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

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

GMJ.2019;8:e1085 www.gmj.ir

Received 2017-12-16 Revised 2018-01-16 Accepted 2018-04-03

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

Faezeh Feizi1, Nazli Namazi2, Roja Rahimi3, Mohammad Hossein Ayati4

1 School of Pharmacy, Islamic Azad Medical University, Tehran, Iran 2 Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular- Cellular Sciences Institute, Tehran Univer- sity of Medical Sciences, Tehran, Iran 3 Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran 4 Department of Traditional Medicine, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Insomnia is one of the most troubling 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 non- , 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. [GMJ.2019;8:e1085] DOI:10.31661/gmj.v8i0.1085

Keywords: Insomnia; Sleep; Herbs; Plants

Introduction during the night. It can be caused by several factors leading to disturbanc- nsomnia is one of the most troubling sleep es. This issue may be a significant contributor Idisorders and can be characterized by an in- to the progression of several neurological or ability to fall asleep and/or inadequate sleep non-neurological disorders. Recently, it has duration and/or waking up multiple times been reported that insomnia may play an in-

GMJ  Correspondence to: Mohammad Hossein Ayati, School of Traditional Copyright© 2019, Galen Medical Journal. This is an open-access article distributed under the terms of Medicine, Tehran University of Medical Sciences, Teh- the Creative Commons Attribution 4.0 International ran, Iran License (http://creativecommons.org/licenses/by/4.0/) Telephone Number: +982188990837 Email:[email protected] Email Address: [email protected] Feizi F, et al. Review of Herbs for Insomnia Review of Herbs for Insomnia Feizi F, et al.

fluential role in the incidence of Alzheimer tain drugs, which leads to significantly higher disease, suicidal ideation, anxiety, obesity, hy- consumption of sleeping pills, along with anx- pertension, and diabetes mellitus [1]. Insom- iolytic agents such as alprazolam [4]. There- nia can be caused by different neurological by, additional approaches are needed to treat disorders, such as Parkinson disease, restless or manage sleep disorders. The use of natural legs syndrome, depression, gastrointestinal products, including herbs, is increasing across problems, and several endocrine disorders. In- the world. International organizations, such as somnia can be managed using medication ap- the World Health Organization (WHO), are propriate for the main cause of insomnia [2]. also making more efforts and paying more at- There have been various chemical medicinal tention to the development and promotion of interventions so far, with proven efficacy in the quality of natural products [5]. Addition- rectifying patients’ sleep patterns. Benzodiaz- ally, non-pharmaceutical therapies, especially epine (BZD) receptor agonists, and for mild to moderate conditions and symp- orexin receptor antagonists, and histamine toms such as non-severe insomnia and for the antagonists (selective H1 antagonists such as elderly, are highly recommended as first-line ) are the most commonly indicated therapies prior to chemical medication [6]. drugs for treating insomnia. Orexin receptor Owing to their cost-effectiveness, easy ac- antagonists may cause , fatigue, cess, and lower side effects, medicinal plants and dry mouth in patients. (mel- are popular across the world. Medicinal herbs, atonin receptor agonist) likely promotes sleep regardless of their probable impurities, are be- by acting on the melatonin receptor 1A (MT1) lieved to contain effective agents for the treat- by attenuating wake-promoting signals from ment of insomnia and other sleep disorders the suprachiasmatic nucleus and might in- [7]. This study aimed to review medicinal fluence the timing of sleep via the melatonin plants investigated experimentally or clinical- receptor 1B (MT2). The off-label use of an- ly for sleep disorders, as well as their potential tidepressants may be proven effective, even mechanisms of action and active components. though various adverse effects such as suicid- al ideation may occur in patients. Mirtazap- Search Strategies ine (which promotes sleep via antagonism of serotonin 5HT2 and 5HT3, histamine H1, Electronic databases including PubMed, Sco- and alpha-1-adrenergic receptor antagonists), pus, Web of Science, and Google Scholar, and alpha-1-adrenergic antagonists such as were searched over a period from 1990 to prazosin can also be indicated (off-label use), 2016. All studies retrieved were investigat- being an antihypertensive agent used in the ed to assess all reported in vitro and in vivo treatment of and sleep disturbanc- trials or clinical evidence of the efficacy and es in patients with posttraumatic stress disor- potential mechanisms of action which played der (PTSD). can also be used a major role in the induction of sleep or treat- for treating insomnia (off-label use) but may ment of insomnia. In this review, only pub- cause sedation, blurred vision, dizziness, dry lished reports and literature in English were mouth, and urinary inconsistencies in the short included. The search terms were “insomnia” term and increased appetite and subsequent or “sleep” or “plant” or “herb” or “extract” weight gain in the long-term. Anticonvulsant in the title. Articles in languages other than drugs used to treat insomnia include gabapen- English, review articles, studies on the mix- tin, , and, less frequently, tiagabine ture of plants and other agents, experimental [3]. The major caveat of these interventions studies on plants without relevant biological is their associated adverse effects and conse- effects, case reports, and case-control stud- quently low patient compliance, causing mal- ies were excluded. Articles without full texts treated insomnia. To date, the routine drugs were also excluded. Figure-1 shows the study for insomnia cause drowsiness during the selection process. The reference lists of the fi- daytime and disturbances in activities that re- nal selected reports were also reviewed to find quire cognition and consciousness. Moreover, other pertinent studies. The selected articles a majority of patients become tolerant to cer- were studied to retrieve the plant’s scientific

