Caffeine is undoubtedly one of the most widely consumed
and studied dietary supplements.
It is found in many products, including numerous foods and
drugs. Approximately 50% of the U.S. adult population
regularly uses one or more dietary supplements, but
80% or more regularly consumes caffeine. Thousands
of studies have investigated this substance, and a comprehensive
discussion of all aspects of the literature on
caffeine would require hundreds of pages of text. Substantial
literature on caffeine can be found in multiple
scientific fields including pharmacology, exercise and cardiovascular
physiology, psychology, psychiatry, and epidemiolog.
Caffeine occurs naturally in beverages and foods,
including coffee, tea, and chocolate.
Additional caffeine is added to beverages,
including colas, which naturally contain caffeine, because
manufacturers of these products have determined
that optimal levels of caffeine should be greater than
their naturally occurring concentration. Caffeine is behaviorally
active in the doses present in foods (3) and
is the most widely consumed psychoactive substance in
the world. Caffeine is recognized in scientific and regulatory
domains as both a naturally occurring food and
a drug, a distinction that few, if any, other substances hold.
HISTORY OF CAFFEINE USE
The first written mention of a caffeine-containing food or
beverage, tea, is in a Chinese dictionary from about AD 350
(4). However, it is likely that tea was in use long before
then. Coffee was cultivated in Ethiopia as early as the sixth
century AD, where it originated. Coffee beans were probably
first eaten whole or mixed with food (4). Coffee came
into use as a hot beverage around AD 1000 in the Middle
East but did not spread to Europe until the 17th century.
Coffee is currently second only to water as the beverage
of choice around the world, with an estimated 400 billion
cups of coffee consumed each year (5). The two most
common species of the coffee plant are Coffea arabica and
Coffea canephora Pierre ex. A. Froehner (commonly known
as robusta). Approximately two-thirds of the world’s coffee
comes from arabica plants, whereas one-third comes
from robusta (5). Arabica coffee has a smoother and superior
taste but requires extensive care in growing. Arabica
beans contain approximately 1.5% or less of caffeine by
dry weight (5). Robusta beans, grown in regions such as
Brazil, have a higher caffeine content, 2.4% to 2.8%, which
may explain their less-preferred flavor, because caffeine
itself is quite bitter (5). At least 60 species of plants contain
is not known, but caffeine protects plants from certain
Tea [Camellia sinensis (L.) Kuntze] is the caffeinated
beverage of choice in a large part of the world, although it
contains less caffeine than coffee (Table 1). It appears that
caffeine-containing beverages originated independently
in at least four different locations throughout the world.
In both North and South America, caffeine-containing
beverages were made by the native inhabitants prior to
contact with Europe. The sources of caffeine in North
America were the cassina or Christmas berry tree (Ilex
vomitoria Ait.) and in South America guarana (Paullinia
cupana Kunth) and yoco (4). Caffeine is present in cocoa
beans (Theobroma cacao L.), native to Central and South
America. A compound chemically similar to caffeine,
theobromine, is also found in cocoa but in substantially
greater amounts than caffeine. Although the popularity of
caffeine is widely recognized, the rationale for its unique
status in the diets of humans is not known, but many have
speculated its mild stimulant properties account for its
PHARMACOLOGY OF CAFFEINE
Caffeine is a methylated xanthine, 1,3,7-trimethylxanthine;
theophylline and theobromine are two other methylated
xanthines found in foods and/or drugs (Fig. 1).
Theobromine, 3,7-dimethylxanthine, is not behaviorally
active in doses found in foods (7). Theophylline, 1,3-
dimethylxanthine, used to treat asthma, is not present in
coffee but found in small quantities in tea (C. sinensis).
The parent compound of these methylated compounds
is xanthine, a dioxypurine structurally similar to uric
When ingested, caffeine is rapidly absorbed into the
systemic circulation and reaches peak levels in 45 minutes
or less (9). Caffeine is distributed to all tissues and
readily crosses the blood–brain barrier, which explains
its behavioral activity. Caffeine is initially absorbed by the
buccal membranes (in the mouth) and, when consumed in
chewing gum, enters the circulatory system more rapidly
than when ingested in pill form (10).
