Hindawi

BioMed Research International

Volume 2017, Article ID 6596241, 11 pages
https://doi.org/10.1155/2017/6596241

Review Article
Therapeutic Effects of Phytochemicals and Medicinal
Herbs on Depression

Gihyun Lee1,2 and Hyunsu Bae1

1
Department of Physiology, College of Korean Medicine, Kyung Hee University, 26 Kyunghee-daero, Dongdaemun-gu,
Seoul 02447, Republic of Korea
2
Department of Research and Development, National Development Institute of Korean Medicine, 94 Hwarang-ro,
Gyeongsan-si, Gyeongsangbuk-do 38540, Republic of Korea

Correspondence should be addressed to Hyunsu Bae; hbae@khu.ac.kr

Received 14 December 2016; Revised 22 March 2017; Accepted 4 April 2017; Published 19 April 2017

Academic Editor: Gail B. Mahady

Copyright © 2017 Gihyun Lee and Hyunsu Bae. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Depression is a recurrent, common, and potentially life-threatening psychiatric disease related to multiple assignable
causes. Although conventional antidepressant therapy can help relieve symptoms of depression and prevent relapse of the illness,
complementary therapies are required due to disadvantage of the current therapy such as adverse effects. Moreover, a number of
studies have researched adjunctive therapeutic approaches to improve outcomes for depression patients. Purpose. One potential
complementary method with conventional antidepressants involves the use of medicinal herbs and phytochemicals that provide
therapeutic benefits. Studies have revealed beneficial effects of medical herbs and phytochemicals on depression and their central
nervous system mechanism. Here, we summarize the current knowledge of the therapeutic benefits of phytochemicals and
medicinal herbs against depression and describe their detailed mechanisms. Sections. There are two sections, phytochemicals against
depression and medical herbs against depression, in this review. Conclusion. Use of phytomedicine may be an alternative option for
the treatment of depression in case conventional drugs are not applicable due to their side effects, low effectiveness, or inaccessibility.
However, the efficacy and safety of these phytomedicine treatments for depression have to be supported by clinical studies.

1. Introduction childhood adversity may contribute to the disease, especially

if epigenetic changes are involved [4, 5]. Structural and func-
Depression is a recurrent, chronic, and incapacitating psy- tional brain abnormalities seem to be related with abnormal
chiatric ailment connected to significant mortality and mor- function of the hypothalamic–pituitary–adrenal axis, low
bidity [1]. This life-threatening psychic disorder is one of the levels of brain-derived neurotrophic factor, and glutamate
most crucial reasons of disability in adults. The incidence of mediated toxicity [6].
depression is about 3–10% in general; however, it is much There are three major categories in the conventional phar-
higher in patients with chronic disorders, ranging between macological agents for the treatment of depression: the mo-
22 and 46% [2]. Although the exact cause of depression is noamine oxidase (MAO) inhibitors, the tricyclic antidepress-
not known, it is thought to be influenced by the complex ants, and the second-generation antidepressants. MAO in-
interactions of several genetic factors and subsequent wide hibitors are chemicals that inhibit the activity of the mono-
exposure to environmental variables throughout lifetime. amine oxidase enzyme family. MAO inhibitors including tran-
Researchers have been showing that psychological, genetic, ylcypromine, isocarboxazid, phenelzine, and moclobemide
and environmental factors remarkably increase the risk of are often used as first-line therapy [7]. The MAO inhibitors
developing this illness. The risk of this disease involves block norepinephrine and serotonin transporter, which enhan-
trauma, stress, and viral infections [3]. Environment-gene ces their synaptic c levels and thus increases neurotransmis-
interplays seem to forecast a person’s risk for the disease sion [8]. Recently, tricyclic antidepressants are being increas-
better than environment or genes alone. In addition, the ingly replaced by new antidepressants, which have fewer
2 BioMed Research International

adverse effects. The new second-generation antidepressants to be mediated by the dopaminergic brain pathways in
include the norepinephrine reuptake inhibitors, the select- mice [19]. Zotti et al. showed that carvacrol administration
ive serotonin reuptake inhibitors, and the serotonin–norep- (12.5 mg/kg, by mouth [PO] for 7 days) can raise 5-HT and
inephrine reuptake inhibitors. Despite the development of dopamine ranges in the hippocampus and prefrontal cortex
those conventional drugs, depression treatment still fails to [20].
lead clinical remission in lots of cases [9]. It is explained by
the number of interconnected systems related to depression. 2.2. Curcumin. Curcumin is a key active constituent of Cur-
Moreover, many patients still display intolerant or refractory cuma longa. This yellow natural phenol has been used histor-
responses with these drugs [10]. Indeed, use of these agents ically in Oriental medicine; its potential medicinal properties
is limited by unexpected side effects and some of them show are under investigation [21]. Curcumin oral administration
contradictive outcomes [11, 12]. Adverse effect of antidepres- exhibited low levels in tissues and plasma, rapid metabolism,
sant drugs involves anxiety, diaphoresis, tachycardia, tremor, and extensive rapid excretion [22]. Insolubility in water and
sedation, insomnia, serotonin syndrome, parkinsonism, pos- nonabsorption are potential factors which limit the bioa-
tural hypotension, blurred vision, and so forth [13, 14]. vailability of curcumin; therefore multiple approaches to
Because of these, many studies have investigated alterna- increase curcumin bioavailability are ongoing with the use
tive curative approaches that improve clinical results against of absorption factors, a structural analogue, liposomes, or
depression. Phytomedicine is one of the major comple- nanomaterials [23]. Antidepressant benefit of curcumin sup-
mentary remedies with conventional drugs. Some phyto- plement has been proven in various murine models. In rats,
chemicals/medical herbs have been examined for depression curcumin administration (1.25–10 mg/kg, PO for 14 days)
care and there has been a material progress. We conducted improved damage in step-down passive avoidance and behav-
an open-ended, English restricted search of MEDLINE
ioral abnormalities in the open field. Curcumin treatment, in
(Pubmed) and Scopus for all available articles up until August
addition, decreased the immobility time in the forced swim-
31, 2016, using terms pertaining to phytomedicine, phyto-
ming test and completely improved the bilateral olfactory
chemical, herb, depression, and major depressive disorder.
In this review, we summarize the current knowledge of the bulbectomy-induced alteration of 5-HT, noradrenaline, and
phytochemicals/herbs and how they can improve symptoms dopamine in the hippocampus [24]. Kulkarni et al. demon-
of depression and reduce its occurrence. We also provide their strated that curcumin (20 and 40 mg/kg, intraperitoneal
mechanisms of actions. injection [IJ]) administration increases 5-HT level in mice
and the antidepressant effect of curcumin can be increased
by various kinds of antidepressants including bupropion,
2. Phytochemicals against Depression fluoxetine, and venlafaxine when given jointly [25]. They also
Phytochemicals derived from herbs are known to decrease showed that this phytochemical can restore biochemical and
the risk of some severe disorders including autoimmune and behavioral changes induced by the chronic stress [26]. Wang
cardiovascular diseases as well as neurodegenerative diseases. et al. also examined that the antidepressant benefit of cur-
Indeed, popular polyphenols such as curcumin, ferulic acid, cumin (10 mg/kg, PO) involves 5-HT receptors, specifically
proanthocyanidin, quercetin, and resveratrol have shown 5-HT1A/1B and 5-HT2C subtypes [27]. Xu et al. again showed
potent anti-inflammatory and antioxidant properties. These that curcumin (10 and 20 mg/kg, PO) can reverse 5-HT1A
phytochemicals repeatedly have demonstrated their neuro- mRNA alteration in rat hippocampus [28]. Additionally,
protective effects, strongly suggesting that they can improve Hurley et al. demonstrated that the antidepressant action
the symptoms of depression. The antidepressant activity of of curcumin may be related to the increase of hippocampal
these phytochemicals is detailed in Table 1. brain-derived neurotrophic factor closely implicated in the
pathophysiology of depression [29].
2.1. Carvacrol. Carvacrol is a monoterpenic phenol isolated
from aromatic herbs including oregano and thyme. This 2.3. Ferulic Acid. Ferulic acid is phytochemical that is known
aromatic phytochemical has anti-inflammatory, analgesic, to have powerful antioxidant capacity [30].
antiarthritic, antiallergic, anticarcinogenic, antidiabetic, car- This compound is derived from phenylalanine, which is
dioprotective, gastroprotective, hepatoprotective, and neu- converted to 4-hydroxycinnamic acid and then caffeic acid
roprotective properties [15]. This monoterpenoid phenol and has shown various medicinal actions including anti-
regulates human ion channels transient receptor potential inflammatory, antitumor, antidiabetic, and neuroprotective
V3 and A1 causing a sensation of warmth [16]. It is also properties [31–34]. Yabe et al. found that oral administration
known that carvacrol can activate PPAR and suppress COX- of ferulic acid (100 and 250 mg/kg) can mitigate stress-
2 mediated inflammation [17]. Dong et al. demonstrated that induced abnormal behavior in mouse depression model.
enzyme cytochrome P450 2A6 (CYP2A6) is the predominant Moreover, they demonstrated that ferulic acid can enhance
drug-metabolizing enzyme involved in the metabolism of phosphorylation of CREB and brain-derived neurotropic
carvacrol requesting attention when carvacrol is coadminis- factor mRNA level in the hippocampus [35].
trated with other compounds mainly undergoing CYP2A6-
mediated metabolism [18]. Orally administered carvacrol 2.4. L-Theanine. L-Theanine is an amino acid discovered as a
(12.5–50 mg/kg) induces antidepressant effects that seem component of Camellia sinensis (green tea) in 1949. This
BioMed Research International 3

