Natural Products from Single Plants as Sleep Aids: A Systematic Review

Abstract

Insufficient sleep, insomnia, and sleep-related problems are important health issues, as their overall prevalence accounts for about 30% of the general population. The aim of this study was to systematically review previous studies investigating the effects of orally administered single plant-derived extracts on sleep-related outcomes in humans. Data sources were PubMed, Google Scholar, and Cochrane Library. The data search was conducted in two steps: step 1, names of plants which have been studied as sleep aids in humans were searched and retrieved; and step 2, each ingredient listed in step 1 was then added into the search term. Only original articles or reviews were applicable to the scope of this review. Studies on human subjects, with or without sleep-related disorders, were included. Sleep-related disorders refer to not only insomnia or sleep behavior disorders but also diseases with sleep-related symptoms. Studies were considered eligible for this review when the plant extracts were administered orally. Outcome measures relevant to sleep quality, duration, or other sleep-related problems were included. Twenty-one plants were listed in the first step of the search as potential candidates for natural sleep aids. Seventy-nine articles using these single plant-derived natural products were included in the final review. Although valerian was most frequently studied, conflicting results were reported, possibly due to the various outcome measures of each study. Other plants were not as rigorously tested in human studies. There was limited evidence with inconclusive results regarding the effects of single plant-derived natural products on sleep, warranting further studies.

Introduction

The prevalence of insufficient sleep was reported to be over 30% among the U.S. population.^1
–3 Occasional insomnia, defined as having one or more symptoms of difficulty initiating or maintaining sleep, waking up too early, and poor quality of sleep, was also reported to be experienced by ∼25% of the U.S. general population.¹

About 37% of the responders from the national survey in the United States reported that they had fallen asleep during the day at least once in the previous 30 days due to insufficient sleep.¹ More seriously, 4.7% of the people had experienced nodding off or falling asleep while driving.³ Sleep-related problems, including falling asleep during the day while working or driving, not only would be related to personal health issues but also could cause social burden related to higher risk of industrial or traffic accidents and disorders precipitated by sleep insufficiency.

Insomnia is characterized by dissatisfaction with sleep quality and/or quantity, with difficulties in sleep initiation or maintenance, or with early morning awakening (Box 1). A general concept of etiologic model which can be summarized as the interplay between genetic diathesis and environmental stress altering the neurobiological psychobehavioral processes is shown in Figure 1.⁴ However, pathophysiologic mechanisms of insomnia disorder have not yet been fully elucidated and there is a lack of evidence supporting a universally accepted disease model;⁴ insomnia has been treated with various medications clinically.

FIG. 1.

General concept of etiologic model of insomnia.

Box 1.

Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) Criteria for Insomnia Disorder

Dissatisfaction with sleep quality or quantity and ≥1 of the following:

- Difficulty initiating sleep

- Difficulty maintaining sleep

- Early morning awakening with inability to return to sleep

Sleep difficulty occurs at least 3 nights/week

Sleep difficulty is present for at least 3 months

Sleep difficulty occurs despite adequate opportunity for sleep

Insomnia is not better explained by another sleep–wake disorder, a coexisting mental disorder, or the physiological effects of a substance

American Psychiatric Association.⁷⁶

However, the currently available and commonly used sleep aids are often related to adverse reactions such as daytime drowsiness, dependency, depression, and even suicidal thoughts/attempts.⁵ To address this critical unmet need, alternative approaches are warranted. Consequently, availability of effective sleep aids with fewer adverse effects has been recognized as a clinically unmet need and developing new investigational drugs or dietary supplements are two potential approaches to meet these needs. Considering the historical use of plant-derived natural products as the source of new investigational drugs or dietary supplements,^6
–8 a systematic review of literature could further elucidate the current status and future directions of the research of plant-derived natural products as sleep aids.

Plants have historically been a source of numerous drugs and medicinal foods. Examples of medications widely used in medical treatments range from opiates (e.g., morphine) to antibiotics (e.g., quinine) and antineoplastic agents (e.g., vincristine and paclitaxel). Medicinal plants have also been used in the fields of traditional Chinese medicine or complementary and alternative medicine. Plant-derived natural products were noticed as potential sleep aids as some herbal teas or extracts have traditionally been used as sleep remedies. Adverse reactions of commonly used sleep aids such as antihistamines and benzodiazepines also necessitate the consideration of natural products as possible alternatives.

We aimed to perform a systematic review of original articles that investigated the effects of the single plant-derived extracts, which were administered orally, on sleep-related outcomes in humans. Detailed methods for systematic review- search strategies, flow charts, and participant characteristics of each study are presented in Supplementary Data (Supplementary Tables S1, Supplementary Table S2, and Supplementary Figure S1; Supplementary Data are available online at www.liebertpub.com/jmf).

