Medicinal Plants for Management of Insomnia: A Systematic Review of Animal and Human Studies

Insomnia is one of the most troubling sleep disorders and can be characterized by an inability to fall asleep and/or inadequate sleep duration and/or waking up multiple times during the night. Herbal medicine has been used to treat a range of sleep disorders for centuries. This study aimed to review medicinal plants investigated experimentally or clinically for sleep disorders, as well as their potential mechanisms of action and active components. Electronic databases and literature were systematically investigated to assess all in vitro and in vivo trials and clinical evidence of the efficacy and potential mechanisms of actions playing major roles in sleep induction or insomnia treatment. Among many herbal studies and trials on insomnia, some showed no significant difference between herbal remedies and placebos. While others showed improvements in sleep parameters (sleep latency, total sleep, non-rapid eye movement (NREM) and rapid eye movement (REM) sleep duration, delta activity in NREM sleep, wakefulness anxiety-associated insomnia). In this study, in vitro, animal, and clinical studies investigating a variety of herbal treatments for insomnia were systematically reviewed. The mechanisms of action of herbal medicines in treating insomnia are mainly related to gamma-aminobutyric acid (GABA)-synthesizing and GABA-metabolizing enzymes that influenced sleep outcomes. Overall, herbal remedies were not associated with more benefits than nonbenzodiazepines, although side effects were less. The results suggest that herbs have some benefits in improving the quantity and quality of sleep and could be a promising alternative therapy.


Introduction
I nsomnia is one of the most troubling sleep disorders and can be characterized by an inability to fall asleep and/or inadequate sleep duration and/or waking up multiple times during the night. It can be caused by several factors leading to circadian rhythm disturbances. This issue may be a significant contributor to the progression of several neurological or non-neurological disorders. Recently, it has been reported that insomnia may play an in-GMJ.2019;8:e1085 www.gmj.ir fluential role in the incidence of Alzheimer disease, suicidal ideation, anxiety, obesity, hypertension, and diabetes mellitus [1]. Insomnia can be caused by different neurological disorders, such as Parkinson disease, restless legs syndrome, depression, gastrointestinal problems, and several endocrine disorders. Insomnia can be managed using medication appropriate for the main cause of insomnia [2]. There have been various chemical medicinal interventions so far, with proven efficacy in rectifying patients' sleep patterns. Benzodiazepine (BZD) receptor agonists, melatonin and orexin receptor antagonists, and histamine antagonists (selective H1 antagonists such as doxepin) are the most commonly indicated drugs for treating insomnia. Orexin receptor antagonists may cause somnolence, fatigue, and dry mouth in patients. Ramelteon (melatonin receptor agonist) likely promotes sleep by acting on the melatonin receptor 1A (MT1) by attenuating wake-promoting signals from the suprachiasmatic nucleus and might influence the timing of sleep via the melatonin receptor 1B (MT2). The off-label use of antidepressants may be proven effective, even though various adverse effects such as suicidal ideation may occur in patients. Mirtazapine (which promotes sleep via antagonism of serotonin 5HT2 and 5HT3, histamine H1, and alpha-1-adrenergic receptor antagonists), and alpha-1-adrenergic antagonists such as prazosin can also be indicated (off-label use), being an antihypertensive agent used in the treatment of nightmares and sleep disturbances in patients with posttraumatic stress disorder (PTSD). Antipsychotics can also be used for treating insomnia (off-label use) but may cause sedation, blurred vision, dizziness, dry mouth, and urinary inconsistencies in the short term and increased appetite and subsequent weight gain in the long-term. Anticonvulsant drugs used to treat insomnia include gabapentin, pregabalin, and, less frequently, tiagabine [3]. The major caveat of these interventions is their associated adverse effects and consequently low patient compliance, causing maltreated insomnia. To date, the routine drugs for insomnia cause drowsiness during the daytime and disturbances in activities that require cognition and consciousness. Moreover, a majority of patients become tolerant to cer-tain drugs, which leads to significantly higher consumption of sleeping pills, along with anxiolytic agents such as alprazolam [4]. Thereby, additional approaches are needed to treat or manage sleep disorders. The use of natural products, including herbs, is increasing across the world. International organizations, such as the World Health Organization (WHO), are also making more efforts and paying more attention to the development and promotion of the quality of natural products [5]. Additionally, non-pharmaceutical therapies, especially for mild to moderate conditions and symptoms such as non-severe insomnia and for the elderly, are highly recommended as first-line therapies prior to chemical medication [6].
Owing to their cost-effectiveness, easy access, and lower side effects, medicinal plants are popular across the world. Medicinal herbs, regardless of their probable impurities, are believed to contain effective agents for the treatment of insomnia and other sleep disorders [7]. This study aimed to review medicinal plants investigated experimentally or clinically for sleep disorders, as well as their potential mechanisms of action and active components.

