Food and Chemical Toxicology 40 (2002) 1243–1255
Center for Occupational and Health Psychology, School of Psychology, Cardiﬀ University, UK
The literature suggests that the following eﬀects on behavior of adult humans may occur when individuals consume moderate
amounts of caﬀeine. (1) Caﬀeine increases alertness and reduces fatigue. This may be especially important in low arousal situations(e.g. working at night). (2) Caﬀeine improves performance on vigilance tasks and simple tasks that require sustained response.
Again, these eﬀects are often clearest when alertness is reduced, although there is evidence that beneﬁts may still occur when theperson is unimpaired. (3) Eﬀects on more complex tasks are diﬃcult to assess and probably involve interactions between the caf-feine and other variables which increase alertness (e.g. personality and time of day). (4) In contrast to the eﬀects of caﬀeine con-sumption, withdrawal of caﬀeine has few eﬀects on performance. There is often an increase in negative mood following withdrawalof caﬀeine, but such eﬀects may largely reﬂect the expectancies of the volunteers and the failure to conduct ‘‘blind’’ studies. (5)Regular caﬀeine usage appears to be beneﬁcial, with higher users having better mental functioning. (6) Most people are very goodat controlling their caﬀeine consumption to maximise the above positive eﬀects. For example, the pattern of consumption over theday shows that caﬀeine is often consumed to increase alertness. Indeed, many people do not consume much caﬀeine later in the daysince it is important not to be alert when one goes to sleep. In contrast to eﬀects found from normal caﬀeine intake, there arereports that have demonstrated negative eﬀects when very large amounts are given or sensitive groups (e.g. patients with anxietydisorders) were studied. In this context caﬀeine has been shown to increase anxiety and impair sleep. There is also some evidencethat ﬁne motor control may be impaired as a function of the increase in anxiety. Overall, the global picture that emerges depends onwhether one focuses on eﬀects that are likely to be present when caﬀeine is consumed in moderation by the majority of the popu-lation or on the eﬀects found in extreme conditions. The evidence clearly shows that levels of caﬀeine consumed by most peoplehave largely positive eﬀects on behavior. Excessive consumption can lead to problems, especially in sensitive individuals. # 2002Published by Elsevier Science Ltd.
Keywords: Caﬀeine; Mental performance; Mood; Attention; Memory; Caﬀeine withdrawal
sumed from food and drinks, and the very diﬀerenteﬀects observed with excessive amounts or in very sen-
The aim of the present article is to review the eﬀects
sitive individuals. Unlike other areas of research (e.g.
of caﬀeine on human behavior. The main areas of
studies of health eﬀects), most studies of the behavioral
behavior reviewed are mood, mental performance and
eﬀects of caﬀeine have examined acute changes follow-
sleep. Certain areas, although related to behavior, such
ing a single dose. Less is known about eﬀects of regular
as the underlying CNS mechanisms, are not reviewed in
consumption, although there are now enough data on
detail. This is because most of the research in this area
this topic to draw tentative conclusions. In addition to
has involved animal studies. These have provided plau-
studying the eﬀects of caﬀeine consumption, the research
sible mechanisms for many of the eﬀects observed in
has also considered possible changes in behavior as a
humans, but whether speciﬁc details (e.g. eﬀects of dose)
function of caﬀeine withdrawal. A critical appraisal of
generalize across species is unknown. Other areas, such as
claims that caﬀeine withdrawal inﬂuences performance
the claims that caﬀeine is addictive, are not covered here
but are discussed in a paper by Dews et al. in this issue.
It is important to note that in research reviewed in all
In all areas it is important to make a distinction between
subsequent sections, there is considerable variation in
the eﬀects of amounts of caﬀeine that are normally con-
the methodology and measuring devices. This has thedisadvantage that it is often diﬃcult to compare diﬀerentstudies. However, persistence of eﬀects across a range of
* Tel.: +44-2920-874757; +44-2920-874758.
methodologies enhances the validity of the reported
E-mail address: smithap@cardiﬀ.ac.uk (A. Smith).
0278-6915/02/$ - see front matter # 2002 Published by Elsevier Science Ltd.
P I I : S 0 2 7 8 - 6 9 1 5 ( 0 2 ) 0 0 0 9 6 - 0
A. Smith / Food and Chemical Toxicology 40 (2002) 1243–1255
masked by increases in negative mood. Indeed, a num-ber of results suggest that caﬀeine may increase anxiety
A large number of studies have shown that consump-
Anecdotal evidence suggests that when individuals
tion of caﬀeine leads to increased alertness (or reduced
have an excessive amount of caﬀeine they may become
fatigue). These eﬀects have often been demonstrated
anxious. Similarly, some psychiatric patients attribute
using paradigms involving low alertness situations (e.g.
their problems to consumption of caﬀeine, which has
following administration of benzodiazepines—Johnson
led to a diagnosis of ‘‘caﬀeinism’’. Other patients, espe-
et al., 1990; early morning—Smith et al., 1992; working at
cially those with anxiety disorders, report that caﬀeine
night—Smith et al., 1993a; when the person has a cold—
may exacerbate their problems. The validity of these
Smith et al., 1997a; and sleeploss—Bonnet et al., 1995).