Table 1: Phytochemicals against depression.

Phytochemical Dose Study design Effects and mechanisms Reference

Induce antidepressant effects that seem to be dependent
Oral administration
12.5–50 mg/kg on an interaction with the dopaminergic brain [19]
in mice
pathways
Carvacrol Raise 5-HT and dopamine ranges in the hippocampus
Oral administration and prefrontal cortex
12.5 mg/kg [20]
in rats Influence neuronal activity through modulation of
neurotransmitters
Reduce immobility time in the forced swimming test
Oral administration Reverse bilateral olfactory bulbectomy-induced
1.25–10 mg/kg [24]
in rats hyperactivity in the open field and deficits in step-down
passive avoidance
Intraperitoneal Enhance 5-HT level [25]
20–40 mg/kg
injection in mice Restore biochemical and behavioral changes induced by
Curcumin the chronic stress
[26]
Reverse the decreased immobility period and MAO
activity induced chronic stress
Oral administration Reduce duration of immobility in forced swimming test
10 mg/kg [27]
in mice May be associated with 5-HT1A/1B and 5-HT2C subtypes
Oral administration Attenuate the stress-induced hippocampus 5-HT1A
10–20 mg/kg [28]
in rats mRNA
Attenuate stress-induced behavior
Oral administration
Ferulic acid 100–250 mg/kg Increase CREB phosphorylation and brain-derived [35]
in mice
neurotropic factor mRNA level in the hippocampus
Reduce immobility time in the forced swimming test
Oral administration and tail suspension test without ambulation in the open
L-Theanine 1–20 mg/kg [41]
in mice field test
Antagonize reserpine-induced ptosis and hypothermia
Reduce immobility period in the forced swimming test
Oral administration and tail suspension test
Proanthocyanidin 25–50 mg/kg [46]
in mice Enhance 5-HT levels in hypothalamus, hypothalamus,
and frontal cortex
Oral administration
Quercetin 20–40 mg/kg Prevent hyperactivation of the HPA axis [50]
in mice
Decrease immobility period in the despair tests without
Oral administration influence on locomotor activity
20–80 mg/kg [59]
in mice Enhance 5-HT and noradrenaline concentrations in the
brain
Resveratrol Reverse less weight gain, reduce sucrose preference and
deficits in the shuttle box
Oral administration
40–80 mg/kg Raise 5-HT, dopamine, and noradrenaline [60]
in rats
concentrations in brain
Reduce MAO activity

amino acid has been demonstrated to have various therapeu- receptors and as an agonist of the NMDA receptor [38]. L-
tic benefits including improving concentration and learning Theanine have shown effects in the central nervous system,
ability, enhancing antitumor activity, preventing the vascu- including the potentiation of 𝛾-aminobutyric acid, dopamine,
lar diseases, reducing blood pressure, providing antiobe- and serotonin and inhibition of glutamate reuptake [39].
sity effect, improving the immune system, and displaying With potentiation of 𝛾-aminobutyric acid, the brain’s main
neuroprotection [36]. This behaviourally and physiologically inhibitory transmitter, L-theanine, may act as a mild anxi-
active compound is structurally similar to the excitatory olytic. Gomez-Ramirez et al. demonstrated the effect of L-
neurotransmitter glutamate and, in accordance, binds to theanine on attentional process. L-Theanine influenced con-
glutamate receptors, though with much lower affinity in tinuous processes accountable for maintaining attention over
comparison [37]. Specifically, it binds to ionotropic glutamate a period of difficult work rather than on specific moment-to-
receptors and acts as an antagonist of the AMPA and kainate moment phase deployment processes [40]. Administration
4 BioMed Research International

of L-theanine (1, 4, and 20 mg/kg for 10 days) exhibited activity support the idea that resveratrol interacts with the
an antidepressant action in mice. In addition, L-theanine monoaminergic system for its antidepressant effect [60].
treatment markedly blocked ptosis and hypothermia induced
by reserpine [41]. In the open-label clinical trial, L-theanine 3. Medical Herbs against Depression
administration (250 mg/day for 8 weeks) was safe and man-
ifested various beneficial effects on depressive symptoms, Herbal medicine is the most popular complementary ther-
cognitive impairments, sleep disturbance, and anxiety in apy [61]. Depression has prominent indications for herbal
patients with depression [42]. medicines [62–65] and the majority of people with depression
try complementary medicines [66]. Some medicinal herbs
2.5. Proanthocyanidins. Proanthocyanidins are oligomeric and have improved the symptoms of depression in preclinical
polymeric flavan-3-ols found in various plants including and clinical trials (Table 2). The psychopharmacological
apple, cocoa bean, grape, and tea. Researchers have proven effects of these antidepressant herbs involve regulation of 5-
that these phytochemicals have extensive pharmacological HT/dopamine/noradrenaline reuptake, MAO inhibition, and
properties including cardioprotective, antioxidant effect, and neuroendocrine modulation [67, 68].
antinociceptive effects [43–45]. Xu et al. have demonstrated
that proanthocyanidin (25 and 50 mg/kg PO for 7 days) 3.1. Camellia sinensis (Green Tea). Leaf of Camellia sinensis is
decreases immobility time in both forced swimming and a source of green tea. Green tea has shown anticancer, antifi-
tail suspension tests in mice. In addition, proanthocyanidin brotic properties, anti-inflammatory, and antineurodegener-
treatment increased 5-HT concentrations in hypothalamus, ative activities [69]. Recently, preclinical study demonstrated
hippocampus, and frontal cortex. Authors suggest that the polyphenols (5, 10, and 20 mg/kg PO for 7 days) obtained
antidepressant benefit of proanthocyanidin may be asso- from Camellia sinensis improved depression-like behavior
ciated with the central monoaminergic neurotransmitter and decreased serum level of corticosterone. These results
systems [46]. suggest that green tea polyphenols can regulate the HPA axis
involved in the pathology of depression [70].
2.6. Quercetin. Quercetin is a polyphenolic flavonoid found
in many fruits, vegetables, and medicinal herbs. This fla- 3.2. Crocus sativus (Saffron). Crocus sativus is best known
vonol has been reported to inhibit the oxidation of other as the spice saffron, which is produced from parts of the
molecules by acting as a scavenger of free radicals that are flower. In two randomized controlled trials using saffron
responsible for oxidative chain reactions [47]. Quercetin is a (30 mg/day), patients exhibited remarkable improvement of
nonspecific protein kinase enzyme inhibitor [48] but it depression over placebo on the Hamilton Rating Scale for
activates estrogen receptors [49]. In preclinical studies, quer- Depression [71, 72]. They also reported equivalent effects
cetin (20–40 mg/kg, PO) prevented depression-like behaviors on Hamilton Rating Scale for Depression in three inde-
resulting from hyperactivation of the hypothalamic–pitu- pendent randomized controlled trials comparing saffron to
itary–adrenal (HPA) axis in mice. The effect was comparable imipramine or fluoxetine [73–75]. A limited meta-analysis
with fluoxetine (10–20 mg/kg, IP) [50]. concluded that saffron supplementation can improve symp-
toms in patients with depression [76] and another review lit-
2.7. Resveratrol. Resveratrol is a type of natural phenol found erature indicated that it helps with mild to moderate depres-
in grapes and red wine. In a clinical study with oral adminis- sion [77]. Authors propose that saffron’s antidepressant effects
tration of 500 mg over 13 weeks, resveratrol was measured in potentially are due to its serotonergic, antioxidant, anti-
cerebrospinal fluid [51]. Although 70% of orally administered inflammatory, neuroendocrine, and neuroprotective effects.
resveratrol is absorbed, its bioavailability is around 0.5% A recent double-blind, randomized, and placebo-controlled
because of extensive hepatic glucuronidation and sulfation trial conducted by Mazidi et al. showed that saffron treatment
[52]. One way to overcome this obstacle may be buccal (100 mg/day PO for 12 weeks) had a significant impact in the
delivery absorbed directly via tissues on the inside of the treatment of depression with rare side effects [78].
mouth. When 1 mg of resveratrol in 50 ml 50% alcohol/water
solution was retained in the mouth for 1 minute, 37 ng/ml of 3.3. Echium amoenum (Borage). Echium amoenum is a member
resveratrol was detected in plasma 2 minutes later. This con- of the Borage family that grows in most parts of Europe and
centration could be achieved with 250 mg of resveratrol taken in northern parts of Iran. The flower of Echium amoenum
in a pill form [53]. Its anti-inflammatory and neuroprotective is used in alternative medicine as an antifebrile, as an anti-
effects are proven by various researchers [54–57]. Yáñez inflammatory, as a possible cancer protective, and as well
et al. showed that resveratrol inhibits 5-HT/noradrenaline as an antidepressant agent [79]. To elucidate the effects of
uptake and MAO activity in rats [58]. Moreover, it is Echium amoenum against depression, Sayyah et al. con-
showed that trans-resveratrol (20–80 mg/kg) could provide ducted a preliminary randomized, double-blind clinical trial.
an antidepressant action, with the enhanced levels of 5- Results revealed that aqueous extract of Echium amoenum
HT/noradrenaline in mouse brain [59]. Recently, Yu et (375 mg/day PO) is superior to placebo in improving the
al. also demonstrated that this phytochemical can inhibit Hamilton Rating Scale for Depression at week four of the
chronic stress-induced depression-like behaviors. Enhanced study, although the difference was not significant at week six
levels of 5-HT/dopamine/noradrenaline and decreased MAO (𝑝 = 0.07) [80].
BioMed Research International 5

