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Performance-Maintaining and Performance-Enhancing Drugs and Food Components

Chapter 4

PERFORMANCE-MAINTAINING AND 

PERFORMANCE-ENHANCING DRUGS 

AND FOOD COMPONENTS

HARRIS R. LIEBERMAN, PhD*; JESSICA CAIL, PhD†; and KARL E. FRIEDL, PhD‡

INTRODUCTION

SEDATIVE-HYPNOTICS AND ANTIANXIETY AGENTS

Barbiturates

Benzodiazepines and Related Compounds

Antihistamines

Melatonin

Buspirone

STIMULANTS

Dextroamphetamine and Methamphetamine

Methylphenidate

Pemoline

Other Amphetamine-Like Stimulants

Summary of Traditional Stimulants

Modafinil 

FOOD CONSTITUENTS THAT MAY ENHANCE OR SUSTAIN PERFORMANCE

Tryptophan

Tyrosine

Caffeine

Carbohydrate Foods

POTENTIAL APPLICATIONS OF CAFFEINE

ETHICAL ISSUES ASSOCIATED WITH THE SANCTIONED USE OF DRUGS IN 

THE MILITARY

SUMMARY

*Research Psychologist, Military Nutrition Division, US Army Research Institute of Environmental Medicine, Building 42, Kansas Street, Natick, 

Massachusetts 01760-5007 

†Visiting Professor of Psychology, Social Science Division, Pepperdine University, 24255 Pacific Coast Highway, Malibu, California 90263; formerly, 

Experimental Psychologist, Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, Massachusetts 

‡Colonel, Medical Service Corps, US Army; Director, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel 

Command, Building 1054, Patchel Street, Fort Detrick, Maryland 21702-5012; formerly, Commander, US Army Research Institute of Environmental 

Medicine, Natick, Massachusetts 
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Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

INTRODUCTION

issue and that—other than mild rebound depression 

and fatigue when the drugs were discontinued—no 

adverse effects were reported. In addition, he noted 

that the LRRPs found that such drugs were particularly useful when a rapid return to base camp was 

necessary after completing a mission.1 Amphetamines 

and caffeine have been the most studied performance 

enhancers in the military, with significant research programs focused on fatigue countermeasures in aviators 

conducted by the Naval Aviation Medical Research 

Laboratory (NAMRL; Pensacola, Fla), the US Army 

Aeromedical Research Laboratory (USAARL; Fort 

Rucker, Ala), and the Human Performance Effectiveness Division (School of Aerospace Medicine, Brooks 

Air Force Base, San Antonio, Tex). 

The medical literature contains few published reports on the use of performance-enhancing or performance-sustaining drugs in combat or in combat-like 

conditions. To illustrate some of the issues associated 

with the use of drugs during military combat operations, a detailed discussion of one report is presented 

This chapter discusses drugs and food constituents 

that could potentially enhance mental performance on 

the battlefield or in other intense military operations. 

Other strategies to enhance cognitive performance, 

such as behavioral techniques (including training 

and behavior modification), are not addressed, nor 

is physical performance enhancement. Psychoactive 

substances have been used in combat for thousands of 

years. Alcohol has a long history of use on the battlefield, probably as a result of the euphoric feeling and 

loss of inhibition it can produce. In modern times, the 

most extensive, officially sanctioned use of drugs to 

enhance performance in combat has been the use of 

amphetamines by most armies, including the US Army, 

during World War II. These stimulants prevented 

fatigue and drowsiness, and improved concentration 

and memory.1 According to a psychiatrist assigned to 

the 25th Infantry Division during the Vietnam War, 

Long-Range Reconnaissance Patrol (LRRP) soldiers 

used methylphenidate and dextroamphetamine regularly.1 He stated that these compounds were standard 

Fig. 4-1. These technologically advanced aircraft permit long duration missions that push the limits of human endurance, 

requiring special consideration to fatigue countermeasures for the aircrew.

Photograph: Reproduced from the US Air Force. Image ID: 060214-F-6911G-135. Available at: http://www.af.mil/photos.
95

Performance-Maintaining and Performance-Enhancing Drugs and Food Components

to provide a frame of reference for the reader. This 

report, which provided considerable valuable (albeit 

anecdotal) information on the use of drugs during a 

combat mission, appeared in the 1988 issue of Aviation, 

Space, and Environmental Medicine as the first “Operational Note” ever published in that journal.2 It was 

written by a US Air Force flight surgeon who provided 

support to an EF-111A Raven unit that was responsible 

for electronic warfare during an air strike on Libya in 

April 1986 (Figure 4-1). The mission originated in the 

United Kingdom and lasted approximately 13 hours, 

with the aircraft departing at 1800 hours and returning 

the next morning. Even though it was only a single 

12-hour flight, the anticipated fatigue and stress of 

this combat mission were sufficient enough for the 

unit commander to request pharmacological support 

for his pilots. The flight surgeon was asked to provide 

go/no-go medications to the unit. Thus, he issued 

secobarbital (Seconal, 100 mg [Eli Lilly and Company, 

Indianapolis, Ind]) and dextroamphetamine sulfate 

(Dexedrine, 5 mg [GlaxoSmithKline, Philadelphia, Pa]) 

to all crew members. Operational requirements of the 

one-time mission provided a striking illustration of 

the complex and difficult physiological and behavioral 

factors associated with even a single combat mission. 

Many problems that occur in short duration missions 

are exacerbated during sustained operations. The 

severe decrements in cognitive performance associated with sustained, combat-like operations are much 

greater than those produced by alcohol intoxication or 

clinical hypoglycemia.3,4 For a detailed discussion of 

fatigue, sleep, and cognitive performance, see Chapter 

3 (Measuring and Predicting Sleep and Performance 

During Military Operations) in this volume.

Before the Libya mission, almost all aircrew members reported an inability to sleep for 24 hours because 

of the high level of physical and mental stress associated with preflight preparations. However, none of 

the crew used the secobarbital reportedly because 

they did not have confidence in it, although all of them 

had documented ground testing with the drug in their 

medical records. Perhaps their prior experience with 

the drug convinced the crew members that it could 

have adverse effects on their next-day performance. 

Indeed, some crew members explicitly reported that 

they did not trust using the medication before such a 

crucial mission. This may have been an appropriate 

decision because barbiturates can impair performance 

the day after they are used as hypnotics. During the 

prestrike portion of the mission, the crew members 

reported nervousness (including gastrointestinal distress), but had no problem staying alert. However, on 

the return leg of the mission, after their final in-flight 

refueling, the crew definitely noticed the fatigue and 

stress of the previous 24 hours. All of them took the 

dextroamphetamine and reported benefiting from 

it. This may have occurred at the nadir of the crews’ 

circadian cycle because they landed between 0600 and 

0700 hours. No definitive conclusions should be drawn 

from this illustration, but military physicians must be 

prepared to consider the issues associated with the use 

of drugs and other performance-enhancing strategies 

in combat.

Similar reports regarding the use of go/no-go medications by aviation units during the sustained, highintensity air operations of the Persian Gulf War have 

also appeared in the literature, although they have only 

been published as abstracts.5–7 One report concluded 

that approximately 60% of US Air Force Tactical Air 

Command aircrew occasionally used dextroamphetamine during operations in the Persian Gulf War.7

Dextroamphetamine was also used by the US Air Force 

during Operation Enduring Freedom in Afghanistan. 

Its use was widely publicized because several pilots 

were using it when they were involved in a friendly 

fire incident, and there was some concern that the pilots’ judgment may have been impaired by the drug.8

This chapter is not intended as a comprehensive 

review of all the literature available on each class of 

drugs or food constituents of interest nor has every 

compound that could potentially enhance performance 

been reviewed. Rather, classes of compounds that are 

likely to be considered for use or that have previously 

been used on the battlefield or in intense, stressful military operations will be discussed. The improvement 

in our understanding of structure–function relationships of these drugs and advances in neurophysiology 

should enable a more systematic modeling of when 

and how drugs and nutritional supplements can most 

effectively optimize performance (see Chapter 3, Measuring and Predicting Sleep and Performance During 

Military Operations). 

SEDATIVE-HYPNOTICS AND ANTIANXIETY AGENTS

The use of compounds that are generally categorized as central nervous system (CNS) depressants to 

enhance or sustain performance would, at first glance, 

seem to be a paradox. However, such compounds have 

repeatedly been studied and used in military operations to promote sleep at desired times9

 (Figure 4-2). 

By ensuring that soldiers sleep at appropriate times, 

subsequent mental performance will be preserved or 

improved. A number of studies have been conducted 

to induce or maintain sleep at desired times with 
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Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

the use of drugs, as well as other compounds with 

sedative-like properties (eg, the dietary amino acid 

tryptophan and the hormone melatonin). Hypnotics 

or sedatives have also been used in attempts to speed 

reentrainment of circadian rhythms when military 

units cross multiple time zones or shift from day to 

night operations.10–12 Many drugs with hypnotic or 

sleep-inducing properties also have potent antianxiety 

effects. Such properties could, in theory, also be useful 

on the battlefield or in other high-intensity, stressful 

operations. However, the hypnotic-sedative effects of 

these compounds, including their adverse effects on 

mental performance, generally exclude their use as 

antianxiety agents in combat.

Sedative-hypnotic drugs are used to treat anxiety 

and insomnia, and in some cases to prevent epileptic 

seizures. Although each drug has its preferred clinical 

usage, sedative-hypnotics are often capable of inducing various states of sedation, ranging from mild relief 

to deep sedation, depending on the dose. Thus, a drug 

commonly prescribed for its antianxiety effects may 

induce lethargy and sleep at higher doses. The decision 

regarding which drug to prescribe for a particular clinical condition is often based on its elimination half-life 

and side-effect profile.

Many of the older sedative-hypnotics, such as 

the barbiturates, produce widespread depression 

of the CNS. However, the benzodiazepine sedativehypnotics—that interact with g-aminobutyric acid 

(GABA)-benzodiazepine receptor sites—are potent 

antianxiety agents, have excellent utility as hypnotics, and rarely produce nonspecific CNS depression 

when used in appropriate doses. Zolpidem (Ambien 

[Sanofi-Aventis U.S., Bridgewater, NJ]), an imidazopyridine, and similar compounds such as zaleplon 

(Sonata [King Pharmaceuticals, Inc, Bristol, Tenn]) 

also act at these sites, although these compounds have 

a higher affinity for benzodiazepine type 1 receptor 

sites than the type 2 sites. The traditional benzodiazepines are nonselective, binding with equal affinity 

to both type 1 and type 2 receptors. The azaspirone 

compound, buspirone—an antianxiety agent not 

pharmacologically related to the benzodiazepines, 

barbiturates, or any other sedating hypnotic—does 

not seem to have potent hypnotic properties and 

could, at least in theory, be used for its antianxiety 

properties in military operations. Although its precise 

mechanism of action is unknown, it has a high affinity for serotonin receptors, but not GABA receptors. 

There is a low incidence of nonspecific depression 

when buspirone is used appropriately.

The following sections are subdivided by class of 

drug discussed. Barbiturates, benzodiazepines and 

related compounds, and buspirone are discussed in 

detail. Melatonin, which has hypnotic properties, 

will also be reviewed. For practical purposes, a key 

question for ongoing review is, “What are the residual 

effects when a sedative-hypnotic is used to promote 

sleep the night before an important activity?” Another 

issue is whether the compound impairs performance 

during the period of time when it is being used to 

induce and maintain sleep. This is an important issue 

in military applications, because emergencies may 

arise even when personnel are off duty. Of course, the 

answer to these questions varies among drugs, dosages, and even individual subjects; but experimental 

examples are given to illustrate the most probable effects. From the hundreds of relevant articles, special 

consideration was given to those with applicability to 

military situations. Another key issue that has rarely 

been addressed is whether the use of such compounds 

in an operational setting actually improves next-day 

performance in addition to enhancing sleep.

Barbiturates

Barbiturates are fat soluble and are thus rapidly and 

completely absorbed in the stomach. Therefore, they 

are usually administered by mouth, with the exception 

of intravenous use of a very short-acting compound 

as a general anesthetic. Their duration of action is 

determined by the drugs’ metabolism and excretion. 

For example, a short-acting drug such as thiopental is 

extremely fat soluble. It is very rapidly absorbed, but 

Fig. 4-2. Marines sleeping on a transport aircraft. Pharmacological fatigue countermeasures must not interfere with 

opportunities for restorative sleep because this is the best 

available fatigue countermeasure.

