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Current Neuropharmacology, 2015, 13, 71-88 71
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Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive
Drug?
Simone Cappelletti
1
, Piacentino Daria
2
, Gabriele Sani
2
and Mariarosaria Aromatario
1,
*
1
Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, “Sapienza”
University of Rome, Rome, Italy;
2
NESMOS (Neuroscience, Mental Health, and Sensory Organs)
Department, School of Medicine and Psychology, “Sapienza” University of Rome, Rome, Italy
Abstract: Caffeine use is increasing worldwide. The underlying motivations are mainly concentration
and memory enhancement and physical performance improvement. Coffee and caffeine-containing
products affect the cardiovascular system, with their positive inotropic and chronotropic effects, and
the central nervous system, with their locomotor activity stimulation and anxiogenic-like effects.
Thus, it is of interest to examine whether these effects could be detrimental for health. Furthermore,
caffeine abuse and dependence are becoming more and more common and can lead to caffeine
intoxication, which puts individuals at risk for premature and unnatural death. The present review summarizes the main
findings concerning caffeine’s mechanisms of action (focusing on adenosine antagonism, intracellular calcium
mobilization, and phosphodiesterases inhibition), use, abuse, dependence, intoxication, and lethal effects. It also suggests
that the concepts of toxic and lethal doses are relative, since doses below the toxic and/or lethal range may play a causal
role in intoxication or death. This could be due to caffeine’s interaction with other substances or to the individuals' pre-
existing metabolism alterations or diseases.
Keywords: Abuse, caffeine, coffee, dependence, energy drinks, safety doses, toxicity.
INTRODUCTION
The use of caffeine to stay awake and alert is a long-
standing habit. Coffee is the most popular beverage after
water and is consumed worldwide in daily amounts of
approximately 1.6 billion cups, which is quite an impressive
figure.
There is some uncertainty about the etymology of the
word “coffee”. The botanical name of the plant from which
coffee is derived is Coffea Arabica: it finds its origins in
Ethiopia and is an exceptionally hardy self-pollinating plant.
The Persian physician Rhazes was the first to mention it in
his manuscripts. Yemen was the first country to cultivate the
coffee plants, whilst Turkey was the first country to roast the
green coffee beans. So it is not surprising that the word
“coffee” finds its roots in Arabia, where it was called
“qahwah”. Although there is no doubt about the origin of the
word, researchers do not agree on how the language process
led the English word “coffee”. It is likely that the latter
found its way into European languages in the 17
th
century
from the Italian word “caffé”, stemming, in turn, from the
word “kahveh”, which was the Turkish way to pronounce
“qahwah”. Over the centuries, the habit of drinking coffee
spread from Arabia to all the world.
Caffeine is contained in more than sixty plants, which is
a remarkable number, thus it has been hypothesized that
*Address correspondence to this author at the Department of Anatomical,
Histological, Forensic Medicine and Orthopedic Sciences, “Sapienza”
University of Rome, Viale Regina Elena, 336 – 00161 Rome, Italy;
Tel: +390649912607; Fax: +39064455335;
E-mail: aromatario@hotmail.com
caffeine was originally a minor nutrient, not essential for the
plant, but extremely useful as a pesticide. In fact, caffeine is
toxic for several insects and animals, especially herbivores.
Through caffeine the plant may defend itself and have a
better chance of survival: in this view, caffeine can be
considered as a “co-evolutionary protecting agent” [1].
“The Canon of Medicine”, written in 1025 by the Persian
physician Avicenna, is the first text mentioning coffee as a
medication. At the time, coffee was used to “clean the skin,
dry up the humidities that are under it, and give a better odor
to the body”. In the 15
th
century, the diffusion of coffee,
initially employed by Muslim dervishes for providing
energy, had remarkably increased and countless coffee
houses had opened in Arabia. In the late 17
th
and in the 18
th
century, as sea shipping had expanded, the use of coffee
became common in Europe [2].
