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Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and clinical evidence


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Research in the area of herbal psychopharmacology has increased markedly over the past decades. To date however, a comprehensive review of herbal antidepressant, anxiolytic and hypnotic psychopharmacology and applications in depression, anxiety and insomnia has been absent. A search of MEDLINE (PubMed), CINAHL, PsycINFO, and the Cochrane Library databases was conducted (up to February 21st 2011) on commonly used psychotropic herbal medicines. A review of the literature was conducted to ascertain mechanisms of action of these botanicals, in addition to a systematic review of controlled clinical trials for treatment of mood, anxiety and sleep disorders, which are common comorbid psychiatric disorders. Specific emphasis was given to emerging phytomedicines. Analysis of evidence levels was conducted, as were effect sizes (Cohen's d) where data were available. Results provided evidence of a range of neurochemical, endocrinological, and epigenetic effects for 21 individual phytomedicines, which are detailed in this paper. Sixty six controlled studies were located involving eleven phytomedicines. Several of these provide a high level of evidence, such as Hypericum perforatum for major depression, and Piper methysticum for anxiety disorders. Several human clinical trials provide preliminary positive evidence of antidepressant effects (Echium amoenum, Crocus sativus, and Rhodiola rosea) and anxiolytic activity (Matricaria recutita, Ginkgo biloba, Passiflora incanata, E. amoenum, and Scutellaria lateriflora). Caution should however be taken when interpreting the results as many studies have not been replicated. Several herbal medicines with in vitro and in vivo evidence are currently unexplored in human studies, and along with use of emerging genetic technologies "herbomics", are areas of potential future research.
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Herbal medicine for depression, anxiety and
insomnia: A review of psychopharmacology and
clinical evidence
Jerome Sarris
, Alexander Panossian
, Isaac Schweitzer
Con Stough
, Andrew Scholey
The University of Melbourne, Faculty of Medicine, Department of Psychiatry, Australia
Swinburne University of Technology, Centre for Human Psychopharmacology, Australia
Swedish Herbal Institute Research & Development, Sweden
Received 1 December 2010; received in revised form 9 March 2011; accepted 6 April 2011
Herbal medicine;
St John's wort;
Research in the area of herbal psychopharmacology has increased markedly over the past decades.
To date however, a comprehensive review of herbal antidepressant, anxiolytic and hypnotic
psychopharmacology and applications in depression, anxiety and insomnia has been absent. A search
of MEDLINE (PubMed), CINAHL, PsycINFO, and theCochraneLibrarydatabaseswas conducted (up to
February 21st 2011) on commonly used psychotropic herbal medicines. A review of the literature was
conducted to ascertain mechanisms of action of these botanicals, in addition to a systematic review
of controlled clinical trials for treatment of mood, anxiety and sleep disorders, which are common
comorbid psychiatric disorders. Specific emphasis wasgiven to emergingphytomedicines. Analysis of
evidence levels was conducted, as were effect sizes (Cohen's d) where data were available. Results
provided evidence of a range of neurochemical, endocrinological, and epigenetic effects for 21
individual phytomedicines, which are detailed in this paper. Sixty six controlled studies were located
involving eleven phytomedicines. Several of these provide a high level of evidence, such as
Hypericum perforatum for major depression, and Piper methysticum for anxiety disorders. Several
human clinical trials provide preliminary positive evidence of antidepressant effects (Echium
amoenum,Crocus sativus,andRhodiola rosea) and anxiolytic activity (Matricaria recutita,Ginkgo
biloba,Passiflora incanata,E. amoenum,andScutellaria lateriflora). Caution should however be
taken when interpreting the results as many studies have not been replicated. Several herbal
medicines with in vitro and in vivo evidence are currently unexplored in human studies, and along
with use of emerging genetic technologies herbomics, are areas of potential future research.
© 2011 Elsevier B.V. and ECNP. All rights reserved.
Corresponding author at: The University of Melbourne, Department of Psychiatry &The Melbourne Clinic, 2 Salisbury Street Richmond,
Victoria 3121, Australia. Tel.: +613 9420 9255; fax: +61 3 9427 7558.
E-mail address: (J. Sarris).
0924-977X/$ - see front matter © 2011 Elsevier B.V. and ECNP. All rights reserved.
European Neuropsychopharmacology (2011) xx, xxxxxx
NEUPSY-10384; No of Pages 20
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
1. Introduction
1.1. Overview of herbal psychopharmacology
Mood, anxiety, and sleep disorders are prevalent and highly
comorbid psychiatric conditions (Kessler et al., 2005) that
have been treated with botanical medicines since antiquity.
Contemporaneously, herbal medicine and Complementary
and Alternative Medicine (CAM) use is widespread amongst
sufferers of mood and anxiety disorders. Data from a
nationally representative sample of 2055 people interviewed
during 19971998 revealed that 57% of those suffering
anxiety attacks, and 54% of those with severe depression
reported using herbal medicine and CAM therapies during the
previous 12 months to treat their disorder (Kessler et al.,
2001). Interviews of 82 psychiatric North American inpatients
hospitalised for acute care for various psychiatric disorders
revealed that 44% had used herbal medicine (mainly for
psychiatric purposes) during the previous 12 months (Elkins
et al., 2005).
Scientific understanding of psychoactive plants has
significantly advanced over the last two centuries, after
the isolation of active constituents, such as morphine from
opium poppies (Pengelly, 1997). Modern research on herbal
medicine in psychiatry although still in its infancy, has
increased in recent years with a 50% increase in the
literature over 5 years up to 2008 (García-García et al.,
2008). Research into psychoactive plants that may affect the
central nervous system (CNS) has flourished, with an
abundance of pre-clinical in vitro and in vivo studies
validating many phytotherapies as having an array of
biopsychological effects (Kumar, 2006). Aside from notable
psychoactive constituents isolated from plants (usually
containing alkaloids) such as cocaine from Erythroxylon
coca (coca), morphine from Papaver somniferum (opium
poppy), or arecoline from Areca catechu (betel nut), other
less potent plants, such as Hypericum perforatum (St John's
wort), have developed evidence of beneficial therapeutic
activity over the last several decades (Spinella, 2001). Many
of these that are available as over-the-counterpsychotro-
pic herbal medicines are fairly safe, and present with fewer
side effects in comparison to conventional pharmacother-
apies such as antidepressants (cholinergic symptoms, sexual
dysfunction, insomnia, and withdrawal issues) and benzodi-
azepines (somnolence, dependence and withdrawal issues)
(Baldwin et al., 2007; Papakostas, 2008; Schweitzer et al.,
2009). Regardless, not all commonly used phytomedicines
are safe, for example there are case reports (albeit rare) of
H. perforatum causing switching to mania in bipolar disorder
(Fahmi et al., 2002) and drug interactions (Madabushi et al.,
2006), and liver toxicity with Piper methysticum (kava)
(Teschke, 2010).
Mainstream drug development and, to some degree
traditional pharmacognosy (study of nature-derived drugs),
often use isolated single active principles from plant
material (Heinrich et al., 2004). In some cases this is highly
effective, leading for example to the development of
aspirin, opiate anaesthetics, digitoxin and taxol. However
in certain cases, attempts to isolate the active principles
from plant extracts may be ultimately self-defeating since
overall biological effects often rely on synergistic and
polyvalent interactions between plant components (William-
son, 2001). Thus while in some instances it may be possible to
isolate single active principle from plants, it is more common
for plant extracts to contain numerous potentially psycho-
active components. Presence of several psychoactive com-
pounds in one plant may have a synergisticeffect, defined
as a working together effect seen by a combination of
substances that is greater than would have been expected
from a consideration of individual contributions(Heinrich
et al., 2004). The silver bulletconcept adopted by
orthodox Western medicine for the drug discovery over the
past 100 years, is now increasingly viewed as inadequate in
many clinical situations (Wermuth, 2004). As a result, a
cocktail of drugs are now commonly employed against
conditions such as HIV infection, cancer or hypertension.
These synergistic and polyvalence concepts have been used
in traditional medicinal systems (e.g. TCM and Ayurvedic
medicine) for millennia (Bensky and Gamble, 1991), and now
have become accepted as the practice of polypharmacy. The
use of polypharmacy in psychiatry is increasing, with use of
combinations of antidepressants (Patten and Beck, 2004) and
antipsychotics (Tranulis et al., 2008) being commonly
employed. For example Comer et al. (2010) found that
across a 12 year period (19962007) combination psychotro-
pic treatment in children rose from 14.3% to 20.2% (adjusted
OR = 1.89, 95% CI:1.22,2.94; pb0.01).
An example of synergy can be found in Salvia spp. (sage)
which is known to have pro-cognitive and cholinesterase
inhibiting properties (Scholey et al., 2008). Savelev et al.
(2003) examined the cholinesterase inhibiting properties of
components from Salvia lavandulaefolia essential oil. Com-
binations of constituents demonstrated enhanced cholines-
terase inhibition via in vitro synergy at levels which would
not be predicted from the activities of individual compo-
nents. Epigenetic studies are already demonstrating that
combinations of constituents are not only having an added
effect of triggering the expression of genes, they are in fact
triggering. An example of this can be found in a study of a
multi-compound herbal product Phytodolor which contains
three anti-inflammatory herbs. Epigenetic assays showed
that the gene expression profile of the whole formula was
unique, and did not reflect the effects from the individual
herbs (Jordan et al., 2010).
A related concept to synergy is that of polyvalence
(Houghton, 2009) which, unlike synergy (which strictly
speaking refers to single pharmacological effect), describes
the range of biological activities that a herbal extract may
exhibit which contribute to the overall in vivo or clinical
effect. Polyvalence can occur due to a variety of chemicals
being present, each having different physiological effects, or
to the presence of one particular chemical which has more
than one disease-relevant physiological effect (Houghton,
2009). Alternatively an extract may contain compounds
which do not directly affect the pathophysiological process-
es, but which may modify the absorption, distribution,
metabolism and excretion of bioactive constituents, or
reduce their side-effects (Williamson, 2001). Examples
relevant to the current paper include Valeriana officinalis
(valerian) which contains constituents with a range of
properties relevant to anxiolysis, muscle relaxation, and
sleep promotion (Patočka and Jakl, 2010). These include
γaminobutyric acid (GABA)-ergic compounds such as free
2 J. Sarris et al.
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
GABA, benzodiazepine receptor-binding flavonoids, the
terpenes valerenic acid and valepotriates, which inhibit
GABA breakdown and cause smooth muscle relaxation, as
well as lignans which inhibit serotonin binding (Benke et al.,
2009; Neuhaus et al., 2008). The action of these in concert
may underlie behavioural effects. Similarly H. perforatum
contains at least two widely studied neuro-active compo-
nents: hyperforin and hypericin (Butterweck and Schmidt,
2007), however research has shown that the presence or
absence of a simple flavonoid compound rutinsignificantly
modulates the antidepressant effect of the plant (Wurglics
and Schubert-Zsilavecz, 2006).
A more relevant issue might be the extent to which
botanical extracts used in behavioural research are (or have
the potential to be) standardised. Translating and comparing
the findings of one study to another without knowledge of
any standardisation remains difficult, if not impossible, even
when results appear consistent between studies. Even
standardisation based on concentrations of one or several
psychoactive components does not guarantee that there is
batch-to-batch consistency or phytoequivalence, and this
should be borne in mind when examining literature on herbal
psychopharmacology (Scholey et al., 2005).
1.2. Herbal psychotropic mechanisms of action
Both at the cellular and whole organism level, a plethora of
molecular processes are involved in stress responses mediated
by the CNS. Consequently many compounds may be active
against a range of targets, all contributing to the observed
effect. Given the complexity of psychiatric disorders (e.g.
depression, anxiety or insomnia), modulation of single
neurotransmitter target may not necessarily treat the patient
as successfully as approaches that target multiple neuroendo-
crine systems. This is evidenced by the growing body of
positive studies using adjunctive combinations of interventions
to enhance efficacy in mood disorders (Sarris et al., 2010a).
Mechanisms of action for herbal medicines used for
treatment of psychiatric disorders primarily involve modu-
lation of neuronal communication, via specific plant metabo-
lites binding to neurotransmitter/neuromodulator receptors
(Spinella, 2001), and via alteration of neurotransmitter
synthesis and general function (Sarris, 2007). Other actions
may involve stimulating or sedating CNS activity, and regulating
or supporting the healthy function of the endocrine system
(Kumar, 2006; Sarris, 2007; Spinella, 2001). Herbal medicines
have a range of psychotherapeutic actions which may include
antidepressant, anxiolytic, nootropic (cognitive enhancing),
sedative, hypnotic and analgesic effects (Spinella, 2001). Other
traditionally viewed effects that may not follow standard
terminology include adaptogenicand tonicactions, which
are posited to provide increased adaptation to exogenous
stressors via complex effects on neurochemistry and the
endocrine system (Panossian and Wikman, 2009). Such actions
may be clinically relevant to a range of psychiatric disorders,
including mood, anxiety and sleep disorders, which are
prevalent conditions (Kessler et al., 2005). Similarly, the
mechanisms of action underlying these disorders, while varied,
still interface with each other, and often when certain
underlying neurological, endocrine or circadian factors are
treated, a beneficial effect may be observed in other domains.
This may potentially impact the treatment of other comorbid
psychiatric disorders e.g. if depression is treated then anxiety
may resolve, or if insomnia is addressed then depression may be
One way to explore the psychopharmacological effects of
herbal medicines and to increase their clinical validation is via
the use of omicgenetic technologies (Ulrich-Merzenich et al.,
2007). Omics include pharmacogenomics, proteomics (epige-
netics), and metabolomics. The use of omic technology in
phytotherapy (field of herbal medicine) may be termed
herbomics. Omic technologies may provide answers on
pharmacodynamics, toxicity/safety, synergy effects, and clin-
ical efficacy. One such application of omic technology is the
testing of epigenetic effects of herbal medicines via proteomic
assays. The results of two epigenetic studies conducted in the
area of herbal psychopharmacology, reveal interesting effects.
