Post on 03-Feb-2023
Herbal Medicine for Depression and Anxiety: A Systematic Review with Assessment of Potential Psycho-Oncologic Relevance
K. Simon Yeung1, Marisol Hernandez2, Jun J. Mao1, Ingrid Haviland1, and Jyothirmai Gubili1
1Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY
2Information Systems/Medical Library, Memorial Sloan Kettering Cancer Center, New York, NY
Abstract
Anxiety and depression are prevalent among cancer patients, with significant negative impact.
Many patients prefer herbs for symptom relief to conventional medications which have limited
efficacy/side effects. We identified single-herb medicines that may warrant further study in cancer
patients. Our search included PubMed, Allied and Complementary Medicine, Embase, and
Cochrane databases, selecting only single-herb randomized controlled trials between 1996-2016 in
any population for data extraction, excluding herbs with known potential for interactions with
cancer treatments. 100 articles involving 38 botanicals met our criteria. Among herbs most studied
(≥6 RCTs each), lavender, passionflower, and saffron produced benefits comparable to standard
anxiolytics and antidepressants. Black cohosh, chamomile, and chasteberry are also promising.
Anxiety or depressive symptoms were measured in all studies, but not always as primary
endpoints. Overall 45% of studies reported positive findings with fewer adverse effects compared
with conventional medications. Based on available data, black cohosh, chamomile, chasteberry,
lavender, passionflower, and saffron appear useful in mitigating anxiety or depression with
favorable risk-benefit profiles compared to standard treatments. These may benefit cancer patients
by minimizing medication load and accompanying side effects. However, well-designed larger
clinical trials are needed before these herbs can be recommended and to further assess their
psycho-oncologic relevance.
Keywords
anxiety; depression; herbal medicine; antidepressant; anxiolytic; cancer
BACKGROUND
The National Institutes of Mental Health estimates that depression affects nearly 16 million
people in the United States (Liu et al., 2015). A serious mood disorder, depression is
Corresponding Author: Jyothirmai Gubili, Memorial Sloan Kettering Cancer Center, Bendheim Integrative Medicine Center, 1429 First Avenue, New York, NY, 10021, GubiliJ@mskcc.org, Tel: 507-529-7712, Fax: 212-717-3185.
Conflict of InterestThe authors declare no conflict of interest.
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Published in final edited form as:Phytother Res. 2018 May ; 32(5): 865–891. doi:10.1002/ptr.6033.
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characterized by anhedonia, the reduced ability to experience pleasure, insomnia or
hypersomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness or
guilt, difficulty concentrating, and repetitive thoughts of suicide or death.
According to the American Psychiatric Association, more than 25 million people in the
United States suffer from anxiety disorders involving persistent, excessive worry or fear of
objects or situations, and recurrent panic attacks (2016). Depression and anxiety are
especially common in cancer patients (Anderson and Taylor, 2012), and negatively impact
quality of life (Brown et al., 2010; Bultz and Carlson, 2005). One in three patients (32%)
experience anxiety, depression, or adjustment disorder, which is characterized by feelings of
stress in response to a major event such as a cancer diagnosis. Breast cancer patients were
reported to be most affected (42%), followed by those with head and neck cancer (41%) and
melanoma (39%). Risk factors for depression include poor performance status, as
determined by using a validated version of The Eastern Cooperative Oncology Group Scale
to measure functional status, pain, old age, and low-level education, while poor performance
status, old age, and female gender were predictors of anxiety (Mols et al., 2013; Hong and
Tian, 2014).
Depression and anxiety also contribute to long-term strain in cancer patients. In a recent
survey of 3370 survivors, 40% reported moderate to high anxiety, and in approximately
20%, moderate to high levels of depression lasted up to 6 years post-diagnosis (Inhestern et
al., 2017). Depression can lead to serious consequences that include worsening quality of
life (Higginson and Costantini, 2008), lower adherence to anticancer treatments (Mathes et
al., 2014), suicide (Henriksson et al., 1995), prolonged hospital stays (Prieto et al., 2002),
and reduced survival (Pinquart and Duberstein, 2010).
Conventional management of depression and anxiety disorders is based on pharmacotherapy
and psychotherapy. However, antidepressants and anxiolytics act by modulating
neurotransmitters that play a crucial role in both central and peripheral nervous system
function (Schatzberg, 2015), and current drugs are not very effective in cancer patients
(Ostuzzi et al., 2015). Of greater concern is their association with substantial side effects
which include addiction, seizures, sexual dysfunction, headaches, and suicide (Fajemiroye et
al., 2016), as well as interactions with anticancer treatments (Desmarais and Looper, 2009).
The last few decades have seen a significant rise in the use of natural remedies to treat
various ailments including depression and anxiety. These products are perceived as safer
alternatives to pharmacotherapy, with lower risk of adverse effects or withdrawal. Some, like
chamomile (Srivastava and Gupta, 2007) and black cohosh (Henneicke-von Zepelin et al.,
2007) also have anticancer activities making them attractive choices for cancer survivors.
Analyses of data from the National Health Interview Survey show that compared to the
general population, cancer survivors reported greater use of complementary therapies, with
one-third having taken an herbal medicine (Anderson and Taylor, 2012). In the United
States, because these are regulated as dietary supplements available without a prescription,
patients tend to self-medicate without informing their healthcare providers. While many
herbs used in traditional medicine have been shown to have anti-cancer activities (Tariq et
al., 2017), and some even have the potential to develop into treatments for cancer (Chen, SR
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et al., 2016) or to address the adverse effects of chemotherapy (Chen, MH et al., 2016), few
herbs have been studied in cancer patients and their mechanisms of action, adverse effects,
and potential interactions with anticancer treatments are among the unknowns.
Therefore, the aim of this systematic review is to summarize the evidence from clinical trials
involving botanical supplements for depression and anxiety independent of disease state. We
hope that our findings will provide information that is clinically relevant to oncologists and
cancer patients, facilitate physician-patient communication on this important topic, and
provide guidance on the groundwork laid for herbs that may be worthy of further study in
cancer populations.
Previous reviews have documented herbal remedies for the treatment of depression and/or
anxiety (Farah et al., 2016; Zeng et al., 2017; Muszynska et al., 2015; Bandelow et al., 2015;
Sarris et al., 2011; Lakhan and Vieira, 2010; Ernst, 2006). One study used polyherbal
formulas for both symptoms (Liu et al., 2015). Although such combinations are thought to
have greater therapeutic value compared with single herbs (Parasuraman et al., 2014), it is
difficult to identify the level to which each herb may contribute to overall effects. Therefore,
we restricted our review to studies involving single herbs or extracts that are available in the
United States as dietary supplements, and to randomized controlled trials. We also excluded
those with known potential for herb-drug interactions that should be avoided by cancer
patients, so as to better identify the herbs that have been studied, or may warrant future
study, in this population.
MATERIALS AND METHODS
We conducted this systematic review according to the Cochrane Collaboration framework. A
review protocol is not available. A comprehensive electronic literature search for articles in
multiple languages was conducted in the following databases: PubMed, Allied and
Complementary Medicine (AMED), Embase, and Cochrane. The date filter was applied on
each database to capture the last 20 years of the literature (1996–2016).
Three broad concept categories were searched, and results were combined using the
appropriate Boolean operators (AND, OR). The broad categories included: clinical trials,
botanical supplement products, and select mood disorders. Related terms were also
incorporated into the search strategy to ensure all relevant papers were retrieved (Table 1).
Inclusion and Exclusion Criteria
Only randomized controlled trials (RCTs) were included in this review. Meeting abstracts,
comments, review articles and case reports were excluded. Studies involving St. John’s Wort
were also excluded because it has been extensively researched, revealing many potential
interactions with drugs that are P-glycoprotein and/or CYP3A substrates (Whitten et al.,
2006). Also, the large body of literature merits a separate review.
Details of our screening selection process are provided in Figure 1.
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Data Extraction and Analysis
Two reviewers (KSY, JG) independently reviewed the articles to be included. Any
discrepancies were identified and resolved by additional deliberation. Details of herbs
evaluated in multiple studies are summarized in Table 2, and include study design, sample
population, intervention, control, treatment length, outcomes, and adverse events. Study
details of herbs for which there is currently only 1 RCT available are described in Table 3.
RESULTS
A total of 100 articles involving 38 botanicals were identified that met the inclusion criteria.
They appear here in the order of most to least studied botanicals, but appear alphabetically
for ease of location in the tables. Among RCTs that met our criteria and had more than two
RCTs (Table 2), saffron, kava, ginkgo, lavender, brahmi, and passionflower appeared to be
the most studied.
Saffron, derived from the stigma of Crocus sativus flower, is commonly used as a spice and
as medicine in the Middle-East and in South Asia. In patients with mild to moderate anxiety,
extracts of saffron were reported to be effective in relieving symptoms in several RCTs
(Mazidi et al., 2016; Akhondzadeh et al., 2005; Talaei et al., 2015). Studies also show that
the effects are comparable to standard antidepressant drugs such as fluoxetine (Noorbala et
al., 2005)(Moosavi et al., 2014; Shahmansouri et al., 2014) and imipramine (Akhondzadeh
et al., 2004). In addition, the less expensive petal extracts have also been tested and found to
be effective substitutes (Akhondzadeh Basti et al., 2008; Akhondzadeh Basti et al., 2007;
Movafegh et al., 2008). Saffron reduced anxiety and depression scores in women with
premenstrual syndrome as well (Agha-Hosseini et al., 2008).
Kava kava (Piper methysticum) originated from tropical islands and is used in traditional
medicine. Dietary supplements containing kava extracts are promoted as a natural treatment
for anxiety and insomnia. WS®1490, a standardized dry root extract, has been employed in
several clinical trials (Gastpar and Klimm, 2003; Geier and Konstantinowicz, 2004; Malsch
and Kieser, 2001; Volz and Kieser, 1997) and shown to have anxiolytic effects that were
superior to placebo. Another extract demonstrated effects similar to those of buspirone and
opipramol, prescription drugs used for anxiety and depression (Boerner et al., 2003).
Aqueous extracts of kava have also been investigated by Sarris et al. who reported their
anxiolytic activity to be better than placebo with short-term (3 weeks) use (Sarris et al.,
2009), but not as effective as oxazepam when given in acute doses for one week (Sarris et
al., 2012). In another study, this extract increased sexual drive in female users and reduced
anxiety significantly (Sarris et al., 2013b). Kava extract also reduced anxiety and depression
scores in both peri- (Cagnacci et al., 2003) and postmenopausal women (De Leo et al.,
2000).
Ginkgo biloba is an ancient plant recognized for its medicinal value throughout history, and
is cultivated around the world. The leaf extract is marketed as a dietary supplement to
improve memory because it promotes blood flow. Quite a few clinical trials over the last two
decades used EGB 761®, a standardized dry leaf extract of G. biloba. In patients with
cognitive impairment (Gavrilova et al., 2014; Scripnikov et al., 2007; Cieza et al., 2003; van
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Dongen et al., 2000), this product was shown to be superior to placebo in relieving anxiety
and depression. Similar findings were reported in patients with anxiety (Woelk et al., 2007)
or multiple sclerosis (Johnson et al., 2006), with significant reductions in anxiety scores
following use of EGB 761® compared to a placebo. However, results from a pilot study
indicate that EGB 761® is no better than the prescription drug donepezil in Alzheimer’s
patients (Yancheva et al., 2009), and another G. biloba extract (PN246) was no better than
placebo in preventing seasonal affective depression (Lingaerde et al., 1999).
The flower of lavender (Lavandula angustifolia) is used in perfumes and in aromatherapy
because its fragrance has a purported calming effect. Oral supplements from this plant are
also available for a wide variety of symptoms. Silexan®, a product derived from steam
distillation of lavender flowers, has been tested in several human studies that show its
anxiolytic activity to be better than placebo (Kasper et al., 2010; Kasper et al., 2014; Kasper
et al., 2015), and comparable to prescription drugs such as paroxetine (Kasper et al., 2014)
and lorazepam (Woelk and Schlafke, 2010) with fewer adverse effects. Lavender tea may
also enhance the effect of the antidepressant citalopram (Nikfarjam et al., 2013). Similar
benefits were observed when lavender extract drops were taken with imipramine
(Akhondzadeh et al., 2003).
Brahmi (Bacopa monnieri) is a plant native to South Asia and commonly used in Ayurvedic
medicine. Preliminary studies show that it acts as an acetylcholinesterase inhibitor
suggesting it may benefit those with cognitive dysfunction. KeenMind®, an ethanolic extract
derived from the stem, leaves, and root, was tested in adults in two studies. Results showed
positive effects in improving cognitive function but not anxiety (Benson et al., 2014;
Roodenrys et al., 2002). Studies using other extracts showed a general reduction in anxiety
scores (Sathyanarayanan et al., 2013; Kumar et al., 2011; Calabrese et al., 2008; Stough et
al., 2001). However, all studies were conducted only in healthy subjects with placebo
controls. Whether similar benefits could be conferred on patients with anxiety and
depression, and how this herb compares with standard medications for anxiety or depression
remains unclear.
Passionflower is derived from the flower of Passiflora incarnata, a plant prevalent in
Southeastern parts of the Americas. Native Americans used it as a remedy to improve sleep
and to reduce anxiety. One study that employed a traditional tea preparation taken before
bedtime found that it can improve sleep quality, but had no significant effect on anxiety
when compared to a placebo (Ngan and Conduit, 2011). An aqueous extract of
passionflower produced a slight but statistically significant improvement in anxiety scores in
patients undergoing spinal anesthesia without disrupting psychomotor function or sedation
(Aslanargun et al., 2012). In another trial, a standardized P. incarnata extract was reported to
reduce preoperative anxiety in patients undergoing inguinal herniorrhaphy (Movafegh et al.,
2008). When used as an adjuvant, passionflower extract improved mental symptoms more
effectively than clonidine alone for opioid withdrawal (Akhondzadeh et al., 2001a). In
patients with anxiety disorder, passionflower extract was no better than oxazepam in
reducing symptoms, but had fewer adverse effects (Akhondzadeh et al., 2001b). Similar
findings were reported in another study that compared passionflower with sertraline
(Nojoumi et al., 2017).
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Rhodiola (Rhodiola rosea) is a perennial plant used in traditional medicine in Asia and in
Eastern Europe to improve physical endurance and mental performance. Results from
studies of the root extract involving patients with anxiety (Cropley et al., 2015) and
depression (Darbinyan et al., 2007) show that it can reduce symptoms when compared with
placebo. In adults with stress-related fatigue, an R. rosea extract was no better than a placebo
in reducing depression scores (Olsson et al., 2009). A root extract was also less effective
than the standard antidepressant drug sertraline in patients with mild to moderate depression,
but was associated with fewer adverse events and was better tolerated (Mao et al., 2015).
Black cohosh (Cimicifuga racemosa) is an herb chiefly marketed for menopausal symptoms.
But in a study of postmenopausal women, it was not as effective as fluoxetine in reducing
depression, although it had a positive effect on hot flashes (Oktem et al., 2007). Another
study in the same population showed that a standardized black cohosh extract Remifemin®
was as effective as low-dose transdermal estradiol treatment in reducing hot flashes, anxiety,
and depression, but without the hormonal changes exhibited with estradiol (Nappi et al.,
2005). However, one trial that employed a different black cohosh extract did not find it more
effective than a rice flour placebo (Amsterdam et al., 2009b). Variations in methods of
preparation and dosage may account for the lack of effects.
Chamomile (Matricaria recutita) is an herb popular for its relaxant effects. In patients with
mild to moderate generalized anxiety disorder, a chamomile extract demonstrated modest
anxiolytic activity when compared with placebo (Amsterdam et al., 2009a). A follow-up
study of chamomile’s long-term effects showed that it continued to be effective after 38
weeks although there was no significant reduction in relapse time (Mao et al., 2016).
Guarana (Paullinia cupana) is an herb indigenous to South America. Its extract is marketed
as a dietary supplement mainly for its stimulant effects, which are likely due to the high
caffeine content. However, in healthy volunteers, guarana was ineffective in reducing
anxiety or improving well-being and mood (Silvestrini et al., 2013). In post-chemotherapy
breast cancer patients, guarana was better than placebo in reducing fatigue, but not anxiety
or depression (de Oliveira Campos et al., 2011). And in breast cancer patients undergoing
radiation therapy, there were no significant differences in either fatigue or depression when
compared to a placebo (da Costa Miranda et al., 2009).
Asian Ginseng (Panax ginseng) found in Northeast Asia has been used as a “cure all” in
Traditional Chinese Medicine. P. ginseng root extract reduced anxiety in patients with
fibromyalgia, but it was not as potent as amitriptyline, an antidepressant drug (Braz et al.,
2013). In another trial of postmenopausal women, Ginsana®, a standardized P. ginseng root
extract, reduced depression but not general well-being scores (Wiklund et al., 1999).
Chasteberry (Vitex agnus castus) is often recommended for relief from premenstrual
symptoms. Studies show that chasteberry drops are similar to placebo in relieving depressive
symptoms (Zamani et al., 2012). When compared to fluoxetine, chasteberry was more
effective in reducing physical symptoms, while fluoxetine was better for relieving
psychological symptoms (Atmaca et al., 2003).