The stimulant effects of caffeine on the central nervous
system have been known for centuries [3]. In the 19
th
century
a well-known consumer was Honoré De Balzac. Saying that
he loved the coffee is not enough. He was completely
dependent on it and in the period in which he wrote “The
Human Comedy” he went on to drink up to 50 cups a day. In
1830, he published an article in a French magazine called
“Pleasures and pains of coffee”, which recounted: "coffee
slips into the stomach and you immediately feel a general
commotion. Ideas begin to move like the battalions of the
Grand Army on the field of the battle and the battle takes
place. Memories come at a gallop, carried by the wind”.
Nowadays, caffeine is believed to be the most frequently
consumed psychostimulant worldwide, being ingested
predominantly as coffee. Many other caffeine-containing
Simone Cappelletti
72 Current Neuropharmacology, 2015, Vol. 13, No. 1 Cappelletti et al.
beverages and products exist and contain significant amounts
of the substance, for example, tea, chocolate, cocoa
beverages, soft drinks, and energy drinks. Coffee and
caffeinated beverages are part of the diet in all countries.
With regard to cognitive functions, caffeine’s properties
have been investigated in both human and animal studies. In
epidemiological reports, a link between chronic caffeine
consumption and a significantly lower risk of developing
neurodegenerative diseases, such as Alzheimer’s disease, has
been described [4]. Likewise, chronic treatment with caffeine
has been shown to be effective in preventing β-amyloid (Aβ)
production and memory deficits in experimental models of
Alzheimer’s disease [5, 6]. While caffeine seems to prevent
or restore memory impairment due to disturbances in brain
homeostasis [7], its cognition-enhancing properties are still a
matter of debate [8, 9]. Besides, moderate-to-high consumers
develop tolerance to caffeine and only low or nonconsumers
can eventually benefit from an acute administration [10].
In addition, in epidemiological reports [11] and
experimental models [12, 13], caffeine has been found to
have a role in the prevention of motor symptoms and loss of
dopaminergic neurons in Parkinson’s disease.
With regard to physical activity, it should be noted that
until 2004 the International Olympic Committee listed
caffeine in its prohibited substances list. Professional athletes
who tested positive for more than 12 µg/l of urine – which
corresponds to drinking about 5-6 cups of coffee in a day –
were banned from the Olympic games [14].
In the past years, a relationship between coffee
consumption and several types of cancers, such as colon,
bladder, and pancreatic ones, has been postulated. Yet, the
recent literature has provided no evidence of this relationship
[15, 16].
METHODS
Eligibility Criteria
The present conceptual review was performed by
including retrospective, prospective, and transversal (i.e.,
cross-sectional) studies examining caffeine’s mechanisms of
action, use, abuse, dependence, and intoxication, which may
lead to death.
Search Criteria and Critical Appraisal
As regards the search strategy, an electronic search of
Pubmed, INFORMA healthcare, Excerpta Medica Database
(EMBASE), and PsycINFO from the inception of these
databases to July 20, 2014 was performed. The search
included publications in any language. Search terms were
caffeine AND “pharmacokinetics” OR “pharmacodynamics”
OR “heart” OR “brain” OR “abuse” OR “dependence” OR
“intoxication” OR “death” in title, abstract, and key-words.
Reference lists of all located articles were further searched
for the detection of still unidentified literature and its
evaluation.
Search Results and Included Studies
From each electronic database, we read all titles and
selected those promising ones to be relevant, which were
29,421. Through a hand search of reference lists 20 other
potentially eligible articles were singled out.
Risk of Bias
No evidence of language bias was found, as the search
was not limited to English language studies. This limited the
possibility of missing relevant studies. Moreover, no proof of
significant publication bias was found. The database search
produced no unpublished study, initiating, ongoing, or
finished.
