NEUROSCIENCE AND

BIOBEHAVIORAL
REVIEWS

PERGAMON Neuroscience and Biobehavioral Reviews 23 (1999) 563–576

Are we dependent upon coffee and caffeine?

A review on human and animal data
Astrid Nehlig*
INSERM U 398, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg, France
Received 13 October 1997; received in revised form 23 April 1998; accepted 17 June 1998

Abstract
Caffeine is the most widely used psychoactive substance and has been considered occasionally as a drug of abuse. The present paper
reviews available data on caffeine dependence, tolerance, reinforcement and withdrawal. After sudden caffeine cessation, withdrawal
symptoms develop in a small portion of the population but are moderate and transient. Tolerance to caffeine-induced stimulation of
locomotor activity has been shown in animals. In humans, tolerance to some subjective effects of caffeine seems to occur, but most of
the time complete tolerance to many effects of caffeine on the central nervous system does not occur. In animals, caffeine can act as a
reinforcer, but only in a more limited range of conditions than with classical drugs of dependence. In humans, the reinforcing stimuli
functions of caffeine are limited to low or rather moderate doses while high doses are usually avoided. The classical drugs of abuse lead to
quite specific increases in cerebral functional activity and dopamine release in the shell of the nucleus accumbens, the key structure for
reward, motivation and addiction. However, caffeine doses that reflect the daily human consumption, do not induce a release of dopamine in
the shell of the nucleus accumbens but lead to a release of dopamine in the prefrontal cortex, which is consistent with caffeine reinforcing
properties. Moreover, caffeine increases glucose utilization in the shell of the nucleus accumbens only at rather high doses that stimulate most
brain structures, non-specifically, and likely reflect the side effects linked to high caffeine ingestion. That dose is also 5–10-fold higher than
the one necessary to stimulate the caudate nucleus, which mediates motor activity and the structures regulating the sleep-wake cycle, the two
functions the most sensitive to caffeine. In conclusion, it appears that although caffeine fulfils some of the criteria for drug dependence and
shares with amphetamines and cocaine a certain specificity of action on the cerebral dopaminergic system, the methylxanthine does not act on
the dopaminergic structures related to reward, motivation and addiction. 䉷 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Caffeine; Dependence; Withdrawal; Tolerance; Discrimination; Drugs of abuse

1. Introduction clinical data, the possibility that caffeine withdrawal but

Caffeine is the most widely used psychoactive substance
in the world [69]. Most of the caffeine consumed comes
from dietary sources such as coffee, tea, cola drinks and
chocolate. The most notable behavioral effects of caffeine
occur after low to moderate doses (50–300 mg) and are
increased alertness, energy and ability to concentrate.
Moderate caffeine consumption leads very rarely to health
risks [19, 40, 109]. Higher doses of caffeine rather induce
negative effects such as anxiety, restlessness, insomnia and
tachychardia, these effects being seen primarily in a small
portion of caffeine-sensitive individuals. On the other hand,
caffeine was considered in one study as a potential drug of
abuse [71] and more recently described as ‘‘a model drug of
abuse’’ [99]. Finally, based on a review of science and
* Corresponding author. Tel: ⫹ 33-388-243357; fax:
243360; e-mail: nehlig@neurochem.u-strasbg.fr.
0149-7634/99/$ - see front matter 䉷 1999 Elsevier Science Ltd. All rights reserved.
PII: S0149-763 4(98)00050-5
not abuse and dependence should be added to diagnostic
manuals has been considered in the United States [107].
The present paper will review the available data on coffee
and caffeine consumption, caffeine dependence, withdrawal
and reinforcement, and try to assess in which respect
caffeine differs from drugs of abuse such as amphetamines,
cocaine and morphine. It will also consider the reasons why
caffeine could be considered a potential drug of dependence.
2. Coffee and caffeine consumption
2.1. Coffee consumption
After having been limited to the Arab world until the
fifteenth century, coffee consumption reached the European
world during the sixteenth century and rapidly spread
⫹ 33-388- throughout Europe [42]. According to recent surveys,
consumption of coffee varies greatly among the different
564 A. Nehlig / Neuroscience and Biobehavioral Reviews 23 (1999) 563–576
Table 1
Content of caffeine in a cup of coffee according to the mode of preparation
(data from Refs. [36, 38])
Mode of preparation Volume of serving Caffeine content
Boiled 150–190 ml 111–177 mg/cup
Filter 50–190 ml 28–161 mg/cup
Espresso 50–150 ml 74–99 mg/cup
Percolated 150–190 ml 55–88 mg/cup
Instant 50–190 ml 19–34 mg/cup
countries. The highest consumption (more than 10 kg/
person/year) is encountered in all Scandinavian countries
plus Austria and the Netherlands. In most western European
countries, as well as in Brazil and Costa Rica, coffee
consumption ranges from 6–9 kg/person/year. The lowest
consumption (less than 5 kg/person/year) occurs in the
United States, Italy, Algeria, Nicaragua and Paraguay [42,
70].
The content of caffeine per cup of coffee also varies
largely according to the size of the serving, the mode of
preparation of the coffee (boiled, filter, percolated, espresso
or instant), and the type of coffee used (Arabica or Robusta)
[42, 44]. Indeed, as can be seen in Table 1, the size of a cup
of coffee can range from 50–190 ml and the standard
content of caffeine in a cup of coffee can be as low as
19 mg/cup for instant coffee and reach a maximum value
of 177 mg/cup in boiled coffee.
From these data, the caffeine content of a cup of coffee
ranges from 0.7–1.1 mg/ml for boiled or filter coffee, 0.6–
3.3 mg/ml for espresso and 0.2–0.6 mg/ml (eventually up to
1.0 mg/ml) in instant coffee [42].