questions will now be assessed by consideration of the
However, beneﬁcial eﬀects of caﬀeine have been demon-
strated in individuals in an alert state (e.g. Leathwood and
Lieberman (1992) stated that ‘‘. . . it appears that caf-
Pollet, 1982; Rusted, 1994, 1999; Smith et al., 1994a,b;
feine can increase anxiety when administered in single
Warburton, 1995). Many of these studies have used quite
bolus doses of 300 mg or higher, which is many times
high doses of caﬀeine (e.g. 250 mg—Johnson et al.,
greater than the amount present in a single serving of a
1990; 3 mg/kg—Smith et al., 1994a,b), which would not
typical caﬀeine-containing beverage. However, in lower
be consumed typically in a single drink in real-life
doses it appears to have little eﬀect on this mood-state
situations. However, other studies have demonstrated
or, under certain circumstances, it may even reduce
similar eﬀects with realistic doses (e.g. Leathwood and
anxiety levels. It has also been observed that caﬀeine
Pollet, 1982; Warburton, 1995). These results have
reduces self-rated depression when administered in
implications for many practical situations in that safety
is often at risk when alertness is low. However, a better
The literature supports Lieberman’s view since only a
impression of this will be seen when the data from per-
small proportion of the studies reviewed show increases
formance tasks are considered. Many of the studies
in anxiety following administration of caﬀeine. Stern et
have administered caﬀeine in coﬀee and it is unclear
al. (1989) found that individuals who choose a high dose
whether it is the caﬀeine alone, or caﬀeine in combina-
of caﬀeine reported positive mood changes whereas
tion with other compounds in the coﬀee, which under-
non-choosers reported anxiety and dysphoria. Loke
lies the behavioral eﬀects. Recent research (Smith et al.,
(1988) found that caﬀeine reduced fatigue but also led
1999b) has shown that it is the caﬀeine rather than the
to increased tension and nervousness. Increased anxiety
combination of the caﬀeine and the type of drink in
was also reported following caﬀeine by Loke et al.
which it is presented that is important. Similar results
(1985) where the doses were high (either 3 or 6 mg/kg).
have also been demonstrated with caﬀeine given as a
Similarly, Sicard et al. (1996) found increased anxiety
capsule and in a drink. Other research also shows few
following 600 mg of caﬀeine. Green and Suls (1996) also
diﬀerences between decaﬀeinated coﬀee and drinks such
found that caﬀeine increased anxiety, and again the
as fruit juice. All of these pieces of evidence point to
volunteers were consuming very high amounts (125 mg
caﬀeine as the main determinant of the behavioral
caﬀeine per cup of coﬀee over the day). Overall, these
results suggest that increases in anxiety following caf-
One must now consider why some studies have failed
feine are often only found following consumption of
to ﬁnd eﬀects of caﬀeine on alertness. For example,
amounts that would rarely be ingested by the majority
Svensson et al. (1980) found no eﬀect of 100 mg of caf-
feine on the mood state of 23 volunteers. Similarly,
It is now important to assess whether caﬀeine leads to
Swift and Tiplady (1988) found no eﬀect of 200 mg of
mood problems when the person ingesting it already has
caﬀeine on the mood of elderly volunteers. This lack of
a high level of anxiety. It has been claimed that some
eﬀect could possibly reﬂect sample size or other details
people abstain from caﬀeinated drinks because of the
of the methodology. Lieberman (1992) suggests that
accompanying jitteriness and nervousness (Goldstein et
beneﬁcial eﬀects of caﬀeine on alertness are most easily
al., 1969). Other authors have even gone as far as to
demonstrated when circadian alertness is low and mood
suggest that caﬀeine acts as a ‘‘fairly convincing model
is measured in the context of doing demanding perfor-
of generalised anxiety’’ (Lader and Bruce, 1986). Caf-
mance tasks. Rusted (1999) also suggests that mood
feinism refers to a constellation of symptoms associated
eﬀects occur after changes in performance, and this may
with very high caﬀeine intake that are virtually indis-
account for the absence of eﬀects in certain studies.
tinguishable from severe chronic anxiety (Greden, 1974).
Another possible explanation of the failure to ﬁnd
Caﬀeinism is usually associated with daily intakes of
positive mood changes in certain studies is that they are
between 1000 and 1500 mg. However, it appears to be a
A. Smith / Food and Chemical Toxicology 40 (2002) 1243–1255
rather speciﬁc condition and there is little evidence for
period of abstinence or the greater eﬀects of caﬀeine
correlations between caﬀeine intake and anxiety in
when arousal is low. Finally, claims about the negative
either non-clinical volunteers (Lynn, 1973; Hire, 1978)
eﬀects of caﬀeine withdrawal require closer examination
or psychiatric outpatients (Eaton and Mcleod, 1984).
since they can often be interpreted in ways other than caf-
Correlational studies of associations between caﬀeine
feine dependence (e.g. expectancy—Smith, 1996a; Rubin
and anxiety have a number of methodological pro-
and Smith, 1999). Indeed, in most of the studies that have
blems. Although it is better to examine the anxiety-pro-
demonstrated increases in negative eﬀect following caﬀeine
ducing eﬀects of a direct caﬀeine challenge, much of this
withdrawal, the subjects have not been blind but have been
research has used very high doses (e.g. 6.6 mg/kg—
told or even instructed to abstain from caﬀeine. This is
Veleber and Templer, 1984; 10 mg/kg—Charney et al.,
clearly very diﬀerent from the double-blind methodology
1985), which makes it diﬃcult to determine whether the
typically used to study eﬀects of caﬀeine challenge.
issue is relevant to doses more representative of normalconsumption. Other studies have used a caﬀeine chal-
lenge with psychiatric patients with anxiety disorders(e.g. Bruce et al., 1992), although even with this group
The preceding sections conﬁrm the suggestions about
there is little evidence that smaller doses exacerbate the
eﬀects of caﬀeine on mood that were made at the start.
existing anxiety (Mathew and Wilson, 1990).
