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*Corresponding author: E-mail: heidari_62@yahoo.com;
Journal of Pharmaceutical Research International
19(4): 1-12, 2017; Article no.JPRI.36836
ISSN: 2456-9119
(Past name: British Journal of Pharmaceutical Research, Past ISSN: 2231-2919,
NLM ID: 101631759)
Medicinal Plants Effective on Serotonin Level: A
Systematic Review
Kamal Solati
1
, Majid Asadi-Samani
2
and Saeid Heidari-Soureshjani
3*
1
Social Determinants of Health Research Center, Shahrekord University of Medical Sciences,
Shahrekord, Iran.
2
Young Researchers and Elite Club, Islamic Azad University, Shahrekord Branch, Shahrekord, Iran.
3
Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical
Sciences, Shahrekord, Iran.
Authors’ contributions
This work was carried out in collaboration between all authors. Authors MAS and SHS searched the
databases and wrote the draft. Author KS edited the manuscript. All authors read and approved the
final version.
Article Information
DOI: 10.9734/JPRI/2017/36836
Editor(s):
(1)
Mahadeva Rao, Professor, School of Basic Medical Sciences, Faculty of Medicine, Universiti Sultan Zainal Abidin,
Malaysia.
(2)
Othman Ghribi, Department of Pharmacology, Physiology & Therapeutics, University of North Dakota, USA.
(3)
Ali Nokhodchi, Professor, Pharmaceutics and Drug Delivery, School of Life Sciences, University of Sussex, UK.
Reviewers:
(1) Maria Rosa Avila-Costa, National University of Mexico, Mexico.
(2)
Milan Fedurco, Switzerland.
(3)
Suprakash Chaudhury, Dr. D. Y. Patil University, India.
Complete Peer review History:
http://www.sciencedomain.org/review-history/21810
Received 19
th
September 2017
Accepted 6
th
November 2017
Published 8
th
November 2017
ABSTRACT
In recent years, the prevalence of depression and mood disorders has been on the rise. With
regards to increased popularity of traditional medicine and medicinal plants, we conducted this
review to identify and study the action mechanisms of the medicinal plants that are effective on
serotonin, as one of the neurotransmitters of happiness and mood, and depression symptoms. To
conduct this systematic review, the key words of interest were used to retrieve articles from the
Information Sciences Institute (ISI) and the PubMed. The articles, published between 2010 and
2017, about the medicinal plants’ and their products’ potential effects on serotonin and brain
serotonergic system were analyzed. Plants and their derivatives may not only exert therapeutic
effects on mild depression but also exhibit suitable therapeutic response in treating severe
disorders such as major depressive disorder (MDD) to improve mood conditions and eliminate
Review Article
Solati et al.; JPRI, 19(4): 1-12, 2017; Article no.JPRI.36836
2
depressed mood through affecting the serotonergic system. Plants and their compounds affect
serotonergic system function through anti-inflammatory mechanisms, inhibiting noradrenaline and
serotonin reuptake, inhibiting monoamine oxidase (MAO), and increasing expression of serotonin
transporter (5-HTT) and hepatic tryptophan 2, 3-dioxygenase. They can therefore be used as
options for discovering new drugs effective on happiness and depression.
Keywords: Medicinal plant; serotonin; depression; happiness.
1. INTRODUCTION
In recent years, the prevalence of depression
and anxiety has been on the rise. Depression
and anxiety disrupt different dimensions of
human life, including social and occupational,
and quality of life [1,2]. Meanwhile, serotonin
(hydroxytryptamine, 5-HT-5) is one of the
hormones that contribute fundamentally to
regulating the mood and cognition in human. The
serotonergic system is a complicated system
whose dysfunction leads to development of
certain diseases such as depression [3].
Currently despite the availability of various
psychotherapies [4-10] and chemical treatments
for chronic and psychiatric disorders, treatment
of depression remains ambiguous [11]. In
addition, chemical treatments to induce
happiness, to elevate the levels of certain
hormones and treat disorders due to decreased
levels of serotonin, including depression and
other psychiatric disorders, lead to several
complications such as certain behavioral
disorders in addition to imposing costs on the
patients [12-14]. In addition, psychotherapies
may be stigmatized, which highlights the
significance of alternative treatments [6]. The use
of medicinal plants is increasing day by day due
to fewer side effects and lower cost.
Ethnobotanical and experimental studies have
shown that medicinal plants and herbal drugs
can be used to prevent and treat many diseases
[15-23]. We, therefore, conducted this study to
identify and study the action mechanisms of
medicinal plants that are effective on serotonin,
as one of the neurotransmitters of happiness and
mood, and depression symptoms.