Caffeine Estimated Caffeine Content of Selected Beverages, Foods, and Dietary Supplements
- Coffee (5 oz)
- Drip method 90–150
- Instant 40–108
- Decaffeinated 2–5
- Tea, loose or bags
- 1-minute brew (5 oz) 9–33
- 5-minute brew (5 oz) 20–50
- Iced tea (12 oz) 22–36
- Chocolate products
- Hot cocoa (6 oz) 2–8
- Chocolate milk (8 oz) 2–7
- Milk chocolate (1 oz) 1–15
- Baking chocolate (1 oz) 35
- Cola beverages (12 oz)
- Coca-Cola R Classic 35 Diet Coke R 47
- Pepsi R 38
- Diet Pepsi R 36
Other Soft drinks (12 oz)
- Dr Pepper R
- Mountain Dew R 55
- Pibb Xtra R 41
- Barq’s Root Beer 23
Energy drinks and shots
- AMPTM (16 oz) 142
- Monster EnergyTM (16 oz) 160
- Monster EnergyTM Lo-Carb (16 oz) 135
- Red Bull R (8.3 oz) 80
- Rockstar R (16 oz) 160
- 5-Hour Energy R Shot (2 oz) 138
- DynaPepTM Micro Shot (4 mL) 80
- Extreme EnergyTM 6-Hour Shot 220
- Endurance Shot 200
- Thermogenic HydroxycutTM Advanced (2 pills) 200a
- Zantrex R 3 (2 pills) 320
- Stacker 2 R Ephedra Free (1 pill) 200
- MetaboliftTM (2 pills) 176
- SlenderiteTM (2 pills) 75
- Skinny Fast R (3 pills) 0
- Nature’s Plus R Fat Busters (2 pills) 0
The period of time caffeine remains in the circulatory system,
measured as half-life, varies dramatically. Half-life of
caffeine in a healthy adult is approximately four to five
hours, but in women taking oral contraceptives, it can increase
substantially. In cigarette smokers, caffeine is metabolized
more rapidly and has a half-life of about three
Caffeine is metabolized in the liver by a complex series
of processes. The principal metabolic pathway, which
accounts for approximately 95% of initial breakdown of
caffeine, is catalyzed by the cytochrome P450 enzyme
Chemical structures of caffeine, its demethylated derivatives
(theobromine, theophylline, paraxanthine), its parent compound (xanthine),
and uric acid.
group to form paraxanthine and, to a lesser extent, theobromine
Various factors alter CYP1A2 activity. For example,
both pregnancy and severe liver disease result in
decreased caffeine clearance (13,14). Conversely, smoking
induces CYP1A2 activity, thereby decreasing half-life
of caffeine (14). Many pharmacological substances also affect
this enzyme: oral contraceptives and cimetidine inhibit
the enzyme and slow caffeine clearance (14), whereas
other drugs (e.g., phenytoin, carbamazepine) induce the
enzyme, accelerating caffeine metabolism.
Dietary practices influence CYP1A2 activity. Caffeine
intake itself induces this enzyme, so heavy consumers
metabolize caffeine more rapidly (15), explaining,
in part, why they are less sensitive to its behavioral and
physiological effects. Cruciferous vegetables (e.g., broccoli,
kale, turnip) increase CYP1A2 activity, whereas apiaceous
vegetables (e.g., cilantro, parsnip, celery) inhibit
Genetic Differences in Caffeine Metabolism
Genetic variation is partly responsible for different phenotypes
of caffeine metabolism (17). Several CYP1A2 single
nucleotide polymorphisms (SNPs) have been characterized
(18). One, CYP1A2∗1F, is a substitution (A → C) at
position 734 on the CYP1A2 gene. Approximately 10%
to 16% of individuals have the CYP1A2 C/C (homozygous)
genotype, whereas about half possess two A alleles
(18). Individuals with the CYP1A2∗1F A → C polymorphism
are slower to metabolize caffeine and less likely
to increase CYP1A2 activity following exposure to inducers.
There may be physiological consequences of genetic
differences in caffeine metabolism. For example, a recent
study linked the slow-metabolizing CYP1A2∗1F C/C genotype,
with increased risk of heart disease associated with
coffee consumption (19).
Metabolic pathways of caffeine and its derivatives. Only pathways that begin with N-demethylation are shown, which account for almost 95% of
initial breakdown. Less than 3% of caffeine is excreted unchanged in the urine; the remainder is metabolized to 1,3,7-trimethyl uric acid (not shown). Source:
From Ref. 17.