RESULTS
Pharmacokinetics and Pharmacodynamics
After ingestion, caffeine is quickly absorbed from the
gastrointestinal tract into the circulatory system [17, 18]. The
maximum plasma concentration is reached after 30-60
minutes from consumption. However, maximum plasma
concentrations reached between 15 and 120 min have been
reported, due to inter-individual differences and delayed
gastric emptying. Caffeine is widely distributed through the
body. The pre-systemic (i.e., first-pass) metabolism takes
place in the liver, since orally ingested substances are
absorbed through the small intestine into the portal
circulation, before entering the systemic one. Caffeine’s pre-
systemic metabolism is negligible [17] and, once caffeine is
absorbed, it promptly gets into all the body tissues and
crosses the blood-brain, blood-placenta, and blood-testis
barriers [17, 19]. The hepatic microsomal enzyme system is
in charge of caffeine metabolism in the liver. The main
enzyme responsible for caffeine metabolism is cytochrome
P450 1A2 (CYP1A2), which accounts for about 95% of
caffeine clearance. Caffeine metabolism rate is controlled
not only by CYP1A2, but also by xanthine oxidase and N-
acetyltransferase 2 (NAT2) [20]. Only from 0.5% to 2% of
ingested caffeine is excreted as such in the urine, as it
undergoes an almost complete tubular reabsorption [17].
Caffeine’s half-life in humans ranges from a minimum of 2
to a maximum of 12 hours [21, 22], mainly due to the inter-
individual variability in absorption and metabolism. When
levels of intake are higher, a prolonged duration of action
can be observed, possibly because of a delay in caffeine
clearance and an accumulation of paraxanthine and other
xanthines. In fact, caffeine is subjected to demethylation,
resulting mostly in the release of paraxanthine (84%),
followed by theobromine (12%) and theophylline (4%). The
chemical structure of the xanthines theobromine and
theophylline is very similar to that of caffeine [23]. These
metabolites are further transformed in the liver through
demethylation and oxidation, resulting in the production of
urates [24].
Paraxanthine, the key metabolite of caffeine, has a
similar chemical structure and half-life to those of caffeine
and is easily measured in serum and urine. About 60% of
orally ingested paraxanthine is excreted unmodified.
Compared to caffeine, paraxanthine’s production and
degradation rates are similar, but serum concentration is
more stable throughout the day, even if it reflects only recent
consumption [25]. Paraxanthine’s plasma levels decrease
more slowly, even after accounting for inter-individual
metabolism variations, and they become higher after 8-10
Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug? Current Neuropharmacology, 2015, Vol. 13, No. 1 73
hours from ingestion [17]. Paraxanthine is then metabolized
through two alternative pathways: the former produces
8-hydroxyparaxanthine, the latter, consisting in the
7-demethylation of paraxanthine, produces three metabolites,
i.e., 5-acetylamino-6-formylamino-3-methyluracil (AFMU),
1-methylxanthine, and 1-methylurate [26]. AFMU makes up
for 67% of paraxanthine metabolites [17] and is converted to
5-acetyl-6-amino-3-methyluracil (AAMU), which can be
measured in the urine without any difficulty. The paraxanthine
metabolites are excreted in the urine almost as rapidly as
they are produced, as a result of an active renal tubular
secretion [26]. Because of the high caffeine doses and the
repeated consumption of coffee that are typical of the daily
caffeine consumer, paraxanthine accumulates in the plasma
and this process reduces caffeine elimination. Paraxanthine,
as mentioned above, has many similar effects to those of
caffeine and, consequently, daily caffeine consumption
generates high levels of both caffeine and paraxanthine,
which are biologically active.
Theobromine constitutes the higher proportion of the
biologically active metabolites [27]. It is rapidly absorbed
and about 50% is excreted through the urine in 8-12 hours
[28]. Its effects include diuresis induction, cardiovascular
system stimulation, smooth muscle relaxation, and glandular
secretion [29]. CYP1A2 and, to a smaller extent, CYP2E1,
are responsible for theobromine’s metabolism, as they
determine 86% of its demethylation [30]. Theobromine’s
half-life is approximately 7-11 hours [28, 31] and plasma
and renal clearance are about 46% and 67%, respectively
[32]. Plasma clearance is influenced by smoking: smokers
show a 30% higher clearance than nonsmokers [33].
