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Appendixes

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A Workshop Agenda and Abstracts AGENDA Caffeine Formulations for Sustainment of Mental Task Performance During Military Operations Committee on Military Nutrition Research February 2-3, 1999 Tuesday February 2, 1999 8:30 a.m. Welcome on Behalf of the Food and Nutrition Board Dr. Allison A. Yates, Director, Food and Nutrition Board 8:40 Welcome on Behalf of Me Committee on Military Nutrition Dr. John Vanderveen, Chair, Committee on Military Nutrition Research Opening Comments on Behalf of the Military LTC Karl E. Friedl, U.S. Army Medical Research and Materiel Command, Fort Detrick, Frederick, MD Part I. Effects on Mental and Physical Performance Moderator: Dr. Robin Kanarek 9:00 9:35 General Overview of Military Interest and Research on Role of Caffeine in Physical and Cognitive Performance COL David Penetar, U.S. Army Research Institute of Environmental Medicine, Natick, MA Caffeine and Muscle Metabolism During Prolonged Exercise Dr. Lawrence Spriet, University of Guelph, Ontario, Canada 115

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116 10:10 10:45 10:55 1 1:30 CAFFEINE FOR MENTAL TASKPE~O~ANCE Effect of Caffeine on Cognitive Function and Alertness Dr. Harris Lieberman, U.S. Army Research Institute of Environmental Medicine, Natick, MA BREAK Caffeine and Sentry Duty Performance Dr. Richard Johnson, U.S. Army Research Institute of Environmental Medicine, Natick, MA Eyelid Movement as a Physiological Predictor of Cognitive Impairment During Sleep Deprivation Dr. Robert Stickgold, Harvard Medical School, Boston, MA 12:05 p.m. Circadian and Sleep Homeostatic Modulation of Sleep and Performance Dr. James Wyatt, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 12:40 LUNCH Moderator: Dr. Johanna Dwyer Caffeine Effects During Sleep Deprivation and Recovery Dr. Steven Smith, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA Circadian and Homeostatic Interactions in Waking Neurobehavioral Functions During Partial and Total Sleep Deprivation: Effects of Caffeine Dr. Hans Van Dongen, University of Pennsylvania School of Medicine, Philadelphia Caffeine Research in the Navy Dr. W.K. Prusacyk, Naval Health Research Center, San Diego, CA 3:30 DISCUSSION 3:50 BREAK

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APPENDIXA Part II. Safety Issues of Caffeine Supplementation Moderator: Dr. John Fernstrom 4:00 5:10 5:30 6:00 117 Caffeine as a Model Drug of Abuse Dr. Steve Holtzman, Emory University School of Medicine, Atlanta, GA Caffeine Physical Dependence and the Consequences of Caffeine Abstinence Dr. Roland Gri~iths, Johns Hopkins University School of Medicine, Baltimore, MD Positive Effects of Caffeine or Negative Effects of Withdrawal Dr. Andrew Smith, University of Bristol, United Kingdom DISCUSSION ADJOURN Wednesday, February 3, 1999 Part III. Caffeine Dose and Formulations Moderator: Dr. Gail Butterfield 9:00 a.m. Pharmacology of Caffeine Dr. Gary Kamimori, Walter Reed Army Institute of Research, Washington, DC 9:35 10:10 10:45 10:55 1 1:30 Caffeine Usage on Submarines Christine Schlichting, Naval Submarine Medical Research Laboratory, Groton, CT Design of a Food Matrix for the Delivery of Performance- Enhancing Components Dr. Jack Briggs, Natick Soldier Center, Natick, MA BREAK Caffeine and Carbohydrate Supplements for Physical Performance Dr. John Ivy, University of Texas, Austin DISCUSSION 12:00 noon LUNCH

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118 CAFFEINE FOR MENTAL TASKPE~O~ANCE Part IV. Alternatives to Caffeine for Mental and Physical Task Performance Moderator: Dr. Esther Sternberg 1: 15 p.m. Cognitive Performance Effects of Caffeine Versus Amphetamines Following Sleep Deprivation C~lPTMaryKautz,WalterReedArmyInstituteofResearch,Silver Spring, MD 1:50 2:25 3:00 4:00 Use of Amphetamine to Counteract Sleep Deprivation in Aviators Dr. John Caldwell, U.S. Army Aeromedical Research Laboratory, Fort Rucker, AL Effect of Prophylactic Naps and Caffeine on Alertness During Sleep Loss and Nocturnal Work Periods Dr. Michael Bonnet, Dayton Department of Veteran Affairs Medical Center, Dayton, OH DISCUSSION Summary and Closing Remarks Dr. John Vanderveen, Chair, Committee on Military Nutrition Research ADJOURN