To conduct this systematic review, the key words
serotonin combined with medicinal plant or herb
and phyto combined with depress or happiness
and pleasure were used to search for relevant
articles indexed in the Information Sciences
Institute and the PubMed using EndNote
software. After detecting available articles and
references as well as library information that was
drawn from other sources, the articles that
directly addressed the effects of medicinal plants
and their products on serotonin levels,
improvement of mood, and elimination of
depression and were published between 2010
and 2017 were retrieved and analyzed. The
exclusion criteria were inaccessible full text, no
positive effects, review articles, non-English
language articles, and the articles that were
irrelevant to the purpose of the study. Fig. 1
illustrates the flowchart according to which some
articles were included and some others were
excluded from final analysis.
Plants and their derivatives may not only exert
therapeutic effects on mild depression but also
exhibit suitable therapeutic response in treating
severe disorders such as major depressive
disorder (MDD) to improve mood conditions and
eliminate depressed mood through affecting the
serotonergic system. Available research findings
have indicated that the plants [24-45] (Table 1)
and several phytocompounds [46-56] (Table 2)
can play a role in inducing feelings of happiness
in human through affecting serotonin synthesis
and absorption.
In addition, many other plants, combined or
formulated, that have antidepressant or anti-
anxiety effects have been used in traditional
medicine or experimental studies. For example,
Yuanzhi-1 is a Chinese herbal drug that, if used
at 10 mg/kg concentration, can increase the
extracellular concentration of HT-5 and imitate
antidepressant properties via triple reuptake
inhibitor [57]. Combination of St. John's Wort
(Hypericum perforatum) and passion flower
(Passiflora incarnata) can decrease the
complications of depression and enhance feeling
of happiness through synaptic uptake of
serotonin. However, the combination dose of
these two plants should be also taken into
account to bring about synergistic effect to
achieve optimal therapeutic effect [58]. Perment
is another plant-based combination that is used
for this purpose. This combination consists of
Clitoria ternatea Linn., Withania somnifera Dun.,
Asparagus racemosus Linn., and Bacopa
monniera Lin. A study on the effects of this
combination's compounds on mice showed that
the serum levels of serotonin and noradrenaline
increased after treatment [59]. A study
Solati et al.; JPRI, 19(4): 1-12, 2017; Article no.JPRI.36836
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investigated antioxidant effects of
Suanzaorenhehuan formula. This combination is
made up of Semen ziziphi Spinosae, Cortex
albiziae, Radix paeoniae Alba, and Semen
platycladi. After 2-week treatment with this
combination, MAO-A and MAO-B were inhibited
and therefore depression symptoms improved
via elevating the levels of serotonin [60]. Kai Xin
San (Ding-Zhi-Xiao-Wan) is a Chinese herbal
formula (consisting of Poria, Ginseng, Polygala,
and Chang Pu) that was reported to exert
antidepressant effects through affecting the
central monoaminergic neurotransmitter system
and HT-5 in mouse model of depression [61].
Kai-xin-san can be used as a complementary
therapy or dietary supplement by increasing
happiness neurotransmitters in the brain as well
as improving the expression of neurotrophic
factors and their receptors’ response [62]. In
addition, Dong et al. reported that Kai-xin-san
promoted the synthesis of HT-5 in the
hippocampus and prefrontal cortex in mouse
through eliminating defects in the HT-5 system
[63]. The combination pill called Sini San that is
used in Chinese traditional medicine can interact
synergistically when combined with fluoxetine
and affect HT-5 levels [64]. Wang et al. [65]
studied the antidepressant effects of Zuojin pill
(made up of Coptis chinensis Franch. and
Evodia rutaecarpa). They observed that this pill
acted through the central monoaminergic
neurotransmitter system and 5-HT. Besides that,
Zhi-Zi-Hou-Po is a Chinese herbal formulation
that helps treat depression through affecting the
monoaminergic system [66]. In the other studies
with rats, Yiqi Huatan [67], Jie Yu Chu Fan
capsule [68], Suanzaorenhehuan Formula [69],
and Zhimu-Baihe (Zhimu: Anemarrhena
asphodeloides; Baihe: Lilium brownii var.
viridulum) [70], which are Chinese herbal
combinations, caused increase in the HT-5 levels
in the hypothalamus and decrease in the
symptoms of depression through modulating the
monoaminergic neurotransmitters. Kaixin Jieyu
decoction was studied for its potential effects in
modulating behavior and improving depressive
moods. Results demonstrated that treatment led
to increased expression of HT2A receptor
mRNA-5 and its modulation in the cerebrum [71].