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Maca (Lepidium meyenii) is a plant indigenous to South America. It has been used to
enhance fertility and sexual performance in both men and women, and to relieve menopausal
symptoms. Powdered roots (Stojanovska et al., 2015) as well as the dried methanolic extract
(Brooks et al., 2008) have been tested on postmenopausal women in two studies with a
crossover design. These products alleviated depression and anxiety without exerting
hormonal effects.
Red clover (Trifolium pratense) is commonly used to address premenstrual and menopausal
symptoms because it acts as a phytoestrogen. In studies of postmenopausal women,
standardized T. pratense capsules were reported to relieve anxiety and related symptoms
(Lipovac et al., 2010; Hidalgo et al., 2005).
Studies of soy isoflavones (de Sousa-Munoz and Filizola, 2009), whole soy, and daidzein
(Liu et al., 2014) failed to find any reductions in depressive symptoms.
Valerian (Valeriana officinalis) is known for its calming effects, and valerian tea is often
used to aid sleep. In patients with anxiety disorder, a valerian root extract had anxiolytic
effects similar to diazepam (Andreatini et al., 2002). When used as a sleep-aid, its benefits
and adverse event profile were comparable to oxazepam (Dorn, 2000).
Wormwood (Artemisia absinthium) is used both as an herbal medicine and as a spice in
alcoholic drinks. Two studies were conducted using SedaCrohn®, a standardized A. absinthium leaf and stem powder, on patients with Crohn’s disease. When compared to
standard medications (Krebs et al., 2010) or a placebo (Omer et al., 2007), this product
improved depression symptom scores.
There were a number of herbal medicines for which our criteria yielded only 1 RCT (Table
3).
American skullcap (Scutellaria lateriflora) has been compared with stinging nettle leaf
(Urtica dioica folia) for its effects on improving mood in healthy participants (Brock et al.,
2014). No significant differences were found, but this may be due to low levels of anxiety at
baseline.
Flax oil is derived from the seed of Linum usitatissimum. Flax oil containing alpha-linolenic
acid (α-LNA) was reported to be similar to olive oil in reducing depressive symptoms in
children and young adults with bipolar disorder (Gracious et al., 2010).
Garlic (Allium sativum) has been investigated in a study to determine its cholesterol-
lowering activity. Psychopathologic parameters including depression were also evaluated,
but no changes were observed (Peleg et al., 2003).
Sage (Salvia officinalis) is generally used as a spice. Essential oil and extracts of sage are
thought to inhibit cholinesterase, an enzyme that breaks down the neurotransmitter
acetylcholine. In a study that compared different dosages of a dried leaf extract with
placebo, a lower dose (300 mg/d) was more effective than the higher dose (600 mg/d) in
reducing anxiety in healthy young adults (Kennedy et al., 2006).
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In menopausal women, extracts of blue green algae (Aphanizomenon flos-aquae)
(Genazzani et al., 2010), Cimicifuga foetida (Zheng et al., 2013), grape seed (Vitis vinifera)
(Terauchi et al., 2014), rhapontic rhubarb (Rheum rhaponticum) (Kaszkin-Bettag et al.,
2007), rose tea (Tseng et al., 2005), and wild yam (Dioscorea alata) (Hsu et al., 2011) helped
decrease symptom scores related to anxiety and depression. Whereas wild yam appears to
work via estrogenic pathway, the blue green algae extract did not demonstrate any hormonal
effects.
Extracts from gotu kola (Centella asiatica) (Bradwejn et al., 2000), green tea (Camelia sinensis) (Zhang et al., 2013), holy basil (Ocimum sanctum) (Sampath et al., 2015), and
Sceletium tortuosum (Terburg et al., 2013), when administered to healthy adults were more
effective than placebo in reducing anxiety and/or depression scores.
Bitter orange blossom (Citus aurantium) (Akhlaghi et al., 2011), curcumin (Curcuma longa)
(Yu et al., 2015), Melissa officinalis (Alijaniha et al., 2015), and Siberian ginseng
(Eleutherococcus senticosis) (Schaffler et al., 2013) were also found to have some benefit in
lowering anxiety and depression in clinical studies, but these symptoms were not the
primary endpoints.
Ashwagandha (Withania somnifera) (Chengappa et al., 2013), black cumin (Nigella sativa)
(Bin Sayeed et al., 2014), and Chlorella vulgaris (Panahi et al., 2015) were not effective in
relieving anxiety and depression in patients with related symptoms.
DISCUSSION
In this review, we found that the majority were early-phase studies, with no phase III trials.
Study designs varied considerably with subjects including menopausal women and patients
with anxiety disorders. Some studies that used healthy volunteers with low baseline
symptom levels may have produced misleading results. Anxiety or depressive symptoms
were measured in all the studies, but were not always the primary endpoints. In addition,
different scales were used to measure the severity of symptoms. We chose to include only
RCTs to reduce bias. Most trials used placebos or standard pharmaceutical agents in the
control group. Overall, 45% of studies reviewed indicate significant improvements in
anxiety or depression scores. Many studies that compared the effects of herbs with standard
pharmaceutical agents reported that herbs are not as potent, but are safer than prescription
drugs. These include saffron (Noorbala et al., 2005; Moosavi et al., 2014; Shahmansouri et
al., 2014; Akhondzadeh Basti et al., 2007), black cohosh (Oktem et al., 2007; Nappi et al.,
2005), and chasteberry (Atmaca et al., 2003). These herbs did not outperform fluoxetine, but
were associated with fewer adverse events, which can include changes in appetite, sexual
dysfunction, nausea, headache, insomnia, and tremors.
Although several studies reported herbal supplements to be safe, their potential for
interactions with other drugs were not discussed. For example, black cohosh (Li et al.,
2011), chasteberry (Ho et al., 2011), chamomile (Ganzera et al., 2006), and rhodiola
(Hellum et al., 2010) are known to modulate the actions of cytochrome P450 enzymes, and
may increase the toxicity or decrease therapeutic effects of substrate drugs (Gurley et al.,
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2012) including many used in cancer treatment, like cyclosporine (Sridharan and
Sivaramakrishnan, 2016) and most of the tyrosine kinase inhibitors (Gay et al., 2017). Even
though the clinical significance of these interactions is yet to be determined, the potential
exists and therefore should be given due consideration. In addition, herbs such as chamomile
(Segal and Pilote, 2006) and lavender (Denner, 2009) have anticoagulant/antiplatelet
properties, and may therefore elevate the risk of bleeding with concurrent use of drugs that
have similar actions (Ge et al., 2014). These include warfarin and heparin drugs that are
often used to treat or prevent deep vein thrombosis in bedridden cancer patients. These herbs
may also further increase the cardiovascular complication of antiangiogenic drugs like
bevacizumab (Totzeck et al., 2017). In addition, the debate continues about phytoestrogenic
herbs that include lavender (Diaz et al., 2016) and chasteberry (Dugoua et al., 2008), and
their potential for interference with anti-hormonal therapies or for exerting pro-proliferative
effects in patients with hormone-sensitive cancers (Fritz et al., 2013). It is prudent to
understand these risks because cancer patients often tend to use herbal products
concomitantly with prescription drugs. Another concern is the intrinsic toxicity associated
with some herbs. For instance, kava is a traditional herbal remedy with proven anxiolytic
and antidepressant properties, but has been associated with hepatotoxicity (Teschke, 2010).
This can be detrimental for cancer patients who often have compromised liver function as a
side effect from chemotherapy (Vincenzi et al., 2016). However, aqueous extracts were
reported to be safe in preclinical testing (Sarris et al., 2009; Sarris et al., 2013a). Clinical
trials are needed to determine safety in humans.
Based on these data, black cohosh, chamomile, chasteberry, lavender, passionflower, and
saffron appear to be worthy of consideration for the treatment of depression and anxiety with
minimal risk of serious side effects. They appear to be reasonable options for patients who
prefer a natural approach. Future research efforts should focus on elucidating the
mechanisms of action as well as the safety and efficacy of these herbs. Also, clinical trials
should employ well-characterized standardized agents. Optimal dosages, potential
interactions, and adverse effects should be determined in early phase trials, preferably in
cancer survivors.
Other limitations of this review include significant variability among the studies included
along with publication bias, as many trials were sponsored by the manufacturers, and
employed proprietary products.
CONCLUSIONS
Available evidence suggests utility of some herbal medicines in mitigating anxiety and
depression, but conclusive data to show superiority in benefit/risk ratio of these products
over current pharmaceuticals are lacking. Due to the heterogeneity of previous trials, future
studies should focus on using the standardized forms of these products in large-scale trials
with robust methodology to determine their comparative effectiveness. A just-published
review reported increased participation in studies with longitudinal design compared to
randomized trials (Wakefield et al., 2017). Studies to elucidate mechanisms and
pharmacokinetics are also needed. The findings can help establish reliable dosage guidelines
and effectiveness of herbal products, which appear to have a better benefit-to-risk profile
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than standard pharmacologic options. Cancer patients, known to have higher rates of
depression and anxiety, might especially benefit from such research as conventional
management is often not favorable.
Acknowledgments
Funding
This manuscript was supported in part by NIH/NCI Cancer Center Support Grant P30 CA008748.
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Fig. 1. Overview of study selection
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Table 1
Search Strategies and Terms Used
Medical Subject Headings (MeSH) Keyword terms
(Clinical Trials as Topic[Mesh] OR “Controlled Clinical Trials as Topic” [Mesh] OR “Clinical Trials, Phase IV as Topic” [Mesh] OR “Clinical Trials, Phase III as Topic” [Mesh] OR “Clinical Trials, Phase II as Topic” [Mesh] OR “Clinical Trials, Phase I as Topic” [Mesh] OR “Clinical Trial” [Publication Type]) AND (“Herbal medicine” [Mesh] OR Phytotherapy[Mesh] OR “Plant Extracts” [Mesh] OR “Plants, Medicinal” [Mesh]) AND (Anxiety[Mesh] OR “Depression” [Mesh] OR “Mood Disorders” [Mesh] OR “Antidepressive Agents” [Mesh] OR “Anti-Anxiety Agents ” [Mesh])
Clinical Trials AND (phytotherapy OR biological product OR biological products OR plant extract OR plant extracts) AND (anxiety OR depression OR mood disorders) AND (antidepressive agent OR anti-anxiety agents OR herb OR herbs OR natural product OR natural products OR antidepressant OR antidepressants OR anxiolsytic OR anxiolytics)
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Tab
le 2
Her
bal M
edic
ines
Mos
t Fre
quen
tly E
valu
ated
for
Anx
iety
and
Dep
ress
ion
in R
CT
s O
ver
the
Las
t 20
Yea
rs (
1996
–201
6)
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Asi
an G
inse
ng
Pan
ax g
inse
ng
extr
act
(PG
E)
2 st
udie
s
Bra
z 20
13(B
raz
et a
l.,
2013
)E
ffec
ts v
s am
itrip
tylin
ePt
s w
ith f
ibro
mya
lgia
38D
B-R
CT
PGE
100
mg/
dR
oot e
xtra
ct, 2
7%
gins
enos
ides
Am
itrip
tylin
e25
mg/
d–o
r– P
BO
12 w
kV
AS;
Fib
rom
yalg
ia I
mpa
ctQ
uest
ionn
aire
(FI
Q)
VA
S: P
GE
red
uc p
ain
(P<
.00
01)
and
impr
sle
ep (
P<.
001)
, but
no
BG
D; i
mpr
an
xiet
y (P
<.0
001)
, but
mor
e im
pr w
ith a
mitr
ipty
line
FIQ
: PG
E r
educ
num
ber
of
tend
er p
oint
s an
d im
pr Q
oL
but n
o B
GD
Wik
lund
199
9(W
iklu
nd e
t al
., 19
99)
QoL
and
phy
siol
ogic
al
para
met
ers
Sym
ptom
atic
PM
P w
omen
384
DB
-RC
T M
ultic
ente
rPG
E 2
00 m
g/d
Gin
sana
, ST
D P
G r
oot
extr
act g
115
®
PBO
16 w
k1°
-OC
: PG
WB
; Wom
en’s
H
ealth
Que
stio
nnai
re
(WH
Q),
VA
S
Tota
l PG
WB
I no
t sig
, but
sig
ef
fect
s fo
r de
pres
sion
, wel
l-be
ing
and
heal
th s
ubsc
ales
; no
sig
eff
ects
for
WH
Q, V
AS
or p
hysi
olog
ical
par
amet
ers,
in
cl V
MS
Bla
ck c
ohos
h C
imic
ifug
ae
race
mos
ae
extr
act
(CR
E)
3 st
udie
s
Am
ster
dam
20
09(A
mst
erda
m e
t al.,
20
09b)
MP
anxi
ety
MP
wom
en28
DB
-RC
TD
ose
esc
CR
E 6
4–12
8 m
g/d
STD
to 5
.6%
act
ive
trite
rpen
e gl
ycos
ides
PBO
: ric
e fl
our
Up
to 1
2 w
k1°
-OC
: HA
MA
2°-O
C: B
AI,
PG
WB
I, G
reen
C
limac
teri
c Sc
ale
(GC
S), %
pt
s w
ith ≥
50%
HA
MA
sco
re
chan
ge
No
sig
anxi
olyt
ic e
ffec
ts; 1
su
bjec
t dis
cont
d du
e to
AE
Okt
em 2
007(
Okt
em e
t al.,
20
07)
Eff
icac
y on
MP
sym
ptom
s vs
flu
oxet
ine
PMP
wom
en
120
RC
TC
RE
40
mg/
dR
emix
in®
Fluo
xetin
e20
mg/
d6
mo
Hot
flu
sh/n
ight
sw
eats
#/in
tens
ity; M
o 3
(beg
/end
):
mod
ifie
d K
uppe
rman
Ind
ex
(mK
I), B
eck’
s D
epre
ssio
n Sc
ale
(BD
S), R
AN
D-3
6 Q
oL
At M
o 3
end:
CR
E s
ig d
ecr
mK
I; f
luox
etin
e si
g de
cr
BD
SA
t Mo
6 en
d: C
RE
hot
flu
sh
scor
e re
duc
by 8
5% v
s fl
uoxe
tine
62%
; 40
(20
each
gr
oup)
dis
cont
inue
dFl
uoxe
tine
mor
e ef
fect
ive
for
depr
essi
onC
RE
mor
e ef
fect
ive
for
hot
flus
hes
/ nig
ht s
wea
ts
Nap
pi 2
005(
Nap
pi e
t al.,
20
05)
Clim
acte
ric
com
plai
nts
PMP
wom
en64
RC
TC
RE
40
mg/
dR
emif
emin
®:
Isop
ropa
nolic
aqu
eous
ex
trac
t
Low
-dos
e tr
ansd
erm
al
estr
adio
l 25
μg q
7d +
di
hydr
oges
tero
ne 1
0 m
g/d
for
last
12
d of
3-
mo
tx
3 m
oD
aily
hot
flu
shes
; VM
S,
urog
enita
l sym
ptom
s;
horm
onal
par
amet
ers;
Sy
mpt
om R
atin
g Te
st
At M
o 1:
Bot
h re
duc
# da
ily
hot f
lush
es (
P<.0
01)
and
VM
S (P
<.0
01);
eff
ects
m
aint
aine
d at
3 m
o w
/o s
ig
BG
DA
t Mo
3: B
oth
redu
c an
xiet
y (P
<.0
01)
and
depr
essi
on (
P<.