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APPENDIX A 119 Workshop Abstracts The abstracts appear in the order in which they were presented during the workshop on "Caffeine Formulations for Sustainment of Mental Task Perform- ance During Military Operations," which was held on February 2-3, 1999, in Washington, D.C. GENERAL OVERVIEW OF MILITARY INTEREST AND RESEARCH ON ROLE OF CAFFEINE IN PHYSICAL AND COGNITIVE PERFORMANCE David Penetar, Ph.D. U.S. Army Research Institute of Environmental Medicine, Natick, MA The military's interest in caffeine is manifold and revolves around some of caffeine's basic behavioral effects: those of enhancing alertness, improving cognitive performance, and increasing physical capabilities. The degree and extent to which caffeine is an effective agent for producing these changes, espe- cially with regard to the stressful, severe, and at times life-threatening environ- ments in which military personnel operate, is a complex area for psychopharma- cological research. Modern warfare pushes the limits of human performance in many ways. Military operations can have severe disrupting effects on normal sleep patterns and contain periods of sustained high rates of work and carrying of heavy loads. This disrupted sleep coupled with heavy physical demands can affect critical decision making and other cognitive skills. Under certain circum- stances, pharmacological interventions may be warranted to prevent cognitive decrements as well as, possibly, the enhancement of physical performance. Sev- eral avenues of research have been pursued. The most notable effects of re- stricted and fragmented sleep are on alertness, mood, and cognitive abilities. Caffeine and other stimulants have been studied in both laboratory and field settings. These studies explore the effective dose range and time course of ac- tion. The use of caffeine to enhance physical performance in extreme environ- ments (e.g., high altitude) or under high workload is also an area of military interest. The question of enhancing cognitive performance beyond the normal well-rested state is not yet completely answered. Continued research will con- tribute to policies outlining the acceptability and usefulness of caffeine in mili- tary operations.

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120 CAFFEINE FOR MENTAL TASKPE~O~ANCE CAFFEINE AND MUSCLE METABOLISM DURING PROLONGED EXERCISE Lawrence L. Spriet, Ph.D. Human Biology and Nutritional Science, University of Guelph, Ontario, Canada Caffeine is a dietary pharmacological agent that is routinely ingested by people worldwide. It rapidly appears in the blood following ingestion, is taken up by the tissues of the body, and therefore has the potential to significantly alter metabolism. Many athletes also routinely ingest caffeine and there has been considerable interest in the ability of caffeine to enhance performance during prolonged aerobic exercise (Spriet, 1995~. Several, well-controlled studies have established that moderate doses of caffeine (3-6 mg/kg body mass, about 2 - , 8- oz cups of coffee) ingested 1 hour prior to exercise enhance endurance perform- ance in the laboratory at intensities of 70-85 percent of maximal oxygen uptake VO2maX (Costill et al., 1978; Graham and Spriet, 1995; Ivy et al., 1979; Pasman et al., 1995~. Moderate caffeine doses produce urinary caffeine levels well below the allowable limit set by sports governing bodies (12 ~g/mL), meaning that athletes can legally enhance their performance in this manner. Higher doses of caffeine (9-13 mg/kg body mass) also produce increases in laboratory endur- ance performance but are often associated with "illegal" urinary caffeine levels (> 12 ~g/mL) and a higher incidence of adverse side effects (Graham and Sphet, 1991; Pasman et al., 1995; Spriet et al., 1992~. The performance results are spe- cific to well-trained elite or recreational athletes. These studies also demonstrate a large variability between individuals in the metabolic and performance re- sponses to caffeine. Lastly, it is not known if these findings improve perfo~- ance in competitions because controlled caffeine field studies are lacking. The precise mechanisms responsible for improved performance during pro- longed exercise remain elusive. A central nervous system contribution to the improved performance is always a possibility when studying humans, since it is not possible to separate the "central" and 'peripheral" (skeletal muscle) effects of caffeine. However, it does appear that metabolic mechanisms are part of the explanation for the improvement in endurance performance following caffeine ingestion (5-13 mg/kg), except at low caffeine doses (2 - mg/kg) where this has not been fully examined. The decreased respiratory exchange ratio, increased concentration of plasma-free fatty acids (FFAs) at the onset of exercise, glycogen sparing in the initial 15 minutes of exercise, and increased intramuscular triacyl- glycerol use during the first 30 minutes of exercise suggest a greater role for fat metabolism early in exercise following caffeine ingestion (Chesley et al., 1998; Essig et al., 1980; Graham and Spriet, 1991; Ivy et al., 1979; Spriet et al., 1992~. It has been suggested that the increased fat oxidation and decreased glycogen use in muscle following caffeine ingestion could be explained by the classic glu- cose-fatty acid cycle. In this scheme, elevated FFA availability to the muscle produced increases in muscle citrate and acetyl-coenzyme A, that were believed to