2 GMJ.2019;8:e1085 www.gmj.ir Review of Herbs for Insomnia Feizi F, et al.

Figure 1. Study Selection Diagram

name, part used, type of extract used, active ment were also collected. The ↑ and ↓ signs components, and type of animal model (for in were used to indicate significant increases and vivo studies). The authors searched for alter- decreases in the implied variables, respective- ations in test groups compared with control ly. From a total of 385 results, 180 studies groups in sleep related-parameters such as were excluded because of duplication (from sleep latency, sleep maintenance, total sleep different databases). Seventy studies were duration, wakefulness, and effects on sleep excluded because they were review articles. waves. In the studies on humans, study de- Seventy studies were excluded because they sign, Jadad score, interventions, duration of were general information about herbs, not tri- treatment, and data related to the efficacy and al studies. Two studies were excluded because tolerability of the patients on the herbal treat- they did not have English full text. Thirty-six

2 GMJ.2019;8:e1085 GMJ.2019;8:e1085 3 www.gmj.ir www.gmj.ir Feizi F, et al. Review of Herbs for Insomnia Review of Herbs for Insomnia Feizi F, et al.

studies were excluded based on their title and significant changes in the abstract: of these, eight were related to the (PSG) and anxiety parameters [13]. Although use of plants in combination with non-herbal Xylaria nigripes indicated no significant dif- materials, 22 evaluated the effects of plants ferences compared with a placebo, an intra- on sleep disorders incidental to health condi- comparison revealed an improvement in the tions, such as asthma and menopause, and six intervention group. The researchers suggested did not mention the complete ingredients of that the active component, 5-methylmellein, the combination. Figure-1 shows the diagram can increase GABA in the brain and improve of the study selection process. insomnia [14]. Three studies evaluated the ef- fects of Valeriana officinalis () in hu- Results man models. Coxeter et al. reported that vale- rian lowered the falling asleep time and had a In Tables 1-3, the medicinal herbs mentioned minor effect on sleep quality. In another study, for the management of insomnia and all piec- it was shown that this plant caused long-term es of evidence confirming their efficacy are slow-wave sleep (important in recovery) in described individually. According to the latest non-rapid eye movement (NREM) sleep in the literature on medicinal plants and their appli- intervention group, compared with a placebo. cations in treating insomnia, in both humans It also showed positive effects on mild psy- and animals, the following plants and their chological insomnia [17]. However, in anoth- related information can be found in Table-1. er study, no significant difference was shown Matricaria recutita had modest benefits on between 300 mg/day and 600 mg/day vale- daytime function, low sleep latency, and rian tablets and placebos regarding recorded nighttime awakening. The possible mech- sleep (EEG), mood, anism could be due to the effects of the fla- and psychometric performance [18]. Another vonoid component. It has been demonstrated medicinal herb is Valeriana edulis (Valeriana that it can modulate gamma-aminobutyric mexicana). It has been indicated that V. mex- acid (GABA) receptors [8]. It has been shown icana increased rapid eye movement (REM) that Melissa officinalis (lemon balm) caused sleep (more than V. officinalis) and delta activ- significant improvements in insomnia:- anx ity, while it decreased the duration of stage 1 iety manifestations and anxiety-associated and 2 in NREM sleep, sleep