Current Nutrition & Food Science, 2010, 6, 13-18 13
1573-4013/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
Polyphenols: A Potential New Strategy for the Prevention and Treatment
of Anxiety and Depression
Department Environment and Agro-Biotechnologies, Centre de Recherche Public - Gabriel Lippmann, 41 rue du Brill,
4422 Belvaux, Luxembourg
Abstract: Following recent evidence that disturbances in oxidative metabolism are involved in anxiety disorders, high
anxiety levels and depression, the use of antioxidants has been proposed as a novel approach for the prevention or
treatment of these conditions. Polyphenols are naturally-occurring antioxidant substances which can have pharma-
cological actions on the central nervous system. This mini-review aims to examine the current evidence for the potential
use of dietary polyphenols as neuroprotective agents to reduce anxiety and to manage depression. I will outline recent
findings which demonstrate that polyphenols have anti-anxiety effects at higher doses (300/60/30/20 mg/kg body weight)
as well as at lower doses (2-4 mg/kg); this can be compared to conventional anxiolytics, which only have anxiolytic
effects at lower doses (1-5 mg/kg). To circumvent problems associated with polyphenols (e.g., quercetin) having difficulty
crossing the blood-brain barrier and to effectively reduce the active dose, intranasal administration in the form of
liposomes could be an interesting approach. I also suggest that dietary polyphenols could be a new alternative approach to
treat depression, because they exhibit antidepressant activity with relatively lower doses (0.3-2 mg/kg) than commonly-
used antidepressants such as imipramine (10 mg/kg). The polyphenols discussed in this mini-review are found in
vegetables and fruits such as apples, plums, cherries, onions and tea. Therefore, a varied diet that is rich in naturally-
occurring polyphenols could be an effective means to prevent (or delay) anxiety, depression and other diseases linked to
Keywords: Polyphenols, antioxidants, oxidative stress, neuroprotective, anxiety and depression.
In the past decade, increasing evidence has been
presented that links disturbances of oxidative metabolism to
anxiety disorders [1,2], high anxiety levels [3-6] and
depression [7-9]. Anxiety may coexist with depression, in
what is defined in psychiatric nosography as an anxio-
depressive syndrome that makes coping more difficult
[10,11]. Anxiety is a psychological state in which the feeling
of fear is disproportionate to the nature of the threat .
Anxiety is not a unitary phenomenon but can be divided into
various forms including ‘normal’ and ‘pathological’ anxiety
. Anxiety is a normal emotional response to a threat or
potential threat [6,12]. When this aversive emotion is
inappropriate, extreme and persistent, it is classified as
pathological [12,14]. It is estimated that one-eighth of the
total population worldwide suffers from inappropriate
anxiety . Depression is a common mental disorder in
which sufferers exhibit depressed mood, loss of interest or
pleasure, feelings of guilt or low self-worth and disturbed
sleep or appetite . It is estimated that at least 20% of all
individuals suffer from a depressive episode at least once in
their lifetime . Research on anxiety and depression has
predominantly focused on the regulatory systems, including
gamma-aminobutyric acidergic (GABAergic) and serotoni-
nergic systems among others [6,18]. The most popular drugs
*Address correspondence to this author at the Department Environment and
Agro-Biotechnologies, Centre de Recherche Public - Gabriel Lippmann, 41
rue du Brill, 4422 Belvaux, Luxembourg; Tel: + 352-470-261-436;
used to treat anxiety and depression are benzodiazepines
[13,19] and selective serotonin reuptake inhibitors (SSRIs)
[18,20], respectively. Benzodiazepines, agonists of the
benzodiazepine site on GABAA receptors, exert their thera-
peutic effects by potentiating chloride flux through the
GABAA receptor ion channel complex [19,21,22]. Both
classical antidepressants and many of the novel generation of
antidepressants such as SSRIs stabilize the mood of depres-
sive patients by increasing the availability of serotonin,
noradrenalin and/or dopamine in the synaptic cleft [23-25].
However, the recent findings of a link between oxidative
stress and both psychological stress [1-6] and mood
disorders [7-9] have introduced new perspectives for the
prevention and/or treatment of anxiety and depression.