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APPENDIXA 121 inhibit the enzymes phosphotructokinase and pyruvate dehydrogenase. The subse- quent decrease in glycolytic activity increased glucose 6-phosphate content, lead- ing to inhibition of hexokinase and ultimately decreased muscle glucose uptake and oxidation. However, these mechanisms were not involved in the glycogen sparing during exercise at approximately 85 percent VOW,, with caffeine inges- tion (Spriet et al., 1992~. Instead, the mechanism for muscle glycogen sparing following caffeine ingestion appeared related to the regulation of glycogen phos- phate activity via a more "defended" energy status of the cell. Subjects who spared muscle glycogen used less muscle phosphocreatine and had smaller increases in free adenosine 5'-monophosphate (AMP) and inorganic phosphate during exercise in the caffeine versus placebo trials (Chesley et al., 1998~. The lower inorganic phosphate and AMP concentrations decreased the flux through glycogen phospho- rylase and decreased glycogen use. There were no differences in these metabolites between trials in subjects who did not spare muscle glycogen. Presently, it is not clear how caffeine defends the energy state of the cell, but it may be related to an increased availability of fat and reducing equivalents (reduced nicotinamide-ade- nine dinucleotide) in the mitochondria at the onset of exercise. Therefore, while it is clear that metabolic changes contribute to the ergo- genic effect of caffeine during endurance exercise, aspects of the metabolic contribution have not been adequately examined in all situations. Measurements of muscle glycogen and triacylglycerol use and plasma FFA turnover are re- quired to determine the magnitude of the metabolic link to improved perform- ance at all caffeine doses and endurance exercise situations. EFFECT OF CAFFEINE ON COGNITIVE FUNCTION AND ALERTNESS Harris R. Lieberman, Ph.D. U.S. Army Research Institute of Environmental Medicine, Natick, MA Although the behavioral effects of caffeine have been a subject of scientific investigation for more than 100 years, it was not until recently that a clear pic- ture of the substance's effects have started to emerge. Caffeine's effects on cog- nitive function and mood can be detected in rested and sleep-deprived volun- teers using a variety of standardized tests. Only certain behavioral functions appear to be susceptible to the influence of moderate doses of caffeine. In par- ticular, it appears that in well-rested volunteers, low and moderate doses of caffeine (32-256 ma) preferentially affect functions related to vigilance the ability of individuals to maintain alertness and appropriate responsiveness to the external environment for sustained periods of time. Self-reported mood states that are related to vigilance, such as alertness, also are clearly improved by moderate doses of caffeine. Higher cognitive functions, such as memory and

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122 CAFFEINE FOR MENTAL TASKPERFORMANCE visuospatial reasoning, do not appear to be affected in any substantial manner when the substance is administered in moderate doses to rested volunteers. Among individuals who have been deprived of sleep, vigilance tests and mood questionnaires remain highly sensitive to the beneficial effects of caffeine. In addition, certain more complex cognitive functions also improve, although these effects may be secondary to improved vigilance. Recently we conducted a field study that demonstrated that even when volunteers are exposed to severe sleep deprivation in combination with mental, physical, and psychological stress, moderate doses of caffeine can partially restore vigilance and other key aspects of cognitive performance. This study may provide useful insight into the optimal dose of caffeine to employ under such circumstances. Maintenance of vigilance is critical for a variety of military duties such as standing watch, sentry duty, communication monitoring, and operating vehicles, including aircraft and vessels. During military operations a single individual can be responsible for the safety of hundreds of individuals traveling in his or her vehicle or being protected by his or her weapons system. Therefore, lapses in vigilance can have devastating consequences. Even in well-rested individuals vigilance significantly deteriorates after brief periods of attempting to maintain optimal alertness during boring but critical activities. During wartime or other intense operations, sleep loss and environmental and psychological stress greatly reduce the ability of individuals to maintain even marginally adequate vigilance. Therefore, administration of caffeine in appropriate doses at the correct times may be an effective method for substantially improving key aspects of cognitive function in rested and sleep-deprived war fighters. CAFFEINE AND SENTRY DUTY PERFORMANCE Richard F. Johnson, Ph.D. U.S. Army Research Institute of Environmental Medicine, Na tick, MA Proficient sentry duty performance requires both rifle marksmanship accu- racy and sufficient alertness to detect the infrequent appearance of targets. At the U.S. Army Research Institute of Environmental Medicine, the Weaponeer M16 Rifle Marksmanship Simulator, a U.S. Army training device, has been adapted for assessing the components of sentry duty (target detection and rifle firing accuracy). Our research has shown that during 3 hours of baseline sentry duty, the soldier's speed of target detection becomes slower while rifle firing . . . accuracy remams ummpalrec . In our first caffeine study with the sentry duty model, we tested the effects of the ingestion of 200 mg of caffeine on male soldiers' target detection speed and rifle firing accuracy. Target detection speed under the placebo condition deteriorated with time and was significantly slower after 60-90 minutes on the task. Under the caffeine condition, the impairment in target detection speed was

