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5 Doses and Delivery Mechanisms Numerous studies exist in the scientific literature evaluating the safety and efficacy of caffeine. These studies have used a wide array of caffeine dosages and delivery mechanisms. This chapter briefly reviews that information (see Chapters 3 and 4 for detailed reviews) and provides recommendations on the doses and forms of delivery most appropriate for military purposes. OPTIMUM CAFFEINE DOSAGE The effective doses of caffeine vary from individual to individual, depend- ing on a variety of factors including time of day, usual caffeine intake, whether the individual is rested or fatigued, whether they smoke, or whether they use oral contraceptives. Similarly, the response to sleep deprivation also varies be- tween individuals. Caffeine doses experimentally evaluated for their effects on both physical and cognitive performance have ranged from as little as 32 mg of caffeine (Lieberman et al., 1987) to as much as 1,400 mg (Streutert et al., 1997~. Physical Performance The levels of caffeine that have consistently enhanced endurance perform- ance, as discussed in Chapter 3, range from about 200 to 600 ma. Pasman et al. (1995) evaluated the effects of 0, 5, 9, and 13 mg of caffeine per kg of body weight on endurance performance as measured using a cycle ergometer. These doses were equivalent to approximately 360, 648, and 936 mg of total caffeine. 61
62 CAFFEINE FOR MENTAL TASK PERFORMANCE Caffeine significantly increased time to exhaustion compared to the placebo, and there were no differences between levels of caffeine, thus the 360 mg dose (5 mg/kg) was as effective as the higher doses. A series of extensive reviews (Dodd et al., 1993; Graham et al., 1994; Spriet, 1995; Tarnopolsky, 1994) of the scientific literature have consistently concluded that caffeine enhances endurance performance in a variety of activi- ties with doses from 2 to 9 mg mg/kg of body weight (approximately 150-650 ma) However, the mechanism by which caffeine improves endurance exercise performance is unclear, and has variously been attributed to increased lipolysis, decreased glycogenolysis, increased secretion of ,B-endo~ph~ns, and decreased plasma potassium concentrations. Hogervorst and colleagues (1999) examined the effects of 0, 150, 225, and 320 mg of caffeine, administered in a carbohydrate-electrolyte solution, on cognitive performance of endurance-trained athletes before and after strenuous physical exercise. Prior to exercise, 150 mg of caffeine significantly improved delayed memory recall. Exercise alone improved selective attention and both simple and complex motor functions. Immediately following exercise, 225 mg of caffeine significantly improved signal detection efficiency and reaction time. Cognitive Performance Numerous studies of the effects of different caffeine dosages on various as- pects of cognitive performance have been conducted in both civilian and military settings. For example, Dimpfel et al. (1993) measured the effects of placebo, 200, and 400 mg of caffeine on human electroencephalogram (EEG) patterns at rest and during mental concentration tests. In addition to the finding that the effects of caffeine can be quantified with EEG spectral densities, they also found that sub- jects achieved the best results on concentration tests when given 200 mg of caf- feine. This included both the number of problems solved per unit time and the percentage of correct solutions. Results of treatment with 400 mg of caffeine tended to be below those of the placebo condition. Foreman et al. (1989) com- pared the effects of placebo, 125, and 250 mg of caffeine on cognitive perform- ance using memory tests and the Stroop test. They found no effect of caffeine on performance in either test, but there was a trend toward fewer words recalled in the short-term memory test with 250 mg of caffeine. However, Lieberman et al. (1987) found improved performance on four-choice reaction time tests and the Wilkinson vigilance test at all levels of caffeine evaluated (0, 32, 64, 128, and 256 ma) with no effect on self-rated feelings of tension or anxiety. Warburton (1995) examined the effects of 0, 75, and 150 mg of caffeine on attentional, verbal memory, nonverbal working memory, and problem-solving speed and accuracy in 18 men who were regular coffee drinkers (no more than 3 cups/day). Caffeine improved speed and accuracy on attentional tests (visual information processing) in a dose-dependent manner. Similar to the data of
