoconstrictor of the cerebral arteries, reducing regional blood flow. Caffeine withdrawal also causes changes in cerebral blood flow, resulting in vasodilation in persons with high caffeine intake that is thought to be associated with a throbbing, vascular-type headache, one of the most commonly observed symptoms of caffeine withdrawal. This withdrawal phenomenon could conceivably lead to decrements in performance during military operations. Caffeine and Stress Among the variables that may contribute to differences in caffeine sensitiv- ity are baseline levels of stress exposure and genetically mediated stress reactiv- ity. Stress may include physical stress (e.g., exercise), physiological stress (e.g., heat stress, infection, sleep deprivation), or psychological stress. After stress exposures, stress-responsive neurohormonal and neurotransmitter systems are activated, with associated release of the stress hormones and the adrenergic neurotransmitters (epinephrine, norepinephnne, corteotrophin-releasing hor- mone, adrenocorticotropic hormone, and cortisol), which all interact with caf- feine. Caffeine alters the degree of responsiveness of these systems to stressful stimuli. For example, caffeine has been shown to increase plasma norepineph- rine and to potentiate epinephrine and cortisol stress-reactivity to acute psycho- social stress. The degree of responsiveness in these studies varied according to previous caffeine consumption (habitual users versus nonusers). Conclusions The acute presser effects of caffeine are well documented, but at present there is no clear epidemiological evidence that caffeine consumption is causally related to hypertension. One potential risk should be noted, however. A number of studies have demonstrated that caffeine consumption produces a transient elevation in blood pressure and that this occurs regardless of whether or not the individual is a habitual user of caffeine. In borderline-hypertensive men, the use of caffeine in situations of behavioral stress may elevate blood pressure to a clinically meaningful degree; it has been hypothesized that these types of blood

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86 CAFFEINE FOR MENTAL TASK PERFORMANCE pressure increases in hypertensives would be large enough to transiently reduce the therapeutic effects of antihypertensive medication. However, other studies have found no differences in the effect of caffeine in individuals with or without a family history of hypertension, and no difference in 24-hour ambulatory blood pressure in treated hypertensives between caffeinated and decaffeinated coffee. Thus, high caffeine intake may be an additional risk factor for hypertension at the individual level due to long-lasting stress or to a genetic susceptibility to hypertension. Since military scenarios in which the use of caffeine supplements might be desirable would frequently occur when personnel are also under acute mental and/or physical stress, this could be a concern to those personnel with family histories of hypertension. In spite of numerous studies attempting to show a relationship between caf- feine and cardiovascular health, results have failed to show a consistent adverse effect of ingestion of moderate amounts of caffeine. Increased risk of coronary heart disease resulting from the use of caffeine supplements by the military would not appear to be of major concern. Results of studies of the effects of caffeine on reproduction have been very mixed, and many of those showing increased reproductive problems have been confounded with other life-style factors, particularly smoking. The most con- vincing evidence relates to caffeine and the increased risk of spontaneous abor- tion. However, since this requires caffeine consumption during the first trimester of pregnancy, it is likely to be a concern for sustained military operations only if female personnel are unaware of their pregnancy at the time of deployment. The preponderance of research on caffeine and osteoporosis has found no relationship. Although caffeine can increase calcium diuresis, this is compen- sated by subsequent lower than normal calcium excretion. The use of caffeine in this case is less of a concern than is low calcium intake. Caffeine functions as a diuretic, and this effect appears to increase with in- creasing caffeine level. Evidence is equivocal as to whether acute doses of caf- feine cause a total body water deficit. The increased risk of dehydration may be of concern for military personnel in operational environments where dehydra- tion may already be a concern, such as desert environments, or where thirst mechanisms are inadequate, such as in cold or high-altitude environments. High doses of caffeine (> 600 ma) can cause decrements in cognitive func- tion. Negative effects may be more pronounced in nonusers than in regular users of caffeine. Caffeine can also potentiate the effects of stress. Recommendations Use of caffeine under conditions of sustained operations (SUSOPS) would not appear to pose any acute or chronic health risks for military personnel.