Accordingly, the potential use of antioxidants has emerged
as a novel approach to prevent or treat anxiety and depres-
sion. In support of this approach, some authors have
examined the antioxidant effects of anxiolytic treatments
such as citalopram and other antidepressants [7,26,27].
Additionally, it has been revealed that vitamin E deficiency
in the mouse brain significantly increases both the levels of
central oxidative stress markers and anxiogenic behavior of
mice . Souza et al.  pointed out that imbalanced
nutrition (diet enriched with sucrose) induces brain oxidative
stress and anxious behavior in rats. Recently it has been
demonstrated that mice treated with vitamin C showed an
antidepressant-like effect in the tail suspension test .
Overall, these recent findings raise the possibility that
anxiety and depression could be prevented or treated either
by a diet rich in naturally-occurring antioxidants or by daily
14 Current Nutrition & Food Science, 2010, Vol. 6, No. 1 Jaouad Bouayed
antioxidant supplementation. Polyphenols such as flavonoids
and phenolic acids are well known for their high antioxidant
activity and are the major class of antioxidants derived from
the diet [31-34]. The use of these phytochemical secondary
metabolites could be an interesting approach to prevent and
treat anxiety and depression [19,22,35,36]. These natural
antioxidants have received considerable attention because
they have been reported to exhibit a wide range of beneficial
biological actions, such as antibacterial, antiviral , anti-
inflammatory, antiallergenic [37,38], vasodilatory [37,39],
antimutagenic , antidepressant [35,36] and anti-anxiety
In this mini-review, I present a brief insight into the
metabolism of oxygen and the links between disturbance of
this process and certain diseases. I then highlight the
cytoprotective effects of dietary polyphenols, which may
play a key role in antioxidant compensatory mechanisms in
living organisms. Finally, I examine recent work that
demonstrates the anxiolytic and antidepressant effects of
dietary polyphenols and discuss the underlying mechanisms
of their actions.
THE METABOLISM OF OXYGEN: BENEFICIAL
AND DELETERIOUS EFFECTS
Oxygen is a free biradical because each atom of this
molecule contains one unpaired electron in its external
orbital [43-46]. In vivo, the one electron reduction of oxygen
results in formation of the superoxide radical (O2·), which is
considered to be the precursor of reactive oxygen species
(ROS) [43-47]. Indeed, the superoxide anion (O2·) is the
source of ROS which are either non-radicals (molecules with
no unpaired electrons such as hydrogen peroxide (H2O2),
hypochlorous acid (HOCl), and singlet oxygen (1O2)), or
oxyradicals (free radicals with one unpaired electron, such as
hydroxyl radical (OH·), alkoxyl radical (RO·), and peroxy-
radical (ROO·) among others) [43-47]. The principal cellular
pathways that consume oxygen and are responsible for
generating the largest portion of ROS are: mitochondrial
respiration (in which 85% of oxygen is metabolized), and
processes catalyzed by NAD(P)H oxidase (especially the
oxidative burst stimulated by phagocytosis in immune cells)
and xanthine oxidase [43-48].
In vivo, the antioxidant defense system is divided into
enzymatic antioxidants (including superoxide dismutase,
catalase, glutathione peroxidase, etc) and non-enzymatic
antioxidants (which includes both the endogenous reducers
of cells such as glutathione and uric acid, and also exo-
genous reducers which are provided especially from nutri-
tion such as vitamins, polyunsaturated fatty acids, poly-
phenols and carotenoids) [32,43-48]. In this regard, it is
interesting to note that polyphenols are the major class of
antioxidants derived from the diet .
ROS are well recognized for playing a dual role as both
beneficial and deleterious species [43,45,46]. The beneficial
role of ROS is established when there is a balance between
oxidant production and antioxidant protection [43,45,46].
The balance between antioxidation and oxidation is believed
to be critical to maintain a healthy biological system
[43,45,46]. However, when the ROS concentration exceeds
the antioxidative capacity of an organism, cells enter a state
termed oxidative stress in which the excess ROS induces
oxidative damage of cellular components [6,43-48]. In the
oxidative stress state there are differences in gene expres-
sion, protein conformation and cellular signaling [6,43-48].