latency, awaken- symptoms. The components of lemon balm, ing episodes, and morning drowsiness (more including rosmarinic acid, pentacyclic triter- than V. officinalis) [19]. penoids, ursolic and oleanolic acids, might act as inhibitors of GABA catabolism [9]. More- Animal Studies over, in a clinical trial on Piper methysticum Eleven animal studies were included in (), non-psychotic anxiety sleep disorders the current systematic review (Table-2). can be treated efficiently and safely with kava P. methysticum increased delta activity in extract (WSR 1490) [9].Other clinical trials NREM sleep (against ) in rats. did not indicate positive effects of medici- However, it had no effect on the total waking nal herbs on insomnia. Two clinical trials on and NREM sleep time. It also significantly Lavandula angustifolia (lavender) [10, 11] decreased sleep latency. The extract was not did not show significant beneficial effects. mediated by the BZD receptors (because the Lillehei et al. found that lavender made the effect was not antagonized with BZD anti- patients feel refreshed after waking up. How- dotes such as flumazenil) [20]. An experimen- ever, it had no useful effect on sleep quanti- tal study showed that Matricaria chamomilla ty [10]. Additionally, Lewith et al. conclud- or P. incarnata decreased the sleep latency ed that lavender improved sleep quality in and then antagonized by 3mg/kg flumazenil women and younger subjects. However, its (a BZD antagonist); thus, it is possible to cal- effect was not significant [11]. According to culate that has BZD-like the study by Ngan et al., Passiflora had only activity. However, it had positive effects on short-term benefits on sleep quality. Passiflo- neither NREM nor REM sleep. Also, delta ra incarnata (passionflower) also showed no activity and wakefulness time did not change

4 GMJ.2019;8:e1085 www.gmj.ir Review of Herbs for Insomnia Feizi F, et al. 8 9 10 Reference - - receptors Mechanism Flavonoid con lation of GABA action presented action presented sedate by modu stituent apigenin no mechanism of no mechanism of - - - tity and Result 1490® nighttime with kava and ↓sleep latency and functioning awakenings extract WSR extract Waking feel Waking anxiety sleep no difference no difference ing refresher, disorders can be effectively be effectively Modest bene Safely treated in sleep quan fits of daytime Non-psychotic - 28days treatment Duration lowing up 5nightsand 2weeks fol double-blind 1week singles blind +4weeks years Patients 6-months on criteria 79 college 34 patients 61 patients IV primary IV aged 18-65 with DSM- sleep issues self-reported (DSM-III-R) students with and insomnia suffered from suffered insomnia for ≥ various anxiety - - - - bo(n=17) bo(n=27) ly(n=17)/ patch(n=40 Intervention Control group: hygiene and an received place daily in the eve their chest(n=39) Received 200 mg 270 mg twice dai hygiene and blank ning(n=34) / place received good sleep 55 µl of lavender on Received good sleep inhalation patch with 5 4 5 score Jadud - - trial trolled trial trolled pilot double-blind placebo-con placebo-con Randomized, Randomized, Randomized, double-blind, double-blind, Study design controlled trial - - tion tops (90 mg 70% ka Flowering water) and chamomile of apigenin WS®1490: va(acetonic root of kava 100mg dried to up absorp ancillary30% (-a-bisabolol) and 1.8 mg of extract:3.9 mg Part (extract) - Clinical Trials on the Efficacy and Mechanism of Action of Certain Medicinal Plants for Treatment of Insomnia Action of Certain Medicinal Plants for on the Efficacy and Mechanism of Trials Clinical Piper Piper (kava) recutita (English (German Scientific lavender) Lavandula Matricaria mon name) chamomile) angustifolia name (com methysticum Table 1. Table