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APPENDIX A 123 significantly attenuated. Regardless of drug condition, rifle firing accuracy showed no impairment during sentry duty. Our second caffeine study was sponsored by the Defense Women's Health Research Program and focused on the sentry duty performance of both men and women. Both men's and women's target detection speeds deteriorated with time on sentry duty, and this performance decrement was eliminated by 200 mg of caffeine. While men's rifle-firing accuracy remained constant over time, women's rifle firing accuracy deteriorated after 90 minutes, regardless of drug condition. Our third caffeine study, recently completed, was a replication and exten- sion of the second and introduced the requirement to discriminate friendly from enemy targets. The decrement in both men's and women's target detection speed with time on sentry duty was again eliminated by 200 mg of caffeine. As in the second study, women's rifle firing accuracy was poorer than that of men's, but the relationship with time on the task was complex and did not clearly replicate the results of the second study. Compared to placebo, the number of correct target identifications (friend versus foe) was significantly improved by 200 mg of caffeine. Conclusions 1. Efficacy: Without impairing rifle-f~ring accuracy, 200 mg of caffeine improves target detection speed and increases the likelihood of correct friend- foe target identifications during simulated sentry duty. 2. Safer: No adverse effects of caffeine were observed during these studies. 3. Dose: In sentry duty, effects of caffeine in doses other than that used in these studies (200 ma) is unknown. 4. Alternatives: Sentry duty of less than 60 minutes' duration does not lead to a decrement in performance and would not benefit from the prior ingestion of caffeine. 5. Formulation: We have tested caffeine only in the 200-mg tablet form. EYELID MOVEMENT AS A PHYSIOLOGICAL PREDICTOR OF COGNITIVE IMPAIRMENT DURING SLEEP DEPRIVATION Robert Stickgold, Ph.D. Department of Psychiatry, Harvard Medical School, Boston, MA Overall cognitive performance is modulated during sleep deprivation by both homeostatic and circadian factors. However, on a shorter time scale, performance decrements can be reversed by heightened interest and attention on the part of the subject. Within this context, it would be valuable to be able to easily monitor levels of functional arousal using physiological rather than behavioral measures. From a theoretical perspective, this would allow clarification of the role of atten-

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132 CAFFEINE FOR MENTAL TASK PERFORMANCE repeated past exposure) and physical dependence (behavioral disruptions upon termination of repeated drug administration). POSITIVE EFFECTS OF CAFFEINE OR NEGATIVE EFFECTS OF CAFFEINE WITHDRAWAL Andrew Smith, Ph.D., and G.H. Rubin Health Psychology Research Unit, Department of Experimental Psychology University ofBristol, United Kingdom This paper will consider the extent to which differences between caffeinated and decaffeinated conditions reflect the positive effects of caffeine or the nega- tive effects of caffeine withdrawal. The background to this debate is presented and the relevant literature reviewed. It is concluded that the absence of strong negative effects of caffeine withdrawal on performance, and the demonstration of positive effects in nonconsumers, support the view that caffeine enhances performance and does not just remove impairments induced by withdrawal. The second part of the paper will consider in detail the health consequences of withdrawal. Results on headaches and caffeine withdrawal will be discussed and it will be concluded that the increased incidence of headaches following caffeine withdrawal reflects factors such as expectancies and the ability to de- termine whether the caffeine has been withdrawn or not. This view will be con- trasted with those suggesting a pharmacological addiction to caffeine. Abstract Previous research has shown that cessation of caffeine consumption may be associated with a distinct withdrawal syndrome, typified by an increase in head- aches. Recent research suggests that low to moderate consumers of caffeine may report an increase in headaches if they perceive caffeine to have been withdrawn regardless of whether it has been or not. The present study provides additional support for the role of subjective perceptions in the caffeine withdrawal syn- drome. Forty-four low-caffeine consumers recorded the incidence of headaches when drinking caffeinated or decaffeinated beverages. When caffeine was with- drawn the incidence of headaches increased, but this effect was significant only in those individuals who could discriminate whether they were consuming caf- feinated or decaffeinated beverages. This result suggests a major role of subjec- tive perceptions and expectancies in the caffeine withdrawal syndrome, a view that contrasts the notion that a significant proportion of caffeine consumers are physically dependent upon caffeine.