In addition, Xiachaihutang, after 4-week gavage,
caused increase in the HT-5 levels in mouse
hippocampus [72]. Another study also reported
that this herbal combination helped improve
depressive behaviors in mouse through
increasing hypothermia and 5-hydroxytryptophan
(5-HTP), 5-HT, and hydroxyindoleacetic acid (5-
HIAA)-5 as well as increasing HT-5 reversal [73].
Danzhi Xiaoyao San is another combination that
is effective on the levels of tryptophan and HT-5
such that it can serve as a nature-based
treatment for depression [74]. Chaihu-Shugan-
San decreases the symptoms of depression
through increasing the expression of HT1A
receptor mRNA-5 and hippocampal cell
proliferation in the dentate gyrus in epileptic rats
[75]. Wang et al. [76] studied the effect of
Ziziphi spinosae lily powder suspension on
depression in rats. They observed that this
combination could enhance happiness and
improve depressive symptoms in rat through
the mechanism of increasing serum
levels of peripheral blood and 5-HIAA-5 in the
brain.
It has been shown that medicinal plants and their
phytochemicals have anti-inflammatory and
antioxidant activities [17,77-85]. It is thought that
many plants prevent inflammation of the central
nervous system (CNS) via anti-inflammatory and
antioxidant properties, and decrease the
symptoms of depression and improve depressive
mood through pro-inflammatory cytokines [86].
Plants can improve depression and induce
happiness in the patients through exerting
antioxidant properties in the brain, decreasing
pro-inflammatory cytokines, increasing pro-
opiomelanocortin, and exerting neuroprotective
properties [87].
Plants are effective in enhancing happiness and
decreasing symptoms of depression due to
certain compounds such as flavonoids, lignanes,
phenolic acids, coumarins, diterpene alkaloids,
terpenes, saponins, amines, naringenin,
quercetin derivatives, eugenol, piperine,
berberine, hyperforin, riparian derivatives, and
ginsenosides [87]. In addition, polyphenol-like
compounds such as curcumin, resveratrol, and
proanthocyanidins induce happiness in patients
with depression through modulating
hypothalamic-pituitary-adrenal (HPA) axis activity
[88]. In fact, many phytocompounds can fight
inflammatory signaling cascades and prevent
degradation of serotonin precursors and
therefore increase synthesis of serotonin due to
antioxidant properties [89]. Certain compounds of
plants such as natural stilbenoid imitate the
properties of antidepressants and decrease
depression and anxiety by inhibiting
noradrenaline and serotonin reuptake [90].
Several mechanisms have been proposed. Some
plants induce their serotonergic properties
directly. Some plants cause increase in serotonin
through inhibiting [(3)H]-serotonin reuptake,
Solati et al.; JPRI, 19(4): 1-12, 2017; Article no.JPRI.36836
4
inhibiting MAO, or increasing monoamines levels
[51,87]. These plants and their derivatives
elevate the levels of serotonin, epinephrine,
dopamine, and other monoamines in the brain
through inhibiting MAO. In addition, plants may
eliminate depressive mood through increasing
the expression of serotonin transporter (5-HTT)
[48]. Some plants increase serotonin levels
through preventing the activity of hepatic
tryptophan 2, 3 dioxygenase and increasing the
expression of synaptic genes [34].
Although the efficacy of plants or their
compounds in inducing happiness depends on
the levels of the serotonergic 5-HT(1A) in the
brain [28], the underlying mechanisms of mood
swings and increase in serotonin levels remain to
be fully identified. In addition, the doses of active
compounds or plant extracts should be
considered in treatment process because they
may be inefficacious in low doses or lead to
poisoning in high doses [24].
Fig. 1. The flowchart of exclusion and inclusion criteria of the studies
A total 517 Studies
were found from
electronic database
90 Studies were considered for
inclusion
86 Studies were excluded for not
fulfilling inclusion criteria
176 Candidate studies retrieved
for initial evaluation
341 Studies excluded due to being out
of the date, scope and duplication
54 Studies with complete data
were included in final analysis
36 Studies excluded for non-
English language
Solati et al.; JPRI, 19(4): 1-12, 2017; Article no.JPRI.36836
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Table 1. Medicinal plants effective on serotonin
References
Study design
Plants
[24] Antidepressant properties through affecting the serotonergic system In the mice
Bupleurum falcatum
[25] Used to induce happiness and as an antidepressant agent; containing SERT active alkaloids
and capable of inducing happiness.