Other research examined whether caﬀeine is capable
of increasing the anxiety induced by other stressors.
caﬀeine, even in low doses, may increase alert-
Shanahan and Hughes (1986) found that 400 mg of
ness and this is readily apparent in low arousal
caﬀeine increased anxiety when paired with a stressful
task. However, other research (e.g. Hasenfratz and
high doses of caﬀeine can lead to increased anxiety
Battig, 1992; Smith et al., 1997b) has not been able to
provide any evidence of interactive eﬀects of caﬀeine
caﬀeine withdrawal increases negative aﬀect but
this may reﬂect expectancy eﬀects. It is also
Overall, the literature suggests that extremely high doses
unlikely that this can account for the positive
of caﬀeine may increase anxiety, but that this is rarely seen
mood eﬀects produced by caﬀeine when given to
within the normal range of ingestive behavior.
non-consumers or to volunteers who have not
The next section considers another area where caf-
feine is claimed to be associated with adverse eﬀects,namely when it is withdrawn.
The next section considers eﬀects of caﬀeine on the
Caﬀeine withdrawal has been widely studied because
it is meant to provide crucial evidence on whether caf-
feine is addictive or leads to some kind of dependence.
The most frequent outcome measure has been reporting
of headache, but mood has been examined in otherstudies. Ratcliﬀ-Crain et al. (1989) reported that caﬀeine
There are already a number of extensive reviews (e.g.
deprivation led to increased reporting of stress by heavy
Lieberman, 1992) which have summarized early studies
coﬀee drinkers. This has recently been conﬁrmed by
of the eﬀects of caﬀeine on human performance. This
Schuh and Griﬃths (1997), who found that caﬀeine
section outlines the main points to emerge from such
withdrawal was associated with feelings of fatigue and
reviews, and is then followed by a critical evaluation of
decreased feelings of alertness. Indeed, Silverman et al.
(1992) found that about 10% of volunteers with a moder-ate daily intake (235 mg per day) reported increased
depression and anxiety when caﬀeine was withdrawn.
There is a great deal of evidence to shows that caﬀeine
Other researchers (e.g. James, 1994) have argued that
blocks the eﬀects of the naturally occurring neuromo-
caﬀeine has no beneﬁcial behavioral eﬀects but merely
dulator adenosine (Snyder, 1984). This produces a net
removes negative eﬀects associated with caﬀeine with-
increase in CNS activity because the inhibitory action of
drawal. Smith (1995) has argued against this general view
adenosine is blocked. The eﬀects of caﬀeine on adenosine
of caﬀeine eﬀects on a number of grounds. First, it cannot
activity, and the subsequent eﬀects for neurotransmitters
account for the behavioral eﬀects seen in animals or non-
such as norepinephrine, occur at concentrations found as
consumers, where withdrawal cannot occur. Secondly,
a function of dietary intake. Other mechanisms have been
caﬀeine withdrawal cannot account for behavioral
demonstrated (e.g. calcium mobilisation, prostaglandin
changes following caﬀeine consumption after a short
antagonism, phosphodiesterase inhibition), but these only
A. Smith / Food and Chemical Toxicology 40 (2002) 1243–1255
become relevant when caﬀeine is administered in doses
vigilance, but there is an absence of data suggesting that
that are at least 20–30 times higher than those found in the
it may actually lead to impairments.
diet (Snyder, 1984). In humans peak plasma levels occur15–45 min after ingestion and its plasma half-life is 5–6 h.
Diﬀerent mammals use diﬀerent pathways to metabolise
Although there have been a large number of early stud-
caﬀeine, and many studies of animal behavior are, there-
ies of eﬀects of caﬀeine on more complex cognitive pro-
fore, not relevant to its eﬀects on humans.
cesses, it is hard to draw deﬁnitive conclusions. If, forexample, one considers verbal learning tasks then one
22.214.171.124. Early views of behavioral effect of caffeine. Most
ﬁnds a large number of studies which have shown no eﬀect
consumers of caﬀeine regard it as a mild stimulant when
of caﬀeine (e.g. Clubley et al., 1979; File et al., 1982; Battig
consumed in moderate doses, as recognised over 400
et al., 1984; Loke et al., 1985). Many of these failures to
years ago by Pietro della Vale (cited by Tannahill,
detect eﬀects on memory were carried out using a meth-
1989). Reviews written in the 1980s (e.g. Sawyer et al.,
odology that was sensitive enough to detect caﬀeine
1982; Dews, 1984) suggested that the eﬀects were highly
eﬀects on psychomotor or sustained attention tasks (e.g.
variable and the subject of considerable controversy.
Lieberman et al., 1987; Roache and Griﬃths, 1987).
Indeed, Dews (1984) has suggested that when caﬀeine is
It would appear from these early studies that the
administered in the doses found in foods, its eﬀects are
eﬀects of caﬀeine on cognitive performance are often
‘‘so slight and subtle that the investigator is usually glad
too small to detect as general groupeﬀects. Some posi-
tive results have been obtained (e.g. Erikson et al., 1985)
The above view probably reﬂects the numerous pro-
but only in very speciﬁc conditions (when testing was
blems associated with early studies of caﬀeine. First,
conducted at a slow, not a fast rate). Again, however,
many studies have used insensitive tests and designs. It
there appears to be little evidence suggesting impair-
is quite plausible that the eﬀects of small doses of caf-
ments following consumption of caﬀeine.
feine will be marginal and many of the negative resultsmay well reﬂect the absence of appropriate statistical
power. This problem is often compounded by the use of
Regina et al. (1974) examined the eﬀects of caﬀeine on
weak experimental designs (e.g. no baseline data) and
a simulated driving task. The results showed beneﬁcial
failure to consider individual diﬀerences.
eﬀects of caﬀeine and conﬁrmed ﬁndings using labora-tory vigilance tasks. Studies conducted by the military
(cited by Lieberman, 1992) have also shown that caf-
126.96.36.199.1. Sensory functions. Lieberman (1992) stated
feine can improve a critical military task, namely sentry
that ‘‘there is no evidence to suggest that moderate
doses of caﬀeine have direct eﬀects on sensory function,although well controlled studies using state-of-the-art
188.8.131.52. Caﬀeine and daytime sleepiness
methods have not been conducted’’.