Theophylline and caffeine share a similar chemical
structure, however theophylline lacks one N-methyl group
and determines more potent effects than caffeine and
theobromine. Its half-life is quite unpredictable, varying
from 3 to 9 hours [34]. Theophylline is subjected to hepatic
and renal clearance. Hepatic clearance is mediated essentially
by CYP1A2, via an N-demethylation that leads to the
production of monomethylxanthines and an 8-hydroxylation
that leads to the production of 1,3-dimethyl-uric acid.
In conclusion, there are significant inter-individual
differences in the metabolism, clearance, and elimination of
caffeine and its metabolites. Several extrinsic factors
influence metabolic and excretion rates, such as smoking,
food intake, gastric emptying speed, pregnancy, hepatic and
cardiovascular diseases, viral infections, and concomitant
drug use.
In particular, smokers are characterized by a metabolism
rate that is almost twice the one of nonsmokers [35].
Cigarettes contain polycyclic aromatic hydrocarbons that
promote a greater liver enzyme activity, thereby increasing
caffeine metabolism [26, 36]. Smoking may accelerate the
pre-systemic (i.e., first-pass) and systemic (i.e., second-pass)
metabolism of caffeine, with the hepatic microsomal
oxidative enzymes causing a faster demethylation [37, 38].
Pregnancy decreases the clearance and excretion of
caffeine, thus the latter and its metabolites, such as
theophylline, can accumulate in the body [34]. Variations in
enzyme activity, especially with regard to CYP1A2, are
reported. As a result, there is a growing effort to identify
genetic polymorphisms influencing caffeine metabolism
[26, 39].
Mechanisms of Action
The potential effects of caffeine, at the cellular level, can
be explained by three mechanisms of action: the antagonism
of adenosine receptors, especially in the central nervous
system; the mobilization of intracellular calcium storage; the
inhibition of phosphodiesterases.
Antagonism of Adenosine
Caffeine blocks adenosine receptors, mainly A
1
and A
2A
subtypes, competitively antagonizing their action [40, 41]
and causing an increased release of dopamine, noradrenalin,
and glutamate [42, 43]. Caffeine is able to reduce cerebral
blood flow [44]. It is also able to reduce myocardial blood
flow, by inhibiting A
1
, A
2A
and A
2B
adenosine receptors in
blood vessels and limiting adenosine-mediated vasodilation
[45]. A
1
receptors can be found in almost all brain areas. The
highest concentration is in the cerebral and cerebellar
cortices, the hippocampus, and a number of thalamic nuclei
[46, 47], whereas only a modest concentration is found in the
corpus striatum, i.e. the caudate and putamen, and the
nucleus accumbens. Pre-synaptic A
1
receptors inhibiting the
release of neurotransmitters are present in almost all types of
neurons.
There is significant evidence of a relationship between
adenosine A
2A
and dopamine D
1
receptors [42]. Adenosine
A
2A
and D
2
receptors show a high concentration in the
dopamine-rich areas of the brain, i.e., the corpus striatum,
the nucleus accumbens, and the tuberculum olfactorium,
where they are co-localized. There is little evidence
supporting their presence outside these areas, even if,
according to recent functional neuroimaging studies, they
may be present in the cerebral cortex and the hippocampus.
The blockade of A
2A
receptors in the basal ganglia, i.e., the
corpus striatum and globus pallidus, appears to be fundamental
for the stimulatory effects of caffeine [48]. These effects
largely depend on an intact dopaminergic neurotransmission.
Finally, it has been shown that the effects of caffeine in low
doses can be replicated by a selective A
2A
receptor antagonist,
but not by a selective A
1
receptor antagonist [49]. These
findings suggest that the interaction between caffeine in
high doses and dopaminergic transmission finds its roots
in the increase of post-synaptic D
2
receptor transmission.
The antagonistic effects of caffeine on the A
2A
adenosine
receptors in the corpus striatum are in line with the
reduced risk of developing Parkinson’s disease when
caffeine consumption is increased [9].