For these reasons, disturbances in oxidative metabolism have
been implicated in a large number of acute and chronic
diseases, including cancer, diabetes, male infertility, auto-
immune diseases, atherosclerosis and cardiovascular disor-
ders [6,43-49]. Oxidative stress in the brain may affect
overall brain activity, in particular by causing alterations in
neurotransmission and neuronal function, disruptions in
membrane integrity, and sometimes even neuronal cell death
[6,43,45,46]. As a result, oxidative stress is also known to be
involved in specific diseases of the nervous system, such as
neurodegenerative diseases and neuropsychiatric diseases
such as schizophrenia, depression and anxiety disorders
[6,27,43,45,46]. Overall, it is estimated that oxidative stress
is associated with in excess of 100 human diseases .
Until recently, it was unclear whether oxidative stress is the
pathogenic factor for diseases such as depression and
anxiety, or whether the oxidative imbalances result from the
pathology [6,50]. Nevertheless, the available data are
consistent with the theory that oxidative stress is one of the
causal factors for the genesis of anxiety .
ANTIOXIDANT ACTIVITY OF POLYPHENOLS
Polyphenols are a large class of chemicals that can be
divided into a number of varieties including stilbenes,
lignans and flavonoids [31,51,52]. Certain authors consider
(poly)phenols to be all secondary phytochemicals that have
at least two phenol subunits [51,53]. However, Kim et al.
 define (poly)phenols as all secondary metabolites with
an aromatic benzene ring that is substituted with at least two
hydroxyl groups, including their functional derivatives.
Moreover, in their classification Manach et al.  include
even those phenolic acids that bear only one hydroxyl group
on the aromatic ring and acrylic acid, such as coumaric
acids. It is worth noting that the high antioxidant activity of
polyphenols has been well documented [31-34]. Antioxi-
dants are chemical compounds that detoxify reactive oxygen
species (ROS) (such as superoxide radical (O2·), hydrogen
peroxide (H2O2), hydroxyl radical (OH·), peroxyradical
(ROO·)), and prevent oxidative damage such as lipid
peroxidation, and protein and DNA oxidation [32,43].
Epidemiological and scientific research has identified the
key role of dietary antioxidants for maintaining human
health [54-59]. Epidemiological studies have described the
beneficial effects of consuming fruits and vegetables with
high phenolic content for preventing manifold human
diseases such as cardio- and cerebrovascular diseases [54-56]
and cancer [57-59]. The protective effects provided by fruits
and vegetables against these diseases, which are markedly
associated with oxidative stress, has been attributed to their
antioxidant compounds [60,61]. The main antioxidant
capacity of fruits, vegetables and plants is not only derived
from vitamin C, vitamin E or -carotene, but is also due to
other compounds such as polyphenols . In this regard,
many studies have suggested that polyphenolic compounds
in fruits, vegetables and medicinal plants provide substantial
antioxidant activity. This assumption was based on the direct
and statistically significant relationships found either
Polyphenols Current Nutrition & Food Science, 2010, Vol. 6, No. 1 15
between total phenolic or flavonoid contents and the total
antioxidant capacities of fruits, vegetables and medicinal
plants [33,34,52,63-65]. Chlorogenic acid, quercetin and its
derivatives such as rutin (quercetin 3-rutinoside) are the most
common polyphenols found in fruit and vegetables such as
plums, cherries, apples and onions [31,33,34,41,52,63,65].
