Success Chemistry

Improve who you are | Become unforgettable


GlossarySuccess Chemistry Staff

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.


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

caffeine. The reason so many plants contain caffeine

is not known, but caffeine protects plants from certain

insects (6).

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



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

acid (8).

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

Caffeine content

Item (mg/serving)

  • 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

Dietary supplements

  • 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

hours (11,12).

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

CYP1A2 (13).

 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

and theophylline.

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

it (16).

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.


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

receptors (22,23).

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:


  • receptors

  • Ca2+-release

  • Inhibition of

  • phosphodiesterase

  • A1-receptors

  • A2a-receptors

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.
Ref. 26.

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

arousal (22).

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).


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

brewing technique.



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

et al. (34) estimated caffeine intake in caffeine consumers

(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

210 mg/day.

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).



In the United States, complex regulations govern use of

caffeine. Once caffeine is ingested and enters circulation,

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

foods, caffeine added to foods, and caffeine in OTC and

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).



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

and nonmonotonic.


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;

caffeine vs. placebo). Caffeine consistently improved cognitive

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

targets hit.

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).



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

made (68).


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

benefit (32,68).



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).




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

consumption (47,48,51).



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

receptors (21).



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.



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

with skepticism.



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.



1. Spiller GA. Caffeine. Boca Raton, FL: CRC Press LLC, 1998.

2. Committee of Military Nutrition Research, Food and Nutrition

Board. Caffeine for the Sustainment of Mental Task

Performance: Formulations for Military Operations. Washington,

D.C.: National Academy Press, 2001.

3. Lieberman HR, Wurtman RJ, Garfield GS, et al. The effects

of low doses of caffeine on human performance and mood.

Psychopharmacology 1987; 92:308–312.

4. Roberts H, Barone JJ. Biological effects of caffeine: History

and use. Food Technol 1983; 37(9):32–39.

5. Illy E. The complexity of coffee. Sci Am 2002; June:86–91.

6. Nathanson JA. Caffeine and related methylxanthines: Possibly

naturally occurring pesticides. Science 1984; 226:


7. Judelson DA, Griel AE, Miller D, et al. Effects of theobromine,

a caffeine-like substance found in cocoa and

chocolate, on mood and vigilance. FASEB J 2010; 24:209. 5.

8. Serafin WE. Drugs used in the treatment of asthma.

In: Hardman JG, Limbird LE, Molinoff PB, Ruddon

RW, Gilman Goodman A, eds. Goodman and Gilman’s

The Pharmacological Basis of Therapeutics. New York:

McGraw-Hill, 1996:659–682.

9. Liguori A, Hughes JR, Grass JA. Absorption and subjective

effects of caffeine from coffee, cola and capsules. Pharmacol

Biochem Behav 1997; 58:721–726.

10. Kamimori GH, Karyekar CS, Otterstetter R, et al. The rate

of absorption and relative bioavailability of caffeine administered

in chewing gum versus capsules to normal healthy

volunteers. Int J Pharm 2002; 234:159–167.

11. MayDC, Jarboe CH,VanBakel AB,et al. Effects of cimetidine

on caffeine disposition in smokers and nonsmokers. Clin

Pharmacol Ther 1982; 31:656–661.

12. Meyer FP, Canzler E, Giers H, et al. Time course of inhibition

of caffeine elimination in response to the oral depot

contraceptive agent Deposiston. Hormonal contraceptives

and caffeine elimination. Zentralbl Gynakol 1991; 113:297–


13. Nurminen ML, Niittynen L, Korpela R, et al. Coffee, caffeine

and blood pressure: A critical review. Eur J Clin Nutr 1999;


14. Curatolo PW, Robertson D. The health consequences of caffeine.

Ann Intern Med 1983; 98:641–653.

15. Chen L, Bondoc FY, Lee MJ, et al. Caffeine induces cytochrome

P4501A2: Induction of CYP1A2 by tea in rats.

Drug Metab Dispos 1996; 24:529–533.

16. Peterson S, Schwarz Y, Li SS, et al. CYP1A2, GSTM1, GSTT1

polymorphisms and diet effects on CYP1A2 activity in a

crossover feeding trial. Cancer Epidemiol Biomarkers Prev

2009; 18:118–125.