Wong et al. (2004) conducted gene expression tests in an animal
model comparing 8 weeks of a single daily intravenous dose of
imipramine, H. perforatum, or saline control. Results showed
that the herb differentially regulated 66 genes and expression
sequence tags, while imipramine regulated 74. Six common
transcripts (concerning synaptic and energy metabolism func-
tions) were expressed by both treatments. Another proteomic
animal model study conducted by Pennington et al. (2009)
compared genetic protein expression in H. perforatum to the
antidepressant clomipramine, and traditional Chinese medicine
formulation Xiao-yao-san(XYS: used for mood disorders in
Asia). From the 1616 protein spots analysed, H. perforatum was
found to differentially express, in HT22 cells derived from
mouse rat hippocampal cells, 64 proteins, XYS 40 proteins, and
clomipramine 90 proteins. Mass spectrometry revealed that
forty-three protein spots were found to have overlapping
expressions, with the most affected involving energy metabo-
lism. Western blotting analysis revealed that both the herb and
clomipramine increased expression of two forms of DRP-2, a
protein involved with axonal outgrowth and regeneration, while
heat shock protein 70 (neuronal-protein folding gene) was also
found to be increased. The significance of these studies is that
they provide evidence that H. perforatum not only affects the
transcription of many genes, but modulates similar genetic
expressions to a conventional antidepressant. Future similar
proteomic studies of other herbal psychotropics hold the
promise of revealing similar genetic expressions common to
conventional pharmacotherapies.
1.3. Aims of review
While other key reviews exist in the area of natural products
and psychiatric disorders, these have either focused on an
individual disorder e.g. anxiety (Lakhan and Vieira, 2010), a
specific plant medicine e.g. H. perforatum (Kasper et al.,
2010a), or covered the area in a relatively cursory manner
(Sarris, 2007). None have provided a review of both the
mechanistic underpinnings and clinical applications across a
broad range of psychiatric disorders, nor calculated effect sizes
for the clinical studies. So while research is increasing in the
area of herbal psychopharmacology, to date no comprehensive
review exists exploring the use of botanicals in the treatment of
unipolar depression, anxiety disorders, and insomnia. These are
highly comorbid and have common pathophysiological un-
derpinnings, and as psychotropic herbal medicines exert an
3Herbal Psychopharmacology
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
array of psychopharmacological actions, it is of value to provide
a review which encompasses these interrelated areas. Thus, in
this novel paper we provide 1) a review of preclinical studies to
provide a mechanistic understanding of the activity (or
activities) of major psychotropic herbal medicines (to relate
this to psychiatric applications), and 2) a systematic review of
relevant randomised controlled clinical trials to identify and
analyse current evidence (including calculation of effect sizes
where possible).
2. Methods
A search of the electronic databases MEDLINE (PubMed), CINAHL,
PsycINFO, and The Cochrane Library was conducted up to February 21st
2011 to review the evidence of herbal medicines with anxiolytic,
antidepressant and hypnotic activity. Databases were searched firstly
for in vitro and in vivo data on the mechanisms of action of major herbal
medicines used commonly in modern phytotherapy (Mills and Bone,
2000). Next, a systematic search of controlled clinical trials using the
search terms DepressionOR Major Depressive DisorderOR Anxiety
OR Generalised Anxiety DisorderOR Panic DisorderOR Social
AnxietyOR Post-Traumatic Stress DisorderOR Obsessive Compulsive
DisorderOR Anxiety DisorderOR InsomniaOR Sleep Disorderwas
combined with the search terms Herbal MedicineOR Herb*OR
Medicinal PlantsOR Botanical Medicinein addition to thirty
individual herbal medicines (common names and Latin binomial
names) e.g. St John's wortOR Hypericum perforatum.Aforward
search of key identified papers was subsequently performed using Web
of Science cited reference search, in addition to hand-searching the
literature. Papers that met the inclusion criteria for evidence of efficacy
were human clinical trials using individual herbal medicines to treat
mood, anxiety or sleep disorders. Specific inclusion criteria: 1) rando-
mised and controlled trials (RCTs) i.e. using either an inert placebo or
active comparator control (e.g. antidepressant), 2) have a total sample
size of N10 (case studies were not included), 3) sufficient data available
for analysis, and 4) be written in English. No criteria were set for gender,
age, or ethnicity. All other papers that did not meet these criteria were
excluded. As H. perforatum,P. methysticum,andV. officinalis have an
abundance of studies, meta-analyses were primarily reviewed.
was formed from review of pre-clinical and clinical evidence in the area,
while traditional knowledge was assessed primarily via an established
pharmacopoeia: King's Dispensatory (Felter and Lloyd, 2008 (b) (1898)).
Analysis of the level of evidence in the clinical studies table was
performed by the researchers, with disagreements resolved by mutual
consensus. Levels of evidence were defined as: Level Ameta-analyses
or replicated RCTs with positive results; Level Bone unreplicated RCT,
or studies with mixed but mainly positive results; Level Cone or more
clinical trials with poor methodology, or mixed or unsupportive evidence
from clinical trials. Where sufficient data of the clinical trials where
available, we calculated effect sizes as Cohen's dby firstly subtracting
the differences in scores between placebo and intervention (between
baseline and endpoint), then dividing this by the pooled baseline
standard deviation. Post treatment standard deviations were used when
baseline data was absent (Cohen, 1988).
3. Results
3.1. Preclinical psychopharmacology
3.1.1. Herbal antidepressants and depression
It is estimated that by the year 2020, depression will result in
the second greatest increase in morbidity after cardiovascular
disease, presenting a significant socioeconomic burden (WHO,
2006). The pathophysiology of major depressive disorder (MDD)
is complex, and it appears that a variety of overlapping
biological causations exist (Belmaker and Agam, 2008). In the
last several decades, the main premise concerning the
biopathophysiology of MDD has focused on monoamine impair-
ment (dysfunction in monoamine expression and receptor
activity), lowering of monoamine production, or secondary
messenger (e.g. G proteins or cyclic AMP) system malfunction
(Hindmarch, 2001; Ressler and Nemeroff, 2000). In recent
years, added attention has also focused on the role of neuro
endocrinological abnormalities involving cortisol excess and its
impeding effects on neurogenesis via reducing brainderived
neurotropic factor, as well as impaired endogenous opioid
function, changes in GABAergic and/or glutamatergic transmis-
sion, cytokine or steroidal alterations, and abnormal circadian
rhythm (Antonijevic, 2006; Hindmarch, 2001; Plotsky et al.,
1998; Raison et al., 2006; Ressler and Nemeroff, 2000).
Several herbal medicines revealed an array of pre-clinical
antidepressant activity, with seven being detailed in Table 1.
Some antidepressant herbal medicines such as H. perforatum,
Rhodiola rosea (roseroot), Crocus sativus (saffron) offer promise
for the treatment of this disorder via known psychopharmaco-
logical actions including inhibition of monoamine re-uptake
(such as serotonin, dopamine and noradrenaline), enhanced
binding and sensitisation of serotonin receptors, monoamine
oxidase inhibition, and neuro-endocrine modulation (Kumar,
2006; Sarris, 2007; Spinella, 2001). Other effects may include
GABAergic effects, cytokine modulation (especially in depres-
sive disorders with a comorbid inflammatory condition), and
opioid and cannabinoid system effects (Spinella, 2001). In the
case of most phytomedicines the antidepressant mechanisms of
action are not as clearly defined as with SSRIs, having a
multitude of biological effects on reuptake and receptor binding
of various monoamines, commonly in addition to endocrine and
psychoneuroimmunological modulation (Butterweck and
Schmidt, 2007; Sarris and Kavanagh, 2009).
Some herbal medicines with mood elevating effects (such as
R. rosea and C. sativus) also display anxiolytic effects. This may
be due to modulation of neurological pathways that have both
antidepressant and anxiolytic effects (e.g. GABA, serotonin,
and noradrenaline systems), or this may be due to a halo
effectwhereby when depression is effectively treated, anxiety
may also be reduced (Brady and Verduin, 2005; Nierenberg,
2001). This was found in the case in a recent RCT involving
participants with generalised anxiety, which found that
P. methysticum (an established anxiolytic) in addition to
anxiety reduction, also provided a statistically significant
reduction of comorbid depression on the MontgomeryAsberg
Depression Rating Scale (Sarris et al., 2009a).
3.1.2. Herbal anxiolytics and anxiety
Anxiety disorders such as generalised anxiety disorder (GAD),
social phobia, and post traumatic stress disorder present with a
marked element of psychological anxiety and distress (American
Psychiatric Association, 2000). The pathophysiology of anxiety
disorders is still being unravelled, although current evidence
indicates that the neurobiology involves abnormalities of
serotonergic, noradrenergic, glutamatergic, and GABA-ergic
transmission (Nutt et al., 2002). The involvement of these
pathways is reflected in the efficacy of selective serotonin
reuptake inhibitors (SSRIs), selective serotonin and noradrenalin
reuptake inhibitors (SNRIs), and benzodiazepines (Tyrer and
Baldwin, 2006).
4 J. Sarris et al.
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
Table 1 Herbal antidepressants: mechanisms of action and clinical applications.
Herbal medicine Mechanisms of actionType of
Major active constituents
Dep Anx Ins
(Echium amoenum)
Anxiolysis shown in an animal model
(elevated plus maze test)
Antidepressant mechanism
currently unknown
(Rabbani et al., 2004)
1,2,3 2,3 Depression
rosmarinic acid thesinine
(Lavandula spp.)
GABA modulation
(based on volatile constituents)
Anxiolysis shown in animal
models (elevated plus maze and
open field tests)
(Atsumi and Tonosaki, 2007;
Bradley et al., 2007; Perry and
Perry, 2006; Shaw et al., 2007;
Toda and Morimoto, 2008)
1,2,3 2,3 2,3 Depression
linalool linayl acetate
Korean ginseng
(Panax ginseng)
HPA-axis modulation
Monoamine modulation
(dopamine, serotonin)
Anti-inflammatory and
antioxidant effects
Nitric oxide synthase
inhibition (Bhattacharya and
Mitra, 1991; Chen, 1996; Dang
et al., 2009; Joo et al., 2005;
Kim et al., 2003; Park et al., 2005)
1,2,3 ––Fatigue
Poor cognition
ginsenoside Rb1
ginsenoside Rg1
(Albizia julibrissin)
receptor binding affinity
receptor binding affinity
Antidepressant, anxiolytic
effects in animal models (elevated
plus maze and tail suspension tests)
Significantly decreased sleep latency
and increased sleep duration
in pentobarbital-induced sleep
(Cao et al., 2010; Cho et al., 2010;
Jung et al., 2005; Kim et al., 2007;
Kim et al., 2004)
2,3 2,3 2,3 Depression
(continued on next page)
5Herbal Psychopharmacology
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
Table 1 (continued)
Herbal medicine Mechanisms of actionType of
Major active constituents
Dep Anx Ins
(Rhodiola rosea)
Neuroendocrine modulation
(inhibition of cortisol, stress-induced
protein kinases, nitric oxide)
Monoamine oxidase A inhibition
Monoamine modulation
Normalisation of 5-HT and anti-stress
effects in animal depression models
(Chen et al., 2009; Panossian et al. 2007,
Panossian et al. 2008; Mattioli et al., 2009;
Perfumi and Mattioli, 2007;
van Diermen et al., 2009)
1,2,3 1,2,3 Fatigue
(Crocus sativus)
Re-uptake inhibition of monoamines
(dopamine, norepinephrine, serotonin)
NMDA receptor antagonism
Anxiolytic effects in animal models
(elevated plus maze and open field test)
(Hosseinzadeh and Noraei, 2009;
Lechtenberg et al., 2008?;
1,2,3 2,3 Depression
St John's wort
(Hypericum perforatum)
Modulation of monoamine
transmission via Na+ channel
Nonselective inhibition of re-uptake
of serotonin, dopamine, norepinephrine
Decreased degradation of neurochemicals
Increased binding/sensitivity/
density to 5-HT
Dopaminergic activity (prefrontal cortex)
Inhibited neuronal release of glutamate
Neuroendocrine modulation
Anti-depressant and anxiolytic
activity in animal models
(Butterweck, 2003; Chang and Wang, 2010;
Franklin et al., 2006; Muller and Rossol, 1994;
Singer et al., 1999; Yoshitake et al., 2004)
1,2,3 2,3 3 Depression
1 Human clinical data, 2 Experimental evidence of activity, 3 Traditional systems of medicine and pharmacopoeias endorse use.
Dep= Depression, Anx = Anxiety, Ins = Insomnia.
6 J. Sarris et al.
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
Table 2 Herbal anxiolytics: mechanisms of action and clinical applications.
Herbal medicine Mechanisms of action Evidence Potential clinical
Major active constituents
Dep Anx Ins
(Bacopa monniera)
Metal chelation/β-amyloid protection
Cholinesterase inhibition
Antioxidant effects
Antidepressant effects in forced swim and learned
helplessness animal models (Krishnakumar et al.,
2009; Limpeanchob et al., 2008; Sairam et al., 2002;
Stough et al., 2001; Tripathi et al., 1996)
2,3 2,3 3 Cognitive impairment
Nervous exhaustion bacoside A bacoside P
California poppy
(Eschscholzia californica)
Binding affinity with GABA receptors
(flumazenil antagonist)
Anxiolysis in animal models (familiar
environment and anti-conflict tests)
(Hanus et al., 2004; Kleber et al., 1995; Rolland
et al., 2001; Rolland et al., 1991; Schafer et al., 1995)
2,3 2,3 Anxiety
Pain escholidine
(Matricaria recutita)
Binding to GABA receptors
Modulates monoamine neurotransmission
Neuroendocrine modulation (Avallone et al.,
2000; Awad et al., 2007; Salgueiro et al., 1997;
Viola et al., 1995; Zanoli et al., 2000)
1,2,3 3 Anxiety
Stress apigenin
(Ginkgo biloba)
Modulation of cholinergic and monoamine pathways
Antioxidant, anti-PAF, anti-inflammatory effects
GABAergic effects
Nitric oxide activity
(Di Renzo, 2000; Woelk et al., 2007)
2 1,2 Cognitive
Depression ginkolide bilobalide
Gotu cola
(Centella asiatica)
GABA transaminase inhibition
Animal models have shown anxiolytic effects (elevated
plus maze, open field, social interaction tests)
Inhibition of acoustic startle response in human RCT
(Awad et al., 2007; Bradwejn et al., 2000; Wijeweera
et al., 2006)
3 1,2,3 Anxiety
(Piper methysticum)
GABA channel modulation (lipid membrane
structure and sodium channel function)
Weak GABA binding (increased synergistic effect of
[3H]muscimol binding to GABA-ɑreceptors)
1,2,3 1,2,3 1,2,3 Anxiety
Comorbid depression
Anxious insomnia
ADHD kawain dihydrokawain
(continued on next page)
7Herbal Psychopharmacology
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
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Table 2 (continued)
Herbal medicine Mechanisms of action EvidencePotential clinical
Major active constituents
Dep Anx Ins
β-adrenergic downregulation
MAO-B inhibition
Re-uptake inhibition of norepinephrine in
the prefrontal cortex (Boonen and Haberlein,
1998; Davies et al., 1992; Jussofie et al., 1994;
Magura et al., 1997; Uebelhack et al., 1998)
(Melissa officinalis)
Potent in vitro inhibitor of rat brain GABA
transaminase (GABA-T)
MAO-A inhibition
Acute dosing caused a significant increase
in self-rated calmness on a human stress tests
(Awad et al., 2009; Kennedy et al., 2004;
Kennedy et al., 2002; Lopez et al., 2009)
2,3 1,2,3 3 Acute stress
citranellal geraniol
(Passiflora spp.)