001)
; no
sig
horm
onal
ch
ange
s
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Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Bra
hmi B
acop
a m
onni
eri e
xtra
ct
(BM
E)
6 st
udie
s
Ben
son
2014
(Ben
son
et
al.,
2014
)A
nxio
lytic
, ant
idep
ress
ant,
seda
tive,
and
ada
ptog
enic
ac
tions
dur
ing
mul
titas
king
Hea
lthy
subj
ects
17D
B-R
CT
Cro
ssov
erB
ME
320
or
640
mg
befo
re ta
sks
Kee
nMin
d® (
CD
RI
08):
ste
ms,
leav
es, a
nd
root
s; 5
0% e
than
ol
extr
act
PBO
: ine
rt p
lant
-bas
ed
mat
eria
ls3
stud
y vi
sits
se
para
ted
by 1
wk
was
hout
s
Cog
nitiv
e, m
ood,
and
sa
livar
y co
rtis
ol m
easu
res
pre-
post
mul
titas
king
se
ssio
ns
Ass
ocia
ted
with
pos
itive
co
gniti
ve a
nd m
ood
effe
cts
and
redu
c co
rtis
ol le
vels
, but
su
bjec
tive
moo
d/an
xiet
y ra
tings
wer
e in
cons
iste
nt
Sath
yana
raya
nan
2013
(Sat
hyan
aray
anan
et
al.,
2013
)
Lea
rnin
g, m
emor
y,
proc
essi
ng, a
nd a
nxie
tyE
duca
ted
adul
ts in
urb
an
Indi
a
72D
B-R
CT
BM
E 4
50 m
g/d
STD
BM
E d
ried
her
bPB
O: s
tarc
h12
wk
STA
I; A
udito
ry V
erba
l L
earn
ing
Test
(A
VLT
); I
nspe
ctio
n T
ime
Task
; Rap
id V
isua
l In
form
atio
n Pr
oces
sing
Tes
t; St
roop
Tas
k
Tre
nd f
or lo
wer
STA
I w
ith
BM
E; n
o B
GD
for
cog
nitiv
e m
easu
res
Kum
ar 2
011(
Kum
ar e
t al.,
20
11)
Neu
roph
arm
acol
ogic
eff
ects
Hea
lthy
volu
ntee
rs a
ge 2
0–75
y
54D
B-R
CT
Cro
ssov
erB
ME
300
mg/
dB
ESE
B-C
DR
I-08
PBO
: lac
tose
6 m
o on
eac
h tx
Anx
iety
, wel
l-be
ing,
sle
ep,
and
wal
king
Inte
rven
tion
sig
impr
he
mog
lobi
n, o
xyge
n ca
paci
ty, w
ell-
bein
g,
wal
king
, han
d gr
ip, a
nxie
ty,
slee
pD
ecr
puls
e an
d gl
ucos
e le
vels
Cal
abre
se 2
008(
Cal
abre
se
et a
l., 2
008)
Cog
nitiv
e fu
nctio
nE
lder
ly v
olun
teer
s54
par
ticip
ants
48 c
ompl
eter
sD
B-R
CT
BM
E 3
00 m
g/d
Met
hano
l/wat
er f
or
50:1
dry
ext
ract
with
m
in 5
0% b
acos
ides
A
and
B
PBO
6-w
k PB
O r
un-i
n +
12
wk
tx1°
-OC
: AV
LT d
elay
ed r
ecal
l sc
ore
2°-O
C: S
troo
p Ta
sk; D
ivid
ed
Atte
ntio
n Ta
sk (
DA
T);
W
echs
ler
Adu
lt In
telli
genc
e Sc
ale
(WA
IS);
STA
I; C
ente
r fo
r E
pide
mio
logi
c St
udie
s D
epre
ssio
n sc
ale
(CE
SD)-
10;
POM
S
Enh
ance
d A
VLT
del
ayed
w
ord
reca
ll m
emor
y sc
ores
, St
roop
res
ults
; dec
r C
ESD
-10
and
com
bine
d ST
AI
scor
es, a
nd h
eart
rat
eN
o ef
fect
s on
DA
T, W
AIS
, m
ood,
or
BP;
few
AE
s,
prim
arily
sto
mac
h up
set
Roo
denr
ys
2002
(Roo
denr
ys e
t al.,
20
02)
Mem
ory
and
anxi
ety
Adu
lts a
ge 4
0– 6
5 y
76D
B-R
CT
BM
E 3
00 m
g/d
for
thos
e w
eigh
ing
<90
kg
–or–
450
mg/
d if
>90
kg K
eenM
ind®
; dos
es
equi
v to
6 g
and
9 g
dr
ied
rhiz
ome,
re
spec
tivel
y
PBO
3 m
oD
epre
ssio
n, A
nxie
ty a
nd
Stre
ss S
cale
Sig
effe
cts
on n
ew-i
nfo
rete
ntio
n, b
ut n
one
on s
hort
-te
rm, e
very
day
or w
orki
ng
mem
ory,
atte
ntio
n, in
fo
retr
ieva
l, de
pres
sion
, anx
iety
or
str
ess
Stou
gh 2
001(
Stou
gh e
t al.,
20
01, 2
015)
Cog
nitiv
e fu
nctio
nH
ealth
y vo
lunt
eers
46D
B-R
CT
BM
E 3
20 m
g/d
Eac
h 16
0-m
g ca
p eq
uiv
to 4
g d
ried
her
b
PBO
12 w
kIT
task
, AV
LT, S
TAI
Sig
impr
in S
TAI
(P<
.001
) w
ith m
ax e
ffec
ts a
fter
12
wk;
al
so im
pr v
isua
l inf
o pr
oces
sing
(IT
task
), le
arni
ng
rate
and
mem
ory
cons
olid
atio
n (A
VLT
)
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 23
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Cha
mom
ile
Mat
rica
ria
recu
tita
extr
act
(MR
E)
3 st
udie
s
Cha
ng 2
016(
Cha
ng a
nd
Che
n, 2
016)
Eff
ects
on
slee
p qu
ality
, fa
tigue
, dep
ress
ion
Slee
p-di
stur
bed
post
nata
l Ta
iwan
ese
wom
en
80SB
-RC
TC
ham
omile
tea
stee
ped
in 3
00 m
L h
ot w
ater
fo
r 10
–15
min
Ger
man
ori
gin;
2 g
dr
ied
flow
ers
in e
ach
teab
ag
Reg
ular
pos
tpar
tum
car
e on
ly2
wk
Post
part
um S
leep
Qua
lity
Scal
e (P
SQS)
, Edi
nbur
gh
Post
nata
l Dep
ress
ion
Scal
e,
Post
part
um F
atig
ue S
cale
Sign
ific
ant i
mm
edia
te-t
erm
lo
wer
sco
res
for
phys
ical
-sy
mpt
oms-
rela
ted
slee
p in
effi
cien
cy: t
=−
2.48
2, P
=.
015;
dep
ress
ion:
t=−
2.37
2,
P=.0
20. H
owev
er, 4
-wee
k po
st-t
est s
core
s w
ere
sim
ilar
for
both
gro
ups.
Mao
201
6(M
ao e
t al.,
20
16)
Lon
g-te
rm u
se f
or
prev
entio
n of
GA
D
sym
ptom
rel
apse
am
ong
tx
resp
onde
rsO
utpt
adu
lts w
ith D
SM-I
V
mod
erat
e-to
-sev
ere
GA
D
179
enro
lled
in
Ph 1
93 r
espo
nder
s ra
ndom
ized
DB
-RC
T o
f re
spon
ders
(P
hase
2)
Ph1
OL
tria
l ide
ntif
ied
resp
onde
rs
MR
E p
harm
aceu
tical
gr
ade
extr
act 1
500
mg
(500
mg
caps
ule
3 tim
es d
aily
) co
ntin
uatio
n tx
am
ong
resp
onde
rs f
rom
Ph
1
PBO
Ph2:
26
wk
(Res
pond
ers
DB
-R
CT
)Ph
1: 1
2 w
k (O
L;
All
MR
E)
Tim
e to
rel
apse
dur
ing
cont
inua
tion
tx a
nd lo
ng-
term
fol
low
up; p
ropo
rtio
n w
ho r
elap
sed;
AE
s
Did
not
sig
nifi
cant
ly r
educ
e ra
te o
f re
laps
e (m
ean
time:
M
RE
, 11.
4 ±
8.4
wk;
PB
O,
6.3
± 3
.9 w
k)Fe
wer
MR
E p
artic
ipan
ts
rela
psed
(n=
7/46
; 15.
2%)
vs
PBO
-sw
itche
d (n
=12
/47;
25
.5%
)Si
g lo
wer
GA
D s
ympt
oms
with
MR
E th
an P
BO
(P=
.00
32)
Sig
wei
ght r
educ
tions
(P=
.04
6), m
ean
arte
rial
BP
(P=
.00
63);
low
AE
rat
es
Am
ster
dam
20
09(A
mst
erda
m e
t al.,
20
09a)
Anx
iety
, eff
icac
y/to
lera
bilit
yPt
s w
ith m
ild to
mod
erat
e G
AD
61 e
nrol
led
57 r
ando
miz
edD
B-R
CT
Dos
e es
cM
RE
220
–110
0 m
g/d
STD
to 1
.2%
api
geni
nPB
O: l
acto
se8
wk
1°-O
C: H
AM
A2°
-OC
: BA
I, P
GW
BI,
CG
I-S,
% p
ts w
ith ≥
50%
HA
MA
sc
ore
chan
ge
Sig
redu
c in
mea
n to
tal
HA
MA
sco
re (
P=.0
47)
Posi
tive
chan
ges
in a
ll 2°
-O
C; n
onsi
g A
Es
Cha
steb
erry
V
itex
agnu
s ca
stus
(V
AC
)2
stud
ies
Zam
ani 2
012(
Zam
ani e
t al
., 20
12)
Mild
/mod
erat
e PM
SW
omen
with
PM
S13
4 en
rolle
d12
8 ev
alua
ted
DB
-RC
TV
AC
40
drop
s fo
r 6
d be
fore
men
ses
up u
ntil
men
stru
atio
n
PBO
6 m
enst
rual
cyc
les
VA
S fo
r he
adac
he, a
nger
, ir
rita
bilit
y, d
epre
ssio
n, b
reas
t fu
llnes
s, b
loat
ing,
and
ty
mpa
ni
Sig
diff
fro
m B
L a
nd B
GD
fo
r V
AC
vs
PBO
(P<
.000
1);
wel
l tol
erat
ed; n
o A
Es
Atm
aca
2003
(Atm
aca
et
al.,
2003
)Pr
emen
stru
al d
ysph
oric
di
sord
er (
PMD
D)
Wom
en w
ith D
SM-I
V
PMD
D
41SB
/rat
er-b
lind
RC
TV
AC
20–
40 m
g/d
Fluo
xetin
e 20
–40
mg/
d2
mo
Penn
Dai
ly S
ympt
om R
epor
t (D
SR),
HA
MD
, CG
I-Se
veri
ty o
f Il
lnes
s (C
GI-
SI)
and
Impr
ovem
ent (
CG
I-I)
Sim
ilar
resp
onse
s: V
AC
(5
7.9%
, n=
11)
vs f
luox
etin
e (6
8.4%
, n=
13)
with
no
BG
D,
but g
reat
er e
ffec
t with
fl
uoxe
tine
for
psyc
holo
gica
l an
d V
AC
for
phy
sica
l sy
mpt
oms
Gin
kgo
bilo
ba
extr
act
(GB
E)
9 st
udie
s
Gav
rilo
va 2
014(
Gav
rilo
va
et a
l., 2
014)
Neu
rops
ychi
atri
c sy
mpt
oms
and
cogn
ition
Pts
with
mild
cog
nitiv
e im
pair
men
t
160
DB
-RC
T M
ultic
ente
rG
BE
240
mg/
dE
Gb
761®
dry
leaf
ST
D to
22–
27%
fl
avon
e gl
ycos
ides
and
5–
7% te
rpen
e la
cton
es
PBO
24 w
k1°
-OC
: Neu
rops
ychi
atri
c In
vent
ory
(NPI
); S
TAI
stat
e su
b-sc
ore;
Ger
iatr
ic
Dep
ress
ion
Scal
e (G
DS)
2°-O
C: T
rail-
Mak
ing
Test
(T
MT
) A
/B, g
loba
l im
pres
sion
of
chan
ge (
GIC
)
Mea
n N
PI c
ompo
site
sco
re
decr
by
7.0±
4.5p
oint
s w
ith
GB
E v
s 5.
5±5.
2 fo
r PB
O
(P=
.001
); ≥
4 po
int i
mpr
with
G
BE
78.
8% v
s PB
O 5
5.7%
(P
=.0
02)
GB
E s
ig s
uper
ior
for
STA
I,
info
rman
t GIC
, and
TM
T
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 24
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
scor
es; t
rend
s fa
vore
d G
BE
on
GD
S an
d pt
GIC
sco
res
No
seri
ous
AE
s
Litv
inen
ko
2014
(Litv
inen
ko e
t al.,
20
14)
Cog
nitio
n, a
nxie
ty,
depr
essi
on, s
leep
dis
orde
rs,
and
activ
ityPt
s w
ith d
isci
rcul
ator
y en
ceph
alop
athy
and
co
gniti
ve im
pair
men
t
45R
CT
GB
E 2
40 m
g/d
EG
b 76
1®O
ther
dru
gs24
wk
Cog
nitiv
e/ne
urop
sych
olog
ical
test
ing
incl
FA
B, M
MSE
, HA
DS
Anx
iety
and
dep
ress
ion
sig
decr
on
the
12th
and
24t
h w
eek,
res
pect
ivel
y; b
est
effe
cts
obse
rved
for
anx
iety
Yan
chev
a 20
09(Y
anch
eva
et a
l., 2
009)
Eff
ects
and
tole
rabi
lity
Pts
with
Alz
heim
er’s
dis
ease
an
d ne
urop
sych
iatr
ic
feat
ures
95D
B-R
CT
GB
E 2
40 m
g/d
±
done
pezi
lE
Gb
761®
Don
epez
il in
itial
5 m
g/d;
then
10 m
g/d
afte
r 4
wk
22 w
kT
E4D
; SK
T c
ogni
tive
test
ba
ttery
; NPI
; Got
tfri
es-
Bra
ne-S
teen
Sca
le to
tal s
core
an
d A
DL
sub
scor
e; H
AM
D;
Clo
ck-D
raw
ing
Test
; Ver
bal
Flue
ncy
Test
Cha
nges
and
res
pons
e ra
tes
sugg
est n
o si
g di
ff b
tw G
BE
an
d do
nepe
zil a
nd p
oten
tial
favo
ring
com
bina
tion
txA
E r
ate
low
er w
ith G
BE
and
co
mbi
natio
n tx
Scri
pnik
ov
2007
(Scr
ipni
kov
et a
l.,
2007
)
Eff
ects
on
dem
entia
sy
mpt
oms
and
care
give
r di
stre
ssPt
s w
ith d
emen
tia a
ssoc
iate
d w
ith n
euro
psyc
hiat
ric
feat
ures
400
DB
-RC
TG
BE
240
mg/
dE
Gb
761®
PBO
22 w
k1°
-OC
: SK
T c
ogni
tive
test
ba
ttery
2°-O
C: N
PI
Sig
supe
rior
to P
BO
for
SK
T
and
all 2
°-O
C v
aria
bles
NPI
mea
n co
mpo
site
: with
G
BE
, dro
pped
fro
m 2
1.3
to
14.7
; with
PB
O, i
ncr
from
21
.6 to
24.
1N
PI m
ean
care
give
r di
stre
ss:
with
GB
E, d
ecr
from
13.
5 to
8.
7; w
ith P
BO
incr
fro
m 1
3.4
to 1
3.9
(P<
.001
BG
D)
Lar
gest
dru
g–PB
O d
iff
favo
red
GB
E f
or: a
path
y/in
diff
eren
ce, a
nxie
ty,
irri
tabi
lity/
labi
lity,
de
pres
sion
/dys
phor
ia, a
nd
slee
p/ni
ghtti
me
beha
vior
Woe
lk 2
007(
Woe
lk e
t al.,
20
07)
Whe
ther
clin
ical
ly
mea
ning
ful a
nxio
lytic
ef
fect
s ca
n be
ach
ieve
dPt
s w
ith D
SM-I
II-R
GA
D o
r ad
just
men
t dis
orde
r w
ith
anxi
ous
moo
d
107
DB
-RC
TG
BE
480
mg/
d –o
r–
240
mg/
dE
Gb
761®
PBO
4 w
k1°
-OC
: HA
MA
2°-O
C: C
GI
chan
ge (
CG
I-C
);
EA
AS;
list
of
com
plai
nts
(B-
L’)
; Pt r
atin
g of
cha
nge
Sig
decr
s in
HA
MA
tota
l sc
ores
vs
PBO
(hi
gh-d
ose:
P=
.000
3; lo
w-d
ose:
P=
.01)
; w
ith to
tal d
ecr
by −
14.3
±8.
1 (h
igh-
dose
), −
12.1
±9.