17. Welfare MR, Aitkin M, Bassendine MF, et al. Detailed

modeling of caffeine metabolism and examination of the

CYP1A2 gene: Lack of a polymorphism in CYP1A2 in Caucasians.

Pharmacogenetics 1999; 9:367–375.

18. Sachse C, Brockmoller J, Bauer S, et al. Functional significance

of a C→A polymorphism in intron 1 of the cytochrome

P450 CYP1A2 gene tested with caffeine. Br J Clin

Pharmacol 1999; 47:445–449.

19. El-Sohemy A. Nutrigenetics. Forum Nutr 2007; 60:


20. Snyder SH. Adenosine as a mediator of the behavioral effects

of xanthines. In: Dews PB, ed. Caffeine. New York:

Springer, 1984:129–141.

21. Davis JM, Zhao Z, Stock HS, et al. Central nervous system

effects of caffeine and adenosine on fatigue. Am J Physiol

Regul Integr Comp Physiol 2003; 284:R399–R404.

22. Fisone G, Borgkvist A, Usiello A. Caffeine as a psychomotor

stimulant: Mechanism of action. Cell Molec Life Sci 2004;


23. Landolt HP. Sleep homeostasis: A role for adenosine in humans?

Biochem Pharmacol 2008; 75:2070–2079.

24. Varani K, Portaluppi F, Gessi S, et al. Dose and time effects of

caffeine intake on human platelet adenosine A2A receptors.

Circulation 2000; 102:285.

25. Fredholm BB, Battig K, Holmen J, et al. Actions of caffeine

in the brain with special reference to factors that contribute

to its widespread use. Pharmacol Rev 1999; 51:83–133.

26. Fredholm BB. Are methylxanthine effects due to antagonism

of endogenous adenosine? Trends Pharm Sci 1980;


Caffeine 99

27. Nehlig A. Are we dependent upon coffee and caffeine? A

review on human and animal data. Neurosci Biobehav Rev

1999; 23:563–576.

28. Retey JV, Adam M, Gottselig JM, et al. Adenosinergic

mechanisms contribute to individual differences in sleep

deprivation-induced changes in neurobehavioral function

and brain rhythmic activity. J Neurosci 2006; 26:10472–


29. Childs E, Hohoff C, Deckert J, et al. Association between

ADORA2A and DRD2 polymorphisms and caffeineinduced

anxiety. Neuropsychopharmacology 2008; 33:


30. Cornelis MC, El-Sohemy A, Campos H. Genetic polymorphism

of the adenosine A2A receptor is associated with habitual

caffeine consumption. Am J Clin Nutr 2007; 86:240–


31. Barone JJ, Roberts HR. Caffeine consumption. Food Chem

Toxicol 1996; 34:119–129.

32. Lieberman HR. The effects of ginseng, ephedrine and caffeine

on cognitive performance, mood and energy. Nutr Rev

2001; 59:91–102.

33. Frary CD, Johnson RK,Wang MQ. Food sources and intakes

of caffeine in the diets of persons in the United States. J Am

Diet Assoc 2005; 105:110–113.

34. Knight CA, Knight I, Mitchell DC, et al. Beverage caffeine

intake in US consumers and subpopulations of interest: Estimates

from the Share of Intake Panel Survey. Food Chem

Toxicol 2004; 42:1923–1930.

35. Ahuja J, Goldman J, Perloff B. The effect of improved food

composition data on national intake estimates. J Food Compost

Anal 2006; 19:S7–S13.

36. Reissig CJ, Strain EJ, Griffiths RR. Caffeinated energy

drinks—A growing problem. Drug Alcohol Depend 2009;


37. Andrews KW, Schweitzer A, Zhao C, et al. The caffeine

contents of dietary supplements commonly purchased

in the US: Analysis of 53 products with caffeine containing

ingredients. Anal Bioanal Chem 2007; 389:


38. Gregory PJ. Evaluation of the stimulant content of dietary

supplements marketed as “ephedra-free.” J Herb Pharmacother

2007; 7:65–72.