Plant-Derived Natural Products for Sleep

Valerian

Valerian (Valeriana officinalis) is a perennial plant, which has been used as a sleep-promoting herb, and is currently available as a dietary supplement.⁹ Bioactive compounds in this herb include valerenic acid, iridoids, including valepotriates, isovaleric acid, isovaleramide, alkaloids, gamma-aminobutyric acids (GABAs), flavanones, and 6-methylapigenin.^10
–12 Among these ingredients, valerenic acids and valepotriates have been presumed to be the main components which might be related to the sedating effects of the plant. Mechanism of action of valerian as a sleep remedy is still greatly unknown; however, evidence on the effects of increasing GABA concentrations in the synaptic cleft, either by promoting its secretion or by inhibiting its reuptake/degradation, was reported.¹³ Although GABA is one of the active ingredients of valerian, it is still unknown whether GABA in valerian extract could pass across the blood–brain barrier to be used in the brain.

Valerian was studied in 17 human trials, all of which have been included in this review (Table 1). Nevertheless, these studies showed conflicting results, possibly due to the different sleep-related outcome measures used in the studies. Those were the Pittsburgh Sleep Quality Index (PSQI),¹⁴ sleep diary, polysomnography (PSG), and wrist actigraphy. In addition, daily dosage varied from 225 to 1060 mg, usually before bedtime when administered once daily.

Table 1.

