Phytotherapy Research - 2018 - Yeung - Herbal Medicine For Depression and Anxiety A Systematic Review With Assessment of

Received: 5 October 2017 Revised: 8 December 2017 Accepted: 21 December 2017
DOI: 10.1002/ptr.6033
REVIEW
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 | Jyothirmai Gubili1
1
Integrative Medicine Service, Memorial Sloan
Kettering Cancer Center, New York City, NY, Anxiety and depression are prevalent among cancer patients, with significant negative impact.
USA Many patients prefer herbs for symptom relief to conventional medications which have limited
2
Information Systems/Medical Library, efficacy/side effects. We identified single‐herb medicines that may warrant further study in can-
Memorial Sloan Kettering Cancer Center, New
cer patients. Our search included PubMed, Allied and Complementary Medicine, Embase, and
York City, NY, USA
Cochrane databases, selecting only single‐herb randomized controlled trials between 1996 and
2016 in any population for data extraction, excluding herbs with known potential for interactions
Correspondence
Jyothirmai Gubili, Memorial Sloan Kettering
with cancer treatments. One hundred articles involving 38 botanicals met our criteria. Among
Cancer Center, Bendheim Integrative herbs most studied (≥6 randomized controlled trials each), lavender, passionflower, and saffron
Medicine Center, 1429 First Avenue, New produced benefits comparable to standard anxiolytics and antidepressants. Black cohosh, cham-
York 10021, NY, USA.
omile, and chasteberry are also promising. Anxiety or depressive symptoms were measured in all
Email: gubilij@mskcc.org
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,
Funding information
NIH/NCI Cancer Center Support Grant, black cohosh, chamomile, chasteberry, lavender, passionflower, and saffron appear useful in mit-
Grant/Award Number: P30 CA008748 igating anxiety or depression with favorable risk–benefit profiles compared to standard treat-
ments. 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.
KEY W ORDS
antidepressant, anxiety, anxiolytic, cancer, depression, herbal medicine
1 | B A CKG R O U N D experience anxiety, depression, or adjustment disorder, which is char-

acterized by feelings of stress in response to a major event such as a
The National Institutes of Mental Health estimates that depression cancer diagnosis. Breast cancer patients were reported to be most
affects nearly 16 million people in the United States (Liu et al., 2015). affected (42%), followed by those with head and neck cancer (41%)
A serious mood disorder, depression is characterized by anhedonia, and melanoma (39%). Risk factors for depression include poor perfor-
the reduced ability to experience pleasure, insomnia or hypersomnia, mance status, as determined by using a validated version of The
psychomotor agitation or retardation, fatigue, feelings of worthless- Eastern Cooperative Oncology Group Scale to measure functional
ness or guilt, difficulty concentrating, and repetitive thoughts of sui- status, pain, old age, and low‐level education, while poor performance
cide or death. status, old age, and female gender were predictors of anxiety (Hong &
According to the American Psychiatric Association (2016), more Tian, 2014; Mols, Husson, Roukema, & van de Poll‐Franse, 2013).
than 25 million people in the United States suffer from anxiety disor- Depression and anxiety also contribute to long‐term strain in can-
ders involving persistent, excessive worry or fear of objects or situa- cer patients. In a recent survey of 3,370 survivors, 40% reported mod-
tions, and recurrent panic attacks. Depression and anxiety are erate to high anxiety, and in approximately 20%, moderate to high
especially common in cancer patients (Anderson & Taylor, 2012) and levels of depression lasted up to 6 years post‐diagnosis (Inhestern et al.,
negatively impact quality of life (Brown, Kroenke, Theobald, Wu, & 2017). Depression can lead to serious consequences that include wors-
Tu, 2010; Bultz & Carlson, 2005). One in three patients (32%) ening quality of life (Higginson & Costantini, 2008), lower adherence to
Phytotherapy Research. 2018;32:865–891. wileyonlinelibrary.com/journal/ptr Copyright © 2018 John Wiley & Sons, Ltd. 865
10991573, 2018, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ptr.6033 by Cochrane France, Wiley Online Library on [04/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
866 YEUNG ET AL.
anticancer treatments (Mathes, Pieper, Antoine, & Eikermann, 2014), Rojowski, Opoka, & Sulkowska‐Ziaja, 2015; Sarris, Panossian, Schweitzer,
suicide (Henriksson, Isometsa, Hietanen, Aro, & Lonnqvist, 1995), Stough, & Scholey, 2011; Zeng et al., 2017). One study used polyherbal
prolonged hospital stays (Prieto et al., 2002), and reduced survival formulas for both symptoms (Liu et al., 2015). Although such combina-
(Pinquart & Duberstein, 2010). Conventional management of depres- tions are thought to have greater therapeutic value compared with sin-
sion and anxiety disorders is based on pharmacotherapy and psycho- gle herbs (Parasuraman, Thing, & Dhanaraj, 2014), it is difficult to
therapy. However, antidepressants and anxiolytics act by modulating identify the level to which each herb may contribute to overall effects.
neurotransmitters that play a crucial role in both central and peripheral Therefore, we restricted our review to studies involving single herbs or
nervous system function (Schatzberg, 2015), and current drugs are not extracts that are available in the United States as dietary supplements
very effective in cancer patients (Ostuzzi, Matcham, Dauchy, Barbui, & and to randomized controlled trials. We also excluded those with
Hotopf, 2015). Of greater concern is their association with substantial known potential for herb–drug interactions that should be avoided
side effects which include addiction, seizures, sexual dysfunction, by cancer patients, so as to better identify the herbs that have
headaches, and suicide (Fajemiroye, da Silva, de Oliveira, & Costa, been studied, or may warrant future study, in this population.
2016), as well as interactions with anticancer treatments (Desmarais
& Looper, 2009).
The last few decades have seen a significant rise in the use of nat-
2 | MATERIALS AND METHODS
ural remedies to treat various ailments including depression and anxi-
We conducted this systematic review according to the Cochrane
ety. These products are perceived as safer alternatives to
Collaboration framework. A review protocol is not available. A compre-
pharmacotherapy, with lower risk of adverse effects or withdrawal.
hensive electronic literature search for articles in multiple languages
Some, such as chamomile (Srivastava & Gupta, 2007) and black cohosh
was conducted in the following databases: PubMed, Allied and Com-
(Henneicke‐von Zepelin et al., 2007), also have anticancer activities
plementary Medicine, Embase, and Cochrane. The date filter was
making them attractive choices for cancer survivors. Analyses of data
applied on each database to capture the last 20 years of the literature
from the National Health Interview Survey show that compared to
(1996–2016).
the general population, cancer survivors reported greater use of com-
Three broad concept categories were searched, and results were
plementary therapies, with one third having taken an herbal medicine
combined using the appropriate Boolean operators (AND and OR).
(Anderson & Taylor, 2012). In the United States, because these are reg-
The broad categories included clinical trials, botanical supplement
ulated as dietary supplements available without a prescription, patients
products, and select mood disorders. Related terms were also incorpo-
tend to self‐medicate without informing their health care providers.
rated into the search strategy to ensure all relevant papers were
Although many herbs used in traditional medicine have been shown
retrieved (Table 1).
to have anticancer activities (Tariq et al., 2017), and some even have
the potential to develop into treatments for cancer (Chen, Qiu, Hu,
Wang, & Wang, 2016) or to address the adverse effects of chemother- 2.1 | Inclusion and exclusion criteria
apy (Chen, May, Zhou, Zhang, & Xue, 2016), few herbs have been stud- Only randomized controlled trials (RCTs) were included in this review.
ied in cancer patients and their mechanisms of action, adverse effects, Meeting abstracts, comments, review articles, and case reports were
and potential interactions with anticancer treatments are among the excluded. Studies involving St. John's Wort were also excluded
unknowns. because it has been extensively researched, revealing many potential
Therefore, the aim of this systematic review is to summarize the interactions with drugs that are P‐glycoprotein and/or CYP3A sub-
evidence from clinical trials involving botanical supplements for strates (Whitten, Myers, Hawrelak, & Wohlmuth, 2006). Also, the large
depression and anxiety independent of disease state. We hope that body of literature merits a separate review.
our findings will provide information that is clinically relevant to oncol- Details of our screening selection process are provided in Figure 1.
ogists 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.
2.2 | Data extraction and analysis
Previous reviews have documented herbal remedies for the treat- Two reviewers (K. S. Y. and J. G.) independently reviewed the articles
ment of depression and/or anxiety (Bandelow et al., 2015; Ernst, 2006; to be included. Any discrepancies were identified and resolved by addi-
Farah et al., 2016; Lakhan & Vieira, 2010; Muszynska, Lojewski, tional deliberation. Details of herbs evaluated in multiple studies are
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] Clinical Trials AND (phytotherapy OR biological product OR biological
OR “Clinical Trials, Phase IV as Topic”[Mesh] OR “Clinical Trials, Phase III products OR plant extract OR plant extracts) AND (anxiety OR
as Topic”[Mesh] OR “Clinical Trials, Phase II as Topic”[Mesh] OR “Clinical depression OR mood disorders) AND (antidepressive agent OR anti‐
Trials, Phase I as Topic”[Mesh] OR “Clinical Trial” [Publication Type]) AND anxiety agents OR herb OR herbs OR natural product OR natural
(“Herbal medicine” [Mesh] OR Phytotherapy[Mesh] OR “Plant products OR antidepressant OR antidepressants OR anxiolytic OR
Extracts”[Mesh] OR “Plants, Medicinal”[Mesh]) AND (Anxiety[Mesh] OR anxiolytics)
“Depression”[Mesh] OR “Mood Disorders”[Mesh] OR “Antidepressive
Agents”[Mesh] OR “Anti‐Anxiety Agents” [Mesh])
YEUNG ET AL. 867
FIGURE 1 Overview of study selection
summarized in Table 2 and include study design, sample population, Choreishi, Noorbala, Akhondzadeh, & Rezazadeh, 2008; Movafegh,
intervention, control, treatment length, outcomes, and adverse events. Alizadeh, Hajimohamadi, Esfehani, & Nejatfar, 2008). Saffron reduced
Study details of herbs for which there is currently only one RCT avail- anxiety and depression scores in women with premenstrual syndrome
able are described in Table 3. as well (Agha‐Hosseini et al., 2008).
Kava (Piper methysticum) originated from tropical islands and is
used in traditional medicine. Dietary supplements containing kava
3 | RESULTS extracts are promoted as a natural treatment for anxiety and insomnia.
WS®1490, a standardized dry root extract, has been employed in sev-
One hundred articles involving 38 botanicals were identified that met eral clinical trials (Gastpar & Klimm, 2003; Geier & Konstantinowicz,
the inclusion criteria. They appear here in the order of most to least 2004; Malsch & Kieser, 2001; Volz & Kieser, 1997) and shown to have
studied botanicals but appear alphabetically for ease of location in anxiolytic effects that were superior to placebo. Another extract dem-
the tables. Among RCTs that met our criteria and had more than two onstrated effects similar to those of buspirone and opipramol, pre-
RCTs (Table 2), saffron, kava, ginkgo, lavender, brahmi, and passion- scription drugs used for anxiety and depression (Boerner et al.,
flower appeared to be the most studied. 2003). Aqueous extracts of kava have also been investigated by Sarris
Saffron, derived from the stigma of Crocus sativus flower, is com- et al. (2009) who reported their anxiolytic activity to be better than
monly used as a spice and as medicine in the Middle East and in South placebo with short‐term (3 weeks) use but not as effective as oxaze-
Asia. In patients with mild to moderate anxiety, extracts of saffron pam when given in acute doses for 1 week (Sarris et al., 2012). In
were reported to be effective in relieving symptoms in several RCTs another study, this extract increased sexual drive in female users and
(Akhondzadeh et al., 2005; Mazidi et al., 2016; Talaei, Hassanpour reduced anxiety significantly (Sarris, Stough, Teschke, et al., 2013).
Moghadam, Sajadi Tabassi, & Mohajeri, 2015). Studies also show that Kava extract also reduced anxiety and depression scores in both
the effects are comparable to standard antidepressant drugs such as perimenopausal (Cagnacci et al., 2003) and postmenopausal women
fluoxetine (Moosavi, Ahmadi, Amini, & Vazirzadeh, 2014; Noorbala, (De Leo et al., 2000).
Akhondzadeh, Tahmacebi‐Pour, & Jamshidi, 2005; Shahmansouri Ginkgo biloba is an ancient plant recognized for its medicinal value
et al., 2014) and imipramine (Akhondzadeh, Fallah‐Pour, Afkham, throughout history and is cultivated around the world. The leaf extract
Jamshidi, & Khalighi‐Cigaroudi, 2004). In addition, the less expensive is marketed as a dietary supplement to improve memory because it
petal extracts have also been tested and found to be effective promotes blood flow. Quite a few clinical trials over the last two
substitutes (Akhondzadeh Basti et al., 2007; Akhondzadeh Basti, decades used EGB 761®, a standardized dry leaf extract of G. biloba.
868
TABLE 2 Herbal medicines most frequently evaluated for anxiety and depression in RCTs over the last 20 years (1996–2016)
Herbal First Intervention/ Control Treatment Anxiety/depression
medicine author/year Evaluation/population N/n Design preparation comparison duration measures Results
Asian Ginseng Braz 2013 Effects vs. amitriptyline; 38 DB‐RCT PGE 100 mg/d Amitriptyline 12 weeks VAS; fibromyalgia VAS: PGE reduc pain (p < .0001)
Panax ginseng (Braz et al., pts with fibromyalgia root extract, 25 mg/d, or PBO impact and impr sleep (p < .001), but
extract (PGE) 2013) 27% ginsenosides questionnaire (FIQ) no BGD; impr anxiety
2 studies (p < .0001), but more impr
with amitriptyline; FIQ: PGE
reduc number of tender points
and impr QoL but no BGD
Wiklund 1999 QoL and physiological 384 DB‐RCT PGE 200 mg/d PBO 16 weeks 1°‐OC: PGWB; Total PGWBI not sig, but sig
(Wiklund parameters in multicenter Ginsana, STD Women's effects for depression, well‐
et al., 1999) symptomatic PG root health being and health subscales; no
PMP women extract g 115® questionnaire sig effects for WHQ, VAS or
(WHQ), VAS physiological parameters,
incl VMS
Black cohosh Amsterdam 2009 Anxiety in MP 28 DB‐RCT CRE 64–128 mg/d PBO: Rice flour Up to 1°‐OC: HAMA; 2°‐OC: No sig anxiolytic effects;
Cimicifugae (Amsterdam women dose esc STD to 5.6% 12 weeks BAI, PGWBI, green one subject discontd
racemosae et al., 2009) active triterpene climacteric scale (GCS), due to AE
extract (CRE) glycosides % pts with ≥50%
3 studies HAMA score change
Oktem 2007 Efficacy on MP 120 RCT CRE 40 mg/d Fluoxetine 20 mg/d 6 months Hot flush/night sweats At Month 3 end: CRE sig decr
(Oktem symptoms Remixin® #/intensity; Month 3 mKI; fluoxetine sig decr BDS.
et al., 2007) vs. fluoxetine; (beg/end): Modified At Month 6 end: CRE hot flush
PMP women Kupperman index score reduc by 85% vs.
(mKI), Beck's fluoxetine 62%; 40 (20 each
depression scale group) discontinued.
(BDS), Fluoxetine more effective for
RAND‐36 QoL depression; CRE more
effective for hot
flushes/night sweats
Nappi 2005 Climacteric complaints 64 RCT CRE 40 mg/d Low‐dose transdermal 3 months Daily hot flushes; VMS, At Month 1: Both reduc # daily
(Nappi et al., in PMP women Remifemin®: estradiol 25 μg q7d urogenital symptoms; hot flushes (p < .001) and
2005) Isopropanolic + dihydrogesterone hormonal parameters; VMS (p < .001); effects
aqueous extract 10 mg/d for last 12 symptom rating test maintained at 3 months
days of 3‐month tx without sig BGD. At Month 3:
Both reduc anxiety (p < .001)
and depression (p < .001);
no sig hormonal changes
Brahmi, Bacopa Benson 2014 Anxiolytic, 17 DB‐RCT BME 320 or 640 mg PBO: Inert 3 study visits Cognitive, mood, and Associated with positive
monnieri (Benson antidepressant, crossover before tasks plant‐based separated salivary cortisol cognitive and mood effects
extract (BME) et al., 2014) sedative, and KeenMind® materials by 1‐week measures pre‐post and reduc cortisol levels, but
6 studies adaptogenic actions (CDRI 08): Stems, washouts multitasking sessions subjective mood/anxiety
during multitasking leaves, and roots; ratings were inconsistent
in healthy subjects 50% ethanol
extract
Sathyanarayanan Learning, memory, 72 DB‐RCT BME 450 mg/d; STD PBO: Starch 12 weeks STAI; auditory verbal Trend for lower STAI with BME;
2013 processing, and BME dried herb learning test (AVLT); no BGD for cognitive
(Sathyanarayanan anxiety; educated inspection time task; measures
et al., 2013) adults in rapid visual information
urban India processing test;
Stroop task
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(Continues)
ET AL.
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TABLE 2 (Continued)
ET AL.