Photograph: Reproduced from the US Marine Corps, Defense 

Visual Information. Image ID: DM-SD-05-11545. Photographer: LCPL Andrew Williams, US Marine Corps. Available 

at: http://www.dodmedia.osd.mil.
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Performance-Maintaining and Performance-Enhancing Drugs and Food Components

it is also very quickly redistributed from the CNS to 

muscle and fat tissue. Then, it is slowly metabolized 

by the liver and excreted by the kidneys. This explains 

why individuals who have been sedated or anesthetized by thiopental wake up within a few minutes, but 

remain groggy for several hours.

A long-acting barbiturate such as phenobarbital, 

however, is only slowly absorbed by fat tissue and 

muscle. Thus, the barbiturate circulates in the blood 

in concentrations sufficient to keep the individual 

sedated until it can be metabolized by the liver or 

excreted by the kidneys.13 Barbiturates are no longer 

generally used as hypnotics. They have been replaced 

by benzodiazepines and related compounds, and are 

a particularly poor choice in situations in which nextday performance is important.

McKenzie and Elliott14 studied the effects of secobarbital on the performance of 48 pilots on a simulated 

air mission. The goal was to investigate the effect of 

premission sedation, prescribed in instances in which 

the pilot must retire in late afternoon and be awakened 

8 hours later for an early morning flight. The subjects 

were given 200 mg secobarbital when they retired at 

2100 hours. They were awakened for breakfast at 0545 

hours. As previously noted, secobarbital was issued 

by a flight surgeon before an actual combat mission, 

but a dose of 100 mg was used.2 The simulated mission designed by McKenzie and Elliott14 began at 0700 

hours and lasted 12 hours, with two meals given en 

route. The 200-mg dose produced performance decrements not only at the start of the mission, which was 

10 hours postdosage, but also throughout the entire 

12-hour simulation.

A thorough review of 23 studies on the effects of 

barbiturates on performance indicated that administration of these drugs produced impairment in 29.9% 

of the placebo-barbiturate comparisons. The tasks 

most sensitive to barbiturate-induced impairment 

were those involving tracking, concentrated visual 

searching, and sorting. Tasks that were least affected 

were those involving manual dexterity, arithmetic, and 

choice reaction time.15 Although only a limited number 

of studies tested performance at standardized intervals after dosage, available data for the 7- to 10-hour 

postadministration period showed a 32% decrement 

in overall performance, compared with 36% at 11 to 

14 hours and 24% at 15 to 22.5 hours. The magnitude 

and duration of the deficits were not necessarily consistent with the half-lives of the drugs. Overall, these 

are very substantial and sustained adverse effects on 

performance. There seems to be little reason to use 

barbiturates as sleep enhancers in military operations; 

other compounds (eg, the benzodiazepines) are generally preferred as hypnotics. Furthermore, the adverse 

effects of the barbiturates on next-day mental performance are probably greater at equipotent doses than 

those of the benzodiazepines.

Benzodiazepines and Related Compounds

All benzodiazepines are lipid soluble. However, the 

pharmacokinetic activity of the benzodiazepines varies 

widely because their solubility can differ by as much as 

a factor of 50.13 Many benzodiazepine metabolites are 

also pharmacologically active, effectively prolonging 

clinical effects. Thus, in choosing an appropriate benzodiazepine, a physician must consider both the desired 

speed of onset and the overall duration of action.

Typically, chronic anxiety and epilepsy are best 

treated using a drug with a long duration of action, 

whereas induction of sleep is optimally achieved with 

a rapid-onset, short-acting agent. Rapid-onset drugs 

minimize morning hangover effects, although early 

morning awakening has been reported when shortduration benzodiazepines are used.16 Benzodiazepines 

are widely used for their antianxiety, sedative, and 

hypnotic properties. Zolpidem, a nonbenzodiazepine, 

acts at the same GABA receptor sites as the benzodiazepines and has nearly identical effects. Adverse effects 

of these compounds include daytime sedation, motor 

incoordination, and cognitive impairments, especially 

anterograde amnesia. Long-term use has additional 

risks, including physical dependence, withdrawal, and 

rebound insomnia.17 Buspirone, which acts at serotonergic receptor sites, is widely used as an antianxiety agent 

and may have advantages over the benzodiazepines 

and zolpidem for this indication because its sedative 

effects seem to dissipate when used for several days.18

Benzodiazepines in Operational Scenarios

Cluydts and colleagues19 investigated the effects of 

the benzodiazepines—lormetazepam and zolpidem—

in operational scenarios. Twelve subjects were given 

either 2 mg lormetazepam or 10 mg zolpidem when 

they went to bed at 2245 hours. For the next 8 hours, 

traffic noise ranging from 32 to 77 dB was played 

continuously. Such disruptions of sleep produced by 

external stimuli are very likely to occur in operational 

situations and combat. Although both hypnotics significantly increased total sleep time, lormetazepam had 

the most profound effects, with a mean increase of 24 

minutes, compared with 16 minutes for zolpidem. Although lormetazepam produced a significant decrease 

in the number of sleep-stage transitions, arousals, and 

awakenings throughout the night, there was no difference between the drugs on subjective measures of 

sleep quality, mood, or morning alertness. Behavioral 
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Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

testing the following morning showed significant adverse effects of lormetazepam, but not zolpidem, on 

the four-choice reaction test, particularly a significant 

increase in overall reaction time.

Benzodiazepines and Memory Impairments

O’Donnell et al20 investigated the effects of triazolam 

(Halcion [Pfizer, Inc, New York, NY]), another short 

half-life benzodiazepine, on performance and sleep 

after exposure to a stressful movie. At 0930 hours, 49 

subjects watched a short movie titled “Subincision,” 

which was used in previous studies to increase autonomic arousal. The subjects were then given 0.125 

mg, 0.25 mg, or 0.5 mg triazolam and instructed to 

try to sleep in an environment that was similar to that 

experienced by airline passengers. The 0.5-mg dose 

of triazolam significantly increased the continuity 

and duration of sleep. However, at 90 minutes postadministration, that same dosage was also associated 

with slowed performance and impairments in learning 

new material. This impairment of short- and long-term 

memory is a classic side effect of the benzodiazepines. 

Deficits were no longer apparent at 6 hours postadministration, and no deficits were seen with the lower 

doses at either time period. In other studies, similar 

doses of triazolam have been shown to impair performance the next day. 

In one of the few military field studies of benzodiazepines, Penetar and colleagues21 administered 0.5 

mg triazolam or placebo to 68 airborne soldiers on 

the first leg of a flight from the United States to the 

Middle East. During a refueling stop 8 hours later, 

the soldiers’ mood and performance were assessed. 

Triazolam did not improve the duration or continuity 

of sleep as measured by wrist-worn activity monitors, 

nor did it alter mood or sleepiness. However, significant impairments in memory function were observed 

when behavioral testing was conducted. The authors 

concluded that this dose of triazolam was not suitable for use when unimpaired cognitive function was 

essential immediately on arrival. (For a review of the 

effects of the benzodiazepines on memory and mood, 

see the study by Curran.22)

Benzodiazepines and the Sleep-Rest Cycle

Seidel and colleagues23 tested the effects of triazolam 

and flurazepam on sleepiness, objective performance, 

and mood during a forced shift in the sleep-rest cycle. 

For three 24-hour periods, subjects were shifted 12 

hours in their sleep-wake cycle by postponing sleep 

until noon. At that time, they received either 0.5 mg 

triazolam or 30 mg flurazepam, then went to bed for 

an 8-hour interval. Triazolam has an elimination halflife of 2 to 5 hours, whereas the major metabolite of 

flurazepam has a half-life of 50 to 100 hours. Postsleep 

testing showed that, although both drugs produced 

similar increases in sleepiness and mood disturbance, 

subjects receiving flurazepam displayed deficits in 

vigilance and visual tracking. Triazolam, however, 

maintained or improved performance on all tests. 

The authors stated that, by facilitating good sleep, the 

compound with a shorter half-life—triazolam—was 

able to preserve daytime performance despite the 12-

hour phase shift. Subjects receiving the long half-life 

hypnotic showed decrements greater than those seen 

in placebo controls.23

Benzodiazepines and Military Duty

Caldwell et al24 conducted a study at the US Army 

Aeromedical Research Laboratory (Fort Rucker, Ala) to 

determine whether aviators who had taken a benzodiazepine as a sleep aid before bedtime could adequately 

perform their duties the following day. The authors also 

investigated whether the volunteers could perform 

their duties if they were awakened in the middle of the 

night (if, for example, an urgent mission unexpectedly 

arose). Ten Army helicopter pilots were given 0.25 mg 

triazolam or placebo 15 minutes before retiring to bed 

at 2200 hours. Sleep was monitored, and the subjects 

were assessed on subjective sleepiness, cognitive function, and simulated helicopter flight performance the 

morning and afternoon following drug administration. Testing occurred after an 8-hour sleep period on 

one night and after 2 hours of sleep on another night.

Triazolam produced decrements in five of nine 

simulated flight maneuvers the morning following the 

full night of sleep.24 Three of these maneuvers were less 

affected during the afternoon test session. Although 

testing 2 hours after the dose was taken revealed decrements in only two maneuvers, compared with the 

placebo, performance at this hour was poorer overall 

than for all groups in the afternoon sessions. Some subjects who received triazolam were difficult to awaken 

for this “emergency” test session, but all subjects 

were able to return to sleep faster than those who had 

received placebo. There were no differences between 

triazolam and placebo on subjective sleepiness, but 

two of the ten pilots were unable to recall portions of 

the midnight flight following triazolam. Based on these 

results, the authors state that performance following 

8 hours of sleep with triazolam is affected, but not to 

the extent that an aviator cannot control an aircraft. 

They suggest that, before triazolam is used as a sleep 

aid, it should be administered in a controlled trial to 

determine how long it would take a subject to awaken 
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Performance-Maintaining and Performance-Enhancing Drugs and Food Components

and whether any other negative effects would occur. In 

general, preoperational testing of compounds that may 

alter cognitive performance is recommended, because 

this gives personnel an opportunity to experience the 

effects of the drug prior to its operational use and may 

reveal any idiosyncratic adverse effects. 

In a study conducted by Caldwell et al,25 temazepam (30 mg; Restoril [Mallinckrodt Medical, Inc, 

Hazelwood, Mo]) was tested on helicopter pilots to 

determine if it would enhance daytime sleep and prevent the deterioration in performance seen during the 

subsequent night shift. Temazepam is rapidly eliminated and has no long-acting metabolites. The drug 

clearly improved daytime sleep, as well as cognitive 

performance that night, as measured by a computerized reaction time task. However, performance in a 

flight simulator was not clearly improved by enhanced 

daytime sleep.25

The US Air Force School of Aerospace Medicine 

conducted a study with FB-111A aircrew members who 

used 30 mg temazepam as a sleep aid before either a 

simulated or a real training mission.26 The study was 

designed to simulate surge operations requiring two 

consecutive nighttime missions with daytime sleep 

periods interspersed. Temazepam enhanced sleep 

duration and continuity, as measured with activity 

monitors. However, 12 hours after administration, 

there were some subtle, adverse effects of the drug on 

cognitive performance.

This study was motivated by a report that, during 

the Falkland Islands War in 1982, temazepam was 

extensively and successfully used by British aviators who were required to fly very long flights with 

limited rest periods.9 Typically, aircrews took 20 mg 

temazepam at least 8 hours before flying missions. 

Crew members reported that they could fly as soon 

as 6 hours after taking the drug without ill effects. It 

is difficult to interpret this and similar observational 

reports regarding the use of drugs in actual combat. 

Obviously, rigorous studies cannot be conducted in 

such situations, and they are difficult, if not impossible, 

to adequately simulate in the laboratory. 

A number of studies have been conducted by military 

laboratories comparing various sleep-inducing compounds. For example, Paul and colleagues27 compared 

the effect of a single dose of zaleplon (10 mg), zopiclone 

(7.5 mg), temazepam (15 mg), and melatonin (6 mg in 

a timed-release preparation) on psychomotor performance and attempted to quantify the postingestion time 

required for return to normal performance. They determined that, “The recovery time to baseline subjective 

sleepiness levels for zaleplon, zopiclone, temazepam, 

and melatonin were 4.25, >6.25, 5.25, and >4.25 hours, 

respectively. However, they noted that, “[i]n spite of a 

prolonged period of perceived sleepiness, melatonin 

was superior to zaleplon in causing no impact on performance.”27 The remaining drugs listed in increasing 

order of performance impact duration are zaleplon, 

temazepam, and zopiclone. The hormone melatonin 

is discussed later. A study by Whitmore et al28 also indicates that zaleplon is a useful sleep aid that has few 

residual effects, which is consistent with its relatively 

short half-life, compared with benzodiazepines and 

similar compounds. However, it is reasonable to anticipate that a drug with a shorter half-life will maintain 

sleep for a shorter period of time, compared with one 

with a longer half-life. Melatonin also has an extremely 

short half-life29 unless it is administered in a time-release 

preparation, as done by Paul and colleagues.27

Risks and Benefits

Overall, the documented adverse effects of many 

of the benzodiazepines and related compounds, even 

those that are widely used with shorter half-lives 

(eg, triazolam [Halcion] and zolpidem [Ambien]), 

on performance the day after they are administered 

makes their use in combat or other intense operations 

a difficult medical/operational judgment. These compounds, like any drug, may sometimes have greater 

risks than benefits. As demonstrated in a study by Paul 

and colleagues,27 the shortest-acting compounds (eg, 

zaleplon) probably have the lowest risk. Although the 

value of sleep cannot be overestimated, the adverse 

effects that these compounds have the next day could 

be potentially life-threatening in combat conditions. 