Studies of Valerian for Sleep

Study	Design	Participants (N)	Intervention	Treatment duration	Outcome measurement	Main results	Quality rating (Jadad scale)
Taavoni et al. ²¹	RCT, triple-blind, placebo-controlled	Postmenopausal women (100)	Valerian group (50): 1060 mg/day (530 mg twice a day, valerian root extract); placebo group (50)	4 weeks	PSQI	↓ PSQI (P < .001) and higher rate of subjective sleep improvement (30% vs. 4%, P < .001) in valerian group	4
Barton et al. ²²	RCT, double-blind, placebo-controlled	Cancer patients (119)	Valerian group (62): 450 mg 1 h before bedtime (root); placebo group (57)	8 weeks	PSQI; FOSQ; BFI	No significant effectiveness in PSQI AUC, FOSQ; ↑ amount of sleep; ↓ sleep latency (baseline vs. week 4 P = .03); ↓ fatigue in BFI	4
Cuellar and Ratcliffe¹⁸	RCT, triple-blind, placebo-controlled	RLS patients (37)	Valerian group (17): 800 mg/day 1 h before bedtime (root); placebo (20)	8 weeks	PSQI; ESS	No differences in PSQI; ↓ PSQI (5 components, P < .05) only in nested subgroup analysis of sleepy vs. nonsleepy persons	5
Taibi et al. ¹⁶	RCT, double-blind, crossover	Elderly women with insomnia (16)	Valerian group (16): 300 mg 0.5 h before bedtime (root); placebo (16)	2 weeks	MSQ; PSQI; wrist actigraphy; sleep logs	No significant difference on PSQI, MSQ	5
Taibi et al. ¹⁷	RCT, double-blind, placebo-controlled	Arthritis and mild sleep disturbance patients (15)	Valerian group (7): 600 mg 1 h before bedtime (root); placebo group (8)	5 days	Sleep assessment; sleep logs; wrist actigraphy	No significant difference on all sleep outcomes	5
Koetter et al. ⁴⁹	RCT, double-blind, placebo-controlled, prospective clinical study	Nonorganic sleep disorders (20)	Valerian group (10): 500 mg valerian extract; placebo group (10)	4 weeks	Ambulatory, sleep recording device (QUISI); proportion of sleep stage; REM latency; CGI	↓ Sleep latency (no superior valerian vs. placebo, valerian/hops group is superior to placebo group)	4
Oxman et al. ²⁰	RCT, double-blind, parallel group, placebo controlled	Insomnia patients (405)	Valerian group (202): 600 mg/day; placebo group (203)	14 days	Sleep diary; global self-assessment	No significant difference on self-reported sleep quality	5
Diaper and Hindmarch⁵⁰	RCT, single center, double-blind, placebo-controlled, crossover	Sleep disturbed participants (16)	Valerian group (16): 300 mg or 600 mg; placebo group	1 day	EEG; LSEQ	No significant difference	4
Coxeter et al. ¹⁹	RCT, double-blind, crossover study	Chronic insomnia patients (42)	Valerian group (42): 225 mg/day; placebo group (42)	1 week	Sleep diary	No significant differences	5
Francis et al. ⁵¹	RCT, double-blind, placebo-controlled, single-case methodology	Children with intellectual deficits (5)	Valerian group (5): 500 mg 1 h before bedtime (whole-root extract); placebo group (5)	2 weeks	Sleep diary	↓ Night awakenings (P = .008); ↑ total sleep time (P = .030); ↑ parent-rated sleep quality (P = .002); no significant difference for sleep latency (P = .188)	3
Poyares et al. ⁵²	RCT, placebo-controlled	Insomnia patients who continued to sleep poorly after long-term use of BZDs (37)	Valerian group (19): 300 mg/day; placebo group (18)	15 days	Sleep diary; EEG	↑ SQ (P = .000); ↑ sleep latency (P = .142); ↑ alpha count in SWS (P < .0001); ↓ amount of sleep (P = .006); ↓ WASO	2
Ziegler et al. ²³	RCT, double blind, multicenter	Nonorganic insomnia patients (202)	Valerian group (102): 600 mg/day 1 h before bedtime	6 weeks	SF-B (SQ; GES; PSYE; PSS; TRME; SWR)	↑ SQ (P < .01) and lower adverse events (28.4%) in valerian group	3
Herrera-Arellano et al. ⁵³	RCT, double-blind, crossover, controlled	Insomnia patients (20)	Valerian group (20): 450 mg/day 1 h before lights out; positive control (20): 450 mg/day (Valeriana officinalis extract)	1 day	PSG	↑ REM sleep duration; ↑ sleep efficacy; ↑ sleep architecture; ↓ sleep latency	3
Donath et al. ⁵⁴	RCT, double-blind, placebo-controlled, crossover	Patients with psychophysiological insomnia (16)	Valerian group (16): 600 mg, 1 h before bedtime; placebo group (16)	15 days (total 44 days)	EEG; EOG; EMG; ECG; VAS	No significant differences in ST, SQ, morning feeling, and daytime performance; ↑ sleep efficacy; ↑ SPT; ↑ REM sleep duration; ↑ SWS (P < .05)	3
Schulz et al. ⁵⁵	Double-blind, placebo-controlled	Poor female sleepers (14)	Valerian group (8): 405 mg three times/day; placebo group (6)	8 days	Sleep diary, PSG	↑ SWS (P = .0273)	2
Balderer and Borbely⁵⁶	Double blind, (crossover design for home study)	Home study: healthy people (10)	Valerian 450 mg; 900 mg; or placebo made of brown sugar	3 consecutive weeks × 3 (total 9 weeks)	Sleep questionnaires; self-rating scales; motor activity record	No significant differences in nighttime motor activity; ↓ sleep latency; ↓ wake time; ↓ night awakenings	2
Balderer and Borbely⁵⁶	Double blind, (crossover design for home study)	Laboratory study: healthy people (8)	Valerian group (8): 900 mg/day	5 consecutive nights (1 adaptation +4 nights)	Questionnaires, self-rating scales; polygraphic sleep record; EEG	No significant differences	2
Leathwood et al. ⁵⁷	Double-blind, repeated measures, random-order	People with subjective sleep complaints (8)	Valerian: 450 mg/day or 900 mg/day	12 days	Wrist activity meters; sleep questionnaires	↑ Stable sleep (P < .05); ↓ sleep latency (P < .1); ↑ sleepiness (P < .05)	2

AUC, area under curve; BFI, brief fatigue inventory; BZDs, benzodiazepines; CGI, clinical global impression; ECG, electrocardiogram; EEG, electroencephalography; EMG, electromyogram; EOG, electrooculogram; ESS, Epworth Sleepiness Scale; FOSQ, functional outcomes of sleep questionnaire; GES, feeling of refreshment after sleep; LSEQ, Leeds Sleep Evaluation Questionnaire; MSQ, Minnesota Satisfaction Questionnaire; PSG, polysomnography; PSQI, Pittsburgh Sleep Quality Index; PSS, psychosomatic symptoms in the sleep phase; PSYE, psychic exhaustion in the evening; QUISI, ambulatory, sleep recording device; RCT, randomized control trial; REM, rapid eye movement; RLS, restless leg syndrome; SED, symptom experience diary; SF-B, Sleep Questionnaire (Schlaffragebogen)-B; SPT, single patient trial; SQ, sleep quality; ST, sleep time; SWR, slow wave ratio; SWS, slow wave sleep; TRME, dream recall; VAS, visual analog scale; WASO, wake after sleep onset.