Most of the coffee consumed throughout the world is
Arabica. In most countries, Arabica represents 70%–
100% (100% in Finland and Sweden) of the whole coffee
consumed. The only exceptions are France, Italy, Portugal
and the UK, where Robusta represents 42%–70% of the
whole coffee consumption [42, 44]. The average content
of caffeine is about twice as high in Robusta as in Arabica
coffee. Indeed, the content of caffeine, expressed as percent
of dry weight, ranges from 0.9%–1.2% in green Arabica
beans and averages 1.3% in roasted Arabica beans. In
Robusta coffee, the content of caffeine is 1.6%–2.4% and
2.0% of the dry weight for green and roasted beans, respec-
tively. As a consequence, in a standard 150 ml cup, the
content of caffeine ranges from 71–120 mg/cup for Arabica
coffee and from 131–220 mg/cup for Robusta [42, 191,
192].
World coffee consumption is increasing. The average
consumption of coffee in 1990 ranged from 1.41 cups/day
in Japan, to 1.73 cups/day in the United States and
3.87 cups/day in Germany [42]. In the United States, coffee
consumption (numbers of cups/person/day) decreased in
1986 and has not changed since then. In Japan, coffee
consumption has been constantly increasing over the last
10 years, while in Germany the consumption has been stable
over the same period [42]. The results of a survey performed
in France [173] indicate that four attitudes are positively
linked to the quantity of coffee consumed. They are, in
decreasing order of importance, the need for a stimulant,
the preference for strong coffee, the knowledge of coffee,
and the preference for the coffee roasting shop.
2.2. Caffeine consumption
Caffeine is present in a number of dietary sources
consumed worldwide, i.e. tea, coffee, cocoa beverages,
candy bars, and soft drinks. The content of caffeine of
these various food items ranges from 71–220 mg/150 ml
for coffee, to 32–42 mg/150 ml for tea, 32–70 mg/330 ml
for cola and 4 mg/150 ml for cocoa [44]. Caffeine consump-
tion from all sources can be estimated as 76 mg/person/day
but reaches 210–238 mg/day in the United States and
Canada and more than 400 mg/person/day in Sweden and
Finland where 80%–100% of the caffeine intake comes only
from coffee [16, 17, 44, 191, 192]. In the UK, the consump-
tion is as high as in the later two countries but 72% is
represented by tea [44]. According to the recent survey of
Barone and Roberts [17], the daily intake of caffeine from
all sources in the United States is estimated at 3 mg/kg/
person, two thirds of it coming from coffee in subjects
aged more than 10 years. If only consumers are taken into
account, the daily caffeine consumption reaches a value of
2.4–4.0 mg/kg (170–300 mg) in a 60–70 kg individual. In
children, the soft drinks represent 55%, chocolate foods and
beverages 35%–40% and tea 6%–10% of the total caffeine
intake [51].
3. Caffeine absorption and pharmacokinetics
Caffeine absorption from the gastrointestinal tract is rapid
and reaches 99% in humans about 45 min after ingestion
[13, 21–23, 132]. Caffeine absorption is also complete in
animals [10, 11]. Pharmacokinetics are comparable after
oral or intravenous administration of caffeine in humans
and animals, leading to superimposable plasma curves [13].
Peak plasma caffeine concentration is reached between
15–120 min after oral ingestion in humans and equals 8–
10 mg/l for doses of 5–8 mg/kg [14, 23]. For doses lower
than 10 mg/kg, the caffeine half-life ranges from 0.7–1.2 h
in rats and mice, 3–5 h in monkeys [24] and 2.5–4.5 h in
humans [12]. There are no differences in the caffeine half-
life in young and elderly humans [22]. Conversely, the
caffeine half-life is increased during the neonatal period
due to the lower activity of cytochrome P-450 [7] and to
the relative immaturity of some demethylation and acetyla-
tion pathways [9, 32]. The half-life of caffeine is about 80 ^
23 h for the full-term newborn infant [8, 125] and can be
over 100 h in premature infants [154]. Thereafter, the half-
life of caffeine decreases exponentially with postnatal age to
reach 14.4 h and 2.6 h in 3–5 and 5–6 month-old infants,
respectively [2, 152, 154, 156]. The clearance of caffeine is
low in one-month-old infants (31 ml/kg/h), but increases to
 A. Nehlig / Neuroscience and Biobehavioral Reviews 23 (1999) 563–576
a maximum value of 331 ml/kg/h at 5–6 months, compared
with 155 ml/kg/h in adult humans [7]. In adult males, the
caffeine half-life is reduced by 30%–50% in smokers,
compared with nonsmokers [90, 111, 137], while it is
approximately doubled in women taking oral contraceptives
[155] and largely prolonged (up to 15 h) during the last
trimester of pregnancy [3, 28, 118].
Caffeine is metabolized through liver biotransformation
into dimethylxanthines, dimethyl and monomethyl uric
acids, trimethyl- and dimethyl-allantoin, and uracil deriva-
tives. The metabolic pathways show multiple and separate
demethylation, C-8 oxidation and uracil formation in
humans and rodents, that occur predominantly in liver
microsomes. The main difference between rodents and
humans is that, in the rat, 40% of the caffeine metabolites
are trimethyl derivatives, while they do not exceed 6% in
humans. Conversely, in humans, the 3-methyl demethyla-
tion, leading to the formation of paraxanthine, represents
72%–80% of caffeine metabolism [12, 13].
