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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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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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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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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 80°F and 6 months at
100°F 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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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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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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Representative terms from entire chapter:
caffeine withdrawal