Kumar 2011 Neuropharmacologic 54 DB‐RCT BME 300 mg/d; PBO: 6 months Anxiety, well‐being, Intervention sig impr
(Kumar effects in healthy crossover BESEB‐CDRI‐08 Lactose on each tx sleep, and walking hemoglobin, oxygen capacity,
et al., 2011) volunteers age well‐being, walking, hand grip,
20–75 years anxiety, sleep decr pulse and
glucose levels
Calabrese 2008 Cognitive function in 54 participants; DB‐RCT BME 300 mg/d; PBO 6‐week PBO 1°‐OC: AVLT delayed Enhanced AVLT delayed word
(Calabrese elderly volunteers 48 completers methanol/water for run‐in + recall score; 2°‐OC: recall memory scores, Stroop
et al., 2008) 50:1 dry extract 12 weeks tx Stroop task; divided results; decr CESD‐10 and
with min 50% attention task (DAT); combined STAI scores, and
bacosides Wechsler adult heart rate; no effects on DAT,
A and B intelligence scale WAIS, mood, or BP; few AEs,
(WAIS); STAI; Center primarily stomach upset
for Epidemiologic
Studies Depression
scale (CESD)‐10; POMS
Roodenrys 2002 Memory and anxiety 76 DB‐RCT BME 300 mg/d for PBO 3 months Depression, anxiety, Sig effects on new‐info retention,
(Roodenrys in adults age those weighing and stress scale but none on short‐term, every
et al., 2002) 40–65 years <90 kg—or—450 mg/d day or working memory,
if >90 kg; KeenMind®; attention, info retrieval,
doses equiv to 6‐ and depression, anxiety or stress
9‐g dried rhizome,
respectively
Stough 2001 Cognitive function in 46 DB‐RCT BME 320 mg/d; each PBO 12 weeks IT task, AVLT, Sig impr in STAI (p < .001) with
(Stough et al., healthy volunteers 160‐mg cap equiv to STAI max effects after 12 weeks;
2001, 2015) 4‐g dried herb also impr visual info
processing (IT task), learning
rate and memory
consolidation (AVLT)
Chamomile Chang 2016 Effects on sleep quality, 80 SB‐RCT Chamomile tea Regular 2 weeks Postpartum sleep Significant immediate‐term lower
Matricaria (Chang & fatigue, depression; steeped in 300 ml postpartum quality scale scores for physical‐symptoms‐
recutita Chen, 2016) sleep‐disturbed hot water for care only (PSQS), Edinburgh related sleep inefficiency:
extract (MRE) postnatal Taiwanese 10–15 min; German postnatal t = −2.482, p = .015;
3 studies women origin; 2‐g dried depression scale, depression: t = −2.372,
flowers in each teabag postpartum p = .020. However, 4‐week
fatigue scale post‐test scores were
similar for both groups.
Mao 2016 Long‐term use for 179 enrolled DB‐RCT of MRE pharmaceutical PBO Ph2: 26 weeks Time to relapse during Did not significantly reduce rate
(Mao et al., prevention of GAD in Ph 1; 93 responders grade extract (responders continuation tx and of relapse (mean time: MRE,
2016) symptom relapse responders (Phase 2); Ph1 1500 mg (500 mg DB‐RCT) long‐term follow up; 11.4 ± 8.4 weeks; PBO,
among tx responders; randomized OL trial capsule 3 times Ph 1: 12 weeks proportion who 6.3 ± 3.9 weeks). Fewer MRE
Outpt adults with identified daily); continuation (OL; all MRE) relapsed; AEs participants relapsed (n = 7/46;
DSM‐IV moderate‐ responders tx among responders 15.2%) vs. PBO‐switched
to‐severe GAD from Ph 1 (n = 12/47; 25.5%); sig lower
GAD symptoms with MRE
than PBO (p = .0032); sig
weight reductions (p = .046),
mean arterial BP (p = .0063);
low AE rates
(Continues)
869
TABLE 2 (Continued)
870

Amsterdam 2009 Anxiety, efficacy and 61 enrolled; 57 DB‐RCT dose MRE 220–1,100 mg/d; PBO: Lactose 8 weeks 1°‐OC: HAMA; 2°‐OC: Sig reduc in mean total HAMA
(Amsterdam tolerability in randomized esc STD to 1.2% apigenin BAI, PGWBI, CGI‐S, % score (p = .047); positive
et al., 2009a) pts with mild to pts with ≥50% HAMA changes in all 2°‐OC; nonsig
moderate GAD score change AEs
Chasteberry Vitex Zamani 2012 Mild/moderate PMS; 134 enrolled; DB‐RCT VAC 40 drops for PBO Six menstrual VAS for headache, anger, Sig diff from BL and BGD for
agnus castus (Zamani et al., women with PMS 128 evaluated 6 days before cycles irritability, depression, VAC vs. PBO (p < .0001);
(VAC) 2 studies 2012) menses up until breast fullness, bloating, well tolerated; no AEs
menstruation and tympani
Atmaca 2003 Premenstrual dysphoric 41 SB/rater‐ VAC 20–40 mg/d Fluoxetine 2 months Penn Daily Symptom Similar responses: VAC (57.9%,
(Atmaca et al., disorder (PMDD); blind RCT 20–40 mg/d Report (DSR), HAMD, n = 11) vs. fluoxetine (68.4%,
2003) women with CGI‐Severity of Illness n = 13) with no BGD, but
DSM‐IV PMDD (CGI‐SI) and greater effect with fluoxetine
Improvement (CGI‐I) for psychological and VAC for
physical symptoms
Ginkgo biloba Gavrilova 2014 Neuropsychiatric 160 DB‐RCT GBE 240 mg/d; EGb PBO 24 weeks 1°‐OC: Neuropsychiatric Mean NPI composite score decr by
Extract (GBE) 9 (Gavrilova symptoms and multicenter 761® dry leaf Inventory (NPI); STAI 7.0 ± 4.5 points with GBE vs.
studies et al., 2014) cognition; pts with STD to L22– state sub‐score; 5.5 ± 5.2 for PBO (p = .001); ≥4
mild cognitive 27% flavone geriatric depression point impr with GBE 78.8% vs.
impairment glycosides and scale (GDS); 2°‐OC: PBO 55.7% (p = .002). GBE sig
5–7% terpene Trail‐making test (TMT) superior for STAI, informant GIC,
lactones A/B, global impression and TMT scores; trends favored
of change (GIC) GBE on GDS and pt GIC scores;
no serious AEs
Litvinenko 2014 Cognition, anxiety, 45 RCT GBE 240 mg/d; Other drugs 24 weeks Cognitive/ Anxiety and depression sig decr
(Litvinenko, depression, sleep EGb 761® neuropsychological on the 12th and 24th week,
Naumov, & disorders, and testing incl FAB, respectively; best effects
Odinak, 2014) activity; pts with MMSE, HADS observed for anxiety
discirculatory
encephalopathy
and cognitive
impairment
Yancheva 2009 Effects and tolerability; 95 DB‐RCT GBE 240 mg/d Donepezil initial 22 weeks TE4D; SKT cognitive test Changes and response rates
(Yancheva pts with Alzheimer's ± donepezil; 5 mg/d; then battery; NPI; Gottfries– suggest no sig diff btw GBE
et al., 2009) disease and EGb 761® 10 mg/d after Brane–Steen scale total and donepezil and potential
neuropsychiatric 4 weeks score and ADL favoring combination tx. AE
features subscore; HAMD; rate lower with GBE and
clock‐drawing test; combination tx
verbal fluency test
Scripnikov 2007 Effects on dementia 400 DB‐RCT GBE 240 mg/d; PBO 22 weeks 1°‐OC: SKT cognitive test Sig superior to PBO for SKT and
(Scripnikov symptoms and EGb 761® battery; 2°‐OC: NPI all 2°‐OC variables. NPI mean
et al., 2007) caregiver composite: With GBE, dropped
distress; pts with from 21.3 to 14.7; with PBO,
dementia incr from 21.6 to 24.1. NPI
associated with mean caregiver distress: With
neuropsychiatric GBE, decr from 13.5 to 8.7;
features with PBO incr from 13.4 to
13.9 (p < .001 BGD). Largest
drug–PBO diff favored GBE
for: Apathy/indifference,
anxiety, irritability/lability,
depression/dysphoria, and
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sleep/nighttime behavior
ET AL.
(Continues)
YEUNG
ET AL.
TABLE 2 (Continued)