4. Mechanism of action of caffeine
The effect of caffeine on the release of intracellular
calcium and as an inhibitor of cyclic nucleotide phospho-
diesterases has been mainly shown in vitro at 500 micro- or
milli-molar concentrations, respectively, i.e. at doses higher
than those usually achieved by human consumption [139,
140] and cannot therefore account for most of the physio-
logical effects of caffeine. One exception is the respiratory-
stimulant effect of caffeine that appears to be prominently
mediated by the inhibition of type IV phosphodiesterase
[102]. In fact, it is now widely accepted that the main
mechanism of action of caffeine occurring at circulating
concentrations achieved after the consumption of one or
two cups of coffee, is the antagonism at the level of adeno-
sine receptors [62, 63, 139, 140]. Indeed, in animals, most
pharmacological effects of adenosine in the brain can be
suppressed by relatively low concentrations of circulating
caffeine, i.e. less than 100 mM, which are attained after the
consumption of one to three cups of coffee. Adenosine
decreases the firing rate of neurones and exerts an inhibitory
effect on synaptic transmission and on the release of most
neurotransmitters, while caffeine increases the turnover of
many neurotransmitters, including monoamines and acetyl-
choline [139, 140].
The A1 and A2a adenosine receptors are the subtypes that
are primarily involved in the effects of caffeine, while the
A2b and A3 receptors play only a minor role. The A1 recep-
tors are negatively linked to adenyl cyclase, while the A2a
receptors are positively linked to the enzyme. Adenosine A1
receptors are widely distributed throughout the brain with
high levels in the hippocampus, cerebral and cerebellar
cortex, and thalamus [43, 54, 77]. Conversely, A2a recep-
tors are almost exclusively located in the striatum, nucleus
accumbens and olfactory tubercle [110, 149, 153]. In the
565
latter regions, A2a receptors are coexpressed with enkepha-
lin and dopamine D2 receptors in the same kind of striatal
neuronal cells [58, 149, 171]. There is direct evidence for a
central functional interaction between adenosine A2a and
dopamine D2 receptors. Indeed, the administration of
adenosine A2a receptor agonists decreases the affinity of
dopamine binding to D2 receptors in striatal membranes
[57]. The interaction between adenosine A2a receptors
and dopamine D2 receptors in the striatum might underlie
some of the behavioral effects of methylxanthines. By
antagonizing the negative modulatory effects of adenosine
receptors on dopamine receptors, caffeine leads to the inhi-
bition and blockage of adenosine A2 receptors, leading to a
potentiation of dopaminergic neurotransmission [56, 65,
158]. The latter interaction is very interesting since it
could explain the adenosine receptor antagonists-induced
increase in behaviors related to dopamine [41], such as,
e.g. caffeine-induced rotational behavior [67].
5. Addiction and drug dependence
Drug dependence has been defined as ‘a pattern of beha-
vior focused on the repetitive and compulsive seeking and
taking of a psychoactive drug’ [92]. However, it is necessary
to demonstrate psychoactive effects to differentiate drug
dependence from other habitual or controlled behaviors,
such as the daily ingestion of some types of medication
like aspirin or vitamins. Moreover, it appears necesary to
demonstrate that the drug is positively reinforcing its own
ingestion. Therefore, the following section will consider the
criteria used for the definition of dependence.
The recent diagnostic manuals from the World Health
Organization (WHO) [197] and the American Psychiatric
Association (APA) [4, 5] proposed a new set of criteria
for dependence. The diagnosis of dependence requires the
fulfillment of three (non specified) of the six WHO [196] or
seven APA [4, 5] criteria. The seven criteria of dependence
as proposed by the APA [5] in DSM-IV (Diagnostic and
Statistical Manual of Mental Disorders, 4th ed.) are: (i)
tolerance (not specified for severity); (ii) substance-specific
withdrawal syndrome (psychic or physiological, not speci-
fied for severity); (iii) substance is often taken in larger
amounts or over a longer period than intended; (iv) persis-
tent desire or unsuccessful efforts to cut down or control use;
(v) a great deal of time spent in activities necessary to
obtain, use, or recover from the effects of the substance;
(vi) important social, occupational or recreational activities
given up or reduced because of substance use; and (vii) use
continued despite knowledge of a persistent or recurrent
physical or psychological problem that is likely to have
been caused or exacerbated by the substance. The six
criteria proposed by the WHO [197] differ only slightly
from those of the APA, mainly by a different sequence,
slightly different formulations and the combination of
criteria (v) and (vi) into a single one. The only possibility
566 A. Nehlig / Neuroscience and Biobehavioral Reviews 23 (1999) 563–576
to differentiate between substances that can lead to depen-
dence is to classify them according to the number of criteria
met and specify for severity of symptoms and frequency of
occurrence.
The possible dependence on caffeine has been considered
by several groups for over a decade [71, 78, 83, 84, 88, 92,
93, 186] and caffeine has even been postulated as a ‘poten-
tial model of drug of abuse’ [99]. In two recent studies using
the criteria cited above, a dependence on caffeine was
shown in a subset of the general population. As a result of
a random telephone survey in Vermont, Hughes et al. [106]
showed that 14% and 3% of the 166 caffeine users inter-
viewed met the criteria for moderate and severe caffeine
dependence, respectively. After telephone screening
performed on 99 subjects in the United States, Strain et al.
[187] found 16 individuals that fulfilled four out of the seven
criteria cited above, and were thus considered dependent on
caffeine. The criteria met were criteria (i), (ii), (iv) and (vii)
of DSM-IV. Criteria (iii), (v) and (vi) were excluded
because they do not apply to a substance widely available
and culturally accepted. The dependence was not related to
the daily caffeine intake which ranged from 129–2548 mg/
day. The median daily caffeine intake for the caffeine-
dependent individuals was 360 mg and about 40% of them
had a daily caffeine intake of 300 mg or less [187].
However, in spite of the absence of current psychiatric
disorders at the time of the study in most of the individuals
(14 out of 16), 11 of the 16 persons diagnosed with ‘caffeine
dependence’ had a history of psychiatric disorders, mainly
substance abuse disorders (10 subjects) and mood disorders
(seven subjects). The prevalence of these disorders is higher
than that encountered in the general population, i.e. 50%
[117]. Moreover, the tendency to an association between
caffeine, alcohol, and nicotine consumption [122], as well
as between mood disorders and nicotine dependence has
been previously reported [29, 116].