For a discussion of the importance of sleep and the 

effects of sleep deprivation, see Chapter 3 (Measuring 

and Predicting Sleep and Performance During Military 

Operations) in this volume. Unfortunately, there is 

limited evidence demonstrating that the use of benzodiazepines to improve sleep also improves subsequent 

military performance, although it does appear that 

short-acting benzodiazepines speed reentrainment to 

new daily schedules of activity. The benzodiazepines 

and related compounds are particularly useful when 

it is likely that duty the next day will not be required. 

When military physicians consider the use of these 

drugs operationally, they must consult official doctrine 

and carefully weigh the risks and benefits.

Belenky30 has advanced a possible solution to the 

problem of next-day hangover effects induced by the 

benzodiazepines, as well as the issue of emergency 

awakening soon after benzodiazepine administration. 

He has suggested that an antagonist of the benzodiazepines, flumazenil, could be used operationally to 

rapidly reverse the effects of the benzodiazepines.30

Although flumazenil is a US Food and Drug Adminis-
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Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

tration (FDA)-approved drug, it is currently available 

only as an injectable formulation. It has been shown 

to reverse the adverse effects of both triazolam and 

zolpidem on memory.31

Antihistamines

Antihistamines are another class of compounds 

that can clearly have sedative effects and are sometimes used as mild sleep aids. These drugs are most 

commonly used to treat allergic rhinitis and other allergic symptoms. Newer forms that have little or no 

sedative effects (eg, loratadine and terfenadine) have 

been developed. Several of the older antihistamines 

(eg, doxylamine and diphenhydramine) are sold as 

over-the-counter (OTC) sleep aids, but they do not 

appear to have the potency of the barbiturates or 

benzodiazepines. These antihistamines may be useful 

in military operations as substitutes for more potent 

sleep-inducing compounds; however, even in low 

doses, antihistamines with sedative properties can 

impair performance.32

Melatonin

One compound that may provide an alternative 

to the use of traditional hypnotic drugs to enhance 

sleep, and thereby improve performance, is the hormone melatonin.33 In humans, melatonin is secreted 

by the pineal gland, predominantly at night in the 

dark. Its function is unknown. When administered in 

pharmacologic doses, it has sedative-like properties 

and rapidly induces sleep.33–35 Melatonin is extremely 

potent and has a very short half-life.29,36 This hormone 

has sleep-inducing properties even when it is administered in doses (0.1 mg) that produce plasma levels not 

much greater than human nocturnal plasma levels.36

Melatonin is sold as a dietary supplement in the United 

States, as permitted by the Dietary Supplement Health 

and Education Act of 1994 (DSHEA). However, from a 

scientific perspective, it should be considered a drug. 

Because of its unique regulatory status, sufficient data 

are not currently available to conclude with certainty 

that it is an effective hypnotic or to determine its optimal dose, although evidence-based reviews conclude 

that melatonin is effective as a sleep aid and circadian 

synchonizer.37–40 Although it can be sold as a dietary 

supplement in the United States, the FDA does not 

require any demonstration of efficacy or safety. Doses 

of melatonin ranging from 0.3 to 10 mg have been 

suggested as appropriate for inducing and maintaining sleep.11,36 It is typically sold in doses of 3 or 5 mg.

Several studies suggest that melatonin may be useful in operational scenarios as a potential treatment for 

transmeridian desynchronization (ie, jet lag). In a study 

with an operational US Army Special Forces aviation 

unit deploying across multiple time zones to evaluate 

melatonin as an operational anti–jet-lag treatment, 

administration of 10 mg melatonin each day before 

the sleep period significantly improved vigilance 

and sleep, as measured indirectly with activity monitors.11 Unlike the benzodiazepines, melatonin does not 

seem to impair memory and has considerably fewer 

adverse effects on cognitive performance, even when 

administered in much higher doses than required to 

enhance sleep.27,33 Paul and colleagues12 conducted a 

study that compared sustained release melatonin (2 

mg) with 5 mg zopiclone, a benzodiazepine-like drug, 

in aircrews who were flying transatlantic missions. 

They found that both compounds were equally effective. A systematic review of the literature addressing 

the utility of melatonin for circadian resynchronization was conducted.37 It concluded that: “Melatonin is 

remarkably effective in preventing or reducing jet-lag, 

and occasional short-term use appears to be safe.” 

However, its classification as a dietary supplement 

in the United States is an obstacle to its sanctioned 

operational use, because legally such products are not 

approved for specific medical uses. It should also be 

noted that, even when melatonin is administered in 

very low doses, it does acutely impair certain aspects 

of cognitive performance.34,36

Buspirone

As described previously, buspirone is an antianxiety 

agent not pharmacologically related to the benzodiazepines, barbiturates, or any other sedative hypnotic. 

It exerts its effects by binding with high affinity to 

5-HT1A (5-hydroxytryptamine [serotonin] receptor 

1A) receptors. Although its precise mechanism of action has not been conclusively demonstrated, a number 

of studies have found that buspirone rarely produces 

nonspecific depression, unlike the other traditional 

sedative hypnotics. Buspirone is a water-soluble compound, it is rapidly absorbed and metabolized, and its 

average elimination half-life is 2 to 3 hours.

Buspirone is used primarily as an antianxiety agent 

to treat various psychiatric disorders, especially generalized anxiety disorder. Like many drugs used in 

psychiatry, buspirone has a very slow onset of action, 

requiring several weeks of administration before its 

therapeutic actions are maximal. Even before it was 

available in the United States, Jones1 suggested that it 

might be useful on the battlefield because of its antianxiety properties and lack of adverse effects on cognitive 

performance. To date, studies have not been conducted 

to determine whether this compound would be useful 
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Performance-Maintaining and Performance-Enhancing Drugs and Food Components

as an antianxiety agent during intense military operations. The high frequency of psychiatric casualties from 

battlefield stress seen in intense military operations41

suggests that a compound with such properties could, 

in theory, be of great benefit to soldiers. However, the 

optimal level of anxiety on the battlefield is a matter 

of some debate. Very low levels of anxiety in the face 

of danger are not desirable and could be fatal. It is 

difficult to envision how appropriate studies to assess 

the utility of buspirone as an antianxiety agent for use 

on the battlefield could be conducted in the laboratory 

or clinic, given the practical and ethical constraints of 

human research. Several studies have demonstrated 

that buspirone lacks many of the adverse effects of the 

benzodiazepines.

Moskowitz and Smiley42—in a study of 48 subjects— 

administered 20 mg buspirone, 15 mg diazepam, or a 

placebo for 9 days. On the ninth day, the volunteers 

were also given alcohol to produce a peak blood alcohol level of 0.10%. On days 1, 8, and 9, subjects were 

tested on a driving simulator using a divided attention task before and 1 hour after dosage. The divided 

attention test was also administered at 3 and 5 hours 

after dosage. Diazepam impaired driving performance 

and attention performance after both a single day of 

treatment and following 8 days of treatment compared 

to placebo. There was no evidence of the development 

of tolerance to the impairments, as performance decrements were more severe and longer lasting on day 8 as 

opposed to day 1. However, treatment with buspirone 

slightly improved performance after the first day of 

treatment, with an increase in benefits by day 8. Although alcohol potentiated the deficits of diazepam, 

buspirone offset some of the alcohol-induced impairments. The authors concluded that buspirone could 

be used effectively as an antianxiety agent for 8 days 

with little fear of impaired performance.

Lader,18 who conducted a similar study, found some 

initial increase in drowsiness induced by buspirone (5 

or 10 mg three times a day) that wore off by the end 

of the week, in contrast to diazepam. Because of this 

relative absence of side effects, buspirone has achieved 

widespread use since its introduction in 1987. However, caution is warranted. LeWitt and colleagues43

have reported instances of dyskinesia and dystonia 

associated with prolonged buspirone use. Whether 

buspirone induced or exacerbated an existing movement disorder is unknown.

STIMULANTS

CNS stimulants are drugs that increase alertness 

and improve mental performance. Several types of 

drugs are referred to as stimulants, and they vary 

widely in their structure and mechanism of action. 

The most important compounds with potential for 

use on the battlefield are amphetamines and drugs 

with similar actions.13 Another well-known stimulant-like compound, caffeine, is found in a variety of 

foods and is consumed on a daily basis by millions 

of people.44 The stimulant-like action of caffeine is 

from its effects on central adenosine receptors. The 

drug theophylline—even though similar in structure 

and mechanism of action to caffeine—is not typically 

used for its stimulant-like actions, but rather to treat 

asthma. Newer stimulant-like compounds, which 

include modafinil and armodafinil, are now available 

for operational use; but, to date, only modafinil has 

been used operationally. 

The following sections describe the effects of stimulants on various aspects of performance by using examples from the scientific literature. From hundreds 

of relevant studies, those with performance measures 

that generalize to military operations were selected. 

The discussion is limited to behavioral stimulants and 

does not include drugs such as strychnine, which is 

also classified as a stimulant. 

Amphetamines and related drugs are sympathomimetic amines that structurally resemble the neurotransmitter norepinephrine. They are typically used 

in the treatment of narcolepsy and attention-deficit 

hyperactivity disorder (ADHD). Amphetamines exert 

their central effects by increasing central norepinephrine and dopamine, although each stimulant may 

do so by a different mechanism.45 The most common 

amphetamine derivatives are dextroamphetamine 

and methamphetamine. Comparatively, dextroamphetamine has a greater effect on the CNS, with less 

pronounced effects on the cardiovascular system than 

the l-isomer or the racemic mixture. Methamphetamine 

and dextroamphetamine are essentially equivalent in 

their effects. 

The stimulants methylphenidate and pemoline, 

which are used primarily in the treatment of children 

with ADHD, are classified as “nonamphetamines.” 

Methylphenidate and pemoline are structurally similar 

to amphetamines and affect the same brain receptors. 

Thus, although they are technically not amphetamines, 

their pharmacological effects are quite similar.13 Several 

OTC drugs or dietary supplements, such as phenylpropanolamine (PPA) and ephedra, are also stimulants with structural similarities to amphetamines 

and they, too, seem to increase alertness. However, in 

recent years, there has been increasing concern about 

their safety. PPA was removed from the market, and 
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Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

ephedra/ephedrine cannot be sold as a dietary supplement, although it is available as an OTC drug to treat 

asthma.

Modafinil and armodafinil have been evaluated as 

potential performance enhancers. Both compounds 

are novel stimulants that are pharmacologically distinct from the amphetamines and methylphenidate. 

A number of studies demonstrate that modafinil 

enhances mental performance and wakefulness, 

without sympathomimetic side effects.46–53 The following sections discuss the most common amphetamine 

derivatives dextroamphetamine and methamphetamine, the closely related compounds methylphenidate and pemoline, and the atypical stimulant 

modafinil. 

Dextroamphetamine and Methamphetamine

Medical applications of amphetamines are primarily related to the treatment of attention deficit 

disorders in children and adults or as an alternative 

to methylphenidate in patients with narcolepsy.45

Although these agents have been used as appetite 

suppressants, this practice has been strongly discouraged because of the rapid development of tolerance 

and the high potential for abuse.45 Amphetamines are 

readily absorbed after oral ingestion and are excreted 

by the kidney. Their half-lives can range from 7 to 30 

hours.45 At therapeutic doses, the amphetamines produce increases in blood pressure, relaxation of bronchial muscle, increased plasma glucose and blood 

flow to skeletal muscle with a concomitant decrease 

in blood flow to internal organs, and pupillary dilation.13 Typically, administration of an amphetamine 

will increase alertness, elevate mood, and improve 

concentration. However, adverse behavioral side effects can include increased irritability, restlessness, 

anxiety, and perhaps aggression.13 At higher doses, 

the drug effects are exaggerated. A slight tremor may 

be induced, respiration and motor activity increase, 

and insomnia occurs. Although amphetamines prevent fatigue, sleep cannot be postponed indefinitely, 

and rebound increases in sleep time will occur.13 The 

limits of this effectiveness have never been tested in 

controlled military studies, although an elegant study 

was proposed in the 1990s by Dr John Caldwell that 

would have continued amphetamine dosing and 

attempted sustainment of wakefulness out to 105 

hours; ultimately, the greatest challenge was in the 

establishment of an effective placebo control group 

for comparison of effects produced by continued 

wakefulness and the effects produced by the drug. 

