Caffeine, Mental Health, and Psychiatric Disorders

Abstract

Caffeine intake is so common that its pharmacological effects on the mind are undervalued. Since it is so readily available, individuals can adjust their own dose, time of administration and dose intervals of caffeine, according to the perceived benefits and side effects of each dose. This review focuses on human studies of caffeine in subjects with and without psychiatric disorders. Besides the possibility of mild drug dependence, caffeine may bring benefits that contribute to its widespread use. These benefits seem to be related to adaptation of mental energy to the context by increasing alertness, attention, and cognitive function (more evident in longer or more difficult tasks or situations of low arousal) and by elevating mood. Accordingly, moderate caffeine intake (< 6 cups/day) has been associated with less depressive symptoms, fewer cognitive failures, and lower risk of suicide. However, its putative therapeutic effects on depression and ADHD have been insufficiently studied. Conversely, in rare cases high doses of caffeine can induce psychotic and manic symptoms, and more commonly, anxiety. Patients with panic disorder and performance social anxiety disorder seem to be particularly sensitive to the anxiogenic effects of caffeine, whereas preliminary data suggests that it may be effective for some patients with obsessive compulsive disorder (OCD). The threshold for the anxiogenic effect of caffeine is influenced by a polymorphism of the A2A receptor. In summary, caffeine can be regarded as a pharmacological tool to increase energy and effortful behavior in daily activities. More populational (cross-sectional and prospective) and experimental studies are necessary to establish the role of caffeine intake in psychiatric disorders, especially its putative efficacy on depressive mood and cognitive/attentional disorders.

Full text

Journal of Alzheimer’s Disease 20 (2010) S239–S248 S239
DOI 10.3233/JAD-2010-1378
IOS Press
Review Article
Caffeine, Mental Health, and Psychiatric
Disorders
Diogo R. Lara∗
Faculdade de Biociˆ
encias, PUCRS, Porto Alegre, Brazil
Abstract. Caffeine intake is so common that its pharmacological effects on the mind are undervalued. Since it is so readily
available, individuals can adjust their own dose, time of administration and dose intervals of caffeine, according to the perceived
benefits and side effects of each dose. This review focuses on human studies of caffeine in subjects with and without psychiatric
disorders. Besides the possibility of mild drug dependence, caffeine may bring benefits that contribute to its widespread use.
These benefits seem to be related to adaptation of mental energy to the context by increasing alertness, attention, and cognitive
function (more evident in longer or more difficult tasks or situations of low arousal) and by elevating mood. Accordingly,
moderate caffeine intake (<6 cups/day) has been associated with less depressive symptoms, fewer cognitive failures, and lower
risk of suicide. However, its putative therapeutic effects on depression and ADHD have been insufficiently studied. Conversely,
in rare cases high doses of caffeine caninduce psychotic and manic symptoms, and more commonly, anxiety. Patients with panic
disorder and performance social anxiety disorder seem to be particularly sensitive to the anxiogenic effects of caffeine, whereas
preliminary data suggests that it may be effective for some patients with obsessive compulsive disorder (OCD). The threshold
for the anxiogenic effect of caffeine is influenced by a polymorphism of the A2A receptor. In summary, caffeine can be regarded
as a pharmacological tool to increase energy and effortful behavior in daily activities. More populational (cross-sectional and
prospective) and experimental studies are necessary to establish the role of caffeine intake in psychiatric disorders, especially its
putative efficacy on depressive mood and cognitive/attentional disorders.
Keywords: Attention, anxiety, caffeine, cognition, depression, mood
INTRODUCTION
Caffeine is so widely consumed in the world that
little attention is paid to the fact that about 80% of the
population voluntarily and routinely manipulate their
mind pharmacologically. Such widespread use sug-
gests that caffeine has at least some reinforcing effect
and that it is well tolerated in habitual doses. Also,
being readily available at a low cost and with high so-
cial acceptance and incentive, at least compared to oth-
er available drugs, individuals can easily adjust their
own dose, time of administration, and dose intervals of
∗Correspondenceto:DiogoR.Lara,FaculdadedeBiociˆencias–
PUCRS, Av. Ipiranga, 6681 – Pd12A, Porto Alegre, RS, Brazil
90619-900. Fax: +55 51 33203612; E-mail: drlara@pucrs.br.
caffeine intake accordingto the perceived benefits and
side effects of each dose.