Woelk 2007 Whether clinically 107 DB‐RCT GBE 480 mg/d PBO 4 weeks 1°‐OC: HAMA; 2°‐OC: CGI Sig decrs in HAMA total
(Woelk et al., meaningful or 240 mg/d; change (CGI‐C); EAAS; scores vs. PBO (high‐dose:
2007) anxiolytic EGb 761® list of complaints (B‐L'); p = .0003; low‐dose: p = .01);
effects can be Pt rating of change with total decr by −14.3 ± 8.1
achieved; pts with (high‐dose), −12.1 ± 9.0
DSM‐III‐R GAD (low‐dose), and −7.8 ± 9.2
or adjustment (PBO). Sig dose–response trend:
disorder with p = .003. A 2°‐OC: GBE sig
anxious mood superior to PBO; safe and
well tolerated
Johnson 2006 Functional 23 DB‐RCT GBE 240 mg/d; PBO 4 weeks Center for Epidemiologic GBE sig impr ≥4 measures
(Johnson performance; EGb 761® Studies of depression with sig larger effect sizes
et al., 2006) individuals with scale (CES‐D); STAI; for fatigue, symptom severity,
multiple sclerosis modified fatigue and functionality; no AEs or
impact scale (MFIS); side effects reported
symptom inventory
(SI); functional
assessment of multiple
sclerosis (FAMS)
Cieza 2003 Short‐term effects 66 DB‐RCT GBE 240 mg/d; PBO 4 weeks POMS, self‐rating Sig BGD for VAS‐MH and
(Cieza et al., on emotional EGb 761® depression scale (SDS), VAS‐QoL; sig BGD for SIS
2003) well‐being; elderly VAS‐QoL, general mood at Week 2 phone call;
with no age‐related health (VAS‐GH), sig impr depression, fatigue,
cognitive mental health anger and SDS from BL
impairments (VAS‐MH), subjective
intensity score mood
(SIS mood)
van Dongen 2000 Efficacy, dose‐ 214; 123 ITT DB‐RCT GBE 240 mg/d PBO 12 24 weeks: Assessed at 12 and No outcome effects for the
(van Dongen dependence, 2‐stage (high) or or 12 weeks, 24 weeks: Trail‐making entire 24‐week period. After
et al., 2000) and durability; random 160 mg/d 24 weeks then speed (NAI‐ZVT‐G); 12 weeks, combined high‐
older people in (usual); randomized to digit memory span and usual‐dose groups
39 Netherland EGb 761® second (NAI‐ZN‐G); verbal (n = 166) had slightly impr
homes for the 12‐week learning (NAI‐WL); self‐reported ADL, but slightly
elderly with period of presence/severity of worse self‐perceived health
mild to moderate ginkgo or PBO geriatric symptoms status vs. PBO. No benefits
Alzheimer's, (SCAG); depressive with high dose or prolonged
vascular dementia, mood (GDS); self‐ GBE tx or to any GBE
or age‐associated perceived health/memory subgroup; no AEs
memory impairment self‐reported ADL
Lingaerde 1999 Winter depression in 27 DB‐RCT GBE 2 tabs/d ~1 month PBO 10 weeks Extended MADRS; self‐ No sig BGD
(Lingaerde pts with seasonal prior to expected rated key symptoms on
et al., 1999) affective disorder symptoms; PN246: VAS q 2 weeks
(SAD) 24 mg flavone glycosides;
6 mg terpene lactones
per tab
(Continues)
871
872
TABLE 2 (Continued)

Guarana, Paulinia Silvestrini 2013 Psychological well‐being, 27 SB‐RCT PCE 360 mg three PBO 5 days on each tx Psychological well‐being No sig diff in any six areas of
cupana extract (Silvestrini anxiety and mood in crossover times daily after with 5‐day (PWB) scales; self‐ the PWB, in SAS, or any of
(PCE) 3 studies et al., 2013) healthy volunteers breakfast; contained washout btw rating anxiety state the 16 mood scales
caffeine tx switch scale (SAS); Bond–
2.5% (w/w) Lader mood scales
de Oliveira Fatigue, sleep quality, 75 DB‐RCT PCE 100 mg/d PBO 3 weeks on each 1°‐OC: Functional Impr FACIT‐F, FACT‐ES, and BFI
Campos 2011 anxiety, depression, crossover (50 mg/twice daily); tx with 7‐day assessment of chronic global scores on Days 21 and
(de Oliveira and MP; breast cancer switch tx mid‐CT; washout btw illness therapy‐fatigue 49 (p < .01); Chalder scale
Campos et al., pts with progressive STD PCE 6.46% tx switch (FACIT‐F); 2°‐OC: impr on Day 21 (p < .01) but
2011) fatigue after Cycle 1 caffeine FACT‐endocrine not Day 49 (p = .27); no AEs,
chemotherapy (CT) symptoms (FACT‐ES), nor worsened sleep, anxiety
BFI, PSQI, Chalder or depression
fatigue scale, HADS
da Costa Miranda Post‐radiation tx (RT) 36 DB‐RCT PCE 75 mg/d; switch PBO 14 days on each Fatigue and depressive No sig diff for any measures
2009 (da Costa depression and crossover tx mid‐RT tx; no washout symptoms
Miranda et al., fatigue; breast cancer due to short
2009) pts undergoing half‐life
adjuvant RT
Kava kava, Piper Sarris 2013 Sexual function/ 75 DB‐RCT KKAqE one tab twice PBO 6 weeks Arizona sexual experience Incr women's sexual drive vs.
methysticum (Sarris, Stough, experience; adults daily; total kavalactones scale (ASEX) PBO (p = .040); no negative
extract (KKE); Teschke, et al., with GAD (KAV) 120 mg/d; non‐ effects for men; sig corr btw
KKAqE, 2013) in Australia responders titrated to reduc in ASEX and anxiety; no
aqueous; KKLE, 2 tabs twice daily; total AEs or sig diff for liver function
lipophilic; 12 KAV 240 mg/d tests, WD or addiction
studies Sarris 2012 Acute neurocognitive, 22 DB‐RCT KKAqE 3 tabs for acute Oxazepam 3 visits 1‐week Cognitive battery test Acute doses of KKAqE did not
(Sarris et al., anxiolytic, and crossover medicinal dose of KAV 30 mg or apart with followed by STAI, produce anxiolytic effects vs.
2012) thymoleptic effects 180 mg (60 mg/tab) PBO acute dose of state–trait, oxazepam (reduc anxiety) or
vs. BZD; moderately different cheerfulness inventory PBO (incr anxiety); it also did
anxious adults in intervention (STCI‐S), and Bond–Lader not negatively affect cognition
Australia and placebo questionnaires
for each week
per patient
Sarris 2009 Effects/toxicity 60 DB‐RCT KKAqE 5 tabs/d for KAV PBO 3 weeks HAMA, BAI, MADRS KKAqE reduc HAMA scores:
(Sarris et al., of aqueous crossover 250 mg/d dried By −9.9 (CI [7.1, 12.7]) vs.
2009) extract, as other types aqueous root extract PBO −0.8 (CI [−2.7, 4.3]) in
had hepatotoxicity STD to KAV 50 mg first phase; by −10.3 (CI = 5.8,
concerns; adult subjects 14.7) vs. PBO +3.3
with ≥1 month elevated (CI = −6.8, 0.2) in 2nd phase.
GAD in Australia Sig pooled effects with KKAqE
across phases (p < .0001) and
substantial effect size
(d = 2.24, eta(2)(p)); sig relative
reduc BAI and MADRS; no
SAEs or clinical hepatotoxicity
Geier 2004 Dosage range for anxiety; 50 DB‐RCT KKE 150 mg/d; WS® PBO 4 weeks + 1°‐OC: HAMA; 2°‐OC: HAMA 1°‐OC: Therapeutically
(Geier & pts with non‐psychotic 1490 50‐mg dry root 2 weeks somatic and psychic anxiety relevant reduc anxiety (>4 pt)
Konstantinowicz, anxiety extract STD to 70% observation subscales; EAAS; brief vs. PBO; 2°‐OC:
2004) KAV personality structure scale Trend in favor of active tx;
(KEPS); adjective checklist well tolerated/safe; no
(EWL 60‐S); CGI AEs or WD symptoms
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TABLE 2 (Continued)
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Lehrl, 2004 Efficacy and safety for 61 DB‐RCT KKE 200 mg/d; PBO 4 weeks 1°‐OC: SF‐B; 2°‐OC: HAMA, Sig group diff favoring KKE for
(Lehrl, 2004) sleep disturbance; multicenter WS® 1490 Bf‐S self‐rating SF‐B sub‐scores of “quality
patients with anxiety scale of well‐being, CGI of sleep” (p = .007),
disorders “recuperative effect after
sleep” (p = .018), and HAMA
psychic anxiety sub‐score
(p = .002). Addtl benefits on
Bf‐S and CGI scores. No AEs
or changes in clinical or
laboratory parameters
Boerner 2003 Acute anxiety tx vs. 129 DB‐RCT KKE 400 mg/d; LI150 Buspirone 8 weeks 1°‐OC: HAMA scale and No sig diff for all measures; ~75%
(Boerner et al., pharmacologic tx; multicenter STD to 30% 10 mg/d; % Week 8 responders of pts were responders (50%
2003) Outpts with GAD kavapyrones; drug‐ Opipramol 2°‐OC: Boerner anxiety reduc of HAMA score) in each
extract ratio 13–20:1 100 mg/d scale (BOEAS), SAS, tx group; ~60% achieved full
CGI, well‐being remission
self‐rating scale (Bf‐S),
sleep questionnaire
(SF‐B), QoL (AL) and
global judgements by
investigator and pts
Week 9 WD or relapse
symptoms
Cagnacci 2003 Effects on mood 80 RCT Calcium + KKE Calcium 1 g/d 3 months STAI; Zung depression KKE: Anxiety declined (p < .001)
(Cagnacci et al., in peri‐MP 100 mg/d or scale (ZDS); Greene at 1 month (−3.8 ± 1.03) and
2003) women 200 mg/d; 55% kavain Climacteric Scale (GCS) 3 months (−5.03 ± 1.2);
per 100‐mg cap depression declined at 3
months (−5.03 ± 1.4; p < .002);
climacteric score declined
(p < .0006) at 1 month
(−2.87 ± 1.5) and 3 months
(−5.38 ± 1.3) but only anxiety
decline was sig greater with
KKE than with controls
(p < .009)
Gastpar 2003 Neurotic anxiety; adults 141 DB‐RCT KKE 150 mg/d; WS® 1490 PBO 4 weeks + 2 weeks Anxiety status inventory ASI total observer score decr
(Gastpar & with DSM‐III‐R multicenter 50‐mg dry root extract observation (ASI); structured more with
Klimm, 2003) neurotic anxiety STD to KAV 35 mg well‐being self‐rating KKLE, but not sig
scale (Bf‐S); post‐tx;
CGI; EAAS; brief test decr >5: KKLE 73%
of personality structure vs. PBO 56%. Diff
(KEPS) btw tx end and
BL favored KKLE
(p < .01, 2‐sided).
Sig impr Bf‐S and
CGI but only minor
diff for EAAS and KEPS;
diff vs. PBO not as large
as prior trials w/ same extract
at 300 mg/d.
Well tolerated; no
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873
874
TABLE 2 (Continued)