Beneﬁcial eﬀects of caﬀeine in low arousal situations
will be considered more closely in a following section.
184.108.40.206.2. Simple and choice reaction time. There are a
However, studies conducted in the 1980s clearly
number of studies which have shown beneﬁcial eﬀects of
demonstrated that caﬀeine can remove the sedative
caﬀeine on simple reaction time (e.g. Clubley et al.,
eﬀects of certain drugs (e.g. diazepam—File et al., 1982;
1979) and choice reaction time (Smith et al., 1977; Lie-
berman et al., 1987; Roache and Griﬃths, 1987). Otherstudies have demonstrated such eﬀects in some groups
220.127.116.11. Caﬀeine, personality and time of day
but not others (e.g. the elderly but not the young—Swift
Research by Revelle and colleagues (see Revelle et al.,
and Tiplady, 1988) and with some doses but not others
1987, for a review) showed that caﬀeine facilitated the
(beneﬁcial eﬀects with 200 and 400 mg but not 600
performance of impulsive individuals and impaired the
performance of non-impulsive individuals taking com-plex cognitive tests in the morning. In the evening, the
opposite pattern of results was observed. This has been
Several papers suggest that caﬀeine, in moderate
interpreted in terms of relationships between optimum
doses, will improve vigilance (Regina et al., 1974; Club-
levels of arousal and complex tasks performance. Such
ley et al., 1979). Indeed, Lieberman (1992) suggests that
eﬀects do not appear with simple tasks, where even high
beneﬁcial eﬀects can be observed with doses as low as 32
levels of alertness facilitate performance.
mg ‘‘when a sensitive test is employed in an appropriatetesting paradigm’’.
18.104.22.168. Adverse eﬀects of caﬀeine on performance
Other researchers (e.g. Loke and Meliska, 1984) have
22.214.171.124.1. Fine motor performance. Anecdotally, it has
failed to demonstrate signiﬁcant eﬀects of caﬀeine on
been suggested that the increased arousal induced by
A. Smith / Food and Chemical Toxicology 40 (2002) 1243–1255
consumption of caﬀeine impairs hand steadiness. How-
of the population increase alertness and the ability
ever, early studies failed to demonstrate such eﬀects
to sustain attention. Adverse eﬀects occur when
(e.g. Lieberman et al., 1987) or found them only in non-
excessive doses are consumed or when caﬀeine is
consumers (e.g. Kuznicki and Turner, 1986).
126.96.36.199.2. Caffeine withdrawal. Lieberman (1992) dis-
cusses the eﬀects of caﬀeine on headache and mood butcites no evidence to suggest that it inﬂuences performance.
Recent studies of eﬀects of caﬀeine on performance
This issue will be discussed again in a later section.
have conﬁrmed many of the earlier results. For example,the beneﬁcial eﬀects of caﬀeine on psychomotor speed
188.8.131.52. A cost–beneﬁt analysis of early studies of the
and vigilance have been replicated (Frewer and Lader,
1991; Mitchell and Redman, 1992; Fine et al., 1994).
Lieberman (1992) reaches the following conclusions
Similarly, the absence of groupeﬀects in more complex
about the beneﬁcial and adverse behavioral eﬀects of
cognitive tasks has also been observed (Loke, 1990,
caﬀeine. ‘‘When caﬀeine is consumed in the range of
1992). Isolated reports of caﬀeine-induced impairments
doses found in many foods, it improves the ability of
are also to be found (e.g. decreased hand steadiness—
individuals to perform tasks requiring sustained atten-
Bovim et al., 1995). Research has continued to study the
tion, including simulated automobile driving. In addi-
eﬀects of caﬀeine on attention tasks with one aim being
tion, when administered in the same dose range, caﬀeine
to identify mechanisms underlying the eﬀects. For
increases self-reported alertness and decreases sleepi-
example, Smith et al. (1999a) and Smith (2001) have
ness’’. ‘‘Adverse behavioral eﬀects occur when caﬀeine
shown that caﬀeine increases the speed of processing
is consumed in excessive doses or by individuals who are
new stimuli, conﬁrming results reported by Streufert et
overly sensitive to the substance’’.
al. (1997). Lorist and Snel (1997) have also shown that
Overall, the early studies suggested that consumption
target detection and response preparation are enhanced
of caﬀeine may have beneﬁcial eﬀects which can
by caﬀeine, and Ruijter et al. (1999) have demonstrated
improve safety in automobile driving, other transport
that the quantity of information processed is greater
operations and industry. The next section reviews more
after caﬀeine. In contrast, no eﬀects of caﬀeine on out-
recent research to see whether adjustments to this view
put processes (e.g. movement time) have been demon-
strated (Lorist, 1998), nor has caﬀeine been shown toreduce resistance to distraction (Kenemans and Verba-
3.1.2. A summary of results from studies of caﬀeine and
Research has also sought to link performance eﬀects
seen with laboratory tasks with possible eﬀects in real-
A number of diﬀerent CNS mechanisms by
life activities. Brice and Smith (2001a) found that caf-
which caﬀeine could change performance were
feine improved both performance on a driving simulator
and laboratory tests of attention. Similarly, when per-
Early reviews of the performance eﬀects sug-
formance of reaction time tasks was measured before
gested that eﬀects were variable and slight
and after a normal working day, caﬀeine consumption
There appeared to be no direct eﬀects of caﬀeine
during the day was seen to reduce the slowing of reac-
tion times seen at the end of the day (suggesting that
A number of studies showed that caﬀeine
caﬀeine may maintain performance levels at work).