In an effort to determine whether dextroamphetamine could overcome the effects of sleep loss on 

arousal, mood, and cognitive functioning, investigators at Walter Reed Army Institute of Research54–56

gave 5, 10, or 20 mg dextroamphetamine to 36 male 

subjects who had been deprived of sleep for 48 hours. 

The subjects were then deprived of sleep for an additional 12 hours for testing. Dextroamphetamine, in 

a dose-related manner, reversed the decrements in 

cognitive performance and self-rated vigor produced 

by sleep deprivation. The drug also antagonized the 

decrease in sleep latency produced by sleep deprivation. A dose of 20 mg dextroamphetamine returned 

subjects to normal levels of performance on arithmetic 

and verbal reasoning tasks, and normalized sleep latency for several hours. Effects of the 10-mg dose were 

smaller and briefer, whereas the 5-mg dose produced 

no significant changes.

Although these performance-enhancing effects 

are significant, this study also provided evidence of 

the residual effects of amphetamine administration 

on subsequent sleep.56 When the test subjects were 

permitted to sleep 14 hours after amphetamine administration, there was a significant decrease in total 

sleep time following the 20-mg dose of amphetamine, 

largely because of a significant decrease in time spent 

in rapid eye movement (REM) sleep. The 20-mg dose 

reduced total sleep time from 8.1 hours on placebo to 

7 hours. Latency to REM sleep was shortened after the 

5-mg dose and the 10-mg dose, but not with the highest 

dosage. Latency to sleep, however, was not affected by 

any dosage. The authors suggest that these effects on 

sleep more than 15 hours after drug ingestion indicate 

a prolonged drug effect.56

Shappell and colleagues57 studied the effects of 

methamphetamine on simulated sustained flight 

operations and performance. Twenty-five subjects 

simulated extended operations by following a 

schedule of 9 hours of work and 4 hours of rest, followed by 14 hours of work. Then they rested for 6 

hours before repeating the work-rest-work schedule. 

Thirteen subjects were given 0.14 mg methamphetamine per 70 kg of body weight approximately 4 

hours and 20 minutes into the second work period. 

Cognitive performance was assessed with a test battery that included four-choice reaction time, pattern 

recognition, serial addition/subtraction, grammatical reasoning, and time estimation. Various mood 

states were assessed, including fatigue and self-rated 

sleepiness. As the simulated mission progressed, 

reaction time decreased, but response accuracy was 

stable. This resulted in an overall increase in the 

number of correct responses, but also an increase in 

errors. According to the authors, subjects adopted 

a more risky response strategy. Methamphetamine 

reduced subjective fatigue and improved perfor-
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mance on two tasks: (1) pattern recognition and (2) 

mental rotation.

Stanny and colleagues58 investigated the effects of 

the same dose (0.14 mg/70 kg body weight) of methamphetamine on vigilance, tracking, and long- and 

short-term memory during a night without sleep. 

Thirteen subjects were tested every 90 minutes, from 

1930 hours to 0900 hours. Seven subjects received 

methamphetamine at about 0100 hours, whereas the 

remaining six subjects received a placebo. Memory, 

vigilance, tracking, and decision speed worsened 

through the night, but methamphetamine reversed 

these effects within approximately 2 hours of administration. Furthermore, analysis of the vigilance data 

showed no tendency toward increased impulsive 

responses. Thus, the improved performance seen in 

the methamphetamine treatment group was in all 

probability the result of a genuine increase in accuracy rather than a change in response strategy. The 

authors concluded that methamphetamine was effective in counteracting the effects of sleep loss during 

sustained operations.

Caldwell et al49 have conducted a series of studies 

to determine whether dextroamphetamine is an effective fatigue countermeasure for use by military pilots 

who are sleep deprived. In one study, they examined 

the ability of dextroamphetamine to maintain flight 

simulator performance during 64 hours without sleep.

Dextroamphetamine (10 mg) was administered 3 

times a day: (1) at midnight, (2) at 0400 hours, and (3) 

at 0800 hours. Simulator flight performance, mood, 

and cognitive performance were assessed and electroencephalographic evaluations conducted. It was 

concluded that dextroamphetamine “sustained aviator 

performance and alertness during periods of extended 

wakefulness, but its use should be well controlled.”49

Recovery sleep was somewhat less restful following 

dextroamphetamine administration. 

In another study, Caldwell and colleagues59 selected 

data from several controlled aviation studies on dextroamphetamine to substantiate the efficacy of this 

drug as a fatigue countermeasure. They observed that 

dextroamphetamine was “effective for maintaining 

flight skills, psychological mood, and physiological 

activation (measured via electroencephalograph data) 

in sleep-deprived pilots.”59 It was concluded that 

dextroamphetamine was an appropriate intervention 

for fatigue in aviation-sustained operations, but not 

a substitute for proper crew-rest scheduling because 

there is no replacement for adequate restful sleep.56

Dextroamphetamine (Dexedrine) is approved by the 

US Air Force for management of aircrew fatigue, but 

“only after all other nonpharmacologic countermeasures have been exhausted.”60

Methylphenidate

Methylphenidate (Ritalin [Novartis Pharmaceuticals, Basel, Switzerland]) is a stimulant primarily used 

in the treatment of narcolepsy in adults and ADHD in 

children. (Although concerns are periodically raised 

about the safety, efficacy, and appropriateness of using 

this medication with children, it has remained on the 

market and is extensively used, as is amphetamine.) 

Rapidly absorbed in oral form, peak plasma levels are 

attained in 1 to 2 hours, with a 4- to 6-hour duration. 

About 80% of methylphenidate is metabolized into 

ritalinic acid, which is excreted in the urine.45 The 

physiological effects of this compound are similar to 

those produced by the amphetamines. For example, 

Oken and colleagues61 investigated the effects of methylphenidate on alertness and attention. Twenty-three 

subjects completed various behavioral and cognitive 

tasks, which included tests of spatial attention and 

visual search. Objective measures included analysis 

of electroencephalogram results and measurement 

of sleep onset. The authors found that performance 

on cognitive tasks improved with methylphenidate. 

Babkoff et al62 also studied this compound, and their 

results are discussed in the next section.

Pemoline

Pemoline is an oxazolidine used for the treatment 

of ADHD in children. It is similar to other stimulants, 

except that it seems to have minimal sympathomimetic 

effects. Taken orally, pemoline is rapidly absorbed, 

with peak serum levels occurring within 2 to 4 hours 

postdosage. It is primarily metabolized by the liver, 

and its half-life is approximately 12 hours.63 It has, 

however, been reported by the National Institutes 

of Health that “pemoline can cause serious and 

sometimes deadly liver damage,”64 and thus careful 

monitoring of liver function must accompany the use 

of this drug in children.

Babkoff and colleagues62 investigated the effects 

of both methylphenidate and pemoline on cognitive 

performance, subjective and objective sleepiness, 

and mood after 64 hours of total sleep deprivation in 

adults. Unlike many other sleep deprivation studies 

with stimulants, they repeatedly administered the two 

drugs throughout the period of sleep deprivation in an 

effort to maintain, rather than recover, predeprivation 

levels of performance. Pemoline was administered in 

37.5-mg doses every 12 hours, and methylphenidate 

was administered in 10-mg doses every 6 hours. 

Overall, pemoline was more effective than methylphenidate at offsetting the effects of sleep loss. Pemoline 

significantly reduced both subjectively and objectively 
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measured sleepiness throughout the deprivation period on all but one test, the tapping test, which showed 

drug effectiveness dropping off 32 hours after the 

drug was first administered. Methylphenidate was 

not effective in reducing sleepiness on any measures. 

On performance tasks, subjects receiving pemoline 

performed more rapidly than the placebo group on 

one or more sessions on five of six measures. However, analysis of accuracy showed significant benefit 

of pemoline on only the four-choice reaction test and 

a trend toward benefit on digit symbol substitution. 

Performance on digit span memory, a matrix test, and 

pattern recognition showed no drug effects. Drug 

performance was worse than with the placebo in one 

quarter of the instances in which there was a significant 

difference between groups. The authors suggested that 

methylphenidate might have a greater beneficial effect 

at a higher dosage. It should be noted that comparisons across drugs when based on studies conducted 

using single doses can be difficult to interpret because 

optimal doses of each drug may not have been tested. 

Additional research with these compounds is necessary before clear conclusions can be made regarding 

their potential utility in combat. 

Other Amphetamine-Like Stimulants

As noted previously, several OTC medications and 

dietary supplements that have been used to treat colds, 

asthma, or to induce weight loss are sympathomimetic 

amine stimulants, which resemble the amphetamines 

in mechanism of action and structure. Amphetamine 

was synthesized based on the naturally occurring compound ephedrine, which had been used for thousands 

of years in traditional Chinese herbal medicine in the 

form of the herb ephedra.65 Ephedrine and its analogs, 

as well as PPA, share many properties with amphetamines. Although it has been noted that ephedrine’s 

effects on the CNS are less pronounced than those of 

the amphetamines,66 it has been demonstrated that 

this compound antagonizes the hypnotic effect of 

sedatives.67 Ephedrine also enhances cognitive performance,68 although only a few studies have investigated 

its behavioral effects. (For a review, see Lieberman.65)

Alone or in combination with caffeine, ephedrine 

is a potent ergogenic aid that enhances aerobic performance.69–71 Ephedrine, in the form of the herb ephedra, 

was an extremely popular dietary supplement in the 

United States that was used to enhance physical performance and increase weight loss. However, the FDA 

banned its sale as a dietary supplement in 2004 because 

of the large number of adverse events thought to be 

attributable to this drug.72 Many of these reported adverse events were serious, including myocardial infarctions, cerebrovascular accidents, seizures, and death.

PPA, which has fewer peripheral effects than 

ephedrine, has also been reported to improve cognitive function73 and antagonize the adverse effects of 

environmental stress.74 However, based on evidence 

that it could increase the risk of stroke, PPA was taken 

off the market in 2000.

The prescription drug fenfluramine is used to induce weight loss, and it resembles amphetamine in 

structure. However, it was reported to have significant 

cardiovascular side effects and was withdrawn from 

the US market in 1997.75–77

Summary of Traditional Stimulants 

There is little doubt that amphetamines enhance 

some aspects of mental performance in sleep-deprived 

subjects. Other stimulants, such as pemoline, also 

enhance cognitive performance, but their effects are 

not as well documented as those of amphetamines. 

The effects of amphetamines have been demonstrated 

not only in laboratory tests of cognitive performance, 

but also in flight simulators. Unfortunately, these 

drugs have significant adverse effects. Amphetamines 

interfere with subsequent sleep and significantly increase blood pressure. They have considerable abuse 

potential; therefore, medical professionals must carefully supervise amphetamine use (see Roehr78 for a 

discussion of amphetamine abuse in the United States). 

Amphetamines have been used in combat, and anecdotal reports from several operations1,2,5–7 suggest that 

it was effective at preventing deterioration in cognitive 

performance when military personnel were severely 

fatigued from sustained sleep loss and stress. Amphetamines improve aerobic physical performance, an 

additional benefit in combat. There are difficult sociopolitical issues associated with the officially sanctioned 

use of amphetamines in combat, and these would be 

greatly magnified if widespread use of the compound 

occurred in US military operations. The ethical and 

command issues regarding its use are discussed herein; 

however, the use of any performance-enhancing drug 

in military operations must be approved by the chain of 

command. The previously noted friendly fire incident 

in Afghanistan is an example of the kind of issues arising from the use of such compounds. In that incident, 

the potential side effects of amphetamines were used 

in the legal defense of the pilots who were involved.8

Modafinil

Modafinil (Provigil [Cephalon, Inc, Frazer, Pa]) 

is a novel stimulant that, unlike the amphetamines, 

appears to have minimal peripheral side effects, has 
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Performance-Maintaining and Performance-Enhancing Drugs and Food Components

a low abuse potential, may not induce tolerance, and 

does not interfere with normal sleep.47,51 Its behavioral 

effects in healthy, sleep-deprived volunteers are of the 

same approximate magnitude as those of amphetamines, depending, of course, on dose. Modafinil 

was initially approved by the FDA for the treatment 

of narcolepsy, and has been approved to treat excessive sleepiness-associated obstructive sleep apnea/

hypopnea syndrome and shift work sleep disorder. Its 

use in a variety of other disorders that impair daytime 

alertness is under investigation. A similar compound, 

armodafinil (Novigil [Cephalon, Inc, Frazer, Pa]), 

which is reportedly more potent, was also approved 

by the FDA in 2007 for the treatment of various sleep 

disorders.79

Saletu and colleagues80 investigated the effects of 

a morning dose of 200, 400, or 600 mg modafinil on 

performance and mood. They found that all three doses 

enhanced concentration, mood, and cognitive function.