influence on liver function

tests; one AE: Tiredness
Connor 2002 Effects on GAD; adults 37 DB‐RCT Kava Week 1: PBO 4 weeks HAMA; HADS; self‐ Impr with both txs with no
(Connor & with DSM‐IV GAD 70 mg twice assessment of diff in principal analysis
Davidson, daily (140 mg/d); resilience and anxiety post‐hoc analyses: Sig
2002) Weeks 2–4: 140 mg (SARA) diff from BL anxiety
twice daily (280 mg/d); severity in SARA scores
KavaPure®; for low anxiety, but PBO
STD to KAV 70 mg was superior for HADS
and SARA in high anxiety.
Kava was well tolerated
Malsch 2001 Non‐psychotic nervous 40 DB‐RCT KKE Week 1 dose esc: PBO 5 weeks 1°‐OC: HAMA, subjective Superior to PBO for HAMA
(Malsch anxiety, tension and 50–300 mg/d + pretx well‐being scale (Bf‐S), (p = .01) and Bf‐S (p = .002)
& Kieser, restlessness states; BZD taper over 2 weeks; BZD WD symptoms total scores, and all 2°‐OC;
2001) adult outpts with then 3 weeks KKE 2°‐OC: EAAS, CGI good tolerance not inferior
DSM‐III‐R anxiety monotx; WS®1490 to PBO
disorders and impaired (Laitan 50®) STD to
work or social 70% KAV
activities
De Leo 2000 PMP anxiety vs. HRT; 40 RCT Physiological‐MP pts: HRT: Estrogen 6 months HAMA For all groups: Sig reduc in HAMA
(De Leo et al., women in HRT + KKE 50 μg/d+ scores after 3 and 6 months tx;
2000) physiological 100 mg or progestin+ both KKE groups had greater
or surgical MP Surgical‐MP pts: PBO or reduc vs. HRT or ERT alone
for 1–12 years ERT + KKE ERT:
100 mg; 55% kavain Estrogen
50 μg/d
+PBO
Volz 1997 Long‐term anxiolytic 101 DB‐RCT KKLE KAV PBO 25 weeks 1°‐OC: HAMA; 2°‐OC: Sig superiority in HAMA scores
(Volz & effects; pts with multicenter 210 mg/d; HAMA somatic/psychic starting at Week 8; 2°‐OCs
Kieser, DSM‐III‐R non‐ WS® 1490 STD anxiety subscores, also superior; rare AEs
1997) psychotic anxiety to KAV 70 mg CGI, self‐report distributed
per cap symptom Inventory‐90 evenly in both groups
items revised, and
adjective mood scale
Lavender Kasper 2016 Effects on mixed 318 DB‐RCT LAE 80 mg/d; Silexan PBO 70 days HAMA and MADRS total Total score changes HAMA:
Lavandula (Kasper, Volz, anxiety and score changes LAE ↓ 10.8 ± 9.6;
angustifolia Dienel, & depressive disorder PBO ↓ 8.4±8.9 (p < .01)
extract (LAE) 7 Schlafke, (MADD); MADRS: LAE ↓9.2 ± 9.9;
studies 2016) Outpt adults with PBO ↓ 6.1 ± 7.6 (p < .001)
ICD 10 MADD and LAE: Better overall outcomes;
at least moderately impr daily living skills,
severe anxious health‐related QoL
and depressed mood AE: Belching
Kasper 2015 Anxiolytic effects; pts 170 DB‐RCT LAE cap 80 mg/d; PBO 10 weeks HAMA, PSQI, the Zung HAMA total score decr 12.0 vs.
(Kasper et al., with anxiety‐related Silexan; from flowers self‐rating anxiety PBO 9.3 (group diff: p = .03);
2015) restlessness by steam distillation scale, a state check for all OCs, LAE effects more
and disturbed sleep inventory and pronounced. HAMA
CGI questionnaire responders (≥50%):
48.8% vs. 33.3%
(p = .04). HAMA remission
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TABLE 2 (Continued)
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(<10): 31.4% vs. 22.6%

(p = .20). AEs: 33.7%
(LAE; GI‐related)
vs. 35.7% (PBO)
Kasper 2014 Anxiolytic effects; adults 539 DB‐RCT double‐ LAE 80 mg/d or PBO or paroxetine 10 weeks 1°‐OC: HAMA Both doses superior to PBO
(Kasper with DSM‐V GAD dummy 160 mg/d; Silexan (PAR) 20 mg in HAMA total score reduc
et al., 2014) (P < .01) while paroxetine had
sig trend (p = .10): 160 mg:
14.1 ± 9.3; 80 mg: 12.8 ± 8.7
PAR: 11.3 ± 8.0
PBO: 9.5 ± 9.0.
≥ 50% HAMA reduc | Total
score < 10 at tx end:
160 mg: 73/121 (60.3%) | 56
(46.3%); 80 mg: 70/135
(51.9%) | 45 (33.3%);
PAR: 57/132 (43.2%) | 45
(34.1%); PBO: 51/135 (37.8%)
| 40 (29.6%). AEs rates lower
than paroxetine/comparable
to PBO
Nikfarjam 2013 Effects on depression; pts 80 RCT Citalopram +2 cups Citalopram 8 weeks HAMD Sig decr HAMD scores at
(Nikfarjam with major depression L. angustifilia (LA) 20 mg 4 weeks (p < .05) and 8 weeks
et al., 2013) taking citalopram infusion prepared twice daily (p < .01), suggesting addtl tx
from 5 g dried benefit; comparable AEs,
shoots but nausea more common
with LA
Kasper 2010 Anxiolytic efficacy; adults 221 RCT in 27 LAE 80 mg/d; Silexan PBO 10 weeks 1°‐OC: HAMA, PSQI HAMA total score sig decr
(Kasper with DSM‐IV or ICD‐10 primary care 2°‐OC: CGI, Zung (p < .01) for LAE 16.0 ± 8.3
et al., 2010) anxiety disorder practices self‐rating anxiety (59.3%) vs. PBO 9.5 ± 9.1
scale, SF‐36 health (35.4%). PSQI total score
survey questionnaire sig decr (p < .01) for
LAE 5.5 ± 4.4 (44.7%) vs.
PBO 3.8 ± 4.1 (30.9%).
% responders favored LAE: 76.9
vs. 49.1%, p < .001.
% remitters favored LAE: 60.6
vs. 42.6%, p = .009
Woelk 2010 Effects on GAD vs. BZD; 77 DB‐RCT LAE (Silexan) Lorazepam 6 weeks 1°‐OC: HAMA; 2°‐OC: HAMA total score decr similarly
(Woelk & patients with DSM‐IV multicenter 80 mg/d + PBO (LOR) (LOR) 0.5 mg SAS (self‐rating anxiety from 25 ± 4 points in both BL
Schlafke, primary diagnosis + PBO (LAE) scale), PSWQ‐PW groups: LAE 11.3 ± 6.7 (45%)
2010) of GAD (Penn State Worry vs. LOR 11.6 ± 6.6 (46%);
Questionnaire), SF 36 somatic/psychic anxiety
health survey subscores decr similarly;
questionnaire and 2°‐OCs also comparable;
CGI items 1–3, LAE had no sedative effects
sleep diary
Akhondzadeh Adjuvant effects on 45 DB‐RCT LAE 60 drops/d + PBO Imipramine tab 4 weeks HAMD LAE less effective than
2003 depression vs. tab or LAE 60 drops/d 100 mg/d imipramine: (F = 13.16,
imipramine alone; + imipramine tab; + PBO drops df = 1, p = .001), with more
(Continues)
875
876
TABLE 2 (Continued)

