Brain Research Reuiews, 17 (19921139-170 139

0 1992 Elsevier Science Publishers B.V. Ail rights reserved 01650173/92/$05.00

BRESR 90147

Caffeine and the central nervous system: mechanisms of action,

biochemical, metabolic and psychostimulant effects

Astrid Nehlig a, Jean-Luc Daval a and GCrard Debry b

’ INSERM U 272 Uniuersite’de Nancy I and b Centre de Nutrition Humaine, Nancy (France)

(Accepted 2 June 1992)

Key work Caffeine; Methybranthine; Adenosine; Psychostimulant effect; Anxiety; Sleep; Monoamine; Dependence

CONTENTS

1. Introduction ........................................................................................ 140

2. Mechanisms of action of caffeine on the central nervous system ................................................... 140

2.1. Mobilization of intracellular calcium ................................................................... 141
2.2. Inhibition of phosphodiesterases ...................................................................... 141
2.3. Antagonism at the level of adenosine receptors ........................................................... 142
2.4. Interactions with benzodiazepine binding sites ............................................................ 142

3. Effects of chronic caffeine consumption on density of cerebral receptors ............................................. 142

3.1. Effects on adenosine receptors ....................................................................... 142
3.2. Effects on benzodiazepine receptors ................................................................... 143

4. Effects of caffeine on neurotransmitters .................................................................... 143

4.1. Catecholamines .................................................................................. 143
4.2. Serotonin ...................................................................................... 144
4.3. Acetylcholine ................................................................................... 144
4.4. Aminoacids .................................................................................... 14.5

5. Effects of caffeine on cerebral blood flow and metabolism ....................................................... 145

6. Effects of caffeine on cerebral electrical activity .............................................................. 146

6.1.Animalstudies .................................................................................. 146
6.2. Humanstudies .................................................................................. 146

7. Effects of caffeine on behavior .......................................................................... 146

7.1. Spontaneous motor activity. ......................................................................... 147
7.2. Learning, memory and mental performance .............................................................. 147
7.3. Simple and complex coordination activities and vigilance .................................................... 148
7.4. Endurance and athletic performance ................................................................... 148
7.5. Social behavior, aggressivity and mood ................................................................. 149
7.6. Effects of caffeine on anxiety ........................................................................ 150
7.7. Effects of caffeine on sleep ......................................................................... . 151
7.7.1. Animalstudies.. ............................................................................ 151
7.7.2. Humanstudies .............................................................................. 151

Correspondence to: A. Nehlig, INSERM U 272, Pathologie et Biologie du Developpement Humain,Universiti de Nancy I, 30, rue Lionnois, Boite
Postale 3069, 54013 Nancy Cedex, France. Fax: (33) 83.32.95.90.
140
7.x. Caffeine intoxication or caffeinism
7.0. Individual variability and age-related variations in the effects of caffeine
7.Y.l. Variations in the effects of caffeine among individuals
7.Y.2. Age-related variations ..
X. Tolerance and dependence towards the effects of caffeine ..
8.1. Tolerance ... ..... .. .........
8.2. Dependence and withdrawal .. . .
9. Conclusion .. . .... .. ...... .. I.. ..
IO. Summary . ..... ...... .. .. . ..
Acknowledgements .. ...... .. .. ... ..
References . . . . . .... .. .. . . .. . .
1. INTRODUCTION
Methylxanthines, and especially caffeine, can be
considered as the central nervous system stimulants
most widely consumed by man414,497~510.As a compo-
nent of tea, coffee and cola drinks, caffeine is the most
commonly ingested methylxanthine. Moreover, caf-
feine, as well as related methylxanthines such as theo-
phylline and aminophylline, are widely used as medica-
tions to treat asthma497~5L0 and apnea in the
newborn’4$1”*6”.Caffeine is also present in many over-
the-counter medications, such as in headache prepara-
tions in association with aspirin and in appetite sup-
pressants.
Caffeine is usually absorbed in small or moderate
doses and, only occasionally, in relatively high doses.
Moderate doses of caffeine are generally considered to
have the effect of a “mild stimulant, helpful in tem-
porarily relieving minor fatigue and boredom with little
risk of any harmful effects”237. The amount of caffeine
consumed by most people in coffee, tea or cola drinks
produces effects that are difficult to detect or so subtle for at least 1 h58y,According to a recent study, average
as to go unnoticed; thus, interpreting the influence of
caffeine on the central nervous system is complex.
Moreover, since caffeine is quite often absorbed in
coffee, its various and complex pharmacological effects
are even more complex, i.e., modified or sometimes
enhanced by the presence of numerous other compo-
nents in coffee. In fact, most of the results obtained to
date remain ambiguous or inconsistent’48-150~174~4’5~569. stances in the brain, both in animals and man324.
Other factors that make interpretation difficult are
individual differences in sensitivity to the psychotropic
effects of caffeine and to the action of methylxanthine
on parameters such as sleep, vigilance, anxiety and
depression’49323’. Finally, when interpreting the data, it
must be kept in mind that acquired tolerance to the
effects of caffeine could also account for variations in
the resultss’4.
.
.
...................
.. .. ...................
. .. ...................
.
.. . I .
..
.. .....
.... .
In addition, no animal species metabolizes caffeine
in a way similar to that of humans570, It is therefore
very difficult to extrapolate the results obtained from
animal studies to humans; it is especially difficult be-
cause some metabolites of caffeine, more active and
potentially more toxic than the methylxanthine itself,
can result in very great variations in the pharmacologi-
cal and toxic effects of caffeine from one species to
another5”. In humans, the metabohsm of methylxan-
thines also varies with age. Indeed, premature babies
are able to synthesize caffeine from theophyllinei416’.
Caffeine, either ingested or administered, diffuses
throughout the entire organism, has a volume of distri-
bution similar to that of body waters2j and quickly
penetrates into the brain 26. Since caffeine is highly
soluble in lipids, it rapidly crosses the blood-brain
barrier both by diffusion and by a saturable transport
system397. Experiments in the dog have shown that
caffeine concentration in cerebrospinal fluid reaches
one-half of its level in plasma within onIy 4-8 minsK8,
and that brain concentration of caffeine remains stable
concentrations of caffeine in plasma and brain are
proportional to the dose of caffeine administered I h
before. This correlation between plasma and brain
concentrations of caffeine and the administered dose is
highly significant. The authors conclude that plasma
concentration of caffeine and its metabolites could be
a precise indicator of the concentration of these sub-
2. MECHANISMS OF ACTION OF CAFFEINE ON THE
CENTRAL NERVOUS SYSTEM
Several hypotheses have been formulated concern-
ing possible mechanisms of action of caffeine at the
cellular level. Three main mechanisms of action have
been described which are, in chronological order of