4 GMJ.2019;8:e1085 GMJ.2019;8:e1085 5 www.gmj.ir www.gmj.ir Feizi F, et al. Review of Herbs for Insomnia Review of Herbs for Insomnia Feizi F, et al. 11 12 13 - - lism and the nolic acids pentacyclic triterpenoids, which inhibit GABA catabo GABA action presented action presented ursolic and olea Rosmarinus acid no mechanism of no mechanism of - - - - - tions, quality sociated improve- insomnia categories Better im Has short- volunteers provement ment in all term bene Significant parameters parameters of the PSG anxiety-as for Women Women for fits in sleep and anxiety and younger studied: anxi ety manifesta -no significant symptoms and changes in any - 5days 4weeks: od (8-14) treatment with 7 days out between washout peri 22 days study per 1weeks as 2w is watched - - IV-TR volunteers difficulties 20 stressed score of >5 aged 18-50y. aged 18-50y. with a global with mild in (18-35y)with 41 volunteers extreme sleep (18- 70) years somnia evalu 5male 5female ated by (PSQI) based on DSM- - - water evening crispum) trol(n=5) -Placebo: were added 300 mg cyracos each night to the containing 2 g of bags: 2 g of dried 250 mL by boiled 250 mL dried Petroselinum -Passionflower Tea -Passionflower plant equivalent to cartridge -100% hy -almond oil for con 6–8 drops of each oil twice in morning and parsley teabags (each drosoil lavender(n=5) 5 0 2 - - ed trial trolled Repeated measures open-label Placebo-con Randomized, Single-Blind a prospective, Double-blind, - - greater Flower flowers than 15% seeds and Cyracos®: namic acid 7% rosma derivatives Leaf extract hydroxycin rinic acid and leaves, stems, Hydroalcholic - - - er) folia inalis Passiflora Incarnata L. augusti (passionflow Melissa offic (lemon balm)

6 GMJ.2019;8:e1085 www.gmj.ir Review of Herbs for Insomnia Feizi F, et al. 14 15 16 - - mellein ↑ intake of active com GABA in brain GABA action presented action presented no mechanism of no mechanism of pound: 5-methyl - time factors quality on sleep No better treatment compare to and Wuling and Effective in Effective pre and post -small effect -small effect than placebo sleep-related -↓ fall asleep in promoting difference be difference No significant tween placebo - - ing up 2weeks 6weeks ment and 2 4weeks treat weeks follow - of >5 patient (22-75) 18-60Y Patients Based on (ICD-10) insomniac 42 enrolled 405 partici 212 cases of (PSQI) score pant(18-75y) had insomnia - - identical times daily) going to bed In per group of control(n=203), one hour before placebo capsule in one bottle) or swallow 3 tablets Patients received a half an hour before (3 capsules orally, 3 (3 capsules orally, To take Wuling cap Wuling take To sule and 63 capsules sule (0.33 g per-cap 2tab(225mg valerian) box with 60 tablets to treatment(n=202) and 5 5 5 - - - trial trolled over trial Televised, Televised, Web-Based Web-Based double-blind placebo-con placebo-con Randomized, Randomized, Randomized, double-blind, double-blind, trolled, cross ------lium zome trates) Forte®: Valerina Valerina (2.94mg 200mg dry sule: myce Tablets con Tablets 1.23mg Val root and rhi root and rhi zome extract V. Officinalis V. acids,0.46mg Valerenal and Valerenal tained 225mg Wuling ®cap Wuling total Valerenic Valerenic total - gripes officinalis Valeriana Valeriana (valerian) Xylaria ni V. officinalis V.