(Akhondzadeh adults with 100 mg/d dried flower observations of headache. LAE
et al., 2003) DSM‐IV mild to extract 1:5 (w/v) in 50% + imipramine more effective
moderate alcohol than imipramine alone
depression (F = 20.83, df = 1, p < .0001)
suggests adjuvant potential
Maca, Lepidium Stojanovska 2015 Effects on hormones, 29 DB‐RCT Maca 3.3 g/d PBO 6 weeks each Greene climacteric scale Sig decrs depression and BP
meyenii 2 (Stojanovska lipids, glucose, crossover powdered root intervention (GCS), SF‐36 V2 (diastolic); no diff in hormonal,
studies et al., 2015) serum cytokines, Women's Health glucose, lipid, cytokine profiles
BP symptoms; Questionnaire, Utian
Chinese PMP quality of life scales,
women hormone/lipid profiles
Brooks 2008 Effects on hormonal 14 DB‐RCT Maca .5 g/d dried PBO 6 weeks each GCS, hormone profiles GCS: Sig reduc in anxiety,
(brooks profile and crossover methanolic root extract intervention depression, and sexual
et al., 2008) climacteric dysfunction subscales vs.
symptoms; BL and PBO; no diff in
PMP women hormonal profiles
Passionflower Nojoumi 2017 Effects of adjunctive 30 DB‐RCT PIE 15 drops three PBO drops 1 month Reaction time at baseline No sig diff except for auditory
Passiflora (Nojoumi tx to sertraline on times daily + sertraline + sertraline and after 1 month omission errors in PIE group
incarnate et al., 2017) reaction time; adults 50 mg/d (↑ to 50 mg/d, post‐tx after 1 month; PIE had
extract (PIE) 6 age 18–50 years with 100 mg/d after ↑ to 100 mg/d no sig AEs
studies DSM‐IV GAD 2 weeks); Pasipy® drop: after 2 weeks
STD hydroalcoholic
extract
Aslanargun 2012 Preoperative anxiety 60 DB‐RCT Aqueous PIE syrup PBO Single‐dose 30 min STAI, psychomotor STAI: Sig BGD for incr score
(Aslanargun with regional 700 mg/5 mL dose; before spinal functions, sedation, obtained just before
et al., 2012) anesthesia; adults contained 2.8 mg anesthesia and hemodynamics anesthesia; no diff for
undergoing benzoflavone psychomotor function,
spinal anesthesia sedation score,
hemodynamics, or side
effects
Ngan 2011 (Ngan Effects on human sleep; 41 DB‐CT repeated‐ PI tea 1 hr before bed; 2 g PBO 1 week each tx STAI; sleep diaries No sig diff for STAI; of six
and conduit, healthy adults with measures + leaves, stems, seeds and separated by 1‐ validated sleep‐diary measures, sleep
2011) mild sleep quality optional PSG flowers infused in 250 ml week washout by polysomnography quality was sig better with
fluctuations sleep study of boiled water for 10 min (PSG overnight on PIE vs. PBO (t(40) = 2.70,
last day of each tx, p < .01)
10 subjects)
Movafegh 2008 Preoperative anxiety; 60 DB‐RCT PIE tab 500‐mg dose; PBO Single‐dose 90 min Numerical rating scale (NRS) Sig lower NRS anxiety scores
(Movafegh adults undergoing Passipy™ 1.01 mg before surgery assessed anxiety and (p < .001) no diff in
et al., 2008) inguinal herniorrhaphy benzoflavone sedation, Trieger dot test, psychological variables
digit‐symbol substitution postanesthesia or recovery of
test, time btw psychomotor function
postanesthesia
care and discharge
Akhondzadeh Adjuvant effects with 65 DB‐RCT Clonidine max 0.8 mg/d Clonidine + 14 days Short opiate Both regimens equally effective
2001 clonidine for opiate divided in 3 doses + PIE PBO drops withdrawal scale for physical WD, but PIE
(Akhondzadeh, detox; adult outpatients 60 drops/d Passipay™ (SOWS) significantly superior for
Kashani, with DSM‐IV opioid extract mental symptoms
et al., 2001) dependence
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TABLE 2 (Continued)
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Akhondzadeh Anxiolytic effects vs. 36 DB‐RCT PIE 45 drops/d + PBO tabs Oxazepam 4 weeks HAMA Both regimens effective for
2001 oxazepam for GAD 30 mg/d GAD with no sig BGD, but
(Akhondzadeh, tx; adults with + PBO drops oxazepam sig impaired job
Naghavi, DSM‐IV GAD performance more than PIE
et al., 2001)
Red clover Lipovac 2010 Anxiety and depressive 109 DB‐RCT RCE isoflavone cap 40 mg PBO 90 days each tx HADS and Zung's Sig decr total HADS, anxiety and
Trifolium (Lipovac symptoms; PMP crossover twice daily; MF11RCE, with 7‐day self‐rating depression subscales and total
pratense extract et al., 2010) women age > 40 y 40 mg isoflavone/cap washout depression scale SDS scores (76.9%, 76%,
(RCE) 2 studies (SDS) 78.3% and 80.6% reduc,
respectively) vs. PBO decr of
only 21.7%
Hidalgo 2005 MP symptoms, lipids, and 60; 53 DB‐RCT RCE isoflavone caps PBO 90 days each tx Kupperman KI decr sig after each tx phase,
(Hidalgo vaginal cytology; PMP completers crossover 80 mg/d; Menoflavon®, with 7‐day index (KI) scores, but more pronounced after
et al., 2005) women age > 40 years 40 mg isoflavone from washout fasting bloods active tx: BL: 27.2 ± 7.7;
not using hormonal tx T. pratense per cap and vaginal isoflavone: 5.9 ± 3.9;
cytology PBO: 20.9 ± 5.3, p < .05.
No sig effect on BMI, weight
or BP after either tx; sig decr
in menopausal symptoms, with
positive effects on vaginal
cytology and triglyceride levels
Rhodiola Rhodiola Cropley 2015 Self‐reported anxiety, 80 RCT RRE tab 200 mg twice No tx 14 days Self‐report measures Sig reduc in self‐reported anxiety,
rosea extract (Cropley stress, cognition, and daily before breakfast/ and cognitive tests stress, anger, confusion and
(RRE), 4 studies et al., 2015) other mood symptoms; lunch; Vitano®, Rosalin depression and impr total
mildly anxious WS® 1375, dry root mood. No relevant diff in
participants extract 1.5–5:1 cognitive performance;
favorable safety profile
Mao 2015 Various dosages vs. 57 RCT dose esc Weeks 1–2: RRE one Sertraline 12 weeks HAMD, BDI, CGI Nonsig reduc were modest with
(Mao et al., sertraline for mild to cap/d; if no response: 50 mg or change no BGD. RRE had significantly
2015) moderate MDD; adults Week 2: 2 caps/d PBO fewer AEs. Odds of improving
with DSM‐IV Week 4: 3 caps/d vs. PBO were greater for
Axis I MDD Week 6: 4 caps/d sertraline (OR 1.90, 95%
SHR‐5; 340 mg per cap CI [0.44, –8.20]) than RRE
STD to rosavin 3.07% and (1.39 [0.38, 5.04]), but more
rhodioloside 1.95% sertraline subjects reported
AEs than RRE or PBO: 63.2%
vs. 30.0%, vs. 16.7%,
respectively; p = .012
Olsson 2009 Effects on stress‐related 60 DB‐RCT RRE 576 mg/d (4 tabs); PBO 28 days SF‐36, Pines' burnout Both groups: Sig impr PBS,
(Olsson et al., fatigue; adults with SHR‐5, 144 mg per tab scale (PBS), MADRS, SF‐36 mental health scores,
2009) stress‐related fatigue Conners' computerised MADRS, and several CCPT II
in Sweden continuous performance indices. Sig BGD favored RRE
test II (CCPT II), saliva for PBS and CCPT II indices.
cortisol awakening CAR sig decr with RRE vs.
response (CAR) PBO; no sig SAEs
Darbinyan 2007 Depressive complaints; 89 DB‐RCT RRE 340 or 680 mg/d; PBO: 2 tabs/d 42 days BDI, HAMD For both dosages, overall
(Darbinyan adults with current multicenter SHR‐5, rhizome extract depression, insomnia,
et al., 2007) episode of DSM‐IV 170 mg/tab emotional instability and
mild/moderate somatization, but not
depression self‐esteem, sig impr vs. PBO;
no SAEs reported
877
(Continues)
878
TABLE 2 (Continued)

Saffron, Crocus Mazidi 2016 Efficacy in adults 60 randomized; DB‐RCT Saffron cap 50 mg twice PBO 12 weeks BDI and BAI Sig effects on BDI and BAI scores
sativus extract (Mazidi et al., with DSM‐IV mild 54 completers daily; C. sativus dried (p < .001); side effects rare
(CSE) 12 2016) to moderate anxiety stigma
studies and depression
Sahraian 2016 Effects of adjunctive 40 randomized; DB‐RCT Saffron powder capsule PBO + fluoxetine 4 weeks BDI No antidepressive or lipid
(Sahraian, tx to fluoxetine on 30 completers 30 mg/d + fluoxetine 20 mg/d lowering effects with the
Jelodar, Javid, depression and lipid 20 mg/d addition of saffron
Mowla, & profiles; adults with
Ahmadzadeh, DSM‐IV major
2016) depression
Talaei 2015 (Talaei Adjunctive to MDD tx; 40 DB‐RCT Crocin tabs 30 mg/d PBO tabs + 1 SSRI 4 weeks BDI, BAI, general Crocin sig impr BDI, BAI and
et al., 2015) Iranian psychiatric (15 mg twice daily) once daily: health questionnaire GHQ scores vs. PBO:
hospital in patients + 1 SSRI; Crocin Fluoxetine 20 mg, (GHQ), mood p < .0001; avg decrs 17.6,
with DSM‐IV MDD, from saffron stigma sertraline 50 mg, disorder 12.7, 17.2 vs. 6.15, 2.6, 10.3,
age 24–50 y or citalopram 20 mg questionnaire respectively
(MDQ)
Shahmansouri 2014 Efficacy/safety vs. 40 DB‐RCT CSE cap 30 mg/d; Fluoxetine 40 mg/d 6 weeks HAMD No sig BGD in scores, remission
(Shahmansouri fluoxetine on SaffroMood®: Ethanolic or response rates; no sig
et al., 2014) depressive stigma extract STD to diff in AEs
symptoms; pts with 0.13–0.15 mg safranal
DSM‐IV‐TR mild and 1.65–1.75 mg crocin
to moderate per 15‐mg cap
depression after
percutaneous
coronary intervention
Moosavi 2014 Dose comparison, as 60 DB‐RCT CSE 80 mg/d + fluoxetine CSE 40 mg/d 6 weeks HAMD CSE effective in both groups,
(Moosavi et al., adjuvant tx with 30 mg/d + fluoxetine but sig diff with 80‐mg tx
2014) fluoxetine; adults with 30 mg/d group (p < .05); no sig diff
DSM‐IV mild to in AEs
moderate depressive
disorders
Agha‐Hosseini Effects on women 78 screened; 50 DB‐RCT Saffron stigma PBO 2 menstrual cycles 1°‐OC: Daily Saffron sig impr Total
2008 (Agha‐ age 20–45 years with randomized 30 mg/d; 15 mg (cycles 3 and 4) symptom premenstrual daily symptoms
Hosseini regular menstrual dried petal extract report; 2°‐OC: (sig BGD at cycle 4: t = 5.92,
et al., 2008) cycles and PMS per cap HAMD df = 48, p < .001) and HAMD
symptoms for scores (t = 8.99, df = 48,
≥6 months p < .001)
Akhondzadeh Antidepressant effects 44 DB‐RCT CSE petal cap 15 mg CSE stigma cap, 6 weeks HAMD; remission Petal and stigma similarly
Basti 2008 of petal (less twice daily; 15 mg twice defined as HAMD effective for mild to moderate
(Akhondzadeh expensive) vs. stigma; STD by safranal daily total score ≤ 7 depression (df = 1, F = 0.05,
Basti et al., Outpts with DSM‐IV 0.30–0.35 mg p = .81); remission rate: 18%;
2008) major depression no sig diff in side effects
Akhondzadeh Antidepressant effects of 40 DB‐RCT CSE petal cap 15 mg Fluoxetine 8 weeks HAMD; remission CSE petal as effective as
Basti 2007 petal vs. fluoxetine; twice daily; STD 10 mg twice defined as HAMD fluoxetine (F = 0.03,
(Akhondzadeh Outpts with DSM‐IV by safranal daily total score ≤ 7 df = 1, p = .84); both tx
Basti et al., 2007) major depression 0.30–0.35 mg produced remission rates of
25%; no sig diff in side effects
Moshiri 2006 Mild‐to‐moderate 40 DB‐RCT CSE petal cap PBO 6 weeks HAMD Sig better HAMD scores than
(Moshiri et al., depression; adults 30 mg/d; 15 mg PBO (df = 1, F = 16.87,
2006) p < .001); no sig diff in AEs
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TABLE 2 (Continued)
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ET AL.
with DSM‐IV major dried petal extract

depression per cap
Akhondzadeh 2005 Mild‐to‐moderate 40 DB‐RCT CSE stigma cap 30 mg/d PBO 6 weeks HAMD Sig better scores than PBO
(Akhondzadeh depression; Outpts Ethanolic extract (df = 1, F = 18.89, p < .001)
et al., 2005) with DSM‐IV no sig diff in AEs
major depression
Noorbala 2005 Mild‐to‐moderate 40 DB‐RCT CSE stigma cap Fluoxetine 6 weeks HAMD CSE similarly effective for mild
(Noorbala et al., depression vs. 30 mg/d; each 20 mg/d to moderate depression as
2005) fluoxetine; adults 15‐mg cap STD fluoxetine (F = 0.13, df = 1,
with DSM‐IV by safranal p = .71); no sig diff in AEs
major depression 0.30–0.35 mg
Akhondzadeh Antidepressant effects 30 DB‐RCT CSE stigma cap 30 mg/d Imipramine cap 6 weeks HAMD CSE stigma similarly as effective
2004 of stigma vs. Ethanolic extract; 100 mg/d as imipramine (F = 2.91,
(Akhondzadeh imipramine; Outpts 10 mg saffron per cap df = 1, p = .09); sig more dry
et al., 2004) with DSM‐IV mouth and sedation with
major depression control group
Soy isoflavones Liu 2014 (Liu Effects of whole soy or 270 randomized; DB‐RCT Soy flour 40 g/d or Daidzein PBO: Low‐fat 6 months each Validated and No sig difference in 6‐month
(SI) 2 studies et al., 2014) purified daidzein 253 63 mg/d soy flour milk powder given as a solid structured changes or % changes for
(one major soy completers contained 12.8 g soy beverage symptom total number, dimension, or
isoflavone + equol protein and 49.3 mg checklist individual frequency of MP
precursor) on MP isoflavones symptoms among groups;
symptoms; urinary isoflavones indicated
Equol‐producing good compliance
prehyper tensive
Chinese PMP
women (most likely
to benefit)
de Sousa‐Munoz Depressive symptoms; 84 DB‐RCT SI extract 120 mg/d; PBO: Starch 16 weeks Brazilian version No sig reduc in depressive
2009 (de Sousa‐ climacteric outpts Isoflavin BetaTM: of the Center symptoms; initial symptom
Munoz & Filizola, at a Brazilian 60 mg isoflavones of Epidemiologic reduc associated with PBO
2009) hospital per cap; 20 mg Studies of effects; no clinically
daidzeine–daidzine, depression relevant AEs
17 mg as (CES‐D)
daidzeine; 14 mg
genisteine–genistine,
9 mg as genisteine
Valerian Andreatini 2002 Anxiolytic effect of 36 DB‐RCT Valepotriates (VAL) Diazepam 4 weeks HAMA, STAI Similar decrease among groups
Valeriana (Andreatini valepotriates; flexible 81.3 mg mean daily 6.5 mg mean in HAMA total and somatic
officinalis, et al., 2002) Outpts with dose dose; Dihydrovaltrate daily dose factor scores; VAL and
2 studies DSM‐III‐R GAD 80%, valtrate 15%, or PBO diazepam sig reduc HAMA
acevaltrate 5% psychic factor scores;
diazepam sig reduc STAI‐trait
Dorn, 2000 Effects on sleep quality 75 DB‐RCT Valerian tabs 2 × 300 mg Oxazepam tab 28 days 1°‐OC: SF‐B sleep In both groups sleep quality impr
(Dorn, 2000) vs. oxazepam; 30 min before bed; 2 × 5 mg quality; 2°‐OC: sig (p < .001), with no sig
non‐organic and LI 156, root extract Other SF‐B sleep BGD. Possible AEs: Valerian,
non‐psychiatric characteristics; n = 2; oxazepam, n = 3;
insomniacs age well‐being no SAEs
18–70 years (Bf‐S); HAMA
(Continues)
879
880
TABLE 2 (Continued)