The ability of caffeine to block adenosine receptors can
be observed also at low doses, such as those contained in a
single cup of coffee.
Other mechanisms of action, such as the mobilization of
intracellular calcium and the inhibition of phosphodiesterases,
require higher doses of caffeine, unlikely to be obtained with
the common daily dietary sources of caffeine.
74 Current Neuropharmacology, 2015, Vol. 13, No. 1 Cappelletti et al.
Mobilization of Intracellular Calcium
Caffeine can induce calcium release from the
sarcoplasmic reticulum [50] and can also inhibit its reuptake
[51]. Through these mechanisms, caffeine can increase
contractility during submaximal contractions in habitual and
nonhabitual caffeine users. Intracellular calcium determines
the activation of endothelial nitric oxide synthase (eNOS),
with the production of higher quantities of nitric oxide [47].
Therefore, some of the effects induced by caffeine might be
partly mediated by neuromuscular function modulation and
contractile force increase in the skeletal muscles [52, 53].
A potential counter effect of caffeine is represented by
diuresis stimulation, accountable for ergolytic effects in
endurance athletes during prolonged workouts and competitions
[54].
Inhibition of Phosphodiesterases
Caffeine acts as a nonselective competitive inhibitor of
phosphodiesterases [55]. These enzymes hydrolyze the
phosphodiester linkages in molecules, such as cyclic adenosine
monophosphate (cAMP), inhibiting their degradation. cAMP
stimulates lipolysis by triggering the activity of the hormone-
sensitive lipase (HSL) and has a vital role in the adrenaline
cascade [56]. It also activates protein kinase A, which in turn
phosphorylates several enzymes implicated in glucose and
lipid metabolism [57]. These mechanisms of action require
very high doses of caffeine, unlikely to be present in the
standard diet, which contains moderate amounts of caffeine.
Further mechanisms of action describe the use of caffeine
in sport activities and as a dietary supplement that are
described below.
Increase of Post-exercise Muscle Glycogen Accumulation
Faster recovery following intense exercise, mediated by a
higher rate of glycogen resynthesis, has been described [58].
It has been maintained that caffeine ingestion has no effect
on glycogen stacking during recovery from exercise in
recreational athletes [59]. However, a recent study has found
that caffeine (8 mg/kg body weight), coingested with
carbohydrates, is responsible for higher rates of post-exercise
muscle glycogen stacking in comparison to the ingestion of
carbohydrates alone in well-trained athletes after the
depletion of glycogen that follows exercise [60]. Although
this finding deserves further investigation in broader
population samples (recreational and professional athletes,
untrained individuals) and occasions (during exercise or
recovery), caffeine in addition to post-exercise carbohydrates
consumption seems to be able to stimulate glycogen
resynthesis.
Increase of Fatty Acid Oxidation
The increase of lipolysis determines a decreased dependence
from glycogen use [61]. Caffeine switches the substrate
preference from glycogen to lipids by stimulating HSL
activity and inhibiting glycogen phosphorylase activity [62].
Effects on the Cardiovascular System
Caffeine has several effects on the cardiovascular system,
which have been examined thoroughly with conflicting
result. Many mechanisms have been suggested in relation to
caffeine toxicity, which primarily affects the cardiovascular
system.
In the heart, adenosine acts through specific receptors
and is a negative inotropic and chronotropic agent. The
blockade of cardiac adenosine receptors inhibits adenosine’s
effects and can cause tachycardia and arrhythmias through
intense β
1
-receptor activity.
High caffeine doses induce adenosine antagonism and
phosphodiesterases inhibition, interacting with the sympathetic
nervous system and inducing β
1
-receptor activation. This
results in positive inotropic and chronotropic effects,
accountable for an augmented heart rate and conductivity
[63]. In fact, higher concentrations of caffeine increase
intracellular cAMP and cyclic guanosine monophosphate
(cGMP) by a nonspecific phosphodiesterases inhibition,
which affects cardiac contractility secondary to calcium
release. The latter mechanism may increase the susceptibility
for arrhythmias. Other caffeine’s mechanisms of action with
indirect effects on the cardiovascular system have been
reported, such as the stimulation of the sodium-potassium-
ATPase, which is an integral membrane protein responsible
for a decrease in the plasma levels of potassium and the ion’s
transfer from the circulation to intracellular compartments,
rendering the membrane potential more negative. This
determines an increased risk of ventricular arrhythmias
[64].