Therefore, to try to assess in which respect caffeine
should or should not be considered a drug of dependence,
in the present review, the consequences of coffee and
caffeine consumption on various criteria, possibly leading
to the diagnosis of dependence, will be considered. Among
the seven criteria for drug dependence that have been cited
above, the four main factors to consider are withdrawal,
tolerance, reinforcement and dependence.
6. Caffeine withdrawal
6.1. Caffeine withdrawal in animals
There are several reports showing caffeine withdrawal
signs in rats, cats and monkeys. They include decreases in
locomotor activity [59, 98], operant behavior [31, 33, 136],
and in the reinforcement threshold for electrical brain stimu-
lation [136]. Other studies have reported changes in the time
spent in various phases of slow wave sleep [180] and
avoidance of a preferred flavor when the latter was paired
with caffeine abstinence [193]. The severity of caffeine
withdrawal depends on the dose, and decreases in locomotor
activity do not appear when caffeine doses lower than
67 mg/kg/day are substituted by water [59, 98]. The length
of the decrease in locomotor activity depends also upon the
dose of caffeine and the duration of the treatment before the
substitution by water [59, 98]. The latency to the onset of
caffeine withdrawal effects usually occurs within 24 h, and
peaks around 24–48 h [31, 33, 59, 98, 136, 180, 193]. The
caffeine withdrawal-induced behavioral changes usually
last a few days [85], except for the sleep-related signs that
have been shown to last up to 30 days after the onset of
caffeine withdrawal [180].
6.2. Characterization of withdrawal symptoms in humans
Caffeine withdrawal translates into typical symptoms.
The most often reported are headaches, feelings of weari-
ness, weakness and drowsiness, impaired concentration,
fatigue and work difficulty, depression, anxiety, irrritability,
increased muscle tension, occasionally tremor, and nausea
and vomiting, as well as withdrawal feelings [83, 105, 140,
164, 177, 186, 187]. Withdrawal symptoms generally begin
about 12–24 h after sudden cessation of caffeine consump-
tion and reach a peak after 20–48 h. However, in some
individuals, these symptoms can appear within only 3–6 h
and last for one week [16, 108, 124, 140]. Withdrawal
symptoms do not relate to the quantity of caffeine ingested
daily [86–88, 96, 97, 107, 187], e.g. the recent study of
Strain et al. [187] showed that withdrawal symptoms
occur in individuals who daily consume anything from
129–2548 mg of caffeine. In the last decade, two studies
[107, 187] suggested that caffeine withdrawal symptoms
(but not abuse or dependence) should be added to the list
of diagnoses recognized by the American Health System
(DSM-IV and ICD-10).
There is a strong positive correlation between caffeine
consumption, fasting and headaches before and after surgi-
cal procedures. For every increase in the usual daily
consumption of 100 mg of caffeine (about a cup of coffee),
the risk of headache immediately before and after surgery is
increased by 12% and 16%, respectively, and correlates also
with the duration of fasting [55, 144]. The risk of headaches
is reduced in individuals who drink caffeine or get substitu-
tive caffeine tablets on the day of the surgery [89, 195, 196].
Therefore, it was advised by three studies that the numerous
healthy patients who drink caffeine-containing beverages
daily and are undergoing minor surgical procedures should
be permitted to ingest preoperative caffeine [144, 195, 196].
In their most recent study, Weber et al. [196] also showed
that in the population selected, 40%–48% of the patients
already suffered regular headaches (at least weekly) at the
time they underwent surgery. Moreover, there is a relation-
ship between caffeine withdrawal, the development of head-
aches and changes in cerebral blood flow. The cerebral
 A. Nehlig / Neuroscience and Biobehavioral Reviews 23 (1999) 563–576
blood flow velocities are increased during withdrawal head-
aches, significantly decreased within 30 min after caffeine
intake in all subjects and return to baseline values after 2 h
[39]. This recent study confirms several previous ones that
suggested that increased blood volume may be involved in
caffeine withdrawal headaches [48, 94, 133, 194]. Caffeine
withdrawal symptoms were even reported in newborns
whose mothers were heavy coffee drinkers during preg-
nancy. The infants displayed irritability, high emotivity
and, eventually, vomiting. Symptoms begun at birth but
spontaneously disappeared after a few days [134].
Recently, Smith [181] reported that in a population of 144
students that discriminated caffeine only at chance level,
there was no difference in the frequency of headaches
between the group in which caffeine was withdrawn and
the one receiving caffeinated coffee over the 3 day protocol.
This effect could be interpreted as an expectancy effect that
might not have occurred in other studies where subjects
were able to discriminate caffeine.
6.3. Relief of abstinence symptoms by caffeine
Caffeine withdrawal symptoms disappear soon after
absorption of caffeine. This effect is strongly linked to the
psychological satisfaction related to the ingestion of
caffeine; this is especially true for the first cup of the day.
The potential reversal of caffeine withdrawal-induced head-
aches and other symptoms by the absorption of caffeine
alone has been known for over 50 years and has been
shown repeatedly [48, 73, 74, 86, 103]. The occurrence of
headaches on substitution of caffeinated by decaffeinated
coffee predicts subsequent caffeine self-administration
[103]. Caffeine content influences coffee consumption [86,
87, 121] and the beneficial effects of caffeine consumption
on mood or alertness seem to incite people to drink coffee or
caffeine-containing beverages [123, 164]. Heavy consumers
of coffee show a preference for coffee that contains caffeine,
while those who used to drink decaffeinated coffee will
choose either decaffeinated or caffeine-containing coffee
[78, 185]. When subjects are categorized between caffeine
choosers and nonchoosers, caffeine choosers tend to report
both positive subjective effects of caffeine (stimulant and
positive effects on mood and vigilance) as well as negative
subjective effects of placebo (headache and fatigue), while
caffeine nonchoosers tend to report negative effects of
caffeine (primarily anxiety and dysphoria) [53, 179, 185].