A major research issue has been whether caﬀeine can
Sustained attention has also been shown to be
remove impairments produced by fatigue or drugs.
These studies are now brieﬂy reviewed.
Eﬀects of caﬀeine on memory have not been
3.2.1. Eﬀects of caﬀeine in low arousal states
Simulations of real-life tasks (e.g. driving) have
A number of studies from the late 1980s and early
1990s show that caﬀeine removes the performance
Caﬀeine has been shown to remove impairments
impairments produced by sleep loss, fatigue, working at
night or by sedative drugs (Rogers et al., 1989; Johnson
Complex interactions between caﬀeine, person-
et al., 1990, 1991; Nicholson et al., 1990; Zwyghuizen-
Doorenbos et al., 1990). These ﬁndings have important
Some studies have shown that caﬀeine impairs
implications for safety-critical jobs and for maintaining
operational eﬃciency in low alertness situations. Indeed,
A cost–beneﬁt analysis suggested that doses of
other research has shown that the decreased alertness
caﬀeine similar to those consumed by the majority
produced by consumption of lunch can be eliminated by
A. Smith / Food and Chemical Toxicology 40 (2002) 1243–1255
consumption of caﬀeinated coﬀee (Smith et al., 1991a;
receptors, which in turn aﬀects the release of a variety of
Smith and Phillips, 1993). Furthermore, alertness is often
neurotransmitters (e.g. noradrenaline, acetylcholine,
reduced by minor illnesses such as the common cold, and
dopamine and the GABA/benzodiazepine system). One
recent research has shown that caﬀeine can remove the
approach to understanding the CNS mechanisms
impaired performance and negative mood associated with
underlying the eﬀects of caﬀeine has been to combine
these illnesses (Smith et al., 1997a). The ability of caﬀeine
pharmacological challenges with administration of caf-
to counteract the eﬀects of fatigue has been conﬁrmed
feine. Alertness can be reduced by changing a number of
using simulations of driving (Horne and Reyner, 1996;
the neurotransmitter systems. For example, by using
Reyner and Horne, 1997) and also simulated assembly-
clonidine, a drug which reduces the turnover of central
line work (Muehlbach and Walsh, 1995). The latter study
noradrenaline, it is possible to mimic sleep deprivation
demonstrated signiﬁcant improvements after caﬀeine on
in a period of a few hours. Smith and Brice (2001)
ﬁve consecutive nights and showed no decrements when
report results from a study combining caﬀeine/placebo
caﬀeine was withdrawn. Eﬀects of caﬀeine on more com-
and clonidine/placebo conditions. Caﬀeine was found to
plex cognitive tasks are again less clear (Linde, 1995),
reverse the eﬀects of clonidine but produce few eﬀects
which may reﬂect the importance of individual diﬀerences.
when the volunteers were alert. However, some eﬀects
Some of the above studies allow one to assess the
of caﬀeine (e.g. the beneﬁcial eﬀect on encoding of new
magnitude of the beneﬁcial eﬀects of caﬀeine. For
information; the cardiovascular eﬀects) were not related
example, Smith et al. (1993a) found that consumption
to changes in the noradrenergic system. Indeed, Rusted
of caﬀeine at night maintained individuals at the levels
and Smith (unpublished) have shown that the encoding
seen in the day. Another approach has been to compare
of new information reﬂects the cholinergic system and
the eﬀects of caﬀeine with other approaches aimed at
there is evidence from other studies (Riedel et al., 1995)
counteracting sleepiness. Bonnet and Arand (1994a,b)
that caﬀeine also inﬂuences this neurotransmitter.
report that the combination of a prophylactic nap and
There are ﬁve other areas that need to be considered
caﬀeine was more eﬀective in maintaining nocturnal
here. The ﬁrst is concerned with the role of individual
Other research has demonstrated that administration
of caﬀeine can remove impairments produced by seda-
tive drugs (e.g. alcohol—Kerr et al., 1991; Hasenfratz et
A number of studies have conﬁrmed the interactive
al., 1993; Rush et al., 1993; Hasenfratz and Battig, 1994;
eﬀects of caﬀeine and the personality dimension of
Scopolamine—Riedel et al., 1995; Lorazepam—Rush et
impulsivity (Smith et al., 1991b, 1994b; Gupta, 1988a,b;
al., 1994a; Triazolam—Rush et al., 1994b).