DOSES AND DELIVER Y MECHANISMS 63 Foreman et al. (1989), there was no effect of caffeine on immediate verbal re- call; however there was a dose-related effect of caffeine on delayed verbal re- call. Caffeine also significantly improved the accuracy, but not the speed, of problem solving. Rogers et al. (1995) found significant improvement in reaction time with 70 mg of caffeine compared to placebo. Similarly, Lorist and Snel (1997) found that caffeine at 3 mg/kg (210 mg for a 70 kg person) given to ha- bitual users improved reaction time and decreased false alarm rates in selective attention tasks. Streufert et al. (1997) evaluated the effects of 400 mg of caffeine added to regular caffeine consumption in moderate to heavy caffeine users (400-1,000 mglday) and found faster responses to incoming information. In sleep-deprived individuals, similar to those engaging in sustained opera- tions, caffeine at levels of approximately 100-600 mg appears to improve per- formance (e.g., vigilance, mood, higher cognitive functions) with few acute adverse behavioral effects; some of the positive effects may persist for 8-10 hours (Gander et al., 1998; Kuznicki and Turner, 1986; Lieberman, 1999; Mitchell and Redman, 1992; Reyner and Home, 2000; Rogers et al., 1995; Smith, 1999; Walsh et al., 1990, 1995~. Even individuals who do not normally consume caffeine appear to obtain these caffeine-related positive effects. An earlier report to the military concerning use of caffeine as a performance enhancer (IOM, 1994) indicated that two of the primary issues still needing resolution in providing caffeine to military personnel were the appropriate car- rier to provide the supplement and the amount required to achieve the desired benefit in personnel both habituated and nonhabituated to caffeine. The data reviewed in this report indicate that caffeine will improve cognitive performance regardless of habituation status and thus there is no need to have different dose levels. Caffeine doses between 100 and 600 mg that can be self-selected would be adequate for all personnel. CAFFEINE DELIVERY MECHANISMS Doses of caffeine could be delivered to military personnel during sustained operations in a variety of ways (e.g., tablet or capsule form, beverage, food, or gum). Each of these forms has advantages and disadvantages. For example, caffeine provided in pill or capsule form may not be as readily absorbed as caf- feine in a food or beverage. Brachtel and Richter (1992), in a letter to the editor of the Journal of Hepatology, described a study in which they compared the bioavailability of a base dose of 366 mg of caffeine from intravenous infusion, an oral dose in aqueous solution, and an oral dose as an uncoated tablet. Using the area under the curve of serum concentration over time, the bioavailability of caffeine in tablet form was found to be 80 ~ 16 percent, significantly lower than the 100 percent bioavailability for the intravenous and oral aqueous solution methods of
64 CAFFEINE FOR MENTAL TASK PERFORMANCE delivery. Liguori et al. (1997) compared absorption and subjective effects of 400 mg of caffeine administered in coffee, cola, and capsule form. Using salivary caffeine levels as an indicator, they found that peak increase in saliva levels was similar for coffee and cola, and somewhat lower from capsules. The time to peak saliva levels of caffeine was also similar for coffee and cola (42 and 39 minutes, respectively), but was slower for the capsule (67 minutes). Because caffeine is commonly consumed in the military (Lieberman, 1999) and most individuals are familiar with its effects, a clearly labeled caffeine product that permits self-dosing to obtain effective dose levels would appear to be appropriate. Such a self-dose might be provided in increments similar to those within the experience of most caffeine users (e.g., 100 lug). For example, a food/energy bar containing a total of 600 mg of added caffeine could be scored in 6 segments of 100 mg each, pills could be provided in doses of 100 mg each, or a pack of chewing gum could contain 100 mg/piece of gum. Caffeine (600 ma) in a beverage would make individual dose control more difficult unless supplied in dehydrated packets of beverage mix containing 100 mg of caffeine per packet to be reconstituted using an individually selected number of packets. Labeling would permit the few individuals who might experience adverse effects from use of caffeine, or whose religious beliefs precluded its use, to avoid it. The advantage of food or beverage delivery of caffeine is that it permits simultaneous