Five studies, which scored the highest with scores of 5 points on the Jadad scale,¹⁵ a scoring system that assesses the methodological quality of a clinical trial, reported that there were no benefits of valerian on sleep-related outcomes, PSQI, sleep logs, sleep diaries, or other types of self-rated assessments. Four out of five studies had small sample sizes: 16 elderly women with insomnia,¹⁶ 15 arthritis patients with mild sleep disturbance,¹⁷ 37 restless leg syndrome patients,¹⁸ and 42 people with chronic insomnia.¹⁹ Oxman et al. ²⁰ reported that minimally important improvement in self-reported sleep quality was not different between valerian and control groups when treated with 600 mg daily dose of valerian for 14 days in a randomized, double-blind, placebo-controlled clinical trial of 405 insomnia patients. Significant differences were only found in the perceived sleep quality question in the global self-assessment questionnaires.²⁰

In two randomized controlled trials (RCTs) with relatively large numbers of subjects, participants experienced insomnia as a postmenopausal symptom or cancer-related symptom. Taavoni et al. ²¹ conducted a triple-blind placebo-controlled RCT in 100 postmenopausal women. The PSQI scores were significantly lower in the valerian group when 530 mg twice daily dose of valerian was administered for 4 weeks. Subjective improvement of sleep quality (30% vs. 4%) were also presented in this study.²¹ Results of Barton et al.'s²² double-blind, placebo-controlled RCT in 119 cancer patients showed that once daily administration of 450 mg valerian before bedtime was not effective in improving sleep quality or fatigue in patients undergoing cancer treatments. The study by Ziegler et al. ²³ was a double-blind RCT on 202 subjects with nonorganic insomnia. A daily dose of 600 mg valerian or 10 mg oxazepam was administered for 6 weeks, and effects on sleep were evaluated using the Sleep Questionnaire (Schlaffragebogen)-B (SF-B).²³ Sleep quality improved in both groups without a between-group difference, showing that valerian's efficacy was comparable to that of oxazepam. However, other objective measures of sleep quality or duration were not available in this study. The rest of the studies that were published before 2002 scored 2 or 3 points in the Jadad scale and performed in 10–20 subjects.

Our conclusion is in concordance with that of a systematic review on the efficacy and safety of valerian: it is safe but has insufficient evidence on its efficacy.²⁴

Lavender

Lavender compounds include linalyl acetate, linalool, 1,8-cineole, β-ocimene, and flavonoids.²⁵ Linalyl acetate and linalool are considered as the main ingredients, which could be related to the sleep-promoting effects of lavender, by modulating actions of glutamate and GABA in animal models.^26,27 However, individual ingredients did not seem to exert their effects if administered separately.²⁵ Although lavender has also been used as an agent in aromatherapy, we reviewed studies in which lavender extracts were administered orally. There is a commercially available Lavender oil product, in the form of a soft gelatin capsule, named Silexan (Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany).

Three RCTs and one open-label exploratory trial were included in our review (Table 2): one in postpartum women and three in patients with anxiety disorders. Chen and Chen²⁸ used lavender tea as an intervention while other studies^29
–31 utilized the commercial drug, Silexan. In the study by Chen and Chen²⁸ postpartum women with sleep problems were treated with lavender tea (2 g of dried lavender flower in 300 mg of water). Although there were no differences in sleep quality scores after 4 weeks of treatment, fatigue level significantly decreased. A study by Uehleke el al.³¹ reported that 6 weeks of Silexan administration increased total sleep time and sleep efficiency and reduced waking-up frequencies, waking-up duration, and tiredness, while improving self-reported mood in the morning. However, it was an open-label exploratory trial in heterogenous groups of patients with posttraumatic stress disorder, neurasthenia, or somatization disorders without a proper control group. The remaining two trials which were performed in patients with anxiety disorders accompanied with sleep disturbances showed conflicting results, although the two studies were performed by the same investigator.^29,30

Table 2.