Table 2: Medical herbs against depression.

Herbs Dose Study design Effects and mechanisms Reference

Decrease immobility in the tail suspension test and
Oral administration
Camellia sinensis 5, 10, and 20 mg/kg forced swimming test [70]
in mice
Modulate the HPA axis
Randomized
30 mg/day controlled clinical Improve the Hamilton Rating Scale for Depression
trials
Crocus sativus [71–75]
Randomized
Improve Beck Depression Inventory and Beck Anxiety
100 mg/day controlled clinical
Inventory Scores with rare side effects
trials
Randomized Improve the Hamilton Rating Scale for Depression at
Echium amoenum 375 mg/day controlled clinical week four of a study, however this result was not [80]
trials maintained at week six
Long-term follow-up
Hypericum
3 × 300 mg/day study involving 426 Prevent relapse after recovery from acute depression [81]
perforatum
patients
16 g containing Improve the Montgomery–Asberg Depression Rating
Randomized
Piper methysticum 250 mg of Scale with no serious adverse effects and no clinical [82]
controlled trials
kavalactones/day hepatotoxicity
Increase hippocampus 5-HT level-induced proliferation
Oral administration
1.5–6 g/kg of neural stem cell, repairing the damaged neuronal [83]
in rats
cells in hippocampus
Revert decreased sucrose intake
Oral administration Reduce moving behavior
Rhodiola rosea 10–20 mg/kg [84]
in rats Minimize weight gain and dysregulation of their
estrous cycle
Randomized Improve overall depression, together with insomnia,
340–680 mg/day controlled phase III emotional instability, and somatization, but not [85]
clinical trial self-esteem with no serious side effects
Inhibit depression-like behaviors in forced swimming
Lavender
Inhalation in rats and elevated plus-maze tests [86]
aromatherapy
Reverse spatial memory deficits
Lavandula Randomized
Reduce stress, anxiety, and depression in pregnant
angustifolia Lavender cream controlled clinical [87]
women
trials
Randomized
Lavender Reduce depressive symptoms
controlled clinical [88–91]
aromatherapy Improve the Edinburgh Postnatal Depression Scale
trials
Oral administration Reverse the decreased sucrose intake and the decreased
4 g/kg [92]
in rats 5-HT1A receptor binding in brain
Oral administration Increase struggling time and first latency time in the
2.1 g/kg [93]
in rats forced swimming test
Nelumbo nucifera Improve the start latency, rearing number, grooming
0–2000 mg/kg for rats time, and decreased visiting counts caused by chronic
Oral administration
0–4000 mg/kg for mild stress in the forced swimming test [94]
in rats or beagle dogs
beagle dogs No toxicity during 28 days of administration in dogs
and 13 weeks of administration in rats

3.4. Hypericum perforatum (St John’s Wort). Hypericum depression while long-term maintenance and tolerability in
perforatum is the most famous herb that has long been continuation were comparable with placebo [81]. Linde et
used to treat depression [95]. A number of clinical stud- al. showed that Hypericum perforatum extract is better than
ies demonstrated that Hypericum perforatum is clinically placebo in depression patients and is as curative as standard
efficacious for depression [96–106]. A long-term follow-up antidepressants but with lesser adverse effects [107]. An
study recruited 426 responders to Hypericum perforatum authoritative systematic review and meta-analysis have come
extract (3 × 300 mg/day) to be assessed for remission rates. to almost the same conclusion [108, 109]. Standardization and
Results showed a beneficial effect of Hypericum perforatum quality, however, prove difficult for Hypericum perforatum, as
extract for prevention from relapse after recovery from acute extracts show diversity of the potential effects due to unequal
6 BioMed Research International