provision of nutrients (e.g., water), consumption of which may otherwise be inadequate under the stress of sustained operations. Food or bever- age delivery also provides the ability to include substances that may potentiate the effects of caffeine (e.g., sugar). Since caffeine is a diuretic, beverages may have a particular advantage in situations in which dehydration is likely. How- ever, adherence to appropriate behavioral directives (e.g., adequate consumption of food and beverages) can reduce this risk. Sustained operations vary in their operational constraints. In aviation mis- sions, for example, low weight and compactness of the caffeine delivery mecha- nism (e.g., pills, gum) may have advantages over beverages and food bars, yet beverages and bars have the advantage of providing additional fluid and nutri- ents. Beverages have some advantages in certain situations. For example, dehy- dration at altitude is often a problem, and the beverage delivery system lessens this hazard; however, under these conditions thirst may not be sufficient to en- sure that an effective caffeine dose is consumed (IOM, 1996~. In addition, use of a caffeinated beverage, while light in weight if dehydrated, would require time and a water source for mixing, thus making it a less viable alternative than gum or a food bar. Foodlenergy bars have the advantage over beverages in their abil- ity to deliver a wider variety of other needed nutrients at equal weight; this is an important consideration in many missions. Pills and gums are both very light in weight and small in size, so they can easily be carried in pockets; gum has the advantage of stimulating salivation and enhancing the speed of absorption. It may be necessary to consider at least two caffeine delivery systems: food bars
DOSES AND DELIVERYMECHANISMS 65 and gum. Both can be manufactured to provide multiple doses in a single pack- age so that the individual can easily customize his or her optimal effective dose. There is some advantage in having caffeine increments constant at 100 mg (e.g., the score on the bar or the contents of one stick of gum should deliver the same dose) regardless of the delivery mechanism, so that the various forms are more or less interchangeable for self-dosing purposes. Often sustained operations missions must be altered with little advance notice. In the committee's judgment, it is important that the caffeine delivered be ab- sorbed and metabolized rapidly so that the beneficial effects on performance are present within an hour after administration. Moreover, the dose should not be released over a long time interval because beneficial effects may be delayed and changes in mission cannot easily be accommodated. Information presented in the previous chapters suggests that repeated caffeine dosing during sleep deprivation does not interfere with recovery sleep, suggesting little benefit other than conven- ience to sustained-release preparations over large single doses (Prusaczyk, 1999~. More frequent dosing with rapidly absorbed and metabolized forms of caffeine therefore appears to offer advantages over sustained-release preparations. SUMMARY Caffeine has been consistently found to enhance physical endurance per- formance when administered in amounts ranging from 150 to 650 ma. Similar amounts have also been found to enhance cognitive performance. Caffeine may be administered in a variety of ways, including as a pill or capsule, in a food bar, in a beverage, and in chewing gum. Delivery of caffeine in a food bar or as chewing gum appears to be most advantageous.
66 Conclusions CAFFEINE FOR MENTAL TASK PERFORMANCE 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 was hypothesized that these types of blood 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. 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 convincing evidence relates to caffeine and the increased risk of spontaneous abortion. 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 compensated by subsequent lower than normal calcium excretion. The use of caffeine in this case is less of a concern than is low calcium intake. High doses of caffeine (> 600 ma) can cause decrements in cognitive function. 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 military operations would not appear to pose any acute or chronic health risks for military personnel. Caffeine use in sustained operations in hot environments or at high altitudes may increase the risk of dehydration, and fluid and food intake of personnel should be closely monitored in these situations.