Studies of Plant-Derived Natural Products Other than Valerian for Sleep

Study	Design	Participants (N)	Intervention	Treatment duration	Sleep outcome measures	Main results	Quality rating (Jadad scale)
Apocynum venetum (dogbane or Indian hemp) leaf
Yamatsu et al. ⁵⁸	Single-blind, placebo-controlled, crossover, nonrandomized trial	Adults with PSQI ≥6 (16)	GABA (100 mg + dextrin 50 mg) vs. AVLE (50 mg + dextrin 50 mg) vs. GABA+AVLE (GABA 100 mg + AVLE 50 mg) vs. Placebo (dextrin 150 mg) crossover with 1 week washout period	1 week	Sleep EEG: sleep onset latency; NREM latency; NREM duration; REM duration; awakening frequency; delta wave power	↑ 7.6% NREM duration	2
Asparagus officinalis (asparagus) stem
Ito et al. ⁵⁹	Study 1: RCT, double-blind placebo controlled; Study 2: RCT, double-blind, placebo-controlled, crossover design	Study 1: healthy men (20); Study 2: healthy men (18)	Study 1: ETAS group: mixture of ETAS and dextrin (50 mg ETAS +200 mg Pinedex/capsule) at the same time after dinner; placebo group: 750 mg dextrin (Pinedex/capsule); Study 2: same dose as in the Study 1, crossover following 2 weeks of washout	Study 1: 7 days; Study 2: 7 days (intervening washout period of 2 weeks)	Study 1: the expression level of HSP70 mRNA in blood; Study 2: actigraphy	Study 1: ↑ expression level of HSP70 mRNA in the ETAS group; no significant differences between the ETAS and placebo groups; Study 2: no significant differences in any sleep parameters	2
Bryophyllum pinnatum (air plant, cathedral bells, life plant, or miracle leaf)
Simoes-Wust et al. ⁶⁰	Observational, case-only	Cancer patients (61)	3–8 chewable tablets/day (350 mg/tablet)	21 days	PSQI, FSS	↓ PSQI [12.2 ± 3.62 to 9.1 ± 3.61 (P = .002)]—subscales on sleep quality; sleep efficiency; sleep latency; and habitual sleep disturbance; ↓ FSS	NA
Lambrigger-Steiner et al. ⁷⁷	Observational, case-only	Pregnant women with sleep problems (60)	3–8 chewable tablets/day (350 mg/tablet)	≥14 days	Questionnaire adapted from the PSQI and including all items in ESS and FSS	↑ Subjective sleep quality; ↓ number of wake-ups per night; ↓ ESS; No difference in sleep duration or FSS	NA
Matricaria recutita (chamomile)
Zick et al. ⁶¹	RCT, double-blind, placebo-controlled pilot trial	Patients with primary insomnia for ≥6 months (34)	Experimental (17): 540 mg daily; control (17)	28 days	Sleep diary (TST, SE); ISI; PSQI; FSS	No significant differences in TST, SE, SL, WASO, sleep quality, and number of awakenings	4
Gardenia jasminoides Ellis (gardenia or cape jasmine)
Kuratsune et al. ⁶²	RCT, double-blind, placebo-controlled, crossover design	Healthy men with mild sleep complaint (17)	Experimental: 7.5 mg of crocetin (capsule) daily between 6 pm and 8 pm; control: dextrin	2 weeks (2 weeks of washout period)	Actigraphy; SMHSQ	Lower number of wake episodes in crocetin group compared to control group (P < .05, paired t-test); no significant differences between before and after intake in each group (from 4.2 ± 2.5 to 3.9 ± 2.9 vs. from 4.4 ± 3.0 to 5.5 ± 2.9 in control group); no differences in SMHSQ	4
Ginkgo biloba (ginkgo)
Murray et al. ⁶³	RCT, placebo-controlled, crossover design	Healthy volunteers (10)	Experimental: Li 1370 (240 mg), 2 h before retiring	1 day each (7 days of washout period)	PSG	No significant differences in all outcome measures	5
Hemmeter et al. ⁶⁴	Observational, not controlled	Adults with major depressive episodes taking Trimipramine (16)	Experimental (8): 240 mg/day (120 mg EGb Li 1370 twice daily, in the morning and in the evening); control (8): age and gender matched, no placebo	4 weeks	PSG	Higher SE, reduced stage 1, prolonged stage 2, lower REM density, and longer duration of NREM sleep in experimental group	NA
Humulus lupulus (hop)
Cornu et al. ⁶⁵	RCT, double-blind, placebo controlled	Adults with chronic primary insomnia (99)	Experimental (50): 2 capsules of Cyclamax^®/day (260 mg of Soya oil [Glycine max], 173 mg of Cade oil [Cannabis sativa], 50 mg of Houblon [Humulus lupulus], and 6 mg [Soya lecithin]); control (49): capsules containing olive oil	30 days	LSEQ; sleep diary; actigraphy; night melatonin; and aMT6s urine rates	No differences between experimental and control groups in all of the outcome measures	4