MECHANISM OF ACTION
Caffeine’s behavioral, as well as ergogenic effects can be attributed
to central adenosine receptors (20,21). Adenosine
is an inhibitory neuromodulator in the central nervous
system that has sedative-like properties. Under normal
physiological conditions, caffeine is a nonselective competitive
antagonist at these receptors. Four subtypes, A1,
A2a, A2b, and A3, of G-protein–coupled adenosine receptors
have been identified, each with a unique tissue distribution,
signaling pathway, and pharmacological profile
(22,23). Through the respective activation of Gi and Gs
proteins, adenosine decreases adenylate cyclase activity,
and hence, cAMP levels, when bound to A1 or A3 receptors,
and increases activity when bound to A2a or A2b
Prior to discovery of caffeine’s action on adenosine
receptors, effects of caffeine were attributed to inhibition
of phosphodiesterase (PDE) (24). However, the concentration
of caffeine required to inhibit PDE substantially exceeds
that achieved from consumption of caffeine in foods
or dietary supplements. While caffeine blocks A1 and A2a
receptors at concentrations in the low micromolar range
(5–30 M), approximately 20 times as much caffeine is required
to inhibit PDE, well above physiological levels as
illustrated in Figure 3, which also presents the approximate
concentration of caffeine from consumption of a cup
of coffee (25,26).
All four adenosine receptor subtypes are expressed
to various extents in the brain and periphery (23). Adenosine
A1 receptors are widely distributed in the periphery,
spinal cord, and brain, with high levels found in
hippocampus, cortex, cerebellum, and hypothalamic nuclei;
lower levels of the A1 subtype are found in the basal Blockade of:
- Inhibition of
Concentration–effect curves for caffeine at various potential sites
of action. Caffeine markedly affects A1 and A2a receptors at low micromolar
concentrations. To inhibit phosphodiesterase (PDE), concentrations as large
as 20-times are required. Approximate caffeine concentration resulting from
a single cup of coffee and toxic doses of caffeine is indicated.
ganglia (23). The A2a, A2b, and A3 receptors are mainly expressed
in the periphery; however, there is marked expression
of the A2a receptors in regions heavily innervated by
dopamine-containing fibers, including the striatum, nucleus
accumbens, and olfactory tubercle, where they are
coexpressed with dopamine D2 receptors (27).
Caffeine binds with highest affinity at A2a receptor
and has slightly lower affinity at the A1 and the A2b receptors;
the A3 subtype has little to no affinity (24). At
standard physiological concentrations (i.e., low micromolar),
effects of caffeine are due to blockade at A1 and A2a
receptors, with binding at A2b and A3 receptors having a
minor role, if any (22,27).
Both adenosine A1 and A2a receptors may be responsible
for behavioral effects of caffeine, but the contribution
of each is uncertain. The A1 receptors are located
predominantly on presynaptic nerve terminals and mediate
release of several neurotransmitters, including glutamate,
dopamine, and acetylcholine. Caffeine is thought
to enhance arousal, vigilance, and attention by blocking
inhibition by adenosine at these receptors, particularly
those in the striatum (22). Caffeine may stimulate arousal
via A1 receptors by preventing inhibition of mesopontine
cholinergic neurons that regulate cortical activity and
Unlike dopaminergic stimulants, such as cocaine
and amphetamine, which facilitate dopamine D2 receptor
transmission, caffeine does not alter dopamine release
in ventral striatum (22). This may explain why caffeine
does not have the abuse potential of these stimulants.
Genetic Differences in Adenosine Receptors
Recently, it was shown in humans that a particular polymorphism
(a T→C substitution at position 1976; also
known as SNP rs5751876 or 1976T→C, and formerly
known as 1083T→C) of the A2a2a receptor gene (ADORA2A)
is associated with effects of caffeine on sleep (28). It appears
that 16% of individuals are homozygous for the T allele
and roughly 35% are homozygous for the C allele (29).
While inhibition of A1 receptors may be partly responsible
for wakefulness promoted by caffeine, most evidence
suggests caffeine-induced arousal is due to blockade at
A2a receptors (23).