According to the aforementioned mechanisms, arrhythmic
episodes have been hypothesized to be responsible for death
in cases of lethal intoxication. Caffeine, especially at high
doses, leads to palpitations and arrhythmias, such as atrial
fibrillation and supraventricular and ventricular ectopic beats
(the latter also known as premature ventricular contractions,
PVCs) [65]. It must be underlined that the positive inotropic
effects of caffeine are reinforced by the positive chronotropic
effects of guarana, a substance that is frequently added
to energy drinks and contains caffeine, theobromine, and
theophylline [66]. Berger et al. [67] reported ventricular
fibrillation after overconsumption of a caffeinated energy
drink in a 28-year-old healthy young man who was hospitalized
and subsequently discharged after six days in healthy
conditions.
Caffeine’s pro-arrhythmic effects at high doses are
supported by animal studies [65, 68], which have been
performed with higher doses of caffeine and evaluation
by invasive techniques. Numerous physiological and
epidemiological human studies have investigated the link
between caffeine and both atrial and ventricular arrhythmias
[69], but their results are not always in agreement.
The first human studies were carried out using invasive
electrophysiology. Gould et al. [70] and Dobmeyer et al.
[71] found a refractory period shortening of the atrio-
ventricular node and of the right atrium and ventricle after
coffee intake: both effects were attributed to catecholamine
release. Opposite results were found in the left atrium, whose
refractory period paradoxically increased with caffeine
intake.
As regards the effects of caffeine on the human
electrocardiogram [69] after the intake of moderate amounts
Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug? Current Neuropharmacology, 2015, Vol. 13, No. 1 75
of caffeine [72] or high-caffeine energy drinks [73], it was
noticed that caffeine does not acutely induce any statistically
and clinically significant changes in P-wave indices, i.e., PR
interval, QRS duration, corrected QT interval (QTc), and RR
interval [74]. Donnerstein et al. [75] observed a modest, but
statistically significant prolongation of approximately 1 ms
of signal-averaged QRS complexes in 12 individuals given a
5 mg/kg body weight dose of caffeine vs. placebo.
In addition, studies of individuals performed with
continuous electrocardiographic monitoring suggested that
caffeine has a limited effect on the circuits underlying
ventricular arrhythmias [69, 76, 77]. Therefore, despite
increases in adrenaline levels, caffeine appears to have no
proarrhythmic effect even in patients with clinical ventricular
arrhythmias; caffeine showed no capacity of modifying the
inducibility or severity of arrhythmias in patients with
malignant ventricular arrhythmias [77] and did not induce an
increase of cardiac ectopy, neither atrial nor ventricular, in
patients with a high prevalence of baseline ectopy [69].
Furthermore, in high-risk patients with recent myocardial
infarction no increase in the frequency or severity of PVCs
or arrhythmias was found [69]. It is interesting to note that
although adrenaline concentration increases with caffeine
ingestion, the degree of the release is six times lower than
the boost noted during exercise [78].
Larger-scale epidemiological studies found no increased
risk of development of atrial arrhythmias after caffeine
intake in healthy subjects [69]. A recent meta-analysis [79]
suggested that it is unlikely that the chronic consumption
of caffeine causes or contributes to atrial fibrillation. It was
also demonstrated that in habitual caffeine consumers,
caffeine’s adrenergic effects were greatly attenuated and
acute proarrhythmic effect was somewhat reduced [80].
Furthermore, as atrial fibrosis is an important substrate for
atrial fibrillation and caffeine has antifibrotic properties [81-
84], this finding might encourage the search for effective
antifibrosis agents or the use of caffeine to prevent atrial
fibrillation.