Franco et al. ⁶⁶	Longitudinal intervention	Healthy female nurses working rotating and/or night shifts (17)	330 mL of alcohol-free beer (San Miguel 0.0% alcohol) with supper	14 days	Actigraphy	Diminished SL (12.01 ± 1.19 min in experimental condition vs. 20.50 ± 1.19 min in control, P < .05); and TL (5284.78 ± 836.99 in experimental condition vs. 7258.78 ± 898.89 in control, P < .05)	NA
Piper methysticum (kava)
Jacobs et al. ³⁵	RCT, 3-arm, double-blind, placebo controlled	Adults with symptoms of anxiety and insomnia (391); Kava (121); Valerian (135); Placebo (135)	Kava group (121): 1 Kava capsule (containing 100 mg of total kavalactones) × 3/day +2 placebo-Valerian capsules 1 h before bedtime; Valerian group (135): 2 Valerian capsules (3.2 mg of valerenic acids; 1% valerenic acid in extract) 1 h before bedtime +1 placebo-Kava capsule × 3/day	4 weeks	ISI; STAI-State	No differences in sleep and anxiety score compared to placebo	5
Lehrl³²	RCT, double-blind, placebo controlled	Adults with sleep disturbance associated with syndromes of anxiety, tension, or restlessness (57)	Experimental (34): 200 mg/day WS^® 1490, taken in the evening; control (23): placebo	4 weeks	The Sleep Questionnaire (SF-A and SF-B); HAMA; Bf-S; CGI	Improved: overall quality of sleep (SF-B subscore 1) in both groups, more pronounced in WS 1490 group; Increased recuperative effects after sleep (SF-B subscore 2) in day 42 of WS 1490 group	5
Wheatley³⁶	Crossover trial, not double-blind, not placebo controlled	Adults with stress-induced insomnia of varying duration and intensity (24)	Kava-only group (24): 120 mg/day daily; Kava followed by Valerian group (19): Valerian 600 mg/day after period of Kava administration	6 weeks each (2 weeks washout period)	Sleep disturbance score in 3 parameters (time to fall asleep; hours slept; and mood on final waking)	Reduced severity of insomnia (mean total score from 178.1 to 126.7) (P < .01, 95% CI: 18.3–84.2)	1
Kudzu root
Bracken et al. ⁶⁷	CCT, double-blind, placebo-controlled, crossover trial	Moderate alcohol drinkers (10)	Experimental: 750 mg/day total isoflavones (NPI-031; Alkontrol-Herbal^®, NPI); placebo: gelatin capsule	9 days (intervening washout period of 21 days)	Wrist actigraphy (SE, SL, TST, number of waking episodes, time awake per episode)	No difference between experimental and placebo phases	2
Lavandula angustifolia (lavender)
Chen et al. ²⁸	RCT	Postpartum women with sleep problems (PSQS score ≥16) (76)	Experimental group (38): drinking lavender tea (2 g of dried lavender flower in 300 mg of water); control group: routine postpartum care (38)	2 weeks	PSQS and PFS	No differences in PSQS in 2 and 4 weeks; ↓ PFS in 2-week posttest	3
Kasper et al. ²⁹	RCT, double-blind, placebo controlled	Adults with anxiety-related restlessness and disturbed sleep (148)	Experimental group (74): Silexan (essential oil from Lavandula angustifolia) 1 capsule (80 mg)/day; control (74)	10 weeks	PSQI	No improvement in PSQI	5
Uehleke et al. ³¹	Open-label, exploratory trial	Adults with neurasthenia, posttraumatic stress disorder, or somatization disorder (50)	80 mg of lavender oil capsules	6 weeks	Sleep diary	From baseline, ↑ TST (P = .04, Wilcoxon test); ↓ waking-up frequency (P = .002); ↓ waking-up duration (P < .001); ↑ sleep efficiency (P = .018); ↓ tiredness (P = .005); better mood in the morning (P = .03)	NA
Kasper et al. ³⁰	RCT, double-blind, placebo controlled, multicenter trial	Adults with anxiety disorder (211)	Experimental group (107): 80 mg of Silexan capsule; placebo (104): 0.08 mg of lavender oil (to match smell)	10 weeks	PSQI, CGI	44.7% (5.5 ± 4.4 points) ↓ of PSQI in experimental group vs. ↓30.9% (3.8 ± 4.1 points) in placebo group in 10 weeks (P = .001, ITT, two-sided t-test)	5
Leonurus cardiaca (motherwort)
Shikov et al. ⁶⁸	Open, prospective pilot study	Patients with arterial hypertension stages 1 and 2 and accompanied by anxiety and sleep disorders (50)	1200 mg of oil extract daily (twice daily, in the morning and in the evening)	28 days	CGI; SCAG scale; SAM	From the baseline, patients with stage 1 and 2 reported reduced sleep disorders in 21 days of treatment	NA
Melissa officinalis L. (lemon balm) leaf
