Plant Extracts for Sleep Disturbances: A Systematic Review

Background Sleep complaints are common health issues in the general population. These conditions are associated with poorer physical and psychological activity, and they may have important social, economic, and personal consequences. In the last years, several food supplements with different plant extracts have been developed and are currently taken for improving sleep. Study Objectives. The aim of this study is to systematically review recent literature on oral plant extracts acting on sleep disorders distinguishing their action on the different symptoms of sleep complaints: difficulty in initiating or maintaining sleep, waking up too early, and quality of sleep. Methods We searched the PubMed database up to 05/03/2020 based on data from randomized, double-blind, placebo-controlled trials, noncontrolled trials, and cohort studies conducted in children and adult subjects. The search words used contained the following terms: oral food supplement and sleep disorders and the like. The most studied compounds were further analyzed with a second search using the following terms: name of the compound and sleep disorders. We selected 7 emerging compounds and 38 relevant reports. Results Although nutraceutical natural products have been used for sleep empirically, there is a scarcity of evidence on the efficacy of each product in clinical studies. Valerian and lavender were the most frequently studied plant extracts, and their use has been associated (with conflicting results) with anxiolytic effects and improvements in quality and duration of sleep. Conclusions Sleep aids based on plant extracts are generally safe and well tolerated by the population. More high-quality research is needed to confirm the effectiveness of food supplements containing plant extracts in sleep complaints; in particular, it would be interesting to evaluate the association between plant extracts and sleep hygiene guidelines and to identify the optimal products to be used in a specific symptom of sleep complaint, giving more appropriate tools to the medical doctor.


Introduction
Insomnia is defined as dissatisfaction with sleep quality or quantity in addition to at least one other symptom among difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening with inability to return to sleep [1]. Occasional insomnia is a very common disturb that has been reported to be experienced by about 30% of the U.S. general population [1][2][3]. Sleep disorders have an important societal and economic impact, with a consequent reduction in labour productivity or increased risk of accidents [4][5][6]. Chronic insomnia is also a risk factor for a variety of significant health problems, such as cardiovascular disease [7,8], diabetes [9], and obesity [10], as well as bad mood and cognitive dysfunction [11][12][13]. Almost half of the individuals with sleep problems had never taken any steps to resolve them, and the majority of respondents had not spoken with a physician about their problems. Of those individuals who had consulted a physician, drug prescriptions had been given to approximately 50% in Western Europe and the USA [14]. e commonly used sleep aids based on benzodiazepine and nonbenzodiazepine hypnotic drugs are often related to negative side effects such as daytime drowsiness, dependency, depression, hypnotic-withdrawal insomnia, and even excess mortality [15]. Moreover, there are limited data on long-term efficacy of hypnotic drugs [16]. Given these concerns and an increasing patient preference for nonpharmacological treatments [17], it is important to offer patients with insomnia evidence-based nonpharmacologic alternatives that may improve their sleep.
As defined in the Dietary Supplement Health and Education Act of 1994 (DSHEA), a dietary supplement is "a product (other than tobacco) intended to supplement the diet that bears or contains one or more dietary ingredients, including a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by humans to supplement the diet by increasing the total dietary intake of any of the aforementioned ingredients [18]." A growing body of evidence has shown promising results for these compounds in supporting health and body functions [19]. In particular, several dietary supplements are popularly used for sleep disorders [20], also in addition to other remedies (e.g., sleep hygiene and mind-body therapies) [21]. Moreover, no golden standard therapy is recommended to treat mild sleep disorders related to specific sleep stages (starting, maintaining, and ending sleep) [22,23].
Our aim in this study was to systematically review recent literature on plant extracts and nutraceuticals administered orally and acting on sleep-related disorders. In particular, we differentiated the interventions and the outcomes of the studies based on the different sleep disorders (difficulty in initiating or maintaining sleep, quality and quantity of sleep, and waking up too early) and reviewed the available clinical data of the 7 most studied natural products: valerian, lavender, chamomile, hop, St. John's wort, hawthorn, and rosemary.