39. Evans RL, Siitonen PH. Determination of caffeine and sympathomimetic

alkaloids in weight loss supplements by

high-performance liquid chromatography. J Chromatogr

Sci 2008; 46:61–67.

40. FDA. Warning on Hydroxycut Products.

Accessed December 2009.

41. Amendola CA, Gabrieli JDE, Lieberman HR. Caffeine’s effects

on performance and mood are independent of age and

gender. Nutr Neurosci 1998; 1:269–280.

42. Rees K, Allen D, Lader M. The influences of age and caffeine

of psychomotor and cognitive function. Psychopharmacology

1999; 145:181–188.

43. Smith A, Sturgess, Gallagher J. Effects of a low dose of caffeine

given in different drinks on mood and performance.

Hum Psychopharmacol Clin Exp 1999; 14:473–482.

44. Tannahill R. Food in History. New York: Crown Publishers,

Inc, 1988.

45. Fine BJ, Kobrick JL, Lieberman HR, et al. Effects of caffeine

or diphenhydramine on visual vigilance. Psychopharmacology

1994; 114:233–238.

46. Lieberman HR, Wurtman RJ, Emde GG, et al. The effects

of caffeine and aspirin on mood and performance. J Clin

Psychopharmacol 1987; 7:315–320.

47. Childs E, de Wit H. Subjective, behavioral and physiological

effects of acute caffeine in light, nondependent caffeine

users. Psychopharmacology 2006; 185:514–523.

48. Hewlett P, Smith A. Effects of repeated doses of caffeine

on performance and alertness: New data and secondary

analyses. Hum Psychopharmacol 2007; 22:339–350.

49. Kaplan GB, Greenblatt DJ, Ehrenberg BL, et al. Dose Dependent

pharmacokinetics and psychomotor effects

of caffeine in humans. J Clin Pharmacol 1997; 37:


50. Lieberman HR, Tharion WJ, Shukitt-Hale B, et al. Effects of

caffeine, sleep loss and stress on cognitive performance and

mood during US Navy SEAL training. Psychopharmacology

2002; 164:250–261.

51. Smith A, Sutherland D, Christopher G. Effects of repeated

doses of caffeine on mood and performance of

alert and fatigued volunteers. J Psychopharmacol 2005; 19:


52. McNairDM,Lorr M, Droppleman LF. Profile of Mood States

Manual. San Diego, CA: Educational and Industrial Testing

Service, 1971.

53. Kuznicki JT, Turner LS. The effects of caffeine on caffeine

users and non-users. Physiol Behav 1986; 37:397–408.

54. Tucha O,Walitza S, Mecklinger L, et al. The effect of caffeine

on handwriting movements in skilled writers. Hum Mov

Sci 2006; 25:523–535.

55. Tharion WJ, Shukitt-Hale B, Lieberman HR. Caffeine effects

on marksmanship during high-stress military training

with 72 hour sleep deprivation. Aviat Space Env Med 2003;


56. Peeling P, Dawson B. Influence of caffeine ingestion on perceived

mood states, concentration, and arousal levels during

a 75-min university lecture. Adv Physiol Educ 2007;


57. Lee MA, Cameron OG, Greden JF. Anxiety and caffeine

consumption in people with anxiety disorders. Psychiatry

Res 1985; 15:211–217.

58. Kamimori GH, Johnson D, Thorne D, et al. Multiple caffeine

doses maintain vigilance during early morning operations.

Aviat Space Environ Med 2005; 76:1046–1050.

59. McLellan TM, Kamimori GH, Bell DG, et al. Caffeine maintains

vigilance and marksmanship in simulated urban operations

with sleep deprivation. Aviat Space Environ Med

2005; 76:39–45.

60. Kamimori GH, Johnson D, Thorne D. Efficacy of multiple

caffeine doses for maintenance of vigilance during early

morning operations. Sleep 2003; 26:A196.

61. Magill RA, Waters WF, Bray GA, et al. Effects of tyrosine,

phentermine, caffeine, d-amphetamine and placebo on cognitive

and motor performance deficits during sleep deprivation.

Nutr Neurosci 2003; 6:237–246.

62. Regina EG, Smith GM, Keiper CG, et al. Effects of caffeine

on alertness in simulated automobile driving. JAp Psychol

1974; 59:483–489.