Using acellular tests such as a 2-2’-Azino-bis (3ethyl-
benzothiazoline-6-sulfonic acid) (ABTS) test, a 1,1-
diphenyl-2 picrylhydrazyl (DPPH) test or an oxygen radical
absorbance capacity (ORAC) test, it has been demonstrated
that chlorogenic acid, quercetin and rutin possess antiradical
actions [34,65,66]. Using cellular assays, we have
demonstrated that these polyphenols have the capacity to
scavenge ROS and to protect cells against H2O2-induced
oxidative stress [34,41]. In vivo, we have demonstrated that
quercetin fully reverses epirubicin-induced oxidative stress
toxicity in rats . In vivo, it has also been revealed that
rutin prevents oxidative injury in the rat mesenteric
ischemia-reperfusion injury model . In conclusion, there
is good agreement between different researchers that dietary
polyphenols play a key role in antioxidant compensatory
mechanisms and protect against both oxidative stress and
POLYPHENOLS: ANTI-ANXIETY AND ANTI-
Prompted by the link between oxidative stress and
anxiety [3-6], we conducted a study to test the effects of an
antioxidant on emotional stress . We used chlorogenic
acid as the antioxidant model because it is one of the most
abundant polyphenols in the human diet and is found in
apples, plums and cherries (Table 1) [33,34,41,65]. We
found that chlorogenic acid significantly decreased anxiety
in mice, without altering locomotion . The dose-res-
ponse curve of chlorogenic acid appeared to have an inverted
U-shape in the light/dark choice test: 20 mg/kg was effec-
tive, but 2, 10 and 40 mg/kg were not . In psycho-
pharmacology, the dose–response curve is usually explained
by the fact that the drug likely acts on different systems
(stimulant, depressant) with different thresholds of
sensitivity . In the elevated plus maze, we confirmed the
anxiolytic-like effect of the active dose of chlorogenic acid
. Combination of flumazenil (5mg/kg, intraperitoneal
injection), a benzodiazepine receptor antagonist, with chloro-
genic acid (20 mg/kg, intraperitoneal injection) reversed the
anti-anxiety effect of chlorogenic acid. This result suggested
that chlorogenic acid diminishes anxiety in mice by acting as
a benzodiazepine receptor agonist . This result
seemingly disproved our initial hypothesis that the anxiolytic
effect of chlorogenic acid is due to its antioxidant potential.
However, we have concluded that chlorogenic acid possesses
dual effects – cytoprotective and anxiolytic - which may be
beneficial to anxious subjects . It has been demonstrated
that chlorogenic acid is absorbed in the small intestine with
no structural change . This increases the nutritional value
of this polyphenol and suggests that the consumption of
fruits such as apples, plums, cherries, etc should be
promoted. Our findings are in keeping with the results of
Vignes et al. , which demonstrated that polyphenols can
interact with the GABAA receptor. These authors found that
green tea polyphenol ()-epigallocatechinn gallate (EGCG)
(Table 1) can be used as a neuroprotective agent to reduce
anxiety . It is interesting to note that the effective
anxiolytic dose of chlorogenic acid (20 mg/kg) and EGCG
(30 and 60 mg/kg) was higher than that of commonly-used
anxiolytics such as diazepam and chlordiazepoxide (1-5
mg/kg) [41,42]. Priprem et al.  demonstrated that
quercetin is an anxiolytic polyphenol (Table 1). However,
anxiolysis was obtained only after one-week of daily oral
administration of this flavonoid. In addition, the active dose
of quercetin is very high (300mg/ kg/day) compared to
conventional anxiolytics such as diazepam and chlordia-
zepoxide, which are active at lower doses after only one-
hour of oral administration. These results may be explained
by the very low distribution of orally-administered quercetin
to the brain due to its poor absorption, its rapid metabo-
lization and the difficulty with which it penetrates the blood-
Table 1. Dietary Polyphenols: Anxiolytic-like Effects, Antidepressant-like Effects, Side Effects and Dietary Sources
Polyphenols Activity on the Nervous System Side Effects Dietary Source
Chlorogenic acid Anxiolytic-like effects  Many types of fruits and vegetables (apples, plums,
cherries, etc) [31,34]
Rosmarinic acid Anxiolytic-like and antidepressant-
like effects [35,69] Skin of apples 
Caffeic acid Antidepressant-like effects  Many types of fruits and vegetables (apples, plums,
cherries, kiwi, etc) [31,34]
Quercetin Anxiolytic-like effects  Sedative effect  Many types of fruits and vegetables (apples, plums,
onions, broccoli, tea) [31,34,74]
Rutin Antidepressant-like effects  Many types of fruits and vegetables (apples, plums,
cherries, onions, tomato, etc) [31,34,74]
EGCG Anxiolytic-like effects  Sedative and amnesic effects
[42,75] Tea [42,74]
Apigenin Anxiolytic-like effects [19,72] Slight sedative effect [19,72] Parsley and celery 
16 Current Nutrition & Food Science, 2010, Vol. 6, No. 1 Jaouad Bouayed
brain barrier . In order to improve the absorption of
quercetin and reduce both the duration of treatment and the
active dose required to treat anxiety, Priprem et al. 