Materials and Methods
A literature search was performed using a primary medical search engine the PubMed database considering all articles published up to 05/03/2020; the registered review protocol can be found at: https://www.crd.york.ac.uk/PROSPEROFILES/ 126991_PROTOCOL_20190301.pdf. e review was registered on PROSPERO (international prospective register of systematic reviews in https://www.crd.york.ac.uk/prospero/), registration number CRD42019126991. e inclusion criteria were randomized, double-blind, placebo-controlled trials, noncontrolled trials, and cohort studies. We used the following search terms to search the PubMed register: (Oral food supplement) OR (Oral nutraceutical) OR (Oral natural products) AND (Sleep disorders) OR (Insomnia) AND "humans" [Filter] AND "English" [Filter]. e most studied compounds were singled out and further analyzed with a second search using the terms: (name of the compound) AND (Sleep disorders) OR (Insomnia) AND "humans"[Filter] AND "English" [Filter]. Only articles written in English and only studies conducted on humans were selected for this review. Additionally, the same research criteria were applied also for the Spanish language but no additional references were found. We contacted the study authors to retrieve the full article where only the abstract was available. We selected 7 emerging compounds and 35 relevant reports, excluding duplicates, nonrelevant articles, reviews, and works with no full article available ( Figure 1). Information was extracted from each included trial in view of: (1) type of food supplement for sleep disorders (herbal component, dose, length of the treatment, and additional substances) and (2) clinical endpoints considering the different stages of sleep and sleep problems: sleep latency, sleep maintenance, quality of sleep, and quantity of sleep. Finally, the risk of bias of individual studies was considered both at study or outcome level, and the Jadad scale [24] for quality rating was used to assess the quality of works. Parameters considered were randomization, blinding, withdrawals, sample size, quality of data reported, and statistical analysis. Publication bias and selective reporting within studies are likely to be affecting the selected literature for this review.

Valerian (Valeriana officinalis).
Valerian is the most studied plant for sleep disorders. We selected 17 articles on this subject to be included in the present review. e results of clinical trials performed to test valerian as a sleep aid are controversial and conflicting. Several studies showed an improvement in sleep quality [25][26][27][28][29][30][31][32] after administration of valerian at doses ranging from 160 to 600 mg a day. Differently, other studies reported no improvement in sleep quality (measured with Pittsburgh sleep quality index, PSQI, or perceived) [33][34][35]. Additionally, valerian was shown to reduce wake time after sleep onset [25,27], to improve sleep latency and duration [36,37], and to ameliorate insomnia severity score [38]. Conversely, a study from Jacobs and collaborators showed no changes in the insomnia severity score (ISI) compared to placebo [39]. Diaper and collaborators in a small study observed no changes in polysomnographic parameters or psychometric measures after one dose of 300 mg or 600 mg of valerian [40], and Coxeter reported no changes in total sleep time or number of nocturnal awakenings in the participants' responses in a nof-1 analysis of 24 subjects [41].
Some trials investigated the possible mechanism of action of the effect of valerian as sleep aid. e study from Mineo and collaborators showed that a single oral dose of Valeriana officinalis extract caused a significant reduction in intracortical facilitation, a change associated with reduced anxiety [42].

Lavender (Lavandula).
In 2010, Woelk and collaborators showed in a double-blind, randomised study with 77 subjects that silexan, an oral lavender oil capsule preparation, is as effective as lorazepam in adults with generalised anxiety disorder (GAD). Hamilton Anxiety Rating Scale (HAM-A) scores for anxiety and sleep diary scores demonstrated comparable positive effects [43]. Two studies from Kasper et al. in 2010 [44] and 2015 [45] with a dose of 80 mg of silexan showed significant improvement in sleep quality (PSQI) and anxiety (HAM-A) compared to placebo. Finally, an open-label trial with silexan and 47 participants indicated a reduction of nocturnal awakening frequency and duration after 6 weeks of assumption of the food supplement [46].

Hop.
A double-blind, randomized placebo-controlled trial on 171 volunteers with sleep difficulties reported no significant changes in sleep quality (PSQI) after assumption of the LZComplex3 (hops 500 mg) for 2 weeks [47]. Another study with 101 volunteers with chronic primary insomnia assuming two gelatine capsules of Cyclamax ® (50 mg hop) per day for a month, showed no effects on sleep quality Leeds 2 Evidence-Based Complementary and Alternative Medicine sleep evaluation questionnaire (LSEQ), melatonin metabolism, and sleep-wake cycle [48].

Chamomile.
A study on sixty elderly people who assumed chamomile extract capsules (200 mg) twice a day for 28 consecutive days reported improvements in general sleep quality and sleep latency (PSQI) [49].
Chang and colleagues conducted a study on the effects of drinking chamomile tea on sleep quality in sleep disturbed postnatal women and found a modest improvement in the PSQS (postpartum sleep quality scale) subscale "physical symptoms-related sleep inefficiency" at 2 weeks but not at 4 weeks [50]. Finally, Zick and colleagues performed a pilot trial with 34 subjects with DSM-IV primary insomnia and found no significant improvements in ISI and PSQI [51].
No trial investigated directly the effects of hawthorn in sleep disorders. John's wort decreased scores of the sleep problem scale compared with placebo in perimenopausal women after 12 weeks of oral administration [53].
No trial investigated directly the effects of St. John's wort in sleep disorders.

Rosemary (Rosmarinus officinalis L.).
A randomized clinical trial from Nematolahi and collaborators on subjects who received 500 mg of rosemary showed a significant improvement in sleep quality using the PSQI after one month, but not on sleep latency and sleep duration [54].