GABA-system mediated anxiolysis
Benzodiazepine receptor partial agonist
Animal behavioural models have shown
non-sedative anxiolytic effects
(elevated-plus maze, light/dark box choice tests)
(Dhawan et al., 2001a, b, 2002; Grundmann
et al., 2009; Grundmann et al., 2008;
Sena et al., 2009)
1,2,3 1,3 Anxiety
(Scutellaria lateriflora)
Posited GABA-αbinding affinity
Anxiolysis in animal maze-test model
(Awad et al., 2003)
3 1,2,3 3 Anxiety
Nervous exhaustion
scutelaterin A
(Withania somnifera)
GABA-mimetic activity
(enhanced flunitrazepam binding)
Anxiolytic effect comparable to that produced
by lorazepam in animal models (elevated plus-
maze, social interaction and feeding latency in an
unfamiliar environment tests) (Bhattacharya
et al., 2000; Bhattacharya and Muruganandam,
2003; Mehta et al., 1991)
2,3 2,3 3 Anxiety
Nervous exhaustion
1 Human clinical data, 2 Experimental evidence of activity, 3 Traditional systems of medicine and pharmacopoeias endorse use.
Dep = Depression, Anx = Anxiety, Ins = Insomnia.
8 J. Sarris et al.
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clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
In Table 2, ten herbal medicines with known anxiolytic
effects are detailed. Phytotherapeutic interventions that may
benefit anxiety disorders such as P. methysticum are classed as
anxiolytics, and usually have effects on the GABA system,
(Sarris, 2007) either via inducing ionic channel transmission by
blockage of voltage-gates, or blockage, or through alteration of
membrane structures, (Sarris and Kavanagh, 2009)GABA
transaminase or glutamic acid decarboxylase inhibition, (Awad
et al., 2007) or less commonly via binding with benzodiazepine
receptor sites (e.g. the αsubunit)(Spinella, 2001). Subsequent
increased GABA neurotransmission has a damping effect of
stimulatory pathways, which ultimately provides a psychologi-
cally calming effect (Baldwin and Polkinghorn, 2005).
A novel study by Awad et al. (2007) was conducted to
determine whether several common botanicals directly af-
fected the primary brain enzymes responsible for GABA
metabolism. In vitro rat brain homogenate assays revealed
that, of the preparations assessed, the aqueous extract of
Melissa officinalis (lemon balm) exhibited the greatest inhibi-
tion of GABA transaminase activity, while Matricaria recutita
(chamomile) and Humulus lupulus (hops) showed significant
inhibition of glutamic acid decarboxylase activity.
3.1.3. Herbal hypnotics and insomnia
Insomnia is a common affliction in Western societies, with
the prevalence of general sleep disturbance experienced by
people over a year is estimated at approximately 85%, while the
estimate of diagnosed primary insomnia is estimated at around
10% (Roth and Roehrs, 2003). The pathophysiology behind sleep
disorders appears to involve hyperarousalof the neuroendo-
crine system caused by abnormalities in circadian rhythm
(involving CLOCK genes, melatonin secretion, and adenosine
receptors), GABA pathways, endocrine factors (high cortisol),
and excitatory pathways involving glutamate and aspartate
(Roth et al., 2007; Sateia and Nowell, 2004).
Herbal hypnotics and sedatives such as Valeriana spp. and
H. lupulus are believed to work via modulation of adenosine
receptors (for example antagonising the adenosine blocking
effects of caffeine), melatonergic effects, or via GABAergic
activity (Sarris, 2007; Sarris and Byrne, 2011; Spinella, 2001).
Anxiolysis that occurs from GABA modulation may also have
follow-on soporific effects (potentially in stress-induced in-
somnia) (Sarris et al., 2009a). This may occur due to shared
common pathways via a general down-regulation of neurologi-
cal stimulatory activity. Due to this, plant medicines such as
Zizyphus jujuba (sour date) and V. officinalis, while commonly
used in phytotherapy for insomnia, can be both potentially also
used to treat anxiety. This is reflected in the continuum that
exists with sedating agents. As Spinella (2001) outlines, at one
end of the sedation spectrum, substances that act as mild
sedatives will cause relaxation and anxiolysis, while as the
strength of the down-regulation of biological arousal increases,
somnolence occurs, followed by marked sedation, coma and
then death. While this continuum may be relevant to plants
such as P. somniferum, it is not representative of many herbal
anxiolytic/hypnotics, which while exerting a dose-dependent
response, do not cause pronounced sedation. While only four
hypnotic herbal medicines are detailed in Table 3, several other
herbal medicines which are potentially beneficial for insomnia
also exist, and are detailed in Table 2. These include Passiflora
incanata (passionflower), Eschscholzia californica (California
poppy), P. methysticum, and Scutellaria lateriflora (scullcap).
3.2. Clinical evidence in depression, anxiety, and
3.2.1. Overview of results
A systematic search of the literature revealed 2975 papers
(includingpreclinical and clinicalstudies, meta-analyses, reviews,
and commentaries), of which 66 relevant RCTs (including studies
in meta-analyses) involving eleven individual plant medicines
merited fin al inclusion (Table 4). Clinical study methodology (from
controlled trials and meta-analyses) revealed typical treatment
durations of between 4 and 8 weeks, and sample sizes of
approximately 3060 participants. Three phytomedicines dis-
played level A evidence (evidence analysis discussed in methods);
P. methysticum for generalised anxiety and H. perforatum and C.
sativus for unipolar depression. Meta-analyses and systematic
reviews of P. methysticum and H. perforatum revealed significant
effects over placebo and comparable effects to synthetic agents
(Linde et al., 2008; Pittler and Ernst, 2003; Sarris and Kavanagh,
2009). The majority of phytomedicines (six) had level B evidence,
denoting that many single trials exist but that these are yet to be
replicated, thus more RCTs are required to make firm conclusions.
Four phytomedicines were found to have level C grade of
evidence: Scutellaria officinalis for anxiety (positive but poor
methodology), V. officinalis (mixed evidence) and P. incanata
(positive result only on one outcome) for insomnia, and H.
perforatum with no significant effect in obsessivecompulsive
disorder (OCD) or social phobia.
3.2.2. Clinical evidence in depression
Several herbal medicines with antidepressant effects in
preclinical models have been subjected to clinical trials (see
Table 4). A recent meta-analysis of H. perforatum RCTs was
conducted by Rahimi et al. (2009). Comparison of H. perfor-
atum with placebo yielded a significant relative risk (RR) for
response in favour of the active of 1.22 (95% CI: 1.03, 1.45) and
a weighted mean difference between treatments of 1.33 points
(95% CI: 1.15, 1.51) on the Hamilton Depression Rating Scale
(HAMD). Comparison with SSRIs yielded a non-significant
difference between treatments of 0.32 (95% CI: 1.28, 0.64)
for mean reduction in HAMD score from baseline. Importantly, a
significant difference in favour of H. perforatum over conven-
tional antidepressants for withdrawals due to adverse events
was found: RR of 0.53 (95% CI: 0.35, 0.82). The results of this
meta-analysis is comparable to the Linde et al. (2008) meta-
analysis which provided a RR of 1.48 (95% CI: 1.23, 1.77) from 18
combined studies for response versus placebo, and an equivocal
effect with synthetic antidepressants (SSRIs) RR 1.00 (95% CI:
0.90, 1.15). A recent long-term follow-up study involving 426
responders to extract WS 5570 were assessed for remission rates
after continuation of 26 weeks of randomised WS 5570 (300 mg
three times a day standardised to between 3 and 6% hyperforin
and not less than 6% flavonoids) or placebo (Kasper et al.,
2008). Results revealed a relapse rate for completers of 18%
(51/282) compared to 25.7% (37/144) for placebo. Average
relapse time for SJW was 14 days longer compared to placebo,
which while statistically significant, is still a modest result.
Standardisation and quality is an issue of note with SJW, as
extracts show variability of efficacy potentially due to different
constituent profiles (Kasper et al., 2010a). Due to this, results
using high quality European pharmaceutical grade extracts
cannot be transferred to some inferior extracts.
9Herbal Psychopharmacology
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clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
Table 3 Herbal hypnotics: mechanisms of action and clinical applications.
Herbal medicine Mechanisms of action Evidence Potential
Major active constituents
Dep Anx Ins
Chaste tree
(Vitex agnus castus)
Circadian rhythm modulation
via increased melatonin secretion
(dose-dependent effect that may
benefit sleep latency insomnia)
(Dericks-Tan et al., 2003)
1,2,3 2 Insomnia
(Humulus lupulus)
Melatonin receptor modulation
(binding affinity to M
and M
Hypothermic activity
(Abourashed et al., 2004; Brattstrom,
2007; Butterweck et al., 2007)
2,3 1,2,3 Insomnia
humulone xanthohumol
Sour date
(Zizyphus jujuba)
Inhibits glutamate-mediated pathways
in the hippocampus
Jujubosides increased total sleep time
Animal models using suanzaoren (a TCM
formula containing Z. jujuba as the
principle herb) have found modulation of
central monoamines and limbic system
interaction (Cao et al., 2010; Chen et al.,
1985; Hsieh et al., 1986a; Hsieh et al.,
1986b; Morishita et al., 1987)
2,3 2,3 Insomnia
jujuboside A jujuboside B
(Valeriana spp.)
Adenosine (A
receptor) interactions
GABA modulation (increased binding
and decreased degradation of GABA)
Valerenic acid from valerian has
demonstrated GABA-A receptor (β3 subunit) agonism
partial agonism
Animal models have shown anxiolytic effects
(elevated plus maze)
(Benke et al., 2009; Dietz et al.,
2005; Murphy et al., 2009;
Ortiz et al., 1999; Sichardt et al.,
2007; Trauner et al., 2008)
3 2,3 1,2,3 Insomnia
Somatic tension
CNS stimulant
valerenic acid
1 Human clinical data, 2 Experimental evidence of activity, 3 Traditional systems of medicine and pharmacopoeias endorse use.
Dep=Depression, Anx = Anxiety, Ins = Insomnia.
10 J. Sarris et al.
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Table 4 Herbal psychotropics: human clinical studies.
Herbal medicine First author Methodology Results
(Echium amoenum)
(Sayyah et al., 2006)Depression: 6-week RCT (n=35) using 375mg
of Borage vs. placebo
Statistically significant reduction versus
placebo on HAMD at week but this was not
maintained at week 6. No significant effect on HAMA
(Sayyah et al., 2009a)OCD: 6-week RCT (n=44) using 500mg/day
of Borage vs. placebo
Borage significantly reduced OCD symptoms over
placebo on Y-BOCS at endpoint, in addition to
significantly reducing HAMA rated anxiety
(Matricaria recutita)
(Amsterdam et al., 2009)Anxiety: 8-week RCT (n=57) using standardised
Chamomile extract (220mg-1100mg of titrated,
depending on response) vs. placebo tablets
Chamomile significantly reduced participant's anxiety
scores on HAMA compared to placebo at the end
of eight weeks of treatment
(Ginkgo biloba)
(Woelk et al., 2007)Anxiety: 4-week RCT (n=107) 240mg, 480mg
Ginkgo extract EGb761 vs. placebo
Dose-dependent significant reduction of anxiety
over placebo of 2.2 and 6.5 points on HAMA for
480mg and 240mg doses of EGb 761, respectively
(Piper methysticum)
(Pittler and Ernst, 2003)
(Witte et al., 2005)
Anxiety: Review of 11 RCTs (N=645) and a
meta-analysis of 6 RCTS (N=345)
Anxiety: Meta-analysis
Kava WS1490 extract
6 RCTs included
Significantly greater anxiolysis from
Kava than placebo; 5.0 point reduction over
placebo on HAMA (95% CI: 1.18.8)
Odds ratio in favour of Kava= 3.3
(95% CI: 2.095.22)
(Lavandula spp.)
(Akhondzadeh et al., 2003)Depression: 4-week RCT (n=45) using
Lavender tincture (1:5 50% alcohol, 60 drops)
vs. imipramine, or the combination
Imipramine was more effective than Lavender.
The addition of Lavender to imipramine was more
effective in reducing HAMD rated depression than
imipramine alone, indicating a synergistic effect
(Passiflora incarnata)
(Akhondzadeh et al., 2001)
(Movafegh et al., 2008)
(Ngan and Conduit, 2011)
Anxiety: 4-week RCT (n=36) using 45drops of
Passionflower vs. 30mg of oxazepam
Anxiety: Acute study RCT (n=60) using 500mg of
Passionflower vs. placebo for pre-surgical anxiety
(n=41) using
2g of Passionflower tea vs. placebo (parsley)
tea before sleep
Passionflower was as effective (with less side effects)
as oxazepam in reducing anxiety
Anxiety scores were significantly lower in the
passionflower group than in the control group on a
numerical rating scale
subjective sleep quality, no significant differences
were found on other sleep outcomes
(Rhodiola rosea)
(Darbinyan et al., 2007)Depression: 6-week 3-arm RCT (n=89)
comparing 340mg vs 680mg of standardised
Roseroot vs. placebo
Both Roseroot groups has significant reduction
on HAMD significant and on insomnia, somatisation
and emotional instability subscale outcome measures
(continued on next page)
11Herbal Psychopharmacology
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Table 4 (continued)
Herbal medicine First author Methodology Results
(Crocus sativus)
(Akhondzadeh et al., 2005)
(Moshiri et al., 2006)
(Akhondzadeh et al., 2004)
(Noorbala et al., 2005)
(Akhondzadeh et al., 2007)
Depression: Five 6-week RCTs:
Two trials using 3090 mg of Saffron vs. placebo;
Three trials using Saffron vs. synthetic
Significant improvement for depression over placebo
on HAMD for Saffron petals and stamen
An equivalent therapeutic response occurred with
Saffron vs. imipramine and fluoxetine on HAMD depression
(Scutellaria lateriflora)
(Wolfson and Hoffmann,
Anxiety: Acute cross-over RCT (n=19) using
Scullcap vs. placebo
Scullcap dose-dependently reduced symptoms of anxiety
and tension after acute administration compared with placebo
St John's wort: SJW
(Hypericum perforatum)
(Rahimi et al., 2009)
(Linde et al., 2008)
(Kobak et al., 2005a)
(Kobak et al., 2005b)
Depression: Meta-analysis
SJW vs. placebo
13 RCTs
Depression: Meta-analyses
SJW vs placebo
18 RCTs (N=3064)
SJW vs Tri/tetracyclics
12 RCTs
OCD: 12-week RCT (n=60) comparing SJW
(600mg-1800mg) vs. placebo
Social Phobia:12-week RCT (n=40) using SJW
(600mg-1800mg) vs. placebo
RR 1.22 (95% CI: 1.03, 1.45) for clinical response (four studies)
Significantly greater reduction over placebo of 1.33 points
(95% CI: 1.15, 1.51) on HAMD (three studies)
SJW showed an effect comparable to synthetics
RR 0.99 (95% CI: 0.91, 1.08) for clinical response
SJW showed a significant effect on HAMD vs.