Caffeine can be obtained from coffee, tea, ener-
gy drinks, soft drinks, chocolate, and over-the-counter
medications. Although many other compounds are
present, caffeine seems to be the most important men-
tally active substance in them [1,2]. For this reason,
coffee consumptionwill be regardedas a proxy for caf-
feine intake in this review. Studies in which caffeine
was acutely administered at much higher doses than
routine use (i.e., over 300 mg), will receive lower em-
phasis, since regular caffeinated drinks have between
40 and 150 mg per serving, although the amount of
coffee (and caffeine) per serving may be getting higher
in some countries [3].
Even at somewhat larger doses, the effects of caf-
feine are ascribed to its antagonistic properties at A1
ISSN 1387-2877/10/$27.50 2010 – IOS Press and the authors. All rights reserved

S240 D.R. Lara / Caffeine and Psychiatry
and A2A adenosine receptors [4,5]. However, both
A1 and A2A receptors interact with other neurotrans-
mitters and proteins. Of particular relevance for this
review, antagonism of A2A receptors increases neuro-
transmission through dopamine D2 receptors, and an-
tagonism of A1 receptors interacts with D1 receptors
and regulates the release of neurotransmitters such as
dopamine, glutamate, and acetylcholine [4,5].
The objective of this article is to review the effects
of caffeine on mood, cognition, and behavior of nor-
mal volunteers and in patients with different psychi-
atric disorders. This was not a systematic review and
articles published in the last 10 years were emphasized.
The role of adenosine in psychiatric disorders and the
effects of specific adenosine antagonists will not be the
focus of this review and can be found elsewhere [6,
7]. As a warning note, psychiatric disorders have not
been validated as distinct or categorical disorders, i.e.
they are often “comorbid”, can be regarded as the ex-
treme of dimensional features, and may share genet-
ic and environmental risk factors [8]. This scenario
arises from a diagnostic strategy based exclusively on
symptoms, the lack of specific diagnostic markers, and
a fragmented view of the mindthat disregards the close
interactions between personality, mood, behavior, and
cognition. However, categorical concepts of such dis-
orders as in ICD10 and DSM-IV are adopted in prac-
tice and in the scientific literature, so both dimensional
and categorical approaches will be considered in this
review.
GENERAL PSYCHOTROPICEFFECTS OF
CAFFEINE
Caffeine has “mental activating” properties, increas-
ingalertness and energy andreducingsleepinessand fa-
tigue (for reviews see [1,4,9]). These effects contribute
to increased performance in some contexts, being par-
ticularly apparent in situations of low alertness, such as
early morning, sleep deprivation, and when sustained
performance is demanded.
At higher doses, especially in sensitive individuals,
caffeine can induce symptoms of a condition called
“caffeinism” such as anxiety, restlessness, nervousness,
dysphoria, insomnia, excitement, psychomotor agita-
tion, and rambling flow of thought and speech [10,11],
mimicking a clinical picture known as mixed mood
state. On the other hand, caffeine withdrawal may
cause headache, fatigue or drowsiness, anxiety, and de-
pressive symptoms that peak 1–2 days after cessation
of intake and may persist for a week [12,13]. Some in-
dividuals show clear caffeine dependenceas evidenced
by withdrawal symptoms, persistent desire or unsuc-
cessful efforts to cut down or control use, and toler-
ance [14]. Abstinence is accompanied by increased
cerebral blood velocity and increased EEG theta and
decreased beta 2 power [15]. Thus, caffeine has mild
to moderate reinforcing effects and has a “therapeutic
window” of psychostimulant properties that may bring
about some benefit. In contrast to other drugs with
dependence potential, caffeine is clearly devoid of im-
portant negative consequences on health, performance,
and social adjustment [16,17]. Specifically for mental
health, in the general population caffeine intake was
moderately associated with risk for a wide range of
psychiatric and substance use disorders, but not as a
causal factor [17]. Familial factors, likely in part ge-
netic, seem to predispose to both caffeine intake and
the risk for psychiatric disorders.
Of note, positive effects of caffeine are highlighted
when the study design favors the reversal of short term
withdrawal, which has not been consistently controlled
for in many studies [18]. Some studies with low doses
of caffeine (50–100 mg) suggest that most effects are
due to withdrawal reversion in regular users [19,20].