Individuals with the ADORA2A C/C genotype
are more likely to report disturbed sleep following
caffeine consumption compared with individuals with
the T/T genotype (28). Consistent with these genetic
differences, associations were observed between self reported
caffeine-sensitivity, assessed by questionnaire,
and ADORA2A genotype.Higher proportion of sensitive
subjects had the C/C genotype, whereas the T/T genotype
was more frequent in insensitive subjects (28). In a
sleep deprivation study conducted in a subset of the survey
population, caffeine-sensitive men reported greater
stimulant-like effects of caffeine compared with those who
were caffeine-insensitive. In addition, ratings of caffeine
sensitivity were positively correlated with psychomotor
vigilance after sleep loss (28). Also, the C allele is associated
with caffeine-induced insomnia, and the T allele
appears to be related to caffeine-induced anxiety. Infrequent
caffeine users consuming less than 300 mg/wk,who
possess the ADORA2A 1976T/T genotype, experienced
greater anxiety following 150 mg caffeine compared with
those who possessed at least one C allele (29). Individuals
with the T/T genotype are significantly more likely
to limit caffeine intake (i.e., consume <100 mg/day) than
those who possess at least one C allele, with the probability
of having the T/T genotype decreasing as caffeine
intake increases (30).
CAFFEINE CONTENT OF VARIOUS PRODUCTS
In the United States, most of caffeine (approximately
80%) is consumed in coffee
(31). Caffeine is also found in
soft drinks, especially colas, energy drinks, tea, chocolate,
over-the-counter (OTC) drugs, and dietary supplements
(Table 1) (32). Some non-cola beverages also contain caffeine
such as Mountain Dew R , Dr Pepper R , and Pibb
Xtra R . There is tremendous variation in the caffeine in a
cup of coffee. Instant coffee (5 oz) can have as little as 40
mg of caffeine, whereas drip-method brewed coffee can
have as much as 150 mg (Table 1). There is considerable
variation in coffee prepared using the same method, due
to differences in caffeine content of different types of coffee
beans, especially arabica versus robusta, and variations in
Recent information on caffeine consumption in the United
States is not available. The most current data are based on
information collected between 1994–1998 (33) and 1999
(34). Using data from the nationally representative U.S.
Department of Agriculture Continuing Survey of Food
Intakes by Individuals (n = 18,081), Frary et al. reported,
in 1994–1998, that 87% of the population was caffeine consumers,
with an average caffeine intake of 193 mg/day
in users. Adult males consumed more caffeine than females
(268 mg/day vs. 192 mg/day). Coffee was the major
source of caffeine for consumers of all ages (68 mg/day),
followed by 15 mg/day from soft drinks and 12 mg/day
from tea (33). However, Ahuja et al. (35) concluded that
Frary et al. overestimated caffeine intake and revised their
estimates downward by about 25%. According to Ahuja
et al., average daily intake of caffeine in the U.S. population
is 131 mg/day, with males and females (20+ years)
consuming 193 and 149 mg/day, respectively (35). Knight
(n = 10,712) from beverages on the basis of data from
the 1999 U.S. Share of Intake Panel as 141 mg/day for
adults. There are other reports of higher caffeine consumption
in the United States. Barone and Roberts (31)
reported that U.S. caffeine intake for all consumers is about
Since these data were collected, changes in availability
of caffeine-containing products have occurred and
consumer preferences have changed (36). Energy drinks,
introduced in the United States in 1997, contain caffeine
(Table 1) and are a popular component of the diet, especially
among young adults (36). Another new product
containing high levels of caffeine (Table 1) termed “energy
shots” is rapidly gaining in popularity.
94 Lieberman et al.
High levels of caffeine are present in many dietary
supplements (Table 1), particularly those intended to promote
weight loss, for example, Zantrex 3 R and new Hydroxycut
AdvancedTM (37–39). Unfortunately, manufacturers
of such products are not required to disclose their
caffeine content, so this information can be difficult to
obtain. These products have not been shown to increase
weight loss, and recently some of the HydroxycutTM family
of products was withdrawn from the market after the
FDA issued a warning (40).
REGULATORY STATUS OF CAFFEINE
In the United States, complex regulations govern use of
its source is of little physiological or health significance,
but U.S. government agencies, in practice, regulate it on
the basis of the medium in which it is consumed. Caffeine
consumed in dietary supplements, occurring naturally in
prescription drugs are all regulated differently. Multiple
sources of caffeine ingestion and regulation can lead to
peculiar consequences. For example, a large cup of coffee
purchased at a coffee shop can contain more caffeine than
the recommended dose of an OTC stimulant. The recent
popularity of energy drinks has lead to calls for additional
regulation of such products, because it has been argued
that these products are abused (36).
BEHAVIORAL EFFECTS OF CAFFEINE
It is likely that caffeine is the most widely studied behaviorally
active compound not only in dietary supplements,
but also in any exogenously administered compound. Caffeine’s
behavioral effects have been examined in a large
number of laboratories and in well-controlled studies conducted
with males, females, young, and older volunteers
(41–43). Effects observed on specific aspects of cognitive
function andmoodstate are usually consistent with the lay
perception of caffeine as a mild stimulant when consumed
in moderate doses, just as Pietro della Valle recognized
400 years ago (44).