Valerian and Hops.
Some clinical trials investigated the combined effect of different plant extracts on sleep related problems; the most studied combination of ingredients is valerian and hop.
Dimpfel and Suter reported that a single dose administration of a valerian and hop fluid extract improved total sleep time and quality of sleep in poor sleepers [55]. Maroo et al. tested a mixture of valerian, passion flower, and hop extract and found significant improvements in sleep time, sleep latency, number of nightly awakenings, and insomnia severity index after a 2 week treatment [56]. Koetter et al. showed a reduction of sleep latency after a treatment period which lasted for 4 weeks with a fixed extract combination of valerian and hop [57].
Conversely, Morin et al. found very modest effects of a valerian and hop combination and only in quality of life scores [58]. Finally, a study from Sun investigated the effects of a mixture of herbal extracts (kava, hop, valerian, and many others) on sleep disturbance in menopausal women. e authors reported that the formula significantly reduced global PSQI score and scores in five components (sleep quality, sleep latency, sleep duration, sleep disturbance, and daytime dysfunction) [59]. Table 1 shows the 35 studies included in this review. Table 2 summarizes the effects of the different compounds on sleep parameters. Evidence-Based Complementary and Alternative Medicine

Discussion
Sleep disturbances are widespread and affect a high percentage of the general population [1][2][3]. Food supplements use for sleep complaints is extensively adopted. In a survey in the province of Quebec on almost 1000 subjects, 18.5% participants reported having used natural products as sleep aids [60]. e most commonly used plant extracts for insomnia are valerian, chamomile, and lavender. In general, the selected studies showed a good quality with an average of 3, 4 points in the Jadad scale (0-5) [24] for quality rating, only 6 studies were evaluated with a score <3 and 10 studies with a score of 5. Many studies, however, are limited by small numbers of participants and, in some instances, inadequate design and sparse use of objective measurements. As mentioned by ere is preliminary but conflicting evidence suggesting valerian and lavender as possible sleep aids for mild problems of quality of sleep, sleep latency, total sleep time, and waking up after sleep onset. Notably, the studies contrasted the efficacy of valerian rated with a high Jadad score (5 studies with score of 5, Table 1). On the other hand, a recent meta-analysis of randomized, placebo-controlled trials showed a significant effect of lavender oil (Silexan) in reducing the HAMA total score for psychic and somatic anxiety and for observer-assessed and self-assessed anxiety [62].
Valerian activity on sleep disturbances has been attributed to the presence of isovaleric acids and valepotriates with reported calming action [63] and GABA reuptake inhibition with sedative effects [64]. Considering the data presented in the literature, valerian seems more effective for chronic insomnia than acute episodes. e main components of the lavender preparations are linalyl acetate and linalool [65]. In mice, these components led to anticonvulsant effects [66], depression of motor activity, and calming effects [65].
Sparse or no scientific data were found to support the efficacy of most products as hypnotics, including chamomile, hop (alone), hawthorn, St. John's wort, and rosemary. Notably, one recently published systematic review and a meta-analysis indicated chamomile as efficacious and safe for improving sleep quality and generalized anxiety disorders but highlighted scarce effect for insomnia [67,68].  Other plant extracts have been proposed and tested in clinical trials. Kava kava has been well studied and has showed good results in reducing anxiety and hypnotic effects [69], but because of its hepatotoxic effects, the prescription has been forbidden [64]. In addition, extracts from poppy, passionflower, and lemon balm (Melissa) to mention the most popular ones have been investigated in sleep disturbances, but so far, the amount of data is not sufficient to evaluate their effect on these disorders.
Unfortunately, not many trials tested the efficacy of a combined nonpharmacological intervention based on the administration of plant extracts and standardized sleep hygiene in subjects with mild to moderate insomnia. is combination could improve the efficacy in many trials where a single herbal extract was tested. In support of this hypothesis, a study by Maroo et al. [56] showed that a composition of valerian, passionflower, and hop improved total sleep time, sleep latency, number of nightly awakenings, and insomnia severity index. Moreover, a pilot study testing a combination of melatonin, vitamin B6, and various plant extract showed a positive result in sleep quality, sleep onset latency, and total sleep duration [70]. e management of sleep complaints relies on both pharmacological and nonpharmacological approaches. e last years evidenced a decrease in using sedative and hypnotic drugs to treat these conditions. On the other hand, the population and the medical community are considering food supplements and other nonpharmacological approaches in the management of mild and recent insomnia [71]. To date, however, as pointed out in various recent systematic reviews [21,72], more high-quality research is needed to confirm the effectiveness of plant extracts in sleep disorders, in particular for chronic conditions and in association with complementary and alternative medicine, such as sleep hygiene and mind-body therapies.

Disclosure
An abstract and preliminary data relevant to this review were presented at the conference Vitafoods 2019 in Geneva in a poster titled as "Food supplements for sleep disorders: a systematic review."

Conflicts of Interest
SG, DFB and SR are employed at Opera CRO, the Contract Research Organization.