component profiles [110] and some clinical studies fail to properties [121]. Hritcu et al. reported that chronic lavender
support the efficacy of Hypericum perforatum in depression oil exposure markedly inhibited depression-like behaviors
[111, 112]. Moreover, Hypericum perforatum’s reputation has in rats in forced swimming and elevated plus-maze tests
been challenged since it is inducer of the enzyme cytochrome [86]. Hancianu et al. reported neuroprotective benefit of
P450 2C9 (CYP2C9), 2C19 (CYP2C19), 3A4 (CYP3A4), and lavender oil through antioxidative effects in a rat dementia
p-glucoprotein and may thus accelerate the metabolism of model [122]. Kasper and his colleagues have reviewed the
drugs excreted or biotransformed via these pathways [13, data on the effect and tolerability of lavender oil to treat
113]. It was uncovered to stimulate cytochrome P450 enzyme anxiety disorders [123] and the clinical trials examining safety
and thus reduce the plasma level of a wide range of con- and potential for drug interactions of lavender oil as well
ventional drugs including warfarin, voriconazole, verapamil, as its anxiolytic effect and tolerability. In the clinical trials,
talinolol, tacrolimus, simvastatin, quazepam, oral contra- lavender oil was devoid of adverse effects except for mild
ceptives, omeprazole, nifedipine, midazolam, methadone, gastrointestinal symptoms. Moreover, it did not provoke
mephenytoin, ivabradine, irinotecan, indinavir, imatinib, gli- withdrawal symptoms or drug interactions at doses of 80
clazide, fexofenadine, erythromycin, digoxin, debrisoquine, or 160 mg daily [124]. They also investigated the anxiolytic
ciclosporin, chlorzoxazone, atorvastatin, amitriptyline, and efficacy of lavender oil administration for the treatment of
alprazolam [114–116]. anxiety-related restlessness and disturbed sleep. It confirmed
the calming and anxiolytic efficacy of lavender oil through
3.5. Piper methysticum (Kava). Root of Piper methysticum randomized and placebo-controlled trial confirms [125].
has been used for a long time to make a psychoactive There are also several reports demonstrating positive effect of
drink in the South Pacific region. These days its extract is lavender in decreasing depressive symptoms. Effati-Daryani
widely consumed as anxiolytic medicine in the whole world, et al. studied the effect of lavender cream on depression in
including Europe and the United States [117]. In 2009, a pregnancy and demonstrated that the cream can be used
3-week double-blind crossover trial involving 60 patients for pregnant women to reduce depression [87]. Lavender
was conducted to examine the anxiolytic and antidepressant oil infusion showed several curative benefits on depression
effects of Piper methysticum extract. The study found that the patients, essentially decreasing mean depression score [88].
aqueous extract of Piper methysticum (16 g containing 250 mg Lavender aromatherapy for 4 weeks improved the Edinburgh
of kavalactones/day) supplies a remarkable improvement of Postnatal Depression Scale in high risk postpartum woman
comorbid depression on the Montgomery–Asberg Depres- [89]. I.-S. Lee and G.-J. Lee also reported that aromatherapy
sion Rating Scale. Importantly, the extract did not show using lavender has a beneficial effect on depression in female
any grave side effects or clinical hepatotoxicity suggesting college students [90]. Complementary therapy of lavender oil
its safety as a drug [82]. However, some manufacturing with imipramine for the treatment of moderate depression
companies withdrew this medicinal plant because of worry in 45 patients led to improved and faster results. Moreover,
about latent hepatotoxicity [118]. the anticholinergic adverse effects of imipramine, including
urinary retention and dry mouth, occurred less often when
imipramine was administered with lavender [91].
3.6. Rhodiola rosea (Rose Root). Rhodiola rosea is a biennial
flowering plant that has been used as a traditional medicine
in some Asian and European countries. Rhodiola rosea has 3.8. Nelumbo nucifera. Fruit of Nelumbo nucifera (Nelumbi-
been referred to as a physical and mental booster [119]. nis semen) has long been used as a natural tranquilizer
In depressive model, Rhodiola rosea extract (1.5–6 g/kg PO) in Asian countries. Our lab and coworkers have revealed
increased 5-HT level in rat hippocampus. In addition, Rho- its psychiatric benefits and mechanism on depression. In a
diola rosea extract induced proliferation of neural stem cell, rat model of depression, Nelumbinis semen showed antide-
repairing the damaged neuronal cells in the hippocampus pressive effects via reversing a decrease in 5-HT1A recep-
[83]. Mattioli et al. showed antidepressant activity of Rhodiola tor binding [92]; interestingly, its therapeutic effect was
rosea extract (10–20 mg/kg, PO for 3 weeks) using behavioral greater than Hypericum perforatum—the most popular nat-
tests in rats. Chronic administration of Rhodiola rosea extract ural antidepressant today [93]. In the forced swimming test,
strongly inhibited chronic mild stress-induced behavioral Nelumbinis semen treatment markedly improved the start
and physiological alterations [84]. van Diermen and his latency, rearing number, and grooming time and decreased
coworkers showed that the antidepressant effect of Rhodiola visiting counts caused by chronic mild stress. During 28 days
rosea resulted from MAO inhibition [120]. A randomized, of administration in dogs and 13 weeks of administration in
double-blind, placebo-controlled, phase III clinical trial using rats, Nelumbinis semen treatment-linked toxicity was not
Rhodiola rosea extract (340–680 mg/day) demonstrated a detected [94].
remarkable recovery in Rhodiola rosea-treated group com-
pared with placebo for mild to moderate depression [85].
4. Conclusion
3.7. Lavandula angustifolia (Lavender). Lavandula angustifo- During the last century, scientific knowledge about psychoac-
lia is a flowering plant in the family Lamiaceae, native to the tive herbs has remarkably progressed. Now it is a common
Mediterranean. The utility of lavender oil involves an antibac- concept that there are powerful neuroprotective phytochem-
terial, antifungal, carminative, sedative, and antidepressant icals in nature. The antidepressive actions of phytochemicals
BioMed Research International 7

and herbs seem to be associated with various mechanisms [4] K. Martinowich and B. Lu, “Interaction between BDNF and
including HPA axis, monoamine neurotransmitters, and neu- serotonin: role in mood disorders,” Neuropsychopharmacology,
rogenesis/neurotrophic factors mechanisms. All these actions vol. 33, no. 1, pp. 73–83, 2008.
appear to involve promotion of the neuronal cell survival and [5] C. Mitchelmore and L. Gede, “Brain derived neurotrophic
differentiation and inhibition of neuronal cell apoptosis. factor: epigenetic regulation in psychiatric disorders,” Brain
As summarized here, numerous preclinical and clinical Research, vol. 1586, pp. 162–172, 2014.
studies have revealed the therapeutic potential of phytochem- [6] M. A. H. Rot, S. J. Mathew, and D. S. Charney, “Neurobiological
icals and medicinal herbs against depression. It is worth mechanisms in major depressive disorder,” Canadian Medical
recommending application of these phytomedicines as an Association Journal, vol. 180, no. 3, pp. 305–313, 2009.
alternative antidepressant for the patients who do not benefit [7] K. I. Shulman, N. Herrmann, and S. E. Walker, “Current place of
or do face side effects from conventional drugs. In addition, monoamine oxidase inhibitors in the treatment of depression,”
these phytomedicines could be useful therapeutic agents for CNS Drugs, vol. 27, no. 10, pp. 789–797, 2013.
the people who live in places where conventional drugs [8] P. K. Gillman, “Tricyclic antidepressant pharmacology and
cannot be supplied to or who cannot afford conventional therapeutic drug interactions updated,” British Journal of Phar-
antidepressants as phytomedicines are considerably safe and macology, vol. 151, no. 6, pp. 737–748, 2007.
affordable. Regardless, caution should be taken when patients [9] C. B. Nemeroff, “Prevalence and management of treatment-
use phytomedicines since not every natural product is safe. In resistant depression,” Journal of Clinical Psychiatry, vol. 68,
addition, positive results or safety in animal models does not supplement 8, pp. 17–25, 2007.
guarantee a clinical efficacy or safety in humans. Moreover, [10] M. H. Trivedi, M. Fava, S. R. Wisniewski et al., “Medication
many medical plants have the potential to interact with augmentation after the failure of SSRIs for depression,” The New
prescribed drugs like in case of Hypericum perforatum [126]. England Journal of Medicine, vol. 354, no. 12, pp. 1243–1252,
Several phytochemicals and medicinal herbs with in vivo and 2006.
in vitro results have still not been investigated in humans. [11] C. B. Baker, M. T. Johnsrud, M. L. Crismon, R. A. Rosenheck,
The efficacy and safety of these phytomedicine treatments for and S. W. Woods, “Quantitative analysis of sponsorship bias
depression have to be supported by clinical studies. Besides, in economic studies of antidepressants,” British Journal of
in vitro and in vivo studies are also needed to discover details Psychiatry, vol. 183, pp. 498–506, 2003.
about their antidepressive mechanisms. [12] W. E. E. Meijer, E. R. Heerdink, W. A. Nolen, R. M. C. Herings,
H. G. M. Leufkens, and A. C. G. Egberts, “Association of risk of
abnormal bleeding with degree of serotonin reuptake inhibition
Conflicts of Interest by antidepressants,” Archives of Internal Medicine, vol. 164, no.
21, pp. 2367–2370, 2004.
The authors declare no conflicts of interest. [13] K. Linde, “St. John’s wort—an overview,” Forschende Komple-
mentarmedizin, vol. 16, no. 3, pp. 146–155, 2009.
Authors’ Contributions [14] E. A. Khawam, G. Laurencic, and D. A. Malone Jr., “Side effects
of antidepressants: an overview,” Cleveland Clinic Journal of
Gihyun Lee and Hyunsu Bae conceived and designed the Medicine, vol. 73, no. 4, pp. 351–361, 2006.
study. Gihyun Lee wrote the manuscript. Both authors revised [15] M. Friedman, “Chemistry and multibeneficial bioactivities of
and approved this manuscript. carvacrol (4-isopropyl-2-methylphenol), a component of essen-
tial oils produced by aromatic plants and spices,” Journal of
Agricultural and Food Chemistry, vol. 62, no. 31, pp. 7652–7670,
Acknowledgments 2014.
[16] H. Xu, M. Delling, J. C. Jun, and D. E. Clapham, “Oregano,
This work was supported by the Convergence of Conven-
thyme and clove-derived flavors and skin sensitizers activate
tional Medicine and Traditional Korean Medicine R&D specific TRP channels,” Nature Neuroscience, vol. 9, no. 5, pp.
program funded by the Ministry of Health and Welfare Korea 628–635, 2006.
through the Korea Health Industry Development Institute
[17] M. Hotta, R. Nakata, M. Katsukawa, K. Hori, S. Takahashi,
(HI15C0214). and H. Inoue, “Carvacrol, a component of thyme oil, activates
PPAR𝛼 and 𝛾 and suppresses COX-2 expression,” Journal of
References Lipid Research, vol. 51, no. 1, pp. 132–139, 2010.
[18] R.-H. Dong, Z.-Z. E. Fang, L.-L. Zhu et al., “Identification
[1] C. B. Nemeroff, “The burden of severe depression: a review of CYP isoforms involved in the metabolism of thymol and
of diagnostic challenges and treatment alternatives,” Journal of carvacrol in human liver microsomes (HLMs),” Pharmazie, vol.
Psychiatric Research, vol. 41, no. 3-4, pp. 189–206, 2007. 67, no. 12, pp. 1002–1006, 2012.
[2] W. F. S. Stewart, J. A. Ricci, E. Chee, S. R. Hahn, and D. [19] F. H. C. Melo, B. A. Moura, D. P. de Sousa et al., “Antidepressant-
Morganstein, “Cost of lost productive work time among US like effect of carvacrol (5-Isopropyl-2-methylphenol) in mice:
workers with depression,” JAMA, vol. 289, no. 23, pp. 3135–3144, involvement of dopaminergic system,” Fundamental and Clini-
2003. cal Pharmacology, vol. 25, no. 3, pp. 362–367, 2011.
[3] O. Berton and E. J. Nestler, “New approaches to antidepressant [20] M. Zotti, M. Colaianna, M. G. Morgese et al., “Carvacrol: from
drug discovery: beyond monoamines,” Nature Reviews Neuro- ancient flavoring to neuromodulatory agent,” Molecules, vol. 18,
science, vol. 7, no. 2, pp. 137–151, 2006. no. 6, pp. 6161–6172, 2013.
8 BioMed Research International