7. Tolerance to the effects of caffeine
Tolerance to a drug refers to an acquired change in
responsiveness of a subject repeatedly exposed to the drug
and can be considered in two ways. First, tolerance might
indicate that the dose necessary to achieve the desired
euphoric or reinforcing effects will increase with time,
thus inciting people to gradually consume more of the
drug. Second, tolerance to the aversive effects of high
567
doses of the drug may occur, hence leading people to
consume higher doses of the drug over time.
Tolerance to many behavioral effects of caffeine occurs in
mice, cats and squirrel monkeys chronically treated with
methylxanthine (for review, see [85, 100]). Thus, tolerance
to caffeine-induced locomotor stimulation [1, 35, 59–61,
98, 100], cerebral electrical activity [35, 95, 98], reinforce-
ment thresholds for electrical brain stimulation [136], sche-
dule-controlled responding maintained by presentation of
food and electric shock [100, 115], and thresholds for
caffeine- [199] or NMDA-induced seizures [68] has been
described. The development of tolerance to caffeine in
animals is rapid, usually insurmountable, shows cross-toler-
ance with other methylxanthines but not with psychomotor
stimulants such as amphetamines and methylphenidate [60,
61, 98, 100]. On the first two days after caffeine disconti-
nuation, depression of locomotor activity is noted with a
return to baseline values on the third day, consistent with
a withdrawal syndrome [59, 60, 98]. Although the exact
mechanism underlying the development of tolerance to
caffeine remains unclear, tolerance to behavioral effects of
caffeine in animals does not seem to involve adaptative
changes in adenosine receptors [68, 101] and may rather
result from compensatory changes in the dopaminergic
system as a result of chronic adenosine receptor blockage
[66].
In humans the tolerance to some physiological actions of
caffeine has been shown to occur. This is the case for the
effect of caffeine on blood pressure and heart rate [6, 45,
165, 169, 175], diuresis [50], plasma adrenaline and nora-
drenaline levels, and renin activity [165], that usually devel-
ops within a few days. Tolerance to some subjective effects
of caffeine, such as increases in tension-anxiety, jitteriness/
nervousness, activity/stimulation/energy, and the strength
of drug effect [53] was recently shown to occur. Conversely,
although tolerance to the enhancement of arithmetic skills
by caffeine was recently shown [169], there is only limited
evidence for tolerance to caffeine-induced alertness and
wakefulness [38, 76, 96, 97]. These effects are paralleled
by the lack of tolerance of cerebral energy metabolism to
caffeine, since an acute administration of 10 mg/kg caffeine
induces the same metabolic increases whether the rats have
been exposed to a previous daily chronic treatment by
caffeine or saline for 15 days [138]. These data show that
every single exposure to caffeine is able to produce cerebral
stimulant effects and this is especially true in the areas that
control locomotor activity (caudate nucleus) and the struc-
tures involved in the sleep-wake cycle (locus coeruleus,
raphe nuclei and reticular formation) [138].
In humans, sleep seems to be the physiological function
most sensitive to the effects of caffeine, as detailed in a
recent review [182]. Generally, more than 200 mg caffeine
are needed to affect sleep significantly. Caffeine has been
shown to prolong sleep latency, shorten total sleep duration
but to preserve the dream phases of sleep. It is not clearly
established yet whether or not the difference in the
568 A. Nehlig / Neuroscience and Biobehavioral Reviews 23 (1999) 563–576
sensitivity to the effects of coffee on sleep could be attribu-
table to tolerance. According to some studies, this difference
could rather reflect the interindividual sensitivity to
caffeine, possibly related to differences in the rate of
caffeine metabolism [126, 190]. Indeed poor sleepers are
reported to metabolize caffeine at a lower rate and four
out of the 10 subjects of the study had elimination half-
lives exceeding 4.8 h [190]. The variability in the subjects
response from one night to the next should also be taken into
account [76, 96, 97, 127]. Nevertheless, there are some
indications of a development of tolerance to sleep distur-
bances related to caffeine intake since heavy coffee drinkers
appear to be less sensitive to caffeine-induced sleep distur-
bances than light coffee drinkers [38]. Likewise, tolerance to
sleep latency and quality to caffeine has been shown to
develop over 2 days of testing in one study [200] and
7 days in another [25]. However, the tolerance is not
complete and the sleep efficiency remains below 90% of
the baseline value after 7 days of caffeine treatment [25].
Thus, tolerance to some of the effects linked to regular
consumption of coffee seems to occur, especially in animals.
In humans, the data are less conclusive and this may under-
lie individual differences in the susceptibility and tolerance
to caffeine-induced effects. Moreover, mechanisms of toler-
ance may be overwhelmed by the nonlinear accumulation of
caffeine and its main metabolites in the human body when
caffeine metabolism becomes saturable under multiple
dosing conditions [45, 46].
8. Discrimination and reinforcement of caffeine in
humans
8.1. Discrimination of caffeine
Human subjects are able to discriminate caffeine against
placebo both when offered in capsules or in coffee. Doses of
300 mg or higher are usually more easily detected and
mainly recognized by their negative effects of jitteriness,
anxiety or nervousness, whereas the lower doses are
detected by their lack of effect or by caffeine withdrawal
symptoms. However, several studies have failed to demon-
strate behavioral effects of caffeine at doses below 200 or
300 mg, i.e. amounts corresponding to the ingestion of two
to three cups of coffee [18, 69]. Doses in the range of
100 mg, which closely approach the caffeine content of a
normal serving are detected poorly or at chance level only in
one study [185], by 30% or 60% of the individuals accord-
ing to two other studies, respectively [86, 103]. However, in
most of these studies, subjects were not withdrawn for a
prolonged period from their habitual daily amounts of
caffeine and thus may have been tolerant.