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APPENDIXA 133 Introduction A number of studies have demonstrated that cessation of caffeine consump- tion may result in a distinct withdrawal syndrome, typified by the occurrence of headaches (Dreisbach and Pfeiffer, 1943; Griffiths et al., 1990; Strain et al., 1994; van Dusseldorp and Katan, 1990~. In the light of this evidence, caffeine withdrawal syndrome has been included in DSM-IV. These studies have tended to use individuals with histories of chronic high-dose caffeine consumption (2 500 ma) or else have increased the caffeine intake of participants to very high levels during the caffeinated condition of the experiment itself. Even with high- caffeine consumers the proportion of participants who report headaches during withdrawal has ranged from 25 to 100 percent. Similarly, those studies that have investigated withdrawal in low-dose consumers (< 200 ma) have found that headache reporting varies from 20 percent of the sample (Fennelly et al., 1991) to 50 percent (Silverman et al., 1992) or even 100 percent (Naismith et al., 1970) Results from a recent study (Smith, 1996) suggest that low- to moderate- caffeine consumers may report an increase in headaches when they perceive caf- feine to have been withdrawn regardless of whether it has been or not. The re- porting of headache is seen, therefore, as a combination of an expectancy that caffeine withdrawal may increase headaches and the ability to discriminate whether caffeine has actually been withdrawn. This view is very different from previous assertions that a significant proportion of low- to moderate-caffeine con- sumers are physically dependent upon caffeine. Support for the role of subjective perceptions comes from our latest study of this issue, which is described below. Method Participants Forty-three regular caffeinated tea and coffee consumers (22 females, 21 males, mean age 21.1 years, range 18-26 years) participated in a study examining the effects of caffeine withdrawal on reporting of headaches. Mean reported daily caffeine consumption from these sources was 175 mg (standard deviation = 91 ma; based on caffeine content of products provided by Debry [19944~. Each vol- unteer carried out a 2-day baseline period during which normal caffeine consump- tion was recorded using a diary, and headaches and other symptoms were meas- ured. For all volunteers, either tea or coffee was the major source of caffeine. Following this the volunteers were given supplies of either caffeinated or decaf- feinated tea and coffee and told to continue with their normal pattern of consump- tion but to use only the coffee and tea supplied. Volunteers were blind with regard to which days they were given decaffeinated products or caffeinated products. They were told to stop their normal consumption of other caffeinated products such as chocolates or soft drir~cs. Each volunteer carried out both caffeinated and

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134 CAFFEINE FOR MENTAL TASKPERFORMANCE decaffeinated conditions for 2 days, the order of conditions being counterbalanced across participants. In addition to recording the presence or absence of headache and other symptoms, volunteers were asked whether they believed the beverages consumed that day to have been caffeinated or decaffeinated. Results The results showed that there was no significant difference in reporting headaches in the baseline (14.0 percent of sample reported a headache) and caffeinated drink conditions (18.6 percent). However, when caffeine was with- drawn, the frequency of headache increased to 39.5 percent (significantly greater than both baseline and caffeinated conditions, p < 0.01~. Further analyses re- vealed that the effect of caffeine withdrawal depended on whether the partici- pants were able to discriminate whether caffeine was present or not (22 partici- pants correctly identified the two conditions). An analysis of variance showed that the condition x ability to discriminate caffeine was significant (F (2, 78) = 4.29, p < 0.05~. For those who could tell whether caffeine was withdrawn or not, headache frequency increased from 7 percent in the baseline and 9.3 percent in the caffeinated condition to 48.8 percent in the decaffeinated condition. In con- trast to this, caffeine withdrawal had little effect on headache reporting in those unable to tell the nature of the beverages (see Figure 1~. Overall, the observed effect of caffeine withdrawal on headache frequency appeared to be due entirely to the reporting of headaches by those participants who were able to correctly identify whether caffeinated or decaffeinated drinks were consumed. Discussion Three possible explanations exist to explain the link between reporting of headaches and ability to discriminate whether or not the drinks were caffeinated. First, some individuals may develop headaches during caffeine withdrawal and use the increased symptoms to help identify the nature of the drinks. Alterna- tively, those individuals who could identify the nature of the drinks would then be influenced by the expectancy that caffeine withdrawal increases headache frequency. In contrast, those unable to discriminate between caffeinated and decaffeinated conditions would show no difference in headache frequency in these two conditions but should report an increase relative to baseline. This was found here. Finally, it is possible that both mechanisms may be involved in the overall pattern of results. In this context, one can view the expectancy effect as a factor that has inflated estimates of the number of people who are dependent on caffeine rather than being a total explanation for the caffeine withdrawal-head- ache association. Studies of headaches in patients withdrawn from caffeine prior to surgery suggest that headache frequency is around 25 percent. Given that