their discovery: intracellular mobilization of calcium,
inhibition of phosphodiesterases, and antagonism at
the level of adenosine receptors. These different mech-
anisms of action have been the topic of numerous
revie.s12~79~93~207~209~329~446,465,491~498~559~ A hypothesis
been formmated suggesting a fourth mechanism of
action of caffeine on the central nervous system, the
binding of caffeine to benzodiazepine receptors61*387.
2.1. Mobilization of intracellular calcium
The effect of methylxanthines on mobilization of
intracellular calcium has been first demonstrated in
skeletal muscle. Caffeine, at a concentration of 1-2
mM lowers the excitability threshold and prolongs du-
ration of the active period of muscle contraction by
promoting translocation of calcium through plasma
membrane and sarcoplasmic reticulum4g-51. Similar
observations have been made subsequently on mammal
cardiac muscleZ3 and on sarcoplasmic reticulum in
vitro530q620+621.The effect of caffeine also depends on
intra- and extracellular concentrations of calcium330.
Recently, it has been shown that caffeine sensitizes the
muscular contractile apparatus to the concentration of
intracellular calcium136~1~~4s4*419; the direct interaction
of methylxanthine with calcium channels has been ob-
served in the sarcoplasmic reticulum524.
Synaptic transmission in central and peripheral ner-
vous systems requires controlled release of neurotrans;
mitters, which in turn depends on the influx of calcium
into nerve endings. In the sympathetic neuron of bull-
frogs, the presence of caffeine induces rhythmic hyper-
polarizations resulting from increased intracellular cal-
cium concentration343,344*558.In this preparation, meth-
y~anthine in concentrations ranging from 6 to 30 m&I
acts on four different types of ion channels, all of
which are affected by calcium release from intracellu-
lar stores, probably the endoplasmic reticulum5T416. In
arterial ceils of rabbit ear, caffeine blocks the voltage-
dependent calcium channels by direct interaction at
the level of the calcium channe13”. Caffeine has a
biphasic effect on calcium shifts in the isolated cere-
bral endoplasmic reticulum. Small or moderate con-
centrations of methylxanthine stimulate both the up-
take and release of calcium by the endoplasmic reticu-
lum407. High concentration of caffeine inhibits calcium
uptake by the endoplasmic reticulum407*592.These ef-
fects are not due to adenosine 3’5’~cyclic monophos-
phate (cAMP)~~~. Also, it has been recently reported
that stores of calcium that are sensitive to the effects of
caffeine might be located in the cell bodies, are not
coupled with release of neurotransmitters like
noradrenaline611, and may or may not affect the
GARA, response 145. Three intracellular pools of cal-
141
cium can indeed be distinguished by their turnover and
mechanisms of Ca2+ a~umulation, storage and re-
Iease’80~568.One pool is exclusively sensitive to inositol
1,4,5_triphosphate, one is sensitive to both inositol
has 1,4,5triphosphate and caffeine, and the third one is
only caffeine-sensitive’80,4”,568,64g.
A minimal concentration of 250 FM of caffeine
seems necessary to produce detectable effects on cal-
cium shifts263,530.The circulating plasma concentration
of caffeine after ingestion of coffee is usually less than
100 PM. Toxic effects are observed with concentration
of this methy~anthine above 200 FM, and lethal intox-
ications are observed with blood concentrations higher
than 500 FM 209Y497. Thus, the mechanisms responsible
for the pharmacological effects of caffeine are probably
activated by concentrations lower than 100 PM. Given
these conditions, it is unlikely that mobilization of
intracellular calcium represents an essential mecha-
nism of caffeine action in the central nervous system.
2.2. Inhibition of phosphodiesterases
The inhibiting properties of methylxanthines on
cyclic nucleotide phosphodiesterases activity were dis-
covered by Sutherland’s group39$s4 who used theo-
phylline and caffeine in their research on regulation of
glycogen metabolism and on peripheral lipolysis. After
identifying the major role of CAMP in the regulation of
these processes, the authors observed that methylxan-
thine prevents enzymatic breakdown of CAMP by in-
hibiting cyclic nucleotide phosphodiesterase3g,84. This
discovery represents a possible mechanism of action of
methylxanthines, i.e., accumulation of CAMP and po-
tentialization of its effects in order to stimulate the
action of substances such as catecholamines2~.
Methylxanthines inhibiting effects on phosphodi-
esterase have been later demonstrated in the central
nervous system606. Cerebral cyclic nucleotide phospho-
diesterases are found in various molecular forms599*600
which are distributed in a non-homogeneous way and
are affected to varying degree by number of inhibi-
tors626. Methylxanthines, which have a structure re-
lated to that of cyclic nucleotides, competitively inhibit
the various isoenzymes of phosphodiesterases to vari-
able degrees depending on the region of the brain.
However, this inhibition is produced only with millimo-
lar concentration of methylxanthines, i.e., a toxic con-
centration that is never found in situ93,610,626.Hence, it
seems very difficult to establish a link between phos-
phodiesterase inhibition and pharmacological proper-
ties of caffeine in concentrations usually found in the
circulating blood. Thus, chronic treatment of caffeine
at a dose of 25 mg/kg/day does not increase intrac-
erebral concentration of CAMP and does not decrease
142
specific activity of the specific phosphodiesterases of
cerebral cyclic nucleotides in vivox3.
2.3. Antagonism at the leuel of adenosine receptors
The hypothesis concerning this third mechanism of
action of methylxanthines comes from the studies of
Sattin and Ra11s34.These authors made the surprising
discovery that, under several conditions, theophylline
reduces the accumulation of CAMP in cerebral slices
instead of increasing it as would be expected from a
phosphodiesterase inhibitor. Therefore, they suggested
that theophylline could block stimulation of CAMP
formation by endogenous adenosine.
The possibility that central stimulant effects of
methylxanthines result from competitive antagonism of
the depressant effects of endogenous adenosine is ap-
pealing for many reasons. Most pharmacologic effects
of adenosine in nerve tissue can be suppressed by
relatively low concentration of circulating methylxan-
thines, e.g., less than 100 PM, which is attained after
drinking l-3 cups of coffee. This concentration appar-
ently has no direct effect on CAMP metabolism nor on
calcium shifts’26,s6”. Administration of adenosine and
its derivatives usually produces effects opposite to those
of caffeine or theophylline446. These effects include
depression of spontaneous electrical activity of the
neurons340,477, inhibition of synaptic transmission4s1~sss
and release of neurotransmitters210,286. Adenosine and
its derivatives also influence behavior644. Injection of
adenosine into the cerebral ventricles is favorable to
the onset of slow-wave sleep and reduces vigilance in
various animal species 183,268,390*483.In humans, thera-
peutic administration of deoxycoformycin increases the
blood concentration of adenosine, and probably its
brain concentration as well, and has side effects of
lethargy and drowsiness 382; this substance, used in the
treatment of leukemia, is an inhibitor of adenosine
deaminase which is the enzyme responsible for the
breakdown of adenosine into inosine. Adenosine
derivatives also cause a dose-dependent decrease in
locomotor activity that can be eliminated by small
doses of caffeine or theophylline1s8~ss9~s60.The relative
efficacy of various xanthine compounds in stimulating
locomotor activity is related to the relative affinity of
these substances for adenosine receptorss6’. Caffeine
and theophylline also act as adenosine receptor antag-
onists in humans4’.
There are two main sub-classes of adenosine recep-
tors, Al receptors have high affinity for adenosine and
A2 have low affinity371,46s,603.Adenosine, via these two
types of receptors, regulates a number of physiological
functions either by inhibition (Al receptors) or by
stimulation (A2 receptors) of adenylate cyclase. Caf-
feine and theophylline exert antagonist actions on these
two types of receptors127~ss”.
2.4. Interactions with benzodiazepine binding sites
Caffeine also binds to benzodiazepine receptor sites
although the affinity is rather weak61,387.This binding
has been suggested as a possible mechanism of action
of methylxanthines because caffeine antagonizes or
modifies the effects of benzodiazepines on anima113s~4”0
and on human behavior 188~221~284~368~39s~s’2. However,
caffeine and theophylline are much more potent antag-
onists of adenosine receptors than of benzodiazepine
site8’. Moreover, the interaction between caffeine and
benzodiazepines might not be due to competition of
the two substances at the level of benzodiazepine re-
ceptors, but could imply action on adenosine recep-
tors133,287,447*480.
Finally, some experimental data sug-
gest that only the toxic effects of high doses of methylx-
anthines would be due to interaction with benzodi-
azepine receptors 62s. Nevertheless, it is advisable to
decrease rather than increase caffeine and benzodi-
azepine consumption in order to maintain an even
mood”“.
3. EFFECTS OF CHRONIC CAFFEINE CONSUMPTION
ON DENSITY OF CEREBRAL RECEPTORS
Methylxanthines interfere with mainly two types of
receptors, i.e., adenosine and benzodiazepine receptors
which, subsequently to chronic treatment, can modify
their number in the brain.
3.1. Effects on adenosine receptors
Numerous studies have shown that chronic adminis-
tration of caffeine or theophylline by intraperitoneal
injection (20-100 mg/kg/day), in food (50-600 mg/kg
of food), in drinking water (1 g/l), or by implantation
(37.5 mg/week), for periods ranging from 1 to 6 weeks,
increases the number of adenosine receptors in rat or
mouse ~~~~~62,130,181,208~270~378,384~434~500,519,585~640~653 in
most studies, the increase in the number of adenosine
receptors is not accompanied by a modification in their
affinity 62,130,208,378,384,434,585,640,653
Modification in the number of adenosine receptors
does not necessarily reflect functional changes393. Thus,
neither accumulation of cyclic AMP in hippocampal
slices nor in isolated adipose tissue nor inhibiting ef-
fects of adenosine on lipolysis are modified by chronic
exposure to caffeine, in spite of the increased number
of adenosine receptors 208,6s2.However, chronic caf-
feine treatment increases sensitivity to adenosine both
in cerebral slices and in the whole anima124s,364s609, and
decreases sensitivity to acetylcholine36s. This last effect