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RESPONSE TO QUESTIONS, CONCLUSIONS, RECOMMENDATIONS 87 Caffeine use in SUSOPS in hot environments, cold environments, or at high altitudes may increase the risk of dehydration, and fluid and food intake of per- sonnel should be closely monitored in these situations. Female military personnel should be advised of the potential for a slight in- crease in risk of spontaneous abortion in the first trimester of pregnancy. 3. Dose and Warning Labels: What dose level should be recom- mended to habituated caffeine users and to nonusers? What warnings should be provided on such a product in the context of ethical, religious, and potential caffeine habituation concerns? The effective doses of caffeine will vary from individual to individual de- pending on a variety of factors including time of day, usual caffeine intake, and whether the individual is rested, smokes, or uses oral contraceptives. Doses evaluated experimentally for their effects on both physical and cognitive per- formance have ranged from as little as 32 mg of caffeine (Lieberman et al., 1987) to as much as 1,400 mg (Streufert et al., 1997~. The levels of caffeine that have consistently enhanced endurance perform- ance, as discussed in Chapter 3, range from about 150 to 600 ma. Numerous studies of the effects of different caffeine dosages on various aspects of cogni- tive performance have been conducted in both civilian and military situations. Levels of caffeine in the range of 100 to 400 mg have consistently demonstrated reductions in reaction time and enhanced performance on vigilance tests, whereas levels of caffeine in excess of 600 mg have shown negative effects on mood and behavior (negative effects may be seen at lower levels in individuals nonhabituated to caffeine). In sleep-deprived individuals (similar to those engaging in SUSOPS), levels in the range of 100 to 600 mg of caffeine appear to Lmprove performance (e.g., vigi- lance, mood, higher cognitive functions) with few acute adverse behavioral effects; some of the positive effects persist for 8-10 hours. Even individuals who do not normally consume caffeine appear to obtain these caffeine-related positive effects. Important ethical considerations include providing personnel with adequate information and training on the use of the product, providing the opportunity for personnel to test the product in a nonoperational situation, and use of a product that allows individual control of the dosage. Regular moderate to heavy users of caffeine may experience headaches, fa- tigue, and drowsiness if denied access to caffeine. Conclusions A caffeine dose of 100-600 mg can be expected to improve vigilance and enhance cognitive performance regardless of an individual's normal caffeine status. A delivery mechanism that provides 100-mg dose increments could be

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88 CAFFEINE FOR MENTAL TASKPE~O~ANCE used to allow individuals of smaller body size, nonhabituated caffeine users, and those with heightened sensitivity to caffeine to individually control their dose. In keeping with the rulings of the U.S. Food and Drug Administration (FDA) with respect to determination of the risks of caffeine as a food additive, no warn- ing label is necessary for a military product designed for maintenance of cogni- tive performance during sustained operations. However, educational and training information is needed for military personnel prior to the use of such a product. Recommendations A caffeine delivery vehicle that provides caffeine in 100-mg increments with a total content not exceeding approximately 600 mg would appear to be the most appropriate dose for use in sustained military operations. Since there is little information regarding the extent to which tolerance to caffeine's cognitive effects in habitual users develops, no differential dosing is recommended for habitual compared to first-time caffeine users. For subsequent dosing, the dosing interval should be based on the considerations that too-frequent dosing might (1) produce a buildup of caffeine (or its primary metabolite, paraxanthine) levels sufficient to precipitate negative effects; and (2) inhibit sleep onset in some individuals at a time when sleep is desired. Since the half-life of caffeine in blood can vary from 1.5 to 9.5 hours, with an average half-life of 4 to 5 hours, a dosing interval of no less than 3 to 4 hours is recommended. Any product that is used as a vehicle for providing caffeine to military per- sonnel should be prominently labeled. The labeling should include a statement on the principal display panel that the product contains added caffeine and should only be used to maintain performance when involved in SUSOPS or sustained vigilance activities. The message on the principal display panel should direct the user to specific information elsewhere on the label that indicates the level of caffeine per unit of product and the total amount per package or con- tainer. An example is shown in Box 7-1. This content information is vital for the command structure to make decisions about directions for use and for individu- als to adapt consumption to their individual needs. An in-depth training program on the benefits, directions for use, and poten- tial side effects or symptoms of excess intake of caffeine should be designed for command personnel. In addition, if caffeine is to be used to enhance perform- ance, military personnel should be given adequate training to ensure the benefits of caffeine supplementation and avoid any potential side effects. Such training should include the use of caffeine during periods of sleep deprivation and possi- bly altered work-rest cycles. All personnel should test the effects of the recom- mended dose in a nonoperational situation prior to use in an operational situation.