[21] R. Wilken, M. S. Veena, M. B. Wang, and E. S. Srivatsan, [36] W. Mu, T. Zhang, and B. Jiang, “An overview of biological
“Curcumin: a review of anti-cancer properties and therapeutic production of L-theanine,” Biotechnology Advances, vol. 33, no.
activity in head and neck squamous cell carcinoma,” Molecular 3-4, pp. 335–342, 2015.
Cancer, vol. 10, article 12, 2011. [37] P. J. Nathan, K. Lu, M. Gray, and C. Oliver, “The neurophar-
[22] J. G. Devassy, I. D. Nwachukwu, and P. J. H. Jones, “Curcumin macology of L-theanine(N-ethyl-L-glutamine): a possible neu-
and cancer: barriers to obtaining a health claim,” Nutrition roprotective and cognitive enhancing agent,” Journal of Herbal
Reviews, vol. 73, no. 3, pp. 155–165, 2015. Pharmacotherapy, vol. 6, no. 2, pp. 21–30, 2006.
[23] M. M. Yallapu, M. Jaggi, and S. C. Chauhan, “Curcumin nano- [38] T. Kakuda, A. Nozawa, A. Sugimoto, and H. Niino, “Inhibi-
formulations: a future nanomedicine for cancer,” Drug Discov- tion by theanine of binding of [3H]AMPA, [3H]kainate, and
ery Today, vol. 17, no. 1-2, pp. 71–80, 2012. [3H]MDL 105,519 to glutamate receptors,” Bioscience, Biotech-
nology and Biochemistry, vol. 66, no. 12, pp. 2683–2686, 2002.
[24] Y. Xu, B.-S. Ku, H.-Y. Yao et al., “Antidepressant effects of
curcumin in the forced swim test and olfactory bulbectomy [39] K. Lu, M. A. Gray, C. Oliver et al., “The acute effects of
models of depression in rats,” Pharmacology Biochemistry and L-theanine in comparison with alprazolam on anticipatory
Behavior, vol. 82, no. 1, pp. 200–206, 2005. anxiety in humans,” Human Psychopharmacology, vol. 19, no. 7,
pp. 457–465, 2004.
[25] S. K. Kulkarni, M. K. Bhutani, and M. Bishnoi, “Antidepressant
activity of curcumin: involvement of serotonin and dopamine [40] M. Gomez-Ramirez, S. P. Kelly, J. L. Montesi, and J. J. Foxe, “The
system,” Psychopharmacology, vol. 201, no. 3, pp. 435–442, 2008. effects of L-theanine on alpha-band oscillatory brain activity
during a visuo-spatial attention task,” Brain Topography, vol. 22,
[26] M. K. Bhutani, M. Bishnoi, and S. K. Kulkarni, “Anti-depressant no. 1, pp. 44–51, 2009.
like effect of curcumin and its combination with piperine in
[41] C. Yin, L. Gou, Y. Liu et al., “Antidepressant-like effects of L-
unpredictable chronic stress-induced behavioral, biochemical
theanine in the forced swim and tail suspension tests in mice,”
and neurochemical changes,” Pharmacology Biochemistry and
Phytotherapy Research, vol. 25, no. 11, pp. 1636–1639, 2011.
Behavior, vol. 92, no. 1, pp. 39–43, 2009.
[42] S. Hidese, M. Ota, C. Wakabayashi et al., “Effects of chronic
[27] R. Wang, Y. Xu, H.-L. Wu et al., “The antidepressant effects of
l-theanine administration in patients with major depressive
curcumin in the forced swimming test involve 5-HT1 and 5-
disorder: an open-label study,” Acta Neuropsychiatrica, vol. 29,
HT2 receptors,” European Journal of Pharmacology, vol. 578, no.
no. 2, pp. 72–79, 2017.
1, pp. 43–50, 2008.
[43] H. G. Preuss, D. Wallerstedt, N. Talpur et al., “Effects of niacin-
[28] Y. Xu, B. Ku, L. Cui et al., “Curcumin reverses impaired bound chromium and grape seed proanthocyanidin extract on
hippocampal neurogenesis and increases serotonin receptor 1A the lipid profile of hypercholesterolemic subjects: a pilot study,”
mRNA and brain-derived neurotrophic factor expression in Journal of Medicine, vol. 31, no. 5-6, pp. 227–246, 2000.
chronically stressed rats,” Brain Research, vol. 1162, no. 1, pp. 9–
18, 2007. [44] S. Uchida, K. Hirai, J. Hatanaka, J. Hanato, K. Umegaki, and
S. Yamada, “Antinociceptive effects of St. John’s wort, Harpago-
[29] L. L. Hurley, L. Akinfiresoye, E. Nwulia, A. Kamiya, A. A. Kulka- phytum procumbens extract and grape seed proanthocyanidins
rni, and Y. Tizabi, “Antidepressant-like effects of curcumin in extract in mice,” Biological and Pharmaceutical Bulletin, vol. 31,
WKY rat model of depression is associated with an increase in no. 2, pp. 240–245, 2008.
hippocampal BDNF,” Behavioural Brain Research, vol. 239, no.
[45] M. Sato, D. Bagchi, A. Tosaki, and D. K. Das, “Grape seed
1, pp. 27–30, 2013.
proanthocyanidin reduces cardiomyocyte apoptosis by inhibit-
[30] M. Srinivasan, A. R. Sudheer, and V. P. Menon, “Ferulic acid: ing ischemia/reperfusion-induced activation of JNK-1 and C-
therapeutic potential through its antioxidant property,” Journal JUN,” Free Radical Biology and Medicine, vol. 31, no. 6, pp. 729–
of Clinical Biochemistry and Nutrition, vol. 40, no. 2, pp. 92–100, 737, 2001.
2007. [46] Y. Xu, S. Li, R. Chen et al., “Antidepressant-like effect of low
[31] K. Kawabata, T. Yamamoto, A. Hara et al., “Modifying effects of molecular proanthocyanidin in mice: involvement of mono-
ferulic acid on azoxymethane-induced colon carcinogenesis in aminergic system,” Pharmacology Biochemistry and Behavior,
F344 rats,” Cancer Letters, vol. 157, no. 1, pp. 15–21, 2000. vol. 94, no. 3, pp. 447–453, 2010.
[32] M. S. Balasubashini, R. Rukkumani, P. Viswanathan, and V. P. [47] A. Murakami, H. Ashida, and J. Terao, “Multitargeted cancer
Menon, “Ferulic acid alleviates lipid peroxidation in diabetic prevention by quercetin,” Cancer Letters, vol. 269, no. 2, pp. 315–
rats,” Phytotherapy Research, vol. 18, no. 4, pp. 310–314, 2004. 325, 2008.
[33] R. Sultana, A. Ravagna, H. Mohmmad-Abdul, V. Calabrese, [48] G. L. Russo, M. Russo, C. Spagnuolo et al., “Quercetin: a
and D. A. Butterfield, “Ferulic acid ethyl ester protects neurons pleiotropic kinase inhibitor against cancer,” Cancer Treatment
against amyloid 𝛽-peptide(1–42)-induced oxidative stress and and Research, vol. 159, pp. 185–205, 2014.
neurotoxicity: relationship to antioxidant activity,” Journal of [49] P. Moutsatsou, “The spectrum of phytoestrogens in nature: our
Neurochemistry, vol. 92, no. 4, pp. 749–758, 2005. knowledge is expanding,” Hormones, vol. 6, no. 3, pp. 173–193,
[34] S. K. Yogeeta, R. B. R. Hanumantra, A. Gnanapragasam, S. 2007.
Senthilkumar, R. Subhashini, and T. Devaki, “Attenuation of [50] P. Bhutada, Y. Mundhada, K. Bansod et al., “Reversal by quer-
abnormalities in the lipid metabolism during experimental cetin of corticotrophin releasing factor induced anxiety- and de-
myocardial infarction induced by isoproterenol in rats: bene- pression-like effect in mice,” Progress in Neuro-Psychopharma-
ficial effect of ferulic acid and ascorbic acid,” Basic and Clinical cology and Biological Psychiatry, vol. 34, no. 6, pp. 955–960, 2010.
Pharmacology and Toxicology, vol. 98, no. 5, pp. 467–472, 2006. [51] R. S. Turner, R. G. Thomas, S. Craft et al., “A random-
[35] T. Yabe, H. Hirahara, N. Harada et al., “Ferulic acid induces ized, double-blind, placebo-controlled trial of resveratrol for
neural progenitor cell proliferation in vitro and in vivo,” Neu- Alzheimer disease,” Neurology, vol. 85, no. 16, pp. 1383–1391,
roscience, vol. 165, no. 2, pp. 515–524, 2010. 2015.
BioMed Research International 9