However, other studies in volunteers without caffeine
withdrawal, either by long term abstinence or ongoing
caffeine use, showed significant effects of caffeine on
performance, alertness, and mood [21–23]. Moreover,
a recent study [24] found that in light, nondependent
caffeine users (mean 116 mg/week) caffeine produced
increased energy,vigour, and arousal and less fatigue at
150 mg, but not 50 mg. Anxiety increased with 450 mg
but not with 150 mg or 50 mg. Caffeine also failed
to produce reinforcing effects of “liking” and “wanting
more” at any dose, contrary to d-amphetamine.
The effects of caffeine have mostly been studied us-
ing a single large dose, which contrasts with repeated
use of smaller doses over a longer time period. How-
ever,Brice and Smith [25,26] found that the improved
mood and enhanced performanceafter a single dose of
200 mg were also present with four doses of 65 mg
given at hourly intervals.
SPECIFIC EFFECTS OF CAFFEINE
Mood and mood disorders
Healthy and pathological mood involve internalized
symptoms such as sadness, anhedonia, apathy, and

D.R. Lara / Caffeine and Psychiatry S241
anxiety as well as externalized manifestations such as
overactivity, euphoria, irritability, and high pleasure-
oriented behavior. Overall, caffeine has been shown
both to induce mood changes, particularly at higher
doses, and to protect from mood symptoms at moderate
doses.
Caffeine has been classically regardedas an inducer
of anxiety at higher doses, typically over 300 mg [10,
24,27,28], but the consumption of caffeine is poorly
correlated with anxiety oranxiety traits [17,29,30]. Be-
sides dosage, the anxiogenic effect of caffeine is influ-
enced by individual factors, such as preference for caf-
feine, presence of some anxiety disorders, and genetic
background.
Regarding preference, individuals who prefer caf-
feine pills over placebo tend to report stimulant and
"positive" mood effects of caffeine, whereas those that
choose placebo tend to ascribe aversive effects after
caffeine (increased anxiety and dysphoria) [31]. Sim-
ilarly, caffeine only had significant reinforcing, mood,
and psychomotor performance effects in caffeine con-
sumers, although caffeine increased self-rated alertness
of both caffeine consumers and non-consumers [32].
Haskell et al. [33] found that caffeine tended to ben-
efit consumers’ mood more, while improving perfor-
mance more in non-consumers. Doses of 50–100 mg
of caffeine are usually sufficient to induce mood effects
and in some individuals the effect of 20–30 mg is still
clearly noticeable [34].
The presence of specific anxiety disorders influences
the perceived effects of caffeine. Earlier studies have
found higher sensitivity to anxiogenic effects of high
dose caffeine (typically higher than 400 mg) in pa-
tients with panic disorder [35,36], generalized anxiety
disorder [37], and to a lesser extent in depressed pa-
tients [38]. More recent studies extended these find-
ings to patients with performance social anxiety dis-
order, but not generalized social anxiety disorder [39],
and to first degree relatives of patients with panic dis-
order [40]. Also, patients with panic disorder who de-
velop caffeine-induced panic attacks have significantly
higher non-specific general psychopathology [41]. In
contrast, a recent randomized controlled trial showed
that caffeine led to clinical response in 7 out of 12
patients with treatment-resistant obsessive compulsive
disorder (OCD) and a 55% reduction of symptom
score in these responders, which was comparable to
d-amphetamine [42]. It should be noted that OCD, al-
though classified as an anxiety disorder, is more relat-
ed to control of thought and behavior than to fear and
worry, as other anxiety disorders.
The genetic basis for the anxiogenic effects of caf-
feine has been investigated. Individuals with the
1976T/T genotypes for A2A adenosine receptors re-
ported greater increases in anxiety after caffeine ad-
ministration than the other genotypic groups [43,44].
This genotype (also referred to as 1083 C>T) was as-
sociated with less caffeine intake [45] as well as with
blood-injury phobia [46] and panic disorder in western
population [47,48], but not in Asians [49,50].
Thus, vulnerability to marked anxiogenic effects of
caffeine seems to be restricted to some individualswith
at least a predisposition for specific anxiety disorders,
and is influenced by genetic and ethnic factors and
higher levels of psychopathology.
Conversely, caffeine intake at low doses can also re-
duce anxiety and elevate mood in humans [33,51–54].