6 GMJ.2019;8:e1085 GMJ.2019;8:e1085 7 www.gmj.ir www.gmj.ir Feizi F, et al. Review of Herbs for Insomnia Review of Herbs for Insomnia Feizi F, et al. 17 18 19 action presented action presented action presented no mechanism of no mechanism of no mechanism of - - - - - inalis) mood , episode, insomnia awakening Officinalis) slow wave differences NREM sleep -↑REM sleep -↓stage 1,2 in mg and 600 mg valerian increased in iness(more by -Positive ef significantly performance ant in recov and placebo, between 300 -↑delta activity morning sleep fects on mild -In long-term psychometric (more by Offic - ↓sleep latency, - ↓sleep latency, in sleep EEG, psychological sleep (import No significant ery) in NREM valerian group - days 2doses 4nights 3weeks. between a washout uled in two were sched period of 12 separated by trial periods, 8 study nights 6days washout - - 1.A.1.) insomnia (22-55Y) 20 patient complaint 16 patients 16 patients DSM-III-R a mild sleep insomnia ac with psycho physiological (29-55y) with cordance with (50-64y) have (ICSD-CODE - - bed at 23:00 mg, placebo EEG recorded Which patients nalis as control, extract of V. edulis V. extract of received both treat ments: 150mg dried 2tab one hour before and 150 mg V. offici V. and 150 mg Valerian 300 mg, 600 Valerian 3times a day (450mg) 2 3 3 - - study trolled trolled, placebo-con Randomised, Placebo-con the crossover Randomized, Randomized, double-blind, double-blind, Double-blind, crossover trial - - - root/ 300mg contains enic acid Each tab: valerianae Hydroalco valepotriate 156 extract: an alcoholic 300 mg dry of European holic extract root of radix Sedonium®: of 70% etha acid dose not Rhizome and V. officinalis. V. Sedonium: Li contain valer extract, by use nol of dry root edulis Valeriana Valeriana (Valeriana (Valeriana Mexicana) V. officinalis V. V. Officinalis V.

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considerably after the intervention [21]. V. the amount and duration of NREM sleep. It officinalis decreased sleep latency (dose-de- increased wakefulness. The increment of the pendent) and delta activity in NREM sleep. dosage from 40 to 80 mg/kg resulted in an in- However, it had no effect on NREM, REM, crease of the number of state alterations from and wakefulness [22]. Coriandrum sativum, wakefulness to NREM sleep and from NREM hydro-alcoholic extract (HAE) and ethyl ace- sleep to wakefulness. It may have mixed par- tate fraction (EAF), N-butanol fraction (NBF) tial dopamine D1 receptor agonist/full D2 an- (HAE and its three fractions, water fraction tagonist properties. Moreover, it stimulated [WF], EAF, and NBF were prepared from C. NREM sleep. The blockade of D2R plays a sativum) increased sleep duration, and NBF key role in the hypnotic action of stepholidine decreased sleep latency. NBF showed the (the active compound in S. tetrandra) and highest hypnotic activity and no neurotox- initiation of sleep-active neurons in the ven- ic effect [25]. It has been demonstrated that trolateral preoptic nucleus VLPO [29]. There Hypericum perforatum (St. John’s wort) in- have been combination therapies studied with creased body weight, locomotor activity, and several factors, which are mentioned in Ta- antianxiety effect, but it decreased oxidation ble-3. damage. When co-administered with imip- ramine, greater improvement was seen. The Discussion compounds in this plant inhibit serotonin do- pamine norepinephrine reuptake (similar to Several studies are indicating that medicinal Selective Serotonin Reuptake Inhibitors [SS- plants had a significant effect in treating in- RIs] and Tricyclic Antidepressants [TCAs]) somnia, and some studies failed to report a sig- and have anti-oxidative effects through poly- nificant efficacy. Medicinal plants might have phenolic acids and flavonoids. Imipramine, as a therapeutic effect on the circadian rhythm, well as St. John’s wort, has antianxiety effects the quality of sleep, sleep maintenance, and [24]. Panax ginseng (Korean red ginseng) in- the quality of wakefulness and alertness af- creased total sleep and NREM sleep and de- ter waking up. Hence, due to their fewer side creased wakefulness and sleep-wake cycles. effects and reasonable efficacy, they may be However, α-wave activity increased during good choices for the treatment of insomnia, in NREM and REM sleep. Additionally, the ex- single usage or when used as a combination pression of α- and β-subunits of GABA re- with approved medications. The disagreement ceptors decreased. The plausible mechanism for their efficacy indicates a requirement for is its impact upon the GABAergic systems further investigations to shed light on the un- [26]. A dose of 10 mg/kg of P. ginseng (Kore- derlying mechanisms of medicinal herbs in an red ginseng) enhanced α-wave activity and treating insomnia. Additionally, the synergic lowered δ-wave activity in REM and NREM effects of active compounds, co-administra- sleep. It also significantly decreased NREM tion of different herbal medicines, and appli- and total sleep. A dose of 50 mg/kg acted like cation route should be subjects of future in- a 10 mg/kg dose, without any notable effect on vestigations. REM sleep. It is worth noting that 100 mg/kg dosage indicated no effect on EEG waves; it Limitations and Strengths only increased total sleep. Lower doses of red Our systematic review had some limitations. ginseng extract (RGE) were more effective for Insufficient number of the studies did not al- sleep regulation, specifically on NREM sleep low us to explore the effects of disease back- [27]. Valerian preparation (BIM) decreased ground and gender on the efficacy of herbs sleep latency significantly (1000 mg of each, on insomnia. In most of the trials, lifestyle with greater effect from valerian than BIM). was not considered, and no sufficient details However, it had no effect on NREM, REM, about diet were mentioned. These issues may wakefulness and delta activity in NREM sleep have affected the overall effect sizes. Besides, for both. It increased the GABA level [28]. the review did not cover resources such as Stephania tetrandra (40 mg/kg, 80 mg/kg) de- books, dissertations, and government reports creased sleep latency in NREM and increased and non-English publications. Future studies