[52] T. Walle, F. Hsieh, M. H. DeLegge, J. E. Oatis Jr., and U. K. Walle, [68] J. Sarris, “Herbal medicines in the treatment of psychiatric
“High absorption but very low bioavailability of oral resveratrol disorders: a systematic review,” Phytotherapy Research, vol. 21,
in humans,” Drug Metabolism and Disposition, vol. 32, no. 12, pp. no. 8, pp. 703–716, 2007.
1377–1382, 2004. [69] M. Afzal, A. M. Safer, and M. Menon, “Green tea polyphenols
[53] M. Asensi, I. Medina, A. Ortega et al., “Inhibition of cancer and their potential role in health and disease,” Inflammophar-
growth by resveratrol is related to its low bioavailability,” Free macology, vol. 23, no. 4, pp. 151–161, 2015.
Radical Biology and Medicine, vol. 33, no. 3, pp. 387–398, 2002. [70] W.-L. Zhu, H.-S. Shi, Y.-M. Wei et al., “Green tea polyphenols
[54] G. Tredici, M. Miloso, G. Nicolini, S. Galbiati, G. Cavaletti, produce antidepressant-like effects in adult mice,” Pharmaco-
and A. Bertelli, “Resveratrol, MAP kinases and neuronal cells: logical Research, vol. 65, no. 1, pp. 74–80, 2012.
might wine be a neuroprotectant?” Drugs under Experimental [71] E. Moshiri, A. A. Basti, A.-A. Noorbala, A.-H. Jamshidi, S.
and Clinical Research, vol. 25, no. 2-3, pp. 99–103, 1999. Hesameddin Abbasi, and S. Akhondzadeh, “Crocus sativus
[55] Y. Feng, Y. Cui, J. L. Gao et al., “Neuroprotective effects of L. (petal) in the treatment of mild-to-moderate depression: a
resveratrol against traumatic brain injury in rats: involvement of double-blind, randomized and placebo-controlled trial,” Phy-
synaptic proteins and neuronal autophagy,” Molecular Medicine tomedicine, vol. 13, no. 9-10, pp. 607–611, 2006.
Reports, vol. 13, no. 6, pp. 5248–5254, 2016. [72] S. Akhondzadeh, N. Tahmacebi-Pour, A.-A. Noorbala et al.,
[56] A. Kumar, P. S. Naidu, N. Seghal, and S. S. V. Padi, “Neuro- “Crocus sativus L. in the treatment of mild to moderate
protective effects of resveratrol against intracerebroventricular depression: a double-blind, randomized and placebo-controlled
colchicine-induced cognitive impairment and oxidative stress trial,” Phytotherapy Research, vol. 19, no. 2, pp. 148–151, 2005.
in rats,” Pharmacology, vol. 79, no. 1, pp. 17–26, 2007. [73] A. Akhondzadeh Basti, E. Moshiri, A.-A. Noorbala, A.-H.
[57] A. Ranney and M. S. Petro, “Resveratrol protects spatial learn- Jamshidi, S. H. Abbasi, and S. Akhondzadeh, “Comparison
ing in middle-aged C57BL/6 mice from effects of ethanol,” of petal of Crocus sativus L. and fluoxetine in the treatment
Behavioural Pharmacology, vol. 20, no. 4, pp. 330–336, 2009. of depressed outpatients: a pilot double-blind randomized
[58] M. Yáñez, N. Fraiz, E. Cano, and F. Orallo, “Inhibitory trial,” Progress in Neuro-Psychopharmacology and Biological
effects of cis- and trans-resveratrol on noradrenaline and 5- Psychiatry, vol. 31, no. 2, pp. 439–442, 2007.
hydroxytryptamine uptake and on monoamine oxidase activ- [74] S. Akhondzadeh, H. Fallah-Pour, K. Afkham, A.-H. Jamshidi,
ity,” Biochemical and Biophysical Research Communications, vol. and F. Khalighi-Cigaroudi, “Comparison of Crocus sativus L.
344, no. 2, pp. 688–695, 2006. and imipramine in the treatment of mild to moderate depres-
[59] Y. Xu, Z. Wang, W. You et al., “Antidepressant-like effect of sion: a pilot double-blind randomized trial [ISRCTN45683816],”
trans-resveratrol: involvement of serotonin and noradrenaline BMC Complementary and Alternative Medicine, vol. 4, article 12,
system,” European Neuropsychopharmacology, vol. 20, no. 6, pp. 2004.
405–413, 2010. [75] A. A. Noorbala, S. Akhondzadeh, N. Tahmacebi-Pour, and
[60] Y. Yu, R. Wang, C. Chen et al., “Antidepressant-like effect A. H. Jamshidi, “Hydro-alcoholic extract of Crocus sativus
of trans-resveratrol in chronic stress model: behavioral and L. versus fluoxetine in the treatment of mild to moderate
neurochemical evidences,” Journal of Psychiatric Research, vol. depression: a double-blind, randomized pilot trial,” Journal of
47, no. 3, pp. 315–322, 2013. Ethnopharmacology, vol. 97, no. 2, pp. 281–284, 2005.
[61] E. Ernst and A. White, “The BBC survey of complementary [76] H. A. Hausenblas, D. Saha, P. J. Dubyak, and S. D. Anton,
medicine use in the UK,” Complementary Therapies in Medicine, “Saffron (Crocus sativus L.) and major depressive disorder: a
vol. 8, no. 1, pp. 32–36, 2000. meta-analysis of randomized clinical trials,” Journal of Integra-
[62] D. M. Eisenberg, R. B. Davis, S. L. Ettner et al., “Trends in tive Medicine, vol. 11, no. 6, pp. 377–383, 2013.
alternative medicine use in the United States, 1990–1997: results [77] A. L. Lopresti and P. D. Drummond, “Saffron (Crocus sativus)
of a follow-up national survey,” Journal of the American Medical for depression: a systematic review of clinical studies and exam-
Association, vol. 280, no. 18, pp. 1569–1575, 1998. ination of underlying antidepressant mechanisms of action,”
[63] E. M. Tait, S. B. Laditka, J. N. Laditka, M. A. Nies, and E. F. Human Psychopharmacology, vol. 29, no. 6, pp. 517–527, 2014.
Racine, “Use of complementary and alternative medicine for [78] M. Mazidi, M. Shemshian, S. H. Mousavi et al., “A double-blind,
physical performance, energy, immune function, and general randomized and placebo-controlled trial of Saffron (Crocus
health among older women and men in the United States,” sativus L.) in the treatment of anxiety and depression,” Journal
Journal of Women and Aging, vol. 24, no. 1, pp. 23–43, 2012. of Complementary and Integrative Medicine, vol. 13, no. 2, pp.
[64] H. C. Kales, F. C. Blow, D. E. Welsh, and A. M. Mellow, “Herbal 195–199, 2016.
products and other supplements: use by elderly veterans with [79] M. Abolhassani, “Antiviral activity of borage (Echium amoe-
depression and dementia and their caregivers,” Journal of num),” Archives of Medical Science, vol. 6, no. 3, pp. 366–369,
Geriatric Psychiatry and Neurology, vol. 17, no. 1, pp. 25–31, 2004. 2010.
[65] P. P. Roy-Byrne, A. Bystritsky, J. Russo, M. G. Craske, C. [80] M. Sayyah, M. Sayyah, and M. Kamalinejad, “A preliminary
D. Sherbourne, and M. B. Stein, “Use of herbal medicine randomized double blind clinical trial on the efficacy of aqueous
in primary care patients with mood and anxiety disorders,” extract of Echium amoenum in the treatment of mild to mod-
Psychosomatics, vol. 46, no. 2, pp. 117–122, 2005. erate major depression,” Progress in Neuro-Psychopharmacology
[66] K. M. Silvers, C. C. Woolley, and D. Hedderley, “Dietary and Biological Psychiatry, vol. 30, no. 1, pp. 166–169, 2006.
supplement use in people being treated for depression,” Asia [81] S. Kasper, H. P. Volz, H. J. Möller, A. Dienel, and M. Kieser,
Pacific Journal of Clinical Nutrition, vol. 15, no. 1, pp. 30–34, “Continuation and long-term maintenance treatment with
2006. Hypericum extract WS 5570 after recovery from an acute
[67] V. Kumar, “Potential medicinal plants for CNS disorders: an episode of moderate depression—a double-blind, randomized,
overview,” Phytotherapy Research, vol. 20, no. 12, pp. 1023–1035, placebo controlled long-term trial,” European Neuropsychophar-
2006. macology, vol. 18, no. 11, pp. 803–813, 2008.
10 BioMed Research International