could be linked to a decrease in the number of cholin-
ergic receptors 365. Also, reduced sensitivity to convul-
sants after chronic theophylline treatment was at-
tributed to increased number of cw-adrenoreceptors585
and to decreased number of /3-adrenoreceptors21”229
induced by this type of treatment.
Chronic administration of caffeine in the food of
pregnant mice (400 mg/kg of food) produces a long-
term increase in the number of adenosine receptors in
the brains of their offspring. This increase lasts until
adult age385. On the other hand, when juvenile rats are
given caffeine (50 mg/kg i.p.> between days 4 and 27
after birth, the increase in the number of adenosine
receptors does not last more than 2 weeks after the
treatment is discontinued3%. In adult mice, the effects
vary with cerebral regions. The increase in the number
of adenosine receptors in the cerebellum is still ob-
served 2 weeks after caffeine treatment is stopped,
while the number of receptors in the forebrain returns
to normal value within 8 days59.
3.2. Effects on benzodiazepine receptors
A double blind clinical study on 51 students showed
that 250 mg of caffeine could neutralize effects result-
ing from administration of 10 mg of diazepam, such as
lowered cognitive ability and increased muscle relaxa-
tion395. Similar results were obtained in another
study ls8.
These results prove that caffeine absorption can
lower the clinical effectiveness of benzodiazepines.
Doses used in this study (125-500 mg of caffeine)
correspond to 2-6 cups of coffee. Conversely, benzodi-
azepines can neutralize the stimulant effects of 5 to 20
mg of caffeine in animals 135. However, the depressant
effect of diazepam on cerebral energy metabolism is
not decreased in the rat after 15 days of chronic
exposure to caffeine 295. It has also been suggested that
patients suffering from some anxiety disorders might
have developed a hypersensitivity to caffeine65.
However, even though the interaction between caf-
feine and benzodiazepine receptors has been demon-
strated61T439,results of studies on the effects of meth-
ylxanthines on benzodiazepine receptors are contradic-
tory. Thus, after intraperitoneal administration of
5-40 mg of caffeine of after addition of caffeine to
food at a dose of 600 mg/kg, some authors report an
increase62,386Y639,others a decrease131, and still others
no change at a11229,306 in the number of benzodiazepine
receptors. Caffeine increases the binding of benzodi-
azepines to their receptor sites in vivo338@‘1but de-
creases this binding in cultured neurons324. It would
appear that caffeine may alter the function of the
chloride channel associated with the benzodiazepine
143
receptors516. These divergences can be explained in
two ways. On the one hand, stress affects the number
of benzodiazepine receptors while caffeine added to
food has no effect373. In some studies, animals were
treated with daily intraperitoneal injection of caffeine;
this requires handling and thus creates a stressful situ-
ation. Moreover, different types of stress can affect the
benzodiazepine receptors in completely opposite
wayP.
On the other hand, the antagonistic effect of caf-
feine on benzodiazepine receptors requires concentra-
tions 5-10 times higher than those that block action of
adenosine receptors439*560.It is probably these concen-
trations that can be attained with intraperitoneal injec-
tion but not with oral ingestion of caffeine. Finally,
part of the effects of methylxanthines on the benzodi-
azepines could be linked to the interaction of the latter
with endogenous adenosine4”. In fact, benzodi-
azepines inhibit uptake of adenosine by isolated nerve
endings69V474and stimulate release of adenosine476,M8.
Therefore, it seems that caffeine does not interact with
benzodiazepine receptors in vivo at the non-toxic doses
usually ingested by man318,364,625.
4. EFFECTS OF CAFFEINE ON NEUROTRANSMIT-
TERS
The effects of caffeine on the formation and release
of neurotransmitters have been the subject of in-depth
studies. Several studies have suggested that some ef-
fects of methylxanthines could be due to enhanced
release of endogenous catecholamines24,46*140,579,631.
However, it must be kept in mind that these animal
studies were performed in vitro using caffeine concen-
trations much greater than those found in humans
after intake of several cups of coffee, and that, con-
versely to the studies on the effects of caffeine on
phosphodiesterase inhibition, Ca*+ mobilization or
adenosine antagonism, little is known at present on the
threshold concentrations of caffeine necessary to in-
duce changes in neurotransmitter metabolism and
function. A primary role of adenosine in the central
nervous system appears to be to inhibit the release of
various neurotransmitters, and possibly glutamate in
particular, through presynaptic receptors. Therefore
adenosine antagonists, such as methylxanthines, can be
expected to increase the release of neurotransmitters.
4.1. Ca techolamines
In most studies, methylxanthines, caffeine and theo-
phylline in doses varying between 2.5 and 100 mg/kg
do not seem to have any effect on intracerebral nora-
drenaline concentration46~‘05~12’~328~538~612~614.
They in-
144
crease the rates of synthesis
and turnover of
~~~ad~ena]in~46~‘“~122,328~5”8,612,6~4
They increase spon-
. hand, decaffeinated coffee has no effect. These same
taneous electrical activity of noradrenaline-containing
neuronsz3’, inducing increased rates of synthesis and
turnover of monoamine’s6. However, the mechanism
by which caffeine activates the noradrenaline neurons
is not known’86,238.Methylxanthines also decrease the
density of #?-adrenoreceptors in the brain in response
to increased release of noradrenaline22”*37’.
On the other hand, the effects of caffeine and other
metylxanthines on dopamine are not as clear. Caffeine
increases intracerebral dopamine concentration167,375,
4’3,573,6’4,
but it can either increase or decrease or leave
unchanged the release, uptake and turnover of dopa-
mine46,92,167,216,229,238,2’9,413
Catecholamine synthesis has
been reported to increase 30 min after administration
of caffeine, 50 or 100 mg/kg, but to decrease 2 h after
exposure to the same dose of methylxanthinez5.
More recently, in vitro studies have shown in ani-
mals that caffeine affects local release of cate-
cholamines, especially dopamine. Indeed, methylxan-
thine selectively depresses the firing rate of dopamine
neurons of the ventral tegmental area that projects to
the frontal cortex and limbic structures, but has no
significant effect on the firing rate of dopamine neu-
rons in substantia nigra pars compacta that projects to
the caudate nucleuss74. Therefore, it appears that, in
the rat, caffeine administration inhibits mesolimbic and
mesocortical projecting dopamine neurons, but has no
effect on dopamine neurons that project to the stria-
turn. In addition to providing a possible site of action
for the effects of caffeine on attention and vigilance,
these results also may explain the clinical observations
of exacerbation of schizophrenic symptoms574. In addi-
tion, caffeine decreases local release of dopamine in
the caudate nucleus in a dose-dependent way423. The
latter effects can be linked to the stimulant action of
caffeine on locomotor activity. Caffeine at a dose of 10
to 50 mg/kg is able to prevent the appareance of
akinesia induced by catecholamine depletion in mice484.
Both dopamine and noradrenaline are necessary for
manifestation of caffeine-induced motor stimulation,
although it is unclear which cate~holamine is most
important i94,578.
4.2. Serotonin
Caffeine increases in vitro serotonin concentration
in the brainstem, especially in raphe nuclei, and in
cerebral cortex and cerebellum44*578. When caffeine
(0.3%), green or roasted coffee, or tea (10%) are
incorporated into the food of rats, cerebral concentra-
tions of tryptophan, serotonin and its main metabolite,
5-hydro~indoleacetic acid, are increased in the brain
starting from the 1st day of exposurem7. On the other
variations are observed after animals are injected with
lo- 100 mg/kg caffeine’X”~220~“27~h46.
Conversely, data on the rates of release, uptake,
synthesis, and turnover of serotonin are less consistent.
Indeed, rates are either increased or decreased or
unchanged by doses of methylxanthines ranging from
10 to 100 mg/kg 91~105~121~125~328~4S6~527~538~602~ These modi_
fications of serotonin cerebral concentration and
metabolism suggest that this neurotransmitter could
play a role in the pharmacological activity of caffeine4’.
The intensity of the effect of methylxanthine on intrac-
erebral serotonin concentration and on behavior varies
as a function of the basis emotional level of the
animal”*. This variability is also observed in man231,3h3.
However, it is difficult to link these biochemical effects
to the stimulant action of methylxanthines in man,
especially in view of the high doses used in most
animal studies.
Caffeine reduces serotonin availability at postsynap-
tic receptor sites”‘; this elicits a reduction in the
sedative effect of the amine on activity, and has re-
percussions on sleep mechanisms, motor function,
and functional regulation of cerebral blood vessels, all
of which are influenced by serotonin’20~137~2’y~262*265~290*
322,333,348,435,463~461,478,505~618, Thus, it is highly probable
that serotonin plays an important role in the mecha-
nism of action of caffeine on the central nervous sys-
tem27R.
Recent studies performed on rodents show that
caffeine increases concentrations and rates of cerebral
utilization of noradrenaline, dopamine, and serotonin,
specially in some structures belonging to the limbic
system. The authors suggest that if similar limbic ef-
fects on neurotransmitters exist in man, they could
have important clinical consequences; theoretically,
they could predispose some individuals to the benefi-
cial psychological effects linked to absorption of cof-
fee265,333.The majority of these neurochemical studies
also confirm the results of behavioral studies showing
that caffeine is only a mild stimuiant compared to
amphetamines and to cocaine505.
4.3. Acetylcholine
Few studies have been performed on the effects of
caffeine on the cholinergic system. Caffeine and theo-
phylline, at doses of 15 and 30 mg/kg i.p. in anes-
thetized rats, increase the outflow of acetylcholine
from the cerebral cortex 478. Acetylcholine turnover in
the hippocampus also is increased by intracerebral
injection of theophylline 435. However, methy~anthines
can produce either activating or inhibiting effects on

acetylcholine release in brain slices; these effects vary
as a function of both caffeine concentration and fre-
quency of electrical stimulation of the slices463,464.Fi-
nally, chronic consumption of high doses of caffeine
modifies the sensitivity of cholinergic neurons to meth-
ylxanthine. This modification is not linked to adenosine
receptors’*‘.
4.4. Amino acids
Caffeine, administered first at a dose of 0.5 mg/ml
in drinking water for 1 week then at 1.0 mg/ml for the
following 2 weeks, increases the amount of glutamine
in the whole brain of mice, while the amounts of
GABA and glycine are decreased, particularly in poste-
rior areas of the brain 348.Modifications in the concen-