In fact, doses of caffeine below 100 mg neither induce
feelings of withdrawal nor negative effects, have rarely been
shown to alter self-reports of mood or performance and are
usually preferred by moderate coffee drinkers [104]. One
study recently showed discrimination of caffeine at doses
as low as 10 mg for one individual, 18 mg for three subjects,
and 56 mg for three others [82]. That study involving the
authors themselves was replicated with subjects less
informed of the potential effects of the drugs under study.
Data in the same range as in the previous study were
obtained with caffeine discrimination in one subject at
18 mg of caffeine, in one at 32 mg, in two at 56 mg and in
four at 100 mg caffeine. The authors suggested that in speci-
fic individuals, caffeine could be considered to affect mood
at doses lower than those previously reported [178]. Indeed,
some groups were able to show enhanced auditory vigilance
and reaction time at 75 mg [36], 64 mg [127], or even 32 mg
[128] of caffeine. It seems that the effects of caffeine are
utilized consciously or unconsciously by the various indivi-
duals in the management of mood state, relevant to the
context of drink choice [64]. The discrimination of low
doses of caffeine is not related to the taste of caffeine
since at the dose of 100 mg, subjects are not able to reliably
differentiate decaffeinated coffee plus lactose from decaffei-
nated coffee plus 100 mg of caffeine [80]. Conversely, at
higher doses, caffeine could be detected in coffee as high
concentrations relate directly to coffee biterness [79].
8.2. Reinforcing effects of caffeine
Reinforcing efficacy of a drug refers to the relative effi-
cacy in establishing or maintaining a behavior on which the
delivery of the drug is dependent. In animals, intravenous
self-administration of caffeine has been studied after the
implantation of venous catheters allowing them by pressing
a lever to self-administer the drug and assess behavioral
reinforcement [84]. In four studies, caffeine was shown to
be self-injected in all animals [47, 49, 81, 84], while three
showed that only a limited subset (25%–33%) of the
animals self-administered caffeine [15, 37, 172]. A sporadic
pattern of caffeine self-administration, characterized by
periods with high rates of self-injection alternating with
periods of rather low intake was found in nonhuman
primates [47, 81, 84]. Thus, although caffeine seems to be
able to act as a reinforcer in some conditions, there is a
marked difference between caffeine and classical drugs of
abuse, such as amphetamines and cocaine, that maintain
self-administration across species and conditions [81,
159]. Recently, caffeine was shown to be able to reinstate
extinguished cocaine-taking behavior in rats. This effect
was more marked when caffeine was given one day, rather
than four days, following the last cocaine self-administra-
tion session. Thus, extended withdrawal is able to increase
the priming effects of caffeine [170, 198]. However, it must
be remembered that these animal studies use intravenous
self-administration while human caffeine consumption is
always by oral route and it is known that the former mode
of administration is by far more addictive than the latter one
[93]. Thus, caffeine dose does not appear to be a very robust
reinforcer in animals.
 A. Nehlig / Neuroscience and Biobehavioral Reviews 23 (1999) 563–576
In humans, the widely recognized behavioral stimulant
and mildly reinforcing properties of caffeine are probably
responsible for the maintenance of caffeine self-administra-
tion, primarily in the form of caffeinated beverages, such as
coffee, tea and cola [84, 140]. In some studies, the choice of
caffeine has been shown to be more potently controlled by
avoiding withdrawal than by its positive effects [166, 175],
while other data support the hypothesis that the true perfor-
mance-enhancing effects of caffeine are responsible for its
self-administration [167]. Most data showed that caffeine
reinforcement occurs in 100% of heavy caffeine consumers
(1020–1530 mg/day) that also had histories of alcohol or
drug abuse [78–80]. For moderate caffeine users (128–
595 mg/day), caffeine reinforcement occurs in about 45%
[88, 103, 104, 147, 148] to possibly 80%–100% of the
subjects [52, 179].
Caffeine reinforcement varies with the dose. Doses of
caffeine encountered in tea and coffee are high enough to
act as reinforcers, since people look for them in case of
withdrawal symptoms [103]. Indeed, a dose of 25–50 mg
caffeine per cup of coffee acts as a reinforcer, while increas-
ing doses beyond 50 or 100 mg tends to decrease the choice
of caffeine or the frequency of caffeine self-administration
[84], and high doses of caffeine (400–600 mg in a single
dose) are avoided [86]. Caffeine reinforcement relates also
to withdrawal syndromes occurring after coffee cessation.
Indeed, subjects that consistently suffer from caffeine with-
drawal headaches increase their chance to select caffeinated
coffee (containing 100 mg caffeine) by 2.6 [105]. Moreover,
the choice of caffeine seems to be more potently controlled
by avoiding withdrawal than it is by its positive effects
[176].
Recently, Bickel et al. [20] reviewed 16 studies dealing
with the behavioral economics paradigm for the study of
drug abuse. Increasing consumption of a fixed price item
when another one becomes more expensive indicates a
substitutive function and appears clearly with opiates,
cocaine and phencyclidine, but not with caffeine. These
data confirm the already-known fact that caffeine is less
reinforcing than amphetamines and related psychomotor
stimulants [34, 36, 112, 120, 185].
8.3. Reinforcing effects of caffeine-containing drinks
unrelated to caffeine
The conditions under which caffeine functions as a rein-
forcer are still not clearly understood. However, the possible
reinforcing effects of coffee unrelated to caffeine, but related
to its smell, taste and social environment usually accompa-
nying coffee consumption should not be totally neglected in
the every day motivations for caffeine-containing or
caffeine-free coffee consumption. Indeed, in subjects with
a habitual coffee consumption of 4–10 cups/day (mean
intake 6 cups/day) and switched without a withdrawal
period to the consumption of 600 mg of caffeine either in
tablets containing 50 mg of caffeine each or decaffeinated
569
instant coffee for three days, the desire for coffee in the next
three days largely increased in the group given caffeine
tablets but remained unchanged in the group given decaffei-
nated instant coffee, although the latter group experienced
marked symptoms of caffeine withdrawal [97].