[82] J. Sarris, D. J. Kavanagh, G. Byrne, K. M. Bone, J. Adams, [97] S. Kasper, I.-G. Anghelescu, A. Szegedi, A. Dienel, and M.
and G. Deed, “The Kava Anxiety Depression Spectrum Study Kieser, “Superior efficacy of St John’s wort extract WS5570
(KADSS): a randomized, placebo-controlled crossover trial compared to placebo in patients with major depression: a ran-
using an aqueous extract of Piper methysticum,” Psychopharma- domized, double-blind, placebo-controlled, multi-center trial
cology, vol. 205, no. 3, pp. 399–407, 2009. [ISRCTN77277298],” BMC Medicine, vol. 4, article 14, 2006.
[83] Q. G. Chen, Y. S. Zeng, Z. Q. Qu et al., “The effects of [98] E. U. Vorbach, K. H. Arnoldt, and W.-D. Hubner, “Efficacy and
Rhodiola rosea extract on 5-HT level, cell proliferation and tolerability of St. John’s wort extract LI 160 versus imipramine in
quantity of neurons at cerebral hippocampus of depressive rats,” patients with severe depressive episodes according to ICD-10,”
Phytomedicine, vol. 16, no. 9, pp. 830–838, 2009. Pharmacopsychiatry, vol. 30, pp. 81–85, 1997.
[84] L. Mattioli, C. Funari, and M. Perfumi, “Effects of Rhodiola [99] M. Philipp, R. Kohnen, and K.-O. Hiller, “Hypericum extract
rosea L. extract on behavioural and physiological alterations versus imipramine or placebo in patients with moderate depres-
induced by chronic mild stress in female rats,” Journal of sion: randomised multicentre study of treatment for eight
Psychopharmacology, vol. 23, no. 2, pp. 130–142, 2009. weeks,” British Medical Journal, vol. 319, no. 7224, pp. 1534–1538,
[85] V. Darbinyan, G. Aslanyan, E. Amroyan, E. Gabrielyan, C. 1999.
Malmström, and A. Panossian, “Clinical trial of Rhodiola [100] H. Woelk, “Comparison of St John’s wort and imipramine
rosea L. extract SHR-5 in the treatment of mild to moderate for treating depression: randomised controlled trial,” British
depression,” Nordic Journal of Psychiatry, vol. 61, no. 5, pp. 343– Medical Journal, vol. 321, no. 7260, pp. 536–539, 2000.
348, 2007. [101] E. Schrader, “Equivalence of St John’s wort extract (Ze 117) and
[86] L. Hritcu, O. Cioanca, and M. Hancianu, “Effects of lavender oil fluoxetine: a randomized, controlled study in mild-moderate
inhalation on improving scopolamine-induced spatial memory depression,” International Clinical Psychopharmacology, vol. 15,
impairment in laboratory rats,” Phytomedicine, vol. 19, no. 6, pp. no. 2, pp. 61–68, 2000.
529–534, 2012. [102] D. Wheatley, “Ll 160, an extract of St. John’s Wort, versus
[87] F. Effati-Daryani, S. Mohammad-Alizadeh-Charandabi, M. amitriptyline in mildly to moderately depressed outpatients—a
Mirghafourvand, M. Taghizadeh, and A. Mohammadi, “Effect controlled 6-week clinical trial,” Pharmacopsychiatry, vol. 30,
of lavender cream with or without foot-bath on anxiety, stress no. 2, pp. 77–80, 1997.
and depression in pregnancy: a randomized placebo-controlled [103] H.-P. Volz and P. Laux, “Potential treatment for subthreshold
trial,” Journal of Caring Sciences, vol. 4, no. 1, pp. 63–73, 2015. and mild depression: a comparison of St. John’s wort extracts
[88] M. Nikfarjam, N. Parvin, N. Assarzadegan, and S. Asghari, “The and fluoxetine,” Comprehensive Psychiatry, vol. 41, no. 2, pp. 133–
effects of lavandula angustifolia mill infusion on depression 137, 2000.
in patients using citalopram: a comparison study,” Iranian Red [104] E.-U. Vorbach, W.-D. Hubner, and K.-H. Arnold, “Effectiveness
Crescent Medical Journal, vol. 15, no. 8, pp. 734–739, 2013. and tolerance of the hypericum extract Li-160 in comparison
[89] P. Conrad and C. Adams, “The effects of clinical aromather- with imipramine—Randomized double-blind-study with 135
apy for anxiety and depression in the high risk postpartum out-patients,” Nervenheilkunde, vol. 12, no. 6, pp. 290–296, 1993.
woman—a pilot study,” Complementary Therapies in Clinical [105] G. Harrer, U. Schmidt, U. Kuhn, and A. Biller, “Comparison of
Practice, vol. 18, no. 3, pp. 164–168, 2012. equivalence between the St. John’s wort extract LoHyp-57 and
[90] I.-S. Lee and G.-J. Lee, “Effects of lavender aromatherapy on fluoxetine,” Drug Research, vol. 49, no. 4, pp. 289–296, 1999.
insomnia and depression in women college students,” Taehan [106] M. Mannel, U. Kuhn, U. Schmidt, M. Ploch, and H. Murck, “St.
Kanho Hakhoe Chi, vol. 36, no. 1, pp. 136–143, 2006. John’s wort extract LI160 for the treatment of depression with
[91] S. Akhondzadeh, L. Kashani, A. Fotouhi et al., “Comparison atypical features—a double-blind, randomized, and placebo-
of Lavandula angustifolia Mill. tincture and imipramine in controlled trial,” Journal of Psychiatric Research, vol. 44, no. 12,
the treatment of mild to moderate depression: a double-blind, pp. 760–767, 2010.
randomized trial,” Progress in Neuro-Psychopharmacology and [107] K. Linde, M. M. Berner, and L. Kriston, “St John’s wort for major
Biological Psychiatry, vol. 27, no. 1, pp. 123–127, 2003. depression,” Cochrane Database of Systematic Reviews, no. 4,
[92] C.-G. Jang, M. Kang, J.-H. Cho et al., “Nelumbinis Semen Article ID CD000448, 2009.
reverses a decrease in 5-HT1A receptor binding induced by [108] R. Rahimi, S. Nikfar, and M. Abdollahi, “Efficacy and tolera-
chronic mild stress, a depression-like symptom,” Archives of bility of Hypericum perforatum in major depressive disorder
Pharmacal Research, vol. 27, no. 10, pp. 1065–1072, 2004. in comparison with selective serotonin reuptake inhibitors:
[93] M. Kang, D. Shin, J.-W. Oh et al., “The anti-depressant effect a meta-analysis,” Progress in Neuro-Psychopharmacology and
of Nelumbinis Semen on rats under chronic mild stress Biological Psychiatry, vol. 33, no. 1, pp. 118–127, 2009.
induced depression-like symptoms,” American Journal of Chi- [109] C. Röder, M. Schaefer, and S. Leucht, “Meta-analysis of effec-
nese Medicine, vol. 33, no. 2, pp. 205–213, 2005. tiveness and tolerability of treatment of mild to moderate
[94] H.-S. Chung, H. J. Lee, I. Shim, and H. Bae, “Assessment of anti- depression with St. John’s Wort,” Fortschritte der Neurologie
depressant effect of nelumbinis semen on rats under chronic Psychiatrie, vol. 72, no. 6, pp. 330–343, 2004.
mild stress and its subchronic oral toxicity in rats and beagle [110] S. Kasper, F. Caraci, B. Forti, F. Drago, and E. Aguglia, “Efficacy
dogs,” BMC Complementary and Alternative Medicine, vol. 12, and tolerability of Hypericum extract for the treatment of mild
article 68, 2012. to moderate depression,” European Neuropsychopharmacology,
[95] V. Butterweck, “Mechanism of action of St John’s wort in vol. 20, no. 11, pp. 747–765, 2010.
depression—what is known?” CNS Drugs, vol. 17, no. 8, pp. 539– [111] J. R. T. Davidson, K. M. Gadde, J. A. Fairbank et al., “Effect
562, 2003. of Hypericum perforatum (St John’s wort) in major depressive
[96] G. Harrer and H. Sommer, “Treatment of mild/moderate disorder—a randomized controlled trial,” The Journal of the
depressions with Hypericum,” Phytomedicine, vol. 1, no. 1, pp. American Medical Association, vol. 287, no. 14, pp. 1807–1814,
3–8, 1994. 2002.
 BioMed Research International 11