0 (l
ow-
dose
), a
nd −
7.8±
9.2
(PB
O)
Sig
dose
-res
pons
e tr
end:
P=
.00
3A
ll 2°
-OC
: GB
E s
ig s
uper
ior
to P
BO
Safe
and
wel
l tol
erat
ed
John
son
2006
(Joh
nson
et
al.,
2006
)Fu
nctio
nal p
erfo
rman
ceIn
divi
dual
s w
ith m
ultip
le
scle
rosi
s
23D
B-R
CT
GB
E 2
40 m
g/d
EG
b 76
1®PB
O4
wk
Cen
ter
for
Epi
dem
iolo
gic
Stud
ies
of D
epre
ssio
n Sc
ale
(CE
S-D
); S
TAI;
Mod
ifie
d Fa
tigue
Im
pact
Sca
le
GB
E s
ig im
pr ≥
4 m
easu
res
with
sig
larg
er e
ffec
t siz
es
for
fatig
ue, s
ympt
om
seve
rity
, and
fun
ctio
nalit
y
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 25
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
(MFI
S); S
ympt
om I
nven
tory
(S
I); F
unct
iona
l Ass
essm
ent
of M
ultip
le S
cler
osis
(F
AM
S)
No
AE
s or
sid
e ef
fect
s re
port
ed
Cie
za 2
003(
Cie
za e
t al.,
20
03)
Shor
t-te
rm e
ffec
ts o
n em
otio
nal w
ell-
bein
gE
lder
ly w
ith n
o ag
e-re
late
d co
gniti
ve im
pair
men
ts
66D
B-R
CT
GB
E 2
40 m
g/d
EG
b 76
1®PB
O4
wk
POM
S, S
elf
Rat
ing
Dep
ress
ion
Scal
e (S
DS)
, V
AS-
QoL
, Gen
eral
hea
lth
(VA
S-G
H),
Men
tal h
ealth
(V
AS-
MH
), S
ubje
ctiv
e In
tens
ity S
core
Moo
d (S
IS
Moo
d)
Sig
BG
D f
or V
AS-
MH
and
V
AS-
QoL
; sig
BG
D f
or S
IS
Moo
d at
Wk
2 ph
one
call;
si
g im
pr d
epre
ssio
n, f
atig
ue,
ange
r an
d SD
S fr
om B
L
van
Don
gen
2000
(van
D
onge
n et
al.,
200
0)E
ffic
acy,
dos
e-de
pend
ence
, an
d du
rabi
lity
Old
er p
eopl
e in
39
Net
herl
and
hom
es f
or th
e el
derl
y w
ith m
ild to
m
oder
ate
Alz
heim
er’s
, va
scul
ar d
emen
tia, o
r ag
e-as
soci
ated
mem
ory
impa
irm
ent
214
123
ITT
DB
-RC
T2-
stag
e ra
ndom
GB
E 2
40 m
g/d
(hig
h)–
or–
160
mg/
d (u
sual
)E
Gb
761®
PBO
12 w
k or
24
wk
24 w
k:12
wk,
then
ra
ndom
ized
to 2
nd
12-w
k pe
riod
of
gink
go o
r PB
O
Ass
esse
d at
12
wk
and
24
wk:
Tra
il-m
akin
g sp
eed
(NA
I-Z
VT-
G);
Dig
it m
emor
y sp
an (
NA
I-Z
N-G
); V
erba
l le
arni
ng (
NA
I-W
L);
Pr
esen
ce/s
ever
ity o
f ge
riat
ric
sym
ptom
s (S
CA
G);
D
epre
ssiv
e m
ood
(GD
S);
Self
-per
ceiv
ed h
ealth
/m
emor
y Se
lf-r
epor
ted
AD
L
No
outc
ome
effe
cts
for
the
entir
e 24
-wk
peri
odA
fter
12
wk,
com
bine
d hi
gh-
and
usua
l-do
se g
roup
s (n
=16
6) h
ad s
light
ly im
pr
self
-rep
orte
d A
DL
, but
sl
ight
ly w
orse
sel
f-pe
rcei
ved
heal
th s
tatu
s vs
PB
ON
o be
nefi
ts w
ith h
igh
dose
or
pro
long
ed G
BE
tx o
r to
an
y G
BE
sub
grou
p; n
o A
Es
Lin
gaer
de 1
999(
Lin
gaer
de
et a
l., 1
999)
Win
ter
depr
essi
onPt
s w
ith s
easo
nal a
ffec
tive
diso
rder
(SA
D)
27D
B-R
CT
GB
E 2
tabs
/d ~
1 m
o pr
ior
to e
xpec
ted
sym
ptom
sPN
246:
24
mg
flav
one
glyc
osid
es; 6
mg
terp
ene
lact
ones
per
tab
PBO
10 w
kE
xten
ded
MA
DR
S; s
elf-
rate
d ke
y sy
mpt
oms
on V
AS
q 2
wk
No
sig
BG
D
Gua
rana
P
aulin
ia c
upan
a ex
trac
t (P
CE
)3
stud
ies
Silv
estr
ini
2013
(Silv
estr
ini e
t al.,
20
13)
Psyc
holo
gica
l wel
l-be
ing,
an
xiet
y an
d m
ood
Hea
lthy
volu
ntee
rs
27SB
-RC
TC
ross
over
PCE
360
mg
thre
e tim
es d
aily
aft
er
brea
kfas
tC
onta
ined
caf
fein
e 2.
5% (
w/w
)
PBO
5 d
on e
ach
tx w
ith
5 d
was
hout
btw
tx
switc
h
Psyc
holo
gica
l wel
l-be
ing
(PW
B)
scal
es; S
elf-
ratin
g A
nxie
ty S
tate
sca
le (
SAS)
; B
ond-
Lad
er m
ood
scal
es
No
sig
diff
in a
ny 6
are
as o
f th
e PW
B, i
n SA
S, o
r an
y of
th
e 16
moo
d sc
ales
de O
livei
ra C
ampo
s 20
11(d
e O
livei
ra C
ampo
s et
al.,
201
1)
Fatig
ue, s
leep
qua
lity,
an
xiet
y, d
epre
ssio
n, a
nd M
PB
reas
t can
cer
pts
with
pr
ogre
ssiv
e fa
tigue
aft
er
Cyc
le 1
che
mot
hera
py (
CT
)
75D
B-R
CT
Cro
ssov
erPC
E 1
00 m
g/d
(50
mg/
twic
e da
ily)
Switc
h tx
mid
-CT
STD
PC
E 6
.46%
ca
ffei
ne
PBO
3 w
k on
eac
h tx
w
ith 7
-d w
asho
ut
btw
tx s
witc
h
1°-O
C: F
unct
iona
l A
sses
smen
t of
Chr
onic
Il
lnes
s T
hera
py-F
atig
ue
(FA
CIT
-F)
2°-O
C: F
AC
T-E
ndoc
rine
Sy
mpt
oms
(FA
CT-
ES)
, BFI
, PS
QI,
Cha
lder
Fat
igue
Sca
le,
HA
DS
Impr
FA
CIT
-F, F
AC
T-E
S,
and
BFI
glo
bal s
core
s on
d
21 a
nd d
49
(P<
.01)
; Cha
lder
Sc
ale
impr
on
d 21
(P<
.01)
bu
t not
d 4
9 (P
=.2
7)N
o A
Es,
nor
wor
sene
d sl
eep,
an
xiet
y or
dep
ress
ion
da C
osta
Mir
anda
200
9(da
C
osta
Mir
anda
et a
l.,
2009
)
Post
-rad
iatio
n tx
(R
T)
depr
essi
on/f
atig
ue36
DB
-RC
TC
ross
over
PCE
75
mg/
dSw
itch
tx m
id-R
TPB
O14
d o
n ea
ch tx
; no
was
hout
due
to
shor
t hal
f-lif
e
Fatig
ue a
nd d
epre
ssiv
e sy
mpt
oms
No
sig
diff
for
any
mea
sure
s
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 26
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Bre
ast c
ance
r pt
s un
derg
oing
adj
uvan
t RT
Kav
a ka
va P
iper
m
ethy
stic
um
extr
act
(KK
E);
K
KA
qE,
aque
ous;
KK
LE
, lip
ophi
lic12
stu
dies
Sarr
is 2
013(
Sarr
is e
t al.,
20
13b)
Sexu
al f
unct
ion/
expe
rien
ceA
dults
with
GA
D in
A
ustr
alia
75D
B-R
CT
KK
AqE
1 ta
b tw
ice
daily
; tot
al
kava
lact
ones
(K
AV
) 12
0 m
g/d
Non
-res
pond
ers
titra
ted
to 2
tabs
twic
e da
ily;
tota
l KA
V 2
40 m
g/d
PBO
6 w
kA
rizo
na S
exua
l Exp
erie
nce
Scal
e (A
SEX
)In
cr w
omen
’s s
exua
l dri
ve v
s PB
O (
P=.0
40);
no
nega
tive
effe
cts
for
men
; sig
cor
r bt
w
redu
c in
ASE
X a
nd a
nxie
tyN
o A
Es
or s
ig d
iff
for
liver
fu
nctio
n te
sts,
WD
or
addi
ctio
n
Sarr
is 2
012(
Sarr
is e
t al.,
20
12)
Acu
te n
euro
cogn
itive
, an
xiol
ytic
, and
thym
olep
tic
effe
cts
vs B
ZD
Mod
erat
ely
anxi
ous
adul
ts
in A
ustr
alia
22D
B-R
CT
Cro
ssov
erK
KA
qE 3
tabs
for
ac
ute
med
icin
al d
ose
of
KA
V 1
80 m
g (6
0 m
g/ta
b)
Oxa
zepa
m 3
0 m
gPB
O3
visi
ts 1
-wk
apar
t w
ith a
cute
dos
e of
di
ffer
ent
inte
rven
tion
and
plac
ebo
for
each
w
eek/
pt
Cog
nitiv
e ba
ttery
test
fo
llow
ed b
y ST
AI,
Sta
te–
Tra
it, C
heer
fuln
ess
Inve
ntor
y (S
TC
I-S)
, and
Bon
d–L
ader
qu
estio
nnai
res
Acu
te d
oses
of
KK
AqE
did
no
t pro
duce
anx
ioly
tic
effe
cts
vs o
xaze
pam
(re
duc
anxi
ety)
or
PBO
(in
cr
anxi
ety)
; it a
lso
did
not
nega
tivel
y af
fect
cog
nitio
n
Sarr
is 2
009(
Sarr
is e
t al.,
20
09)
Eff
ects
/toxi
city
of
aque
ous
extr
act,
as o
ther
type
s ha
d he
pato
toxi
city
con
cern
sA
dult
subj
ects
with
≥1
mo
elev
ated
GA
D in
Aus
tral
ia
60D
B-R
CT
Cro
ssov
erK
KA
qE 5
tabs
/d f
or
KA
V 2
50 m
g/d
Dri
ed a
queo
us r
oot
extr
act S
TD
to K
AV
50
mg
PBO
3 w
kH
AM
A, B
AI,
MA
DR
SK
KA
qE r
educ
HA
MA
sc
ores
: by
−9.
9 (C
I=7.
1,
12.7
) vs
PB
O −
0.8
(CI=
−2.
7,
4.3)
in 1
st p
hase
; by
−10
.3
(CI=
5.8,
14.
7) v
s PB
O +
3.3
(CI=
−6.
8, 0
.2)
in 2
nd p
hase
Sig
pool
ed e
ffec
ts w
ith
KK
AqE
acr
oss
phas
es (
P<.
0001
) an
d su
bsta
ntia
l eff
ect
size
(d=
2.24
, eta
(2)(
p));
sig
re
lativ
e re
duc
BA
I an
d M
AD
RS;
no
SAE
s or
cl
inic
al h
epat
otox
icity
Gei
er 2
004(
Gei
er a
nd
Kon
stan
tinow
icz,
200
4)D
osag
e ra
nge
for
anxi
ety
Pts
with
non
-psy
chot
ic
anxi
ety
50D
B-R
CT
KK
E 1
50 m
g/d
WS®
149
0 50
-mg
dry
root
ext
ract
ST
D to
70
% K
AV
PBO
4 w
k +
2 w
k ob
serv
atio
n1°
-OC
: HA
MA
2°-O
C: H
AM
A s
omat
ic a
nd
psyc
hic
anxi
ety
subs
cale
s;
EA
AS;
Bri
ef p
erso
nalit
y st
ruct
ure
scal
e (K
EPS
);
adje
ctiv
e ch
eckl
ist (
EW
L 6
0-S)
; CG
I
1°-O
C: t
hera
peut
ical
ly
rele
vant
red
uc a
nxie
ty (
>4
pt)
vs P
BO
; 2°-
OC
: tre
nd in
fa
vor
of a
ctiv
e tx
; wel
l to
lera
ted/
safe
; no
AE
s or
W
D s
ympt
oms
Leh
rl 2
004(
Leh
rl, 2
004)
Eff
icac
y an
d sa
fety
for
sle
ep
dist
urba
nce
Patie
nts
with
anx
iety
di
sord
ers
61D
B-R
CT
Mul
ticen
ter
KK
E 2
00 m
g/d
WS®
149
0PB
O4
wk
1°-O
C: S
F-B
2°-O
C: H
AM
A, B
f-S
self
-ra
ting
scal
e of
wel
l-be
ing,
C
GI
Sig
grou
p di
ff f
avor
ing
KK
E
for
SF-B
sub
-sco
res
of
‘Qua
lity
of s
leep
’ (P
=.0
07),
‘R
ecup
erat
ive
effe
ct a
fter
sl
eep’
(P=
.018
), a
nd H
AM
A
psyc
hic
anxi
ety
sub-
scor
e (P
=.0
02).
Add
tl be
nefi
ts o
n B
f-S
and
CG
I sc
ores
. No
AE
s or
cha
nges
in c
linic
al o
r la
bora
tory
par
amet
ers
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 27
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Boe
rner
200
3(B
oern
er e
t al
., 20
03)
Acu
te a
nxie
ty tx
vs
phar
mac
olog
ic tx
Out
pts
with
GA
D
129
DB
-RC
TM
ultic
ente
rK
KE
400
mg/
dL
I150
ST
D to
30%
ka
vapy
rone
s; d
rug-
ex
trac
t rat
io 1
3–20
:1
Bus
piro
ne 1
0 m
g/d
Opi
pram
ol 1
00 m
g/d
8 w
k1°
-OC
: HA
MA
sca
le a
nd %
W
k 8
resp
onde
rs2°
-OC
: Boe
rner
Anx
iety
Sc
ale
(BO
EA
S), S
AS,
CG
I,
wel
l-be
ing
self
-rat
ing
scal
e (B
f-S)
, sle
ep q
uest
ionn
aire
(S
F-B
), Q
oL (
AL
) an
d gl
obal
ju
dgem
ents
by
inve
stig
ator
an
d pt
sW
k 9
WD
or
rela
pse
sym
ptom
s
No
sig
diff
for
all
mea
sure
s;
~75%
of
pts
wer
e re
spon
ders
(5
0% r
educ
of
HA
MA
sco
re)
in e
ach
tx g
roup
; ~60
%
achi
eved
ful
l rem
issi
on
Cag
nacc
i 200
3(C
agna
cci
et a
l., 2
003)
Eff
ects
on
peri
-MP
moo
dPe
ri-M
P w
omen
80R
CT
Cal
cium
+ K
KE
100
m
g/d
–or–
KK
E 2
00
mg/
d55
% k
avai
n pe
r 10
0-m
g ca
p
Cal
cium
1 g
/d3
mo
STA
I; Z
ung
depr
essi
on s
cale
(Z
DS)
; Gre
ene
Clim
acte
ric
Scal
e (G
CS)
KK
E: a
nxie
ty d
eclin
ed (
P<.
001)
at 1
mo
(−3.
8±1.
03)
and
3 m
o (−
5.03
±1.
2);
depr
essi
on d
eclin
ed a
t 3 m
o (−
5.03
±1.
4; P
<.0
02);
cl
imac
teri
c sc
ore
decl
ined
(P
<.0
006)
at 1
mo
(−2.
87±
1.5)
and
3 m
o (−
5.38
±1.
