Table 2.

Herbal Combinations.

	First Author	Study design	Intervention and measures	Outcomes	Adverse events	Combined with	Jadad scale
1	Abdellah SA 201988	Open-label, observational Population: Adults with adjustment insomnia (n=22)	Intervention: Combination of V. officinalis extract 32 mg and Eschscholtzia californica extract 80 mg per tablet, Max. 4 tablets per day. For 4 weeks Measures: Insomnia severity (ISI), quality of sleep and waking state (VAS), and anxiety (HAM-A). Sleep diary.	ISI score decreased by approx. 30%, night sleep duration increased, the number of awakening decreased, and anxiety score significantly decreased by 50%. Sleep latency did not improve.	Mild nocturnal pollakiuria in 1 patient. No serious adverse events.	E. californica	n/a
2	Meier S 201877	Randomized, placebo-controlled, double blind Population: Healthy adults (n=72, only male)	Intervention: Combination of V. officinalis 45%MeOH extract 90 mg, Passiflora incarnata 50%EtOH extract 90 mg, Melissa officinalis 20%EtOH extract 60 mg (Ze 185) Measures: Biological (salivary cortisol) and self-reported psychological responses to a standardized psychosocial stress paradigm (TSST)	Attenuated self-reported anxiety. There was no difference between the groups in salivary cortisol levels.	No difference between the groups.	P. incarnata M. officinalis	5
3	Toolika E 201587	Observational Population: Primary insomnia patients (n=30)	Intervention: V. wallichii root/rhizome 4 g with milk after meal, 3 times daily (12 g per day) for 1 month. Measures: initiation of sleep, duration of sleep, disturbed sleep, and disturbance in daily functioning	V. wallichii with milk improved the initiation and duration sleep, reduced sleep disturbance, and improved daily functioning.	Not mentioned	Milk	n/a
4	Gromball J 201484	Observational study Population: Primary school children with hyperactivity and concentration difficulties (n=169)	Intervention: Combination of V. officinalis 62%EtOH extract 640 mg and Melissa officinalis 30%EtOH 320 mg per day, for 7 weeks. Measures: (1) Concentration problems, hyperactivity, impulsiveness, impaired social behavior, difficulties to fall asleep, and morning fatigue (rated by paediatricians). (2) Questionnaire (filled out by parents).	Doctors’ rating: The treatment improved concentration and reduced hyperactivity and impulsiveness. Parents’ rating: Social behavior, sleep and symptom burden improved.	Two patients had transient moderate adverse reactions, however causal relation with the medication was judged unlikely.	M. officinalis	n/a
5	Taavoni S 201376	Randomized, placebo-controlled, triple-blind Population: Menopausal women with sleep problems (n=100)	Intervention: Valerian essence 160 mg and lemon balm 80 mg per day for 1 month Measures: PSQI	Significantly reduced sleep disorder score after 1 month of Valerian/Lemon balm treatment	No adverse events	M. officinalis	3
6	Maroo N 201375	Randomized, controlled, double-blind Population: Primary insomnia patients (n=78)	Intervention: 1. NSF-3: Polyherbal extract of V. officinalis (300 mg with 0.8% valerenic acid), Passiflora incarnata (80 mg with 4% isovitexin), and Humulus lupulus (30 mg with 0.35% rutin) at bedtime for 2 weeks. 2. Control: zolpidem 10 mg Measures: Insomnia (Insomnia severity index and ESS score)	Significant improvement in total sleep time, sleep latency, number of nightly awakenings and severity index score in both groups. No statistically significant difference between the groups.	Mild adverse events (e.g. drowsiness): 12 with herbal treatment (1), 16 with zolpidem (2)	P. incarnata H. lupulus	4
7	Trompetter I 201386	Observational (multicentre) Population: Children (6-12 years) suffering from nervous agitation due to affective disorders (n=115)	Intervention: Herbal triplet containing dried extracts of Valeriana officinalis (40%EtOH extract 28 mg), Hypericum perforatum (38%EtOH extract 60 mg), and Passiflora incarnata (60%EtOH extract 32 mg) per tablet. Average dose: 1-3 tablets per day. Duration: 2-4 weeks. Measures: A physician-completed questionnaire and a standardized parent-report questionnaire	81.6-93.9% of affected children had no or just mild symptoms (depression, anxiety, sleeping problems, and different physical problems) at the end of observation.	A good tolerability for 97.4% of the children. Moderate to poor tolerability in 7 cases. Paradox reactions: restlessness, weepiness, increased irritability, or aggressiveness; redness in cheekbone region (1 case); stomach pain (1 case)	H. perforatum P. incarnata	n/a