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APPENDIX A 50 ~ 45 ~ 40 35 ~ 30 ~ 25 ~ 20 ~ 15 10 ~ 5 ~ O ~ ~ Could Discriminate IO Unable to Discriminate mu. Baseline De-caffeinated Drinks CONDITIONS Caffeinated Drinks FIGURE 1 Percentage of volunteers reporting headaches in the various condi- tions (those who correctly identified the caffeine versus those who could not). 135 baseline headache rate in nonwithdrawn volunteers studied here was nearly 15 percent, one can see that we are clearly not looking at a large effect. Indeed, it may be that individuals who regularly get a lot of headaches do not show an increase when caffeine is withdrawn and are also poor at discriminating whether they have been consuming caffeinated beverages or not. Further research is required to resolve this issue. Conclusion In conclusion, the present study has demonstrated that the increased fre- quency of headaches during caffeine withdrawal reflects participants' detecting they are in that condition and reporting the symptoms they expect to be associ- ated with it. Further research should address the direction of causality between perceptions of caffeine content and withdrawal symptoms. In addition, the ex-

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136 CAFFEINE FOR MENTAL TASK PERFORMANCE tent to which similar effects are observed in those who consume higher doses of caffeine requires further investigation. Acknowledgment Professor Smith's caffeine research is supported by the Physiological Effects of Caffeine Research Fund of the Institute for Scientific Information on Coffee. PHARMACOLOGY OF CAFFEINE Gary H. Kamimori, Ph.D. Department of Neurobiology and Behavior, Division of Neuropsychiatry, Walter Reed Army Institute of Research, Washington, DC Caffeine is one of the most widely used drugs in the world. It is a naturally occurring stimulant that has a variety of unique characteristics. Although the pharmacokinetics and pharmacodynamics of caffeine have been the subject of thousands of studies over the past century, many of its characteristics (e.g., mechanisms of action, stimulant properties) are still unclear. The purpose of this presentation is to provide an overview of current knowledge pertaining to the pharmacokinetic characteristics, efficacy, safety, dynamic effects, and possible formulations for the delivery of caffeine. In addition, we review past and current caffeine research from the Department of Neurobiology and Behavior of the Walter Reed Army Institute of Research. DESIGN OF A FOOD MATRIX FOR THE DELIVERY OF PERFORMANCE-ENHANCING COMPONENTS Jack Briggs, M.S. U.S. Army Soldier Biological Chemical Command, Natick Soldier Center, Natick, MA The utilization of performance-enhancing agents has a two-fold approach. First, the efficacy of the agent must be established using physiological and/or cognitive measurements. Second, a delivery system is necessary that ensures timely availability of the agent to the physiological point of need. There are several delivery systems currently available: transdermal, pills (including time release), inhalants, injections, and incorporation of the agent into food. The mode of delivery for the military is incorporation into common foods and re- striction of any performance agent to that of a natural food constituent such as proteins, amino acids, antioxidants, and caffeine. There are several considera- tions when incorporating performance-enhancing agents into foods:

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APPENDIX A 137 1. compatibility of the agent with the other food components, 2. shelf-life stability, 3. physiological uptake and delivery of the agent to the target organs, and 4. acceptance of the food item to ensure consumption of nutrients in the fortified item. The military shelf-life requirements of 3 years at 80F and 6 months at 100F make this even more challenging than commercially developed products, which have a shorter shelf life. This paper focuses on the development of a chocolate-caffeine food bar and placebo to be used in physiological performance testing. The bar was designed to deliver 6 mg of caffeine per kg weight of the subject (i.e., a 75-g bar for a 105-kg subject would contain 632 mg of caffeine, equivalent to 6 cups of coffee). In order to mask this level of caffeine, a chocolate mocha-flavored bar matrix was chosen. The bar weight was adjusted to maintain consistent dose weight for vari- able subject weights. Caffeine is a very bitter ingredient, which creates food technological challenges in developing an acceptable product, as well as a pla- cebo that looks and tastes like the product. The bars were fed to military subjects prior to physical training. Caffeine uptake and distribution were monitored over a 2-hour period by analysis of caffeine in the subject's saliva. CAFFEINE AND CARBOHYDRATE SUPPLEMENTS FOR PHYSICAL PERFORMANCE John L. Ivy, Ph.D. Exercise and Metabolism Laboratory, Department of Kin esiology and Health Education, University of Texas, Austin Both caffeine and carbohydrate supplementation have been found to have ergogenic effects on aerobic endurance and athletic performance. The means by which these supplements induce their ergogenic effects occur through different mechanisms of action and may be influenced by the type and intensity of exer- cise. There is ample evidence that caffeine improves aerobic endurance by in- creasing fat oxidation and sparing muscle. This is very beneficial for prolonged aerobic exercise in which muscle glycogen is a required fuel source. Caffeine also appears to function as a neurological stimulant and may improve aerobic endurance and exercise performance at high exercise intensities by reducing perception of effort and masking symptoms of fatigue. During prolonged low- intensity exercise, or prolonged exercise that varies from low to moderate inten- sity, carbohydrate supplementation improves aerobic endurance by increasing reliance on blood glucose and sparing muscle glycogen. When the exercise is moderately intense (65 to 75 percent, VO2~,aX)' carbohydrate supplementation does not spare muscle glycogen but enhances aerobic endurance by preventing the onset of hypoglycemia and maintaining an adequate rate of carbohydrate