3)B
ut o
nly
anxi
ety
decl
ine
was
si
g gr
eate
r w
ith K
KE
than
w
ith c
ontr
ols
(P<
.009
)
Gas
tpar
200
3(G
astp
ar a
nd
Klim
m, 2
003)
Neu
rotic
anx
iety
Adu
lts w
ith D
SM-I
II-R
ne
urot
ic a
nxie
ty
141
DB
-RC
TM
ultic
ente
rK
KE
150
mg/
dW
S® 1
490
50-m
g dr
y ro
ot e
xtra
ct S
TD
to
KA
V 3
5 m
g
PBO
4 w
k +
2 w
k ob
serv
atio
nA
nxie
ty S
tatu
s In
vent
ory
(ASI
); S
truc
ture
d w
ell-
bein
g se
lf-r
atin
g sc
ale
(Bf-
S); C
GI;
E
AA
S; B
rief
Tes
t of
Pers
onal
ity S
truc
ture
(K
EPS
)
ASI
tota
l obs
erve
r sc
ore
decr
m
ore
with
KK
LE
, but
not
sig
po
st-t
x; d
ecr
>5:
KK
LE
73%
vs
PB
O 5
6%D
iff
btw
tx e
nd a
nd B
L
favo
red
KK
LE
(P<
.01,
2-
side
d)Si
g im
pr B
f-S
and
CG
I bu
t on
ly m
inor
dif
f fo
r E
AA
S an
d K
EPS
; dif
f vs
PB
O n
ot
as la
rge
as p
rior
tria
ls w
/ sa
me
extr
act a
t 300
mg/
dW
ell t
oler
ated
; no
infl
uenc
e on
live
r fu
nctio
n te
sts;
1 A
E:
tired
ness
Con
nor
2002
(Con
nor
and
Dav
idso
n, 2
002)
Eff
ects
on
GA
DA
dults
with
DSM
-IV
GA
D37
DB
-RC
TK
ava
Wk
1: 7
0 m
g tw
ice
daily
(14
0 m
g/d)
; W
k 2–
4: 1
40 m
g tw
ice
daily
(28
0 m
g/d)
Kav
aPur
e®; S
TD
to
KA
V 7
0 m
g
PBO
4 w
kH
AM
A; H
AD
S; S
elf
Ass
essm
ent o
f R
esili
ence
and
A
nxie
ty (
SAR
A)
Impr
with
bot
h tx
s w
ith n
o di
ff in
pri
ncip
al a
naly
sis
Post
-hoc
ana
lyse
s: s
ig d
iff
from
BL
anx
iety
sev
erity
in
SAR
A s
core
s fo
r lo
w
anxi
ety,
but
PB
O w
as
supe
rior
for
HA
DS
and
SAR
A in
hig
h an
xiet
yK
ava
was
wel
l tol
erat
ed
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 28
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Mal
sch
2001
(Mal
sch
and
Kie
ser,
2001
)N
on-p
sych
otic
ner
vous
an
xiet
y, te
nsio
n an
d re
stle
ssne
ss s
tate
sA
dult
outp
ts w
ith D
SM-I
II-
R a
nxie
ty d
isor
ders
/im
pair
ed w
ork
or s
ocia
l ac
tiviti
es
40D
B-R
CT
KK
E W
k 1
dose
esc
: 50
–300
mg/
d +
pre
tx
BZ
D ta
per
over
2 w
k;
then
3 w
k K
KE
m
onot
xW
S®14
90 (
Lai
tan
50®
) ST
D to
70%
K
AV
PBO
5 w
k1°
-OC
: HA
MA
, Sub
ject
ive
wel
l-be
ing
scal
e (B
f-S)
, BZ
D
WD
sym
ptom
s2°
-OC
: EA
AS,
CG
I
Supe
rior
to P
BO
for
HA
MA
(P
=.0
1) a
nd B
f-S
(P=
.002
) to
tal s
core
s, a
nd a
ll 2°
-OC
; go
od to
lera
nce
not i
nfer
ior
to
PBO
De
Leo
200
0(D
e L
eo e
t al
., 20
00)
PMP
anxi
ety
vs H
RT
Wom
en in
phy
siol
ogic
al o
r su
rgic
al M
P fo
r 1–
12 y
40R
CT
Phys
iolo
gica
l-M
P Pt
s:
HR
T +
KK
E 1
00 m
g –
or–
Surg
ical
-MP
Pts:
E
RT
+ K
KE
100
mg
55%
kav
ain
HR
T: e
stro
gen
50 μ
g/d
+ p
roge
stin
+ P
BO
–or
– E
RT
: est
roge
n 50
μg/
d +
PB
O
6 m
oH
AM
AFo
r al
l gro
ups:
sig
red
uc in
H
AM
A s
core
s af
ter
3 an
d 6
mo
tx ;
both
KK
E g
roup
s ha
d gr
eate
r re
duc
vs H
RT
or
ER
T
alon
e
Vol
z 19
97(V
olz
and
Kie
ser,
1997
)L
ong-
term
anx
ioly
tic e
ffec
tsPt
s w
ith D
SM-I
II-R
non
-ps
ycho
tic a
nxie
ty
101
DB
-RC
TM
ultic
ente
rK
KL
E K
AV
210
mg/
dW
S® 1
490
STD
to
KA
V 7
0 m
g pe
r ca
p
PBO
25 w
k1°
-OC
: HA
MA
2°-O
C: H
AM
A s
omat
ic/
psyc
hic
anxi
ety
subs
core
s,
CG
I, S
elf-
Rep
ort S
ympt
om
Inve
ntor
y-90
Ite
ms
revi
sed,
an
d A
djec
tive
Moo
d Sc
ale
Sig
supe
rior
ity in
HA
MA
sc
ores
sta
rtin
g at
Wk
8; 2
°-O
Cs
also
sup
erio
r; r
are
AE
s di
stri
bute
d ev
enly
in b
oth
grou
ps
Lav
ende
r L
avan
dula
an
gust
ifol
ia
extr
act
(LA
E)
7 st
udie
s
Kas
per
2016
(Kas
per
et a
l.,
2016
)E
ffec
ts o
n m
ixed
anx
iety
an
d de
pres
sive
dis
orde
r (M
AD
D)
Out
pt a
dults
with
IC
D 1
0 M
AD
D a
nd a
t lea
st
mod
erat
ely
seve
re a
nxio
us
and
depr
esse
d m
ood
318
DB
-RC
TL
AE
80
mg/
dSi
lexa
nPB
O70
dH
AM
A a
nd M
AD
RS
tota
l sc
ore
chan
ges
Tota
l sco
re c
hang
esH
AM
A: L
AE
↓ 1
0.8
± 9
.6;
PBO
↓ 8
.4±
8.9
(P<
.01
MA
DR
S: L
AE
↓9.
2 ±
9.9
; PB
O ↓ 6
.1±
7.6
(P<
.001
)L
AE
: bet
ter
over
all
outc
omes
; im
pr d
aily
livi
ng
skill
s, h
ealth
-rel
ated
QoL
AE
: Bel
chin
g
Kas
per
2015
(Kas
per
et a
l.,
2015
)A
nxio
lytic
eff
ects
Pts
with
anx
iety
-rel
ated
re
stle
ssne
ss a
nd d
istu
rbed
sl
eep
170
DB
-RC
TL
AE
cap
80
mg/
dSi
lexa
n; f
rom
flo
wer
s by
ste
am d
istil
latio
n
PBO
10 w
kH
AM
A, P
SQI,
the
Zun
g Se
lf-r
atin
g A
nxie
ty S
cale
, a
Stat
e C
heck
inve
ntor
y an
d C
GI
ques
tionn
aire
HA
MA
tota
l sco
re d
ecr
12.0
vs
PB
O 9
.3 (
grou
p di
ff: P
=.
03);
for
all
OC
s, L
AE
eff
ects
m
ore
pron
ounc
edH
AM
A r
espo
nder
s (≥
50%
):
48.8
% v
s 33
.3%
(P=
.04)
HA
MA
rem
issi
on (
<10
):
31.4
% v
s 22
.6%
(P=
.20)
AE
s: 3
3.7%
(L
AE
; GI-
rela
ted)
vs
35.7
% (
PBO
)
Kas
per
2014
(Kas
per
et a
l.,
2014
)A
nxio
lytic
eff
ects
Adu
lts w
ith D
SM-V
GA
D53
9D
B-R
CT
Dou
ble-
dum
my
LA
E 8
0 m
g/d
or 1
60
mg/
dSi
lexa
n
PBO
Paro
xetin
e (P
AR
) 20
mg
10 w
k1°
-OC
: HA
MA
Bot
h do
ses
supe
rior
to P
BO
in
HA
MA
tota
l sco
re r
educ
(P
<.0
1) w
hile
par
oxet
ine
had
sig
tren
d (P
=.1
0): 1
60 m
g:
14.1
± 9
.3 8
0 m
g: 1
2.8
± 8
.7
PAR
: 11.
3 ±
8.0
PB
O: 9
.5
± 9
.0
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 29
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
≥50%
HA
MA
red
uc |
Tota
l sc
ore
<10
at t
x en
d:16
0 m
g:
73/1
21 (
60.3
%)
| 56
(46.
3%)
80 m
g: 7
0/13
5 (5
1.9%
) | 4
5 (3
3.3%
) PA
R: 5
7/13
2 (4
3.2%
) | 4
5 (3
4.1%
) PB
O:
51/1
35 (
37.8
%)
| 40
(29.
6%)
AE
s ra
tes
low
er th
an
paro
xetin
e/co
mpa
rabl
e to
PB
O
Nik
farj
am
2013
(Nik
farj
am e
t al.,
20
13)
Eff
ects
on
depr
essi
onPt
s w
ith m
ajor
dep
ress
ion
taki
ng c
italo
pram
80R
CT
Cita
lopr
am +
2 c
ups
L.
angu
stif
ilia
(LA
) in
fusi
onPr
epar
ed f
rom
5 g
dr
ied
shoo
ts
Cita
lopr
am 2
0 m
g tw
ice
daily
8 w
kH
AM
DSi
g de
cr H
AM
D s
core
s at
4
wk
(P<
.05)
and
8 w
k (P
<.
01),
sug
gest
ing
addt
l tx
bene
fit;
com
para
ble
AE
s, b
ut
naus
ea m
ore
com
mon
with
L
A
Kas
per
2010
(Kas
per
et a
l.,
2010
)A
nxio
lytic
eff
icac
yA
dults
with
DSM
-IV
or
ICD
-10
anxi
ety
diso
rder
221
RC
TIn
27
prim
ary
care
pr
actic
es
LA
E 8
0 m
g/d
Sile
xan
PBO
10 w
k1°
-OC
: HA
MA
, PSQ
I2°
-OC
: CG
I, Z
ung
Self
-ra
ting
Anx
iety
Sca
le, S
F-36
H
ealth
Sur
vey
Que
stio
nnai
re
HA
MA
tota
l sco
re s
ig d
ecr
(P<
.01)
for
LA
E 1
6.0±
8.3
(59.
3%)
vs P
BO
9.5
±9.
1 (3
5.4%
)PS
QI
tota
l sco
re s
ig d
ecr
(P<
.01)
for
LA
E 5
.5±
4.4
(44.
7%)
vs P
BO
3.8
±4.
1 (3
0.9%
)%
res
pond
ers
favo
red
LA
E:
76.9
vs
49.1
%, P
<.0
01%
rem
itter
s fa
vore
d L
AE
: 60
.6 v
s. 4
2.6%
, P=
.009
Woe
lk 2
010(
Woe
lk a
nd
Schl
afke
, 201
0)E
ffec
ts o
n G
AD
vs
BZ
DPa
tient
s w
ith D
SM-I
V
prim
ary
diag
nosi
s of
GA
D
77D
B-R
CT
Mul
ticen
ter
LA
E (
Sile
xan)
80
mg/
d +
PB
O (
LO
R)
Lor
azep
am (
LO
R)
0.5m
g +
PB
O (
LA
E)
6 w
k1°
-OC
: HA
MA
2°-O
C: S
AS
(Sel
f-ra
ting
Anx
iety
Sca
le),
PSW
Q-P
W
(Pen
n St
ate
Wor
ry
Que
stio
nnai
re),
SF
36 H
ealth
Su
rvey
Que
stio
nnai
re a
nd
CG
I ite
ms
1–3,
sle
ep d
iary
HA
MA
tota
l sco
re d
ecr
sim
ilarl
y fr
om 2
5±4
poin
ts in
bo
th B
L g
roup
s: L
AE
11
.3±
6.7
(45%
) vs
LO
R
11.6
±6.
6 (4
6%)
Som
atic
/psy
chic
anx
iety
su
bsco
res
decr
sim
ilarl
y; 2
°-O
Cs
also
com
para
ble;
LA
E
had
no s
edat
ive
effe
cts
Akh
ondz
adeh
20
03(A
khon
dzad
eh e
t al.,
20
03)
Adj
uvan
t eff
ects
on
depr
essi
on v
s im
ipra
min
e al
one
Adu
lts w
ith D
SM-I
V m
ild
to m
oder
ate
depr
essi
on
45D
B-R
CT
LA
E 6
0 dr
ops/
d +
PB
O
tab
–or–
LA
E 6
0 dr
ops/
d +
imip
ram
ine
tab
100
mg/
dD
ried
flo
wer
ext
ract
1:
5 (w
/v)
in 5
0%
alco
hol
Imip
ram
ine
tab
100
mg/
d +
PB
O d
rops
4 w
kH
AM
DL
AE
less
eff
ectiv
e th
an
imip
ram
ine:
(F=
13.1
6, d
f=1,
P=
.001
), w
ith m
ore
obse
rvat
ions
of
head
ache
LA
E+
imip
ram
ine
mor
e ef
fect
ive
than
imip
ram
ine
alon
e (F
=20
.83,
df=
1, P
<.
0001
) su
gges
ts a
djuv
ant
pote
ntia
l
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 30
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Mac
a L
epid
ium
m
eyen
ii2
stud
ies
Stoj
anov
ska
2015
(Sto
jano
vska
et a
l.,
2015
)
Eff
ects
on
horm
ones
, lip
ids,
gl
ucos
e, s
erum
cyt
okin
es,
BP
sym
ptom
sC
hine
se P
MP
wom
en
29D
B-R
CT
Cro
ssov
erM
aca
3.3
g/d
Pow
dere
d ro
ot6
wk
each
in
terv
entio
nG
reen
e C
limac
teri
c Sc
ale
(GC
S), S
F-36
V2
Wom
en’s
H
ealth
Que
stio
nnai
re, U
tian
Qua
lity
of L
ife
Scal
es,
horm
one/
lipid
pro
file
s
Sig
decr
s de
pres
sion
and
BP
(dia
stol
ic);
no
diff
in
horm
onal
, glu
cose
, lip
id,
cyto
kine
pro
file
s
Bro
oks
2008
(Bro
oks
et
al.,
2008
)E
ffec
ts o
n ho
rmon
al p
rofi
le
and
clim
acte
ric
sym
ptom
sPM
P w
omen
14D
B-R
CT
Cro
ssov
erM
aca
.5 g
/dD
ried
met
hano
lic r
oot
extr
act
PBO
6 w
k ea
ch
inte
rven
tion
GC
S, h
orm
one
prof
iles
GC
S: S
ig r
educ
in a
nxie
ty,
depr
essi
on, a
nd s
exua
l dy
sfun
ctio
n su
bsca
les
vs B
L
and
PBO
; no
diff
in
horm
onal
pro
file
s
Pas
sion
flow
er
Pas
sifl
ora
inca
rnat
e ex
trac
t (P
IE)
6 st
udie
s
Noj
oum
i 201
7(N
ojou
mi e
t al
., 20
17)
Eff
ects
of
adju
nctiv
e tx
to
sert
ralin
e on
rea
ctio
n tim
eA
dults
age
18–
50y
with
D
SM-I
V G
AD
30D
B-R
CT
PIE
15
drop
s th
ree
times
dai
ly +
ser
tral
ine
50 m
g/d
(↑ t
o 10
0 m
g/d
afte
r 2
wk)
Pasi
py®
Dro
p: S
TD
hy
droa
lcoh
olic
ext
ract
PBO
dro
ps +
ser
tral
ine
50 m
g/d,
↑ t
o 10
0 m
g/d
afte
r 2
wk
1 m
oR
eact
ion
time
at b
asel
ine
and
afte
r 1
mo
post
-tx
No
sig
diff
exc
ept f
or
audi
tory
om
issi
on e
rror
s in
PI
E g
roup
aft
er 1
mo
PIE
had
no
sig
AE
s
Asl
anar
gun
2012
(Asl
anar
gun
et a
l.,
2012
)
Preo
pera
tive
anxi
ety
with
re
gion
al a
nest
hesi
aA
dults
und
ergo
ing
spin
al
anes
thes
ia
60D
B-R
CT
Aqu
eous
PIE
syr
up 7
00
mg/
5 m
L d
ose
Con
tain
ed 2
.8 m
g be
nzof
lavo
ne
PBO
Sing
le-d
ose
30 m
in
befo
re s
pina
l an
esth
esia
STA
I, p
sych
omot
or
func
tions
, sed
atio
n, a
nd
hem
odyn
amic
s
STA
I: S
ig B
GD
for
incr
sc
ore
obta
ined
just
bef
ore
anes
thes
ia; n
o di
ff f
or
psyc
hom
otor
fun
ctio
n,
seda
tion
scor
e,
hem
odyn
amic
s, o
r si
de
effe
cts
Nga
n 20
11(N
gan
and
Con
duit,
201
1)E
ffec
ts o
n hu
man
sle
epH
ealth
y ad
ults
with
mild
sl
eep
qual
ity f
luct
uatio
ns
41D
B-C
T r
epea
ted-
mea
sure
s +
opt
iona
l PSG
sl
eep
stud
y
PI te
a 1h
bef
ore
bed
2 g
leav
es, s
tem
s, s
eeds
an
d fl
ower
s in
fuse
d in
25
0 m
L o
f bo
iled
wat
er
for
10 m
in
PBO
1 w
k ea
ch tx
se
para
ted
by 1
-wk
was
hout
STA
I; S
leep
dia
ries
val
idat
ed
by p
olys
omno
grap
hy (
PSG
ov
erni
ght o
n la
st d
ay o
f ea
ch
tx, 1
0 su
bjec
ts)
No
sig
diff
for
STA
I; o
f 6
slee
p-di
ary
mea
sure
s, s
leep
qu
ality
was
sig
bet
ter
with
PI
E v
s PB
O (
t(40
)=2.
70, P
<.