Wormwood Krebs 2010 As adjuvant tx for 20 RCT open‐label Wormwood caps CD medications 6 weeks HAMD, VAS HAMD total score decr by avg
Artemisia (Krebs et al., various effects multicenter 750 mg only 9.8 ± 5.8 points for
absinthium, 2010) including on three times daily; wormwood vs. PBO 3.4 ± 6.6
2 studies depression; pts in SedaCrohn:
Germany with A. absinthium
Crohn's disease leaf/stem powder
for ≥3 months STD to 0.32–0.38%
and not treated absinthin
with infliximab or
similar drug
Omer 2007 As adjuvant tx for 40 DB‐RCT Wormwood cap PBO 10 weeks HAMD, VAS Hamilton total scores decr by
(Omer et al., various effects multicenter 3 × 500 mg/d; avg 9.8 (SD 5.8) points for
2007) including on SedaCrohn wormwood vs. PBO 3.4
depression; pts in (SD 6.6). At Week 10, 70%
Germany with of wormwood group and 0%
Crohn's disease in PBO group had remission of
receiving daily depressive symptoms. VAS:
steroids (prednisone Sig impr vs. PBO
40 mg ≥3 weeks)
Note. 1°‐OC = primary outcome measures; 2°‐OC = secondary outcome measures; ADL = activities of daily living; AE = adverse events; BAI = Beck Anxiety Inventory; BDI = Beck Depression Inventory; BFI = Brief Fatigue
Inventory; BGD = between‐group differences; BL = baseline; BP = blood pressure; btw = between; BZD = benzodiazepines; cap = capsule; CGI‐S = Clinical Global Impression‐Severity; CI = confidence interval; corr = cor-
relation; CVD = cardiovascular disease; DB = double‐blind; decr = decrease; diff = difference; DSM‐III/IV/V‐TR = Diagnostic and Statistical Manual of Mental Disorders, 3rd, 4th or 5th edition, Text Revision;
EAAS = Erlangen Anxiety Tension and Aggression Scale; GAD = Generalized Anxiety Disorder; HADS = Hospital Anxiety and Depression Scale; HAMA = Hamilton Anxiety Rating Scale; HAMD = Hamilton Depression
Rating Scale; HRSD‐17 = 17‐item Hamilton Rating Scale for Depression; HT = hormone therapy; HRT = hormone replacement therapy; impr = improved or improvement; incl = including; incr = increase; info = information;
ITT = intention to treat; MDD = major depressive disorder; MADRS = Montgomery‐Asberg Depression Rating Scale; MP = menopause or menopausal; PBO = placebo; PGWBI = Psychological General Well‐Being Index;
PMS = premenstrual syndrome; PMP = postmenopausal; POMS = Profile of Mood States; PSQI = Pittsburgh Sleep Quality Index; pts = patients; QoL = quality of life; RCT = randomized controlled trial; reduc = reduction or
reduced; sig = significant; SB = single‐blind; SNRI = serotonin‐norepinephrine reuptake inhibitors; SSRI = selective serotonin reuptake inhibitor; STAI = State–Trait Anxiety Inventory; STD = standardized; tab = tablet;
tx = treatment; VAS = visual analogue scale; VMS = vasomotor symptoms; w/v = weight per volume; w/w = weight per weight; WD = withdrawal.
YEUNG
ET AL.
TABLE 3 Single RCTs evaluating herbal medicines for anxiety and depression over the last 20 years (1996–2016)
Herbal medicine First author/year Evaluation/population N/n Design Intervention/preparation Control comparison Treatment duration Anxiety/depression measures Results
YEUNG
American skullcap Brock 2014 (Brock Mood; healthy 43 DB‐RCT SL cap 350 mg three times PBO: Freeze‐dried 2 weeks with each tx BAI, POMS No sig diff, but participants were
ET AL.
Scutellaria et al., 2014) participants crossover daily; freeze‐dried aerial stinging nettle leaf separated by 1‐ relatively non‐anxious. Sig group
lateriflora (SL) parts (Urtica dioica folia) week washout effect suggests skullcap
carryover effect. POMS Total
mood disturbance: Highly sig
decr from pre‐test scores
(p < .001) vs. PBO (p = .072). No
reduc in energy or cognition
Ashwagandha Chengappa 2013 As a procognitive 60; 53 DB‐RCT WSE 500 mg/d; Sensoril, STD PBO 8 weeks Penn emotional acuity test, Mood and anxiety scale scores
Withania (Chengappa agent/adjunct to completers WSE: min 8% withanolides MADRS, HAMA remained stable; minor AEs
somnifera et al., 2013) maintenance bipolar and 32% oligosaccharides;
extract (WSE) disorder meds; max 2% withaferin A
euthymic pts with
DSM‐IV bipolar
disorder
Bitter orange Akhlaghi 2011 Preoperative; anxiety pts 60 DB‐RT CA blossom distillate 1 ml/kg PBO: Saline 2 hr pre‐anesthesia STAI, Amsterdam STAI and APAIS scales sig better
blossom, Citrus (Akhlaghi undergoing minor body wt from fresh petals preoperative anxiety and with CA vs. PBO
aurantium (CA) et al., 2011) operation and stamens information scale (APAIS)
Black cumin, Bin Sayeed 2014 Mood, anxiety and 48 DB‐RCT NS 500 mg/d powdered PBO 4 weeks STAI; Bond–Lader scale State anxiety: no sig variation
Nigella (Bin Sayeed cognition; boys age seeds found; mood and trait anxiety:
sativa (NS) et al., 2014) 14–17 in a Bangladesh sig variation from BL but no
boarding school BGD
Blue green algae Genazzani 2010 Alt to HT for 30 RCT Klamath algae extract PBO: Vanilla tab 8 weeks Symptom rating scale—Italian Sig changes in SRT and Zung scales
Apahanizome‐ (Genazzani psychological/ 1,600 g/d Klamin® version, Zung self‐rating for QoL, mood, anxiety and
non flos‐aquae et al., 2010) somatic/VMS; MP scale depressive attitude; no hormonal
women/no HT changes occurred
Chlorella vulgaris Panahi 2015 Adjunct to standard 42 + 50 Pilot CV 1,800 mg/d as AD‐tx add‐ Standard AD tx 6 weeks HADS, BDI‐II scale No serious AEs
(CV) (Panahi antidepressant (AD) tx; exploratory on; ALGOMED® 98% CV
et al., 2015) pts with DSM‐IV MDD trial powder
Cimicifuga foetida Zheng 2013 Climacteric symptoms; 96; 89 RCT Group A: CFE 3 tablets/d; 3 months Kupperman menopause index Both decr KMI scores (p < .001), but
extract (CFE) (Zheng et al., early‐MP Chinese completed Ximingting, triterpenoid (KMI), menopause‐specific CFE scores higher. MENQOL
2013) women saponin extracted from quality of life (MENQOL), scores sig decr for all groups
root HADS (p ≤ .01) except sexual domain
score for group A (p = .103).
Anxiety sig decr in group A
(p = .015) and B (p = .003)
Curcumin, Yu 2015 As adjuvant tx to SSRI 108 DB‐RCT Curcumin caps 1,000 mg/d; PBO: Soybean 6 weeks HAMD Chinese version; Sig antidepressant behavioral
Curcuma (Yu et al., escitalopram; hospital‐ curcumin 70%, powder MADRS responses
longa 2015) recruited men age demethoxy‐curcumin 20%,
31–59 years in China demethoxy‐curcumin 10%
Flax oil Gracious 2010 Symptom severity; youth 51 RCT Flax oil cap titrated to 12 PBO: Olive oil 16 weeks 1°‐OC: Young mania rating No sig diff in 1°‐OC. Clinician‐rated
(Gracious age 6–17 years with caps/d as tolerated; scale, child depression global symptom severity
et al., 2010) bipolar disorder 550 mg α‐linolenic acid rating scale‐revised, CGI‐ negatively correlated with final
per 1 g bipolar; 2°‐OC: Fatty acid serum omega‐3 fatty acid
levels as predictors of tx compositions and positively
response and symptom correlated with final arachidonic
severity acid and docosapentaenoic acid
levels
(Continues)
881
TABLE 3 (Continued)
882
Garlic Peleg 2003 (Peleg Effect on lipids and 33 DB‐RCT Garlic (alliin) 22.4 mg/ PBO + individual 16 weeks BDI, Buss‐Durkee Hostility No effect on psychopathologic
et al., 2003) psychopathologic d + individual dietary dietary counseling Inventory, Impulse Control parameters
parameters; pts with counseling; Inodiel, 5.6 mg Scale, and temperament
primary type 2 alliin per tab evaluation
hyperlipidemia with no
CVD
Gotu kola, Centella Bradwejn 2000 Anxiolytic activity in 40 DB‐RCT CA 12 g (single dose); PBO Single dose Self‐rated mood, acoustic Sig attenuated peak ASR amplitude
asiatica (CA) (Bradwejn et al., healthy 500 mg/cap crude powder startle response (ASR) 30 and 60 min post‐tx. No sig
2000) subjects effects on mood, heart rate, or
blood pressure
Grape seed Terauchi 2014 MP symptoms, body 96; 91 DB‐RCT GSE 100 or 200 mg/d; PBO 8 weeks Menopausal health‐related Sig improved physical symptoms
extract (GSE) (Terauchi et al., composition, and completers Gravinol, 85% QoL, HADS, Athens and hot flash scores. Decr AIS
polyphenol 2014) cardiovascular proanthocyanidin insomnia scale (AIS) with high‐dose; decr HADS, SBP
parameters; middle‐ and DBP with both doses; incr
aged women with ≥1 muscle mass with both doses
MP symptom
Green tea Camelia Zhang 2013 (Zhang Reward learning and 74 DB‐RCT Green tea powder 400 mg in PBO: Micro‐ 5 weeks MADRS, HRSD‐17 Reduc MADRS and HRSD‐17 score
sinensis et al., 2013) depressive symptoms; hot water 3 times a day; crystalline cellulose
healthy subjects age polyphenols in extract up
18–34 years to 20% and more of the
dry weight
Holy basil, Ocimum Sampath 2015 Neuroprotection, 44 DB‐RCT OSE 300 mg/d; Ethanolic leaf PBO 30 days STAI STAI improved with OSE alone
sanctum extract (Sampath et al., cognition and stress extract, ursolic acid >2.7%
(OSE) 2015) relief; healthy male w/w
subjects in India
Melissa officinalis Alijaniha 2015 To confirm commonly 71 recruited; DB‐RCT MO 500 mg twice daily; PBO 14 days 1°‐OC: Diaries for mean Sig reduc in palpitation episodes
(MO) (Alijaniha et al., regarded effects on 55 completers lyophilized aqueous frequency of palpitation (p = .0001) and number of
2015) heart palpitations; extract of leaves 20.9% episodes/wk; VAS for anxious pts (p = .004). No serious
Iranian adult mean palpitation intensity AEs
volunteers with 2°‐OC: General health
benign palpitations Questionnaire‐28 (GHQ‐
28) for somatization,
anxiety, insomnia, social
dysfunction and severe
depression
Rhapontic Kaszkin‐Bettag 2007 Anxiety, health state, and 109 DB‐RCT Rhubarb extract one enteric PBO 12 weeks HAMA, menopause rating HAMA total score sig decr vs. PBO.
rhubarb, Rheum (Kaszkin‐Bettag general well‐being; multicenter coated tab daily; ERr 731, scale II, Women's health Anxiety severity from moderate
haponticum et al., 2007) Peri‐MP women with Phytoestrol N STD root questionnaire, PGWBI or severe to slight in 33/39
extract climacteric complaints extract completers of active tx
and anxiety correlated with reduc number/
severity of hot flushes
Rose tea Tseng 2005 (Tseng Menstrual pain and 130 RCT Rose tea 2 teacups start No tx 12 d·q·mo for 6 cycles Biopsychosocial outcomes of Less perceived menstrual pain,
et al., 2005) psychophysiologic 1 week before period to dysmenorrhea distress, and anxiety and greater
distress; female fifth menstrual day well‐being at 1‐, 3‐, and 6‐month
adolescents with (12 d/mo); each cup made post‐tx
primary dysmenorrhea from 6 dry buds R. gallica
steeped for 10 min in
300 mL hot water
YEUNG
(Continues)
ET AL.
YEUNG
ET AL.
TABLE 3 (Continued)
Sage, Salvia Kennedy 2006 Anxiety and mood 30 DB‐RCT Sage cap 300 or 600 mg; PBO 3 study visits Bond–Lader mood scales Improved mood ratings absent of
officinalis (Kennedy et al., modulating properties crossover S. officinalis dried leaf separated by 1‐ (BLMS) and STAI pre/post stressor: Reduc anxiety with
2006) of 2 separate single week washouts 20 min of defined intensity 300‐mg dose was abolished
doses; healthy young stress simulator (DISS) during DISS; 600‐mg dose incr
adults computerized multitasking alertness, calmness, and
battery contentedness
Sceletium Terburg 2013 Acute effects on anxiety‐ 16 DB‐RCT STE 25 mg Zembrin: STD PBO Single dose fMRI during perceptual‐load Amygdala reactivity to fearful faces
tortuosum (Terburg et al., related amygdala crossover aqueous ethanolic extract and emotion‐matching under low perceptual load
extract (STE) 2013) activity and of above‐ground material tasks conditions was attenuated.
neurocircuitry; Follow‐up connectivity analysis
healthy young adults on emotion‐matching task
showed reduc amygdala‐
hypothalamus coupling
Siberian ginseng Schaffler 2013 Mental fatigue/ 144 RCT ESE 120 mg/d only or 2‐day stress 8 weeks Stress, fatigue, exhaustion, Almost all parameters sig improved
Eleutherococcus (Schaffler et al., restlessness; ESE + 2‐day stress management alertness, restlessness, over time; no BGD. Mental
senticosus 2013) participants with management training training (SMT) mood, QoL, sleep physical fatigue and restlessness favored
extract (ESE) asthenia and reduced (COM); WS® 1070 ES complaints, activities COM vs. ESE. COM was not
working capacity root ethanolic extract ratio superior to SMT
related to chronic 16–25:1
stress
Wild yam Hsu 2011 Safety/efficacy for 50 DB‐RCT dual DAE 12 mg/sachet; 2 sachets PBO 12 months 1°‐OC: Greene climacteric At 6 and 12 months: Generally
Diascorea alata (Hsu et al., 2011) symptoms in MP center daily; Lypholized powder scale (GCS); 2°‐OC: Plasma improved most clinical
extract (DAE) women aqueous tuber extract hormone profiles symptoms. GCS: Sig reduc at 12
mo (p < .01) and most sig for
feeling tense/nervous (p = .007),
insomnia (p = .004), excitability
(p = .047), and musculoskeletal
pain (p = .019). Positive effects
on hormone profiles; good long‐
term safety profile
Note. 1°‐OC = primary outcome measures; 2°‐OC = secondary outcome measures; ADL = activities of daily living; AE = adverse events; BAI = Beck Anxiety Inventory; BDI = Beck Depression Inventory; BFI = Brief Fatigue
Inventory; BGD = between‐group differences; BL = baseline; BP = blood pressure; btw = between; BZD = benzodiazepines; cap = capsule; CGI‐S = Clinical Global Impression‐Severity; CI = confidence interval; corr = cor-
relation; CVD = cardiovascular disease; DB = double‐blind; decr = decrease; diff = difference; DSM‐III/IV/V‐TR = Diagnostic and Statistical Manual of Mental Disorders, 3rd, 4th, or 5th edition, Text Revision;
EAAS = Erlangen Anxiety Tension and Aggression Scale; GAD = Generalized Anxiety Disorder; HADS = Hospital Anxiety and Depression Scale; HAMA = Hamilton Anxiety Rating Scale; HAMD = Hamilton Depression
Rating Scale; HRSD‐17 = 17‐item Hamilton Rating Scale for Depression; HT = hormone therapy; HRT = hormone replacement therapy; impr = improved or improvement; incl = including; incr = increase; info = information;
ITT = intention to treat; MDD = major depressive disorder; MADRS = Montgomery‐Asberg Depression Rating Scale; MP = menopause or menopausal; PBO = placebo; PGWBI = Psychological General Well‐Being Index;
PMS = premenstrual syndrome; PMP = postmenopausal; POMS = Profile of Mood States; PSQI = Pittsburgh Sleep Quality Index; pts = patients; QoL = quality of life; RCT = randomized controlled trial; reduc = reduction or
reduced; sig = significant; SB = single‐blind; SSRI = selective serotonin reuptake inhibitor; STAI = State–Trait Anxiety Inventory; STD = standardized; tab = tab; tx = treatment; VAS = visual analogue scale; VMS = vasomotor
symptoms; w/v = weight per volume; w/w = weight per weight; WD = withdrawal.
883
884 YEUNG ET AL.
In patients with cognitive impairment (Cieza, Maier, & Poppel, 2003; 2001). In patients with anxiety disorder, passionflower extract was
Gavrilova et al., 2014; Scripnikov, Khomenko, & Napryeyenko, 2007; no better than oxazepam in reducing symptoms but had fewer adverse
van Dongen, van Rossum, Kessels, Sielhorst, & Knipschild, 2000), this effects (Akhondzadeh, Naghavi, et al., 2001). Similar findings were
product was shown to be superior to placebo in relieving anxiety and reported in another study that compared passionflower with sertraline
depression. Similar findings were reported in patients with anxiety (Nojoumi, Ghaeli, Salimi, Sharifi, & Raisi, 2017).
(Woelk, Arnoldt, Kieser, & Hoerr, 2007) or multiple sclerosis (Johnson Rhodiola (Rhodiola rosea) is a perennial plant used in traditional
et al., 2006), with significant reductions in anxiety scores following medicine in Asia and in Eastern Europe to improve physical endurance
use of EGB 761® compared to a placebo. However, results from a pilot and mental performance. Results from studies of the root extract