However, it can be difficult to detect effects of caffeine
if insensitive behavioral tests that assess parameters
not affected by caffeine are employed or doses that are
too low or high administered. In addition, it is essential to
control intake of caffeine before testing and monitor and
control for habitual patterns of caffeine consumption, as
these factors can have substantial effects on study findings.
Controlling for tobacco use is also essential, because
smoking significantly decreases caffeine’s half-life. Furthermore,
well-designed studies typically employ a range
of doses, since caffeine’s behavioral effects are dose dependent
Effects on Cognitive Performance and Mood
In rested volunteers, caffeine consistently improves both
auditory and visual vigilance (3,41,45–48). When a dose
of 200 mg of caffeine is given, effects on vigilance are
seen for several hours and are so robust that they can be
detected on a minute-by-minute basis (45) (Fig. 4). Such
effects are present with doses equivalent to a single serving
of a cola beverage, about 40 mg, up to multiple cups of
coffee (3,43,46). However, when higher doses are administered
(approximately 400–500 mg or above), cognitive
performance begins to deteriorate, so optimal dose appears
to be in the range found in foods (49,50). Caffeine
also improves simple and choice reaction time in rested
individuals (51). In general, it appears that sustained tests
of vigilance or tasks with substantial embedded vigilance
components are the most sensitive to behavioral effects of
caffeine in rested individuals.
Mood state is also altered by doses of caffeine equivalent
to those found in single and multiple servings of
dietary supplements, foods, and drugs. Aspects of mood
affected by caffeine are consistent with its effects on cognitive
functions such as vigilance and reaction time.
Effect of a 200-mg caffeine dose administered at
time “0” on visual vigilance reaction time assessed continuously
and plotted in 10 minute time blocks. Slower reaction
time (higher number) indicates worse performance (p < 0.002;
performance for two hours. Source: From Ref. 45.
Effects of 64 to 256 mg of caffeine compared to placebo (mean
°æ SEM) on the fatigue and vigor subscales of the Profile of Mood States
(POMS). Difference scores were computed by subtracting the baseline from
posttreatment values. Higher numbers on the vigor subscale indicate increased
vigor; lower numbers on the fatigue subscale indicate lowered fatigue.
∗p < 0.05 caffeine vs. placebo Source: From Ref. 32.
questionnaire, are altered by caffeine in a dose-dependent
manner (Fig. 5). Caffeine typically increases vigor and reduces
fatigue. At higher doses, these beneficial effects may
be reduced or disappear. An analog scale mood questionnaire
designed to assess effects of caffeine consistently detects
effects on moods such as tired/energetic, listless/full
of go, and efficient/inefficient (41).
Fine Motor Performance
Caffeine consumption has been associated, at least anecdotally,
with impaired fine motor performance. When administered
in a dose of 160 mg, it disrupted hand steadiness
in nonusers but not in users (53). In a study with low
and moderate consumers, doses of 32 to 256 mg of caffeine
had no effect on tests of complex motor function (54). A
recent study examined effect of caffeine on handwriting
in caffeine consumers (54). In this study, subjects were administered
caffeine in doses of 0, 1.5, 3.0, or 4.5 mg/kg and
performed a writing exercise on a digitized tablet. Compared
to placebo, high doses of caffeine improved aspects
of handwriting, such as fluidity of movement (54). Caffeine
has also been reported to improve marksmanship, a
task that requires fine motor performance (55).
Caffeine and Anxiety
It appears that caffeine increases anxiety when administered
in single bolus doses of 300 mg or higher, a dose
not ordinarily found in single servings of beverages, although
there are some exceptions. Generally, large servings
of beverages, such as 16 oz of coffee, that contain high
amounts of caffeine, are consumed slowly over time. Some
products, for example certain brands of energy drinks
or energy shots, do contain such high levels of caffeine
and may be consumed quickly, especially energy shots
(Table 1). The effects of caffeine on anxiety at lower doses
are unclear, with both positive and adverse effects reported,
perhaps due to differences in the testing environment
Several papers suggest caffeine consumption can
adversely affect individuals suffering from anxiety disorders.
Also, consumption of more than 600 mg of caffeine
per day may induce, in normal individuals, a syndrome
known as “caffeinism,” characterized by anxiety,
disturbed sleep, and psychophysiological complaints (57).
