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
American Skullcap Scutellaria lateriflora (SL)	Brock 2014(Brock et al., 2014)	Mood Healthy participants	43	DB-RCT Crossover	SL cap 350 mg three times daily Freeze-dried aerial parts	PBO: Freeze-dried stinging nettle leaf (Urtica dioica folia)	2 wk with each tx separated by 1 wk washout	BAI, POMS	No sig diff, but participants were relatively non-anxious Sig group 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 Withania somnifera extract (WSE)	Chengappa 2013(Chengappa et al., 2013)	As a procognitive agent/adjunct to maintenance bipolar disorder meds Euthymic pts with DSM-IV bipolar disorder	60 53 completers	DB-RCT	WSE 500 mg/d Sensoril, STD WSE: min 8% withanolides and 32% oligosaccharides; max 2% withaferin A	PBO	8 wk	Penn Emotional Acuity test, MADRS, HAMA	Mood and anxiety scale scores remained stable; minor AEs
Bitter orange blossom Citrus aurantium (CA)	Akhlaghi 2011(Akhlaghi et al., 2011)	Preoperative anxiety Pts undergoing minor operation	60	DB-RT	CA blossom distillate 1mL/kg body wt From fresh petals and stamens	PBO: saline	2h pre-anesthesia	STAI, Amsterdam Preoperative Anxiety and Information Scale (APAIS)	STAI and APAIS scales sig better with CA vs PBO
Black cumin Nigella sativa (NS)	Bin Sayeed 2014(Bin Sayeed et al., 2014)	Mood, anxiety and cognition Boys age 14–17 in a Bangladesh boarding school	48	DB-RCT	NS 500 mg/d Powdered seeds	PBO	4 wk	STAI; Bond-Lader scale	State anxiety: no sig variation found; Mood and trait anxiety: sig variation from BL but no BGD
Blue Green Algae Apahanizome-non flos-aquae	Genazzani 2010(Genazzani et al., 2010)	Alt to HT for psychological/ somatic/VMS MP women/no HT	30	RCT	Klamath algae extract 1600 g/d Klamin®	PBO: vanilla tab	8 wk	Symptom Rating Scale - Italian version, Zung Self-Rating Scale	Sig changes in SRT and Zung scales for QoL, mood, anxiety and depressive attitude No hormonal changes occurred
Chlorella vulgaris (CV)	Panahi 2015(Panahi et al., 2015)	Adjunct to standard antidepressant (AD) tx Pts with DSM-IV MDD	42+50	Pilot exploratory trial	CV 1800 mg/d as AD-tx add-on ALGOMED® 98% CV powder	Standard AD tx	6 wk	HADS, BDI-II Scale	No serious AEs
Cimicifuga foetida extract (CFE)	Zheng 2013(Zheng et al., 2013)	Climacteric symptoms Early-MP Chinese women	96 89 completed	RCT	Group A: CFE /d Ximingting, triterpenoid saponin extracted from root		3 mo	Kupperman Menopause Index (KMI), Menopause-Specific Quality of Life (MENQOL), HADS	Both decr KMI scores (P<.001), but CFE scores higher MENQOL scores sig decr for all groups (P≤.01) except sexual domain score for Group A (P=.103) Anxiety sig decr in Group A (P=.015) and B (P=.003)
Curcumin Curcuma longa	Yu 2015(Yu et al., 2015)	As adjuvant tx to SSRI escitalopram Hospital-recruited men age 31–59 y in China	108	DB-RCT	Curcumin caps 1000 mg/d Curcumin 70%; demethoxy-curcumin 20%; demethoxy-curcumin 10%	PBO: soybean powder	6 wk	HAMD Chinese version; MADRS	Sig antidepressant behavioral responses
Flax oil	Gracious 2010(Gracious et al., 2010)	Symptom severity Youth age 6–17 y with bipolar disorder	51	RCT	Flax oil cap titrated to 12 caps/d as tolerated 550 mg α-linolenic acid per 1 g	PBO: Olive oil	16 wk	1⁰-OC: Young Mania Rating Scale, Child Depression Rating Scale-Revised, CGI-Bipolar 2⁰-OC: Fatty acid levels as predictors of tx response and symptom severity	No sig diff in 1⁰-OC Clinician-rated Global Symptom Severity negatively correlated with final serum omega-3 fatty acid compositions and positively correlated with final arachidonic acid and docosapentaenoic acid levels
Garlic	Peleg 2003(Peleg et al., 2003)	Effect on lipids and Pts with primary type 2 hyperlipidemia with no CVD	33	DB-RCT	Garlic (alliin) 22.4 mg/d + individual dietary counseling Inodiel, 5.6 mg alliin per tab	PBO + individual dietary counseling	16 wk		No effect on psychopathologic parameters
Gotu kola Centella asiatica (CA)	Bradwejn 2000(Bradwejn et al., 2000)	Anxiolytic activity Healthy subjects	40	DB-RCT	CA 12 g 500 mg/cap crude powder	PBO	Single dose	Self-rated mood, acoustic startle response (ASR)	Sig attenuated peak ASR amplitude 30 and 60 min post-tx No sig effects on mood, heart rate, or blood pressure
Grape seed extract (GSE) polyphenol	Terauchi 2014(Terauchi et al., 2014)	MP symptoms, body composition, and cardiovascular parameters Middle-aged women with ≥1 MP symptom	96 91 completers	DB-RCT	GSE 100 or 200 mg/d Gravinol, 85% proanthocyanidin	PBO	8 wk	Menopausal Health-Related QoL, HADS, Athens Insomnia Scale (AIS)	Sig improved physical symptoms and hot flash scores Decr AIS with high-dose; decr HADS, SBP and DBP with both doses; incr muscle mass with both doses