63. Philip P, Taillard J, Moore N, et al. The effects of coffee

and napping on night time highway driving: A randomized

trial. Ann Intern Med 2006; 144:758–791.

64. Johnson RF, Merullo DJ. Caffeine, gender, and sentry duty:

Effects of a mild stimulant on vigilance and marksmanship.

In: Friedl KE, Lieberman HR, Ryan DH, Bray GA, eds.

Countermeasures for Battlefield Stressors Pennington Center

Nutrition Series. Vol. 10. Baton Rouge, LA: Louisiana

State University Press, 2000:272–289.

65. Montain SJ, Baker-Fulco CJ, Niro PJ, et al. Efficacy of eat-onmove

ration for sustaining physical activity, reaction time,

and mood. Med Sci Sports Exerc 2008; 40:1970–1976.

66. Cook DB, Davis JM. Introduction: Mental energy: Defining

the science. Nutr Rev 2006; 64:S1.

67. Lieberman HR. Mental energy: Assessing the cognitive dimension.

Nutr Rev 2006; 64:S10–S13.

68. Lieberman HR. Cognitive methods for assessing mental energy.

Nutr Neurosci 2007; 10:229–242.

100 Lieberman et al.

69. Childs NM. Consumer perceptions of energy. Nutr Rev

2001; 59:S2–S4.

70. O’Connor PJ. Mental energy: Assessing the mood dimension.

Nutr Rev 2006; 64:S7–S9.

71. Smith A. Effects of caffeine on human behavior. Food Chem

Toxicol 2002; 40:1243–1255.

72. Brice C, Smith A. The effects of caffeine on simulated driving,

subjective alertness and sustained attention. Hum Psychopharmacol

2001; 16:523–531.

73. Jarvis MJ. Does caffeine intake enhance absolute levels

of cognitive performance? Psychopharmacology 1993; 110:


74. Levy M, Zylber-Katz E. Caffeine metabolism and coffee attributed

sleep disturbances. Clin Pharmacol Ther 1983;


75. Walsh JK, Muehlbach MJ, Humm TM, et al. Effect of caffeine

on physiological sleep tendency and ability to sustain

wakefulness at night. Psychopharmacology 1990; 101:271–


76. Carrier J, Fernandez-Bolanos M, Robillard R, et al. Effects of

caffeine are more marked on daytime recovery sleep than on

nocturnal sleep. Neuropsychopharmacology 2007; 32:964–


77. Rogers PJ, Martin J, Smith C, et al. Absence of reinforcing,

mood and psychomotor performance effects of caffeine in

habitual non-consumers of caffeine. Psychopharmacology

2003; 167:54–62.

78. James JE, Rogers PJ. Effects of caffeine on performance and

mood: Withdrawal reversal is the most plausible explanation.

Psychopharmacology 2005; 182:1–8.

79. Sinclair CJ, Geiger JD. Caffeine use in sports. J Sports Med

Phys Fitness 2000; 40:71–79.

80. Graham TE, Spriet LL. Metabolic, catecholamine, and exercise

performance responses to various doses of caffeine. J

Appl Physiol 1995; 78:867–874.

81. Graham TE, Hibbert E, Sathasivam P. Metabolic and exercise

endurance effects of coffee and caffeine ingestion. J

Appl Physiol 1998; 85:883–839.

82. Pasman WJ, Van Baak MA, Jeukendrup AE, et al. The effect

of different dosages of caffeine on endurance performance

time. Int J Sports Med 1995; 16:225–230.

83. Hirsh K. Central nervous system pharmacology of the dietary

methylxanthines. In: Spiller GA, ed. The Methylxanthine

Beverages and Foods: Chemistry, Consumption, and

Health Effects. New York: Allan R. Liss, Inc, 1984.

84. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal:

Empirical validation of symptoms and signs, incidence,

severity and associated features. Psychopharmacology

2004; 176:1–29.

85. Holtzman SG. Caffeine as a model drug of abuse. Trends

Pharmacol Sci 1990; 11(9):355–356.

86. Griffiths RR, Woodson PP. Caffeine physical dependence:

A review of human and laboratory animal studies. Psychopharmacology

1988; 94:437–451.