Caffeine cessation over a couple of days may increase
anxiety and depression scores in about 10% of volun-
teers with a moderate daily intake (mean 235 mg per
day), and lead to headache in about 50% of volun-
teers [55]. Also, in one of the few population studies
on regular caffeine intake, Smith [56] has shown that
consumption of caffeine, even at low doses, was asso-
ciated with a reduced risk of depression (OR =0.32,
CI 0.2–0.5; OR =0.18, CI 0.1–0.3 and OR =0.12,
CI 0.1–0.2 for 1–140 mg/day, 141–260 mg/day and >
260 mg/day, respectively, compared to those with no
caffeine intake). This study was conducted in a non-
working population, which may have higher baseline
levels of depression, probably making it easier to iden-
tify this effect compared to a working population.
Regarding suicide, uses of coffee and tea were asso-
ciated with a lower risk at higher intake (relative risk
per cup of coffee per day =0.87, 95% confidence in-
terval =0.77 to 0.98) [16]. Also, a significant in-
verse association was reported between moderate cof-
fee drinking (2–6 cups/day) and the risk of suicide [57].
However, another study suggests that caffeine has a J-
shaped relationship with suicide [58]: a similar trend
was found for lower suicide rates at low and moderate
doses but suicide was significantly increased in those
who take 8 or more cups of coffee/day. This pattern
is mimicked by the dose – response trend to improved
performance in those who take around 400 mg caffeine
per day regularly.
Adenosine has been hypothesized to mediate the
rapid onset antidepressant effects of sleep depriva-
tion [59]. If this were the case, caffeine may be delete-
rious to depressed patients undergoing such treatment.
However,caffeine(150mg three times overnight)failed
to affect mood improvement in the next day of sleep

S242 D.R. Lara / Caffeine and Psychiatry
deprivation [60]. The only observed effect was lack of
decreased energy during sleep deprivation, suggesting
that adenosine is not involved in the therapeutic antide-
pressanteffectsof caffeine,and that caffeine intake may
make it easier for patients to undergo the procedure of
depriving from sleep.
A few case reports have also suggestedthat caffeine
can induce mania [61] and that excessive caffeine in-
take may hamper the recoveryof patients with bipolar
disorder or manic-type mood episodes [62–64]. These
observations are in line with both its psychostimulant
and antidepressant effects. Of relevance for mania,
caffeine can increase elation in healthy volunteers at
250 mg and irritability at higher doses (500 mg) [65].
Moreover, highcoffee intake was associated with suici-
dal behavior in patients with bipolar disorder, although
causality cannot be established with the transversal de-
sign of this study [66] and the lack of genetic control, as
performed by Kendler et al. [17]. Expert opinions and
guidelines for the treatment of bipolar disorder recom-
mend discontinuation of caffeine intake as one of the
first steps in the treatment of mania [67,68], although
no systematic study is cited. These are important obser-
vations, but given the widespread use of caffeine by the
general population and patients with psychiatric disor-
ders, these few case reports suggest that problematic
use of caffeine is quite an exception rather than the rule.
Based on the data reviewed here and clinical experi-
ence, the most conservative approach is that high caf-
feine intake should be avoided in patients with bipolar
disorder, especially during manic or mixed episodes,
but complete abstinence may also be detrimental. In
most patients, low to moderate intake of caffeine is
probably not harmful and may play a role against de-
pressive symptoms. However, this topic needs further
study.
In summary, for mood and anxiety disorders, caf-
feine may have beneficial effects for depressive or low
energy states, and may be detrimental for some hyper-
sensitive patients with panic and/or performance anx-
iety disorder, as well as for patients with bipolar dis-
order. However, total abstinence is unlikely to lead to
significant improvement in patients with low to mod-
erate caffeine intake, and may be detrimental to others
with predominant depressive symptomatology.
Psychosis and schizophrenia
Case reports also support the idea that caffeine may
induce psychotic symptoms in some individuals with-
out previous psychotic disorders [69–71]. Howev-
er, this may result from an exacerbation of underly-
ing paranoid traits. Also, reduction of caffeine in-
take has been associated with symptom improvement
in some cases of patients with psychotic disorders [71–
73], and in a hospital setting with patients suffering
from chronic schizophrenia [74]. However, other stud-
ies did not find significant differences when caffeine
intake was restricted in patients with schizophrenia [75,
76]. Lucas et al. [77] tested patients with chronic
schizophrenia with 10 mg/kg, which led to increased
psychosis, thought disorder, unusual thought content,
and euphoria-activation. In these patients, anxiety was
not increased by caffeine, which may be particular to
patients with schizophrenia, but may also be related to
concurrent treatment with antipsychotics.