The question of whether the taste of coffee and caffeine
may influence its intake is still a matter of debate. If water
containing caffeine is given chronically to rats between 29
and 40 days of postnatal life, rats exposed to caffeine as
adults will drink more caffeinated water than tap water.
Likewise the previous administration of an adenosine
agonist increases caffeine intake. Thus, it seems that
caffeine intake could be at least partly related to its pharma-
cological properties, although the influence of taste cannot
be eliminated [143]. Coffee and caffeine would in fact have
two components, an appetitive and an aversive one. The
absorption of low quantities of caffeine could favor the
appetitive effect of caffeine [193], whereas higher quantities
could exacerbate its aversive effects [183]. In man, the
gustatory response to caffeine is not influenced by previous
exposure to a series of methylxanthines or adenosine [30,
135] or by caffeine deprivation [27]. However, the taste of
coffee is an important aspect of caffeine consumption and
subjects prefer caffeine in coffee to caffeine in capsules [80].
Another possiblity is that caffeine is a constituent of
coffee and tea which are liked for reasons independent
from their caffeine content. Thirst could be one factor but
is is probably not the main one involved in the consumption
of tea or coffee, while it could contribute more to the
consumption of soft drinks. Liking the sensory properties
of tea and coffee can also be related to the nutritional benefit
derived from the milk, cream and/or sugar added to the
beverage. The last possibility is the influence of situational
conditions on mood that can play an important role in rein-
forcing preferences for specific foods and beverages.
Indeed, coffee and tea are often consumed in social contexts
and during breaks from work [166]. Therefore, the influence
of caffeine on the consumption of tea, coffee or soft drinks
may be relatively subtle and depend both on the accumu-
lated dose over the day and the mood state in which it is
consumed. For example, if an individual is already quite
stimulated, the ingestion of a caffeine-containing beverage
may lead to unpleasant effects. Indeed, it was shown
recently that, at least in some individuals, the choice to
drink coffee is influenced by the interaction between the
mood state before coffee and the effects anticipated based
on the content of caffeine in the drink [26, 64].
9. Molecular mechanisms underlying drug dependence
The molecular mechanisms underlying reinforcement
and drug dependence were recently reviewed [174] and
the critical role of the mesolimbic dopamine system empha-
sized. The mesolimbic dopamine system consists of the
dopaminergic neurons originating in the ventral tegmental
570 A. Nehlig / Neuroscience and Biobehavioral Reviews 23 (1999) 563–576
area and ending in the nucleus accumbens. Rats self-
administer amphetamines and dopamine directly into
the nucleus accumbens and the ventral tegmental area
as well as in other brain regions connected to the
mesolimbic dopaminergic system such as the cerebral
cortex, hippocampus and lateral hypothalamus [114, 119,
174].
The nucleus accumbens that plays a central role in the
mechanism of drug dependence is functionally and morpho-
logically divided into a core and a shell part. The medio-
ventral shell part is related to the limbic ‘extended
amygdala’ assumed to play a role in emotional, motivational
and reward functions, whereas the laterodorsal core part
regulates somatomotor functions [91]. The specificity of
cocaine, amphetamines, morphine, alcohol, D 9tetrahydro-
cannabinol, and also nicotine, is to selectively activate the
dopaminergic neurotransmission in the shell of the nucleus
accumbens as compared with the caudate nucleus [159, 160,
188], a property that has been related to the strong addictive
properties of these drugs [119, 174]. Dopamine D2 recep-
tors are necessary for opiate rewarding, since in transgenic
mice lacking these receptors, the motivational component of
drug addiction is specifically suppressed while the behavior
oriented at food rewarding is maintained [131]. Likewise,
the dopamine transporter is an obligatory target of cocaine
and amphetamines, as these psychoactive drugs have no
effect on dopamine release and uptake in mice lacking the
dopamine transporter [72]. Conversely to the drugs of abuse
that selectively lead to a release of dopamine in the shell of
the nucleus accumbens [159, 160, 188], caffeine increases
dopamine release in the caudate nucleus [145, 146], which
relates to the stimulatory properties of caffeine on locomo-
tor activity [139, 140], but does not induce any release of
dopamine in the shell of the nucleus accumbens when
injected at doses ranging from 0.5–5.0 mg/kg [189]. This
data is consistent with the low addictive potential of
caffeine. However, at the latter doses, caffeine stimulates
the release of dopamine in the prefrontal cortex, the terminal
area of the mesolimbic dopaminergic system which is
consistent with its reinforcing and psychostimulant proper-
ties [189].
10. Effects of drugs of dependence and caffeine on
cerebral functional activity
Amphetamines, cocaine, and also nicotine, induce paral-
lel increases in the release of dopamine and the rates of
cerebral glucose utilization and blood flow in the nucleus
accumbens [129, 160–163, 184], with a specific activation
of the shell of the nucleus, while there are no changes in
these parameters in the core of the nucleus accumbens
[150, 160, 162, 163, 184]. Conversely, the acute adminis-
tration of caffeine does not lead to a release of dopamine
and a metabolic increase in the shell of the nucleus accum-
bens at doses ranging from 1–5 mg/kg in the rat. The
caffeine-induced metabolic increase in the shell of the
nucleus accumbens can only be recorded after the admin-
istration of 10 mg/kg of caffeine, at which dose rates of
cerebral glucose utilization are simultaneously increased in
the core of the nucleus accumbens ([138, 141] and unpub-
lished personal data), which differs from the specific meta-
bolic changes in the shell of the nucleus accumbens
recorded with addictive drugs [160, 162, 184]. Moreover,
the dose of 10 mg/kg of caffeine at which a metabolic
increase is recorded in both the shell and the core of the
nucleus accumbens is about five times higher than the
mean human daily caffeine consumption [44]. In addition
to the metabolic increase in both parts of the nucleus
accumbens, that dose of caffeine leads to widespread cere-
bral metabolic increases recorded in most structures of the
extrapyramidal motor system, many limbic and thalamic
regions, as well as several areas of the cerebral cortex
[138, 141]. Conversely, the doses of addictive drugs that
elicit the increase in functional activity in the shell of the
nucleus accumbens are rather low and activate only a very
limited number of brain regions together with the latter
structure, such as the caudate nucleus in the case of amphe-
tamines, for example [163].