In another study, Saletu and colleagues81 investigated 

the effects of 100 or 200 mg modafinil, given at bedtime, and assessed self-rated and polysomnographic 

sleep parameters over the course of five nights. They 

found that, unlike dextroamphetamine, modafinil 

did not induce a reduction in the amount of stage 2 

and REM sleep. In addition, subjective sleep quality 

was rated significantly better when subjects received 

modafinil, compared with the reference compound. 

Subjective awakening quality and morning well-being 

showed no significant decrements following modafinil 

administration. The authors emphasized the need to 

differentiate the effects of modafinil and amphetamine, 

with modafinil having greater benefits and fewer side 

effects.81

In another modafinil study using a recovery 

paradigm, Lagarde and Batejat46 tested the effects on 

performance of 200 mg modafinil given three times 

a day. Eight healthy subjects were deprived of sleep 

for 60 hours, during which time they were given 

part of the STRESS (Standardized Tests for Research 

with Environmental Stressors) battery of tests, which 

includes reaction time, memory, spatial processing, 

and divided attention tasks. When modafinil was 

administered, the cognitive performance of sleepdeprived volunteers was equivalent to the performance observed in non–sleep-deprived control trials. 

Furthermore, performance while taking modafinil 

remained constant until the 44th hour of sleep deprivation, when it began to deteriorate somewhat toward 

placebo levels (hours 44–60). The authors concluded 

that modafinil appears to be a vigilance-promoting 

substance capable of maintaining psychomotor performance during 60 hours of sleep deprivation.46 Like 

amphetamines, modafinil also enhances physical 

aerobic performance.82

In a study conducted at a Canadian military laboratory, 41 military subjects received either 300 mg 

modafinil, 20 mg dextroamphetamine, or a placebo on 

three separate occasions during 64 hours of continuous 

cognitive work and sleep loss. Both modafinil and amphetamine improved cognitive performance and mood 

state, compared with placebo; however, modafinil 

had fewer side effects. The authors concluded that 

modafinil was a good alternative to amphetamines 

for counteracting mood and cognitive effects of sleep 

loss during sustained operations.48,83

A number of additional studies have been conducted in military laboratories, or with the support 

of military organizations, to examine the effects of 

modafinil in militarily relevant scenarios. For example, 

Wesensten and colleagues52,53 conducted a laboratory 

study in which 50 healthy young adults were sleep 

deprived for 54.5 hours. They reported that 400 mg 

modafinil attenuated fatigue in a manner comparable 

with that seen with 600 mg caffeine and that the effects 

were particularly salient during the circadian nadir 

of performance (0600 through 1,000 hours); 200 mg 

modafinil also reversed fatigue, but was less effective 

than 400 mg modafinil or 600 mg caffeine.

Caldwell and colleagues84 have studied the effects 

of modafinil in several studies. In one study, conducted in a helicopter simulator, they demonstrated 

that modafinil was a promising countermeasure for 

sleep loss, but noted that additional studies of possible side effects were needed before it could be recommended for aviators. In a second study, conducted 

with F-117 Nighthawk (a stealth ground attack 

aircraft) pilots in a simulator, it was demonstrated 

that modafinil had beneficial effects on simulator 

performance and mood state. However, because the 

dose tested (100 mg) did not have subjectively salient 

effects, the authors stated that personnel should be 

cautioned regarding this characteristic of the drug, 

since they might mistakenly perceive the drug was 

not working. In particular, they were concerned that 

the dosage might be escalated by crew members 

without flight surgeon approval.50

It can be concluded, based on evidence from a 

number of military and civilian laboratories, that 

modafinil has considerable potential as an operational 

performance enhancer because it appears to have the 

benefits of amphetamines without the adverse risks 

of abuse potential, increased blood pressure, and 

interference with sleep. In December 2003, modafinil 

was approved by the US Air Force for management of 

aircrew fatigue in dual-piloted bombers only after all 

other nonpharmacological countermeasures had been 

exhausted (Exhibit 4-1).60
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Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

EXHIBIT 4-1

COMPARATIVE EFFECTS OF STIMULANTS IN SLEEP-DEPRIVED SOLDIERS 

In World War II, amphetamines (eg, Benzedrine, metamphetamine) were extensively used by armies to combat fatigue, depression, and to enhance endurance performance.(1) Some of the earliest evaluations were conducted by A C 

Ivy from the Harvard Fatigue Laboratory and involved caffeine comparisons with Benzedrine.(1,2) This interest was 

stimulated by the use of methamphetamine by the Germans during the early years of the Blitzkrieg.(1) The US Army 

continued to use amphetamines even after other countries like Germany and the United Kingdom were beginning to 

recognize problems associated with unrestricted use of the drugs.(1,3) Both pill and inhaler forms were available (Exhibit 

Figures E1-1 and E1-2). The Army and Navy evaluated the benefits in fatigued men, published in numerous technical 

reports.(1) Other studies published after the war noted concerns about impaired judgment and willingness to continue 

nonproductive or dangerous performance.(4) 

Other options have become available, notably two products that originated from French military medical researchers, 

modafinil (Cephalon, Frazer, Pa; as discussed in this chapter) and sustained release caffeine. The field was substantially 

Figure E1-1. Smith, Kline & French Laboratories (Philadelphia, 

Pa) advertised their Benzadrine sulfate tablets to demonstrate 

their support for the warfighter. This advertisement originally 

appeared in Minnesota Medicine. 

Data source: Minnesota Medicine. 1944;27(October). 

Photograph: Courtesy of the Minnesota Medical Association, 

Minneapolis, Minnesota. 

Figure E1-2. Amphetamines taken by inhaler were also widely 

used by US troops in World War II.This advertisement originally 

appeared in the Journal of the American Medical Association.

Data source: Journal of the American Medical Association. 1943;123. 

Photograph: Courtesy of the American Medical Association, 

Chicago, Illinois.

(Exhibit 4-1 continues)

advanced by important sleep, fatigue, and jet lag studies 

by Alain Buguet, Didier Lagarde, and their colleagues in 

the French military medical research laboratories, in ad-
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Performance-Maintaining and Performance-Enhancing Drugs and Food Components

dition to several collaborations with Ross Pigeau at the Defence and Civil Institute of Environmental Medicine (North 

York, Ontario, Canada) and Paul Naitoh at the Naval Health Research Center (San Diego, Calif). Their studies with 

modafinil identified this drug as a preferred option for emergency conditions when adequate sleep is not feasible.(5,6)

Advantages include reduced side effects, such as behavioral effects, and an improved ability to sleep when sleep opportunities occur.(7,8) Another pharmacological option is sustained release caffeine (“Caffeine LP” or “Libération Prolongée,” 

300-mg caplets), studied in a series of transatlantic time zone experiments by Didier Lagarde and his colleagues in 

collaborations with Jon French from the Human Effectiveness Directorate performance laboratory at Brooks Air Force 

Base.(9–11) Caffeine LP is produced in the French military bioproduction facility and is available only for military use. 

Caffeine and modafinil were also shown to have a beneficial interaction with zolpidem in enhancing performance.(12) 

A series of research studies led by W Scott Killgore at the Walter Reed Army Institute of Research (WRAIR; Washington, 

DC) provided important insights into drug-specific actions and their interaction with the effects of extending periods 

of sleeplessness.(13–15) These studies expanded on some of the earlier comparative studies conducted at WRAIR and 

by John Caldwell at the US Army Aeromedical Research Laboratory and later at the Air Force Research Laboratory 

(described in this chapter). Killgore identified different effects of modafinil, high-dose caffeine, and amphetamine in 

healthy subjects with 2 days of sleep deprivation. The many published studies resulting from this work included effects 

of drug-sustained and placebo-treated sleep deprivation on higher order mental functions, such as moral judgment, 

executive function, and subtleties of humor appreciation; psychomotor performance; olfactory memory and detection; 

and personality effects on response to stimulants. 

A very significant finding in the work of Killgore and colleagues is the finding that amphetamine, differently than 

caffeine and modafinil, increased risk-taking at the same time that prolonged wakefulness increasingly impaired judgment.(15) Optimal modafinil dosing for sustained human performance is still being refined for use in combat conditions 

(French military medical research, private communication, 2011).

Data sources: (1) Rasmussen N. On Speed: The Many Lives of Amphetamine. New York, NY: New York University Press; 2008. (2) Ivy 

AC, Krasno LR. Amphetamine (Benzedrine) sulfate: a review of its pharmacology. War Med. 1941;1:15–42. (3) Davis DR. Psychomotor effects of analeptics and their relation to “fatigue” phenomena in air-crew. Br Med Bull. 1947;5:43–45. (4) Tyler DB. The effect of 

amphetamine sulfate and some barbiturates on the fatigue produced by prolonged wakefulness. Am J Physiol. 1947;150:253–262. (5) 

Lagarde D, Batejat D, van Beers P, Sarafian D, Pradella S. Interest of modafinil, a new psychostimulant, during a sixty-hour sleep 

deprivation experiment. Fundam Clin Pharmacol. 1995;9:271–279. (6) Pigeau R, Naitoh P, Buguet A, et al. Modafinil, d-amphetamine and 

placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature. J Sleep 

Res. 1995;4:212–228. (7) Lagarde D. Effects of modafinil on the nocturnal activity and behavioural sleep of Rhesus monkeys (Maccaca 

mulatta). Med Sci Res. 1990;18:397–399. (8) Chapotot F, Pigeau R, Canini F, Bourdon L, Buguet A. Distinctive effects of modafinil and damphetamine on homeostatic and circadian modulation of the human waking EEG. Psychopharmacology. 2003;166:127–138. (9) Lagarde 

D, Batejat D, Sicard B, et al. Slow-release caffeine: a new response to the effects of a limited sleep deprivation. Sleep. 2000;23:651–661. 

(10) Beaumont M, Batejat D, Pierard C, et al. Slow release caffeine and prolonged (64-h) continuous wakefulness: effects on vigilance 

and cognitive performance. J Sleep Res. 2001;10:265–276. (11) Lagarde D, Chappuis B, Billaud F, Ramont L, Chauffard F, French J. 

Evaluation of pharmacological aids on physical performance after a transmeridian flight. Med Sci Sports Exerc. 2001;33:628-634. (12) 

Batejat D, Coste O, Van Beers P, Lagarde D, Pierard C, Beaumont M. Prior sleep with zolpidem enhances the effect of caffeine or 

modafinil during 18 hours continuous work. Aviat Space Environ Med. 2006;77:515–525. (13) Wesensten NJ, Killgore WDS, Balkin TJ. 

Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation. J Sleep Res. 2005;14:255–266. 

(14) Killgore WDS, Lipizzi EL, Kamimori GH, Balkin TJ. Caffeine effects on risky decision making after 75 hours of sleep deprivation. 

Aviat Space Environ Med. 2007;78:957–962. (15) Killgore WDS, Grugle NL, Killgore DB, et al. Restoration of risk-propensity during 

sleep deprivation: caffeine, dextroamphetamine, and modafinil. Aviat Space Environ Med. 2008;79:867–874.