Despite this suspected induction or exacerbation of
psychotic symptoms, some reports have shown that caf-
feine intake may be higher in patients with schizophre-
nia, or at least in a subgroup of them[75,78]. This high
intake is at least partially associated with the excessive
cigarette smoking often observed in these patients [79,
80]. The role of these drugs in schizophrenia remains
to be elucidated. One hypothesis is that nicotine may
be used as self-medication since it corrects sensory
gating deficits found in schizophrenia [81]. However,
the xanthines, theophylline and caffeine, were found
to induce such alterations in normal volunteers [82,
83]. Other possibilities to be further studied are that
caffeine may improve negative and cognitive symp-
toms and motor side effects of antipsychotics, which
may contribute to high intake of caffeine by some pa-
tients with schizophrenia. Interestingly, subchronic
treatment with caffeine attenuates cognitive deficits in-
duced by an NMDA receptor antagonist used to model
schizophrenia in rodents [84], and chronic treatment
with caffeine renders rats less susceptible to motor ef-
fects of a typical antipsychotic [85].
Attention, impulsivity, cognitive performance, and
attention deficit and hyperactivity disorder
ADHD is a heterogeneous syndrome characterized
by inattention, impulsivity, hyperactivity, motivation-
al/effort deficit, executive dysfunction, and impaired
performance that arises during childhood and usual-
ly persists, sometimes at lower levels, during adult-
hood [86]. This disorder involves structural and
functional pathological changes in frontal-subcortical-
cerebellar circuits and monoaminergic alterations [87].
The main pharmacological strategy is the use of the
psychostimulants, such as methylphenidate and am-

D.R. Lara / Caffeine and Psychiatry S243
phetamine derivatives [86]. Thus, in contrast to po-
tentially problematic use of caffeine in subjects with
psychotic, bipolar, and anxiety disorders, caffeine may
have a therapeutic role in ADHD. Since the symp-
toms of ADHD are normally distributed in thepopula-
tion [88], this section discusses the effects of caffeine
on these cognitive and behavioral functionsin both nor-
mal volunteers and patients with ADHD.
Caffeine is often used as a strategy to increase the
ability to sustain attention, particularly in situations of
low arousal or fatigue. The effects of caffeine on atten-
tion and performance have been studied using several
paradigms and protocols.
Caffeine has been repeatedly shown to attenuate per-
formance impairments due to decreases in arousal in-
duced by sleep loss, fatigue, working at night, or by
sedative drugs [89–93]. Furthermore, caffeine can re-
move the impaired performance and negative mood
associated with the common cold [94] and attenuate
memory impairment induced by scopolamine in hu-
mans [95]. In general, effects of small doses of caf-
feine are detected in low alertness paradigms, where-
as more global and positive effects can be observed
with doses of 200–300 mg (1,53,96). Consistent pos-
itive effects of caffeine have been shown in reaction
times and vigilance performance [34,51,97]. Haskell
et al. [33] showed that caffeine enhanced self-reported
alertness and performance in attention and working
memory tasks in both nonconsumers and consumers af-
ter overnight abstinence. Additionally, Christopher et
al. [23] reported that caffeine increased self-rated alert-
ness and decreased reaction times on visual, cognitive,
and verbal reasoning tasks in regularcaffeine users who
were not in withdrawal. Also light, non-dependent caf-
feine users increase vigilance parameters with 150 mg
of caffeine [24]. Addicot and Laurienti [98] showed
that caffeine had a greater effect on mood and choice
reaction time in the abstained state than in the normal
caffeinated state, but caffeine improved selective atten-
tion and memory in both states. Smith [54] found that
caffeinated gum containing 40 mg led to better perfor-
mance, particularly in tasks requiring sustained atten-
tion. These studies suggest that despite the develop-
ment of tolerance and withdrawal reactions to some ex-
tent, caffeine can produce these effects in regular users
without abstinence and in non-regular users.
Caffeine can also influence stimulus processing.