Search Strategies
Electronic databases including PubMed, Scopus, Web of Science, and Google Scholar, were searched over a period from 1990 to 2016. All studies retrieved were investigated to assess all reported in vitro and in vivo trials or clinical evidence of the efficacy and potential mechanisms of action which played a major role in the induction of sleep or treatment of insomnia. In this review, only published reports and literature in English were included. The search terms were "insomnia" or "sleep" or "plant" or "herb" or "extract" in the title. Articles in languages other than English, review articles, studies on the mixture of plants and other agents, experimental studies on plants without relevant biological effects, case reports, and case-control studies were excluded. Articles without full texts were also excluded. Figure-1 shows the study selection process. The reference lists of the final selected reports were also reviewed to find other pertinent studies. The selected articles were studied to retrieve the plant's scientific  studies were excluded based on their title and abstract: of these, eight were related to the use of plants in combination with non-herbal materials, 22 evaluated the effects of plants on sleep disorders incidental to health conditions, such as asthma and menopause, and six did not mention the complete ingredients of the combination. Figure-1 shows the diagram of the study selection process.

Results
In Tables 1-3, the medicinal herbs mentioned for the management of insomnia and all pieces of evidence confirming their efficacy are described individually. According to the latest literature on medicinal plants and their applications in treating insomnia, in both humans and animals, the following plants and their related information can be found in Table-1.
Matricaria recutita had modest benefits on daytime function, low sleep latency, and nighttime awakening. The possible mechanism could be due to the effects of the flavonoid component. It has been demonstrated that it can modulate gamma-aminobutyric acid (GABA) receptors [8]. It has been shown that Melissa officinalis (lemon balm) caused significant improvements in insomnia: anxiety manifestations and anxiety-associated symptoms. The components of lemon balm, including rosmarinic acid, pentacyclic triterpenoids, ursolic and oleanolic acids, might act as inhibitors of GABA catabolism [9]. Moreover, in a clinical trial on Piper methysticum (kava), non-psychotic anxiety sleep disorders can be treated efficiently and safely with kava extract (WSR 1490) [9].Other clinical trials did not indicate positive effects of medicinal herbs on insomnia. Two clinical trials on Lavandula angustifolia (lavender) [10,11] did not show significant beneficial effects.
Lillehei et al. found that lavender made the patients feel refreshed after waking up. However, it had no useful effect on sleep quantity [10]. Additionally, Lewith et al. concluded that lavender improved sleep quality in women and younger subjects. However, its effect was not significant [11]. According to the study by Ngan et al., Passiflora had only short-term benefits on sleep quality. Passiflora incarnata (passionflower) also showed no significant changes in the polysomnography (PSG) and anxiety parameters [13]. Although Xylaria nigripes indicated no significant differences compared with a placebo, an intracomparison revealed an improvement in the intervention group. The researchers suggested that the active component, 5-methylmellein, can increase GABA in the brain and improve insomnia [14]. Three studies evaluated the effects of Valeriana officinalis (valerian) in human models. Coxeter et al. reported that valerian lowered the falling asleep time and had a minor effect on sleep quality. In another study, it was shown that this plant caused long-term slow-wave sleep (important in recovery) in non-rapid eye movement (NREM) sleep in the intervention group, compared with a placebo. It also showed positive effects on mild psychological insomnia [17]. However, in another study, no significant difference was shown between 300 mg/day and 600 mg/day valerian tablets and placebos regarding recorded sleep electroencephalography (EEG), mood, and psychometric performance [18]. Another medicinal herb is Valeriana edulis (Valeriana mexicana). It has been indicated that V. mexicana increased rapid eye movement (REM) sleep (more than V. officinalis) and delta activity, while it decreased the duration of stage 1 and 2 in NREM sleep, sleep latency, awakening episodes, and morning drowsiness (more than V. officinalis) [19].