RR 1.48 (95% CI: 1.23, 1.77)
Comparable to synthetics
RR 1.00 (95% CI: 0.90, 1.15)
RR 1.02 (95% CI: 0.90, 1.15)
No significant result occurred between treatments
on Y-BOCS, nor on response rates
No significant result occurred between treatments on
the Liebowitz Social Anxiety Scale
(Valeriana spp.)
(Bent et al., 2006)
et al., 2010)
Insomnia: Systematic review 16 RCTs (N=1093)
and meta-analysis. Valerian vs. placebo or vs.
active controls
Insomnia: Systematic review and meta-analysis
of 18 RCTs, Valerian vs. placebo or active
Six studies included in meta-analysis revealed significantly
improved quality over placebo on the dichotomous outcome
of sleep quality (RR of improved sleep = 1.8, 95% CI: 1.2, 2.9)
However the review revealed 9/16 studies revealed
no positive outcomes
Valerian reduced sleep latency over placebo by only 0.70 min
(95% CI 3.44, 4.83), with the standardised mean differences
between the groups measured being statistically equivocal
0.02 (95% CI 0.35, 0.31)
Level A: Meta-analyses or replicated RCTs with positive results Level B: One unreplicated RCT, or mixed but mainly positive results Level C: One or more clinical trials with poor methodology, or
consistent mixed or unsupportive evidence. RR: relative risk ~ Evidence-based on Lavender as an adjuvant rather than as a monotherapy, HAMD: Hamilton Depression Rating Scale, HAMA:
Hamilton Anxiety Rating Scale, Y-BOCS: Yale-Brown Obsessive Compulsive Scale.
Significantis pb0.05.
Two 1-week crossover periods, with a 1-week washout between.
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clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
H. perforatum has better tolerability over some conven-
tional antidepressants, as demonstrated by Kasper et al.
(2010b) comparative analysis between paroxetine and Hyper-
icum extract WS 5570, which revealed 10 to 38 fold higher
adverse events rate for the synthetic comparator. While
concerns exist over interactions of H. perforatum with
pharmaceuticals, it should be noted that this mainly concerns
high hyperforin extracts (Izzo, 2004). This is reflected in a
systematic review of 19 studies that showed that high-dose
hyperforin extracts (N10 mg/day) had outcomes consistent with
CYP3A induction, while studies using low-dose hyperforin
extracts (b4 mg/day) demonstrated no significant effect on
CYP3A (thereby lessening the chance of increased metabolisa-
tion of many common drugs) (Whitten et al., 2006).
Two RCTs using 6090 mg of concentrated C. sativus extract
demonstrated significant improvement of depression over
placebo on the HAMD (Akhondzadeh et al., 2005; Moshiri et
al., 2006). The Akhondzadeh et al. (2005) RCT using the stamen
had a large effect size of d= 1.51, while the Moshiri et al. (2006)
study which used the cheaper petals revealed a similar large
effect size of d= 1.78. Equivalent effects on HAMD occurred in
three RCTs comparing C. sativus to imipramine and fluoxetine
(Akhondzadeh et al., 2007; Akhondzadeh et al., 2004; Noorbala
et al., 2005). Clinical trials have detailed anxiety, tachycardia,
nausea, dyspepsia and changes in appetite as possible side
effects (non-significant statistical trend against placebo)
(Akhondzadeh et al., 2005; Moshiri et al., 2006). This reflects
traditional knowledge of adverse reactions (Schmidt et al.,
2007). Although the results are encouraging, limitations exist in
confirming efficacy. Trial lengths are commonly short (4
6 weeks), sample sizes are small (n =3040). Potential bias also
exists, due to the same fraternity of researchers conducting the
only human clinical trials. Other institutions are encouraged to
validate this research, as C. sativus appears to be a promising
Only one human clinical trial was located evaluating Echium
amoenum in the treatment of depression (Sayyah et al., 2006).
Results revealed that the herb was superior to placebo in
reducing depression on the HAMD at week four of a study with
an effect size dof 0.92, however this result was not maintained
at week 6 (p= 0.07). E. amoenum also revealed no significant
anxiolytic activity on the HAMA over placebo. This plant is
currently scheduled in Australia due to the pyrrolizidine
alkaloids. In this study the only notable difference between
side effects of the herb and placebo groups were increased dry
mouth in the active group (seven participants: 41%), although
this was non-significant. One clinical trial compared Lavandula
spp. against imipramine and the combination in patients with
MDD (Akhondzadeh et al., 2003). Results revealed that although
Lavandula spp. was not as effective as its synthetic counterpart,
the combination of both was more effective than imipramine
alone, indicating a synergistic effect.
Currently there is only one readily accessible study on R. rosea
for depression, as previous research on its putative antidepressant
activity are Russian in origin, and the original papers could not be
obtained for this review. A three-arm study using R. rosea SHR-5
standardised extract (340 mg and 680 mg/day) against placebo in
the treatment of mild-moderate depressive disorder revealed a
significant dose-dependent improvement occurred in the active
groups compared with placebo (Darbinyan et al., 2007). Effect
sizes were large for both treatment groups, however conclusion
from these strong results should be tempered as there was an
unusually low response to placebo and a rather small standard
deviation, which is not typical for trials using antidepressant
compounds (Fournier et al., 2010). Although promising, confidence
in the use of R. rosea to treat MDD cannot be established until more
rigorous RCTs are undertaken.
3.2.3. Clinical evidence in anxiety
Several promising anxiolytics with traditional evidence as
relaxants have been studied in clinical trials (see Table 4). A
Cochrane review and meta-analysis of seven RCTs using
P. methysticum in various anxiety disorders (Pittler and Ernst,
2003) revealed a statistically significant mean reduction of 3.9
points on the Hamilton Anxiety Scale (HAMA) over placebo (95%
CI: 0.1, 7.7). A recent pooled analysis of P. methysticum studies
in English (Sarris et al., 2010b), including a newly published
positive study (Kava Anxiety Depression Spectrum Study) (Sarris
et al., 2009a), revealed a similar conclusion, with a positive
result occurring in four out of six studies reviewed (mean pooled
Cohen's d=1.10). Not all studies however are positive, with a
methodologically rigorous 4 week GAD study (n= 37) by Connor
and Davidson (2002) finding no significant difference between a
standardised kava extract and placebo.
P. methysticum was withdrawn from European and UK
markets in 2002 due to concerns over reported hepatotoxicity.
Research has been conducted over recent years to determine
the pathogenesis, and present understanding of factors poten-
tially responsible for hepatotoxicity include incorrect cultivar
(medicinal, tudie or wichmanni varieties) being used, indivi-
duals' hepatic insufficiency to metabolise kavalactones (cyto-
chrome P450 (CYP) 3A4 and 2D6), preparations made using
acetonic or ethanolic media low in glutathione, potentially
contaminated or poorly stored material, and use of aerial parts
or root peelings which are higher in alkaloids (Sarris et al.,
2010c). Due to this, use of only the peeled roots from noble
cultivars (cultivated species that are traditionally considered
safe and therapeutic) using a water solute extraction method is
advised (Teschke et al., in press).
S. lateriflora has been studied in one clinical trial to
examine its anxiolytic activity. A clinical trial revealed that
acute administration of the herb dose-dependently attenuated
anxiety and tension on a numerical rating scale (Wolfson and
Hoffmann, 2003). However, the methodology was poor and
quantitative results on the outcome measures were not clearly
elucidated (thereby precluding the calculation of an effect
size). A pilot RCT using P. incanata extract revealed equivocal
efficacy to oxazepam (30 mg/day) in reducing anxiety, with
fewer side effects (Akhondzadeh et al., 2001). A non-statistical
trend towards decreased sedation and impaired job perfor-
mance occurred in the herbal medicine group. While the results
are positive, no definitive conclusion can be reached, as anxiety
conditions are notorious for high placebo response, and no
placebo arm was used. An acute study using P. incanata against
placebo control for pre-surgical anxiety revealed a significant
reduction of anxiety in favour of the herb on a numerical rating
scale (d=1.30) (Movafegh et al., 2008). Importantly, no
difference in the anaesthetic sedation levels occurred between
groups. Analysis of side effects of P. incanata studies in a
Cochrane Review revealed no current evidence of any safety
concerns with the plant (Miyasaka et al., 2007).
A recent RCT was conducted using a flexible dose of
M. recutita in patients with diagnosed GAD and a moderate
level of anxiety. Results revealed a significant effect in favour
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oftheinterventionwithalargeeffectsized=0.90(Amsterdam et
al., 2009). No significant adverse reactions were found in the M.
recutita group, even with higher doses. An RCT using Ginkgo biloba
(ginkgo) EGb 761 extract (480 mg or 240 mg/day) or placebo in
patients with GAD and adjustment disorder with anxious mood,
revealed a significant dose-dependent reduction on the HAMA over
placebo in both groups (Woelk et al., 2006). Effects sizes for GAD
were large in both the 480 mg/day group (d=1.14), and the
240 mg/day group (d=0.76). While increased idiosyncratic bleed-
ing time has been documented in rare case studies, the herb is
regarded as having a good safety profile (Koch, 2005).
Aside from application in depression, H. perforatum has been
studied for use in social phobia and OCD. In one controlled study,
participants with a primary diagnosis of OCD were randomised to
12 weeks of treatment of H. perforatum (flexible dosing 600 mg
1800 mg depending on response) or matching placebo (Kobak et
al., 2005a). Results revealed that the meanreduction on the Yale
Brown Obsessive Compulsive Scale (Y-BOCS) in the active group
(3.43) did not significantly differ from the placebo group
(3.60). Significant differences were also not found on any of
the Y-BOCS subscales. A recent 6-week controlled study by Sayyah
et al. (2009b) used the dried flower of E. amoenum versus placebo
in patients with diagnosed OCD. Results revealed that while no
significant effect occurred in the first weeks, a significant
difference between the active and placebo on Y-BOCS and HAMA
scores occurred at endpoint. However it should be noted that
participants in both groups experienced only a slight reduction of
OCD symptoms (five to six points on Y-BOCS). There was no
significant difference between the two groups in terms of side
effects, excepting an increase in constipation inthe placebo group
(potentially due to the use of talcum powder as an excipient). In
social phobia one controlled study using an herbal medicine was
found. A placebo-controlled pilot study testing H. perforatum
(flexible-dose 6001800 mg daily) in participants with social
phobia (assessed via the Liebowitz Social Anxiety Scale), found
no significant differential benefit over placebo, although a trend
towards improvement was demonstrated (Kobak et al., 2005b).
Many of the anxiolytic plant medicines reviewed have
potential additional applications. These include improving mood
(M. officinalis or P. methysticum), providing a sedative or hypnotic
action for insomnia (P. incanata or S. lateriflora), reducing muscle
tension or pain (E. californica), or enhancing cognition via nootropic
activities (Bacopa monniera:brahmiorG. biloba)(Mills and Bone,
2000; Spinella, 2001). Herbal medicines (such as Withania
somnifera: withania, and Centella asiatica: gotu kola) may also
provide an adaptogenic effect applicable in cases of comorbid
fatigue (Panossian and Wikman, 2009).
3.2.4. Clinical evidence in insomnia
V. officinalis is the only botanical with sufficient research of
adequate rigour in the area of insomnia (aside from a recently
conducted isolated study using P. incanata). Meta-analyses and
reviews by Bent et al. (2006) and Fernandez-San-Martin et al.
(2010) reveal that the evidence concerning the soporific plant
medicine is quite varied, and currently does not support its use in
treating insomnia. The Bent et al. (2006) meta-analysis, which
included 16 eligible RCTs on Valeriana spp. monotherapy or in
combination with other herbal medicines, found that 9 out of 16
studies did not have positive outcomes in regard to improvement of
sleep quality. The Fernandez-San-Martin et al. (2010) meta-
analysis of 18 RCTs found that Valerian a spp. interventions reduced
sleep latency over placebo by only 0.70 min (95% CI: 3.44, 4.83),
with the standardised mean differences between the groups
measured being statistically equivocal 0.02 (95% CI: 0.35,
0.31).The safety profile of Valeriana spp. appears good, however
traditional pharmacopoeias caution it as a cerebral stimulant
(Felter and Lloyd, 2008 (b) (1898)), thus it may not consistently
provide somnolence. A recent 2 week crossover RCT (two 1-week
phases with a 1-week washout in between) was conducted using P.
incanata tea (2 g) versus a parsley placebo tea in healthy volunteers
(Ngan and Conduit, 2011). Results revealed that differences at the
conclusion of the active and placebo week of treatment were only
significant (in favour of P. incanata) on the outcome of subjective
sleep quality, with an effect size dof 0.44 (rated via sleep diary). No
significant effects were found between treatments for total sleep
time, sleep latency, sleep efficiency, or feeling of refreshment.
Major flaws of this study included the lack of baseline measure-
ment, non-standardisation of P. incanata, and short duration of
treatment with a low once per day dose. Thus these results do not
clearly inform on efficacy.