8	Chen JH 201274	Randomized, controlled Population: Stable and less critical ICU patients (n=95)	Intervention: Valerian acupressure (application of 2.5% V. officinals essential oil 2 drops per point before acupressure). Compared to regular treatment Measures: Sleep (observation, actigraphy measures (10pm-6 am), Stanford Sleepiness Scale (SSS) measures on the next morning	Valerian acupressure increased sleeping hours, reduced wake frequency and SSS grades. Heart rate variability indicated immediate relaxation response.		Acupressure	n/a
9	Melzer J 200973	Randomized, controlled, double-blind Population: Somatoform disorder patients (n=167)	Intervention: (1) Ze185 (4-combination) containing 90 mg of V. officinalis (45%MeOH extract), 90 mg of Petasites (90%EtOH extract), 90 mg of Passiflora incarnata (50%EtOH extract), and 60 mg of Melissa officinalis (20%EtOH extract); (2) 3-combination without Petasites; (3) placebo. 3 times daily for 2 weeks Measures: Anxiety (VAS) and depression (BDI)	Significantly reduced anxiety in both treatment groups (3- and 4- combination), but not in placebo. Effectiveness: 4-combination > 3-combination > placebo	Adverse events (1) 4-combination: vomiting and flatulence (2) 3-combination: nausea and constipation	P. incarnata M. officinalis Petasites	4
10	Dimpfel W 200872	Randomized, placebo-controlled, double-blind Population: Otherwise healthy volunteers having poor sleep (n=42)	Intervention: V. officinalis (tinct. 1:10) 460 mg and Humulus lupulus (tinct. 1:12) 460 mg. Single administration, 15 min before the lights were turned off at 22:00. Measures: (1) Depth of sleep (EEG); (2) Sleep quality (sleep inventory SF-A sub-score)	Time spent in sleep and deeper sleep was significantly higher in the treatment group, which was correlated with the difference in sleep quality.		H. lupulus	3
11	Koetter U 200765	Randomized, placebo-controlled, double-blind Population: Patients suffering from non-organic sleep disorders (n=27)	Intervention: (1) V. officinalis 45%MeOH extract 500 mg; (2) V. officinalis 45%MeOH extract 500 mg and Humulus lupulus 45%MeOH extract 120 mg (fixed combination Ze91019); (3) placebo. For 4 weeks. Measures: (1) the reduction of the initially prolonged sleep latency; (2) WASO, sleep efficiency, relative proportion of the sleep stages, REM latency and CGI	The fixed combination was significantly superior to placebo in reducing the sleep latency, whereas the single valerian extract did not differ significantly from placebo.	No adverse events.	H. lupulus	3
12	Müller SF 200689	Observational study Population: Children (average age: 8.3 years) with motor restlessness and sleep disturbance (n=918)	Intervention: V. officinalis 62%EtOH extract 160 mg and Melissa officinalis 30%EtOH extract 80 mg per tablet (Euvegal forte, Schwabe Pharmaceuticals, Germany), Max. 2x2 tablets/day (average: 3.5 tablets/day) for 4±1 weeks (average: 31.9 days). Measures: Severity of symptoms and improvement efficacy. Scored by the investigators and the parents.	Dyssomnia and restlessness were reduced from moderate/severe to mild or absent in most of the patients. (80.9% of dyssomnia patients and 70.4% of restlessness patients improved.) Both parents and investigators assessed efficacy to be very good or good (60.5% and 67.7%). Tolerability was good or very goof in 96.7% of the patients.	No adverse events.	M. officinalis	n/a
13	Kennedy DO 200678	Randomized, placebo-controlled, double-blind, cross-over Population: Healthy volunteers (n=24)	Intervention: 600 mg, 1200 mg, and 1800 mg of a standardized V. officinalis and Melissa officinalis extracts (V. officinalis: M. officinalis 3: 2). Three single doses, separated by a 7 day wash out period. Measures: (1) Modulation of mood and anxiety (Bond-Lader scales, STAI) after DISS battery exposure; (2) DISS performance	The 600 mg dose ameliorated the negative effects of DISS on anxiety, however 1800 mg increased anxiety. All 3 doses led to decrements in performance on the Stroop task module, and the 2 lower doses led to decrements on the overall score generated on DISS.		M. officinalis	3