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RESPONSE TO QUESTIONS, CONCLUSIONS, RECOMMENDATIONS 89 Military personnel who regularly consume caffeine-containing products should not be denied access to these products in anticipation of the use of a caffeine supplement. Symptoms of withdrawal such as fatigue, decreased alert- ness, and headaches could cause decrements in performance prior to the con- sumption of the caffeine supplement. 4. Alternatives: Are there practical alternatives to caffeine that would better serve the intended purpose of enhancing or maintaining performance in fatigued service members? Sleep is the most effective means of reconstituting the decrements in cogni- tive functioning brought on by sleep deprivation. Thus, in situations where it is feasible, sleep should be promoted. There is a dose effect for the restorative effects of sleep duration on cognitive performance (Bonnet, 1999; Bonnet and Arand, 1994a,b; Bonnet et al., 1995; Dinges et al., 1987~. Any amount of sleep from as little as a 15-minute nap can restore some degree of function, although the longer the sleep episode, the greater the amount of cognitive function re- stored (Bonnet et al., 1995~. Dinges et al. (1987) demonstrated that prophylactic naps were better than restorative naps and were more important than circadian placement of naps. Combination of Caffeine and Naps The most effective nonprescription drug alternative to caffeine administra- tion alone when a normal sleep regimen is not possible, is a combination of caffeine and naps. The combination of caffeine and naps increased alertness during long periods of sleep deprivation compared to either caffeine or naps alone. The committee recommends that wherever possible, commanders adopt strategies that incorporate the use of caffeine with short naps for maintaining vigilance, alertness, and other physiological and cognitive functions needed for SUSOPS. According to the literature reviewed in this report, naps taken early in

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9o CAFFEINE FOR MENrTAL TASK PERFORMANCE the period of extended wakefulness followed by caffeine taken around the time of circadian troughs would be most effective. Amphetamine In extensive simulator and in-flight testing, amphetamine was observed by investigators (Caldwell and Caldwell, 1997; Caldwell et al., 1995) to "improve subjective feelings of fatigue, confusion, and depression while increasing feel- ings of vigor". Amphetamine is, however, a controlled substance and thus re- quires an individual medical evaluation to determine risk factors and health status before a prescription can be issued. With appropriate supervision and control, the use of amphetamine has benefited individuals with unique skills whose performance was critical to the safety of personnel and complex military hardware. In contrast to caffeine in food, beverages, chewing gum, and pill or tablet form, there is little experience with amphetamine pill self-dosing for most military personnel, and the hazards and adverse effects of self-dosing might therefore be expected to be greater. It would be preferable if ergogenic effects can be achieved without such substances. The potential for abuse of ampheta- mines is considerable, and the appropriate monitoring of its dispensing and use may add unnecessary burdens to medical personnel in the intense and demand- ing tasks that are directly involved in guaranteeing the success of SUSOPS. Although amphetamine (20 ma) was effective in reversing the negative effects on alertness during sleep deprivation and these effects are greater than those of caffeine at 300 ma, it had deleterious effects on recovery sleep, which also may be important in the ultimate success of demanding and constantly changing SUSOPS (Bray et al., 1999~. Amphetamine should not be considered as a sub- stitute for sleep, and more nights of recovery sleep may be needed after its ad- ministration (Caldwell, 1999~. Therefore, considerable caution is warranted, and use of this stimulant should be restricted to only the most extreme circumstances when such measures are considered essential to the success of highly sensitive operations. Clearly, more research should be done before consideration can be given to the routine use of amphetamine. Modafinil Modafinil is a new prescription drug approved by the FDA as a wakeful- ness-promoting substance. It has undergone evaluation as a treatment for exces- sive daytime sleepiness (EDS) in narcolepsy (Broughton et al., 1997~. This drug appears to be useful in reducing EDS without effecting voluntary nap or noctur- nal sleep initiation. These properties suggest that the stimulant may be useful in extending high levels of vigilance in SUSOPS. A number of studies have ex- amined the effects of modafinil on cognitive performance and sleep recovery in sleep-deprived, but otherwise healthy, volunteers. Modafinil (300 ma) was as