4. Discussion
As this review details, there is a growing abundance of
preclinicaland clinical studies which reveal a range of complex
psychotropic activity from herbal medicines potentially
beneficial for treating depression, anxiety and sleep disorders.
However several caveats exist in being over-enthused by the
current field of herbal psychopharmacology. Concerns exist
over poor reporting of data in some studies, and the many
unreplicated studies with small samples. Regarding study
replication, only three herbal medicines reviewed have
multiple replicated RCTs that have been analysed via meta-
analysis (H. perforatum,P. methysticum, and V. officinalis).
Another potential issue is that many herbal medicines with in
vitro evidence have not yet been rigorously tested in robust
human studies. As detailed in the mechanisms of action and
clinical evidence tables, several herbal medicines (10 out of
21) that have in vitro or in vivo evidence of pharmacodynamic
effects, have not been studied as monotherapies in human
clinical trials. Regardless, an important consideration is that in
vivo, plant constituents undergo significant metabolism via
enzymatic and hepatic processes, being biotransformed into
new chemical structures. Thus in vitro evidence cannot always
be extrapolated to clinical efficacy in humans. A further
consideration is that while studies conducted in Europe using
P. methysticum or H. perforatum haveoftenbeenpositive
(Sarris and Kavanagh, 2009), these results are not always
replicated in countries such as the United States cf. (Connor
and Davidson, 2002; Hypericum Depression Trial Study Group,
2002). In the case of H. perforatum,recenttrialshave
revealed smaller effect sizes, thereby newer meta-analytic
studies have provided weaker results than previous ones (Linde
et al., 2008; Werneke et al., 2004). This also mirrors the
modestresult of a recent meta-analysis of antidepressants
in MDD of mild to moderate severity, which revealed a Cohen's
deffect size of 0.20 (Fournier et al., 2010).
Herbal medicines such as Albizia julibrissin (Mimosa), M.
officinalis,Z. jujuba,andE. californica have been researched
over the past three decades in preclinical models with positive
results, however surprisingly these have not been studied as
monotherapies in the treatment of psychiatric disorders.
Preclinical evidence in these phytomedicines reveals an array
14 J. Sarris et al.
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
of monoamine and neuropeptide modulatory activity that have
potential to benefit sufferers of depression, anxiety and insom-
nia. Although, as stated above, positive in vitro or animal models
do not always translate into clinical efficacy in humans, this
information does provide a guidepost to potential future
research. Promising anxiolytics that to date have not been
tested as monotherapies by RCTs for anxiety disorders include B.
monniera,E. calfornica,M. officinalis,andW. somnifera.
Promising antidepressants include Panax ginseng (Korean
ginseng), and A. julibrissin;whileH. lupulus and Z. jujuba
should be studied in the treatment of insomnia. It is interesting
to note that while the plant medicines reviewed in this paper are
used in modern phytotherapeutic practice to treat anxiety,
depression, and insomnia, some have specific applications that
may be utilised for complex conditions. For example B.
monniera is considered beneficial in treating cognitive insuffi-
ciency; (Stough et al., 2001)E. californica has been used for
insomnia and pain; (Rolland et al., 1991)M. officinalis is used for
gastrointestinal complaints e.g. nervous dyspepsia; (Muller and
Klement, 2006)whileW. somnifera (Bhattacharya and Muruga-
nandam, 2003)andP. ginseng (Rege et al., 1999) are regarded
as tonicsthat via neuroendocrine modulation may allay
In addition to exploring promising individual psychotropics
for range of psychiatric disorders, future research could centre
on combinations of various botanicals with preclinical and
clinical evidence of activity. While gold standard methodology
will usually be in the form of an RCT using a monotherapy,
combination formulations may also be of merit. Such an
example is found in a large, open label practice-orientated
study, using a combination of H. perforatum and V. officinalis to
treat depression co-occurring with anxiety (Muller et al., 2003).
The results demonstrated marked success for the herbal
combination which ameliorated anxiety more effectively than
H. perforatum monotherapy. It should be noted however that
not all combination studies are positive. A 4 week 2009 RCT
using a combination of H. perforatum and P. methysticum for
the treatment of MDD with comorbid anxiety had mixed results
(Sarris et al., 2009b). Although there was significant relief of
self-reported depression on the Beck Depression Inventory (BDI-
II) over placebo in the first controlled phase, no effects were
found in the pooled analysis or on anxiety outcomes. Regardless,
other potential combinations exist that may be beneficial in the
treatment of depression. Formulations involving combinations
of R. rosea,C. sativus, A. julibrissin,andH. perforatum may
provide increased synergistic antidepressant effects for treat-
ment of depression. In the treatment of anxiety, novel
formulations including P.incanata,S.lateriflora
tion with P. methysticum may prove beneficial. While further
research using Z. jujuba and Vitex agnus castus (chaste tree) in
combination with other hypnotics may also provide benefit in
insomnia. These combinations do exist commonly in over-the-
counter herbal medicine products, however at present a paucity
of research has been conducted to validate claims of efficacy.
This remains a research area of great potential.
Currently, a lack of bioequivalencebetween extracts
studied hampers the advancement of botanicals as viable
mainstream medicines. While medicinal plants, or their
combinations, have a multi-target polyvalent and synergistic
mechanism of action (due to a complex mixture of active
constituents), this potential strength also brings with it
associated potential drawbacks. It is challenging to evaluate
evidence of efficacy and safety due to differing bioequivalence
between preparations used in the clinical trials. When results of
different clinical studies are not consistent this limitation must
be taken in consideration. Results derived from different herbal
preparations produced by different manufactures (with differ-
ing bioequivalence) have not currently been evaluated.
Evaluation and clinical assessment of efficacy of medicinal
plants in general is a complicated task, with the chemical
such as: genetic differences (phytochemical variability);
environmental differences (climate, temperature, light, and
rain); soil quality (pH, fertilisation, and heavy metals); exposure
to airborne vectors (insects, pests, and microbiological infec-
tion raw material production); differences in plant parts used
after flowering time); and preparation methods (from storage
to extraction and manufacture). Consequently, it is very
difficult to produce standardised extracts with reproducible
chemical composition, and consequently with reproducible
pharmacological activity, particularly when extracts are pro-
duced by different manufacturers. While preclinical studies of
main active constituents are helpful, the evidence cannot
guarantee the same efficacy of total extract in replicated
herbomicstudies potentially assisting in providing greater
assurance of bioequivalence (Ulrich-Merzenich et al., 2007).
Future herbomictrials have the potential to greatly
advance the field of herbal psychopharmacology, and should
explore various different domains such as 1) Specific neuro-
chemical pathways implicated in the pathogenesis of psychiat-
ric disorders, and the phytomedicines which are known to
affect these pathways, 2) Cytochrome P450 and P-glycoprotein
polymorphisms which effect the metabolisation of the herbal
medicine's active constituent and 3) Epigenetic differences
affected between single active constituents versus whole
extracts and complex prescriptive formulas. The nascent field
of herbomicshas the potential to provide over the coming
years increased validation of the psychotropic effects of herbal
medicines. As our knowledge advances in this area, herbal
formulas may be personalised to take into account an
individual's neurological and hepatic polymorphisms, and can
monitor the epigenetic effects that occur in the person.
Epigenetic studies can be used as a proofofconceptin
psychiatry, to show that whole extracts have specific affects on
gene transcription that may be aligned with conventional
pharmacotherapies. Furthermore, investigations of individua-
lised prescriptions may demonstrate unique epigenetic effects.
In conclusion, while the literature reviewed in this paper
provides encouraging evidence for the use of herbal
medicines in the treatment of depression, anxiety and
insomnia, further research utilising robust methodology,
pharmaceutical good manufacturing practice and the use of
biotechnologies to ensure bioequivalence of product, and
greater application of genetic technologies, is still required
to promote confidence in this area. This will provide the next
significant step in the field of herbal psychopharmacology.
Role of the funding source
No direct funding was received for this manuscript. Dr. Jerome Sarris is
funded by an Australian National Health & Medical Research Council
15Herbal Psychopharmacology
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
fellowship (NHMRC funding ID 628875), in a strategic partnership with
The University of Melbourne and Swinburne University of Technology.
All authors contributed to the design, writing and proofing of the
Conflicts of Interest
No conflicts of interest noted.
Dr. Jerome Sarris is funded by an Australian National Health & Medical
Research Council fellowship (NHMRC funding ID 628875), in a strategic
partnership with The University of Melbourne and the National Institute
of Complementary Medicine Collaborative Centre for the Study of
Neurocognition at Swinburne University of Technology. Thanks are
extended to Genevieve Houghton for assistance with formatting the
Abourashed, E.A., Koetter, U., Brattstrom, A., 2004. In vitro binding
experiments with a Valerian, hops and their fixed combination
extract (Ze91019) to selected central nervous system receptors.
Phytomedicine 11, 633638.
Akhondzadeh, S., Naghavi, H.R., Vazirian, M., Shayeganpour, A.,
Rashidi, H., Khani, M., 2001. Passionflower in the treatment of
generalized anxiety: a pilot double-blind randomized controlled
trial with oxazepam. J. Clin. Pharm. Ther. 26, 363367.
Akhondzadeh, S., Kashani, L., Fotouhi, A., Jarvandi, S., Mobaseri, M.,
Moin, M., Khani, M., Jamshidi, A.H., Baghalian, K., Taghizadeh, M.,
2003. Comparison of Lavandula angustifolia Mill. tincture and
imipramine in the treatment of mild to moderate depression: a
double-blind, randomized trial. Prog Neuropsychopharmacol Biol
Psychiatry 27, 123127.
Akhondzadeh, S., Fallah-Pour, H., Afkham, K., Jamshidi, A.H.,
Khalighi-Cigaroudi, F., 2004. Comparison of Crocus sativus L. and
imipramine in the treatment of mild to moderate depression: a
pilot double-blind randomized trial [ISRCTN45683816]. BMC
Complement. Altern. Med. 4, 12.
Akhondzadeh, S., Tahmacebi-Pour, N., Noorbala, A.A., Amini, H.,
Fallah-Pour, H., Jamshidi, A.H., Khani, M., 2005. Crocus sativus
L. in the treatment of mild to moderate depression: a double-
blind, randomized and placebo-controlled trial. Phytother. Res.
19, 148151.
Akhondzadeh, B., Moshiri, E., Noorbala, A., Jamshidi, A., Abbasi, S.,
Akhondzadeh, S., 2007. Comparison of petal of Crocus sativus L.
and fluoxetine in the treatment of depressed outpatients: a pilot
double-blind randomized trial. Prog Neuropsychopharmacol Biol
Psychiatry 30, 439442.
American Psychiatric Association, 2000. Diagnostic and Statistical
Manual of Mental Disorders, 4th Text Revisioned. American
Psychiatric Association, Arlington.
Amsterdam, J.D., Li, Y., Soeller, I., Rockwell, K., Mao, J.J., Shults,
J., 2009. A randomized, double-blind, placebo-controlled trial of
oral Matricaria recutita (chamomile) extract therapy for
generalized anxiety disorder. J. Clin. Psychopharmacol. 29,
Antonijevic, I.A., 2006. Depressive disorders is it time to endorse
different pathophysiologies? Psychoneuroendocrinology 31, 115.
Atsumi, T., Tonosaki, K., 2007. Smelling lavender and rosemary
increases free radical scavenging activity and decreases cortisol
level in saliva. Psychiatry Res. 150, 8996.
Avallone, R., Zanoli, P., Puia, G., Kleinschnitz, M., Schreier, P., Baraldi,
M., 2000. Pharmacological profile of apigenin, a flavonoid isolated
from Matricaria chamomilla.Biochem.Pharmacol.59,13871394.
Awad, R., Arnason, J.T., Trudeau, V., Bergeron, C., Budzinski, J.W.,
Foster, B.C., Merali, Z., 2003. Phytochemical and biological
analysis of skullcap (Scutellaria lateriflora L.): a medicinal plant
with anxiolytic properties. Phytomedicine 10, 640649.
Awad, R., Levac, D., Cybulska, P., Merali, Z., Trudeau, V.L.,
Arnason, J.T., 2007. Effects of traditionally used anxiolytic
botanicals on enzymes of the gamma-aminobutyric acid (GABA)
system. Can. J. Physiol. Pharmacol. 85, 933942.
Awad, R., Muhammad, A., Durst, T., Trudeau, V.L., Arnason, J.T.,
2009. Bioassay-guided fractionation of lemon balm (Melissa
officinalis L.) using an in vitro measure of GABA transaminase
activity. Phytother. Res. 23, 10751081.
Baldwin, D.S., Polkinghorn, C., 2005. Evidence-based pharmaco-
therapy of Generalized Anxiety Disorder. Int. J. Neuropsycho-
pharmacol. 8, 293302.
Discontinuation symptoms in depression and anxiety disorders.
Int. J. Neuropsychopharmacol. 10, 7384.
Belmaker, R.H., Agam, G., 2008. Major depressive disorder. N. Engl.
J. Med. 358, 5568.
Benke, D., Barberis, A., Kopp, S., Altmann, K., Schubiger, M., Vogt, K.,
Rudolph, U., Möhler, H., 2009. GABA(A) receptors as in vivo substrate
for the anxiolytic action of valerenic acid, a major constituent of
valerian root extracts. Neuropharmacology 56, 174181.
Bensky, D., Gamble, A., 1991. Chinese Herbal Formulas. Eastland
Press, Seattle.
Bent, S., Padula, A., Moore, D., Patterson, M., Mehling, W., 2006.
Valerian for sleep: a systematic review and meta-analysis. Am. J.
Med. 119, 10051012.
Bhattacharya, S.K., Mitra, S.K., 1991. Anxiolytic activity of Panax
ginseng roots: an experimental study. J. Ethnopharmacol. 34,
Bhattacharya, S.K., Muruganandam, A.V., 2003. Adaptogenic activity
of Withania somnifera: an experimental study using a rat model of
chronic stress. Pharmacol. Biochem. Behav. 75, 547555.
Bhattacharya, S.K., Bhattacharya, A., Sairam, K., Ghosal, S., 2000.
Anxiolytic-antidepressant activity of Withania somnifera glyco-
withanolides: an experimental study. Phytomedicine 7, 463469.
Boonen, G., Haberlein, H., 1998. Influence of genuine kavapyrone
enantiomers on the GABA-A binding site. Planta Med. 64, 504506.
