Herbal Medicine for Depression and Anxiety - Moodle@Units

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, [email protected], Tel: 507-529-7712, Fax: 212-717-3185.

Conflict of InterestThe authors declare no conflict of interest.

HHS Public AccessAuthor manuscriptPhytother Res. Author manuscript; available in PMC 2019 May 01.

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

Yeung et al.

Phytother Res. Author manuscript; available in PMC 2019 May 01.

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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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Yeung et al.

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

)


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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,


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Yeung et al.

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

eigh

t; W

D, w

ithdr

awal

.


Herbal Medicine for Depression and Anxiety - Moodle@Units

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Transcript of Herbal Medicine for Depression and Anxiety - Moodle@Units