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RESPONSE TO QUESTIONS, CONCLUSIONS, RECOMMENDATIONS 91 effective as 20 mg of dextroamphetamine in maintaining both subjective esti- mates of mood and fatigue, and objective measures of cognitive performance when administered three times during 64 hours of sleep deprivation (Pigeau et al., 1995), with no effects on recovery sleep (Buguet et al., 1995~. Another study compared the effects of 300 mg of modafinil every 24 hours to placebo in healthy individuals during 60 hours of sleep deprivation using the visual search paradigm for assessing speed and accuracy in target detection. Slow search rates and number of errors increased linearly in the placebo condition with increasing time without sleep, but remained the same as rested controls with modafinil (Stivalet et al., 1998~. Batejat and Lagarde (1999) examined the effects of 200 mg of modaf~nil in conjunction with naps on performance during two 27-hour periods of sleep deprivation. Modafinil maintained an efficient level of central nervous system (CNS) general activation close to awakening. As in previous studies, modafinil did not prevent sleep if sleep opportunities were available. Caldwell et al. (1999) recently reported on the use of modafinil in a helicopter simulator study with pilots exposed to two 40-hour periods of sleep deprivation. Three 200-mg doses of modafinil or placebo were administered during the 40-hour period. Modafinil significantly attenuated the effects of sleep deprivation on four of six flight maneuvers, reduced the amount of slow-wave electroencephalogram activity (indicative of reduced CNS activation), lessened self-reported problems with mood and alertness, and curtailed the performance decrements that were found with placebo. The most noticeable benefit of the drug was seen when the combined impact of sleep loss and circadian trough was most severe. Conclusions Providing the opportunity and environment for adequate sleep is the ideal but is obviously impractical for continuous military operations. Combining naps with judicious caffeine use may be the best remedy for sleep deprivation- induced decrements in cognitive function in military situations where adequate sleep cannot be obtained. When naps are not an option, caffeine alone could be used to mitigate sleep deprivation-induced impairments in cognitive behavior for up to 24 hours of sleep deprivation. The Department of Defense (DOD) has precedents for the use of prescrip- tion drugs in healthy individuals, such as the use of amphetamines. Furthermore, in the United States, physicians are permitted to prescribe drugs for off-label use (i.e., for uses not included in the product's labeling). The use of amphetamine is superior to caffeine in offsetting decrements in cognitive performance; however, the risks outweigh the benefits for most situa- tions. It is a controlled substance, it has a high abuse potential, and it interferes with recovery sleep. In addition, it is assumed that the majority of combat per- sonnel would not have had previous experience with the drug.