Bradley, B.F., Starkey, N.J., Brown, S.L., Lea, R.W., 2007. Anxiolytic
effects of Lavandula angustifolia odour on the Mongolian gerbil
elevated plus maze. J. Ethnopharmacol. 111, 517525.
Bradwejn, J., Zhou, Y., Koszycki, D., Shlik, J., 2000. A double-blind,
placebo-controlled study on the effects of Gotu Kola (Centella
asiatica) on acoustic startle response in healthy subjects. J. Clin.
Psychopharmacol. 20, 680684.
Brady, K.T., Verduin, M.L., 2005. Pharmacotherapy of comorbid
mood, anxiety, and substance use disorders. Subst. Use Misuse
40, 20212041 2043-2028.
Brattstrom, A., 2007. Scientific evidence for a fixed extract combina-
tion (Ze 91019) from valerian and hops traditionally used as a sleep-
inducing aid. Wien. Med. Wochenschr. 157, 367370.
Butterweck, V., 2003. Mechanism of action of St John's wort in
depression : what is known? CNS Drugs 17, 539562.
Butterweck, V., Schmidt, M., 2007. St. John's wort: role of active
compounds for its mechanism of action and efficacy. Wien. Med.
Wochenschr. 157, 356361.
Butterweck, V., Brattstrom, A., Grundmann, O., Koetter, U., 2007.
Hypothermic effects of hops are antagonized with the compet-
itive melatonin receptor antagonist luzindole in mice. J. Pharm.
Pharmacol. 59, 549552.
16 J. Sarris et al.
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
Cao, J.X., Zhang, Q.Y., Cui, S.Y., Cui, X.Y., Zhang, J., Zhang, Y.H.,
Bai, Y.J., Zhao, Y.Y., 2010. Hypnotic effect of jujubosides from
Semen Ziziphi Spinosae. J. Ethnopharmacol. 130, 163166.
Chang, Y., Wang, S.J., 2010. Hypericin, the active component of St.
John's wort, inhibits glutamate release in the rat cerebrocortical
synaptosomes via a mitogen-activated protein kinase-dependent
pathway. Eur. J. Pharmacol. 634, 5361.
Chen, X., 1996. Cardiovascular protection by ginsenosides and their
nitric oxide releasing action. Clin. Exp. Pharmacol. Physiol. 23,
Chen, H.C., Hsieh, M.T., Lai, E., 1985. Studies on the suanzaor-
entang in the treatment of anxiety. Psychopharmacology Berl 85,
Chen, Q.G., Zeng, Y.S., Qu, Z.Q., Tang, J.Y., Qin, Y.J., Chung, P.,
Wong, R., Hagg, U., 2009. The effects of Rhodiola rosea extract on
5-HT level, cell proliferation and quantity of neurons at cerebral
hippocampus of depressive rats. Phytomedicine 16, 830838.
Cho, S.M., Shimizu, M., Lee, C.J., Han, D.S., Jung, C.K., Jo, J.H.,
Kim, Y.M., 2010. Hypnotic effects and binding studies for GABA
(A) and 5-HT(2C) receptors of traditional medicinal plants used in
Asia for insomnia. J. Ethnopharmacol. 132, 225232.
Cohen, J., 1988. Statistical Power Analyses for the Behavioral
Sciences. Erlbaum, Hillsdale.
Comer,J.S., Olfson, M.,Mojtabai, R., 2010. National trends inchild and
adolescent psychotropic polypharmacy in office-based practice,
19962007. J. Am. Acad. Child Adolesc. Psychiatry 49, 10011010.
Connor, K.M., Davidson, J.R., 2002. A placebo-controlled study of
Kava kava in generalized anxiety disorder. Int. Clin. Psychophar-
macol. 17, 185188.
Dang, H., Chen, Y., Liu, X., Wang, Q., Wang, L., Jia, W., Wang, Y.,
2009. Antidepressant effects of ginseng total saponins in the forced
swimming test and chronic mild stress models of depression. Prog
Neuropsychopharmacol Biol Psychiatry 33, 14171424.
Darbinyan, V., Aslanyan, G., Amroyan, E., Gabrielyan, E., Mal-
mstrom, C., Panossian, A., 2007. Clinical trial of Rhodiola rosea
L. extract SHR-5 in the treatment of mild to moderate
depression. Nord. J. Psychiatry 61, 343348.
Davies, L.P., Drew, C.A., Duffield, P., Johnston, G.A., Jamieson, D.D.,
1992. Kava pyrones and resin: studies on GABAA, GABAB and
benzodiazepine binding sites in rodent brain. Pharmacol. Toxicol.
71, 120126.
Dericks-Tan, J.S., Schwinn, P., Hildt, C., 2003. Dose-dependent
stimulation of melatonin secretion after administration of Agnus
castus. Exp. Clin. Endocrinol. Diabetes 111, 4446.
Dhawan, K., Kumar, S., Sharma, A., 2001a. Anti-anxiety studies on
extracts of Passiflora incarnata Linneaus. J. Ethnopharmacol. 78,
Dhawan, K., Kumar, S., Sharma, A., 2001b. Anxiolytic activity of
aerial and underground parts of Passiflora incarnata. Fitoterapia
72, 922926.
Dhawan, K., Kumar, S., Sharma, A., 2002. Comparative anxiolytic
activity profile of various preparations of Passiflora incarnata
Linneaus: a comment on medicinal plants' standardization. J
Altern Complement Med 8, 283291.
Di Renzo, G., 2000. Ginkgo biloba and the central nervous system.
Fitoterapia 71 (Suppl 1), S43S47.
Dietz, B.M., Mahady, G.B., Pauli, G.F., Farnsworth, N.R., 2005.
Valerian extract and valerenic acid are partial agonists of the 5-
HT5a receptor in vitro. Brain Res. Mol. Brain Res. 138, 191197.
Elkins, G., Rajab, M.H., Marcus, J., 2005. Complementary and
alternative medicine use by psychiatric inpatients. Psychol. Rep.
96, 163166.
Fahmi, M., Huang, C., Schweitzer, I., 2002. A case of mania induced
by hypericum. World J. Biol. Psychiatry 3, 5859.
Felter, H.W., Lloyd, J.U., 2008 (b) (1898). King's American
Fernandez-San-Martin, M.I., Masa-Font, R., Palacios-Soler, L.,
Sancho-Gomez, P., Calbo-Caldentey, C., Flores-Mateo, G.,
2010. Effectiveness of Valerian on insomnia: a meta-analysis of
randomized placebo-controlled trials. Sleep Med. 11, 505511.
Fournier, J., DeRubeis, R., Hollon, S., Dimidjian, S., Amsterdam, J.,
Shelton, R., Fawcett, J., 2010. Antidepressant drug effects and
depression severity: a patient-level meta-analysis. JAMA 303,
Franklin, M., Hafizi, S., Reed, A., Hockney, R., Murck, H., 2006.
Effect of sub-chronic treatment with Jarsin (extract of St John's
wort, Hypericum perforatum) at two dose levels on evening
salivary melatonin and cortisol concentrations in healthy male
volunteers. Pharmacopsychiatry 39, 1315.
García-García, P., López-Muñoz, F., Rubio, G., Martín-Agueda, B.,
Alamo, C., 2008. Phytotherapy and psychiatry: bibliometric
study of the scientific literature from the last 20 years.
Phytomedicine 15, 566576.
Grundmann, O., Wang, J., McGregor, G.P., Butterweck, V., 2008.
Anxiolytic activity of a phytochemically characterized Passiflora
incarnata extract is mediated via the GABAergic system. Planta
Med. 74, 17691773.
Grundmann, O., Wahling, C., Staiger, C., Butterweck, V., 2009.
Anxiolytic effects of a passion flower (Passiflora incarnata L.)
extract in the elevated plus maze in mice. Pharmazie 64, 6364.
Hanus, M., Lafon, J., Mathieu, M., 2004. Double-blind, randomised,
placebo-controlled study to evaluate the efficacy and safety of a
fixed combination containing two plant extracts (Crataegus
oxyacantha and Eschscholtzia californica) and magnesium in mild-
to-moderate anxiety disorders. Curr. Med. Res. Opin. 20, 6371.
Fundamentals of Pharmacognosy and Phytotherapy. Churchill
Livingstone, London.
Hindmarch, I., 2001. Expanding the horizons of depression: beyond the
monoamine hypothesis. Hum. Psychopharmacol. 16, 203218.
Hosseinzadeh, H., Noraei, N.B., 2009. Anxiolytic and hypnotic effect
of Crocus sativus aqueous extract and its constituents, crocin and
safranal, in mice. Phytother. Res. 23, 768774.
Houghton, P., 2009. Synergy and polyvalence: paradigms to explain
the activity of herbal products. In: Mukherjee, P., Houghton, P.
(Eds.), Evaluation of Herbal Medicinal Products: Perspectives on
Quality, Safety and Efficacy. Pharmaceutical Press.
Hsieh, M.T., Chen, H.C., Hsu, P.H., Shibuya, T., 1986a. Effects of
Suanzaorentang on behavior changes and central monoamines.
Proc Natl Sci Counc Repub China B 10, 4348.
Hsieh, M.T., Chen, H.C., Kao, H.C., Shibuya, T., 1986b. Suanzaor-
entang, and anxiolytic Chinese medicine, affects the central
adrenergic and serotonergic systems in rats. Proc Natl Sci Counc
Repub China B 10, 263268.
Hypericum Depression Trial Study Group, 2002. Effect of Hypericum
perforatum (St John's wort) in major depressive disorder: a
randomized controlled trial. Jama 287, 18071814.
Izzo, A.A., 2004. Drug interactions with St. John's Wort (Hypericum
perforatum): a review of the clinical evidence. Int. J. Clin.
Pharmacol. Ther. 42, 139148.
Joo, S.S., Won, T.J., Lee, D.I., 2005. Reciprocal activity of
ginsenosides in the production of proinflammatory repertoire,
and their potential roles in neuroprotection in vivo. Planta Med.
71, 476481.
Jordan, S.A., Cunningham, D.G., Marles, R.J., 2010. Assessment of
herbal medicinal products: challenges, and opportunities to
increase the knowledge base for safety assessment. Toxicol.
Appl. Pharmacol. 243, 198216.
Jung, J.W., Cho, J.H., Ahn, N.Y., Oh, H.R., Kim, S.Y., Jang, C.G.,
Ryu, J.H., 2005. Effect of chronic Albizzia julibrissin treatment
on 5-hydroxytryptamine1A receptors in rat brain. Pharmacol.
Biochem. Behav. 81, 205210.
Jussofie, A., Schmiz, A., Hiemke, C., 1994. Kavapyrone enriched
extract from Piper methysticum as modulator of the GABA
binding site in different regions of rat brain. Psychopharmacology
Berl 116, 469474.
17Herbal Psychopharmacology
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
Kasper, S., Volz, H.P., Moller, H.J., Dienel, A., Kieser, M., 2008.
Continuation and long-term maintenance treatment with Hyper-
icum extract WS 5570 after recovery from an acute episode of
moderate depressiona double-blind, randomized, placebo con-
trolled long-term trial. Eur. Neuropsychopharmacol. 18, 803813.
Kasper, S., Caraci, F., Forti, B., Drago, F., Aguglia, E., 2010a. Efficacy
and tolerability of Hypericum extract for the treatment of mild to
moderate depression. Eur. Neuropsychopharmacol. 20, 747765.
Kasper, S., Gastpar, M., Moller, H.J., Muller, W.E., Volz, H.P.,
Dienel, A., Kieser, M., 2010b. Better tolerability of St. John's
wort extract WS 5570 compared to treatment with SSRIs: a
reanalysis of data from controlled clinical trials in acute major
depression. Int. Clin. Psychopharmacol. 25, 204213.
Kennedy, D.O., Scholey, A.B., Tildesley, N.T., Perry, E.K., Wesnes,
K.A., 2002. Modulation of mood and cognitive performance
following acute administration of Melissa officinalis (lemon
balm). Pharmacol. Biochem. Behav. 72, 953964.
Kennedy, D.O., Little, W., Scholey, A.B., 2004. Attenuation of
laboratory-induced stress in humans after acute administration of
Melissa officinalis (Lemon Balm). Psychosom. Med. 66, 607613.
Kessler, R.C., Soukup, J., Davis, R.B., Foster, D.F., Wilkey, S.A., Van
Rompay, M.M., Eisenberg, D.M., 2001. The use of complementary
and alternative therapies to treat anxiety and depression in the
United States. Am. J. Psychiatry 158, 289294.
Kessler, R.C., Chiu, W.T., Demler, O., Merikangas, K.R., Walters,
E.E., 2005. Prevalence, severity, and comorbidity of 12-month
DSM-IV disorders in the National Comorbidity Survey Replication.
Arch. Gen. Psychiatry 62, 617627.
Kim, D.H., Moon, Y.S., Jung, J.S., Min, S.K., Son, B.K., Suh, H.W.,
Song, D.K., 2003. Effects of ginseng saponin administered
intraperitoneally on the hypothalamo-pituitary-adrenal axis in
mice. Neurosci. Lett. 343, 6266.
Kim, W.K., Jung, J.W., Ahn, N.Y., Oh, H.R., Lee, B.K., Oh, J.K.,
Cheong, J.H., Chun, H.S., Ryu, J.H., 2004. Anxiolytic-like effects
of extracts from Albizzia julibrissin bark in the elevated plus-
maze in rats. Life Sci. 75, 27872795.
Kim, J.H., Kim, S.Y., Lee, S.Y., Jang, C.G., 2007. Antidepressant-
like effects of Albizzia julibrissin in mice: involvement of the 5-
HT1A receptor system. Pharmacol. Biochem. Behav. 87, 4147.
Kleber, E., Schneider, W., Schafer, H.L., Elstner, E.F., 1995.
Modulation of key reactions of the catecholamine metabolism
by extracts from Eschscholtzia californica and Corydalis cava.
Arzneimittelforschung 45, 127131.
Kobak,K.A., Taylor, L.V., Bystritsky, A., Kohlenberg, C.J., Greist, J.H.,
Tucker, P., Warner, G., Futterer, R., Vapnik, T., 2005a. St John's
wort versus placebo in obsessivecompulsive disorder: results
from a double-blind study. Int. Clin. Psychopharmacol. 20,
Kobak, K.A., Taylor, L.V., Warner, G., Futterer, R., 2005b. St. John's
wort versus placebo in social phobia: results from a placebo-
controlled pilot study. J. Clin. Psychopharmacol. 25, 5158.