14	Morin CM 200579	Randomized, placebo-controlled Population: Mild insomnia patients (n=184)	Intervention: (1) Combination of V. officinalis (45%MeOH extract) 187 mg and Humulus lupulus (45%MeOH extract) 41.9 mg, nightly for 28 days; (2) placebo for 28 days; (3) diphenhydramine 25 mg for 14 days followed by placebo for 14 days. Measures: Sleep parameters measured by daily diaries and polysomnography, clinical outcome ratings from patients and physicians, and quality of life.	Modest improvements of subjective sleep parameters in valerian-hops (1) and diphenhydramine (3). Valerian-hops produced slightly greater reductions of sleep latency relative to placebo and diphenhydramine after 14 days, and greater reductions than placebo after 28 days. No group difference on polysomnography. Quality of life was significantly more improved in valerian-hops group than the placebo group after 28 days.	No serious adverse events	H. lupulus	3
15	Schellenberg R 200480	Randomized, placebo-controlled Population: Healthy volunteers (n=32)	Intervention: Single doses of V. officinalis / Humulus lupulus 45%MeOH extract combination (500 mg / 120 mg, or 1500 mg / 360 mg). Valerian extract contained 0.388% if valerenic acids. Measures: competition between caffeine and valerian/hop on the central nervous system (EEG)	Valerian 500mg/hops 120 mg reduced, and valerian 1500mg/hops 360 mg inhibited caffeine-induced arousal, 60 min after oral administration.	Not mentioned	H. lupulus	3
16	Farag NH 200381	Randomized, placebo-controlled, double-blind, cross-over Population: Sleep onset insomnia (n=25)	Intervention: Combination of V. wallichi 320 mg, Rosa centifolia, Nardostachys jatamansi, Tinospora cordifolia, Withania somnifera, Piper negrum, Zingiber officinalis, Convolvulus pluricalis, and Glycyrrhiza glabra. Compared to placebo. 4 nights each with 10 days washout. Measures: Sleep latency (questionnaire)	The supplement reduced sleep latency. The effect was greater in subjects with worse insomnia.	None	Ayurvedic herbs	4
17	Müller D 200385	Observational Population: Patients suffering from mild to moderately severe depression (n=2,462)	Intervention: (1) V. officinalis 70%EtOH extract (Euvegal Balance) 500 mg or 1000 mg and Hypericum perforatum 60%EtOH extract (Neuroplant) 600 mg per day. For 6 weeks. Measures: Rating of 16 symptoms during each doctor’s visit (ICD-10 and HAM-A).	Core symptoms of depression and the main symptoms of anxiety disorder receded significantly. Efficacy was ‘very good’ or ‘good’ in 87.2%, and ‘poor’ in 1.6%. Tolerability was ‘very good’ or ‘good’ in 96.8%. Higher Valerian dosage could be more effective.	No significant side effects	H. perforatum	n/a
18	Vonderheid-Guth B 200082	Randomized, placebo-controlled, single-blind, cross-over Population: Young healthy male volunteers (n=12)	Intervention: Single dosages of V. officinalis and H. lupulus 45%MeOH extract combination (Ze91019). Low dosage: Valerian 500 mg and hops 120 mg. High dosage: valerian 1500 mg and hops 360 mg. Measures: Quantitative topographical EEG (qEEG). Performance Test (CPT) according to Dueker and Lienert (1965). Prior to, 1, 2, and 4 hours after drug intake.	qEEG: High dosage led to power increases in delta, decreases in alpha and beta. CPT: Concentration and performance capability were hardly influenced. (A minimal increase of mean answer time and mean time for correct answer was observed after 4 h after high dosage intake and 1 h after low dosage intake. – More pronounced after the low dosage.)		H. lupulus	2
19	Lindahl O 198983	Randomized, placebo-controlled, double-blind, cross-over Population: Volunteers with sleep difficulties and fatigue. (n=27)	Intervention: Single doses of (1) test preparation: V. officinalis extract (equivalent to 400 mg of the root), H. lupulus extract (375 mg equivalent) and M. officinalis extract (160 mg equivalent) or (2) Control: same amounts of hops and lemon balm and V. officinalis 4 mg equivalent Measures: Subjective rating of sleep quality	78% rated high valerian preparation better than the control.	No side effects.	H. lupulus M. officinalis	2

Abbreviations: BDI-Beck Depression Inventory, DISS-Defined Intensity Stress Simulator, DSST-Digit Symbol Substitution Test, DST-Digit Span Test, EEG-Electroencephalogram, HAM-A-Hamilton Anxiety Rating Scale, ICD-10-International Classification of Diseases 10th Revision, ISI-Insomnia Severity Index, PSQI-Pittsburgh Sleep Quality Index, TSST -, WASO-Wake Time After Sleep Onset