01)
Mov
afeg
h 20
08(M
ovaf
egh
et a
l., 2
008)
Preo
pera
tive
anxi
ety
Adu
lts u
nder
goin
g in
guin
al
hern
iorr
haph
y
60D
B-R
CT
PIE
tab
500-
mg
dose
Pass
ipy™
1.0
1 m
g be
nzof
lavo
ne
PBO
Sing
le-d
ose
90 m
in
befo
re s
urge
ryN
umer
ical
rat
ing
scal
e (N
RS)
as
sess
ed a
nxie
ty a
nd
seda
tion,
Tri
eger
Dot
Tes
t, D
igit-
Sym
bol S
ubst
itutio
n Te
st, t
ime
btw
pos
tane
sthe
sia
care
and
dis
char
ge
Sig
low
er N
RS
anxi
ety
scor
es (
P<.0
01)
No
diff
in p
sych
olog
ical
va
riab
les
post
anes
thes
ia o
r re
cove
ry o
f ps
ycho
mot
or
func
tion
Akh
ondz
adeh
20
01a(
Akh
ondz
adeh
et
al.,
2001
a)
Adj
uvan
t eff
ects
with
cl
onid
ine
for
opia
te d
etox
Adu
lt ou
tpat
ient
s w
ith
DSM
-IV
opi
oid
depe
nden
ce
65D
B-R
CT
Clo
nidi
ne m
ax 0
.8
mg/
d di
vide
d in
3 d
oses
+
PIE
60
drop
s/d
Pass
ipay
™ e
xtra
ct
Clo
nidi
ne +
PB
O d
rops
14 d
Shor
t Opi
ate
With
draw
al
Scal
e (S
OW
S)B
oth
regi
men
s eq
ually
ef
fect
ive
for
phys
ical
WD
, bu
t PIE
sig
nifi
cant
ly s
uper
ior
for
men
tal s
ympt
oms
Akh
ondz
adeh
20
01b(
Akh
ondz
adeh
et
al.,
2001
b)
Anx
ioly
tic e
ffec
ts v
s ox
azep
am f
or G
AD
txA
dults
with
DSM
-IV
GA
D
36D
B-R
CT
PIE
45
drop
s/d
+ P
BO
ta
bsO
xaze
pam
30
mg/
d +
PB
O d
rops
4 w
kH
AM
AB
oth
regi
men
s ef
fect
ive
for
GA
D w
ith n
o si
g B
GD
, but
ox
azep
am s
ig im
pair
ed jo
b pe
rfor
man
ce m
ore
than
PIE
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 31
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Red
clo
ver
Tri
foliu
m
pret
ense
ext
ract
(R
CE
)2
stud
ies
Lip
ovac
201
0(L
ipov
ac e
t al
., 20
10)
Anx
iety
and
dep
ress
ive
sym
ptom
sPM
P w
omen
age
>40
y
109
DB
-RC
TC
ross
over
RC
E is
ofla
vone
cap
40
mg
twic
e da
ilyM
F11R
CE
; 40
mg
isof
lavo
ne/c
ap
PBO
90 d
eac
h tx
with
7-
day
was
hout
HA
DS
and
Zun
g’s
Self
R
atin
g D
epre
ssio
n Sc
ale
(SD
S)
Sig
decr
tota
l HA
DS,
anx
iety
an
d de
pres
sion
sub
scal
es a
nd
tota
l SD
S sc
ores
(76
.9%
, 76
%, 7
8.3%
and
80.
6% r
ed,
resp
ectiv
ely)
vs
PBO
dec
r of
on
ly 2
1.7%
Hid
algo
200
5(H
idal
go e
t al
., 20
05)
MP
sym
ptom
s, li
pids
, and
va
gina
l cyt
olog
yPM
P w
omen
age
>40
y n
ot
usin
g ho
rmon
al tx
60 53 c
ompl
eter
sD
B-R
CT
Cro
ssov
erR
CE
isof
lavo
ne c
aps
80 m
g/d
Men
ofla
von®
; 40
mg
isof
lavo
ne f
rom
T.
prat
ense
per
cap
PBO
90 d
eac
h tx
with
7-
day
was
hout
Kup
perm
an in
dex
(KI)
sc
ores
, fas
ting
bloo
ds a
nd
vagi
nal c
ytol
ogy
KI
decr
sig
aft
er e
ach
tx
phas
e, b
ut m
ore
pron
ounc
ed
afte
r ac
tive
tx: B
L: 2
7.2
± 7
.7; i
sofl
avon
e: 5
.9 ±
3.9
; PB
O: 2
0.9
± 5
.3, P
<.0
5)N
o si
g ef
fect
on
BM
I, w
eigh
t or
BP
afte
r ei
ther
txSi
g de
cr in
men
opau
sal
sym
ptom
s, w
ith p
ositi
ve
effe
cts
on v
agin
al c
ytol
ogy
and
trig
lyce
ride
leve
ls
Rho
diol
a R
hodi
ola
rose
a ex
trac
t (R
RE
)4
stud
ies
Cro
pley
201
5(C
ropl
ey e
t al
., 20
15)
Self
-rep
orte
d an
xiet
y, s
tres
s,
cogn
ition
, and
oth
er m
ood
sym
ptom
sM
ildly
anx
ious
par
ticip
ants
80R
CT
RR
E ta
b 20
0 m
g tw
ice
daily
bef
ore
brea
kfas
t/lu
nch
Vita
no®
; Ros
alin
WS®
13
75, d
ry r
oot e
xtra
ct
1.5–
5:1
No
tx14
dSe
lf-r
epor
t mea
sure
s an
d co
gniti
ve te
sts
Sig
redu
c in
sel
f-re
port
ed
anxi
ety,
str
ess,
ang
er,
conf
usio
n an
d de
pres
sion
an
d im
pr to
tal m
ood
No
rele
vant
dif
f in
cog
nitiv
e pe
rfor
man
ceFa
vora
ble
safe
ty p
rofi
le
Mao
201
5(M
ao e
t al.,
20
15)
Var
ious
dos
ages
vs
sert
ralin
e fo
r m
ild to
mod
erat
e M
DD
Adu
lts w
ith D
SM-I
V A
xis
I M
DD
57R
CT
Dos
e es
cW
k 1–
2: R
RE
1 c
ap/d
If n
o re
spon
se: W
k 2:
2
caps
/dW
k 4:
3 c
aps/
dW
k 6:
4 c
aps/
dSH
R-5
; 340
mg
per
cap
STD
to r
osav
in 3
.07%
an
d rh
odio
losi
de 1
.95%
Sert
ralin
e 50
mg
–or–
PB
O12
wk
HA
MD
, BD
I, C
GI
chan
geN
onsi
g re
duc
wer
e m
odes
t w
ith n
o B
GD
RR
E h
ad s
igni
fica
ntly
few
er
AE
sO
dds
of im
prov
ing
vs P
BO
w
ere
grea
ter
for
sert
ralin
e (O
R 1
.90
[95%
CI:
0.4
4–8.
20])
than
RR
E (
1.39
[0.
38–
5.04
]), b
ut m
ore
sert
ralin
e su
bjec
ts r
epor
ted
AE
s th
an
RR
E o
r PB
O: 6
3.2%
vs
30.0
%, v
s 16
.7%
, re
spec
tivel
y; P
=.0
12
Ols
son
2009
(Ols
son
et a
l.,
2009
)E
ffec
ts o
n st
ress
-rel
ated
fa
tigue
Adu
lts w
ith s
tres
s-re
late
d fa
tigue
in S
wed
en
60D
B-R
CT
RR
E 5
76 m
g/d
(4 ta
bs)
SHR
-5; 1
44 m
g pe
r ta
bPB
O28
dSF
-36,
Pin
es’
Bur
nout
Sca
le
(PB
S), M
AD
RS,
Con
ners
’ C
ompu
teri
sed
Con
tinuo
us
Perf
orm
ance
Tes
t II
(CC
PT
II),
sal
iva
cort
isol
aw
aken
ing
resp
onse
(C
AR
)
Bot
h gr
oups
: sig
impr
PB
S,
SF-3
6 m
enta
l hea
lth s
core
s M
AD
RS,
and
sev
eral
CC
PT
II in
dice
sSi
g B
GD
fav
ored
RR
E f
or
PBS
and
CC
PT I
I in
dice
sC
AR
sig
dec
r w
ith R
RE
vs
PBO
; no
sig
SAE
s
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 32
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Dar
biny
an
2007
(Dar
biny
an e
t al.,
20
07)
Dep
ress
ive
com
plai
nts
Adu
lts w
ith c
urre
nt e
piso
de
of D
SM-I
V m
ild/m
oder
ate
depr
essi
on
89D
B-R
CT
Mul
ticen
ter
RR
E 3
40 o
r 68
0 m
g/d
SHR
-5; r
hizo
me
extr
act 1
70 m
g/ta
b
PBO
: 2 ta
bs/d
42 d
BD
I, H
AM
DFo
r bo
th d
osag
es, o
vera
ll de
pres
sion
, ins
omni
a,
emot
iona
l ins
tabi
lity
and
som
atiz
atio
n, b
ut n
ot s
elf-
este
em, s
ig im
pr v
s PB
O; n
o SA
Es
repo
rted
Saff
ron
Cro
cus
sativ
us e
xtra
ct
(CSE
)12
stu
dies
Maz
idi 2
016(
Maz
idi e
t al.,
20
16)
Eff
icac
y in
anx
iety
and
de
pres
sion
Adu
lt w
ith D
SM-I
V m
ild to
m
oder
ate
anxi
ety
and
depr
essi
on
60 r
ando
miz
ed54
com
plet
ers
DB
-RC
TSa
ffro
n ca
p 50
mg
twic
e da
ilyC
. sat
ivus
dri
ed s
tigm
a
PBO
12 w
kB
DI
and
BA
ISi
g ef
fect
s on
BD
I an
d B
AI
scor
es (
P<.0
01);
sid
e ef
fect
s ra
re
Sahr
aian
201
6(Sa
hrai
an e
t al
., 20
16)
Eff
ects
of
adju
nctiv
e tx
to
fluo
xetin
e on
dep
ress
ion
and
lipid
pro
file
sA
dults
with
DSM
-IV
maj
or
depr
essi
on
40 r
ando
miz
ed30
com
plet
ers
DB
-RC
TSa
ffro
n po
wde
r ca
psul
e 30
mg/
d +
flu
oxet
ine
20 m
g/d
PBO
+ f
luox
etin
e 20
m
g/d
4 w
kB
DI
No
antid
epre
ssiv
e or
lipi
d lo
wer
ing
effe
cts
with
the
addi
tion
of s
affr
on
Tala
ei 2
015(
Tala
ei e
t al.,
20
15)
Adj
unct
ive
to M
DD
txIr
ania
n ps
ychi
atri
c ho
spita
l in
patie
nts
with
DSM
-IV
M
DD
, age
24–
50 y
40D
B-R
CT
Cro
cin
tabs
30
mg/
d (1
5 m
g tw
ice
daily
) +
1
SSR
IC
roci
n fr
om s
affr
on
stig
ma
PBO
tabs
+ 1
SSR
I on
ce d
aily
: flu
oxet
ine
20 m
g, s
ertr
alin
e 50
mg,
or
cita
lopr
am 2
0 m
g
4 w
kB
DI,
BA
I, g
ener
al h
ealth
qu
estio
nnai
re (
GH
Q),
moo
d di
sord
er q
uest
ionn
aire
(M
DQ
)
Cro
cin
sig
impr
BD
I, B
AI
and
GH
Q s
core
s vs
PB
O:
P<.0
001;
avg
dec
rs 1
7.6,
12
.7, 1
7.2
vs 6
.15,
2.6
, 10.
3 re
spec
tivel
y
Shah
man
sour
i 20
14(S
hahm
anso
uri e
t al.,
20
14)
Eff
icac
y/sa
fety
vs
fluo
xetin
e on
dep
ress
ive
sym
ptom
sPt
s w
ith D
SM-I
V-T
R m
ild
to m
oder
ate
depr
essi
on a
fter
pe
rcut
aneo
us c
oron
ary
inte
rven
tion
40D
B-R
CT
CSE
cap
30
mg/
dSa
ffro
Moo
d®:
Eth
anol
ic s
tigm
a ex
trac
t ST
D to
0.1
3–0.
15 m
g sa
fran
al a
nd
1.65
–1.7
5 m
g cr
ocin
pe
r 15
-mg
cap
Fluo
xetin
e 40
mg/
d6
wk
HA
MD
No
sig
BG
D in
sco
res,
re
mis
sion
or
resp
onse
rat
es;
no s
ig d
iff
in A
Es
Moo
savi
201
4(M
oosa
vi e
t al
., 20
14)
Dos
e co
mpa
riso
n, a
s ad
juva
nt tx
with
flu
oxet
ine
Adu
lts w
ith D
SM-I
V m
ild
to m
oder
ate
depr
essi
ve
diso
rder
s
60D
B-R
CT
CSE
80
mg/
d +
fl
uoxe
tine
30 m
g/d
CSE
40
mg/
d +
fl
uoxe
tine
30 m
g/d
6 w
kH
AM
DC
SE e
ffec
tive
in b
oth
grou
ps,
but s
ig d
iff
with
80-
mg
tx
grou
p (P
<.0
5) ;
no s
ig d
iff
in
AE
s
Agh
a-H
osse
ini
2008
(Agh
a-H
osse
ini e
t al
., 20
08)
Eff
ects
on
PMS
Wom
en a
ge 2
0–45
y w
ith
regu
lar
men
stru
al c
ycle
s an
d PM
S sy
mpt
oms
for
≥6 m
o
78 s
cree
ned
50 r
ando
miz
edD
B-R
CT
Saff
ron
stig
ma
30 m
g/d
15 m
g dr
ied
peta
l ex
trac
t per
cap
PBO
2 m
enst
rual
cyc
les
(cyc
le 3
and
4)
1°-O
C: D
aily
Sym
ptom
R
epor
t2°
-OC
: HA
MD
Saff
ron
sig
impr
Tot
al
Prem
enst
rual
Dai
ly
Sym
ptom
s (s
ig B
GD
at c
ycle
4:
t=5.
92, d
f=48
, P<
.001
) an
d H
AM
D s
core
s (t
=8.
99,
df=
48, P
<.0
01)
Akh
ondz
adeh
Bas
ti 20
08(A
khon
dzad
eh B
asti
et a
l., 2
008)
Ant
idep
ress
ant e
ffec
ts o
f pe
tal (
less
exp
ensi
ve)
vs
stig
ma
44D
B-R
CT
CSE
pet
al c
ap 1
5 m
g tw
ice
daily
CSE
stig
ma
cap,
15
mg
twic
e da
ily6
wk
HA
MD
; Rem
issi
on d
efin
ed
as H
AM
D to
tal s
core
≤7
Peta
l and
stig
ma
sim
ilarl
y ef
fect
ive
for
mild
to
mod
erat
e de
pres
sion
(df
=1,
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 33
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Out
pts
with
DSM
-IV
maj
or
depr
essi
onD
ried
pet
al o
r st
igm
a ST
D b
y sa
fran
al 0
.30–
0.35
mg
F= 0
.05,
P=
.81)
; rem
issi
on
rate
: 18%
No
sig
diff
in s
ide
effe
cts
Akh
ondz
adeh
Bas
ti 20
07(A
khon
dzad
eh B
asti
et a
l., 2
007)
Ant
idep
ress
ant e
ffec
ts o
f pe
tal v
s fl
uoxe
tine
Out
pts
with
DSM
-IV
maj
or
depr
essi
on
40D
B-R
CT
CSE
pet
al c
ap 1
5 m
g tw
ice
daily
Dri
ed p
etal
ST
D b
y sa
fran
al 0
.30–
0.35
mg
Fluo
xetin
e 10
mg
twic
e da
ily8
wk
HA
MD
; Rem
issi
on d
efin
ed
as H
AM
D to
tal s
core
≤7
CSE
pet
al a
s ef
fect
ive
as
fluo
xetin
e (F
=0.
03, d
f=1,
P=
.84
); b
oth
tx p
rodu
ced
rem
issi
on r
ates
of
25%
No
sig
diff
in s
ide
effe
cts
Mos
hiri
200
6(M
oshi
ri e
t al
., 20
06)
Mild
-to-
mod
erat
e de
pres
sion
Adu
lt w
ith D
SM-I
V m
ajor
de
pres
sion
40D
B-R
CT
CSE
pet
al c
ap 3
0 m
g/d
15 m
g dr
ied
peta
l ex
trac
t per
cap
PBO
6 w
kH
AM
DSi
g be
tter
HA
MD
sco
res
than
PB
O (
df=
1, F
=16
.87,
P<
.001
)N
o si
g di
ff in
AE
s
Akh
ondz
adeh
20
05(A
khon
dzad
eh e
t al.,
20
05)
Mild
-to-
mod
erat
e de
pres
sion
Out
pts
with
DSM
-IV
maj
or
depr
essi
on
40D
B-R
CT
CSE
stig
ma
cap
30
mg/
dE
than
olic
stig
ma
extr
act
PBO
6 w
kH
AM
DSi
g be
tter
scor
es th
an P
BO
(d
f=1,
F=
18.8
9, P
<.0
01)
No
sig
diff
in A
Es
Noo
rbal
a 20
05(N
oorb
ala
et a
l., 2
005)
Mild
-to-
mod
erat
e de
pres
sion
vs
fluo
xetin
eA
dult
with
DSM
-IV
maj
or
depr
essi
on
40D
B-R
CT
CSE
stig
ma
cap
30
mg/
dE
ach
15-m
g ca
p ST
D
by s
afra
nal 0
.30–
0.35
m
g
Fluo
xetin
e 20
mg/
d6
wk
HA
MD
CSE
sim
ilarl
y ef
fect
ive
for
mild
to m
oder
ate
depr
essi
on
as f
luox
etin
e (F
=0.
13, d
f=1,
P=
.71)
No
sig
diff
in A
Es
Akh
ondz
adeh
20
04(A
khon
dzad
eh e
t al.,
20
04)
Ant
idep
ress
ant e
ffec
ts o
f st
igm
a vs
imip
ram
ine
Out
pts
with
DSM
-IV
maj
or
depr
essi
on
30D
B-R
CT
CSE
stig
ma
cap
30
mg/
dE
than
olic
stig
ma
extr
act 1
0 m
g sa
ffro
n pe
r ca
p
Imip
ram
ine
cap
100
mg/
d6
wk
HA
MD
CSE
stig
ma
sim
ilarl
y as
ef
fect
ive
as im
ipra
min
e (F
=2.