Exhibit 4-1 continued

FOOD CONSTITUENTS THAT MAY ENHANCE OR SUSTAIN PERFORMANCE

of caffeine when it is suddenly withdrawn from their 

diet.85,86 Interested readers are directed to comprehensive reviews of the militarily relevant literature 

in this area.87

For many years, it was believed that the blood–brain 

barrier protected the CNS from the effects of most peripheral metabolic events, such as changes in plasma 

concentrations of food constituents or metabolites 

after meal consumption. This assumption was not 

The relationship between nutrition and behavior is 

a relatively new and understudied area, although there 

are many popular and often unsubstantiated beliefs 

about the behavioral effects of foods. Recent research 

has shown that relationships between nutrition and 

behavior are complex, and certain food constituents 

have acute effects on behavior. There can also be unanticipated consequences of changes in the diet, such 

as the adverse symptoms that occur in heavy users 
108

Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

correct. The blood–brain barrier is selectively permeable, allowing a wide variety of biologically relevant substances to enter the brain.44 Not only is the 

blood–brain barrier permeable to both endogenous 

and exogenous behaviorally active, lipid-soluble 

compounds (eg, melatonin),33 but also a number of 

non–lipid-soluble substances can enter the brain via 

special transport mechanisms.88 One such transport 

system conveys the large neutral amino acids—tryptophan, tyrosine, phenylalanine, and others—into the 

brain; another mechanism transports choline. Furthermore, under certain circumstances, many of these 

food constituents can affect central neurotransmitter 

synthesis and, potentially, behavior.44,88 Nutrients such 

as tryptophan, tyrosine, phenylalanine, and choline are 

precursors for neurotransmitters, and their availability 

can, under certain conditions, influence the levels of 

specific neurotransmitters. Tryptophan is converted 

to the neurotransmitter serotonin, and tyrosine and 

phenylalanine are converted to the catecholamines—

dopamine, norepinephrine, and epinephrine. The 

nutrient choline is a precursor of acetylcholine.

Tryptophan

One of the neurotransmitter precursors that most 

clearly influences behavior, with effects similar to the 

sedative-hypnotic drugs, is the large neutral amino 

acid tryptophan. Tryptophan is an essential amino 

acid found in nearly all protein-containing foods and 

is the precursor of the neurotransmitter serotonin. 

Serotonin is believed to have a variety of functions in 

the brain, including a role in the regulation of mood 

state, particularly alertness and depression. Serotonincontaining neurons in the CNS also participate in the 

regulation of pain sensitivity, aggression, and food 

consumption.87,89,90

Although tryptophan is not approved for use as 

a hypnotic in the United States, it has sedative-like 

effects on humans when it is administered in pure 

form and in sufficient quantity. When tryptophan is 

administered in doses of several grams, subjects report 

feeling less vigorous and more fatigued.91 However, 

tryptophan does not seem to affect performance even 

immediately after its administration.10,88,89 A number of 

investigators92,93 have consistently detected the effects 

of tryptophan on sleepiness, reporting it to be a useful 

hypnotic, although this is a subject of considerable 

controversy.87,94–96

Even though tryptophan seems to lack the potency 

of many hypnotic drugs, it may be useful as a mild 

sleep aid in operational scenarios when sleep is desired (eg, when soldiers are suffering from jet lag). 

In a study of US Marines, tryptophan administration 

was reported to hasten the reentrainment of circadian 

rhythms of performance following air deployment 

from California to Okinawa.10 As discussed previously, 

more potent sedatives (eg, benzodiazepines) impair 

many types of performance, not only immediately after 

administration, but also when subjects are tested the 

day following bedtime administration.15

Unfortunately, ingestion of tryptophan supplements 

has been associated with a rare disorder termed eosinophilia-myalgia syndrome (EMS).97 EMS was caused 

by a contaminant found in the tryptophan produced 

by one manufacturer.98 When EMS was first linked 

to consumption of tryptophan, public health officials 

learned that millions of Americans had been taking 

this amino acid for its reputed therapeutic benefits 

(as opposed to its nutritional benefits). Because it is 

a nutrient and, therefore, less stringently regulated 

than drugs in the United States, tryptophan had been 

readily available at pharmacies and health food stores 

without prescription. Because of the association of 

tryptophan and tryptophan-containing supplements 

with EMS, the FDA withdrew these compounds from 

the market. Individuals who were taking tryptophan 

typically used it as a sleep aid, but it also has been 

recommended as an antidepressant and for treatment 

of premenstrual syndrome. The FDA has not approved 

tryptophan for any of these uses. Melatonin, also 

sold in the United States as a dietary supplement (as 

discussed previously), apparently has replaced tryptophan as a widely used, supposedly “natural,” dietary 

sleep aid, although it is not found in foods.

Tyrosine

The behavioral effects of another amino acid, tyrosine, the precursor of the catecholamines, have also 

been examined because administration of this amino 

acid may antagonize many of the adverse cognitive 

changes associated with severe acute stress. The synthesis and release of central catecholamines, especially 

norepinephrine, increase when animals are subjected 

to a variety of stressors. Pretreatment with tyrosine 

seems to mitigate some of the adverse effects of acute 

stress in animals74,99,100 and possibly humans.101–104

Tyrosine appears to affect the same neurotransmitter 

systems as the amphetamines and related drugs and 

has similar effects in animal models of acute stress.74

A number of studies have been conducted with volunteers—including soldiers, Navy SEALs, and pilots—to 

determine whether tyrosine may reduce some of the 

adverse behavioral consequences of exposure to severe 

stress. To date, tyrosine has been shown to have beneficial effects under a variety of adverse environmental 

conditions, including cold, hypoxia, and psychologi-
109

Performance-Maintaining and Performance-Enhancing Drugs and Food Components

TABLE 4-1

CAFFEINE CONTENT OF SELECTED 

BEVERAGES AND FOODS

Item Caffeine Content (mg)

Coffee (5-oz cup)

Drip method 90–150

Percolated 64–124

Instant 40–108

Decaffeinated 2–5

Instant decaffeinated 2

Tea, loose or bags (5-oz cup)

1-min brew 9–33

3-min brew 20–46

5-min brew 20–50

Tea products

Instant (5-oz cup) 12–28

Iced tea (12-oz can) 22–36

Chocolate products

Hot cocoa (6 oz) 2–8

Dry cocoa (1 oz) 6

Milk chocolate (1 oz) 1–15

Baking chocolate (1 oz) 35

Sweet dark chocolate (1 oz) 5–35

Chocolate milk (8 oz) 2–7

Chocolate-flavored syrup (2 tbsp) 4

Cola beverages (12 oz) 36–48

Other soft drinks* 12–54

(Dr Pepper, Mountain Dew, 

Mellow Yellow, Mr. Pibb, etc)

*Dr Pepper: Dr Pepper Snapple Group, Plano, Tex; Mountain Dew: 

PepsiCo, Inc, New York, NY; Mellow Yellow and Mr. Pibb: Coca-Cola 

Company, Atlanta, Ga. 

Source: Reproduced with permission from Lieberman HR. Caffeine. 

In: Jones D, Smith A, eds. Factors Affecting Human Performance. Vol 

II. The Physical Environment. London, England: Academic Press; 

1992: 49–72. 

cal stress. (For a recent review, see the report by the 

Committee on Military Nutrition Research/Institute of 

Medicine105 and the summary by Lieberman.87)

For example, in a study conducted at the US 

Army Research Institute of Environmental Medicine 

(USARIEM; Natick, Mass), tyrosine (100 mg/kg body 

weight) was tested during acute exposure to cold and 

high altitude, and significantly improved cognitive 

performance and the symptoms associated with both 

cold and hypoxia.101 Another study conducted by the 

US Army Natick Soldier Research, Development and 

Engineering Center (Natick, Mass), in collaboration 

with USARIEM, used cold-water immersion to induce 

physiological and psychological stress. Beneficial 

effects of 300 mg/kg tyrosine, administered in food 

bars (twice in 150 mg/kg doses), were observed, 

including significant improvements in the match-tosample task, a test of working memory (short-term 

memory).106 Simulated markmanship was also significantly improved by tyrosine in that study.107A study 

conducted by the Naval Medical Research Laboratory 

(Silver Spring, Md) demonstrated that tyrosine improved learning and memory in volunteers exposed 

to the cold.103

Tyrosine (100 mg/kg of body weight) has also been 

tested in pilots who were required to fly a difficult, 

all-night mission in a flight simulator. Overall, flight 

performance was significantly improved when tyrosine (versus a placebo) was administered.102 In a study 

conducted during a very stressful military training 

course, tyrosine had beneficial effects on cognitive 

performance.104 Because tyrosine has no detectable effects when individuals are not exposed to significant 

stressors and it is normally found in protein foods, it 

may have a variety of benefits compared with drugs. 

However, like most or all nutrients, the magnitude 

of its effects cannot be expected to be as substantial 

as drugs with similar mechanisms of action. For 

example, in a recent study of tyrosine conducted in 

sleep-deprived volunteers, it was found to enhance 

cognitive performance, but was not as effective as 

caffeine or amphetamines.108 A review of the literature regarding the use of tyrosine as a component in 

performance-enhancing rations is available,105 and 

another review of this literature was also published 

in 2003.87

Caffeine 

In many countries, caffeine is the preeminent legal 

stimulant. Caffeine—a xanthine—is a behaviorally 

active, natural food constituent that is present in only 

a few foods. For comprehensive reviews of the mechanisms of action of caffeine and its behavioral effects, see 

Lieberman et al109 and Smith.110 However, these foods 

are regularly consumed by a large part of the world’s 

population. Coffee, tea, and colas are particularly 

popular in the industrialized world. Many individuals 

mistakenly believe that the primary stimulant in tea 

is theophylline, another xanthine compound. In fact, 

caffeine, not theophylline, is the principal, behaviorally 

active component found in tea.111 Theophylline also 

improves cognitive performance when administered in 

clinically effective doses.112 A number of investigators 

have recommended the use of caffeine as a stimulant 

in military operations when it is desirable to optimize 

cognitive and physical performances and prevent the 
110

Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

degradation in performance associated with sleep 

loss.1,3,30,52,105,113–116

Although the levels of caffeine in foods vary greatly, 

coffee typically contains the most caffeine (about 

65–110 mg per cup), whereas tea contains an intermediate amount (about 40–60 mg per cup), and cola 

and some other soft drinks contain about 40 mg per 

serving (Table 4-1).65,114 Recently, two new categories 

of caffeine-containing beverages and dietary supplements have become very popular; these are energy 

drinks and energy shots. An example is the popular 

energy drink Red Bull (Red Bull North America, Inc, 

Santa Monica, Calif), which contains 80 mg of caffeine 

per serving.

Caffeine appears to exert its effects on the brain 

via modulation of the putative inhibitory neuromodulator, adenosine.111,117,118 Adenosine, a cyclic 

nucleotide, can be found in many brain regions. 

Functional adenosine receptors have been localized to specific brain regions, some of which are 

involved in the regulation of arousal level. Caffeine, which readily crosses the blood–brain barrier, 

blocks the effects of adenosine on brain neurons.109,111

The beneficial effects of caffeine on specific types of 

performance in well-rested volunteers are well documented. In particular, it seems that tasks that require 

sustained vigilance are sensitive to the effects of caffeine in low and moderate doses. Sustained vigilance 

is a key element of a wide variety of essential military 

activities, such as performing sentry duty, monitoring 

surveillance equipment, and operating vehicles. Both 

auditory and visual vigilance tasks reliably detect the 

effects of caffeine in doses of 32 to 300 mg.44,87,119–122 

In addition, caffeine’s effects on vigilance have been 

documented in both young and elderly men and 

women.123 The foods with equivalent doses range 

from just a single serving of a cola beverage to several 

cups of coffee.

In a series of studies of direct relevance to potential military applications of caffeine, Johnson 

and colleagues121,124,125—using an M16 assault rifle 

marksmanship simulation task—have demonstrated 

that caffeine in a dose of 200 mg improves marksmanship when there is a substantial vigilance component 

included in the task (Figure 4-3). Caffeine administration does not increase errors in marksmanship or 

decrements in other tests of cognitive performance, 

including those requiring fine motor skills, when 

it is administered in single doses equivalent to, or 

slightly higher than, those consumed in foods and 

beverages.3,120,126

Performance of tasks that do not require sustained 

vigilance (eg, memory and complex cognitive function) appears less likely to be affected by moderate 

doses of caffeine, except when volunteers are sleep 

deprived.3,44,87,113,114,122,123 Caffeine also has effects on 

self-reported mood states, most notably decreasing 

fatigue and increasing alertness.87,123 These changes 

are consistent with the stimulatory effects of caffeine 

observed in vigilance and other performance tests. 

Of course, individuals vary in their sensitivity to this 

substance, apparently because of both innate differences and daily level of consumption.109,127

In military operations, caffeine is likely to be particularly useful when soldiers are sleep deprived, 

as illustrated by a study conducted at Walter Reed 

Fig. 4-3. (a) Sentry duty performance assessed using the Weaponeer M16 rifle marksmanship simulator. (b) Speed of Weaponeer marksmanship target detection in rested volunteers given 200 mg caffeine or a placebo in pill form.