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138 CAFFEINE FOR MENTAL TASK PERFORMANCE oxidation. Because the ergogenic effects of caffeine and carbohydrate supple- mentation occur through different mechanisms of action, it can be theorized that their effects on endurance performance would be additive. However, carbohy- drate supplementation blunts the exercise-induced increase in lipolysis and in- hibits fat oxidation. Therefore, the ergogenic effect of caffeine may actually be blunted, rather than enhanced, by the addition of carbohydrate to a caffeine supplement. Whether the combination of caffeine and carbohydrate supplements functions additively or antagonistically may depend on the type and intensity of exercise being performed and the timing of the supplementation. These condi- tions are discussed with regard to the ergogenic effects of each supplement. COGNITIVE PERFORMANCE EFFECTS OF CAFFEINE VERSUS PHETAMINE FOLLOWING SLEEP DEPRIVATION Mary A. Kautz, Ph.D. Department of Neurobiology and Behavior, Walter Reed Army Institute of Research' Washington' DC With sustained military operations, round-the-clock work schedules often lead to sleep deprivation. It has been well documented that sleep deprivation impairs cognitive performance and alters mood, with a consequent increased threat to safety and productivity in a variety of industrial and military settings. Stimulants have long been used to reduce the effects of sleep loss and to coun- teract the sleepiness resulting from irregular work-rest hours. A number of studies in our laboratory at Walter Reed Army Institute of Research have ex- amined the effects of stimulant administration following prolonged periods of wakefulness. Here, we present a comparison of the effects of caffeine and am- phetamine in subjects who are tested through a total of 64 hours sleep depriva- tion. Performance, alertness, and mood measurements were taken throughout the study. At 48 hours of sleep deprivation, a dose of caffeine (150, 300, or 600 mg), amphetamine (5, 10, or 20 mg), or placebo was administered, and testing continued for at least 12 hours postdose. Both compounds, at the highest dose tested for each, produced comparable results in the following ways: cognitive performance improved and was sustained for 12 hours; measures of objective alertness improved; and there was an improvement in self-ratings of mood. There were also some adverse side effects, with amphetamine producing mild cardiovascular disturbances, disruptions in recovery sleep, and feelings of euphoria, while caffeine resulted in increased subjective reports of tremor and ratings of anxiety. Our recommendation is that given the universal availability and socially acceptable use of caffeine (with relatively few adverse side effects), it can be used only to "postpone" sleep up to 12 hours, not to replace it. Future studies in our laboratory will assess the synthetic compound modafinil, currently indicated for improving alertness in narcoleptics, and compare modafinil to

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APPENDIX A 139 caffeine and amphetamine in our standard paradigm of measuring cognitive performance, alertness, and mood. USE OF AMPHETA1VIINE TO COUNTERACT SLEEP DEPRIVATION IN AVIATORS John Caldwell, Ph.D. Sustained Operations Research, U.S. Army Aeromedical Research Laboratory, Fort Rucker, AL The purpose of this investigation was to establish the efficacy of dexedrine for sustaining aviator performance despite 64 hours of extended wakefulness. Although earlier flight studies yielded favorable results with no significant side effects, they were restricted to sleep deprivation periods of only 40 hours. Due to requirements for longer periods of sustained wakefulness, it was necessary to study the efficacy of dexedrine in maintaining aviator performance during 3 days and 2 nights without sleep. To accomplish this, computerized evaluations of aviator flight skills were conducted at regular intervals as subjects completed standardized flights in a UH-60 helicopter simulator, under both dexedrine and placebo. Laboratory-based assessments of cognitive, psychological, and central nervous system status were completed as well. Dexedrine (10 ma) was given prophylactically (prior to signs of fatigue) at midnight, 0400, and 0800 on both deprivation days in one cycle, and placebo was given on both days in the other. Results indicated that simulator flight performance was maintained by dexedrine for up to 58 hours, while performance under placebo deteriorated significantly. The drug was most beneficial at 0500 and 0900 on the first depri- vation day, but it continued to attenuate impairments throughout 1700 on the second deprivation day (after 58 hours awake). Dexedrine likewise lessened the slowing of response times, the impairments in problem identification, and the reductions in performance capabilities that were evident in the cognitive data under placebo. The positive effects of dexedrine were noticeable after only 22 hours of sustained wakefulness but were most evident between 0500 and 1200 on both deprivation days (the times at which performance under placebo suf- fered the most). These were the same times at which the differences between dexedrine and placebo were most apparent in the flight data. Dexedrine sup- pressed the increases in slow-wave electroencephalogram (EEG) activity (asso- ciated with impaired alertness), which began to occur under the placebo condi- tion after 23 hours of continuous wakefulness. The medication then attenuated a further increase in slow EEG activity that was present throughout 55 hours (and sometimes 59 hours) of deprivation. At the same time, dexedrine (compared to placebo) clearly sustained self-perceptions of vigor, alertness, energy, and talka- tiveness, while reducing problems with fatigue, confusion, and sleepiness. Mood declines were observed after 20 hours without sleep under the placebo condition,