Streufert et al. [99] have shown that caffeine increases
the speed of processing new stimuli, which was lat-
er confirmed [53]. Lorist and Snel [100] have also
shown better target detection and response preparation
by caffeine, whereas Ruijter et al. [101] have demon-
strated that the quantity of information processed is
greater after caffeine. Recently, caffeine was shown
to improve alerting and executive control function in a
dose-response manner, peaking at 200 mg [102]. More
rapid encoding of new informationwas also found with
40 mg caffeinated gum in volunteers with mean daily
consumption of 138 mg [54]. However, caffeine failed
to reduce resistance to distraction [103].
Three important cross-sectional populational studies
evaluated the association between cognitive function-
ing and caffeine intake in real-life situations [56,104,
105]. Jarvis [104] found a dose-response trend to im-
proved performancein simple reaction time, choice re-
action time, incidental verbal memory, and visuospatial
reasoning with higher levels of coffee consumption (P
<0.001in each task). Bestperformancewasassociated
with about 400 mg caffeine per day. For tea consump-
tion the associations were similar but weaker. Interest-
ingly, these results were more apparent in older that in
younger people. Smith [105] studied full time workers
who had a median daily caffeine intake between 120
and 159 mg. Caffeine consumption was significantly
associated with fewer cognitive failures (e.g., forget-
ting where things are, failures of concentration or doing
the wrong thing). Those who had higher caffeine con-
sumption (>than the median) had about half the risk of
self-reporting frequent/very frequent cognitive failures
and accidents at work compared to those with low caf-
feine intake. A similar study was conducted in a non-
working sample and again all caffeine groups showed
around 50% less risk of cognitive failures compared
to those who abstain from caffeine (lowest quartile of
caffeine intake) [105]. Also, the findings extended to
much lower risk of depression, as mentioned above.
These beneficial effects of caffeine did not seem to be
associated with negative health consequences and may
be related or add to the putative neuroprotective action
of caffeine [106] (and companion articles of this issue).
Thus, caffeine consumption is associated with better
cognitive functioning and reduced risk of depression,
and these effects do not seem to undergo significanttol-
erance. However, since these are cross-sectional stud-
ies, two main interpretations are possible: i) caffeine
produces benefits in cognitive functioning and mood,
or ii) those who naturally take more caffeine have bet-
ter functioning, i.e., higher caffeine intake is a behav-
ioral marker of personality traits associated with better
cognitive performance or healthier mood.
Regarding personality traits, high consumers of caf-
feine are more sensation-seekers and impulsive accord-

S244 D.R. Lara / Caffeine and Psychiatry
ing to two studies [30,107], whereas impulsive indi-
viduals, particularly men, were found to have higher
caffeine intake [108]. Two other studies failed to find
correlations of caffeine intake with personality mea-
sures [109,110]. Importantly, these results go against
the interpretation that caffeine is a behavioral marker
of traits associated with better performance or more
elevated mood, since impulsivity would increase the
chance of making cognitive mistakes, and it is not
particularly associated with better mood. Also, harm
avoidance and self-directedness, which are associat-
ed with mood, performance and adjustment (i.e., high
harm avoidance and low self-directedness are consis-
tently found in subjects with mood disorders [111,
112]), were not different among low, moderate, and
high caffeine consumers [30]. Thus, the interpretation
that caffeine produces better functioning is the most
likely based on current data. Another possibility is that
higher caffeine intake may be a self-medication strate-
gy in some impulsive individuals. Indeed, caffeine fa-
cilitates the performance of impulsive individuals and
impairs the performance of non-impulsive individuals
taking complex cognitive tests in the morning, but not
in the evening [113,114].
Few studies with a small number of patients and
using far from ideal protocols have tested the effica-
cy of caffeine in children with minimal brain dysfunc-
tion, a diagnosis that nowadays corresponds to AD-
HD [115–120]. In comparison to methylphenidate and
d-amphetamine, caffeine was in general less effective.
However, some ADHD patients responded well or par-
ticularly well to caffeine [119,120], and addition of
caffeine to methylphenidate was also beneficial [117].
Unfortunately, clinical trials with larger and broad-
er samples (e.g. adults), wide dosage range, or flexi-
ble dose protocols are yet to be conducted. Interest-
ingly, caffeine improves cognitive performance in an
animal model of ADHD [121] and promotes effort-
related behavior in animals treated with dopamine an-
tagonists [122]. Therefore, based on observational and
experimental studies, caffeine is a candidate treatment
for ADHD. If proven effective, caffeine has the ad-
vantage of being easily available without the level of
abuse potential of methylphenidate and amphetamine
derivatives.