Taken together, these data show that caffeine increases
cerebral functional activity in the shell of the nucleus
accumbens only at doses at which it already activates
numerous other brain regions. In fact, caffeine primarily
acts on the extrapyramidal motor system leading to a release
of dopamine in the caudate nucleus [145, 146] and on cere-
bral structures related to the sleep-wake cycle such as the
reticular formation, raphe nuclei and locus coeruleus [138,
141]. These data are in good accordance with the facilitated
motor output [108, 130], the increase in wakefulness
reported in humans after caffeine ingestion [108], and the
caffeine-induced dopamine release in the caudate nucleus
and the prefrontal cortex [145, 146, 188]. Conversely, the
effects of amphetamines, cocaine and nicotine on the neural
substrates underlying addiction are quite specific and occur
at doses that do not usually lead to the activation of many
other brain regions [160, 162, 184]. Moreover, cocaine,
amphetamines and nicotine induce the expression of the
immediate early gene c-fos in the nucleus accumbens and
structures related to the ‘extended amygdala’ while the
expression of c-fos is only increased in the caudate nucleus
after caffeine [113, 151].
Thus, the effect of caffeine on the dopamine-mediated
brain reward system occurs only at high doses, i.e. 10 mg/
kg in rats that correspond to the ingestion of 200–300 mg of
caffeine in a 70 kg individual and lead to a plasma
concentration of 13–16 mg/ml [138]. This dose is higher
than those necessary to activate the motor system and the
sleep-wake cycle and induces a widespread increase in rates
of cerebral energy metabolism [138, 141] that also reflects
the numerous side effects of the ingestion of rather high
doses of caffeine and is already related to somewhat
aversive effects.
 A. Nehlig / Neuroscience and Biobehavioral Reviews 23 (1999) 563–576
11. Conclusion
The objective of the present review was to analyze the
possible dependence potential of coffee and/or caffeine.
Specifically, three main factors were considered: withdra-
wal, tolerance, and reinforcement. In addition, the molecu-
lar basis for the action of the classical drugs of dependence
and of caffeine was considered.
A withdrawal syndrome to caffeine has been described
which does not seem to relate to the quantity of caffeine
ingested daily. Tolerance to behaviorally-induced effects of
caffeine occurs in animals. In humans, tolerance to some
subjective effects of caffeine as well as partial tolerance to
sleep seems to occur, at least in some individuals. Caffeine
does not act consistently as a reinforcer in animals and
obviously in a more limited range of conditions than do
classsical drugs of dependence. In humans, the reinforcing
stimuli functions of caffeine are limited to low or rather
moderate doses that are usually present in a classical serving
of coffee or soft drink.
When considering the molecular basis for drug depen-
dence, it appears that the classical drugs of abuse such as
amphetamines, cocaine and nicotine induce specific
increases in dopamine release and functional activity in
the shell of the nucleus accumbens, the key structure for
reward, motivation and addiction. Conversely, caffeine
does not induce the release of dopamine and increase
glucose utilization in the shell of the nucleus accumbens.
Glucose utilization in the latter structure increases only at
rather high doses that are usually avoided by the general
population, probably since they activate the whole brain
energy metabolism. Caffeine acts as amphetamines and
cocaine on the dopaminergic system. Nicotine activates
other brain areas, but shares with amphetamines and cocaine
the property of specifically affecting the release of dopa-
mine in the nucleus accumbens. Other drugs, such as phen-
cyclidine, barbiturates and benzodiazepines, that can create
withdrawal, reinforcement and tolerance, do not clearly
share dopaminergic mechanisms of action with ampheta-
mines, nicotine and cocaine.
Usually, the consumption of caffeine occurs by the oral
route and is gradual over the day, and the delay in the
absorption of caffeine reduces the likelihood of a strong
dependence, unlike drugs of abuse that are most often admi-
nistered via the intravenous or inhaled form. When caffeine
is administered intravenously to subjects with histories of
stimulant drug abuse, the methylxanthine increases dose-
dependently ratings of positive mood (i.e. liking the drug)
and the frequency of identification to a stimulant like
cocaine [168]. Likewise, cocaine specifically increases cere-
bral glucose utilization when given to rats by the intrave-
nous route, but does not do so when given intraperitoneally
[161]. A typical example of the difference in the addictive
effects of a psychoactive stimulant is the case of nicotine,
which is highly addictive when inhaled in the form of cigar-
ettes while it is used as a gum or a transdermal patch to
571
reduce its addictive potential and help people to progres-
sively quit smoking [142, 157]. However, it must be remem-
bered that drug dependence can occur in some cases by the
oral route, with alcohol, oral amphetamines, barbiturates
and benzodiazepines.
In conclusion, it appears that, although caffeine fulfils
some of the criteria for drug dependence, the relative risk
of addiction of caffeine is quite low and, as reported
previously, is the lowest among seven drugs or drug classes
considered [75].
Acknowledgements
This study was suppported by a grant from the Institute
for Scientific Information on Coffee (I.S.I.C), Paris, France.
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