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92 CAFFEINE FOR MENTAL TASK PERFORMANCE The drug modafanil, which was developed more than 10 years ago as a treatment for narcolepsy, shows considerable promise. It appears to be as effec- tive as amphetamines in offsetting performance degradation, does not interfere with recovery sleep, is not an appetite suppressant. and appears to have a much lower abuse potential. Recommendations It is recommended that the military have in place a doctrine related to the importance of sleep prior to extended missions and the importance of naps whenever possible during operations. Naps would be most effective when taken early in the period of sleep deprivation. Of the psychostimulant compounds, caffeine would be the compound of choice, since many personnel would have personal experience with the compound, it is not a restricted substance, it does not interfere with recovery sleep following periods of sleep deprivation, and it is generally considered to have very low abuse potential. The DOD should continue to research the drug modafinil to further explore its potential for sustaining cognitive performance during military operations. Research published to date indicates that it may prove far superior to caffeine in maintaining cognitive performance over extended periods of sleep deprivation, without the adverse side effects and abuse potential of amphetamines. 5. Formulation: (a) Does the inclusion of other components (e.g., glu- cose) improve the beneficial effects of caffeine in sustained operations, as previously suggested by the committee? (b) Is there a better approach to caffeine delivery than the nutrient bar currently produced for the military? The evidence is unclear on the utility of adding glucose or other carbohy- drates to caffeine to further enhance physical performance. Caffeine enhances the availability of free fatty acids and decreases glycogenolysis, whereas carbo- hydrate as glucose increases the availability, and presumably the use, of this substrate. Some researchers have proposed that caffeine be delivered in a carbo- hydrate-containing medium to further enhance performance. However, most studies to date have been flawed in some way and reported variable results. Additional well-designed research is still necessary regarding the combined effects of caffeine and carbohydrate on physical performance. No studies were found in the published literature that examined the effects of caffeine combined with other nutrients on cognitive performance, and this may be an area for fur- ther research. There may be nutritional reasons (e.g., provision of food energy, nutrients, or fluid) for including caffeine in a food form. A chocolate bar has been fo~u- lated by the military and found to be acceptable in preference studies. The bars have also been used as delivery vehicles for other food constituents such as

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RESPONSE TO QUESTIONS, CONCLUSIONS, RECOMMENDS TIONS 93 tyrosine, creatine, and antioxidant nutrients that might enhance performance under certain circumstances. The committee considered various approaches to caffeine delivery for SUSOPS, including the food/energy bar and other alternatives such as caffein- ated chewing gum, tablets (both sustained release and regular), and beverages. In assessing the alternatives, the pros and cons of each of these vehicles were considered. Their major characteristics are summarized in Table 7-1. There is good evidence that caffeine is absorbed rapidly and completely from the gut when supplied in a liquid form, with virtually all (99 percent) of the adminis- tered dose absorbed in about 45 minutes (Blanchard and Sawers, 1983; Chvasta and Cooke, 1971~. However, the committee is unaware of evidence on the ab- sorption of caffeine from a food matrix, as in solid foods such as bars. Theoreti- cally, absorption should be slower than it is from liquids because gastric emp- tying time might be slower. Lipid solubility and possibly caffeine absorption in the stomach may influence these processes as well. Studies of the rapidity of absorption and action of caffeine are needed for such bars if they are to be con- sidered as a caffeine delivery vehicle. A caffeine delivery vehicle that is most appropriate in one setting may not be so in another, as presented in Table 7-1. Caffeine in a food matrix may be advantageous when it is important to deliver nutrients, fluid, or other food con- stituents simultaneously, but the satiating effects of the food may somewhat limit consumption, especially if high intakes are required to obtain a sufficient dose. Chewing gums are more appropriate if rapid absorption and action are needed, and would facilitate tailoring of individual doses. Caffeine in a fluid or gel matrix may be more appropriate when dehydration is an issue. Various characteristics of the individual also alter the effects of a given dose of caffeine. These involve both individual factors (e.g., age, sex, smoker versus nonsmoker) and states that can vary greatly from one situation to another (e.g., stress hormonal status, ingestion of certain drugs, illness, heat stress, sleep status); thus, the delivered dose may have different psychological and physio- logical effects at one time than it does at another. Conclusions A summary of the characteristics of different methods of caffeine delivery is presented in Table 7-1. Although evidence of a potentiating effect of carbohy- drates on caffeine effectiveness is equivocal, there are other reasons to consider providing supplemental nutrients along with the caffeine. For example, inade- quate food and fluid intake is a common problem during military operations. The use of a caffeinated chewing gum would appear to provide the most rapid absorption.