tration of these two inhibitory neurotransmitter amino
acids could be the source of an increased excitability of
the central nervous system348. On the other hand,
caffeine has little or no effect on cerebral transport
systems of neurotransmitter amino acids13’. Rats given
drinking water containing gradually increasing concen-
trations of caffeine until they exhibit symptoms of
self-mutilation, similar to those described in the
Lesch-Nyhan syndrome 4oo, have increased amounts of
taurine, histidine, ornithine and aspartate in their
brains, while tyrosine is unchanged and the amounts of
GARA and glutamate are decreased”7*486. According
to the authors, changes in the concentration of amino
acids in the cortex could be responsible for behavioral
abnormalities observed in these animals. Furthermore,
these variations are similar to those observed in experi-
mental uremiaa6.
Cerebral tyrosine concentration is increased in the
brain of newborn rats whose mothers were exposed to
caffeine (0.04% in drinking water) during gestation
and/or during lactation 586. Hence, maternal intake of
caffeine could induce disturbances in the metabolism
of catecholamines, of which tyrosine is the precursor,
as well as behavioral abnormalities in developing
rats586.
5. EFFECTS OF CAFFEINE ON CEREBRAL BLOOD
FLOW AND METABOLISM
The stimulant effects of caffeine on the central
nervous system are associated with changes in local
rates of cerebral energy metabolism. Administration of
an acute dose of 10 mg/kg caffeine or continuous
perfusion of methylxanthine, at a rate of 0.30
mg/kg/min, induces an increase in the rates of local
cerebral glucose utilization; this increase is significant
in monoaminergic cell groupings, like substantia nigra
and ventral tegmental area, which are rich in dopamine,
145
medial and dorsal raphe nuclei, which contain sero-
tonin and locus coeruleus, rich in noradrenaline. Caf-
feine increases the rates of energy metabolism in the
structures of the extrapyramidal motor system and in
numerous thalamic nuclei and motor or limbic relays,
as well as in limbic areas such as the hippocam-
Pus 257,258,438@o-443. These local increases of cerebral
glucose utilization in structures which are involved in
the control of locomotor activity and especially in the
sleep/wake cycle, correlate very well with the methylx-
anthine-induced behavioral modifications described in
detail in this chapter. Finally, the increase in glucose
utilization rates is of the same amplitude after acute or
2-week chronic administration of 10 mg/kg caffeine.
Thus, cerebral energy metabolism does not seem to
develop tolerance to the stimulant effects of methyl-
xanthine438.
Methylxanthines such as caffeine or theophylline
induce vasodilation, except in the central nervous
system where they raise cerebrovascular resistance;
this actually contributes to a reduction in cerebral
blood flow. The vasoconstrictive properties of meth-
ylxanthines have been demonstrated in man89*236,381,391.
393,394,427,549,622 and in animals257,258,440,443,492. Caffeine
induces a decrease in local cerebral blood flow, mainly
in the areas where it increases metabolism, i.e., in
monoaminergic cell groupings, in the motor and limbic
systems, and in the thalamus257,258,444.
In most situations, cerebral blood flow and glucose
utilization are closely coupled in all cerebral re-
gions 147,495,516,
so that modifications in cerebral activity
elicit parallel changes in glucose utilization and in
cerebral blood flow256,331,346Y398,561.
In general, changes
in cerebral blood flow are the consequence of varia-
tions in cerebral energy metabolism256,331*398. Contrary
to the majority of pharmacological agents to which
man is frequently exposed, caffeine has the property of
inducing cerebral hypoperfusion accompanied by si-
multaneous increase in glucose utilization256,438+r0-443;
in other words, it resets the level of coupling between
cerebral blood flow and energy metabolism. Methybt-
anthines thus seem to modify the regulating mecha-
nism between blood flow and cerebral metabolism.
Although this mechanism is not yet well understood,
adenosine, with which methylxanthines compete, is
known to be one of the modulators of regulation in the
relationship of blood flow to metabolism in the central
nervous system47*346,635.
Caffeine is very frequently used in the treatment of
idiopathic apnea in the preterm infant 14J6,66.Several
studies have shown that modifications of cerebral blood
flow in the premature newborn play a very important
role in the pathology of intraventricular hemorrhage
146
and in the development of periventricular leuco-
malacia’6”~4’2. Ho wever, a recent study showed that a
bolus dose of caffeine usually used for treatment of
apnea in the preterm neonate, i.e., 20 mg/kg, does not
modify the velocity of cerebral blood flow in the pre-
mature infant and therefore can be administrated with-
out risk”2x. The innocuousness of aminophylline, an-
other methylxanthine used in the treatment of apnea in
the premature infant, has been proven. In fact, this
substance reduces cerebral blood flow but does not
affect cerebral functions4”“.
6. EFFECTS OF CAFFEINE ON CEREBRAL ELECTRI-
CAL ACTIVITY
6.1. Animal studies
Caffeine has long been believed to have an overall
stimulant effect on the central nervous system, espe-
cially on the cerebral cortex5”, by increasing vigilance
and lessening the feeling of weariness. Electrophysio-
logical studies in the rat have shown that cortical
electrical activity is stimulated by intravenous adminis-
tration of lo-100 mg/kg of caffeine20,475. In the cat, a
dose of 10 mg/kg of caffeine produces an activation of
the cortical EEG similar to the activity recorded at the
time of physiological awakening or to the activity pro-
duced by direct stimulation of the reticular
formation323,544, a structure which plays an important
role in vigilance and awakening42h. However, stimula-
tion of spontaneous electrical activity in neurons of the
reticular formation appears with much lower doses of
caffeine, l-2.5 mg/kg i.v. 200,2R1.On the other hand,
this structure does not seem to be indispensable for the
activating effects of caffeine to be seen on the
EEG ‘99,s44,591.The response of reticular formation
neurons to caffeine is dose-dependent, and the dura-
tion of activation lengthens in proportion to the dose
given2s’.
Caffeine and other methylxanthines also elevate the
excitability observed in vitro in rat hippocampal
slices1”7,24”and activate the B-rhythm of the EEG in
rabbit hippocampus 48s. Caffeine lengthens the post-fir-
ing duration in the hippocampus and this effect lasts
longer than the changes induced by caffeine on the
EEG 157,246,48s,601.High doses of caffeine provoke elec-
trical modifications in the hippocampus similar to those
that are recorded during generalized seizures4s5. The
great stimulant effect of caffeine on the hippocampus
shows the importance of the limbic system in develop-
ment of the convulsant and anxiogenic effects of this
methylxanthine4s5. Caffeine also elevates reinforce-
ment threshold for electrical brain self-stimulation,
perhaps corresponding to the anxiogenic component of
action of caffeine that predominates at high doses in
humans4”-43”. This effect does not seem to be medi-
ated by adenosine systems432.
At the same time that caffeine increases cortical
electrical activity, it induces a significant decrease in
electrical activity in thalamic neurons, even in very
small doses, 0.1 mg/kg i.v.“‘“.“‘7.‘99.This lowering of
thalamic activity correlates well with sleep disturbances
induced by caffeine’~‘7~‘yy~27H~h”‘.Similarly, direct ion-
tophoretic administration of caffeine decreases the
spontaneous electrical activity of neurons in the cau-
date nucleus of the rat59x. Thus, the methylxanthine
seems capable of activating the nigrostriatal pathway,
resulting in decreased activity in the caudate nucleus
subsequent to stimulation of dopamine release by the
nigrostriatal nerve endings2’“.
6.2. Human studies
In man, stimulant agents of the central nervous
system generally increase the number of p-waves and
decrease 8- and a-activity on thk’ EEG19’. However,
the observed effects of caffeine on resting EEG are
variable and quite conflicting. Caffeine administration
has been reported to cause either ,a decrease235 or an
increase”’ in amplitude of a-activity or else an in-
crease in power in the lo-13 Hz bandwidth accompa-
nied by a decrease of power in the 5.5-9.5 Hz band-
width5’“. The divergence in results is due to differences
in the dose of caffeine, to the time of recording in
relation to the time of administration of methylxan-
thine, and to methods used to analyse the EEG4”.
The effect of caffeine on evoked brain activity are
also discordant. At comparable intervals after adminis-
tration of 300 mg of caffeine, amplitudes of contigent
negative variations increase in one case” and decrease
in another one2”‘. A bolus dose of 300 mg of caffeine
either reduces334 or does not modify the amplitude of
auditory evoked responsesh3x. Lastly, caffeine de-
creases the power of EEG in resting conditions and
after stimulation by sine wave modulated lights79.
7. EFFECTS OF CAFFEINE ON BEHAVIOR
This section deals with the effects of caffeine on
spontaneous motor activity, learning and memory, sim-
ple and complex coordination, endurance and athletic
performance, aggressivity and mood, anxiety and sleep,
in both man and animals.
7.1, Spontaneous motor activity
Experimental studies on this subject have been per-
formed on the effects of caffeine given orally, subcuta-
neously or intraperitoneally. Measurement of sponta-

neous activity is performed mainly in open fields, run-
ning wheels, and conditioning boxes crossed by two
infrared beams that provide a record of an animal’s
global activity.
The stimulant effects of caffeine on the motor activ-
ity of mice and rats were demonstrated in the 1930s
and 1940~~~~~~~‘. This stimulant action has been later
confirmed by numerous st~dies46,S5,81,115,163,213,272,275,283,
288,3”9,324,325,345,354,366,369,410,417~437~44”~442~472,S6”,~~9~6~3-6~5
Furthermore, it has been noted that the range of active
do& was similar in many species33,115,148,213,278,3"9,468,
and that this range is of the same order of magnitude
in the recently weaned 24day-old rat as it is in the
adult anima1288.A dose-response relationship has been
demonstrated224~278~283~324V58g, In animals the minimal
dose of methylxanthine to produce an effect is 1.5-10
mg/kg and the dose to produce maximal effect is
lo-20 mg/ kg 46,55,~1,272,2?5~2~3,3”2,4”9,417,437,56”,5~,589 ln
general, spontaneous motor activity does not in-
crease with doses above 30 mg/kg, and even de-
creases with higher doses, between 40 and 60 mg/
kg 81~275,324*366*4r7,589.
Surprisingly, the higher the caffeine
dose, the longer the delay in increase of motor re-
sponse 278,283*437,589_
Locomotor activity can be enhanced
in rats by intrastriatal injections of caffeine. These
effects are mediated by antagonism of endogenous
adenosine which, in turn, functionally increases
dopamine function 321.Therefore, the behavioral effects
of intrastriatal caffeine are uitimately mediated by
dopamine32’. At very high doses, caffeine may potenti-