CHO: carbohydrate

Data source: McLellan TM, Bell DG, Lieberman HR, Kamimori GH. The impact of caffeine on cognitive and physical performance and marksmanship during sustained operations. Can Mil J. 2003–2004;4:47–54.

a b

Hours on a Simulated Sentry Duty Task

0.25 0.75 1.25 1.75 2.25 2.75

Placebo 6% CHO 

1700

1600

1500

1400

1300

1200

1100

Reaction Time (ms)

200 mg

Caffeine
111

Performance-Maintaining and Performance-Enhancing Drugs and Food Components

Army Institute of Research using doses of 150, 300, 

and 600 mg per 70 kg of body weight.128 In that study, 

volunteers were deprived of sleep for 49 hours. Caffeine was administered, and a series of behavioral and 

polysomnographic tests were given. Caffeine at 

various doses significantly reduced sleepiness and 

improved several aspects of cognitive performance, 

including choice reaction time, serial addition/subtraction, and logical reasoning.

Caffeine also seems to be effective in circumstances 

designed to simulate combat. We conducted a study 

with Navy SEAL trainees who were exposed to severe 

environmental, physical, and psychological stress 

and were deprived of sleep for 3 days (Figure 4-4). 

In this study, caffeine in doses of 200 and 300 mg 

had significant positive effects on both vigilance and 

more complex cognitive tasks. Caffeine did not impair 

any aspect of marksmanship in this study, including 

measures designed to detect any caffeine-induced 

degradation in fine motor control (Figure 4-5).3,126 In 

fact, caffeine improved certain aspects of marksmanship in this study,116 a finding that has been replicated 

by another laboratory.129

A study discussed previously compared 600 mg caffeine with 200 and 400 mg modafinil in sleep-deprived 

volunteers.52,53 It was observed that caffeine was as 

effective as 400 mg and more effective than 200 mg 

modafinil with regard to its ability to attenuate fatigue. 

However, this high a bolus dose of caffeine may have 

adverse effects on certain aspects of performance and 

mood. (See reviews by Lieberman et al,87,109 the 1994 

report by the Committee on Military Nutrition Research,105 and Smith.130) Lieberman et al3

 conducted a 

study in a sustained combat-like scenario with Navy 

SEAL trainees in which the effects of caffeine seemed 

to be optimal at the 200-mg dose level. The Committee on Military Nutrition Research recommended that 

caffeine be administered in 100-mg increments with 

a maximum dose of 600 mg. (See reviews by Lieberman89,109 and the 2001 report by the Committee on 

Military Nutrition Research.131)

A series of studies have been conducted with 

caffeine-containing gum (Figure 4-6) to determine 

if it would enhance a variety of militarily relevant 

functions in sleep-deprived volunteers.115,116,129 Caffeine was formulated in gum to help speed entry 

Fig. 4-4. Navy SEAL trainees in boats attempt to cross the 

surf line during Hell Week. The boats frequently capsized, 

thus soaking the trainees. Navy SEAL trainees are subjected 

to a variety of stressors designed to simulate combat. Hell 

Week (1 week of training) is especially intense and includes 

near continuous exposure to environmental, physical, and 

psychological stressors. 

Fig. 4-5. Navy SEAL trainees during marksmanship testing 

in a caffeine study.

Fig. 4-6. Caffeine-containing gum has been developed and 

tested in a series of studies and is currently in the DoD supply system.
112

Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

into the circulation.132 These studies demonstrate 

unequivocally that caffeine in moderate doses improves both physical and cognitive performance. 

Caffeine is currently used operationally by U-2 pilots 

in a specially formulated tube food suitable for use 

by encapsulated personnel (Figures 4-7 and 4-8). This 

product has been tested and shown to enhance cognitive performance in simulated overnight aviation 

missions.133A five-piece pack of chewing gum, which 

contains 200 mg of caffeine per piece, is included 

in the US Army’s assault-type First Strike Rations.

Carbohydrate Foods 

The scientific literature addressing the effects of 

macronutrients—protein, carbohydrate, and fat—on 

cognitive function is quite limited.82 If clearly beneficial behavioral effects of particular macronutrients 

could be documented, this would be of great use to 

the military. Parametric studies to address the cognitive consequences of consuming foods varying in 

protein, carbohydrate, and fat content have not been 

conducted, and many other studies in this area appear 

contradictory.87,134,135

We conducted a study with important military implications in which unequivocally beneficial behavioral effects of providing supplemental energy, in the 

form of a carbohydrate beverage, were observed.124

The study used a double-blind, placebo-controlled 

design and was conducted with a US Army Special 

Operations unit. It was designed to assess the effects 

of a specially formulated carbohydrate beverage, 

the ERGO (Energy Rich, Glucose Optimized) drink, 

on physical and cognitive performance136 (Figure 

4-9). Although the beneficial effects of carbohydrate 

supplementation on physical performance are well 

documented, the effects of such supplementation 

on cognitive performance are quite controversial.87

The beverage was formulated at the US Army Natick 

Soldier Center (Natick, Mass), the food developer for 

the Department of Defense (DoD). Unlike commercial carbohydrate sport drinks, the ERGO drink was 

Fig. 4-7. U-2 reconnaissance aircraft in flight. 

Photograph: Reproduced from the US Air Force. Image 

ID: 091021-F-2185F-970. Available at: http://www.af.mil/

photos.

Fig. 4-8. (a) Pressure suit worn by U-2 pilots prevents consumption of ordinary food. (b) Tube foods currently used in U-2 

operations. 

Photographs: (a) Reproduced from the US Air Force. Image ID: 060905-F-7441T-035. Available at: http://www.af.mil/photos. 

(b) Reproduced from the US Air Force. Image ID: 060905-F-7441T-016. Available at: http://www.af.mil/photos.

a b
113

Performance-Maintaining and Performance-Enhancing Drugs and Food Components

predominately composed of maltodextrin, a complex 

carbohydrate, in contrast to the simple sugars used 

in typical commercial products. For the purposes of 

the study, the military unit that the authors tested 

was engaged in a training exercise we designed in 

collaboration with their officers to simulate a typical 

light infantry combat operation. The exercise—lasting about 10 hours—included marching, running, 

and a live fire rifle marksmanship test (Figure 

4-10). During the study, the authors continuously 

assessed auditory vigilance with custom-designed 

and custom-constructed ambulatory vigilance monitors137 (Figure 4-11). Vigilance is the ability to sustain 

attention to boring stimuli for relatively long periods 

of time. Many operational duties require sustained 

vigilance, such as sentry duty. Regular meals provided during the exercise were not sufficient to 

meet the energy needs of the study volunteers—a 

typical situation during such training exercises and 

actual operations.138 The 143 male volunteers were 

randomly divided into three groups who received, 

on six occasions over the test day, either (1) a placebo 

beverage, (2) a 6% carbohydrate beverage, or (3) a 

12% carbohydrate beverage (Figure 4-12). These 

beverages were identical in taste and appearance, 

and provided equal fluid volumes to the volunteers. 

In this situation, carbohydrate supplementation not 

only enhanced physical performance—a well-known 

benefit of such beverages—but also significantly 

improved vigilance136 (Figure 4-13). The effects of 

energy/carbohydrate supplementation were robust 

and dose-related: the moderate (6%) dose of carbohydrate (35 kJ/kg) had effects on vigilance that 

Fig. 4-9. The ERGO drink is a 12% carbohydrate beverage base designed by the US Army Natick Soldier Center 

(Natick, Mass) to act as an ergogenic aid. It is 2% glucose, 

9% maltodextrin (a complex carbohydrate), and 1% fructose. 

It is available in orange, lemon, raspberry, lemon-lime, and 

tropical punch flavors. A 12% base carbohydrate concentration can deliver more calories and provides flexibility to 

make less concentrated mixtures for different requirements.

Fig. 4-10. US Army Rangers (a) marching during the ERGO drink study and (b) on a typical extended patroling exercise 

where a convenient carbohydrate supplement, such as the ERGO drink, provides specific physical and mental performance 

enhancements. 

Photograph (b): Reproduced from the US Army, Fort Benning. Image ID: 1189641511-TZ2hB-L. 

a b

were intermediate between the placebo condition 

(0 kJ/kg) and the higher (12%) dose treatment (70 

kJ/kg). Positive changes in mood state—specifically 

increased vigor and decreased confusion among 

volunteers receiving the ERGO drink—corroborated 

the vigilance results. Additional research to extend 

this work by determining whether other foods have 

similar effects is necessary.87,136
114

Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

POTENTIAL APPLICATIONS OF CAFFEINE 

Fig. 4-13. Mean differences from baseline in auditory vigilance reaction times over the 10 hours of the ERGO drink 

study. Each subject’s vigilance was tested continuously by 

the ambulatory monitor that was worn on the nonpreferred 

wrist. Each subject’s performance was summed over five 

time periods: (1) march, (2) 30-min rest, (3) run 1, (4) 4-hour 

rest, and (5) run 2. Because the values plotted are the differences from baseline values, the higher the number on the y

axis, the better the performance. 

CHO: carbohydrate; Diff: differences; SEM: standard error 

of the mean Mean Diff from Baseline (sec)

March 30-Min Rest Run 1 4-Hr Rest Run 2

Placebo 6% CHO 12% CHO

4

2

0

-2

-4

-6 

Average SEM

-0.3780

-0.3893

Fig. 4-11. The latest version of the ambulatory vigilance 

monitor with all sensors, output devices, and push buttons 

identified. LED: light-emitting diode.

may be greater than the optimal dose required to enhance cognitive function.139

Overall, it is clear that caffeine can improve key aspects 

of cognitive performance, especially vigilance. Lapses in 

vigilance during critical military duties—such as operFig. 4-12. US Army ranger ingesting the ERGO drink.

The food constituent with the most definitive, widely replicated ability to enhance cognitive and aerobic 

physical performance consistently and to be useful in 

operational scenarios is caffeine3,52,62,66,103,108,113,115,122,126

(Exhibit 4-2). Under many conditions, caffeine can 

improve specific aspects of performance, most notably 

vigilance. When individuals are deprived of sleep, caffeine’s beneficial effects appear to be more pervasive, 

and a number of critically important aspects of cognitive function are substantially enhanced by its administration. Furthermore, decrements in performance 

attributable to caffeine are not usually observed unless 

caffeine is administered in pharmacological doses.87

Sudden withdrawal of caffeine from the diet of 

individuals who regularly consume caffeine can 

produce adverse psychological and physiological 

consequences, including headache, impaired performance, and negative changes in mood.85,86 This should 

be taken into consideration when soldiers who consume caffeine in garrison do not have the opportunity 

to continue its use in the field, or when physicians or 

others recommend significant reduction in caffeine 

consumption. It seems that gradual withdrawal of 

caffeine-containing foods and beverages would be 

preferable to a sudden halt in all caffeine consumption. In addition to its documented beneficial effects on 

cognitive performance, caffeine also improves certain 

aspects of aerobic performance, although the optimal 

doses for this purpose have not been established and 
115

Performance-Maintaining and Performance-Enhancing Drugs and Food Components

activities (eg, marksmanship).3,52,53,115,126 The amino acid 

tyrosine also has significant potential as a unique performance enhancer that exerts its effects only when individuals are subjected to stressful situations. In addition, 

the use of liquid carbohydrate supplementation when 

soldiers are not consuming adequate amounts of food, 

a situation that typically occurs in the field,138 appears 

to improve both cognitive and physical performance.3

ating vehicles, performing sentry duty, and monitoring 

electronic surveillance equipment or communications 

devices—can have devastating effects on a unit. For a 

discussion of injuries and accidents in a military environment, see Chapter 12 on Injury Control. When individuals are sleep deprived, caffeine’s effects generalize to a 

wide variety of cognitive functions, including learning, 

memory and reasoning, as well as militarily relevant 

EXHIBIT 4-2

MILITARY COFFEE USE THROUGH THE ERAS

In his text summarizing medical research studies on Union soldiers during the Civil War, Dr Benjamin Apthorp 

Gould described observations on soldier road march performance during campaigns to Gettysburg and elsewhere 

that included an attempt to quantify energy intake and coffee consumption.(1) Coffee has been a key element of soldier 

provisioning throughout the US Army’s existence (Exhibit Figure E2-1). It has provided a morale boost in addition to 

the specific benefits of the caffeine component (eg, countermeasure to fatigue and depression). In 2001, the standing 

Committee on Military Nutrition Research of the Institute of Medicine issued recommendations for the Department 

of Defense on appropriate use and safe upper limits of caffeine supplementation to counter fatigue in military operations.(2) This permitted the fielding of caffeine gum, with appropriate labeling for use by service members. Additional 

benefits of caffeine to soldiers have been discovered since that report and are covered, in part, in a new report from the 

committee on neuroprotective nutrition.(3) Several studies funded through the Army Neurotoxin Exposure Treatment 

(Parkinson’s) Research (NETPR) program contributed to the finding that coffee consumption and, specifically caffeine, 

has a neuroprotective action associated with reduction in long-term neurodegenerative disease risk.(4,5) Thus, coffee 

drinking and caffeine consumption may be an effective intervention to reduce long-term health risks in soldiers from 

head impact and other brain injury (no randomized controlled study of this specific benefit has yet been conducted). 