In Vitro
Some plants from
Amaryllidaceae family
[26] Inducing antidepressant properties through affecting serotonergic system and synthesis of
serotonin
In the Rats
Tagetes lucida Cav.
[27] Used to enhance sensations and euphoria; inducing antidepressant property via affecting
monoamine neurotransmitters serotonin
In the mice
Hemerocallis citrina
[28] Ethanolic extract of this plant can help increase HT and 5-HIAA-5 in the cerebral cortex of
laboratory mouse.
In the mice Uncaria lanosa Wallich var.
appendiculata Ridsd
[29] Its monoglycosides can lead to inhibition of [(3)H]-serotonin reuptake in rat.
In the mice
Cynanchum auriculatum Royle
ex Wight
[30]
Fructus akebiae extracts at 12.6, 25, and 50 mg/kg doses cause increase in extracellular HT-
5 according to vivo microanalysis and therefore induction of happiness and antidepressant
properties.
In the Rats
Fructus Akebiae
[31] Extract of S. species, as a triple monoamine reuptake inhibitor, can be used to treat certain
diseases such as depression and anxiety.
In the Rats
Sideritis species
[32] Exerting antidepressant effects through increasing the levels of certain neurotransmitters
such as serotonin due to curcumin.
In the mice
Curcuma longa
[33] Increasing reversal of HT-5 in mouse brain and therefore decreasing depression In the mice
Annona cherimolia
[34]
H. perforatum extract increases serotonin levels and improves mood in mouse through
inhibiting hepatic tryptophan 2, 3 dioxygenase and expression of its genes in mouse.
In the Rats
Hypericum perforatumm
[35] Increasing serotonin levels In the Rats
Areca catechu nut
[36] Increasing serotonin levels through affecting serotonin transporter
In Vitro Borago officinalis
[36] Increasing serotonin levels through the MAO-A activity
In Vitro Trigonella foenum-graecum
[36]
In Vitro
Apium graveolens
[36] Increasing serotonin levels through the MAO-A activity
In Vitro Calluna vulgaris
[37] Capable of imitating antidepressant drugs properties through affecting serotonergic, nitrergic
pathway and sigma receptors.
In the mice
Tagetes erecta L.
[38] Paeonia glycosidic compounds increase the levels of serotonin (5-HT) and its metabolite 5-
hydroxyindoleacetic acid in the hippocampus of the brain.
In the mice
Paeonia
[39]
The polyphenols of R. officinalis cause upregulation of tyrosine hydroxylase and pyruvate
carboxylase.
In the mice
Rosmarinus officinalis
[40]
The flavonoids of H. citrina cause modulation of mood via affecting the serotonergic and
dopaminergic systems.
In the mice
Hemerocallis citrina
Solati et al.; JPRI, 19(4): 1-12, 2017; Article no.JPRI.36836
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References
Study design
Plants
[41] The chloroform of this plant exerts anti-depressive properties without preventing the MAO
enzymes and involving the serotonergic and catecholaminergic systems.
In the mice
Lafoensia pacari A. St.-Hil.
[42] Ethanolic M. oleifera extract imitates selective serotonin reuptake inhibitors via affecting the
noradrenergic-serotonergic neurotransmission pathway.
In the mice Moringa oleifera
[43] It has serotonergic antidepressant-like activity and it plays a role in modulation of
serotonergic
In the Rats
Melissa officinalis L.
[44] It can cause modulation of mood via interaction with 5-HT2 receptor, alpha2-adrenoceptor
and dopamine D2-receptors
In the mice
Mangifera indica
[45]
Aqueous G. elata extract can increase cerebral reversal of serotonin and dopamine and
decrease depressive behaviors through regulating the monoamine neurotransmitters.
In the Rats
Gastrodia elata Blume
Table 2. Phytochemicals effective on serotonin
References
Main effects and mechanisms
Study
design
Phytocompounds
name
[46] Inducing serotonergic property via weakening mitochondrial monoamine oxidase-A (MAO-A) in the central
nervous system
In the mice Quercetin
[47] Capable of elevating serotonin levels In the Rats
Equol
[48] Increasing the expression of serotonin transporter (5-HTT) and therefore enhancing happiness
In Vitro
Evodiamine
[48,49] Increasing the expression of serotonin transporter (5-HTT) and therefore enhancing happiness; considered
to be an antidepressant drug due to reinforcing monoamine neurotransmission.