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94 CAFFEINE FOR MENTAL TASKPE~O~ANCE TABLE 7-1 Summary of Potential Caffeine Delivery Approaches Vehicle Dose of Caffeine Food bar 600 mg caffeine, scored in 150- Other Components That Improve Weight or Beneficial Effects of Caffeine? Volume Yes sucrose and corn syrup are sim- 70 g ple sugars that may enhance the positive effects of caffeine on cer- mg increments Food bar, 100 mg incre- modified meets dose lain aspects of physical perform- ance (depending on the type of ex- ercise being performed); also contains complex carbohydrate, fat, and protein Yes sucrose and corn syrup are sim- 50 g ple sugars that may enhance the positive effects of caffeine on cer- tain aspects of physical perform- ance (depending on the type of ex- ercise being performed); also contains complex carbohydrate, fat, and protein Caffeinated Caffeine content Yes Sucrose and corn syrup are pre- 12 fluid oz soft drinks varies from 5 to sent in regular brands, aspartame in (36 g) 50 mg de- diet brands pending on type and source Caffeinated 100 mg/stick chewing gum Caffeine pills 100 mg Yes sucrose, corn syrup; also con- tains small amounts of glycerin, lecithin, and aspartame No Sustained re- 200 or 300 mg No lease caf- feine ? 5 g

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RESPONSE TO QUESTIONS, CONCLUSIONS, RECOMMENDATIONS 95 Possible Ra- pidity of Likely Rapidity Abuse Absorption of Action Potential Comments ? Slower ? Slower Low Bioavailability uncertain; good vehi- cle for providing other nutrients or food constituents such as sugars if these prove to be useful; more bulky than chewing gum or pills; satiating effects possible if caffeine content is low ? Slower ? Slower Low Bioavailability uncertain; good vehi- cle for providing other nutrients or food constituents such as sugars; satiating effects possible if caffeine content low; more bulky than chewing gum or pills Rapid (< 60 Rapid Low min) Most rapid Most rapid Low Provide fluid; good vehicle for sugars if these prove useful; more bulky than chewing gum or pills; a dehy- drated beverage powder requires water and time to mix Absorbed sublingually and rapidly; low bulk; no or little satiating ef- fects likely Rapid Rapid Low Bioavailability somewhat lower than from caffeinated drinks; no satiat- ing effects likely Initial dose Initially rapid fol- Low Permits longer intervals between rapid, sus- lowed by slower doses but less flexibility during tained re- absorption suddenly altered operational situa- lease lions

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96 CAFFEINE FOR MENTAL TASK PERFORMANCE Environmental circumstances and individual characteristics may make one caffeine delivery vehicle appropriate in some circumstances and inappropriate in another. Recommendations If food/energy bars are used, they must be tested for the rapidity of caffeine absorption and action. Under certain circumstances such as heat stress or desert operations, chewing gums may offer practical operational advantages over a food/energy bar, but under other conditions, such as reconnaissance operations from a central point, the bar may be preferable. Thus, more than one delivery vehicle should be considered, provided complete data on absorption and rapidity of action are available. In terms of convenience, pills or capsules could be con- sidered, however, the little data available suggest that the bioavailability of caffeine in this form is less than in oral liquids. In addition, the use of pills or capsules does not meet the Anny's stated preference of providing performance aids in the context of a food or beverage. ADDITIONAL RESEARCH RECOMMENDATIONS In reviewing the caffeine literature for this report, it became clear that there are still gaps in the knowledge database concerning caffeine and other potential cognitive enhancers that may be of military relevance. These are: orally; . bioavailability of caffeine from substances other than liquids consumed . additional research on the effectiveness and optimal doses of the wake- fulness-promoting drug, modafinil, in simulated combat environments; effectiveness of various combinations of naps and caffeine; . effects of consumption of greater than recommended doses of caffeine on fluid homeostasis in different environments (e.g., consumption of the total 600 mg caffeine delivery product in a hot, cold, or high-altitude environment); and . properly designed studies on the effects of caffeine combined with other nutrients (e.g., carbohydrate, fat) on physical and cognitive performance.