ate the action of other convulsants154~‘55*436.4”7 and even
cause convulsions422Y424,425V483P497. Moreover, recent re-
ports indicate that seizures may occur in both
~hiIdren457,509and adults29.468 with so-called therapeu-
tic or mildly toxic levels (14-35 mg/l> of theophylhne,
the methylxanthine currently used to treat asthma.
Rats exposed to caffeine in utero show increased
locomotor activity and decreased emotivity postnataily;
this effect is more pronounced in males than in
females3”“,301. Conversely, when caffeine is absorbed
after birth or during the 1st week of life, as is the case
in newborn infants suffering from apnea, it has a
depressant effect on locomotor activity of rats accord-
ing to some authors”9,655 and a delaying effect on its
stimulation of locomotor activity according to othersz5’.
Only few studies have been performed on the ef-
fects of caffeine on spontaneous motor activity in man.
Some investigators report increases in typing rate after
caffeine285,297,298V59”, others observe no effect6p’97 or
even a decrease228. Gross motor activity measured with
an accelerometer worn on the belt is increased after 3
and 10 mg/kg caffeine in children. In adults, the high
dose of caffeine increases activity in the ‘high’ con-
147
sumer group (more than 300 mg caffeine daily) but not
in the ‘low’ consumer one (less than 100 mg caffeine
daiiy)“‘.
7.2. Learning, memory and mental perjormance
It is difficult to establish precisely from the data
pubhshed to date if caffeine influences superior cogni-
tive skills in animals. Some studies have clearly shown
that caffeine improves learning abilities, memory, and
spatial orientation in various tests98~48”~522~627,
while oth-
ers have shown no changes 38**23,175x577.
Rats exposed to
caffeine do not make fewer errors and do not decrease
their latency in mazes of varying complexity, although
exploration is stimulated 450,453*577. Thus, several au-
thors agree that while caffeine may not improve learn-
ing ability, it might influence attention, vigilance, activ-
ity and performance, a11of which are difficult to distin-
guish from learning per se 86*224.However, the effects of
caffeine on learning vary with the degree of novelty of
the task to be accomplished. Thus, caffeine would have
little effect on learning, or even inhibits it, when the
animal is placed in an unfamiliar environment; but it
improves learning performance when the animal is
familiar with its environment or with the task to be
accomplished75~4w~453. In fact, caffeine seems to act by
slowing habituation during repetitive stimulation, thus
maintaining heightened arousal*32. Also, caffeine en-
hances learning in maze tests that do not include a
reward, but makes no difference in tests that include a
food reward453.
In operant responding tests, caffeine increases the
frequency of answers when tests involve a food reward
both at fIxed94,“3,134,4”3,4”5,554,555 and variable inter_
vaIs13,4”2,53’,6’9.
The increase in answers varies with the
dose given; however, this effect disappears or is re-
versed with high doses94,175*4”*,564. In avoidance tests
that use electrical shocks, noise signals, or light signals,
caffeine increases the frequency of avoidance response
in monkeys and rats, even at high doses, 50-80
mg/kg 271~533 , but decreases this response in hamsters
and in one species of highly emotional rats99.533.
In man, memory per se is not improved but response
tends to be quicker and keener37*“0,315*367. Intellectual
performances such as reading, operations of arithmetic
and some verbal tests might be slightly improved espe-
cially when normal performance is lowered by weari-
ness or boredom; however, most often there is no
change 37*168,202q374,482,627.
The effects of methylxanthine
are dose-related but high quantities of caffeine reduce
performance in some tests2”i.
Susceptibility to caffeine is also linked to sex’sJ70.
Results from two studies performed on women are
conflicting: one study indicates that caffeine hinders
148
memorization of word lists170 while the other indicates
that it enhances it”. This discrepancy is attributed to
differences in estrogen levels in circulating blood”.
However, the authors of this study tested memoriza-
tion without taking into account the phase of the
women’s menstrual cycle or whether or not they took
oral contraceptives”“. By contrast, in the second study,
women who were not taking oral contraceptives, which
are known to contain estrogens, were tested only dur-
ing the first 5 days of their cycle’s. Accordingly, it has
been suggested that cognitive task performance in
women varies according to the phase of menstrual
cycle”j. However, variation in caffeine effects with es-
trogen levels in blood remains unexplained.
Susceptibility to caffeine also seems to depend on
personality type; the response could be different in
introverts and extroverts52~‘77~361~508~557.Introverts in-
crease speed and precision of performance when they
ingest caffeine but only at small doses; their perfor-
mance decreases with high doses. On the other hand,
extroverts increase their speed and precision with any
given dose of caffeine s2. Susceptibility to caffeine also
varies with the subject’s degree of alertness which can
be assessed by skin conductance responsezo4.
Children given a single dose of caffeine, even a high
one (10 mg/kg), or daily doses of theophylline, show
no change in learning ability or attention during a test
measuring performance, although they appear more
jittery168~s37.Chronic administration of caffeine to chil-
dren does not seem to have any beneficial effects,
although some results are ambiguous”‘. Moreover,
great individual variability in the effects of methylxan-
thine has been reported in childrens3’. Finally, it seems
that children are not more sensitive to the effects of
caffeine than are adults148,537.
7.3. Simple and complex coordination activities and vigi-
lance
Caffeine, in a single dose as high as 450 mg, has
little or no effect on simple coordination activities in
adult men36,9s,188.One dose of 750 mg could enhance
these activities2t3, but this single dose is much higher
than that corresponding to average coffee or methylx-
anthine intake from other sources.
Complex coordination activities usually are spread
out over a period of time, so that testing these activites
also tests wakefulnesss6s. Caffeine increases
prevents the decline
vigilance 109,232-234,3’7,497SlO,435,656,
in attention usually observed after meals, especially
after 1unchss6 and improves information processing af-
ter lunch2s7. Since increased vigilance induced by caf-
feine remains unchanged after a period of sleep depri-
vation, there does not seem to be any interaction
between the sleep/wake cycle and the effects of meth-
ylxanthinesl”. Caffeine also improves performances
such as visual perception15’,363, driving a car (speed
of reaction to road signs, braking and accelerating
reaction time)30,504, or reactions in a flight simu-
lator h,269,s42.
Susceptibility to caffeine also depends on
personality type; the acoustic vigilance of extroverts
increases after a dose of 200 mg of caffeine but that of
introverts does not 332.
The effects of caffeine on some activities of complex
coordination are ambiguous; caffeine has no effect
according to some authors6,197Z212,while others con-
sider it a stimulant 297,298,s66V590V630.
Moreover, the time
required to accomplish a complex task varies with the
dose of caffeine; time is shorter with small doses (120
mg), longer with average doses (180 to 240 mg) and
biphasic with high doses (360 mg)297,29s,312,590,630.
Caffeine also seems to induce arm and hand tremors
which interfere with measured performances. Arm
trembling has been described in numerous studies ei-
ther after a single cup of coffee312 or after administra-
tion of 300-900 mg of caffeine 228,232,298,312,358,583,584,619
Only one study failed to demonstrate the effect of
caffeine on arm stability 312, but the reason for the
discrepancy might be that the subjects were tired.
Coffee and caffeine can also exacerbate the arm and
hand tremors observed in Parkinson’s disease and in
patients treated with lithium317,339.Caffeine counter-
acts the psychomotor disturbance caused by alcohol in
man and animals only when caffeine doses are small,
for example less than 20 mg/kg in the mouse. Surpris-
ingly, high doses of caffeine actually amplify the effects
of alcoholL28,448*449.
7.4. Endurance and athletic performance
Many athletes absorb caffeine or methylxanthines
before a sports event. Caffeine is believed to improve
performance whenever endurance is involved; however,
this hypothesis is controversial because experimental
procedures used to explore this matter are not stan-
dardized74,141,605.This type of study is complex because
the effects of caffeine vary with the weight of the
subjects, the kind of physical activity considered, and
the environmental conditions at the time of activity6’“.
Caffeine might act directly on the central nervous
system by stimulating release of p-endorphins and of
hormones capable of modifying the perception of pain
and discomfort caused by physical exertion’7,520.
Administration of caffeine in situ increases muscle
contractility3’“. However, numerous studies have
demonstrated that this methylxanthine does not have
an ergogenic effect on muscle strength or fatigue54s2,
work output2”, work capacity’, swimmer’s maximal

speed266, or on any short and intense effort85. These
conflicting results might be attributed to the following:
at low frequencies of stimulation, i.e., at rest, caffeine
increases the tension developed by muscle, whereas it
does not have such an effect at higher frequencies or
during maximal voluntary contractions, i.e., during ef-
fort372*“5. Caffeine does not seem to improve perfor-
mance during intense muscle effort of short duration.
Thus, regular coffee (containing 250 mg of caffeine)
and decaffeinated coffee given in a double blind study
both caused similar performance improvement in long
jump, weight throwing, and lOO-meter race’@‘.
Caffeine also has contradictory effects on maximal
oxygen consumption and on delay before exhaustion4”.
According to some authors, caffeine has no ergogenic
effect on work capacity 152,217*389,487 or during ergomet-
ric cycling tests of increasing difficulty467,497,517.Yet,
other authors claim that caffeine increases work capac-
ity during exercises of increasing difficulty’96~‘98*591.
Caffeine could mask fatigue, thereby increasing work
productive 54.
On the other hand, it seems that caffeine can im-
prove physical performance or work output during
prolonged exercise at submaximal intensity, such as
cross-country skiing, running and cycling43,122,1g5,310,
511,627.Caffeine does not modify the delay before ex-
haustion for an athlete who is acclimated to the envi-
ronment, either at sea level or at high altitude’78~2’4,
but it does attenuate perception of the effort
required’78%5’7. The effect of caffeine is more pro-
nounced in skiing at an altitude of 2900 m than at 300
m; similarly, caffeine clearly increases the delay before
exhaustion in an athlete who is not acclimated to the
altitude214.
Improved performance has been attributed to stimu-