8 GMJ.2019;8:e1085 GMJ.2019;8:e1085 9 www.gmj.ir www.gmj.ir Feizi F, et al. Review of Herbs for Insomnia Movassaghi S, et al. Honey/PVA with Erythromycin for Wound Healing 20 21 Reference - pine flumazenil) Mechanism with flumazenil) was antagonized with receptors (because the through the benzodiaze Chamomile has BZD-like effect was not antagonized effect The extract is not mediated hypnotic activity (the effect effect (the activity hypnotic - - time time Result the total trazepam) flumazenil NREM and waking and REM sleep, wakefulness NREM sleep es by 3mg/kg (against fluni Delta activity, ↓sleep latency by chamomile - Significantly -No effects on -No effects on -No effects that antagoniz -↑delta activity in NREM sleep - ↓sleep latency rats rats type Male Male Animal 7 day 7 day intervals intervals Duration - - rats rats drug test drug test administered orally at 9:00 Intervention cellulose orally doses of 1,3 and kava-kava extract mg/kg chamomile Received 3,10,300 cellulose solution and kg or flunitrazepam at zenil in 10% dimethyl zenil in 10% dimethyl in 0.5% carboxymethyl in 0.5% carboxymethyl -control: sleep-deprived -control: sleep-deprived kg passiflora Suspended sulfoxide injected before sulfoxide injected before -Antagonism test: fluma -Antagonism test: fluma 10 mg/kg both suspended and300,1000,3000 or mg/ at a dose of 30,10,300 mg/ By filled water Model surface water to 1cm below the grid a grid that was placing rats on placing rats on a grid in cage suspended over Part Root roots of the Piper extractvs (extract) passiflora chamomile / (kava-kava is aerial parts of methysticum) -96% ethanolic Flower parts of an extract of the - Animal Studies for Insomnia ticum incarnate Passiflora Matricaria chamomilla/ Piper methys Piper Scientific name (common name) (common Table 2. Table