91, d
f=1,
P=
.09)
Sig
mor
e dr
y m
outh
and
se
datio
n w
ith c
ontr
ol g
roup
Soy
isof
lavo
nes
(SI)
2 st
udie
s
Liu
201
4(L
iu e
t al.,
201
4)E
ffec
ts o
f w
hole
soy
or
puri
fied
dai
dzei
n (1
maj
or
soy
isof
lavo
ne +
equ
ol
prec
urso
r) o
n M
P sy
mpt
oms
Equ
ol-p
rodu
cing
pre
hype
r-te
nsiv
e C
hine
se P
MP
wom
en (
mos
t lik
ely
to
bene
fit)
270
rand
omiz
ed25
3 co
mpl
eter
sD
B-R
CT
Soy
flou
r 40
g/d
or
Dai
dzei
n 63
mg/
dSo
y fl
our
cont
aine
d 12
.8 g
soy
pro
tein
and
49
.3 m
g is
ofla
vone
s
PBO
: low
-fat
milk
po
wde
r6
mo
Eac
h gi
ven
as a
so
lid b
ever
age
Val
idat
ed a
nd s
truc
ture
d sy
mpt
om c
heck
list
No
sig
diff
eren
ce in
6-m
o ch
ange
s or
% c
hang
es f
or
tota
l num
ber,
dim
ensi
on, o
r in
divi
dual
fre
quen
cy o
f M
P sy
mpt
oms
amon
g gr
oups
Uri
nary
isof
lavo
nes
indi
cate
d go
od c
ompl
ianc
e
de S
ousa
-Mun
oz 2
009(
de
Sous
a-M
unoz
and
Fi
lizol
a, 2
009)
Dep
ress
ive
sym
ptom
sC
limac
teri
c ou
tpts
at a
B
razi
lian
hosp
ital
84D
B-R
CT
SI e
xtra
ct 1
20 m
g/d
Isof
lavi
n B
etaT
M: 6
0 m
g is
ofla
vone
s pe
r ca
p;
20 m
g da
idze
ine–
daid
zine
, 17
mg
as
daid
zein
e; 1
4 m
g ge
nist
eine
–gen
istin
e, 9
m
g as
gen
iste
ine
PBO
: sta
rch
16 w
kB
razi
lian
vers
ion
of th
e C
ente
r of
Epi
dem
iolo
gic
Stud
ies
of D
epre
ssio
n (C
ES-
D)
No
sig
redu
c in
dep
ress
ive
sym
ptom
s; in
itial
sym
ptom
re
duc
asso
ciat
ed w
ith P
BO
ef
fect
sN
o cl
inic
ally
rel
evan
t AE
s
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 34
Her
bal M
edic
ine
Fir
st a
utho
r/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
olC
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Val
eria
n Va
leri
ana
offi
cina
lis2
stud
ies
And
reat
ini
2002
(And
reat
ini e
t al.,
20
02)
Anx
ioly
tic e
ffec
t of
vale
potr
iate
sO
utpt
s w
ith D
SM-I
II-R
G
AD
36D
B-R
CT
Fle
xibl
e do
seV
alep
otri
ates
(V
AL
) 81
.3 m
g m
ean
daily
do
seD
ihyd
rova
ltrat
e 80
%;
valtr
ate
15%
; ac
eval
trat
e 5%
Dia
zepa
m 6
.5 m
g m
ean
daily
dos
eor
PB
O
4 w
kH
AM
A, S
TAI
Sim
ilar
decr
ease
am
ong
grou
ps in
HA
MA
tota
l and
so
mat
ic f
acto
r sc
ores
; VA
L
and
diaz
epam
sig
red
uc
HA
MA
psy
chic
fac
tor
scor
es; d
iaze
pam
sig
red
uc
STA
I-tr
ait
Dor
n 20
00(D
orn,
200
0)E
ffec
ts o
n sl
eep
qual
ity v
s ox
azep
amN
on-o
rgan
ic a
nd n
on-
psyc
hiat
ric
inso
mni
acs
age
18–7
0 y
75D
B-R
CT
Val
eria
n ta
bs 2
× 3
00
mg
30 m
in b
efor
e be
dL
I 15
6, r
oot e
xtra
ct
Oxa
zepa
m ta
b 2
× 5
mg
28 d
1°-O
C: S
F-B
sle
ep q
ualit
y2°
-OC
: oth
er S
F-B
sle
ep
char
acte
rist
ics;
wel
l-be
ing
(Bf-
S); H
AM
A
In b
oth
grou
ps s
leep
qua
lity
impr
sig
(P<
.001
), w
ith n
o si
g B
GD
Poss
ible
AE
s: v
aler
ian,
n=
2;
oxaz
epam
, n=
3; n
o SA
Es
Wor
mw
ood
Art
emis
ia
absi
nthi
um2
stud
ies
Kre
bs 2
010(
Kre
bs e
t al.,
20
10)
As
adju
vant
tx f
or v
ario
us
effe
cts
incl
udin
g on
de
pres
sion
Pts
in G
erm
any
with
C
rohn
’s d
isea
se f
or ≥
3 m
o an
d no
t tre
ated
with
in
flix
imab
or
sim
ilar
drug
20R
CT
Ope
n-L
abel
Mul
ticen
terW
orm
woo
d ca
ps 7
50
mg
thre
e tim
es d
aily
Seda
Cro
hn: A
. ab
sint
hium
leaf
/ste
m
pow
der
STD
to 0
.32–
0.38
% a
bsin
thin
CD
med
icat
ions
onl
y6
wk
HA
MD
, VA
SH
AM
D to
tal s
core
dec
r by
av
g 9.
8±5.
8 po
ints
for
w
orm
woo
d vs
PB
O 3
.4±
6.6
Om
er 2
007(
Om
er e
t al.,
20
07)
As
adju
vant
tx f
or v
ario
us
effe
cts
incl
udin
g on
de
pres
sion
Pts
in G
erm
any
with
C
rohn
’s d
isea
se r
ecei
ving
da
ily s
tero
ids
(pre
dnis
one
40
mg
≥3 w
k)
40D
B-R
CT
Mul
ticen
ter
Wor
mw
ood
cap
3 ×
50
0 m
g/d
Seda
Cro
hn
PBO
10 w
kH
AM
D, V
AS
Ham
ilton
tota
l sco
res
decr
by
avg
9.8
(SD
5.8
) po
ints
for
w
orm
woo
d vs
PB
O 3
.4 (
SD
6.6)
. At W
k 10
, 70%
of
wor
mw
ood
grou
p an
d 0%
in
PBO
gro
up h
ad r
emis
sion
of
depr
essi
ve s
ympt
oms
VA
S: s
ig im
pr v
s PB
O
Abb
revi
atio
ns: 1
°-O
C, p
rim
ary
outc
ome
mea
sure
s; 2
°-O
C, s
econ
dary
out
com
e m
easu
res;
AD
L, a
ctiv
ities
of
daily
livi
ng; A
E, a
dver
se e
vent
s; B
AI,
Bec
k A
nxie
ty I
nven
tory
; BD
I, B
eck
Dep
ress
ion
Inve
ntor
y; B
FI,
Bri
ef F
atig
ue I
nven
tory
; BG
D, b
etw
een-
grou
p di
ffer
ence
s; B
L,
base
line;
BP
, blo
od p
ress
ure;
btw
, bet
wee
n; B
ZD
, ben
zodi
azep
ines
; cap
, cap
sule
; CG
I-S,
Clin
ical
Glo
bal I
mpr
essi
on-S
ever
ity; C
I, c
onfi
denc
e in
terv
al; c
orr,
cor
rela
tion;
CV
D, c
ardi
ovas
cula
r di
seas
e; D
B, d
oubl
e-bl
ind;
dec
r, d
ecre
ase;
dif
f, d
iffe
renc
e; D
SM-I
II/I
V/V
-TR
, D
iagn
ostic
and
Sta
tistic
al M
anua
l of
Men
tal D
isor
ders
, 3rd
, 4th
or
5th
editi
on, T
ext R
evis
ion;
EA
AS,
Erl
ange
n A
nxie
ty T
ensi
on a
nd A
ggre
ssio
n Sc
ale;
GA
D, G
ener
aliz
ed A
nxie
ty D
isor
der;
HA
DS,
Hos
pita
l Anx
iety
and
Dep
ress
ion
Scal
e; H
AM
A, H
amilt
on A
nxie
ty R
atin
g Sc
ale;
HA
MD
, Ham
ilton
Dep
ress
ion
Rat
ing
Scal
e; H
RSD
-17,
17-
item
Ham
ilton
Rat
ing
Scal
e fo
r D
epre
ssio
n; H
T, h
orm
one
ther
apy;
HR
T, h
orm
one
repl
acem
ent t
hera
py; i
mpr
, im
prov
ed o
r im
prov
emen
t; in
cl, i
nclu
ding
; inc
r, in
crea
se; i
nfo,
info
rmat
ion;
IT
T, i
nten
tion
to tr
eat;
MD
D, m
ajor
dep
ress
ive
diso
rder
; MA
DR
S, M
ontg
omer
y-A
sber
g D
epre
ssio
n R
atin
g Sc
ale;
MP
, men
opau
se o
r m
enop
ausa
l; P
BO
, pla
cebo
; PG
WB
I, P
sych
olog
ical
Gen
eral
Wel
l-B
eing
Ind
ex; P
MS,
pre
men
stru
al s
yndr
ome;
PM
P, p
ostm
enop
ausa
l; P
OM
S, P
rofi
le o
f M
ood
Stat
es; P
SQI,
Pitt
sbur
gh S
leep
Qua
lity
Inde
x; p
ts, p
atie
nts;
QoL
, qua
lity
of li
fe; R
CT
, ran
dom
ized
con
trol
led
tria
l; re
duc,
red
uctio
n or
red
uced
; sig
, sig
nifi
cant
; SB
, sin
gle-
blin
d; S
NR
I, s
erot
onin
-nor
epin
ephr
ine
reup
take
inhi
bito
rs; S
SRI,
sel
ectiv
e se
roto
nin
reup
take
inhi
bito
r;
STA
I, S
tate
-Tra
it A
nxie
ty I
nven
tory
; ST
D, s
tand
ardi
zed;
tab
, tab
let;
tx, t
reat
men
t; V
AS,
vis
ual a
nalo
gue
scal
e; V
MS,
vas
omot
or s
ympt
oms;
w/v
, wei
ght p
er v
olum
e; w
/w, w
eigh
t per
wei
ght;
WD
, with
draw
al.
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 35
Tab
le 3
Sing
le R
CT
s E
valu
atin
g H
erba
l Med
icin
es f
or A
nxie
ty a
nd D
epre
ssio
n O
ver
the
Las
t 20
Yea
rs (
1996
–201
6)
Her
bal
Med
icin
e
Fir
stau
thor
/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
ol C
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Am
eric
an S
kullc
apSc
utel
lari
a la
teri
flor
a (S
L)
Bro
ck 2
014(
Bro
ck
et a
l., 2
014)
Moo
dH
ealth
y pa
rtic
ipan
ts43
DB
-RC
TC
ross
over
SL c
ap 3
50 m
g th
ree
times
dai
lyFr
eeze
-dri
ed a
eria
l pa
rts
PBO
: Fre
eze-
drie
d st
ingi
ng
nettl
e le
af (
Urt
ica
dioi
ca fo
lia)
2 w
k w
ith e
ach
tx
sepa
rate
d by
1 w
k w
asho
ut
BA
I, P
OM
SN
o si
g di
ff, b
ut
part
icip
ants
wer
e re
lativ
ely
non-
anxi
ous
Sig
grou
p ef
fect
su
gges
ts s
kullc
ap
carr
yove
r ef
fect
POM
S To
tal M
ood
Dis
turb
ance
: hig
hly
sig
decr
fro
m p
re-t
est
scor
es (
P<.0
01)
vs P
BO
(P
=.0
72)
No
redu
c in
ene
rgy
or
cogn
ition
Ash
wag
andh
a W
ithan
ia
som
nife
ra e
xtra
ct (
WSE
)C
heng
appa
20
13(C
heng
appa
et
al.,
201
3)
As
a pr
ocog
nitiv
e ag
ent/
adju
nct t
o m
aint
enan
ce
bipo
lar
diso
rder
med
sE
uthy
mic
pts
with
DSM
-IV
bip
olar
dis
orde
r
60 53 c
ompl
eter
sD
B-R
CT
WSE
500
mg/
dSe
nsor
il, S
TD
WSE
: m
in 8
% w
ithan
olid
es
and
32%
ol
igos
acch
arid
es; m
ax
2% w
ithaf
erin
A
PBO
8 w
kPe
nn E
mot
iona
l Acu
ity te
st,
MA
DR
S, H
AM
AM
ood
and
anxi
ety
scal
e sc
ores
rem
aine
d st
able
; m
inor
AE
s
Bit
ter
oran
ge b
loss
omC
itrus
aur
antiu
m (
CA
)A
khla
ghi
2011
(Akh
lagh
i et
al.,
2011
)
Preo
pera
tive
anxi
ety
Pts
unde
rgoi
ng m
inor
op
erat
ion
60D
B-R
TC
A b
loss
om d
istil
late
1m
L/k
g bo
dy w
tFr
om f
resh
pet
als
and
stam
ens
PBO
: sal
ine
2h p
re-a
nest
hesi
aST
AI,
Am
ster
dam
Pre
oper
ativ
e A
nxie
ty a
nd I
nfor
mat
ion
Scal
e (A
PAIS
)
STA
I an
d A
PAIS
sca
les
sig
bette
r w
ith C
A v
s PB
O
Bla
ck c
umin
Nig
ella
sat
iva
(NS)
Bin
Say
eed
2014
(Bin
Say
eed
et a
l., 2
014)
Moo
d, a
nxie
ty a
nd
cogn
ition
Boy
s ag
e 14
–17
in a
B
angl
ades
h bo
ardi
ng
scho
ol
48D
B-R
CT
NS
500
mg/
dPo
wde
red
seed
sPB
O4
wk
STA
I; B
ond-
Lad
er s
cale
Stat
e an
xiet
y: n
o si
g va
riat
ion
foun
d; M
ood
and
trai
t anx
iety
: sig
va
riat
ion
from
BL
but
no
BG
D
Blu
e G
reen
Alg
aeA
paha
nizo
me-
non
flos
-aq
uae
Gen
azza
ni
2010
(Gen
azza
ni e
t al
., 20
10)
Alt
to H
T f
or
psyc
holo
gica
l/ so
mat
ic/V
MS
MP
wom
en/n
o H
T
30R
CT
Kla
mat
h al
gae
extr
act
1600
g/d
Kla
min
®
PBO
: van
illa
tab
8 w
kSy
mpt
om R
atin
g Sc
ale
- It
alia
n ve
rsio
n, Z
ung
Self
-Rat
ing
Scal
eSi
g ch
ange
s in
SR
T a
nd
Zun
g sc
ales
for
QoL
, m
ood,
anx
iety
and
de
pres
sive
atti
tude
No
horm
onal
cha
nges
oc
curr
ed
Chl
orel
la v
ulga
ris
(CV
)Pa
nahi
20
15(P
anah
i et a
l.,
2015
)
Adj
unct
to s
tand
ard
antid
epre
ssan
t (A
D)
txPt
s w
ith D
SM-I
V M
DD
42+
50Pi
lot e
xplo
rato
ry tr
ial
CV
180
0 m
g/d
as
AD
-tx
add-
onA
LG
OM
ED
® 9
8%
CV
pow
der
Stan
dard
AD
tx6
wk
HA
DS,
BD
I-II
Sca
leN
o se
riou
s A
Es
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 36
Her
bal
Med
icin
e
Fir
stau
thor
/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
ol C
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Cim
icif
uga
foet
ida
extr
act
(CF
E)
Zhe
ng
2013
(Zhe
ng e
t al.,
20
13)
Clim
acte
ric
sym
ptom
sE
arly
-MP
Chi
nese
wom
en96 89
com
plet
edR
CT
Gro
up A
: CFE
/dX
imin
gtin
g,
trite
rpen
oid
sapo
nin
extr
acte
d fr
om r
oot
3 m
oK
uppe
rman
Men
opau
se I
ndex
(K
MI)
, Men
opau
se-S
peci
fic
Qua
lity
of L
ife
(ME
NQ
OL
),
HA
DS
Bot
h de
cr K
MI
scor
es
(P<
.001
), b
ut C
FE
scor
es h
ighe
rM
EN
QO
L s
core
s si
g de
cr f
or a
ll gr
oups
(P≤
.01
) ex
cept
sex
ual
dom
ain
scor
e fo
r G
roup
A
(P=
.103
)A
nxie
ty s
ig d
ecr
in
Gro
up A
(P=
.015
) an
d B
(P=
.003
)
Cur
cum
in C
urcu
ma
long
aY
u 20
15(Y
u et
al.,
20
15)
As
adju
vant
tx to
SSR
I es
cita
lopr
amH
ospi
tal-
recr
uite
d m
en a
ge
31–5
9 y
in C
hina
108
DB
-RC
TC
urcu
min
cap
s 10
00
mg/
dC
urcu
min
70%
; de
met
hoxy
-cur
cum
in
20%
; dem
etho
xy-
curc
umin
10%
PBO
: soy
bean
pow
der
6 w
kH
AM
D C
hine
se v
ersi
on; M
AD
RS
Sig
antid
epre
ssan
t be
havi
oral
res
pons
es
Fla
x oi
lG
raci
ous
2010
(Gra
ciou
s et
al
., 20
10)
Sym
ptom
sev
erity
You
th a
ge 6
–17
y w
ith
bipo
lar
diso
rder
51R
CT
Flax
oil
cap
titra
ted
to
12 c
aps/
d as
tole
rate
d55
0 m
g α
-lin
olen
ic
acid
per
1 g
PBO
: Oliv
e oi
l16
wk
1⁰-O
C: Y
oung
Man
ia R
atin
g Sc
ale,
Chi
ld D
epre
ssio
n R
atin
g Sc
ale-
Rev
ised
, CG
I-B
ipol
ar2⁰
-OC
: Fat
ty a
cid
leve
ls a
s pr
edic
tors
of
tx r
espo
nse
and
sym
ptom
sev
erity
No
sig
diff
in 1⁰-
OC
Clin
icia
n-ra
ted
Glo
bal
Sym
ptom
Sev
erity
ne
gativ
ely
corr
elat
ed
with
fin
al s
erum
om
ega-
3 fa
tty a
cid
com
posi
tions
and
po
sitiv
ely
corr
elat
ed
with
fin
al a
rach
idon
ic
acid
and
do
cosa
pent
aeno
ic a
cid
leve
ls
Gar
licPe
leg
2003
(Pel
eg
et a
l., 2
003)
Eff
ect o
n lip
ids
and
Pts
with
pri
mar
y ty
pe 2
hy
perl
ipid
emia
with
no
CV
D
33D
B-R
CT
Gar
lic (
allii
n) 2
2.4
mg/
d +
indi
vidu
al
diet
ary
coun
selin
gIn
odie
l, 5.