[112] R. C. Shelton, M. B. Keller, A. Gelenberg et al., “Effectiveness

of St John’s wort in major depression: a randomized controlled
trial,” Journal of the American Medical Association, vol. 285, no.
15, pp. 1978–1986, 2001.
[113] F. Borrelli and A. A. Izzo, “Herb-drug interactions with St
John’s Wort (hypericum perforatum): an update on clinical
observations,” AAPS Journal, vol. 11, no. 4, pp. 710–727, 2009.
[114] J. S. Markowitz, J. L. Donovan, C. L. DeVane et al., “Effect of
St John’s wort on drug metabolism by induction of cytochrome
P450 3A4 enzyme,” The Journal of the American Medical
Association, vol. 290, no. 11, pp. 1500–1504, 2003.
[115] E. Mills, V. M. Montori, P. Wu, K. Gallicano, M. Clarke, and G.
Guyatt, “Interaction of St John’s wort with conventional drugs:
systematic review of clinical trials,” British Medical Journal, vol.
329, no. 7456, pp. 27–30, 2004.
[116] A. A. Izzo and E. Ernst, “Interactions between herbal medicines
and prescribed drugs: an updated systematic review,” Drugs, vol.
69, no. 13, pp. 1777–1798, 2009.
[117] R. Teschke, W. Gaus, and D. Loew, “Kava extracts: safety and
risks including rare hepatotoxicity,” Phytomedicine, vol. 10, no.
5, pp. 440–446, 2003.
[118] F. Pantano, R. Tittarelli, G. Mannocchi et al., “Hepatotoxicity
induced by “the 3Ks”: Kava, kratom and khat,” International
Journal of Molecular Sciences, vol. 17, no. 4, article 580, 2016.
[119] S. K. Hung, R. Perry, and E. Ernst, “The effectiveness and
efficacy of Rhodiola rosea L.: a systematic review of randomized
clinical trials,” Phytomedicine, vol. 18, no. 4, pp. 235–244, 2011.
[120] D. van Diermen, A. Marston, J. Bravo, M. Reist, P.-A. Carrupt,
and K. Hostettmann, “Monoamine oxidase inhibition by Rho-
diola rosea L. roots,” Journal of Ethnopharmacology, vol. 122, no.
2, pp. 397–401, 2009.
[121] H. M. A. Cavanagh and J. M. Wilkinson, “Biological activities
of lavender essential oil,” Phytotherapy Research, vol. 16, no. 4,
pp. 301–308, 2002.
[122] M. Hancianu, O. Cioanca, M. Mihasan, and L. Hritcu, “Neu-
roprotective effects of inhaled lavender oil on scopolamine-
induced dementia via anti-oxidative activities in rats,” Phy-
tomedicine, vol. 20, no. 5, pp. 446–452, 2013.
[123] S. Kasper, M. Gastpar, W. E. Müller et al., “Efficacy and safety
of silexan, a new, orally administered lavender oil preparation,
in subthreshold anxiety disorder—evidence from clinical trials,”
Wiener Medizinische Wochenschrift, vol. 160, no. 21-22, pp. 547–
556, 2010.
[124] S. Kasper, “An orally administered lavandula oil preparation
(Silexan) for anxiety disorder and related conditions: an evi-
dence based review,” International Journal of Psychiatry in
Clinical Practice, vol. 17, supplement 1, pp. 15–22, 2013.
[125] S. Kasper, I. Anghelescu, and A. Dienel, “Efficacy of orally
administered Silexan in patients with anxiety-related restless-
ness and disturbed sleep—a randomized, placebo-controlled
trial,” European Neuropsychopharmacology, vol. 25, no. 11, pp.
1960–1967, 2015.
[126] H.-H. Tsai, H.-W. Lin, A. Simon Pickard, H.-Y. Tsai, and G. B.
Mahady, “Evaluation of documented drug interactions and con-
traindications associated with herbs and dietary supplements:
a systematic literature review,” International Journal of Clinical
Practice, vol. 66, no. 11, pp. 1056–1078, 2012.