lation of lipolysis by caffeine. Hydrolysis of fatty tissue
triglycerides51S,543increases blood concentration of fatty
acids1~40~41,100~s87.
These are then actively used by the
muscle during effort 122~‘95~203~310~591~633,
thus saving gly-
cogen”‘. This mechanism is important because deple-
tion of muscle glycogen could be largely responsible for
fatigue observed during endurance tests’72J73,507.How-
ever, the increase in plasma concentration of free fatty
acids elicited by caffeine152,353 is not always accompa-
nied by a modification in substrate utilization by
muscle99*338. Caffeine also increases production of
plasma catecholamines during and immediately after
effort116*195,203.Involvement of catecholamines is essen-
tial in helping the body adjust to the stress of exercise,
as they contribute to a number of critical processes
including glycogenolysis, glucose uptake, gluconeogen-
esis, muscle and adipose lipolysis, ~ntractili~, in-
otropic and chronotropic responses of the heart, and
149
circulatory adjustments 3g6.At high altitude, it increases
endurance by a mechanism other than mobilization’of
fatty acids22*2*4.However, this mechanism is not yet
understood.
Some authors have suggested that only well-trained
athletes can benefit from the use of caffeine85y’72*513.
However, accomplished athletes undergo intensive
training which in itself produces a rise in lipolytic
activity and an increase in the size and density of
mitochondria9’. In the same way, caffeine does not
modify the plasma concentration of free fatty acids nor
the utilisation of muscle or hepatic glycogen in en-
durance-trained rats”‘.
Finally, the effects of caffeine on physical perfor-
mance are greatly attenuated in regular consumers of
coffee or tea195.203.Thus, it seems that athletes who
want to increase the effects of caffeine during pro-
longed exercise should abstain from consuming caf-
feine in the 4 days preceding the event so as to sup-
press tolerance phenomenon195. It seems preferable to
absorb caffeine 2-3 h prior to effort rather than 1 h
before; in the first case, plasma concentration of free
fatty acids will be at a peak at the time of effort624
while in the latter one, only plasma concentration of
caffeine will be at a peak196.
7.5. Social behavior, aggressivity and mood
It is generally agreed that consumption of caffeine
has a psychotropic effect, and that it can cause ner-
vousness and irritability in people who absorb quite
large quantities of coffees35. Given the difficult in
scientifically evaluating caffeine’s effects on aggressiv-
ity and mood in man161, it is not surprising to learn that
doses of caffeine ranging from 100 to 500 mg can
produce either detectable effects233T352or no effect at
al128~188~197~212.
Thus, caffeine could lessen aggressive-
ness99, improve spirits and moods114,352,363,581 or aug-
ment nervousness367V368,370. However, it is important for
studies on this topic to be double blind because the
effects tend to be positive when the subjects know that
they are being given caffeine4**.
The effects of caffeine and theophylline on aggres-
sivity vary with the species studied. Chronic administra-
tion of relatively high doses of theophylline or caffeine
induces aggressive behavior in rats525*526,which can
result in self-mutilation sometimes leading to death by
hemorrhagic shock471,473.On the other hand, caffeine
reduces aggressivity in cats4i6 and man”“’ and even
counters aggressiveness in mice6’*.
There are only few studies on the effects of caffeine
on social behavior in animals, and apparently none in
man. Caffeine at a dose of 10-20 mg/kg stimulates
sexual behavior654 and enhances gregarious instinct of
150
the male rat”“. Caffeine reduces the amount of time
rats spend in social interaction32~‘87~28y;contacts are
brief but intense, sometimes accompanied by aggres-
sive behavior. Also, caffeine at a dose of lo-40 mg/kg
increases social investigation in juvenile rats of the
same species”“, but this effect is evident only starting
from postnatal day 44”s.
7.6. Effects of caffeine on anxiety
Although a study of the National Institute of Mental
Health performed on a large population of normal
subjects did not find any relation between anxiety
symptoms and tea or coffee consumption15y, the
results of numerous works suggest that absorption
of caffeine and anxiety are correlated in man31’63,65,
"~1O2~l~~Y~227~23Y,243~277~314~335~48Y~5Y4,5Y7~SY8~636 and
animals”“~‘R7~‘89~28s~466.
Thus, when striving to improve
their performance, regular coffee drinkers develop
more anxiety after ingestion of 400 mg of caffeine than
after ingestion of decaffeinated coffee545.
People who drink little or no coffee are probably
more susceptible to the anxiogenic and psychotropic
effects of caffeine than are regular coffee drinkers594.
Caffeine administration elicits an increase in the level
of anxiety which is more pronounced in patients prone
to anxiety or panic attacks than in normal con-
trols63,h4,103,15Y,2ss,355,356,5Y5_5Y’
Moreover these patients
are extremely sensitive to the anxiogknic effects of
caffeine and tend to reduce or eliminate caffeine con-
sumption because of its unpleasant psychological side
effects5y4,5y5,5y7.There is definite improvement in their
condition after caffeine has been discontinued’s. In
35-70% of patients suffering from panic attacks, inges-
tion of 500 mg of caffeine exacerbates their clinical
symptoms and increases the attacks. In ‘normal’ sub-
jects, these doses never trigger panic attacks. However,
attacks can occur in sensitive people after absorption
of only one cup of coffee (85-110 mg of caffeine)5y4.
The biochemical modifications that underlie caf-
feine-induced anxiety are not yet understood. Re-
cently, it has been shown that concentration of kynure-
nine, a neuroactive metabolite of tryptophan, increases
during caffeine-induced anxiety and returns to normal
levels when anxiety disappears455. These studies sug-
gest that kynurenine is involved in caffeine-induced
anxiety in man, but so may be other neurochemical
pathways such as serotonine and adenosine receptor
systems33’.
In addition, according to several studies, anxiety
associated with depression could be related to caffeine
consumption. Correlation is often observed between
high coffee comsumption (5 or more cups per day) and
anxiety accompanied by depressionhs,““,3’“. It also
seems that psychiatric out-patients suffering from
lethargy and hypersomnia associated with depression
often medicate themselves with large quantities of caf-
feine (an average of more than 500 mg per day), thus
triggering a depressive state accompanied by extreme
agitation 445. However, it is difficult to determine if
caffeine intake is the cause or the result of depression,
because there is a dearth of information on this sub-
ject 10'),314,.571
.
Caffeine is also used to lengthen duration of seizure
episodes and to improve the efficacy of electroconvul-
sive therapy in severely depressed patients112~276,54h,547.
Caffeine can exacerbate psychosis and state of suspi-
cion in various mental diseases’“‘, induce psychosis de
IZOL’O~,~~~,~~~, and aggravate symptoms of schizophre-
also in
nia34,307,376.414 or other psychotic syndromes650~651.Re-
ducing caffeine intake of psychiatric patients, espe-
cially schizophrenics, ameliorates their behavior and in
particular minimizes their aggressiveness which is a
major problem in psychiatric hospitals1’12~“07~314~650. It is
possible that psychiatric patients consume more caf-
feine in order to lessen intensity of depressive
thoughtss3’, to pass the time, or remedy dryness in the
mouth caused by medications, especially by the fre-
quently used anticholinergic drugs5”5,“7’. Besides, Mis-
sak4’s proposed that the normal human body may
produce a substance similar to caffeine which main-
tains the brain in a state of wakefulness; conversely to
previous reports on the worsening of schizophrenia
symptoms by caffeine34~307~37h~414, Missak also suggested
that the deficiency of this endogenous caffeine-like
substance might play a pivotal role in the pathogenesis
of schizophrenia4’“,““.
Furthermore, some authors contend that coffee and
tea may form insoluble precipitates with several of the
antipsychotic medications, thus rendering treatment in-
effective’*‘, while others have not observed this precip-
itation or have not found lower blood levels of antipsy-
chotic drugs in the blood in these cases6’. The possible
interaction of caffeine with some drugs, especially ben-
zodiazepines131~284~2”7, should not be underestimated.
Indeed, a recent report suggests that at least part of
the anxiety reaction produced by caffeine in panic
disorders may be due to the combination of caffeine
with a concurrently administered benzodiazepine”“.
However, it has aIso been shown that 250 mg of caf-
feine in the morning prevents the daytime drowsiness
resulting from a nocturnal dose of benzodiazepine
without affecting performance or mood”‘“.
On the other hand, administration of idrocilamide, a
muscle relaxant considerably alters the pharmacokinet-
its of caffeine and specifically multiplies its half-life by

9 (refs. 70, 176). The association of caffeine and
idrocilamide induces neuropsychopatic disorders, in-
somnia, excitation and hyperactivity, mood swings, and
even episodes of delirium or confusion, which were
long mistaken for amphetamine abuse before they were
correctly identified 35g. The same kind of symptoms was
described with association of caffeine and phenyl-
propanolamine, a substance contained in over-the-
counter diet aids349*350.Therefore, it is advisable to
abstain from any beverage or food containing caffeine
while taking idrocilamide”’ or any medication includ-
ing phenylpropanolamine3.
7.7. Effects of caffeine on sleep
There is a consensus of opinion concerning the
effect of caffeine on sleep. The traditional history of
coffee relates that the abbot of a Yemenite monastery
prescribed this beverage to his monks so that they
could stay awake during nighttime prayers.
7.7.1. Animal studies. Caffeine administered to adult
rats at a dose of 12.5-25 mg/kg decreases the overall
dclration of sleep or of its different phases, and length-
ens the latency period recorded before onset of the
different phases of sleep 493.494.608.~~2.
At a dose of 25
mg/kg, caffeine delays return of rapid-eye-movement
(REM) sleep in sleep-deprived rats494. On the other
hand, at a dose of 0.125 and 12.5 mg/kg, caffeine has
no effect on total duration of sleep but increases
duration of slow-wave sleep at the expense of long-wave
sleepM3.
When caffeine is chronically administered to cats at
a dose of 20 mg/kg, total duration of sleep is at first
clearly shortened. When animals become habituated to
methylxanthine, total duration of sleep returns to nor-
mal, but rapid-wave sleep (Sl) lengthens at the expense
of slow-wave sleep (S2). As soon as treatment is dis-
continued, there is a significant increase in the ratio
S2/Sl, and this ratio remains high for at least 30
daysss2.
Duration of REM sleep is increased in adult rats
born of dams that were fed a diet containing 0.025%
0.1% of caffeine during pregnancy. This effect persists
over two generations 169,M2.When female rats receive
high doses of caffeine (60-100 mg/kg/day) in their