6 m
g al
liin
per
tab
PBO
+ in
divi
dual
die
tary
co
unse
ling
16 w
kN
o ef
fect
on
psyc
hopa
thol
ogic
pa
ram
eter
s
Got
u ko
laC
ente
lla a
siat
ica
(CA
)B
radw
ejn
2000
(Bra
dwej
n et
al
., 20
00)
Anx
ioly
tic a
ctiv
ityH
ealth
y su
bjec
ts40
DB
-RC
TC
A 1
2 g
500
mg/
cap
crud
e po
wde
r
PBO
Sing
le d
ose
Self
-rat
ed m
ood,
aco
ustic
sta
rtle
re
spon
se (
ASR
)Si
g at
tenu
ated
pea
k A
SR a
mpl
itude
30
and
60 m
in p
ost-
txN
o si
g ef
fect
s on
moo
d,
hear
t rat
e, o
r bl
ood
pres
sure
Gra
pe s
eed
extr
act
(GSE
) po
lyph
enol
Tera
uchi
20
14(T
erau
chi e
t al
., 20
14)
MP
sym
ptom
s, b
ody
com
posi
tion,
and
ca
rdio
vasc
ular
par
amet
ers
Mid
dle-
aged
wom
en w
ith
≥1 M
P sy
mpt
om
96 91 c
ompl
eter
sD
B-R
CT
GSE
100
or
200
mg/
dG
ravi
nol,
85%
pr
oant
hocy
anid
in
PBO
8 w
kM
enop
ausa
l Hea
lth-R
elat
ed Q
oL,
HA
DS,
Ath
ens
Inso
mni
a Sc
ale
(AIS
)
Sig
impr
oved
phy
sica
l sy
mpt
oms
and
hot f
lash
sc
ores
Dec
r A
IS w
ith h
igh-
dose
; dec
r H
AD
S, S
BP
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 37
Her
bal
Med
icin
e
Fir
stau
thor
/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
ol C
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
and
DB
P w
ith b
oth
dose
s; in
cr m
uscl
e m
ass
with
bot
h do
ses
Gre
en t
eaC
amel
ia s
inen
sis
Zha
ng
2013
(Zha
ng e
t al.,
20
13)
Rew
ard
lear
ning
and
de
pres
sive
sym
ptom
sH
ealth
y su
bjec
ts a
ge 1
8–34
y
74D
B-R
CT
Gre
en te
a po
wde
r 40
0 m
g in
hot
wat
er 3
×/d
Poly
phen
ols
in
extr
act u
p to
20%
and
m
ore
of th
e dr
y w
eigh
t
PBO
: mic
ro-c
ryst
allin
e ce
llulo
se5
wk
MA
DR
S, H
RSD
-17
redu
c M
AD
RS
and
HR
SD-1
7 sc
ore
Hol
y ba
sil
Oci
mum
san
ctum
ext
ract
(O
SE)
Sam
path
20
15(S
ampa
th e
t al
., 20
15)
Neu
ropr
otec
tion,
cog
nitio
n an
d st
ress
rel
ief
Hea
lthy
mal
e su
bjec
ts in
In
dia
44D
B-R
CT
OSE
300
mg/
dE
than
olic
leaf
ext
ract
, ur
solic
aci
d >
2.7%
w
/w
PBO
30 d
STA
IST
AI
impr
oved
with
O
SE a
lone
Mel
issa
off
icin
alis
(M
O)
Alij
anih
a 20
15(A
lijan
iha
et
al.,
2015
)
To c
onfi
rm c
omm
only
re
gard
ed e
ffec
ts o
n he
art
palp
itatio
nsIr
ania
n ad
ult v
olun
teer
s w
ith b
enig
n pa
lpita
tions
71 r
ecru
ited
55 c
ompl
eter
sD
B-R
CT
MO
500
mg
twic
e da
ilyLy
ophi
lized
aqu
eous
ex
trac
t of
leav
es
20.9
%
PBO
14 d
1⁰-O
C: D
iari
es f
or m
ean
freq
uenc
y of
pal
pita
tion
epis
odes
/wk;
VA
S fo
r m
ean
palp
itatio
n in
tens
ity2⁰
-OC
: Gen
eral
Hea
lth
Que
stio
nnai
re-2
8 (G
HQ
-28)
for
so
mat
izat
ion,
anx
iety
, ins
omni
a,
soci
al d
ysfu
nctio
n an
d se
vere
de
pres
sion
Sig
redu
c in
pal
pita
tion
epis
odes
(P=
.000
1) a
nd
num
ber
of a
nxio
us p
ts
(P=
.004
)N
o se
riou
s A
Es
Rha
pont
ic r
huba
rb R
heum
rh
apon
ticum
ext
ract
Kas
zkin
-Bet
tag
2007
(Kas
zkin
-B
etta
g et
al.,
20
07)
Anx
iety
, hea
lth s
tate
, and
ge
nera
l wel
l-be
ing
Peri
-MP
wom
en w
ith
clim
acte
ric
com
plai
nts
and
anxi
ety
109
DB
-RC
TM
ultic
ente
rR
huba
rb e
xtra
ct 1
en
teri
c co
ated
tab
daily
ER
r 73
1; P
hyto
estr
ol
N S
TD
roo
t ext
ract
PBO
12 w
kH
AM
A, M
enop
ause
Rat
ing
Scal
e II
, Wom
en’s
Hea
lth
Que
stio
nnai
re, P
GW
BI
HA
MA
tota
l sco
re v
s PB
OA
nxie
ty s
ever
ity f
rom
m
oder
ate
or s
ever
e to
sl
ight
in 3
3/39
co
mpl
eter
s of
act
ive
tx
corr
elat
ed w
ith r
educ
nu
mbe
r/se
veri
ty o
f ho
t fl
ushe
s
Ros
e te
aT
seng
200
5(T
seng
et
al.,
200
5)M
enst
rual
pai
n an
d ps
ycho
phys
iolo
gic
dist
ress
Fem
ale
adol
esce
nts
with
pr
imar
y dy
smen
orrh
ea
130
RC
TR
ose
tea
2 te
acup
s st
art 1
wk
befo
re
peri
od to
5th
m
enst
rual
day
(12
d/
mo)
Eac
h cu
p m
ade
from
6
dry
buds
R. g
allic
a st
eepe
d fo
r 10
min
in
300
mL
hot
wat
er
No
tx12
d q
mo
for
6 cy
cles
Bio
psyc
hoso
cial
out
com
es o
f dy
smen
orrh
eaL
ess
perc
eive
d m
enst
rual
pai
n, d
istr
ess,
an
d an
xiet
y an
d gr
eate
r w
ell-
bein
g at
1, 3
, and
6
mo
post
-tx
Sage
Salv
ia o
ffic
inal
isK
enne
dy
2006
(Ken
nedy
et
al.,
2006
)
Anx
iety
and
moo
d m
odul
atin
g pr
oper
ties
of 2
se
para
te s
ingl
e do
ses
Hea
lthy
youn
g ad
ults
30D
B-R
CT
Cro
ssov
erSa
ge c
ap 3
00 o
r 60
0 m
gS.
off
icin
alis
dri
ed
leaf
PBO
3 st
udy
visi
ts
sepa
rate
d by
1 w
k w
asho
uts
Bon
d-L
ader
Moo
d Sc
ales
(B
LM
S) a
nd S
TAI
pre/
post
20
min
of
Def
ined
Int
ensi
ty S
tres
s
Impr
oved
moo
d ra
tings
ab
sent
of
stre
ssor
: R
educ
anx
iety
with
30
0-m
g do
se w
as
Phytother Res. Author manuscript; available in PMC 2019 May 01.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Yeung et al. Page 38
Her
bal
Med
icin
e
Fir
stau
thor
/Y
ear
Eva
luat
ion/
Pop
ulat
ion
N/n
Des
ign
Inte
rven
tion
/P
repa
rati
onC
ontr
ol C
ompa
riso
nT
reat
men
tD
urat
ion
Anx
iety
/Dep
ress
ion
Mea
sure
sR
esul
ts
Sim
ulat
or (
DIS
S) c
ompu
teri
zed
mul
titas
king
bat
tery
abol
ishe
d du
ring
DIS
S;
600-
mg
dose
incr
al
ertn
ess,
cal
mne
ss a
nd
cont
ente
dnes
s
Scel
etiu
m to
rtuo
sum
ex
trac
t (S
TE
)Te
rbur
g 20
13(T
erbu
rg e
t al
., 20
13)
Acu
te e
ffec
ts o
n an
xiet
y-re
late
d am
ygda
la a
ctiv
ity
and
neur
ocir
cuitr
yH
ealth
y yo
ung
adul
ts
16D
B-R
CT
Cro
ssov
erST
E 2
5 m
gZ
embr
in: S
TD
aq
ueou
s et
hano
lic
extr
act o
f ab
ove-
grou
nd m
ater
ial
PBO
Sing
le d
ose
fMR
I du
ring
per
cept
ual-
load
and
em
otio
n-m
atch
ing
task
sA
myg
dala
rea
ctiv
ity to
fe
arfu
l fac
es u
nder
low
pe
rcep
tual
load
co
nditi
ons
was
at
tenu
ated
Follo
w-u
p co
nnec
tivity
an
alys
is o
n em
otio
n-m
atch
ing
task
sho
wed
re
duc
amyg
dala
-hy
poth
alam
us c
oupl
ing
Sibe
rian
gin
seng
Ele
uthe
roco
ccus
sen
ticos
us
extr
act
(ESE
)
Scha
ffle
r 20
13(S
chaf
fler
et
al.,
2013
)
Men
tal f
atig
ue/r
estle
ssne
ssPa
rtic
ipan
ts w
ith a
sthe
nia
and
redu
ced
wor
king
ca
paci
ty r
elat
ed to
chr
onic
st
ress
144
RC
TE
SE 1
20 m
g/d
only
or E
SE +
2-d
ay s
tres
s m
anag
emen
t tra
inin
g (C
OM
)W
S® 1
070
ES
root
et
hano
lic e
xtra
ct r
atio
16
–25:
1
2-da
y st
ress
man
agem
ent
trai
ning
(SM
T)
8 w
kSt
ress
, fat
igue
, exh
aust
ion,
al
ertn
ess,
res
tless
ness
, moo
d,
QoL
, sle
epPh
ysic
al c
ompl
aint
s, a
ctiv
ities
Alm
ost a
ll pa
ram
eter
s si
g im
prov
ed o
ver
time;
no
BG
DM
enta
l fat
igue
and
re
stle
ssne
ss f
avor
ed
CO
M v
s E
SEC
OM
was
not
sup
erio
r to
SM
T
Wild
Yam
Dia
scor
ea a
lata
ext
ract
(D
AE
)
Hsu
201
1(H
su e
t al
., 20
11)
Safe
ty/e
ffic
acy
for
MP
sym
ptom
sM
P w
omen
50D
B-R
CT
Dua
l cen
ter
DA
E 1
2 m
g/sa
chet
;2
sach
ets
daily
Lyph
oliz
ed p
owde
r aq
ueou
s tu
ber
extr
act
PBO
12 m
o1⁰
-OC
: Gre
ene
Clim
acte
ric
Scal
e (G
CS)
2⁰-O
C: P
lasm
a ho
rmon
e pr
ofile
s
At 6
and
12
mo:
ge
nera
lly im
prov
ed
mos
t clin
ical
sym
ptom
sG
CS:
Sig
red
uc a
t 12
mo
(P<
.01)
and
mos
t si
g fo
r fe
elin
g te
nse/
nerv
ous
(P=
.007
),
inso
mni
a (P
=.0
04),
ex
cita
bilit
y (P
=.0
47),
an
d m
uscu
losk
elet
al
pain
(P=
.019
)Po
sitiv
e ef
fect
s on
ho
rmon
e pr
ofile
sG
ood
long
-ter
m s
afet
y pr
ofile
Abb
revi
atio
ns:
1⁰-O
C, p
rim
ary
outc
ome
mea
sure
s; 2⁰-
OC
, sec
onda
ry o
utco
me
mea
sure
s; A
DL
, act
iviti
es o
f da
ily li
ving
; AE
, adv
erse
eve
nts;
BA
I, B
eck
Anx
iety
Inv
ento
ry; B
DI,
Bec
k D
epre
ssio
n In
vent
ory;
BF
I, B
rief
Fat
igue
Inv
ento
ry; B
GD
, bet
wee
n-gr
oup
diff
eren
ces;
BL
, ba
selin
e; B
P, b
lood
pre
ssur
e; b
tw, b
etw
een;
BZ
D, b
enzo
diaz
epin
es; c
ap, c
apsu
le; C
GI-
S, C
linic
al G
loba
l Im
pres
sion
-Sev
erity
; CI,
con
fide
nce
inte
rval
; cor
r, c
orre
latio
n; C
VD
, car
diov
ascu
lar
dise
ase;
DB
, dou
ble-
blin
d; d
ecr,
dec
reas
e; d
iff,
dif
fere
nce;
DSM
-III
/IV
/V-T
R,
Dia
gnos
tic a
nd S
tatis
tical
Man
ual o
f M
enta
l Dis
orde
rs, 3
rd, 4
th o
r 5t
h ed
ition
, Tex
t Rev
isio
n; E
AA
S, E
rlan
gen
Anx
iety
Ten
sion
and
Agg
ress
ion
Scal
e; G
AD
, Gen
eral
ized
Anx
iety
Dis
orde
r; H
AD
S, H
ospi
tal A
nxie
ty a
nd D
epre
ssio
n Sc
ale;
HA
MA
, Ham
ilton
Anx
iety
Rat
ing
Scal
e; H
AM
D, H
amilt
on D
epre
ssio
n R
atin
g Sc
ale;
HR
SD-1
7, 1
7-ite
m H
amilt
on R
atin
g Sc
ale
for
Dep
ress
ion;
HT,
hor
mon
e th
erap
y; H
RT,
hor
mon
e re
plac
emen
t the
rapy
; im
pr, i
mpr
oved
or
impr
ovem
ent;
incl
, inc
ludi
ng; i
ncr,
incr
ease
; inf
o, in
form
atio
n; I
TT
, int
entio
n to
trea
t; M
DD
, maj
or d
epre
ssiv
e di
sord
er; M
AD
RS,
Mon
tgom
ery-
Asb
erg
Dep
ress
ion
Rat
ing
Scal
e; M
P, m
enop
ause
or
men
opau
sal;
PB
O, p
lace
bo; P
GW
BI,
Psy
chol
ogic
al G
ener
al W
ell-
Bei
ng I
ndex
; PM
S, p
rem
enst
rual
syn
drom
e; P
MP
, pos
tmen
opau
sal;
PO
MS,
Pro
file
of
Moo
d St
ates
; PSQ
I, P
ittsb
urgh
Sle
ep Q
ualit
y In
dex;
pts
, pat
ient
s; Q
oL, q
ualit
y of
life
; RC
T, r
ando
miz
ed c
ontr
olle
d tr
ial;
redu
c, r
educ
tion
or r
educ
ed; s
ig, s
igni
fica
nt; S
B, s
ingl
e-bl
ind;
SSR
I, s
elec
tive
sero
toni
n re
upta
ke in
hibi
tor;
ST
AI,
Sta
te-T
rait
Anx
iety
Inv
ento
ry; S
TD
, st
anda
rdiz
ed; t
ab, t
ab; t
x, tr
eatm
ent;
VA
S, v
isua
l ana
logu
e sc
ale;
VM
S, v
asom
otor
sym
ptom
s; w
/v, w
eigh
t per
vol
ume;
w/w
, wei
ght p
er w
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t; W
D, w
ithdr
awal
.
Phytother Res. Author manuscript; available in PMC 2019 May 01.