Effects on Cognitive Performance and Mood During
Sleep-Deprivation and Stress
Caffeine has substantial beneficial effects on cognitive performance
and mood when individuals are sleep deprived
or exposed to multiple stressors (50,58,59). Under such
conditions, caffeine positively affects various behavioral
parameters, including vigilance and mood state. For example,
during a night of sleep deprivation, 200 mg of caffeine
administered every two hours maintained vigilance
performance (60). Other behavioral parameters, such as
learning, memory, and reasoning, not altered when caffeine
is administered to rested volunteers, are affected
when individuals are sleep-deprived (50). When individuals
were sleep-deprived for 30 hours but not exposed
to additional stressors, 300 mg of caffeine per 70 kg of
body mass improved working memory, logical reasoning,
mathematical processing, pursuit tracking, and visual vigilance
(61). In a study conducted with U.S. Navy SEAL
trainees exposed to multiple stressors including cold, intense
physical challenges, 72 hours of sleep deprivation,
and severe psychological stress, caffeine in doses of 200
and 300 mg improved visual vigilance, choice reaction
time, and self-reported alertness (50).
Simulator and Applied Behavioral Studies
Based, in part, on studies demonstrating caffeine has
beneficial effects in laboratory studies of cognitive performance
and mood, studies have been conducted to determine
whether caffeine will have beneficial effects in
simulated or real work environments. For example,
Regina et al. (6) tested rested males in a realistic simulation
96 Lieberman et al.
U.S. Navy SEAL trainees are exposed to multiple stressors during
a segment of training known colloquially as “Hell Week.” This provided a
unique opportunity to test the behavioral effects of caffeine during sustained
exposure to severe stress (50). Cold stress serves as a key physiological
stressor during most of Hell Week. As instructors look on, trainees are required
to walk into the cold ocean water. Source: Photo courtesy of H.R. Lieberman.
of highway driving. Caffeine (200 mg) improved several
aspects of driving performance including response time
to accelerations and decelerations of a lead car. Philip
et al. (63) examined effects of approximately 200 mg of
caffeine administered in coffee on rested, young male volunteers
driving a distance of 200 km late at night on a
highway. Caffeine improved ability to maintain control
of the vehicle as measured by deviation from the traffic
lane. In a study simulating sentry duty, Johnson and
Merullo (64) evaluated the effects of 200 mg of caffeine on
marksmanship for three hours following caffeine administration.
Soldiers in the study responded to infrequent
appearance of a target by picking up a rifle, aiming, and
firing as rapidly, and accurately, as possible. Caffeine decreased
detection time but did not increase the number of
Recently, a series of studies have been conducted
by Kamimori and colleagues using a caffeine-containing
gum to determine whether caffeine would enhance performance
under conditions simulating combat, including
intermittent or continuous sleep deprivation and extensive
physical activity. These studies uniformly demonstrate
that in a wide variety of circumstances, various aspects
of cognitive, operational, and aerobic performance
are enhanced by caffeine (58,59).
In aggregate, these behavioral studies have important
practical implications. Use of caffeine in moderate
doses can improve the performance of individuals who
must drive automobiles or stand sentry duty for long periods
of time during the day or night. These beneficial
effects increase in situations where vigilance is reduced
due to sleep loss, jet lag, or circadian variations in arousal.
Recently, at the request of the U.S. Defense Department,
an independent panel conducted a comprehensive review
of the scientific literature and concluded that caffeine, in
doses of 100 to 600 mg, could be used to maintain cognitive
performance of military personnel. As a consequence,
caffeine is currently available in certain field rations (2,65).
CAFFEINE AND MENTAL ENERGY
Considerable attention has focused on dietary supplements
and foods that may increase “mental energy,” and
most of these contain caffeine. As noted above, new product
categories of “energy drinks” and “energy shots” have
emerged as popular products among the population (36).