Gupta and Gupta, 1999). Some of these results ﬁt pre-
One issue is whether positive eﬀects of caﬀeine are
dictions from the Yerkes-Dodson law which states that
largely restricted to low alertness situations. Battig and
performance is an inverted-U function of arousal with a
Buzzi (1986) argued that caﬀeine can improve perfor-
negative relationshipbetween optimal arousal and task
mance beyond a mere restoration of fatigue. Other
diﬃculty. Anderson (1994) found that performance was
studies have shown that fatigued subjects show larger
an interactive function of task diﬃculty, caﬀeine and
performance after caﬀeine than do well-rested volun-
impulsivity. Performance on an easy letter cancellation
teers (Linde, 1994; Lorist et al., 1994a,b). This pattern
task was improved as caﬀeine dose increased, but on a
of results ﬁts with the conclusion of Smith (1994, 1996b,
diﬃcult task impulsive subjects (less aroused) improved
1998), namely that eﬀects of small doses of caﬀeine are
while non-impulsive subjects (more aroused) improved
most easily demonstrated in low alertness paradigms
then deteriorated. Other results do not ﬁt this pattern
whereas more global eﬀects can be observed with doses
and could reﬂect other individual diﬀerences such as
of 200–300 mg. Indeed, very high doses may increase
the risk of producing some of the adverse eﬀects descri-bed earlier, as has been conﬁrmed in a study of the
dose–response relationships of caﬀeine (Hasenfratz and
Fillmore and colleagues (Fillmore and Vogel-Sprott,
Battig, 1994). The results of this last study suggested
1992, 1994, 1995; Fillmore, 1994, 1999) have clearly
that beneﬁcial behavioral eﬀects were found with doses
demonstrated that eﬀects of caﬀeine depend on a per-
comparable to those found in caﬀeine-containing bev-
son’s expectations. Indeed, these expectations can gen-
erages. Furthermore, these levels of caﬀeine do not
eralize to placebo conditions if the individual is led to
exacerbate negative eﬀects produced by stressful condi-
expect that they are consuming a caﬀeinated beverage.
tions (e.g. electrical shocks—Hasenfratz and Battig,
In many experiments the role of expectations has not
been assessed and these could account for at least some
It is highly likely that many diﬀerent CNS mechan-
of the conﬂicting results in the caﬀeine literature.
isms underlie the eﬀects of caﬀeine on behavior. Caf-
Another possible confounding factor is the role of
feine’s major eﬀect is as an antagonist of the adenosine
A. Smith / Food and Chemical Toxicology 40 (2002) 1243–1255
3.2.4. Regular level of caﬀeine consumption
examine performance, and that where they do, any
There has been far less research on the eﬀects of reg-
eﬀects are selective, not very pronounced, and largely
ular caﬀeine consumption than on acute eﬀects. How-
unrelated to the beneﬁcial eﬀects of caﬀeine reported in
ever, a number of papers suggest that high consumers
demonstrate better performance (Loke, 1988, 1989;
Rogers et al. (1995) have reviewed a number of studies
Smith et al., 1993b). This view is conﬁrmed by other
of caﬀeine withdrawal and performance. They conclude
studies which suggest that non-consumers of caﬀeine
that ‘‘. . .in a review of recent studies we ﬁnd no
have the worst performance (Jacobsen and Thurman-
unequivocal evidence of impaired psychomotor perfor-
Lacey, 1992) especially when challenged with caﬀeine.
mance associated with caﬀeine withdrawal’’. Indeed,
There are exceptions which have shown high users to be
they found that caﬀeine improved performance in both
impaired (Mitchell and Redman, 1992), although these
deprived volunteers and non-consumers (Richardson et
eﬀects are often restricted to the performance of speciﬁc
al., 1994). Furthermore, other studies which suggest
that withdrawal may impair performance (e.g. Rizzo et
The strongest evidence for beneﬁcial eﬀects of regular
al., 1988; Bruce et al., 1991) can be interpreted in other
caﬀeine consumption comes from a study by Jarvis
ways than deprivation (e.g. changes in state—Overton,
(1993). He examined the relationshipbetween habitual
1984). Other research (e.g. Griﬃths et al., 1986) has
coﬀee and tea consumption and cognitive performance
failed to demonstrate negative eﬀects of caﬀeine with-
using data from a cross-sectional survey of a repre-
drawal on performance. Another problem for the caf-
sentative sample of over 9000 British adults. Subjects
feine withdrawal explanation of improved performance
completed tests of simple reaction time, choice reaction
following caﬀeine is that it cannot account for the ben-
time, incidental verbal memory and visuo-spatial rea-
eﬁcial eﬀects of caﬀeine observed even when volunteers
soning, in addition to providing self-reports of usual
abstain for a short period of time (Smith et al., 1994b;
coﬀee and tea intake. After controlling extensively for
potential confounding variables, a dose–response trend
The eﬀects of caﬀeine withdrawal are still con-
to improved performance with higher levels of coﬀee
troversial. This can be seen when one looks at reviews of
consumption (best performance associated with about
the topic (Daly and Fredholm, 1999; Nehlig, 1999) and
400 mg caﬀeine per day) was found for all tests. Esti-
at empirical studies. For example, James (1998) showed
mated overall caﬀeine consumption showed a dose–
that caﬀeine withdrawal impaired short-term memory
response relationship to improved cognitive perfor-
performance but caﬀeine ingestion had no eﬀect. In
mance that was strongest in those who had consumed
contrast, Smith (1999) reported that caﬀeine improved
high levels for the longest time period (the 55 years+age
attention in both those who had been deprived of caf-
group). Studies by Hogervorst et al. (1998) and Rogers
feine for a short period and those who had no caﬀeine
and Dernoncourt (1998) have failed to replicate these
for 7 days. In this study caﬀeine withdrawal had no
eﬀects using acute caﬀeine challenges which suggests that
eﬀect on performance. Studies of children (Goldstein
the above eﬀects do reﬂect regular consumption patterns
and Wallace, 1997; Bernstein et al., 1998) have sug-
rather than recent intake of caﬀeine.
gested that caﬀeine withdrawal may have negative
Overall, the previous sections conﬁrm that the eﬀects
eﬀects on mood and performance. Other studies (e.g.