In Vitro
Berberine
[50] Improving mood as a mediator via increasing catecholamine in the synaptic cleft and its interaction effect
with serotonergic 5-HT1A.
In the mice Vitexin
[51] Confirmed antidepressant and happiness-inducing effects via increasing monoamines and decreasing MAO-
A activity.
In the mice Turmerone
[52] Serving as a potent antidepressant agent through affecting the serotonergic system. In the mice
Auraptenol
[53] Inducing happiness via increasing the levels of serotonin (5-HT), brain-derived neurotrophic factor, and
norepinephrine.
In the mice Silibinin
[54] Increasing extracellular 5-HT concentration in mouse hypothalamus in 3.5, 7.0, and 14 mg/kg doses and
imitating antidepressant drugs via the activity of reuptake inhibitor 5-HT and therefore improving behavior.
In the Rats Albiflorin
[55] Eliminating serotonin receptors-associated swings and decreasing depressive moods through modulating
the proteins of the serotonergic system and removing inflammation
In the mice Echinocystic acid
[56] Exerting antidepressant property through reinforcing expression of synapsin I and increasing serotonin
levels.
In the mice Chlorogenic acid
Solati et al.; JPRI, 19(4): 1-12, 2017; Article no.JPRI.36836
7
Certain compounds in plants, such as silymarin,
can act as depressogenic agents through
affecting the HT1A-5 receptors of serotonin.
Therefore, plant-based depressogenic
compounds should be seriously addressed [91].
In certain cases, co-treatment with some
medicinal plants, such as St. John's Wort, and
fluoxetine can lead to spontaneous adverse drug
reaction in the patients [92]. Therefore, It should
be taken into account that treating psychiatric
disorders and mood disorders is complex and
even patient-specific [93]. In addition, the
majority of the treatments for depression have
been focused on serotonin reuptake inhibitors
and/or noradrenaline reuptake inhibitors that
indirectly affect dopaminergic neurotransmission;
therefore, many comorbidities such as impaired
pleasure may remain untreated [94]. Nature-
based drugs for improving mood and enhancing
happiness should therefore focus on a
comparatively wider range of treatments.
2. CONCLUSION
Although introduced medicinal plants and their
derivatives can be used in increasing serotonin
level and may be effective on happiness and
depression, they may exert synergistic effects
and lead to spontaneous adverse drug reaction
in certain cases such as using St. John's Wort
(H. perforatum) with depressive antibiotics. It is
therefore essential to pay attention to drug
dosage and the drug poisoning. Also the
medications should be standardized and their
structure activity relationship, lethal dose, and
effective doses be determined. Finally,
randomized double blind placebo controlled
studies should be undertaken with patients with
definite diagnosis.
CONSENT
It is not applicable.
ETHICAL APPROVAL
It is not applicable.
COMPETING INTERESTS
Authors have declared that no competing
interests exist.
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Background: Mangifera indica (Anacardiaceae) is an important herb in the traditional African and Ayurvedic medicines. The stem barks are used in the treatment of hypertension, insomnia, tumour, depression, rheumatism and as a tonic. This study was carried out to investigate antidepressant- and anxiolytic-like effect of the hydroethanol stem bark extract of M. indica (HeMI) in mice. Methods: HeMI (12.5-100 mg/kg, p.o.) was administered 1 h before subjecting the animal to the forced swim test (FST), tail suspension test (TST) and elevated plus maze tests (EPM). Results: HeMI (12.5-100 mg/kg, p.o.) treatment produced significant reduction in immobility time [F(6.56)=8.35, p<0.001], [F(6,56)=7.55, p<0.001] in the FST and TST, respectively. Moreover, co-administration of sub-therapeutic doses of imipramine or fluoxetine with HeMI (3.125 mg/kg) elicited significant reduction in time spent immobile in the FST. However, pretreatment of mice with parachlorophenylalanine, metergoline, yohimbine or sulpiride abolished the antidepressant-like effect elicited by HeMI. In the EPM, HeMI produced significant [F(5,42)=8.91, p<0.001] increase in open arms exploration by 75.55 % and this effect was blocked by pretreatment of mice with flumazenil or metergoline. Conclusions: Findings from this study showed antidepressant-like effect of M. indica through interaction with 5-HT2 receptor, α2-adrenoceptor and dopamine D2-receptors. Also, an anxiolytic-like effect through its affinity for 5-HT2 and benzodiazepine receptors. Hence, M. indica could be a potential phytotherapeutic agent in the treatment of mixed anxiety-depressive illness.