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140 CAFFEINE FOR MENTAL TASK PERFORMANCE and these were followed by further decrements that were most noticeable after 48 hours of continuous wakefulness. Ratings actually improved under dexedrine at several times. Recovery sleep was slightly less restful under dexedrine even though the last dose was 15 hours before bedtime (dexedrine has an average half-life of 10.25 hours). Thus, at least two nights of recovery sleep should be required after dexedrine is used to delay sleep for 64 hours. There were no clinically significant side effects that led to the discontinua- tion of any participant; however, one subject experienced an increase in diastolic blood pressure that would have been cause for concern had it not decreased when the subject was retested in a prone position. Some aviators complained of palpitations and "jitteriness" under dexedrine, but this did not detract from their performance. One of the subjects became very excitable and talkative under the influence of dexedrine, but he did not become reckless or dangerous. In summary, prophylactic dexedrine administration substantially reduced the impact of sleep loss in the early morning hours and, for the most part, pre- served performance for the remainder of the day in a 64-hour bout of continuous wakefulness. The beneficial effects of dexedrine are most apparent during the circadian trough where performance and alertness under placebo are the worst. Thus, when proper restorative sleep is not available due to operational con- straints, dexedrine should be considered an effective countermeasure; however, it should not be used as a substitute for sleep. Proper crew rest management must remain a top priority to preserve our tactical advantage on the battlefield. EFFECT OF NAPS AND CAFFEINE ON ALERTNESS DURING SLEEP LOSS AND NOCTURNAL WORK PERIODS M.H. Bonnet, Ph.D. and D.L. Arand, Ph.D. Dayton Department of Veterans Affairs Medical Center, Wright State University, and Kettering Medical Center, Dayton, OH This work was performed at the Long Beach Veterans Administration Medical Center and the San Diego Naval Health Research Center and supported by a Merit Review Grant from the Department of Veterans Affairs, the Sleep- Wake Disorders Research Institute, and the Naval Medical Research and Devel- opment Command, Department of the Navy, Bethesda, Maryland, under Re- search Work Unit 61153N MR. 04101-03-6003. The views presented in this paper are those of the authors. No endorsement by the Department of the Navy has been given or should be inferred. Methods Three studies involving 176 male college students or naval recruits have ex- amined alertness and performance over extended periods of sleep loss. Subjects

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APPENDIX A 141 were chosen to be in good health, to have normal sleep habits, and to be moder- ate daily caffeine users (250 mg or less). In the first study, groups either (1) went for 64 hours with no sleep or caffeine, (2) had prophylactic naps of 2, 4, or 8 hours prior to sleep loss, or (3) received caffeine at 150, 300, or 400 mg during sleep loss. In the second study, subjects had a 4-hour prophylactic nap prior to sleep loss and then additionally received caffeine at 200 mg (eleveine) during the night. In the third study, subjects either had a 4-hour prophylactic nap prior to sleep loss and received 200 mg of caffeine (eleveine) during the night or had four 1-hour naps during the night. Results The results of the first study showed a dose-response effect for length of prophylactic nap and caffeine. Alertness and performance during sleep loss were significantly improved compared to the placebo no-nap group. Alertness was increased most by 8 hours of sleep. The improvement after caffeine use was more similar to that seen after 2 - hours of additional sleep, except that the effects of caffeine were limited by its metabolic half-life. None of the interven- tions were able to overcome the profound loss of alertness on the second night of sleep deprivation. The results of the second study indicated that the beneficial effects of caffeine and prophylactic naps were additive (i.e., a prophylactic nap followed by nocturnal use of caffeine left nocturnal alertness and performance at daytime baseline levels). The third study showed that a prophylactic nap fol- lowed by nocturnal use of caffeine was superior in maintaining nocturnal per- formance compared to a series of nocturnal naps, perhaps because the nocturnal naps resulted in sleep inertia.

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