Green tea Camelia sinensis	Zhang 2013(Zhang et al., 2013)	Reward learning and depressive symptoms Healthy subjects age 18–34 y	74	DB-RCT	Green tea powder 400 mg in hot water 3×/d Polyphenols in extract up to 20% and more of the dry weight	PBO: micro-crystalline cellulose	5 wk	MADRS, HRSD-17	reduc MADRS and HRSD-17 score
Holy basil Ocimum sanctum extract (OSE)	Sampath 2015(Sampath et al., 2015)	Neuroprotection, cognition and stress relief Healthy male subjects in India	44	DB-RCT	OSE 300 mg/d Ethanolic leaf extract, ursolic acid >2.7% w/w	PBO	30 d	STAI	STAI improved with OSE alone
Melissa officinalis (MO)	Alijaniha 2015(Alijaniha et al., 2015)	To confirm commonly regarded effects on heart palpitations Iranian adult volunteers with benign palpitations	71 recruited 55 completers	DB-RCT	MO 500 mg twice daily Lyophilized aqueous extract of leaves 20.9%	PBO	14 d	1⁰-OC: Diaries for mean frequency of palpitation episodes/wk; VAS for mean palpitation intensity 2⁰-OC: General Health Questionnaire-28 (GHQ-28) for somatization, anxiety, insomnia, social dysfunction and severe depression	Sig reduc in palpitation episodes (P=.0001) and number of anxious pts (P=.004) No serious AEs
Rhapontic rhubarb Rheum rhaponticum extract	Kaszkin-Bettag 2007(Kaszkin-Bettag et al., 2007)	Anxiety, health state, and general well-being Peri-MP women with climacteric complaints and anxiety	109	DB-RCT Multicenter	Rhubarb extract 1 enteric coated tab daily ERr 731; Phytoestrol N STD root extract	PBO	12 wk	HAMA, Menopause Rating Scale II, Women’s Health Questionnaire, PGWBI	HAMA total score vs PBO Anxiety severity from moderate or severe to slight in 33/39 completers of active tx correlated with reduc number/severity of hot flushes
Rose tea	Tseng 2005(Tseng et al., 2005)	Menstrual pain and psychophysiologic distress Female adolescents with primary dysmenorrhea	130	RCT	Rose tea 2 teacups start 1 wk before period to 5th menstrual day (12 d/mo) Each cup made from 6 dry buds R. gallica steeped for 10 min in 300 mL hot water	No tx	12 d q mo for 6 cycles	Biopsychosocial outcomes of dysmenorrhea	Less perceived menstrual pain, distress, and anxiety and greater well-being at 1, 3, and 6 mo post-tx
Sage Salvia officinalis	Kennedy 2006(Kennedy et al., 2006)	Anxiety and mood modulating properties of 2 separate single doses Healthy young adults	30	DB-RCT Crossover	Sage cap 300 or 600 mg S. officinalis dried leaf	PBO	3 study visits separated by 1 wk washouts	Bond-Lader Mood Scales (BLMS) and STAI pre/post 20 min of Defined Intensity Stress Simulator (DISS) computerized multitasking battery	Improved mood ratings absent of stressor: Reduc anxiety with 300-mg dose was abolished during DISS; 600-mg dose incr alertness, calmness and contentedness
Sceletium tortuosum extract (STE)	Terburg 2013(Terburg et al., 2013)	Acute effects on anxiety-related amygdala activity and neurocircuitry Healthy young adults	16	DB-RCT Crossover	STE 25 mg Zembrin: STD aqueous ethanolic extract of above-ground material	PBO	Single dose	fMRI during perceptual-load and emotion-matching tasks	Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated Follow-up connectivity analysis on emotion-matching task showed reduc amygdala-hypothalamus coupling
Siberian ginseng Eleutherococcus senticosus extract (ESE)	Schaffler 2013(Schaffler et al., 2013)	Mental fatigue/restlessness Participants with asthenia and reduced working capacity related to chronic stress	144	RCT	ESE 120 mg/d only or ESE + 2-day stress management training (COM) WS® 1070 ES root ethanolic extract ratio 16–25:1	2-day stress management training (SMT)	8 wk	Stress, fatigue, exhaustion, alertness, restlessness, mood, QoL, sleep Physical complaints, activities	Almost all parameters sig improved over time; no BGD Mental fatigue and restlessness favored COM vs ESE COM was not superior to SMT
Wild Yam Diascorea alata extract (DAE)	Hsu 2011(Hsu et al., 2011)	Safety/efficacy for MP symptoms MP women	50	DB-RCT Dual center	DAE 12 mg/sachet;2 sachets daily Lypholized powder aqueous tuber extract	PBO	12 mo	1⁰-OC: Greene Climacteric Scale (GCS) 2⁰-OC: Plasma hormone profiles	At 6 and 12 mo: generally improved most clinical 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

Abbreviations: 1⁰-OC, primary outcome measures; 2⁰-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, correlation; 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.