of caﬀeine on performance are largely beneﬁcial. How-
Comer et al., 1997) suggest that eﬀects of withdrawal
ever, this view has recently been questioned by James
are restricted to mood and that performance is unal-
(1994), who argues that the beneﬁcial eﬀects of caﬀeine
tered. Like many areas of caﬀeine research, some of the
are really only removal of negative eﬀects produced by
eﬀects that have been attributed to withdrawal are open
caﬀeine withdrawal. The ﬁnal section considers whether
to other interpretations. For example, Lane (1997),
caﬀeine withdrawal does actually impair performance
Phillips-Bute and Lane (1997) and Lane and Phillips-
Bute (1998) compared days when mid-morning coﬀeewas either caﬀeinated or decaﬀeinated. Caﬀeine con-
3.2.5. Eﬀects of caﬀeine withdrawal on performance
sumption was associated with better performance and
The view that beneﬁcial eﬀects of caﬀeine reﬂect
mood. The authors interpret this as a negative eﬀect of
degraded performance in the caﬀeine-free conditions
caﬀeine withdrawal whereas one could interpret it as a
(James, 1994) crucially depends on the strength of the
positive eﬀect of caﬀeine. Other studies of caﬀeine
evidence for withdrawal eﬀects. James states that ‘‘there
withdrawal eﬀects have methodological problems such
is an extensive literature showing that caﬀeine with-
as the lack of pre-drink baselines (e.g. James, 1998;
drawal has signiﬁcant adverse eﬀects on human perfor-
Robelin and Rogers, 1998) or the consideration of
mance’’. If one examines the details of the studies cited
asymmetric transfer when using within subject designs
to support this view (Griﬃths et al., 1990; Hughes et al.,
(e.g. James, 1998). Indeed, while there have been a great
1990, 1991; van Dusseldorpand Katan, 1990; Silverman
number of studies of the behavioral eﬀects of caﬀeine,
et al., 1992) one ﬁnds that some of them do not even
there are still a large number of methodological issues
A. Smith / Food and Chemical Toxicology 40 (2002) 1243–1255
that need further consideration and these are outlined
Caﬀeine, in doses that would be obtained in normal
consumption of caﬀeinated products, improves
One method that can resolve whether caﬀeine eﬀects
performance of vigilance tasks and simple tasks
are due to removal of caﬀeine withdrawal is to study the
which beneﬁt from a high level of alertness.
eﬀects on caﬀeine on the behavior of non-consumers.
The beneﬁcial eﬀects of caﬀeine can be most
Smith et al. (2001) describe results from three studies that,
easily demonstrated in low arousal situations.
used this technique. All studies were able to show
beneﬁcial eﬀects of caﬀeine in both regular consumers and
shown when reduced alertness is not involved.
non-consumers, which raises serious doubts about the
Caﬀeine improves performance of artiﬁcial tasks
and simulations of driving and industrial work.
These ﬁndings suggest that it will be of beneﬁt in
safety-critical situations and will improve opera-
184.108.40.206. Consumption regimen. Most studies of the
eﬀects of caﬀeine have administered a single large dose,
Eﬀects on more complex cognitive tasks are less
often equivalent to the person’s total daily consumption
clear cut, probably because of the moderating
level. Caﬀeine is usually ingested in a number of smaller
inﬂuence of factors such as personality and time
doses (Brice and Smith, 2002) and it is unclear whether
of day. However, even this area shows few costs
eﬀects observed after a single large dose are the same as
those produced by an identical level produced by con-
It has been claimed that the positive eﬀects of
suming several caﬀeine containing drinks over a longer
caﬀeine really reﬂect removal of negative eﬀects
time period. Smith and Brice (2001a,b) describe a study
of caﬀeine withdrawal. This view cannot account
that examined this issue and found that the improved
for eﬀects observed in non-consumers or non-
mood and enhanced performance found after a single
deprived individuals. In addition, there is little
dose of 200 mg were also observed following four doses
evidence of caﬀeine withdrawal impairing tasks
of 65 mg given at hourly intervals (which resulted in an
which show improvements following ingestion of
identical ﬁnal level to the single 200 mg dose).
More research is required on the eﬀects of reg-
220.127.116.11. Metabolismof caffeine. Most of the beneﬁcial
ular levels of caﬀeine consumption on perfor-
eﬀects of caﬀeine show a linear dose–response relation-
shipupto about 300 mg and this is then followed by
evidence that high consumption is associated
either a ﬂattening of the curve or, sometimes, impaired
with better performance, especially in the elderly.
performance at higher doses. Brice and Smith (2001b)
A cost–beneﬁt analysis of the eﬀects of caﬀeine
examined the relationshipbetween metabolism of a
on performance reveals that this is an area where
ﬁxed dose of caﬀeine (as indicated by saliva levels) and
most of the evidence suggest beneﬁts.
mood and performance changes and found that therewas no strong association between the two. This is nottoo surprising in that it is not caﬀeine levels in the per-iphery per se which produce the behavioral changes but
secondary CNS mechanisms. The individual diﬀerencesin the metabolism of the caﬀeine may be very diﬀerent
Much of the research on caﬀeine and sleephas been
from the individual diﬀerences in the CNS mechanisms
concerned with removing unwanted sleepiness either
which, plausibly, accounts for the lack of a strong
when the person is working at night or when they are
association between plasma (or saliva levels) and beha-
sleepdeprived. The fact that caﬀeine can remove slee-
piness means that it can, of course, interfere with nor-mal sleep. However, patterns of consumption suggest
18.104.22.168. Effects of low doses. A number of studies (e.g.
that individuals usually control their caﬀeine intake to
Lieberman et al., 1987; Durlach, 1998; Smith et al., 1999b)
prevent interference with sleep. If large amounts of caf-
have shown that beneﬁcial eﬀects of doses of caﬀeine typi-
feine are consumed shortly before trying to sleep, then it
cally found in commercial products can now be demon-
will undoubtedly disturb sleep. The experimental evi-
strated in both measures of mood and performance.
dence for such eﬀects is well established and is brieﬂysummarized below.