Cases et al. ⁶⁹	Open-label prospective study	Mild-to-moderate anxiety disorders, sleep disturbance, otherwise healthy adults (20)	600 mg of Cyracos^® daily (twice, one in the morning and the other in the evening before falling asleep)	15 days	HRSD, CGI-I	Insomnia decreased by 42% (from 1.13 ± 0.10 to 0.30 ± 0.06, P < .01); 20/20 participants demonstrated improved insomnia	NA
Alijaniha et al. ⁷⁰	RCT, double-blind, placebo controlled	Adults suffering from benign palpitations (55)	Experimental (28): 1000 mg (500 mg twice a day); control (27)	14 days	General Health Questionnaire-28 (GHQ-28)	↓ Number of patients with anxiety and insomnia symptoms in experimental group (from 75% to 42.8% in the experimental group vs. from 81.5% to 66.6% in placebo group, P = .004)	5
Xylaria nigripes mycelia
Lin et al. ⁷¹	RCT, double-blind, placebo-controlled, multicenter study	Adults with insomnia (186); control (92)	Experimental group (94): 0.99 g of Wuling capsules (0.33 g/capsule, 3 times daily); control group (92)	4 weeks	PSQI	PSQI scores improved in both groups (from 11.78 ± 2.80 to 7.53 ± 3.11 (t = 11.00) in experimental; from 11.55 ± 2.10 to 7.60 ± 3.20 (t = 9.86) in control); no difference between groups	5
Passiflora incarnata (maypop or purple passionflower)
Ngan and Conduit⁷³	CCT, double-blind, placebo-controlled, crossover design	Healthy adults (41)	Experimental: 2 g of dried Passiflora incarnata leaves, stems, seeds, and flowers by aqueous delivery (teabag); control: parsley	1 week (1 week of washout period)	PSG; sleep diary	Higher mean rated SQ in experimental condition; no significant differences in SOL, SE, TST, and NNA	3
St John's Wort (Hypericum perforatum)
Schulz et al. ⁴⁷	RCT, double-blind, placebo-controlled, crossover design	Older adults (12)	900 mg/day of hypericum extract LI 160 (Jarsin^®) (300 mg, 3 times/day)	4 weeks each for experimental and placebo	PSG (visual and automated sleep analyses)	No differences in SO, TST, median SE, and median period awake; Increase in mean percentage of slow-wave sleep (stages 3 and 4) in 9/12 subjects in experimental condition; increase in SWA; delay in the occurrence of the first SWA peaks; early in the occurrence of the first SWA peaks	3
Sharpley et al. ⁴⁵	RCT, double-blind, placebo-controlled, balanced order, crossover design	Healthy volunteers (21)	Study 1 (11): Hypericum as Kira 0.9 mg (Lichtwer Pharma); Study 2 (10): Hypericum 1.8 mg	7–14 days	PSG	Increase in REM latency compared to placebo group: mean not statistically greater with higher dose (Study 2); no effect on REM sleep duration or on any other parameter	1
Al-Akoum et al. ⁴⁶	RCT, double- blind, placebo-controlled, pilot trial	Perimenopausal women with menopausal symptoms (42)	Experimental (20): 900 mg of St. John's Wort (300, 3 times/day) taken at mealtime; control (22)	3 months	Sleep problem scale	Decreased score of sleep problem scale in experimental group (between-group effect size = −0.67)	4
Prunus cerasus (tart Montmorency cherry)
Pigeon et al. ⁷³	RCT, double-blind, placebo-controlled, crossover design	Older adults with chronic insomnia (15)	Experimental: 8-ounce servings of TCJ twice daily (one in the morning between 8 and 10 am and the other in the evening 1–2 h before bedtime); control: placebo juice	2 weeks each	Sleep diary; ISI	Within-group pre- and posttreatment changes: significant for ISI, SL, WASO, TST, and SE with moderate effect sizes in TCJ group compared to control (only improvement in TST); between-group in reduced ISI and WASO; no differences in SL, TST, or SE	5
Howatson et al. ⁷⁴	RCT, double-blind, placebo-controlled, crossover design	Healthy adults (20)	Experimental: 60 mL/day (30 mL within 30 min of wakening and 30 min before the evening meal)	7 days (14 days of washout period)	Actigraphy; online subjective sleep questionnaires; urinary 6-sulfatoxymelatonin	Higher total urinary melatonin content; decreased napping time; increased time in bed, TST, and SE total in TCJ group	2
Withania somnifera (ashwagandha)
Raut et al. ⁷⁵	Open-label, exploratory	Healthy volunteers (18)	Increase in daily dosage every 10 days: 750 mg/day (6 g of crude pulverized roots of WS) × 10 days; 1000 mg/day (8 g) × 10 days; and 1250 mg/day (10 g) × 10 days (administered in the morning and at night)	30 days	Sleep diary	No significant changes in duration of sleep; improved quality of sleep reportedly improved in 6/18 volunteers	NA