Prineas et al. [69] found that nine cups of coffee were
associated with twice the risk of PVCs after adjusting for
other risk factors. The same authors found a very significant
association between heavy coffee intake (10 cups per day)
and increased risk of sudden cardiac death in 117 patients
with a history of coronary artery disease who suffered from
sudden cardiac arrest vs. controls with coronary artery
disease (odds ratio=55.7) [69]. However, a possible
limitation may be represented by the fact that only two of the
controls drank more than 10 cups of coffee per day
Some researchers have conjectured that caffeine is a
vasoconstrictive substance [80, 85, 86]. In vitro studies have
found that the concentration of intracellular calcium in
vascular smooth muscle is modified by caffeine and this
phenomenon could directly determine variations of coronary
artery tone [67]. Caffeine has been shown to elevate blood
pressure in both normotensive and hypertensive prone men,
partly by inhibiting adenosine action, leading to elevated
noradrenalin release and vasoconstriction [87, 88]. A number
of studies have demonstrated that acute caffeine ingestion
increases blood pressure and catecholamine levels and
decreases heart rate [74, 89]. A study of caffeine’s ability to
interfere with pharmacologic cardiac stress testing, showed
in vivo increases in coronary vascular resistance and ascribed
them to the antagonism of A
2
receptors or to the induction of
an α2-adrenoreceptor-mediated vasoconstriction consequent
to the increase in catecholamine release [90]. It is well known
that adenosine causes vasodilation, thus, the antagonization
of adenosine receptors may induce vasoconstriction.
By contrast, caffeine also augments endothelium-
dependent vasodilation by agonist stimulation of endogenous
nitric oxide production in young, healthy individuals. A
double-blind, randomized study [55] showed that caffeine
ingestion produced an increase in systolic and diastolic blood
pressures in the brachial artery, in agreement with previous
studies that highlighted how acute caffeine ingestion elevated
peripheral blood pressure [80, 86, 91] and augmented the
forearm blood flow response to acetylcholine, an endothelium-
dependent vasodilator. It has been reported that caffeine
stimulates nitric oxide synthesis in the endothelium via the
release of calcium from the endoplasmic reticulum by activating
the ryanodine-sensitive calcium channel and inhibiting the
breakdown of cGMP in the aorta: this results in the caffeine-
induced increase of endothelium-dependent vasodilation
[92]. A balance between the vasodilatory effect of caffeine as
an endothelium-dependent vasodilator and its vasoconstrictive
effect as an adenosine receptor antagonist may control
vascular function. High caffeine concentrations may cause
marked hypotension secondary to vasodilation and, thus,
ventricular fibrillation, which could be a possible mechanism
of cardiovascular collapse [93].
Blood pressure changes induced by acute caffeine
ingestion need to be further investigated. Karatzis et al. [94]
observed, after the acute administration of caffeine, an
increase of central blood pressure, but not of peripheral
systolic blood pressure. Therefore, there seems to be a
relevant acute effect of caffeine ingestion on central
hemodynamics, but not on peripheral pressure.
Several factors, such as age, exercise-induced stress, and
hypertension, have been reported to influence blood pressure
changes induced by caffeine [86]. Forman et al. [95]
suggested that high doses of caffeine and low estrogen levels
may act in a synergistic way to induce coronary arteries
vasoconstriction.
These observations highlight the importance of keeping
fairly constant any confounding factor when carrying out
experimental studies, in order to assess correctly the blood
pressure changes during caffeine administration.
Similarly, case-control and prospective studies have
shown differing result with regard to the risk of myocardial
infarction among patient with high coffee intake. A potential
role of caffeine in promoting the development on cardiac
ischemia has been suggested, taking into account the higher
oxygen demand deriving from increased cardiac work levels
and, in addition, caffeine’s direct effect on the coronary
arteries [95]. There are case reports [67, 96] of coronary
artery vasospasm induced by caffeine-containing energy drinks,
but there is not enough evidence to support a relationship
between caffeine and vasospasm. In vitro, caffeine has