Koch, E., 2005. Inhibition of platelet activating factor (PAF)-induced
aggregation of human thrombocytes by ginkgolides: consider-
ations on possible bleeding complications after oral intake of
Ginkgo biloba extracts. Phytomedicine 12, 1016.
Krishnakumar, A., Nandhu, M.S., Paulose, C.S., 2009. Upregulation of
5-HT2C receptors in hippocampus of pilocarpine-induced epileptic
rats: antagonism by Bacopa monnieri. Epilepsy Behav. 16, 225230.
Kumar, V., 2006. Potential medicinal plants for CNS disorders: an
overview. Phytother. Res. 20 (12), 10231035.
Lakhan, S.E., Vieira, K.F., 2010. Nutritional and herbal supplements
for anxiety and anxiety-related disorders: systematic review.
Nutr. J. 9, 42.
Lechtenberg, M., Schepmann, D., Niehues, M., Hellenbrand, N.,
Wunsch, B., Hensel, A., 2008. Quality and functionality of saffron:
quality control, species assortment and affinity of extract and
isolated saffron compounds to NMDA and sigma1 (sigma-1) re-
ceptors. Planta Med. 74, 764772.
Limpeanchob, N., Jaipan, S., Rattanakaruna, S., Phrompittayarat,
W., Ingkaninan, K., 2008. Neuroprotective effect of Bacopa
monnieri on beta-amyloid-induced cell death in primary cortical
culture. J. Ethnopharmacol. 120, 112117.
Linde, K., Berner, M., Kriston, L., 2008. St John's wort for major
depression. Cochrane Database Syst Rev CD000448.
Lopez, V., Martin, S., Gomez-Serranillos, M.P., Carretero, M.E., Jager,
A.K., Calvo, M.I., 2009. Neuroprotective and neurological proper-
ties of Melissa officinalis. Neurochem. Res. 34, 19551961.
Madabushi, R., Frank, B., Drewelow, B., Derendorf, H., Butterweck,
V., 2006. Hyperforin in St. John's wort drug interactions. Eur. J.
Clin. Pharmacol. 62, 225233.
Magura, E.I., Kopanitsa, M.V., Gleitz, J., Peters, T., Krishtal, O.A.,
1997. Kava extract ingredients, (+)-methysticin and (+/)-kavain
inhibit voltage-operated Na(+)-channels in rat CA1 hippocampal
neurons. Neuroscience 81, 345351.
Mattioli, L., Funari, C., Perfumi, M., 2009. Effects of Rhodiola rosea
L. extract on behavioural and physiological alterations induced
by chronic mild stress in female rats. Cochrane Database Syst Rev
23, 130142.
Mehta, A.K., Binkley, P., Gandhi, S.S., Ticku, M.K., 1991. Pharma-
cological effects of Withania somnifera root extract on GABAA
receptor complex. Indian J. Med. Res. 94, 312315.
Mills, S., Bone, K., 2000. Principles and Practice of Phytotherapy.
Churchill Livingstone, London.
Miyasaka, L.S., Atallah, A.N., Soares, B.G., 2007. Passiflora for
anxiety disorder. Cochrane Database Syst Rev CD004518.
Morishita, S., Mishima, Y., Hirai, Y., Saito, T., Shoji, M., 1987.
Pharmacological studies of water extract of the Zizyphus seed
and the Zizyphus seed containing drug. Gen. Pharmacol. 18,
Moshiri, E., Basti, A.A., Noorbala, A.A., Jamshidi, A.H., Hesameddin
Abbasi, S., Akhondzadeh, S., 2006. Crocus sativus L. (petal) in
the treatment of mild-to-moderate depression: a double-blind,
randomized and placebo-controlled trial. Phytomedicine 13 (9
10), 607611.
Movafegh, A., Alizadeh, R., Hajimohamadi, F., Esfehani, F.,
Nejatfar, M., 2008. Preoperative oral Passiflora incarnata
reduces anxiety in ambulatory surgery patients: a double-blind,
placebo-controlled study. Anesth. Analg. 106, 17281732.
Muller, S.F., Klement, S., 2006. A combination of valerian and lemon
balm is effective in the treatment of restlessness and dyssomnia
in children. Phytomedicine 13, 383387.
Muller, W.E., Rossol, R., 1994. Effects of Hypericum extract on the
expression of serotonin receptors. J. Geriatr. Psychiatry Neurol.
7 (Suppl 1), S63S64.
Muller, D., Pfeil, T., von den Driesch, V., 2003. Treating depression
comorbid with anxietyresults of an open, practice-oriented
study with St John's wort WS 5572 and valerian extract in high
doses. Phytomedicine 10 (Suppl 4), 2530.
Murphy, K., Kubin, Z.J., Shepherd, J.N., Ettinger, R.H., 2009.
Valeriana officinalis root extracts have potent anxiolytic effects
in laboratory rats. Phytomedicine 17 (89), 674678.
Neuhaus, W., Trauner, G., Gruber, D., Oelzant, S., Klepal, W., Kopp,
B., Noe, C.R., 2008. Transport of a GABAA receptor modulator
and its derivatives from Valeriana officinalis L. s. l. across an in
vitro cell culture model of the blood-brain barrier. Planta Med.
74, 13381344.
Ngan, A., Conduit, R., 2011. A double-blind, placebo-controlled
investigation of the effects of Passiflora incarnata (passionflow-
er) herbal tea on subjective sleep quality. Phytother. Res.
Nierenberg, A.A., 2001. Current perspectives on the diagnosis and
treatment of major depressive disorder. Am. J. Manag. Care 7,
Noorbala, A.A., Akhondzadeh, S., Tahmacebi-Pour, N., Jamshidi, A.H.,
2005. Hydro-alcoholic extractof Crocus sativus L. versus fluoxetine
in the treatment of mild to moderate depression: a double-blind,
randomized pilot trial. J. Ethnopharmacol. 97, 281284.
18 J. Sarris et al.
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
Nutt, D.J., Ballenger, J.C., Sheehan, D., Wittchen, H.U., 2002.
Generalized anxiety disorder: comorbidity, comparative biology
and treatment. Int. J. Neuropsychopharmacol. 5, 315325.
Ortiz, J.G., Nieves-Natal, J., Chavez, P., 1999. Effects of Valeriana
officinalis extracts on [3H]flunitrazepam binding, synaptosomal
[3H]GABA uptake, and hippocampal [3H]GABA release. Neuro-
chem. Res. 24, 13731378.
Panossian, A., Wikman, G., 2009. Evidence-based efficacy of adapto-
gens in fatigue, and molecular mechanisms related to their stress-
protective activity. Curr. Clin. Pharmacol. 4, 198219.
Panossian, A., Hambartsumyan, M., Hovanissian, A., Gabrielyan, E.,
Wikman, G., 2007. The Adaptogens Rhodiola and Schizandra Modify
the Response to Immobilization Stress in Rabbits by Suppressing the
Increase of Phosphorylated Stress-activated Protein Kinase, Nitric
Oxide and Cortisol. Drug Targets Insights 1, 3954.
Panossian, A., Nikoyan, N., Ohanyan, N., Hovhannisyan, A., Abraham-
yan, H., Gabrielyan, E., Wikman, G., 2008. Comparative study of
Rhodiola preparations on behavioral despair of rats. Phytomedicine
15 (1), 8491.
Papakostas, G., 2008. Tolerability of modern antidepressants. J.
Clin. Psychiatry 69, 813 Suppl.
Park, J.H., Cha, H.Y., Seo, J.J., Hong, J.T., Han, K., Oh, K.W., 2005.
Anxiolytic-like effects of ginseng in the elevated plus-maze
model: comparison of red ginseng and sun ginseng. Prog
Neuropsychopharmacol Biol Psychiatry 29, 895900.
constituents of Valeriana officinalis. J Appl Biomed 8.
Patten, S.B., Beck, C., 2004. Major depression and mental health care
utilization in Canada: 1994 to 2000. Can J Psychiatry 49, 303309.
Pengelly, A., 1997. The Constituents of Medicinal Plants. Fast Books,
Glebe, NSW.
Pennington, K., Focking, M., McManus, C.A., Pariante, C.M., Dunn,
M.J., Cotter, D.R., 2009. A proteomic investigation of similarities
between conventional and herbal antidepressant treatments. J
Psychopharmacol 23, 520530.
Perfumi, M., Mattioli, L., 2007. Adaptogenic and central nervous
system effects of single doses of 3% rosavin and 1% salidroside
Rhodiola rosea L. extract in mice. Phytother. Res. 21, 3743.
Perry, N., Perry, E., 2006. Aromatherapy in the management of
psychiatric disorders. CNS Drugs 20, 257280.
Pittler, M.H., Ernst, E., 2003. Kava extract for treating anxiety.
Cochrane Database Syst Rev CD003383.
Plotsky, P.M., Owens, M.J., Nemeroff, C.B., 1998. Psychoneuroen-
docrinology of depression. Hypothalamicpituitaryadrenal axis.
Psychiatr. Clin. North Am. 21, 293307.
Rabbani, M., Sajjadi, S.E., Vaseghi, G., Jafarian, A., 2004. Anxiolytic
effects of Echium amoenum on the elevated plus-maze model of
anxiety in mice. Fitoterapia 75, 457464.
Rahimi, R., Nikfar, S., Abdollahi, M., 2009. Efficacy and tolerability of
Hypericum perforatum in major depressive disorder in comparison
with selective serotonin reuptake inhibitors: a meta-analysis. Prog
Neuropsychopharmacol Biol Psychiatry 33, 118127.
Raison, C.L., Capuron, L., Miller, A.H., 2006. Cytokines sing the
blues: inflammation and the pathogenesis of depression. Trends
Immunol. 27, 2431.
Rege, N.N., Thatte, U.M., Dahanukar, S.A., 1999. Adaptogenic
properties of six rasayana herbs used in Ayurvedic medicine.
Phytother. Res. 13, 275291.
Ressler, K.J., Nemeroff, C.B., 2000. Role of serotonergic and
noradrenergic systems in the pathophysiology of depression and
anxiety disorders. Depress. Anxiety 12 (Suppl 1), 219.
Rolland, A., Fleurentin, J., Lanhers, M.C., Younos, C., Misslin, R.,
Mortier, F., Pelt, J.M., 1991. Behavioural effects of the American
traditional plant Eschscholzia californica: sedative and anxiolytic
properties. Planta Med. 57, 212216.
Rolland, A., Fleurentin, J., Lanhers, M.C., Misslin, R., Mortier, F.,
2001. Neurophysiological effects of an extract of Eschscholzia
californica Cham. (Papaveraceae). Phytother. Res. 15, 377381.
Roth, T., Roehrs, T., 2003. Insomnia: epidemiology, characteristics,
and consequences. Clinical Cornerstone Chronic Insomnia 5, 515.
Roth, T., Roehrs, T., Pies, R., 2007. Insomnia: pathophysiology and
implications for treatment. Sleep Med. Rev. 11, 7179.
Sairam, K., Dorababu, M., Goel, R.K., Bhattacharya, S.K., 2002.
Antidepressant activity of standardized extract of Bacopa
monniera in experimental models of depression in rats. Phyto-
medicine 9, 207211.
Salgueiro, J.B., Ardenghi, P., Dias, M., Ferreira, M.B., Izquierdo, I.,
Medina, J.H., 1997. Anxiolytic natural and synthetic flavonoid
ligands of the central benzodiazepine receptor have no effect on
memory tasks in rats. Pharmacol. Biochem. Behav. 58, 887891.
Sarris, J., 2007. Herbal medicines in the treatment of psychiatric
disorders: a systematic review. Phytother. Res. 21, 703716.
Sarris, J., Byrne, G., 2011. A systematic review of insomnia and
complementary medicine. Sleep Med. Rev. 15 (2), 99106.
Sarris, J., Kavanagh, D.J., 2009. Kava and St John's wort: current
evidence for use in mood and anxiety disorders. J Altern
Complement Med 15, 827836.
Sarris, J., Kavanagh, D., Byrne, G., Bone, K., Adams, J., Deed, G., 2009a.
The Kava Anxiety Depression Spectrum Study (KADSS): a randomized,
placebo-controlled, cross-over trial using an aqueous extract of
Piper methysticum. Psychopharmacology Berl 205, 399407.
Sarris, J., Kavanagh, D.J., Deed, G., Bone, K.M., 2009b. St. John's
wort and Kava in treating major depressive disorder with
comorbid anxiety: a randomised double-blind placebo-controlled
pilot trial. Hum. Psychopharmacol. 24, 4148.
Sarris, J., Kavanagh, D., Byrne, G., 2010a. Adjuvant use of nutritional
and herbal medicines with antidepressants, mood stabilizers and
benzodiazepines. J. Psychiatr. Res. 44, 3241.
Sarris, J., La Porte, E., Schweitzer, I. Kava: A comprehensive review of
efficacy, safety, and psychopharmacology. Aust N Z J Psychiatry
in press.
Sarris, J., Teschke, R., Stough, C., Scholey, A., Schweitzer, I.,
2010c. Re-introduction of kava (Piper methysticum) to the EU: is
there a way forward? Planta Med. 77 (2), 107110.
Sateia, M.J., Nowell, P.D., 2004. Insomnia. Lancet 364, 19591973.
Savelev, S., Okello, E., Perry, N.S., Wilkins, R.M., Perry, E.K., 2003.
Synergistic and antagonistic interactions of anticholinesterase
terpenoids in Salvia lavandulaefolia essential oil. Pharmacol.
Biochem. Behav. 75, 661668.
Sayyah, M., Sayyah, M., Kamalinejad, M., 2006. A preliminary
randomized double blind clinical trial on the efficacy of aqueous
extract of Echium amoenum in the treatment of mild to
moderate major depression. Prog Neuropsychopharmacol Biol
Psychiatry 30, 166169.
Sayyah, M., Boostani, H., Pakseresht, S., Malaieri, A., 2009a.
Efficacy of aqueous extract of Echium amoenum in treatment
of obsessivecompulsive disorder. Prog Neuropsychopharmacol
Biol Psychiatry 33, 15131516.
Sayyah, M., Boostani, H., Pakseresht, S., Malaieri, A., 2009b.
Efficacy of aqueous extract of Echium amoenum in treatment
of obsessivecompulsive disorder. Progress Neuro Psychophar-
macology Biological Psychiatry 33, 15131516.