AVLE, Apocynum venetum leaf; FSS, Fatigue Severity Scale; GABA, gamma-aminobutyric acid; HAMA, Hamilton Anxiety Scale; HRSD, Hamilton rating scale for depression; ISI, Insomnia Severity Scale; NNA, number of nocturnal awakenings; NREM, nonrapid eye movement; PFS, Postpartum Fatigue Scale; PSQS, Postpartum Sleep Quality Scale; SAM, state-activity-mood; SE, sleep efficiency; SL, sleep latency; SMHSQ, St Mary's Hospital Sleep Questionnaire; SO, sleep onset; SOL, sleep onset latency; STAI, state-trait anxiety inventory; SWA, slow wave activity; TCJ, tart cherry juice; TST, total sleep time.

Kava

Kava is a member of the pepper family and is native to the Pacific islands. Kava roots were used for relaxation in traditional rituals in this area (National Center for Complementary and Integrative Health [NCCIH] Clearinghouse, https://nccih.nih.gov/health/kava). Active ingredients of kava include a class of lactone named as kavalactones or kavapyrones. Kavalactones include kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangostin.^32,33 Results from animal experiments suggest that these ingredients can modulate GABA actitivies.³⁴

Three studies on kava were eligible for this review (Table 2). Two out of three included articles that used kava in combination with or in parallel to valerian. Jacobs et al. ³⁵ reported results from an RCT in 391 individuals with anxiety and insomnia symptoms. Effects of kava on the changes in the Insomnia Severity Index scores were examined in comparison to those of valerian and placebo. However, neither kava nor valerian significantly improved insomnia or anxiety. Wheatley³⁶ divided 24 subjects with stress-induced insomnia into kava-treated, kava followed by valerian-treated, and valerian followed by kava-treated experimental groups. This research was a nonrandomized, nonblinded, and placebo-uncontrolled study.

In an RCT by Lehrl³² improvements in overall quality of sleep, measured using the SF-B, were more pronounced in the kava group than in the control group. A subscore of the SF-B on recuperative effects after sleep remained until the end of treatment and follow-up, while that in the control group returned to baseline after 2 weeks.

In conclusion, kava was reported to be effective for improving sleep in a small number of RCTs. A paucity of literature might be due to the fact that kava has been associated with liver damages.³⁷

St. John's Wort

The major ingredients of St. John's Wort or Hypericum perforatum related to its effects in sleep or other psychological conditions are hyperforin and adhyperforin.^38,39 These ingredients were considered to increase monoamine neurotransmitter concentrations, such as serotonin or noradrenaline, by inhibiting reuptake or degradation as reported in animal models.^40
–42 In contrast, there has also been conflicting evidence that ingredients of St. John's Wort may not affect monoamine neurotransmitter activities.^43,44

Three RCTs that were reviewed involved relatively small sample sizes (Table 2). One was performed in 21 healthy volunteers and reported that rapid eye movement sleep latency measured with home PSG was increased significantly with either 0.9 g or 1.8 g daily dose administered before bedtime.⁴⁵ Al-Akoum et al. ⁴⁶ reported that 900 mg of St. John's Wort decreased scores of the Sleep Problem Scale in perimenopausal women after 12 weeks of oral administration. In contrast, Schulz and Jobert⁴⁷ RCT in 12 older adults showed that 900 mg/day increased mean percentage of slow-wave sleep without changing total sleep time.

Commercial names of drugs containing St. John's Wort extracts were Jarsin^® and Kira™, used in Schulz and Jobert⁴⁷ and Sharpley et al.,⁴⁵ respectively. Both were manufactured by a common manufacturer and considered to be identical.⁴⁴ Although St. John's Wort is considered a safe treatment, it should be considered that there was a notice regarding the possibility of developing serotonin syndrome, by the NCCIH.⁴⁸

Conclusion

Although plant-derived natural products have been used for sleep empirically, there was a paucity of evidence on the efficacy of each plant in RCTs and other types of human trials, warranting future investigations.^80,81 As this review did not retrieve all the ingredients of each plant, further efforts are needed to identify each ingredient from the plants and to pinpoint chemicals that are primarily responsible for their efficacy. However, before these steps are taken, robust supporting evidence for each specific plant's effectiveness for alleviating sleep-related problems is needed, because these procedures of identifying ingredients and pinpointing effective chemicals would require resources of funding and approval or clearance from the authorities.

Footnotes

Acknowledgments

Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through High Value-Added Food Technology Development Program, funded by the Ministry of Agriculture, Food and Rural Affairs (MAFRA) (116004-2), Fire Fighting Safety & 119 Rescue Technology Research and Development Program funded by the Ministry of Public Safety and Security (MPSS-Fire Fighting Safety-2016-86), and the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2015M3C7A1028376).

Author Disclosure Statement

J.E. Kim received research support from NeoCremar Inc. No competing financial interests exist for all other authors.

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