adopted several methods including intranasal administration
of quercetin in the form of liposomes. Interestingly, they
found that a single dose of intranasally-administered
quercetin elicited an anxiolytic effect. They estimated that
the dose of quercetin in the liposomes was 20 μg; this was
6000 times less than the oral active dose (300 mg/kg) given
to rats . Therefore, the use of liposomes is a potentially
novel strategy with which to facilitate the delivery of
polyphenols across the blood-brain barrier and also to
effectively reduce the active dose. It is important to note here
that previous research has also demonstrated that
polyphenols can have anxiolytic effects at lower doses
(similar to those required by reference anxiolytics)
[19,69,72]. Moreover, some natural flavonoids such as
apigenin (Table 1) also have a selective and relatively mild
affinity for benzodiazepine receptors. These substances have
a pharmacological profile that suggests a partial agonistic
action that may produce the anxiolytic-like effects of
polyphenols, but without the side-effects . At 3 mg/kg,
apigenin exerts its anxiolytic effect in mice without sedation
or myorelaxant effects. However, a 10-fold increase in
dosage of this flavonoid produced slight sedative effects
. Another example of polyphenols that reduce anxiety at
lower doses is rosmarinic acid (Table 1), which is a natural
polyphenol antioxidant found in apple skins and in many
plants such as Melissa officinalis [69,73]. At lower doses (2-
4 mg/kg), Pereira et al.  showed that rosmarinic acid
disinhibited behavior towards the aversive spaces of the
elevated plus maze in rats. The dose–response curve for the
anxiolytic-like effects of rosmarinic acid is an inverted U-
shape; this suggests that it likely acts on different systems
(stimulant, depressant) with different thresholds of
sensitivity. In support of this, at a 8 mg/kg dose, Pereira et
al.  found that rosmarinic acid has psychostimulative
effects. Using a mouse model , it has been demonstrated
that rosmarinic acid (2 mg/kg) significantly decreased
immobility behavior in the forced swimming test. These
results suggest that rosmarinic acid has antidepressant-like
effects . These authors also found that caffeic acid (4
mg/kg) (Table 1), which is a major metabolite of rosmarinic
acid, significantly increased the anti-resignation behavior of
mice in the forced swimming test, thus suggesting anti-
depressant like effects of this polyphenol . They found
that neither caffeic acid nor rosmarinic acid affected the
uptake of monoamines to synaptosomes or the activity of
mitochondrial monoamine oxidase in the mouse brain. This
suggested that both phenolic acids may produce antide-
pressive-like activity via some mechanism(s) other than the
inhibition of monoamine transporters and monoamine
oxidase . Using the tail suspension test (another beha-
vioral model of depression), it was revealed that rutin (0.3-3
mg/kg, per os) (Table 1) significantly decreased the duration
of immobility behavior of mice; this suggested anti-
depressant like effects of this polyphenol . These authors
examined the mechanism of action of rutin and found that it
likely exerts its an tidepressant-like effect by increasing the
availability of serotonin and noradrenaline in the synaptic
cleft . It is important to note that in contrast to reference
antidepressants (e.g., imipramine or fluoxetine) which are
active at higher doses ( 10 mg/kg, intraperitoneal injection),
the polyphenols rutin, caffeic acid and rosmarinic acid are
active at relatively low doses. As a consequence, these
phenolic compounds could be an interesting approach for the
treatment of depression.
Polyphenols are interesting naturally-occurring anti-
oxidant substances that can exert pharmacological effects on
the central nervous system (CNS) [35,36,41,69,71]. Poly-
phenols that have partial agonistic properties at benzo-
diazepine receptors may be promising anxiolytic agents due
to the absence of side effects such as dependency, which are
a feature of full agonists such as benzodiazepines . The
intranasal administration of polyphenols in the form of
liposomes  could be an effective strategy both to
facilitate the movement of these substances across the blood-
brain barrier and to effectively reduce the activ e dose. As
some polyphenols have been shown to possess antide-
pressant-like effects [35,36] at lower doses than reference
antidepressants, they can be used to stabilize the mood of
depressive patients. Finally, a varied diet that is rich in natu-
rally-occurring polyphenols could be a good means of pre-
venting (or delaying) anxiety, depression and other diseases
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Received: October 7, 2009 Revised: December 3, 2009 Accepted: January 5, 2010