Schafer, H.L., Schafer, H., Schneider, W., Elstner, E.F., 1995. Sedative
action of extract combinations of Eschscholtzia californica and
Corydalis cava. Arzneimittelforschung 45, 124126.
Schmidt, M., Betti, G., Hensel, A., 2007. Saffron in phytotherapy:
pharmacology and clinical uses. Wien. Med. Wochenschr. 157,
Scholey, A., Kennedy, D., Wesnes, K., 2005. The psychopharmacol-
ogy of herbal extracts: issues and challenges. Psychopharmacol-
ogy Berl 179, 705707 author reply 708711.
Scholey, A.B., Tildesley, N.T., Ballard, C.G., Wesnes, K.A., Tasker,
A., Perry, E.K., Kennedy, D.O., 2008. An extract of Salvia (sage)
with anticholinesterase properties improves memory and atten-
tion in healthy older volunteers. Psychopharmacology Berl 198,
19Herbal Psychopharmacology
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
Schweitzer, I., Maguire, K., Ng, C., 2009. Sexual side-effects of
contemporary antidepressants: review. Aust. N. Z. J. Psychiatry
43, 795808.
Sena, L.M., Zucolotto, S.M., Reginatto, F.H., Schenkel, E.P., De
Lima, T.C., 2009. Neuropharmacological activity of the pericarp
of Passiflora edulis flavicarpa degener: putative involvement of
C-glycosylflavonoids. Exp Biol Med Maywood 234, 967975.
Shaw, D., Annett, J.M., Doherty, B., Leslie, J.C., 2007. Anxiolytic
effects of lavender oil inhalation on open-field behaviour in rats.
Phytomedicine 14, 613620.
Sichardt, K., Vissiennon, Z., Koetter, U., Brattstrom, A., Nieber, K.,
2007. Modulation of postsynaptic potentials in rat cortical
neurons by valerian extracts macerated with different alcohols:
involvement of adenosine A(1)- and GABA(A)-receptors. Phyt-
other. Res. 21, 932937.
Singer, A., Wonnemann, M., Muller, W.E., 1999. Hyperforin, a major
antidepressant constituent of St. John's Wort, inhibits serotonin
uptake by elevating free intracellular Na
. J. Pharmacol. Exp.
Ther. 290, 13631368.
Spinella, M., 2001. The Psychopharmacology of Herbal Medicine:
Plant Drugs That Alter Mind, Brain and Behavior (Paperback). MIT
Press, Cambridge.
Stough, C., Lloyd, J., Clarke, J., Downey, L.A., Hutchison, C.W.,
Rodgers, T., Nathan, P.J., 2001. The chronic effects of an extract
of Bacopa monniera (Brahmi) on cognitive function in healthy
human subjects. Psychopharmacology Berl 156, 481484.
Teschke, R., 2010. Kava hepatotoxicity a clinical review. Ann.
Hepatol. 9 (3), 251265.
Teschke, R., Sarris, J., Glass, X., Schulzes, J. Kava, the anxiolyticherb:
back to basics to prevent liver injury? Br J Clin Pharm in press.
Toda, M., Morimoto, K., 2008. Effect of lavender aroma on salivary
endocrinological stress markers. Arch. Oral Biol. 53, 964968.
Tranulis, C., Skalli, L., Lalonde, P., Nicole, L., Stip, E., 2008.
Benefits and risks of antipsychotic polypharmacy: an evidence-
based review of the literature. Drug Saf. 31, 720.
Trauner, G., Khom, S., Baburin, I., Benedek, B., Hering, S., Kopp,
B., 2008. Modulation of GABAA receptors by valerian extracts is
related to the content of valerenic acid. Planta Med. 74, 1924.
Tripathi, Y.B., Chaurasia, S., Tripathi, E., Upadhyay, A., Dubey,
G.P., 1996. Bacopa monniera Linn. as an antioxidant: mechanism
of action. Indian J. Exp. Biol. 34, 523526.
Tyrer, P., Baldwin, D., 2006. Generalised anxiety disorder. Lancet
368, 21562166.
Uebelhack, R., Franke, L., Schewe, H.J., 1998. Inhibition of platelet
MAO-B by kava pyrone-enriched extract from Piper methysticum
Forster (kava-kava). Pharmacopsychiatry 31, 187192.
Ulrich-Merzenich, G., Zeitler, H., Jobst, D., Panek, D., Vetter, H.,
Wagner, H., 2007. Application of the -Omic-technologies in
phytomedicine. Phytomedicine 14, 7082.
van Diermen, D., Marston, A., Bravo, J., Reist, M., Carrupt, P.A.,
Hostettmann, K., 2009. Monoamine oxidase inhibition by
Rhodiola rosea L. roots. J. Ethnopharmacol. 122, 397401.
Viola, H., Wasowski, C., Levi de Stein, M., Wolfman, C., Silveira, R.,
Dajas, F., Medina, J.H., Paladini, A.C., 1995. Apigenin, a
component of Matricaria recutita flowers, is a central benzodiaz-
epine receptors-ligand with anxiolytic effects. Planta Med. 61,
Wermuth, C.G., 2004. Multitargeted drugs: the end of the one-
target-one-diseasephilosophy? Drug Discov. Today 9, 826827.
John's wort? The evidence revisited. J. Clin. Psychiatry 65,
Whitten, D., Myers, D., Hawrelak, J., Wohlmuth, H., 2006. The
effect of St John's wort extracts on CYP3A: a systematic review
of prospective clinical trials. Br. J. Clin. Pharmacol. 62,
WHO, 2006. Mental and Neurological Disorders Depression.
Wijeweera, P., Arnason, J.T., Koszycki, D., Merali, Z., 2006.
Evaluation of anxiolytic properties of Gotukola (Centella
asiatica) extracts and asiaticoside in rat behavioral models.
Phytomedicine 13 (910), 668676.
Williamson, E.M., 2001. Synergy and other interactions in phytome-
dicines. Phytomedicine 8, 401409.
Witte, S., Loew, D., Gaus, W., 2005. Meta-analysis of the efficacy of
the acetonic kava-kava extract WS1490 in patients with non-
psychotic anxiety disorders. Phytother. Res. 19, 183188.
Woelk, H., Arnoldt, K.H., Kieser, M., Hoerr, R., 2006. Ginkgo biloba
special extract EGb 761((R)) in generalized anxiety disorder and
adjustment disorder with anxious mood: a randomized, double-
Woelk, H., Arnoldt, K., Kieser, M., Hoerr, R., 2007. Ginkgo biloba
special extract EGb 761 in generalized anxiety disorder and
adjustment disorder with anxious mood: a randomized, double-
blind, placebo-controlled trial. J. Psychiatr. Res. 41, 472480.
Wolfson, P., Hoffmann, D., 2003. An investigation into the efficacy
of Scutellaria lateriflora in healthy volunteers. Alt. Ther. Health
Med. NLM MEDLINE 9, 74.
Wong, M.L., O'Kirwan, F., Hannestad, J.P., Irizarry, K.J., Elashoff,
D., Licinio, J., 2004. St John's wort and imipramine-induced gene
expression profiles identify cellular functions relevant to
antidepressant action and novel pharmacogenetic candidates
for the phenotype of antidepressant treatment response. Mol.
Psychiatry 9, 237251.
Wurglics, M., Schubert-Zsilavecz, M., 2006. Hypericum perforatum:
amodernherbal antidepressant: pharmacokinetics of active
ingredients. Clin. Pharmacokinet. 45, 449468.
Yoshitake, T., Iizuka, R., Yoshitake, S., Weikop, P., Muller, W.,
Ogren, S., Kehr, J., 2004. Hypericum perforatum L (St John's
wort) preferentially increases extracellular dopamine levels in
the rat prefrontal cortex. Br. J. Pharmacol. 142, 414418.
Zanoli, P., Avallone, R., Baraldi, M., 2000. Behavioral characterisation
of the flavonoids apigenin and chrysin. Fitoterapia 71 (Suppl 1),
20 J. Sarris et al.
Please cite this article as: Sarris, J., et al., Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and
clinical evidence, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.04.002
... 3 In addition to the nutritional interest acquired, Passiflora species are important sources of biologically active compounds, 4 highlighting some species such as Passiflora incarnata, P. edulis f. edulis, P. edulis f. flavicarpa. 5,6 Among the biologically active compounds, alkaloids, cyanogenic compounds, phenolic acids, flavonoids, and saponins stand out. 7,8 The flavonoids reported in this genus are of the C-glycosylated type and are derivatives of luteolin and epigenin, such as vitexin, isovitexin, orientin, and isoorientin. ...
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The genus Passiflora comprises more than 500 species distributed in tropical and semitropical regions. With a great diversity of species, it is estimated that one-third is found in Colombian territory. Besides the food importance, Passiflora species are important sources of biologically active compounds, such as flavonoids. The most important symbiosis between soil fungi and vascular plants related to plant nutrition and tolerance to stress conditions is mycorrhizae. Passiflora species form arbuscular mycorrhizae, with several species of Glomeromycota. This association has been reported to alter the production of secondary metabolites. Thus, the objective of this study was to determine the relation between flavonoid content, mycorrhization, and soil nutritional content of Passiflora alata, Passiflora quadrangularis, Passiflora maliformis, and Passiflora ligularis in Colombian crops. The extracts were prepared and analyzed using UPLC/PDA-MS, and total flavonoids were quantified with the method of AlCl3. Soil characteristics, including nutritional content and percentage of colonization by arbuscular mycorrhizal fungi, were also determined. All variables were analyzed using Spearman’s correlation and principal component analysis. Chromatographic analysis of the extracts allowed us to visualize the different flavonoid compositions of each extract, identifying several C-glycosylflavonoids. In this paper, we report for the first time the presence of luteolin-8-C-rhamnosyl-4′-O-glucoside, apigenin-6-C-arabinosyl-7-O-glucoside, and orientin for P. maliformis. Statistical analysis showed a negative correlation between available phosphorus (ρ = −0.90, p = <0.05) and magnesium (Mg) saturation (ρ = −0.70, p = <0.05) on flavonoid content, whereas the calcium magnesium (Ca/Mg) ratio was positively correlated (ρ = 0.70, p = <0.01). There was a nonsignificant correlation between mycorrhization and flavonoid content (ρ = −0.70, p = >0.1). These results contribute to understanding the relationship between flavonoid-mycorrhization-soil nutritional content on Passiflora spp.
... In addition, herbal remedies such as valerian and passion flower have been shown to be effective in improving sleep quality and reducing the time it takes to fall asleep. A systematic review concluded that complementary medicine modalities can be used as adjunct therapy for insomnia, but further research is needed to determine the long-term efficacy and safety of these modalities [36]. ...
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Benzodiazepines (BZDs) and Z-drugs are commonly prescribed medications for anxiety and sleep disorders. This review examines their efficacy, associated risks, and alternative treatment options. BZDs enhance the activity of gamma-aminobutyric acid (GABA), reducing anxiety, while Z-drugs selectively target GABA-A receptors' alpha-1 subunits for sedative effects. Despite their effectiveness, both drug classes carry the risk of addiction, physical and psychological dependence, and withdrawal symptoms. Side effects, such as drowsiness, dizziness, and cognitive impairment, are also associated with their use. Recent studies indicate that chronic use of BZDs and Z-drugs may lead to cognitive impairment and an increased risk of dementia in older adults. Furthermore, individual factors, dosage, duration of use, and drug interactions can affect their efficacy. Prescribing trends show a decline in benzodiazepine prescriptions and an increase in Z-drug use due to perceived safety advantages. However, evidence suggests that Z-drugs carry similar risks of adverse effects and addiction potential as benzodiazepines. Healthcare professionals should carefully assess patients before prescribing these drugs and monitor their use to prevent dependence and addiction. Brief interventions, patient education, drug withdrawal support, and cognitive behavioral therapy have shown effectiveness in reducing long-term benzodiazepine and Z-drug use. Alternative treatments, including cognitive behavioral therapy and relaxation techniques, should be considered, particularly for patients with a history of addiction or those at high risk of addiction. In conclusion, the risk of addiction, withdrawal symptoms, and adverse effects associated with benzodiazepines and Z-drugs necessitates cautious prescribing and the exploration of alternative treatment options.
... Traditional Chinese Medicine has been extensively used to treat depression, and some meta-analysis supports that chronic treatment with Chinese herbal medicine has effects comparable to conventional antidepressants, with less side effects (Sarris et al., 2011). Yueju pill, an herbal medicine, was formulated at 800 years ago to treat symptoms associated with mood disorders (Wei et al., 2008). ...
Ethnopharmacological relevance: Gardenia jasminoides Ellis (GJ) is one of the five constituents of Yueju pill, a Traditional Chinese Medicine for treatment of syndromes associated with mood disorders. Recently , preclinical and clinical studies suggest that Yueju pill confers rapid antidepressant effects. GJ is identified as the constituent primary for Yueju pill's rapid antidepressant effects. GJ's antidepressant action is temporally associated with up-regulated expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. The present study aimed to identify chemical fractions responsible for the rapid antidepressant efficacy of GJ and its association with BDNF signaling. Materials and methods: Four fractions of GJ were extracted using standardized procedure. The four fractions were screened for rapid antidepressant potential, using the behavioral paradigm of forced swimming test (FST) and tail suspension test (TST) assessed at 24 h post a single administration. A single dose of the putatively effective fractions was further tested in mice exposed to chronic mild stress (CMS), followed with a comprehensive behavioral testing including TST, FST, sucrose preference test (SPT), and novelty suppressed-feeding (NSF). To test the association of BDNF signaling with rapid antidepressant effects of effective factions, the expressions of BDNF and its receptor tropomyosin receptor kinase B (TrkB) in the hippocampus were assessed at different times post a single administration of effective fractions. Results: Both petroleum ether (GJ-PE) and n-butyl alcohol fraction (GJ-BO) fractions of GJ displayed rapid antidepressant potential in the FST. In the TST, the antidepressant effects of GJ-PE lasted for a longer time than GJ-BO. Acute administration of either GJ-PE or GJ-BO significantly reversed the behavioral deficits in the tests of TST, FST, SPT and NSF in chronically stressed mice, confirming both fractions conferred rapid antidepressant efficacy. Interestingly, GJ-PE, but not GJ-BO, increased the expression of BDNF and TrkB in the hippocampus post a single administration. Conclusion: Two standardized fractions GJ-PE and GJ-BO exhibited comparable rapid antidepressant-like effects on the CMS mice. However, only the effects of GJ-PE was associated with BDNF signaling.