There are also a wide range of noncoffee caffeine products commercially available today (Exhibit Figure E2-2).

Data sources: (1) Gould BA. Investigations in the Military and Anthropological Statistics of American Soldiers. Hurd and Houghton, Cambridge: Riverside Press; 1869: 603–610. (2) Committee on Military Nutrition Research, Food and Nutrition Board, Institute of Medicine. 

Caffeine for the Sustainment of Mental Task Performance—Formulations for Military Operations. Washington, DC: National Academy Press; 

2001. (3) Erdman J, Oria M, Pillsbury L, eds. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in 

Military Personnel. Washington, DC: National Academy Press; 2011. (4) Ross GW, Abbott RD, Petrovitch H, et al. Association of coffee 

and caffeine intake with the risk of Parkinson’s disease. JAMA. 2000;283:2674–2679. (5) Chen JF, Xu K, Petzer JP, et al. Neuroprotection 

by caffeine and A2a adenosine receptor inactivation in a model of Parkinson’s disease. J Neurosci. 2001;21:RC143.

(Exhibit 4-2 continues)

ETHICAL ISSUES ASSOCIATED WITH THE SANCTIONED USE OF DRUGS IN THE MILITARY

Historically, drugs and other stimulants have been 

used during many conflicts. The legal use of substances 

that may enhance performance or alter behavior, such 

as caffeine or alcohol, is common in our culture. US 

forces are also facing enemies who may use drugs to 

alter their behavior. Although some individuals will 

continue to debate the issue of the use of performanceenhancing drugs in military operations, it is apparent 

that such use will continue. Therefore, it is not a question 

of absolute prohibition, but of assigning and defining 

responsibility and setting limits/boundaries. Should 

use be limited to a strong cup of coffee and easily 

assimilated carbohydrates, or should US soldiers be 

given an advantage over enemy combatants by using 

a sophisticated regimen of potent prescription drugs? 

The Byrd amendment (see Exhibit 4-3) reflects an effort 

to address the use of drugs that have not been approved 

for a particular application, such as performance enhancement in times of military necessity. It is unlikely 

that this will ever be used to gain blanket approval of 

performance-enhancing drugs during military operations. It is important that medical officers are aware of 

the ethical questions related to the use of performanceenhancing substances that, in some ways, parallel the 

concerns raised for informed consent in human research. 

There are four parties involved in the transaction: 
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Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

a b

c

d

Figure E2-1. Coffee use through four US military eras, including 

(a) the Spanish-American War (roasting coffee beans), (b) World 

War I, (c) World War II soldiers in the field, (d) World War II 

aviator, and (e) Operation Enduring Freedom.

Photographs: Reproduced from the National Archives and Records Administration, Washington, DC.

e

Exhibit 4-2 continued

(Exhibit 4-2 continues)
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Performance-Maintaining and Performance-Enhancing Drugs and Food Components

Figure E2-2. Examples of the plethora of caffeine products available today. Clockwise from the upper left-hand corner: Jolt Caffeine 

Energy Gum (GumRunners LLC, Jersey City, NJ; 50 mg/chiclet); Stay Alert Caffeine Supplement Gum (Mastix Medica LLC, Hunt 

Valley, Md; 100 mg/stick); Shock-A-Lots candy (Extreme Coffee, Redwood City, Calif; 300 mg/oz candy); CLIF SHOT energy gel (Clif 

Bar & Company, Emeryville, Calif); CLIF Bar–nutrition bar (Clif Bar & Company, Emeryville, Calif); Penguin caffeinated mints (www.

peppermints.com; 7 mg/mint); Caffeine Kicks candy (Caffeine Kicks, Santa Ynez, Calif); UpTime Energy and Diet POWder! fizzy 

crystals (UpTime Nutrition Company, Inc, Minneapolis, Minn; 150 mg/packet); Ripped Fuel chewing gum (Twinlab, New York, NY; 

caffeine and ephedra—the ephedra component is now banned in the United States); Black Black chewing gum (Lotte Confectionery, 

Hangul, South Korea; 5 mg/stick); Warp Energy Mints (Big Sky Brands, Inc, Toronto, Ontario, Canada); XTZ Herbal Energy Mints (XTZ 

Industries, Inc, Edmond, Wash); chewable Metabo Mints (Metabo Corporation, West Chester, Pa); mocha-flavored HooAH! Nutritious 

Booster Bar (D’Andrea Brothers LLC, Los Angeles, Calif); Taster’s Choice packet (Nescafé Taster’s Choice, Wilkes-Barre, Pa; consumed 

dry by Ranger students with dry creamer and sugar, washed down with water); No Doz caffeine pills (Novartis Consumer Health, 

Inc, Parsippany, NJ; 200 mg/pill); and Celestial Seasonings Morning Thunder Tea (Celestial Seasonings, Boulder, Colo; matte tea). 

Exhibit 4-2 continued

1. the soldier as the recipient, who may be naive 

or informed; 

2. the commander, who has the responsibility 

to optimize the tactical situation, preferably by achieving tactical victory, and 

ensuring the health and survival of his or 

her subordinates; 

3. society, which as a whole may be technologically inexperienced and unaware of its collective responsibility; and 

4. the medical officer or scientist, who is the best 

informed about the effects and will probably 

bear the most immediate responsibility for 

the use of drugs on the battlefield.
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Military Quantitative Physiology: Problems and Concepts in Military Operational Medicine

Figure E3-2. Scud missile downed by Patriot. These missiles 

imposed the threat of chemical weapon attacks.

Photograph: Reproduced from Defense Visual Information. VIRIN: 

DD-ST-92-07786. Available at: http://www.defenseimagery.mil.

EXHIBIT 4-3

SPECIAL PROVISIONS FOR THE MILITARY USE OF DRUGS—THE BYRD AMENDMENT 

In Operations Desert Shield/Desert Storm (the first Gulf War, 1990–1991), the Department of Defense (DoD) distributed 

pyridostigmine bromide (PB; Duphar B.V., Amsterdam, Holland) tablets as part of the system of protection against 

chemical agent attack by the Iraqi forces (Exhibit Figures E3-1 and E3-2). On a more limited basis, a vaccine to botulinum 

toxin was used to protect soldiers against the threat of a biological weapon. The US Food and Drug Administration 

(FDA) had not approved these products for these indications even though they were approved as safe and effective 

for other uses. The products were still designated as Investigational New Drugs (INDs) for these military applications. 

This urgent military need created a regulatory issue that was resolved with the issuance of the “Interim Rule” by the 

FDA Commissioner and the Secretary of Health and Human Services. The FDA would allow the use of an IND if (a) 

informed consent was not feasible; (b) there was an impending combat urgency; and (c) the use would likely protect 

health and lives, with no alternative protective strategy available. The FDA granted time-limited waivers for PB and 

botulinum toxin in January 1991. 

This highlighted the issue of off-label use of a drug for military emergencies, but the Interim Rule was never finalized 

by the FDA. This was eventually addressed by the Byrd Amendment (Section 731, National Defense Authorization Act, 

FY 1999; Public Law 105-261, October 17, 1998), which was titled “Process for Waiving Informed Consent Requirement 

(Exhibit 4-3 continues)

Figure E3-1. During the 1990–1991 Gulf War, PB was classified by 

the FDA as an IND for use as a pretreatment for soman poisoning. 

Many veterans reported stopping PB use because they found the 

side effects unpleasant (eg, nausea, abdominal cramps, urinary 

urgency, headache). This illustration shows the instructions for 

use that appear on the blister pack of 21 tablets.

NAPP: nerve agent pyridostigmine pretreatment

Illustration: Reproduced from Field Manual 4-02.285, “Multiservice Tactics, Techniques, and Procedures for Treatment of 

Chemical Agent Casualties and Conventional Military Chemical 

Injuries.” Washington, DC: Headquarters, Department of the 

Army; September 18, 2007. FM 8-285.

for Administration of Certain Drugs to Members of the 

Armed Forces for Purposes of a Particular Military Operation.” This provided rules for the use of an IND or a drug 

unapproved for its applied use with service members. 

These rules include that only the President can waive 

prior consent for the use of the drug. To grant a waiver, the 

President is required to determine that obtaining consent 

is (a) not feasible, (b) contrary to the best interests of the 

member, or (c) not in the interests of national security. 

In addition to these overarching considerations, there 

is an extensive list of requirements and thresholds that 

must be met, including such things as (a) the evidence 

for safety and effectiveness relative to medical risk 

associated with a military operation; (b) the high risk 

to military personnel of an operational threat, such as 
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Performance-Maintaining and Performance-Enhancing Drugs and Food Components

The medical officer may be expected to provide guidance to the commander concerning the use of drugs 

and stimulants on the battlefield, and may have more 

direct involvement by prescribing the specific agents. 

The ethical questions regarding the use of drugs 

and stimulants to improve or modify alertness, cognitive function, and behavior and to counter fatigue 

and anxiety during war are part of a larger ethical 

debate over the role of the physician in the military. 

An entire two-volume set in the Textbooks of Military 

Medicine series (titled Military Medical Ethics) is devoted 

to ethical issues. 

from chemical, biological, nuclear, or other exposures; (c) the lack of an available satisfactory alternative treatment 

or protection; (d) justification for mandatory requirement for individual use or voluntary participation—review of 

off-label experimental use by an institutional review board; (e) explanation of how, when, and why the product will 

be used and how its administration to individuals will be tracked, including in the medical records of individual 

members; (f) provisions for an information sheet to be given to each service member prior to administration of the 

new drug; (g) a plan for follow-up for any adverse health consequences; and (h) other provisions, such as assurances that the DoD is pursuing full FDA approval for the intended application with all due diligence. These steps 

are detailed in the Code of Federal Regulations (21CFR50.23), “Informed Consent of Human Subjects—Exception 

from General Requirements.”

The FDA approved combat use of PB to prevent death from exposure to soman in 2003. As a result of the Gulf War 

experience of undiagnosed chronic multisymptom illnesses at the same time that PB was in use ahead of FDA approval, the DoD gained new understanding of the impact of this use of PB on health risk communication, disease, and 

morale.(1) It is less likely that the DoD will seek permission in the future to use IND products ahead of FDA approval, 

although the Byrd Amendment now provides a regulatory approach for that option. This puts the burden of seeking 

full FDA approval for new applications of drugs, such as performance-enhancing stimulants, on DoD researchers. 

Individual care providers can still prescribe a drug for off-label use for an individual, but not for blanket administration to a group of individuals.

Data source: (1) Friedl KE, Grate SJ, Proctor SP. Neurological issues in modern military deployments—investigation of exposures in 

the DoD Gulf War illnesses research program. Mil Med. 2009;174:335–346.

Exhibit 4-3 continued

SUMMARY 

The appropriate use of psychopharmacological and 

nutritional interventions on the battlefield provides 

a significant benefit to combat soldiers. A variety of 

critical situations occur during intense military operations in which preservation of cognitive function is 

essential, not only for the successful completion of the 

mission, but also for the very survival of the soldier. 

An adequate body of knowledge and definite doctrine 

regarding the use of psychotropic compounds in severely stressful environments does not always exist. 

Therefore, when an operational requirement calling for 

the use of such compounds arises, the unit physician 

should determine if an official doctrine is in place and 

seek the advice of experts in the field. Unfortunately, 

there is little motivation for pharmaceutical, nutrition, 

or biotechnology companies to actively engage in 

research of direct military applicability. A number of 

excellent studies, which provide critical information regarding the beneficial effects of various interventions, 

have been conducted at various DoD laboratories. 

However, these studies have just begun to address the 

numerous issues in this complex research area. In addition, political and ethical considerations may preclude 

the use of performance-enhancing or performancepreserving compounds on the battlefield, especially 

the use of stimulant drugs. Those considerations will 

certainly limit the resources committed to this area of 

research. As noted previously, preoperational testing 

of compounds that may alter cognitive performance is 

highly recommended and may be required by official 

policy, in some instances, because this gives personnel an opportunity to experience the effects of the 

drug prior to its operational use and may reveal any 

idiosyncratic adverse effects.
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