MECHANISMS OF ACTION OF CAFFEINE
WITH REFERENCE TO PSYCHIATRIC
DISORDERS
The primary action of caffeine is to block adenosine
A1 and A2A receptors. However, as adenosine is a
neuromodulator and affects several other neurotrans-
mitters, some indirect actions of caffeine are of partic-
ular relevanceto understand its effects on subjects with
the psychiatric disorders discussed in this paper.
One pivotal interaction of caffeine is with the
dopaminergic system (reviewed in [5,123]). There are
multipleand functionally different antagonistic interac-
tions between adenosine A2A and dopamine D2 recep-
tors, both post- and presynaptically, in such a manner
that activation of A2A receptors reduces D2 receptor
recognition, coupling, and signaling. This interaction
results in reduced reward functions mediated via the
indirect pathway,and lower glutamate drive to the pre-
frontal and motor areas of the cerebral cortex. There
are also relevant antagonistic A1–D1 receptor interac-
tions at the receptor and second messenger levels in the
basal ganglia and prefrontal cortex.
Reduced activity of dopaminergic system is thought
to play a central role in depression [124] and AD-
HD [86,87]. In contrast, higher dopamine activity
leads to increased salience perception, which proba-
bly contributes to bipolar mania [125] and may be the
final common pathway for psychosis [126]. Accord-
ingly, antidepressants and psychostimulants such as
methylphenidate increase dopaminergicactivity [86,?],
whereas D2 receptor antagonists exert antimanic and
antipsychotic effects [126]. Thus, increased dopamin-
ergic activity inducedby caffeine can have positive ef-
fects on mood, cognition, effort-related behavior, and
executive functions, but this effect may, on the other
hand, promote mania (or mood instability) and psy-
chosis.
Other putatively important effects of caffeine for
mood and attention are the increase in noradrenaline,
acetylcholine, and serotonin turnover,and noradrener-
gic and cholinergic firing (reviewed in [4]), but such
interactions need further studies.
CONCLUDING REMARKS
Caffeine acts on two receptors with contrasting ac-
tions, which exert neuromodulating and homeostatic
effects. Thus, there may be optimal levels of adenosin-
ergic activity that can be influenced or manipulated by
the A1 and A2A receptor antagonism of caffeine, de-
pending on the context. The similarity of symptoms
present with high dose caffeine and caffeine withdraw-
al reinforce this notion of an optimum activity level,
which may be reached by adaptation of the adenosin-
ergic system in different situations. Clinically, a sim-

D.R. Lara / Caffeine and Psychiatry S245
ilar phenomena under “opposite” circumstances oc-
curs comparing two psychiatric conditions: i) mixed
mood episodes (mood instability, dysphoria, poor con-
centration, distractibility, insomnia, irritability, agita-
tion), which is compatible with excessive monoamin-
ergic tone since improvementis achieved with atypical
antipsychotics by D2 receptor blockade, and ii) AD-
HD (hyperactivity, distractibility, agitation, inattention,
dysphoria, impulsivity, sleep problems), which may re-
flect deficient monoaminergic tone since psychostimu-
lants are effectiveto treat this condition.
Since caffeine is so easily available, most individuals
tend to naturally select doses that do not produce unfa-
vorable subjectiveand somatic effects, or performance
impairment. In other words, individuals have intrinsic
thresholds that may limit or prevent the repeated intake
of more than optimal doses of caffeine, which may limit
the emergence of anxiety, paranoid symptoms, or mood
instability. On the other hand, the reinforcing effects
of caffeine and emergence of withdrawal symptoms
induce repeated intake.
Besides the possible induction of mild drug depen-
dence, caffeine may bring some kind of benefit that
contributes to its widespread use. These benefits seem
to be related to adaptation of mental energy to the
context by increasing alertness, attention, and cogni-
tive function (more evident in longer or more difficult
tasks or situations of low arousal), and by elevating
mood. Thus, caffeine can be regarded as a pharmaco-
logical tool to increase effortful behaviorin daily activ-
ities. More populational (cross-sectional and prospec-
tive) and experimental studies are necessary to estab-
lish the role of caffeine intake in psychiatric disorders,
especially its putative efficacy on depressive mood and
cognitive/attentional disorders.
DISCLOSURE STATEMENT
The author’s disclosures available online (http://
www.j-alz.com/disclosures/view.php?id=218).
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