Scientific literature on mental energy is quite limited (66–
68), although related factors, such as fatigue and alertness,
have been extensively examined. Scientists have typically
used the term “energy” to describe the concept of physical
energy measured in calories or joules. Mental energy,
however, cannot be easily defined or measured, but a distinction
between physical and mental energy clearly exists
In the United States, surveys have observed a high
prevalence of feelings of low energy. For the lay public,
mental energy is perceived as critical for the conduct
of daily activities and quality of life. On health-related
Internet sites, “fatigue,” “tiredness,” or “absence of energy”
are among the largest concerns for which remedies
are sought. To address consumer demand for such
products, dietary supplements and foods containing caffeine
have been marketed asserting they enhance energy
(36,69). Some have been evaluated by use of cognitive
tests, and the results are usually consistent with the claims
Caffeine is one of the few constituents found in dietary
supplements or foods that clearly increase mental
As noted above, low and moderate doses
improve aspects of cognitive performance and mood associated
with the perception of mental energy such as
vigilance, reaction time, vigor, and fatigue (68,71). Beneficial
effects of caffeine that appear related to mental
energy are observed in simulations of real-world activities
(58,59,62,64,72). Caffeine (100 mg) increases alertness
and self-reported attention in college students attending a
lecture (56). Epidemiological studies of large populations
indicate caffeine consumption has positive effects on factors
related to mental energy in large populations (73). In
a sample of over 7000 British adults, a significant dose–
response relationship between increased overall caffeine
intake and improved cognitive performance was observed
(73). Inclusion of caffeine in products intended to increase
perception of mental energy therefore appears warranted.
Caffeine may be the only active ingredient in such products,
if mental as opposed to physical energy is the implied
EFFECTS OF CAFFEINE ON SLEEP
It is not surprising that caffeine may interfere with sleep,
because it improves ability to sustain vigilance and increases
alertness. Many individuals abstain from caffeine
consumption in the afternoon and evening because they
believe caffeine will disrupt nighttime sleep. Others report
they consume caffeine-containing beverages before
bedtime with no adverse impact on sleep (74). Genetic
differences in sensitivity to caffeine, as discussed above,
and acquired tolerance by individuals who consume caffeine,
probably contribute to these differences. Consumers
of 3 to 6 cups of coffee per day are less likely to report sleep
disturbances than individuals who consume 0 to 1 cups
per day (74).
Anecdotal reports that caffeine interferes with sleep
are supported by the scientific literature. In both high and
low consumers, a high dose of caffeine (4.0 mg/kg) at bedtime
reduced sleep tendency, as measured by the Multiple
Sleep Latency test (75). A recent study examined effects
of moderate doses of caffeine before bedtime on various
sleep parameters assessed with polysomnography. Subjects
received 100 mg of caffeine (or placebo) three hours
and then one hour before sleeping in the laboratory. Caffeine
lengthened sleep latency, increased stage 1 sleep
(light sleep) and reduced slow-wave and stage 2 sleep
(deeper sleep) (76).
BEHAVIORAL EFFECTS OF CAFFEINE: NONUSERS
One of the most controversial issues regarding the behavioral
effects of caffeine is whether it affects performance
and mood independent of withdrawal symptoms. It has
been suggested that behavioral effects of caffeine can only
be observed in habituated individuals experiencing effects
of caffeine withdrawal on performance and mood when
treated with placebo (77). If this hypothesis is correct then
caffeine should have no effects on individuals who are
not regular users. Several studies that fail to find behavioral
effects of caffeine in individuals who are not habitual
users support this hypothesis (77,78). However, there are
several problems with this hypothesis and the experimental
evidence supporting it. No plausible mechanism has
been advanced to explain how a substance could have
no acute effects on cognitive function, yet have effects
when it is withdrawn. Many substances produce tolerance
when administered for sustained periods. However, these
substances have acute behavioral effects consistent with
behavioral consequences of their withdrawal. Examples
include drugs of abuse, such as heroin, and therapeutic
compounds such as the benzodiazepines. To test the hypothesis
advanced by Rogers and colleagues that caffeine
only has behavioral effects on habitual users, a number of
laboratories have conducted studies. These demonstrate
caffeine has behavioral effects on nonusers and affects
users who continue with their typical patterns of caffeine
CAFFEINE AND PHYSICAL PERFORMANCE
Just as caffeine improves specific aspects of cognitive performance
and mood, it also has positive effects on some
aspects of physical performance; however, it not clear that
these effects occur in doses found in most dietary supplements
or foods. Evidence that caffeine enhances aerobic
performance is convincing. A review of the literature
concluded that “caffeine effectively increases athletic performances
in endurance events” (79). For example, when
4 mg/kg of caffeine was administered to eight male volunteers,
time to run to exhaustion increased (80). In another
study, 3 and 6 mg/kg of caffeine enhanced endurance but
a higher dose, 9 mg/kg, did not (81). Beneficial effects of
caffeine assessed with a bicycle ergometer were observed
at doses 5 and 9 mg/kg, a higher dose (13 mg/kg) was no
more effective than lower doses (82).