study indicate that EGB 761® is no better than the prescription involving patients with anxiety (Cropley, Banks, & Boyle, 2015) and
drug donepezil in Alzheimer's patients (Yancheva et al., 2009), and depression (Darbinyan et al., 2007) show that it can reduce symptoms
another G. biloba extract (PN246) was no better than placebo in when compared with placebo. In adults with stress‐related fatigue, an
preventing seasonal affective depression (Lingaerde, Foreland, & R. rosea extract was no better than a placebo in reducing depression
Magnusson, 1999). scores (Olsson, von Scheele, & Panossian, 2009). A root extract was
The flower of lavender (Lavandula angustifolia) is used in perfumes also less effective than the standard antidepressant drug sertraline in
and in aromatherapy because its fragrance has a purported calming patients with mild to moderate depression but was associated with
effect. Oral supplements from this plant are also available for a wide fewer adverse events and was better tolerated (Mao et al., 2015).
variety of symptoms. Silexan®, a product derived from steam distilla- Black cohosh (Cimicifuga racemosa) is an herb chiefly marketed for
tion of lavender flowers, has been tested in several human studies that menopausal symptoms. But in a study of postmenopausal women, it
show its anxiolytic activity to be better than placebo (Kasper et al., was not as effective as fluoxetine in reducing depression, although it
2010; Kasper et al., 2014; Kasper, Anghelescu, & Dienel, 2015) and had a positive effect on hot flashes (Oktem et al., 2007). Another study
comparable to prescription drugs such as paroxetine (Kasper et al., in the same population showed that a standardized black cohosh
2014) and lorazepam (Woelk & Schlafke, 2010) with fewer adverse extract Remifemin® was as effective as low‐dose transdermal estra-
effects. Lavender tea may also enhance the effect of the antidepres- diol treatment in reducing hot flashes, anxiety, and depression but
sant citalopram (Nikfarjam, Parvin, Assarzadegan, & Asghari, 2013). without the hormonal changes exhibited with estradiol (Nappi,
Similar benefits were observed when lavender extract drops were Malavasi, Brundu, & Facchinetti, 2005). However, one trial that
taken with imipramine (Akhondzadeh et al., 2003). employed a different black cohosh extract did not find it more effec-
Brahmi (Bacopa monnieri) is a plant native to South Asia and com- tive than a rice flour placebo (Amsterdam, Yao, et al., 2009). Variations
monly used in Ayurvedic medicine. Preliminary studies show that it in methods of preparation and dosage may account for the lack of
acts as an acetylcholinesterase inhibitor suggesting it may benefit effects.
those with cognitive dysfunction. KeenMind®, an ethanolic extract Chamomile (Matricaria recutita) is an herb popular for its relaxant
derived from the stem, leaves, and root, was tested in adults in two effects. In patients with mild to moderate generalized anxiety disorder,
studies. Results showed positive effects in improving cognitive func- a chamomile extract demonstrated modest anxiolytic activity when
tion but not anxiety (Benson et al., 2014; Roodenrys et al., 2002). Stud- compared with placebo (Amsterdam et al., 2009). A follow‐up study
ies using other extracts showed a general reduction in anxiety scores of chamomile's long‐term effects showed that it continued to be effec-
(Calabrese et al., 2008; Kumar, Srivastav, Wahi, Singh, & Singh, 2011; tive after 38 weeks although there was no significant reduction in
Sathyanarayanan et al., 2013; Stough et al., 2001). However, all studies relapse time (Mao et al., 2016).
were conducted only in healthy subjects with placebo controls. Guarana (Paullinia cupana) is an herb indigenous to South America.
Whether similar benefits could be conferred on patients with anxiety Its extract is marketed as a dietary supplement mainly for its stimulant
and depression and how this herb compares with standard medications effects, which are likely due to the high caffeine content. However, in
for anxiety or depression remain unclear. healthy volunteers, guarana was ineffective in reducing anxiety or
Passionflower is derived from the flower of Passiflora incarnata, a improving well‐being and mood (Silvestrini, Marino, & Cosentino,
plant prevalent in Southeastern parts of the Americas. Native Ameri- 2013). In post‐chemotherapy breast cancer patients, guarana was bet-
cans used it as a remedy to improve sleep and to reduce anxiety. ter than placebo in reducing fatigue but not anxiety or depression (de
One study that employed a traditional tea preparation taken before Oliveira Campos et al., 2011). And in breast cancer patients undergoing
bedtime found that it can improve sleep quality but had no significant radiation therapy, there were no significant differences in either
effect on anxiety when compared to a placebo (Ngan & Conduit, fatigue or depression when compared to a placebo (da Costa Miranda
2011). An aqueous extract of passionflower produced a slight but sta- et al., 2009).
tistically significant improvement in anxiety scores in patients under- Asian Ginseng (Panax ginseng) found in Northeast Asia has been
going spinal anesthesia without disrupting psychomotor function or used as a “cure all” in Traditional Chinese medicine. P. ginseng root
sedation (Aslanargun, Cuvas, Dikmen, Aslan, & Yuksel, 2012). In extract reduced anxiety in patients with fibromyalgia, but it was not
another trial, a standardized P. incarnata extract was reported to as potent as amitriptyline, an antidepressant drug (Braz, Morais, Paula,
reduce preoperative anxiety in patients undergoing inguinal Diniz, & Almeida, 2013). In another trial of postmenopausal women,
herniorrhaphy (Movafegh et al., 2008). When used as an adjuvant, pas- Ginsana®, a standardized P. ginseng root extract, reduced depression
sionflower extract improved mental symptoms more effectively than but not general well‐being scores (Wiklund, Mattsson, Lindgren, &
clonidine alone for opioid withdrawal (Akhondzadeh, Kashani, et al., Limoni, 1999).
YEUNG ET AL. 885
Chasteberry (Vitex agnus castus) is often recommended for relief (600 mg/d) in reducing anxiety in healthy young adults (Kennedy
from premenstrual symptoms. Studies show that chasteberry drops et al., 2006).
are similar to placebo in relieving depressive symptoms (Zamani, In menopausal women, extracts of blue green algae
Neghab, & Torabian, 2012). When compared to fluoxetine, (Aphanizomenon flos‐aquae) (Genazzani et al., 2010), Cimicifuga foetida
chasteberry was more effective in reducing physical symptoms, (Zheng et al., 2013), grape seed (Vitis vinifera; Terauchi et al., 2014),
whereas fluoxetine was better for relieving psychological symptoms rhapontic rhubarb (Rheum rhaponticum; Kaszkin‐Bettag et al., 2007),
(Atmaca, Kumru, & Tezcan, 2003). rose tea (Tseng, Chen, & Yang, 2005), and wild yam (Dioscorea alata;
Maca (Lepidium meyenii) is a plant indigenous to South America. It Hsu, Kuo, Chang, Wu, & Huang, 2011) helped decrease symptom
has been used to enhance fertility and sexual performance in both men scores related to anxiety and depression. Whereas wild yam appears
and women and to relieve menopausal symptoms. Powdered roots to work via estrogenic pathway, the blue green algae extract did not
(Stojanovska et al., 2015) as well as the dried methanolic extract demonstrate any hormonal effects.
(Brooks et al., 2008) have been tested on postmenopausal women in Extracts from gotu kola (Centella asiatica; Bradwejn, Zhou,
two studies with a crossover design. These products alleviated depres- Koszycki, & Shlik, 2000), green tea (Camelia sinensis; Zhang et al.,
sion and anxiety without exerting hormonal effects. 2013), holy basil (Ocimum sanctum; Sampath, Mahapatra, Padhi,
Red clover (Trifolium pratense) is commonly used to address pre- Sharma, & Talwar, 2015), and Sceletium tortuosum (Terburg et al.,
menstrual and menopausal symptoms because it acts as a phytoestro- 2013) when administered to healthy adults were more effective than
gen. In studies of postmenopausal women, standardized T. pratense placebo in reducing anxiety and/or depression scores.
capsules were reported to relieve anxiety and related symptoms Bitter orange blossom (Citus aurantium; Akhlaghi et al., 2011),
(Hidalgo, Chedraui, Morocho, Ross, & San Miguel, 2005; Lipovac curcumin (Curcuma longa; Yu, Pei, Zhang, Wen, & Yang, 2015), Melissa
et al., 2010). officinalis (Alijaniha et al., 2015), and Siberian Ginseng (Eleutherococcus
Studies of soy isoflavones (de Sousa‐Munoz & Filizola, 2009), senticosis; Schaffler, Wolf, & Burkart, 2013) were also found to have
whole soy, and daidzein (Liu, Ho, Woo, Chen, & Wong, 2014) failed some benefit in lowering anxiety and depression in clinical studies,
to find any reductions in depressive symptoms. but these symptoms were not the primary endpoints.
Valerian (Valeriana officinalis) is known for its calming effects, and Ashwagandha (Withania somnifera; Chengappa et al., 2013), black
valerian tea is often used to aid sleep. In patients with anxiety disorder, cumin (Nigella sativa; Bin Sayeed et al., 2014), and Chlorella vulgaris
a valerian root extract had anxiolytic effects similar to diazepam (Panahi, Badeli, Karami, Badeli, & Sahebkar, 2015) were not effective
(Andreatini, Sartori, Seabra, & Leite, 2002). When used as a sleep aid, in relieving anxiety and depression in patients with related symptoms.
its benefits and adverse event profile were comparable to oxazepam
(Dorn, 2000).
Wormwood (Artemisia absinthium) is used both as an herbal med- 4 | DISCUSSION
icine and as a spice in alcoholic drinks. Two studies were conducted
using SedaCrohn®, a standardized A. absinthium leaf and stem powder, In this review, we found that the majority were early phase studies,
in patients with Crohn's disease. When compared to standard medica- with no phase III trials. Study designs varied considerably with subjects
tions (Krebs, Omer, & Omer, 2010) or a placebo (Omer et al., 2007), including menopausal women and patients with anxiety disorders.
this product improved depression symptom scores. Some studies that used healthy volunteers with low baseline symptom
There were a number of herbal medicines for which our criteria levels may have produced misleading results. Anxiety or depressive
yielded only one RCT (Table 3). symptoms were measured in all the studies but were not always the
American skullcap (Scutellaria lateriflora) has been compared with primary endpoints. In addition, different scales were used to measure
stinging nettle leaf (Urtica dioica folia) for its effects on improving mood the severity of symptoms. We chose to include only RCTs to reduce
in healthy participants (Brock, Whitehouse, Tewfik, & Towell, 2014). bias. Most trials used placebos or standard pharmaceutical agents in
No significant differences were found, but this may be due to low the control group. Overall, 45% of studies reviewed indicate significant
levels of anxiety at baseline. improvements in anxiety or depression scores. Many studies that com-
Flax oil is derived from the seed of Linum usitatissimum. Flax oil pared the effects of herbs with standard pharmaceutical agents
containing alpha‐linolenic acid (α‐LNA) was reported to be similar to reported that herbs are not as potent but are safer than prescription
olive oil in reducing depressive symptoms in children and young adults drugs. These include saffron (Akhondzadeh Basti et al., 2007; Moosavi
with bipolar disorder (Gracious et al., 2010). et al., 2014; Noorbala et al., 2005; Shahmansouri et al., 2014), black
Garlic (Allium sativum) has been investigated in a study to deter- cohosh (Nappi et al., 2005; Oktem et al., 2007), and chasteberry
mine its cholesterol‐lowering activity. Psychopathologic parameters (Atmaca et al., 2003). These herbs did not outperform fluoxetine but
including depression were also evaluated, but no changes were were associated with fewer adverse events, which can include
observed (Peleg et al., 2003). changes in appetite, sexual dysfunction, nausea, headache, insomnia,
Sage (Salvia officinalis) is generally used as a spice. Essential oil and tremors.
and extracts of sage are thought to inhibit cholinesterase, an enzyme Although several studies reported herbal supplements to be
that breaks down the neurotransmitter acetylcholine. In a study that safe, their potential for interactions with other drugs were not
compared different dosages of a dried leaf extract with placebo, a discussed. For example, black cohosh (Li et al., 2011), chasteberry
lower dose (300 mg/d) was more effective than the higher dose (Ho, Singh, Holloway, & Crankshaw, 2011), chamomile (Ganzera,
886 YEUNG ET AL.
Schneider, & Stuppner, 2006), and rhodiola (Hellum et al., 2010) are should focus on using the standardized forms of these products in
known to modulate the actions of cytochrome P450 enzymes and large‐scale trials with robust methodology to determine their compar-
may increase the toxicity or decrease therapeutic effects of sub- ative effectiveness. A just‐published review reported increased partic-
strate drugs (Gurley, Fifer, & Gardner, 2012) including many used ipation in studies with longitudinal design compared to randomized
in cancer treatment, such as cyclosporine (Sridharan & trials (Wakefield et al., 2017). Studies to elucidate mechanisms and
Sivaramakrishnan, 2016) and most of the tyrosine kinase inhibitors pharmacokinetics are also needed. The findings can help establish reli-
(Gay, Toulet, & Le Corre, 2017). Even though the clinical significance able dosage guidelines and effectiveness of herbal products, which
of these interactions is yet to be determined, the potential exists appear to have a better benefit‐to‐risk profile than standard pharma-
and therefore should be given due consideration. In addition, herbs cologic options. Cancer patients, known to have higher rates of
such as chamomile (Segal & Pilote, 2006) and lavender (Denner, depression and anxiety, might especially benefit from such research
2009) have anticoagulant/antiplatelet properties and may therefore as conventional management is often not favorable.
elevate the risk of bleeding with concurrent use of drugs that have
similar actions (Ge, Zhang, & Zuo, 2014). These include warfarin ACKNOWLEDGEMENTS
and heparin drugs that are often used to treat or prevent deep vein This manuscript was supported in part by NIH/NCI Cancer Center
thrombosis in bedridden cancer patients. These herbs may also fur- Support Grant P30 CA008748.
ther increase the cardiovascular complication of antiangiogenic drugs
such as bevacizumab (Totzeck, Mincu, & Rassaf, 2017). In addition, CONFLIC T OF IN TE RE ST
the debate continues about phytoestrogenic herbs that include lav-
The authors have declared that there is no conflict of interest.
ender (Diaz, Luque, Badar, Kornic, & Danon, 2016) and chasteberry
(Dugoua, Seely, Perri, Koren, & Mills, 2008) and their potential
ORCID
for interference with antihormonal therapies or for exerting pro‐
Jyothirmai Gubili http://orcid.org/0000-0001-5345-4987
proliferative effects in patients with hormone‐sensitive cancers (Fritz
et al., 2013). It is prudent to understand these risks because cancer
RE FE RE NC ES
patients often tend to use herbal products concomitantly with pre-
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in post‐stroke depression: A systematic review of literature.