10 GMJ.2019;8:e1085 www.gmj.ir MovassaghiReview of Herbs S, et al.for Insomnia Honey/PVA with ErythromycinFeizi for Wound F, et al. Healing 22 23 24 - - - presented flavonoids st.john's wort partially, to the partially, TNFα pathway kines such as TNFα kines such as to SSRIs and TCAs), to SSRIs and -imipramine has anti may be related, at least polyphenolic acids and Inhibit serotonin dopa no mechanism of action Antioxidative effects by Antioxidative effects anxiety effects as well anxiety effects Like modulation of cyto mine NE reuptake (similar ------dent) effect tantly serum, -↑TNFα in -↓oxidation ministration with imipra Wakefulness (dose depen -↑ total sleep mine: greater improvement -No effects on -No effects on -No effects the hypothala NREM, REM, ity, antianxiety ity, -↓sleep latency -↓sleep latency -↑delta activity -↑body weight, SWS and REM in NREM sleep raphe concomi mus, and dorsal time and NREM damages (co-ad locomotor activ rats rats mice Male Male Male 7 day 3 days 5 days intervals - rats rats mg) i.p.) PO) st.johns wort -40 and 80 mg/kg (80mg) application. -Imipramine 10 +200 -TNFα 12.5, 25 ng/rat and administered then - starting 2 days before 6h after administration. -control: sleep-deprived -control: sleep-deprived - Imipramine (10mg/kg, - (200mg and 400mg/kg EMG and EEG measured tration by G. lucidum (40 i.c.v alone and coadminis -TNFα antibody (2.5 g/rat, prior to the last G. lucidum prior to the last G. lucidum 1000,3000mg/kg dissolved i.c.v.) were injected 20 min i.c.v.) - - over water over water 72h Sleep de grid suspended grid suspended prived by plac ing them on the Placing rats on a - tract Root Ethanolic ex Fruiting bodies ethanolic extract - inalis Wort) lucidum (St. Johns Hypericum perforation Ganoderma Valeriana offic Valeriana

10 GMJ.2019;8:e1085 GMJ.2019;8:e1085 11 www.gmj.ir www.gmj.ir Honey/PVAFeizi Fwith, et al.Erythromycin for Wound Healing Review of MovassaghiHerbs for Insomnia S, et al. Review of Herbs for Insomnia Feizi F, et al. 25 26 27 presented presented GABAAergic systems GABAAergic Modulates sleep via the no mechanism of action no mechanism of action - - - sleep. REM effect latency ↑ total sleep NREM sleep and total sleep NBF(more) effect on REM effect ↓wakefulness, -NBF↓sleep activity in REM -Lower doses of ↑total sleep and notic activity activity, ↓δ-wave activity, -50 mg/kg like 10 tive at modulating - NBF showed α- and β-subunits ly affected NREM ly affected -↑α-wave activity -No neurotoxic sleep-wake cycles and NREM sleep,↑ on EEG waves just mg but without any -10 mg/kg ↑α-wave during NREM and ↑sleep duration, -HAE and EAF, -HAE and EAF, the highest hyp significantly NREM sleep and specifical of GABA receptors of GABA -↓ the expression of -100 mg/kg no effect -100 mg/kg no effect effec more RGE are rats rats Mice Male Male - - 7 days gical re post-sur 7 days of days trial covery+9 - - barbital; vs. saline once per day EEG recording - 30 vum extract (HAE); 10,50,100mg/kg was Oral administration of - Vehicles(saline), or 50 Vehicles(saline), - (WF), (EAF) and (NBF) 200 mg/kg orally by dis solving in distilled water mg/kg of HAE fractions: performed 10 min before minutes after injection of before injection of pento saline, diazepam, or C. Sati diazepam, saline, - (NBF) extract Aerial parts / Water extract Water ginseng roots/ and N-butanol extract three fractions: hydro-alcoholic Six-year-old red Six-year-old yl acetate (EAF) water (WF), eth (WF), water sativum Ginseng) Ginseng) (Korea Red (Korea Red (Korea Coriandrum Panax ginseng Panax ginseng