Animal Studies
Eleven animal studies were included in the current systematic review (Table-2). P. methysticum increased delta activity in NREM sleep (against flunitrazepam) in rats. However, it had no effect on the total waking and NREM sleep time. It also significantly decreased sleep latency. The extract was not mediated by the BZD receptors (because the effect was not antagonized with BZD antidotes such as flumazenil) [20]. An experimental study showed that Matricaria chamomilla or P. incarnata decreased the sleep latency and then antagonized by 3mg/kg flumazenil (a BZD antagonist); thus, it is possible to calculate that chamomile has BZD-like hypnotic activity. However, it had positive effects on neither NREM nor REM sleep. Also, delta activity and wakefulness time did not change considerably after the intervention [21]. V. officinalis decreased sleep latency (dose-dependent) and delta activity in NREM sleep. However, it had no effect on NREM, REM, and wakefulness [22]. Coriandrum sativum, hydro-alcoholic extract (HAE) and ethyl acetate fraction (EAF), N-butanol fraction (NBF) (HAE and its three fractions, water fraction [WF], EAF, and NBF were prepared from C. sativum) increased sleep duration, and NBF decreased sleep latency. NBF showed the highest hypnotic activity and no neurotoxic effect [25]. It has been demonstrated that Hypericum perforatum (St. John's wort) increased body weight, locomotor activity, and antianxiety effect, but it decreased oxidation damage. When co-administered with imipramine, greater improvement was seen. The compounds in this plant inhibit serotonin dopamine norepinephrine reuptake (similar to

Selective Serotonin Reuptake Inhibitors [SS-RIs] and Tricyclic Antidepressants [TCAs])
and have anti-oxidative effects through polyphenolic acids and flavonoids. Imipramine, as well as St. John's wort, has antianxiety effects [24]. Panax ginseng (Korean red ginseng) increased total sleep and NREM sleep and decreased wakefulness and sleep-wake cycles. However, α-wave activity increased during NREM and REM sleep. Additionally, the expression of α-and β-subunits of GABA receptors decreased. The plausible mechanism is its impact upon the GABAergic systems [26]. A dose of 10 mg/kg of P. ginseng (Korean red ginseng) enhanced α-wave activity and lowered δ-wave activity in REM and NREM sleep. It also significantly decreased NREM and total sleep. A dose of 50 mg/kg acted like a 10 mg/kg dose, without any notable effect on REM sleep. It is worth noting that 100 mg/kg dosage indicated no effect on EEG waves; it only increased total sleep. Lower doses of red ginseng extract (RGE) were more effective for sleep regulation, specifically on NREM sleep [27]. Valerian preparation (BIM) decreased sleep latency significantly (1000 mg of each, with greater effect from valerian than BIM). However, it had no effect on NREM, REM, wakefulness and delta activity in NREM sleep for both. It increased the GABA level [28].
Stephania tetrandra (40 mg/kg, 80 mg/kg) decreased sleep latency in NREM and increased the amount and duration of NREM sleep. It increased wakefulness. The increment of the dosage from 40 to 80 mg/kg resulted in an increase of the number of state alterations from wakefulness to NREM sleep and from NREM sleep to wakefulness. It may have mixed partial dopamine D1 receptor agonist/full D2 antagonist properties. Moreover, it stimulated NREM sleep. The blockade of D2R plays a key role in the hypnotic action of stepholidine (the active compound in S. tetrandra) and initiation of sleep-active neurons in the ventrolateral preoptic nucleus VLPO [29]. There have been combination therapies studied with several factors, which are mentioned in Table-3.

Discussion
Several studies are indicating that medicinal plants had a significant effect in treating insomnia, and some studies failed to report a significant efficacy. Medicinal plants might have a therapeutic effect on the circadian rhythm, the quality of sleep, sleep maintenance, and the quality of wakefulness and alertness after waking up. Hence, due to their fewer side effects and reasonable efficacy, they may be good choices for the treatment of insomnia, in single usage or when used as a combination with approved medications. The disagreement for their efficacy indicates a requirement for further investigations to shed light on the underlying mechanisms of medicinal herbs in treating insomnia. Additionally, the synergic effects of active compounds, co-administration of different herbal medicines, and application route should be subjects of future investigations.

Limitations and Strengths
Our systematic review had some limitations. should consider publications with no language limitation and cover gray literature apart from easily accessible international databases. The strength of the current systematic review was to summarize the effects of medicinal herbs on insomnia management, derived from both animal and human studies.

Conclusion
Of the ten clinical trials, seven had high quality methodology (score>3). However, due to the limited studies for each medicinal herb, it is not possible to draw a fixed conclusion about the efficacy of herbs on insomnia. Further clinical trials are needed to clarify the positive effects of each medicinal plant on sleep quality and quantity. The discrepancy in studies which evaluated the same herb might be due to differences in study participants, study design, and dosage and duration of the intervention. Concurrently, it is critical to establish the safety and efficacy of herbal medicines for treating insomnia in short-and long-term studies, for the wider application of herbal medicines for sleep disorders. Without these studies, they may potentially result in ineffective agents being used for treating insomnia. Therefore, unless serious mechanistic studies are undertaken to elucidate the mechanisms of action, there will be hesitation regarding the usage of medicinal herbs for treating neurological disorders such as insomnia.