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Received: 5 October 2017 Revised: 8 December 2017 Accepted: 21 December 2017

Herbal medicine for depression and anxiety: A systematic

antidepressant, anxiety, anxiolytic, cancer, depression, herbal medicine

1 | B A CKG R O U N D experience anxiety, depression, or adjustment disorder, which is char-

TABLE 1 Search strategies and terms used

FIGURE 1 Overview of study selection

Herbal First Intervention/ Control Treatment Anxiety/depression

Herbal First Intervention/ Control Treatment Anxiety/depression

Herbal First Intervention/ Control Treatment Anxiety/depression

Herbal First Intervention/ Control Treatment Anxiety/depression

Herbal First Intervention/ Control Treatment Anxiety/depression

Herbal First Intervention/ Control Treatment Anxiety/depression

influence on liver function

Herbal First Intervention/ Control Treatment Anxiety/depression

(<10): 31.4% vs. 22.6%

Herbal First Intervention/ Control Treatment Anxiety/depression

Herbal First Intervention/ Control Treatment Anxiety/depression

Herbal First Intervention/ Control Treatment Anxiety/depression

Herbal First Intervention/ Control Treatment Anxiety/depression

with DSM‐IV major dried petal extract

Herbal First Intervention/ Control Treatment Anxiety/depression

in post‐stroke depression: A systematic review of literature.

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