drinking water during gestation, their offspring show
longer total duration of sleep, mainly due to an in-
crease in slow-wave sleep in males of the BALB/c
strain, and to an increase in REM sleep in females of
the C57BR strain552. A single dose of 10 mg/kg of
theophylIine given to rabbits on day of birth greatly
decreases rapid-wave sleep, delays onset of slow-wave
sleep, and increases REM sleep. These modifications
151
disappear only at age 30 days. However, the transition
between rapid- and slow-wave sleep remains disturbed
for at least 40 dayslU.
Caffeine also reduces the duration of sleep in-
duced by administration of barbiturates in rats and
mice3*“*264*282. This decrease varies with the dose
given3~‘~2”2;decaffeinated coffee has no effect on the
duration of sleep induced by barbiturates’.
7.7.2. Human studies. In man, sleep seems to be the
function most sensitive to the effects of caffeine. A
delay in sleep onset is observed when a dose of 100 mg
of caffeine is ingested one-half h before retiring. How-
ever, doses of less than 100 mg have no effect”“. In
general, when people who usually do drink coffee,
ingest some 30-60 min before going to bed, they expe-
rience a longer delay before falling asleep, and their
sleep is of shorter duration and is more agitatedz4’.
A double blind study showed that students given 200
mg of caffeine fall asleep 33 min later than students
given lactose2”“. Also, the subjects say they sleep Iess
soundly after absorbing doses of 150-20 mg of caf-
feine, although this last effect is less pronounced in
habitual coffee drinkers. In this study, the difference in
sensitivity to the effects of caffeine does not seem
attributable to the phenomenon of tolerance3h’. Rather,
this difference seems linked to individual sensitivity to
the effects of coffee as well as variability in the subject’s
response from one night to the next2”‘.‘h’. However,
other studies have shown the development of tolerance
to the effects of caffeine”‘*“‘.
Habitual coffee drinkers are relatively immune to
the effects of caffeine on sleep’24, while coffee abstain-
ers experience a longer delay before onset of sleep as
well as disturbances in the different sleep phasesllH.
Caffeine increases duration of stage 2 sleep (also called
‘light sleep’), decreases the duration of stages 3 and 4
(or ‘deep sleep’) and has no effect on REM sleep or on
duration of dream episodesy*72~‘24*247~2U. Although some
of the effects of caffeine on sleep are dose-
dependent 272.326,differences in sleep disturbances,
which are unrelated to plasma concentration of meth-
ylxanthine, have been reported among subjects”“‘.
E~e~troencepha~ographic (EEG) studies have shown
that sleep is of lesser quality in the 3-4 h following
ingestion of coffee, which corresponds to the time
required for metabolic disposition of caffeine by the
liver42x*429.According to some authors, the subjects
most indisposed by coffee might metabolize caffeine
more slowly than the others’h2. Actually, what seems
important in the correlation between caffeine intake
and insomnia is the total amount of methy~anthine
consumed during the day rather than the time at which
caffeine is taken before retiring326.5’0.
152
Caffeine increases motility during sleep430~s3h~s~0~s7~. generalized anxiety disorders and hyperthyroidism.
However, this increase is observed only with rather
high doses of caffeine, 260-390 mg. Thus, absorption
of 40 mg of caffeine does not modify the nocturnal
actograms of children 223. Also, there is no change in
the actograms of adults after a total amount of 3
mg/kg of caffeine is given in 3 divided doses at 2-hr
intervals before retiring”ss. Thresholds of arousal by
acoustic stimulus are definitely lower after ingestion of
400 mg of caffeine, which proves that after absorption
of the methylxanthine, sleep is not as deep as usua157,“x.
Finally, the nature of sleep disturbances induced by
caffeine has prompted several authors to suggest using
this specific methylxanthine in models of insom-
nia32h.327.J5?.
Since caffeine has also the property to
increase nocturnal vigilance, its consumption could be
beneficial to people working at night, especially if their
work requires a high degree of vigilanceh16.
Finally, it has been recently proposed that the hu-
man body produces a substance similar to caffeine
which would play a role in the control of the
sleep/wake cycle of humans. This endogenous caf-
feine-like substance would maintain the brain in a state
of wakefulness; when the level of this substance drops
below a certain critical value, the sleep phase of the
sleep/wake cycle starts”s.
7.8. Caffeine intoxication or caffeinism
It is well known that excessive consumption of caf-
feine elicits symptoms of nervousness, agitation, anxi-
ety, and insomnia242. According to a study performed
in the USA, it appears that l/4 of the general popula-
tion and one-half of all psychiatric patients ingest 500
mg of caffeine per day, the equivalent of 5 cups of
coffee52’. The majority of patients suffering from caf-
feinism develop a variety of nervous, gastrointestinal or
cardiac symptoms after consumption of differing quan-
tities of caffeine, usually more than 250 mg”*242. Caf-
feinism must be distinguished from other physical or
mental disorders such as idiopathic anxiety6a7; it is
sometimes misdiagnosed as anxiety neurosis”‘. Acute
states of confusion have also been associated with very
high levels of caffeine intake, more than 1000 mg per
day 42. However, anxiety or somatic abnormalities have
also been observed in chronic coffee drinkers even
after absorption of small quantities of caffeine, less
than 250 mg. Obviously, these subjects have a great
sensitivity to caffeineho7.
In addition to somatic symptoms, anxiety, or even
depression, caffeinism is sometimes associated with
delirium, psychoses or anorexia nervosa562.572.Caffein-
ism diagnosis includes manic episodes, panic disorders,
These symptoms can mimic or aggravate psychiat-
ric2IS,2”“,h2”and medica]2YY conditions. However, when
these symptoms are subsequent to ingestion of a large
amount of caffeine, the diagnosis is usually obvious”.
Several cases of death have also been observed
following intravenous”2”, oral’0~8”~3yyor rectal’h5 ab-
sorption of an excessive quantity of caffeine. The lethal
acute dose for an adult seems to be about 5-10 g
of caffeine administered intravenously or orally 10,xo,
320,3y9.497,
i.e., the equivalent of 75 cups of coffee. Doses
of 100 mg/kg of body weight represent a definite risk
of caffeine poisoning in children. Symptoms observed
in caffeine poisoning are agitation, anxiety, excitation,
convulsions, tachycardia, and coma with death by pul-
monary edema, atelectasis, ventricular fibrillation and
cardiopulmonary arrest 124.
7.9. Indiuidual Llariability and age-related variations in
the effects of caffeine
Results of experiments and surveys confirm the gen-
eral held opinion that the effects of caffeine on the
central nervous system vary greatly from one individual
to another. In addition, it is also common knowledge
that people become more sensitive to caffeine as they
get older.
7.9.1. Variations in the effects of caffeine among indiuid-
uals. Variations are partly linked to physiological fac-
tors such as rate of gastric evacuation and intestinal
absorption’97 and great differences in the metabolic
half-life of caffeine2”‘. Peak plasma concentration of
caffeine measured in nine subjects who, after fas’ ng,
were given 250 mg of caffeine dissolved in 300 m: of
fluid, ranges from 4.2 to 26 mg/12s. Furthermore, &-
feine is metabolized much more slowly in women dur-
ing the last trimester of pregnancy, requiring about
10.5 h 7,7’,336*460; it takes even longer in premature in-
fants, SO-100 h14.3S7.45Y.462, compared to 3.5-6.0 h in
normal adults 53,s6,458.Since caffeine catabolism varies
with the dose, its accumulation in the body is not
linear’43. The fetal liver is even capable of metaboliz-
ing theophylline into caffeine’5,66. Finally, the half-life
of caffeine is also lengthened in people with serious
hepatic diseases’4”*567.
Simultaneous use of caffeine and substances such as
tobacco and alcohol can produce interactive effects.
Thus, consumption of tobacco is decreased after ab-
sorption of 75-300 mg of caffeine342. The half-life of
caffeine is 55% shorter in smokers than in non-smokers;
and smokers eliminate a higher percentage of non-
metabolized caffeine 45x. Therefore, given the same ini-
tial sensitivity, the effects of caffeine are less pro-
nounced in smokers than in non-smokers. Caffeine also

interacts with alcohol and coffee consumption is much
higher in psychiatric patients who are alcoholics than
in those who abstain from alcoho127. Moreover, the
daily average rate of alcohol has been shown to de-
crease significantly in a group of people taking strong
soluble coffee and it has been suggested that some
coffee brands might be of help in controlling al-
coholism532. Conversely, caffeine did not counteract
the effects of alcohol, with the exception of reaction
time, in students who absorbed 30 mg of caffeine and
52.5 g of ethanol for 70 kg of body weight205. Also,
caffeine elimination is siower in women taking oral
contraceptives87~88~46’.
Genetic and personality factors also seem to play a
role in this variability. Thus homozygous twins react in
a more uniform way to the effects of caffeine than
heterozygous twins4695470.Similar observations have
been made with barbiturates493. Reactions to caffeine
also depend on personality type, especially on extrover-
sion or introversion 159,165,274,355,489,5OO,SO8,557,597
7.9.2. Age-related variations. Many children consume
caffeine every day, particularly in soft drinks like
Coca-Cofa. For a long time, it has been thought that
children are more susceptible to caffeine than adults”‘.
At low doses, 3 mg/kg, caffeine does not have any
effect either on prepubertal boys or on adults168~500~501.
Caffeine at a dose of 10 mg/kg has more noticeable
effects on children than on adults. On the whole, these
effects are beneficial, i.e., children speak faster, react
more quickly, and make fewer mistakes. Caffeine at
this dose induces side effects in adults but not in
.children5”. On the other hand, at high doses, sec-
ondary and behavioral effects are recorded in children
consuming more than 500 mg of caffeine per day500.
Therefore, it does not seem that children are specially
sensitive to caffeine when compared with adults, ex-
cept in cases of heavy consumption. Actually, children
seem to be less susceptible to methylxanthine than
adults’48. There exists a positive correlation between
parental and juvenile consumptions of coffee. A similar
correlation has been demonstrated for maternal con-
sumption of tobacco and paternal consumption of
alcohol beveragesPz. Caffeine was long thought,
especially in the USA, to be effective in the treatment
of hyperactive chifdren539. However, caffeine does not
significantly modify behavior, even in these
children218,259,503,628. In fact, studies have confirmed
that hyperactive children have no specific sensitivity to
caffeine.
In older people, caffeine absorption induces in-
creased sleep disturbances, with twice as many phases
of arousal, and increases the phases of light sleep at