3.3. Caﬀeine and mental performance: a summary
A number of studies have shown that caﬀeine increa-
ses sleeplatency (e.g. Zwyghuizen-Doorenbos et al.,
A detailed review of recent studies conﬁrmed views
1990), and reduces sleepduration (Hicks et al., 1983).
described in a review by Lieberman (1992). To reiterate,
Caﬀeine often produces its eﬀects by increasing latencies
in the ﬁrst half of the night (Bonnet and Webb, 1979)
A. Smith / Food and Chemical Toxicology 40 (2002) 1243–1255
which is diﬀerent from the insomnia seen in hypnotic
consumers being more resistant to eﬀects of caﬀeine on
withdrawal (Brezinova et al., 1975). It would not
sleep. Secondly, the impact of caﬀeine-induced changes
appear, therefore, that caﬀeine-induced insomnia acts as
in sleepon behavior the next day and long-term health is
a good general model of insomnia, as suggested by some
not known. Finally, high levels of caﬀeine consumption
do not appear to be strongly related to sleep parameters.
There are large individual diﬀerences in the eﬀects of
This again suggests that consumption is usually con-
caﬀeine on sleep. For example, one study has shown
trolled to avoid any potential adverse eﬀects on sleep.
that even caﬀeine given in the early morning can inﬂu-ence the subsequent night’s sleep(Landolt et al., 1995),
whereas other individuals report that they can consumecaﬀeine-containing beverages before bedtime with noadverse impact on their sleep (Colton et al., 1967; Levy
It is quite clear that high doses of caﬀeine in the
and Zylber-Katz, 1983). There are probably many rea-
late evening will increase the time taken for some
sons for these diﬀerences, but it appears to be estab-
lished that high consumers appear less likely to report
The eﬀects of smaller doses vary from individual to
sleepdisturbance than those who only consume caﬀeine
individual, and even when sleepis aﬀected there is
infrequently (Snyder and Sklar, 1984). Indeed, other
no clear evidence that the eﬀects are of a suﬃcient
results suggest that tolerance develops to eﬀects of caf-
magnitude to inﬂuence health and well-being.
feine on sleep(Zwyghuizen-Doorenbos et al., 1990) but
Indeed, people are usually very good at control-
that there are no withdrawal eﬀects on sleepwhen caf-
ling their caﬀeine intake, which means that there
feine is no longer given (Searle, 1994). It is also unclear
is not any strong evidence relating level of caﬀeine
whether the sleepdisturbance produced by caﬀeine has
an impact on behavior the next day, with one studyshowing no changes in mood and performance followingcaﬀeine disturbed sleep(Smith et al., 1993b).
While it is quite easy to demonstrate eﬀects of late-
night caﬀeine on sleep, it is much harder to ﬁnd evidence
The present article has reviewed the eﬀects of caﬀeine
that high levels of consumption per se will aﬀect sleep.
on mood, mental performance and sleep. In all areas it
Hicks et al. (1983) conducted a survey to examine the
is apparent that there is a big diﬀerence between the
associations between daily caﬀeine consumption, habi-
eﬀects of amounts of caﬀeine that are normally con-
tual sleepduration and sleepsatisfaction. The results
sumed and those observed when excessive amounts are
showed an inverse relationshipbetween level of daily
ingested, or when very sensitive individuals are studied.
consumption of caﬀeinated drinks and habitual sleep
Most of the research has examined acute eﬀects of single
duration, but no signiﬁcant association between caﬀeine
doses, and further studies are needed to produce a more
consumption and sleep satisfaction. Dekker et al. (1993)
detailed proﬁle of eﬀects of regular levels of consump-
examined the impact of caﬀeine consumption on the
tion. However, the general picture to emerge is that
sleepof locomotive engineers and their spouses. For the
when caﬀeine is consumed in moderation by the major-
engineers only, caﬀeine consumption was correlated
ity of the population there are unlikely to be many
with longer sleep latency. The eﬀect was not apparent in
negative eﬀects. Indeed, the positive eﬀects may be
important in maintaining eﬃciency and safety in both
Other surveys have found little evidence of associ-
the workplace and other environments. Excessive con-
ations between caﬀeine consumption and sleep. For
sumption of caﬀeine will produce problems, and appro-
example, Lee (1992) examined data from 760 nurses.
priate information should be given to minimise eﬀects in
The results showed that age and family factors con-
psychiatric patients and other sensitive groups. It is
tributed to diﬀerences in sleepmuch more than caﬀeine.
important to balance this with information on the ben-
Similarly, Greenwood et al. (1995) found no eﬀect of
eﬁts of caﬀeine, for most consumers can usually control
caﬀeine consumption on the sleep of 72 rotating-shift
their intake to maximise the beneﬁcial eﬀects and reduce
workers. Finally, a study of sleepin elderly women
or prevent adverse eﬀects due to over-consumption or
found no diﬀerences in level of caﬀeine consumption in
good and poor sleepers (Bliwise, 1992).
Overall, the research on the eﬀects of caﬀeine on sleep
leads to three main conclusions. First, large amounts of
caﬀeine (e.g. over 3 mg/kg in a single beverage) con-
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Medication Guide Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: N
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