These dose-dependent findings are similar to behavioral
studies with caffeine, in which higher doses can have
adverse effects on mood and do not enhance performance
to the same extent as moderate doses (49,50). It appears
that ergogenic effects of caffeine, like caffeine’s behavioral
effects, are attributable to its effects on central adenosine
Sudden withdrawal of caffeine from the diet, if regularly
consumed in substantial doses, can have adverse
effects in approximately 50% of users. Most notable is
headache, which is relieved by consumption of caffeine.
Onset of symptoms typically occurs in 12 to 24 hours
and may last for several days. Other symptoms can include
fatigue, lower energy, and difficulty concentrating.
Caffeine-withdrawal headaches are relieved by OTC analgesics
(83,84). Individuals who wish to reduce or eliminate
caffeine from their diet should probably do so gradually.
ABUSE POTENTIAL OF CAFFEINE
Although controversial, it has been suggested that caffeine
should be considered an addictive compound and is similar
to drugs that have substantial abuse potential, such
as nicotine and cocaine (85). Evidence for this association
includes adverse physical effects of caffeine withdrawal in
animals and human studies of caffeine self-administration
(84). Hirsh (83) has noted that addiction can best be defined
as compulsion to use a drug, and specifically, involvement
with the abused substances to the exclusion of
other interests. The use of methylxanthines in foods and
beverages would not appear to qualify as such behavior
(83). Most individuals who are regular users of caffeine
can readily halt its use and not feel compelled to continue
consuming caffeine-containing products. It is much more
difficult to stop using drugs of abuse despite the fact that
these substances are known to be extremely harmful. Caffeine
clearly has low abuse potential compared to more
widely recognized drugs of abuse (86).
When caffeine is consumed in doses found in foods and
dietary supplements, it improves ability to perform tasks
requiring sustained vigilance, including real and simulated
automobile driving, and activities that require maintenance
of vigilance (50,58,59). In addition, caffeine increases
self-reported alertness and decreases sleepiness.
Caffeine positively affects a wide range of cognitive functions
in sleep-deprived individuals, including learning,
memory, and reasoning. Caffeine can be found in many dietary
supplements, which are marketed to increase weight
loss, but evidence to support this implied claim is lacking.
Adverse behavioral effects of caffeine occur when
it is consumed in excessive doses or by individuals who
are more sensitive to the substance. Genetic factors and an
98 Lieberman et al.
individual history of caffeine consumption may be the key
factors explaining individual differences. In high doses,
caffeine can increase anxiety but its effects on fine motor
performance vary with improvement and impairment reported.
It also interferes with sleep when consumed by certain
individuals at bedtime. Like many other drugs, regular
caffeine consumption appears to produce tolerance to
its behavioral effects. Sudden withdrawal of caffeine from
the diet will lead to adverse symptoms, such as headache
and undesirable changes in mood state, in approximately
50% of individuals. Some scientists believe that caffeine
has properties that are similar to those exhibited by drugs
of abuse; others strongly disagree with this hypothesis.
An evidence-based determination of the risk-tobenefit
ratio of caffeine consumption is not possible. Positive
behavioral consequences of caffeine are well documented.
These beneficial effects generalize to highway
driving, various military duties, and presumably other
transportation and industrial operations. Use of caffeine
in such circumstances could potentially prevent accidents
attributable to lapses of vigilance such as “falling asleep at
the wheel.” Such accidents are a significant cause of motor
vehicle accidents. However, adverse effects of caffeine on
sleep quality have been observed, and some scientists believe
that caffeine has characteristics of an addictive drug.
It must also be noted that a large and complex literature
on possible beneficial and adverse effects of caffeine
on the incidence of various diseases exists. There are many
methodological concerns with both positive and negative
studies. The difficulty in accurately assessing caffeine intake
is a critical issue in such studies as is the lack of
double-blind, placebo-controlled clinical trials. Therefore,
both positive and negative findings regarding possible
health risks and benefits of caffeine should be regarded
Portions of this chapter are based on previous reviews by
the first author (32,67,68). This work was supported by
the U.S. Army Medical Research and Materiel Command
(USAMRMC). The views, opinions, and/or findings in
this report are those of the authors and should not be
construed as an official Department of the Army position,
policy, or decision, unless so designated by other official
documentation. Citation of commercial organization and
trade names in this report do not constitute an official
Department of the Army endorsement or approval of the
products or services of these organizations.
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