the expense of deep sleep. On the other hand, decaf-
153
feinated coffee causes no modification in sleep2”. It
seems that tolerance to the effects of caffeine dimin-
ishes with age5’l. According to the results of a study
done on six young subjects and six older ones, the
elderly seem more sensitive to the objective effects of
caffeine and less sensitive to its subjective effects than
the young people58’.
8. TOLERANCE AND DEPENDENCE TOWARDS THE
EFFECTS OF CAFFEINE
8.1. Tolerance
There are very few studies concerning toierance of
human central nervous system to caffeine”8*230. An
apparent tolerance to caffeine’s effects on the central
nervous system has been reported in some clinical
studies. It has been noted that the sleep of people
consuming average or large amounts of coffee is less
disturbed than that of abstainers”8.230. However, since
this tolerance to the central effects of caffeine is prob-
ably of small amplitude, it is generally agreed that the
central nervous system is only slightly tolerant to the
stimulant effects of the methy~anthine’04~237~5’o~5~3~627,
whereas tolerance to the diuretic effects of caffeine has
been described a long time ago’“‘. In fact, it is very
difficult to know if moderate users of caffeine present
no symptoms because they have developed a tolerance,
or because, by nature, they were less sensitive than
those who use small amounts”“. It was recentIy shown
that regular consumption of 12 mg/kg/day of caffeine,
i.e., the equivalent of 6-11 cups of coffee, is likely to
produce pharmacological effects that are not entirely
counterbalanced by development of tolerance. Thus,
caffeine accumulates in the body in non-linear way by
metabolic saturationi4*.
Studies done within the last 10 years have demon-
strated tolerance to the central effects of caffeine in
animals regarding locomotor activity4’10X,‘9L-193*
291*294,408,operant conditioning~4, cerebral electrica ac-
tivity 108*280*433,
and caffeine-induced seizures645. On the
other hand, cerebral energy metabolism is only slightly
tolerant to the stimulant effects of caffeine in the
rat438,439.The phenomenon underlying the develop-
ment of tolerance to caffeine in rodents has not yet
been elucidated. Its rapid onset as well as its persis-
tence seem to implicate depletion of a neurotransmit-
ter, especially noradrenaline255.
The possible role of adenosine in the control of
vigilance Ievet24’ shows that the increased number of
adenosine receptors in animals chronically exposed to
caffeine could be responsible for the sedative effects
on activity that are observed in these animals or in
humans abruptly deprived of caffeine295. In fact, some
 154
consequences of caffeine withdrawal could be due to
increased sensitivity of the subjects to endogenous
adenosine”‘. However, according to another study, the
increase in the number of adenosine receptors would
not explain development of tolerance to the stimulant
action of caffeine, at least not in the case of locomotor
activity “‘).
8.2. Dependence and withdrawal
Dependence on caffeine has been studied more
than tolerance to its effects; a recent and very detailed
review is devoted to caffeine dependencez5. In ani-
mais, caffeine withdrawal decreases locomotor
activity2”‘. In humans, when chronic coffee drinkers
stop drinking this beverage, they experience the follow-
ing symptoms: feeling of weariness, apathy, weakness
and drowsiness2Oh,23Y,24j,3f14,308.41 1,496,576,623
, head-
aches73,2”6,22”,239,3~,496..551,6~.623
, anxiety, increased mus-
cle tension222.“22,occasiona tremor 226*2h0, nausea, vom-
iting, as well as a sensation of withdrawal, These symp-
toms disappear after absorption of caffeine. Disap-
pearance of withdrawal symptoms is strongly linked to
the psychologic satisfaction given by ingestion of cof-
fee; this is especially true for the first cup of the day.
Heavy consumers of coffee show a preference for cof-
fee containing caffeine if they have been drinking this
type of coffee for 1 week or more, whereas people who
have been drinking decaffeinated coffee will choose
either decaffeinated or caffeine-containing coffee2481”7”.
Indeed, several studies have shown that caffeine con-
tent influences coffee consumption250,341,47”and that
caffeine alone is able to reverse withdrawal syndroms
induced by caffeinated coffee cessation15h,2”“,2”4,2”X. The
beneficial effects, derived or expected, of coffee con-
sumption on mood or performance would also seem to
incite people to drink coffee347.
In apparent contradiction to these data, it seems
that an animal, rat or baboon, given the choice of
beverage does not automatically choose to self-admin-
ister caffeine continuously, as he would do for drugs
like morphine, amphetamines or cocaine24~25’*2s4. How-
ever, in rats, caffeine can serve as a discriminative
stimulus at both low and high doses292S432*637. The dis-
criminative effects of a low dose of caffeine (10 mg/kg)
appear to derive from a state of behavioral arousal,
possibly mediated by catecholamines, and parallel the
subjective effects produced by a low dose of caffeine in
humans. The origin of the discriminative effects of high
dose of caffeine (56 mg/kg) is not clearly defined at
this time4”“. In humans, the widely recognized behav-
ioral stimulant and mildly reinforcing properties of
caffeinel”‘,248,249.252-254,363
are probably responsible for
the maintenance of caffeine self-administration, pri-
marily in the form of caffeinated beverages, such as
coffee, tea and cola-i”V225. Even though important varia-
tions in individual sensitivity to the effects of caffeine
have been demonstrated, both in man and animals,
abuse of caffeine presents a minimal risk2“.
It appears that some coffee drinkers exhibit com-
mon signs of drug dependence1“*99,~1~. According to a
recent study, it would seem that dependence on the
effects of caffeine can appear with even very slight
doses (one cup of strong coffee or three cans of Coca-
Cola per day) and that caffeine withdrawal can cause
more numerous symptoms than hitherto believed”‘.
Furthermore, it is known that coffee has a reinforcing
effect on its own consumption in man and in
animals2”3~254.However, this reinforcement of con-
sumption is dose-dependent; very high doses can cause
dysphoria in humans*““. Withdrawal symptoms gener-
ally begin 12-24 h after coffee consumption has
CeaSed156,233,234.248,3Y2.634
and reach a peak after 20-4X
hl56,206,226.634, However,
these symptoms can ap-
pear within only 3-6 h”‘~“‘” and can last for 1
week243.248,2Y7,8X0, or even several months after coffee
consumption has stopped4”.
A recent study has been performed on the relation-
ship between consumptions of caffeine, alcohol and
tobacco and pre- and post-operative headaches. There
is a strong positive correlation between caffeine con-
sumption and headaches before and after surgical pro-
cedures. A linear regression analysis shows that for
every increase of 100 mg of caffeine (about one cup of
coffee) the risk of migraine immediately before surgery
is increased by 12% and after surgery by 16%. There is
no relationship between this withdrawal symptom and
age, sex, usual frequency of headaches, consumption of
alcohol or tobacco, and anesthetic drugs or other medi-
cations used during the surgical procedureiS3. With-
drawal symptoms can also be observed in newborn
infants whose mothers are heavy coffee drinkers during
pregnancy. These infants display unusual behavior be-
ginning at birth, characterized by irritability, high emo-
tivity and even vomiting. These symptoms disappear
after a few days400.
Few animal studies have been performed on this
topic, Caffeine withdrawal causes the locomotor activ-
ity of the rat to decrease by about one-half. This effect
lasts for about 4 days, is dose-dependent, and is maxi-
mal on the 2nd day 4@~142 . The same phenomenon is
observed in the threshold response to cerebral electri-
cal stimulation by caffeine in the rat4”“. Also interrup-
tions in operant behavior are observed in the monkey
after caffeine deprivation but these disturbances are
less pronounced than with other drugs’“.

9. CONCLUSION
It seems very difficult to form a definite opinion on
caffeine’s effects on the central nervous system. Inter-
pretation of data is highly subjective, and the effects of
caffeine vary greatly from one subject to another.
Moreover, most animal studies were performed with
doses much higher than those corresponding to the
human consumption of methylxanthine corresponding
to one or several cups of coffee.
Nevertheless, it seems that caffeine increases vigi-
lance and endurance during performance of repetitive
tasks. Also, it postpones onset of sleep, results in
lighter sleep and increases the level of anxiety, espe-
cially in some subjects who are sensitive to this phar-
macological agent.
The human central nervous system does not seem to
develop easily a tolerance to the stimulant effects of
caffeine, although methylxanthine dependence has
been clearly established. Withdrawal symptoms appear
very quickly after caffeine is stopped.
Caffeine has a vasoconstricting effect on the brain
and a vasodilating effect on peripheral blood flow. This
property explains the presence of caffeine in several
medications for migraine headaches.
Finally, the main mechanism of action of methylxan-
thines in the brain suggests their antagonistic action at
the level of the adenosine receptors.
i0. SUMMARY
Caffeine is the most widely consumed central-
nervous-system stimulant. Three main mechanisms of
&ion of caffeine on the central nervous system have
been described. Mobilization of intracellular calcium
and inhibition of specific phosphodiesterases only oc-
cur at high non-physiological concentrations of caf-
feine. The only likely mechanism ‘of action of the
methy~nthine is the antagonism at the level of adeno-
sine receptors. Caffeine increases energy metabolism
throughout the brain but decreases at the same time
cerebral blood flow, inducing a relative brain hypoper-
fusion. Caffeine activates noradrenaline neurons and
seems to affect the local release of dopamine. Many of
the alerting effects of caffeine may be related to the
action of the methylxanthine on serotonine neurons.
The methylxanthine induces dose-response increases in
locomotor activity in animals. Its psychostimulant ac-
tion on man is, however, often subtle and not very easy
to detect. The effects of caffeine on learning, memory,
performance and coordination are rather related to the
methylxanthine action on arousal, vigilance and fa-
tigue. Caffeine exerts obvious effects on anxiety and
155
sleep which vary according to individual sensitivity to
the methy~anthine. However, children in general do
not appear more sensitive to methylxanthine effects
than adults. The central nervous system does not seem
to develop a great tolerance to the effects of caffeine
although dependence and withdrawal symptoms are
reported.
Acknowledgements. The authors wish to thank the Institut National
de la Sante et de la Recherche Medicale (INSERM U 2721, the
Centre de Nutrition Humaine and the Fondation pour la Recherche
Medicale (Cornit& Lorraine) for financial support. The editorial
assistance of V. Koziei is gratefully acknowledged.
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