GMJ.2019;8:e136212 GMJ.2019;8:e10853 www.gmj.ir www.gmj.ir Review of Herbs for Insomnia Feizi F, et al. 28 29 SPD VLPO blockade - Activation of - antagonist properties Mixed partial dopamine in the hypnotic action of - promoted NREM sleep, ↑GABA level for valerian ↑GABA of D2R plays a major role sleep-active neurons in the D1 receptor agonist/full D2 - - both BIM) -no effect -no effect to NREM on NREM, fulness and 40,80mg/kg REM,wake valerian than wakefulness. -↑ the amount ↓sleep latency from wakeful -↓wakefulness ness to NREM sleep and from more effect for more effect -↓sleep latency (sig in 1000mg -40 and 80 mg/ and duration of kg ↑number of delta activity in NREM sleep to state transitions of each one and NREM sleep by NREM sleep for rats mice Male Male - and day) 7-day 2 days imental (Exper baseline intervals - - alone control at 9:00 or stepholidine -diazepam 6mg/kg BIM :(400mg valeri -vehicle (20ml/kg) as of 20, 40 or 80 mg/kg an+100mg golden root 100,300,1000 mg/kg of +50mg L-) dis I.p, bolus Injected doses solved and administration - valerian(30,1000 mg/kg) water A grid floor A was filled with was filled with - - rose) dient extract ylamide) officinalis -Ethanolic -Root of V. -Root of V. + Rhodiola rosea (golden + L-Theanine L-stepholidine, (γ-glutamyleth an active ingre (BIM) Valerian Valerian Stephonia preparation preparation

12 GMJ.2019;8:e1085 GMJ.2019;8:e1085 13 www.gmj.ir www.gmj.ir Feizi F, et al. Review of Herbs for Insomnia Movassaghi S, et al. Honey/PVA with Erythromycin for Wound Healing 30 31 Reference - - atory system neurotrans Mechanism mission in the central nervous action presented decreasing excit no mechanism of sleep. group Result -↑sleep Extract) in NREM for adding differences quantity in the valerian for Ze91019 to placebo in sleep latency sleep latency (=plausibility across groups the treatment is not superior -↑significantly hops extract to -No significant -Led to deeper -single valerian - ence night). 4weeks night and Duration medication 2nights(refer disease Patients 51.0–51.2) 30 patients (ICD 10, F on having a (≥18 years) neurological non-organic non-organic complications 70y) reporting weeks without suffering from suffering sleep disorders 44 patients (30- poor sleep for 2 and any organic - 2 ml G(n=20) orally 15 -Valerian Intervention 91019 (n=10) Ze 911 (n=10) Ze 911 min before EE -placebo(n=22) -placebo (n=10) and administrated - Valerian/hops Ze - Valerian/hops honey flavored water dissolved in 50 ml of 3 2 score Jadud - trolled Placebo- Controlled Randomized, Randomized, Study design Placebo-Con Double-Blind, Double-Blind, - - siccum + Ze 91019: 500 mg va 6.6:1 (hops) 460 mg of V. V. 460 mg of ratio of 5.3:1 120 mg hops lerian extract _45% metha nol m/m with mg H. lupulus a drug extract (valerian) and -Dormeasan®: in 61% ethanol extract siccum Part (extract) officinalis+ 460 -1: 12 dissolved - Combination Therapy for Insomnia Combination lupulus Scientific officinalis Valeriana Valeriana + Humulus mon name) name (com V. officinalis V. + H. lupulus Table 3. Table

14 GMJ.2019;8:e1085 www.gmj.ir MovassaghiReview of Herbs S, et al.for Insomnia Honey/PVA with ErythromycinFeizi for Wound F, et al. Healing 32 33 34 - May: GABA to GABA-A to GABA-A stimulate the receptors and catabolism of release and re 2.bind directly 1.inhibit central action presented action presented uptake of GABA no mechanism of no mechanism of - - - and the by both by kava mance the first by valerian -↑NREM- evaluation -improvements sleep in the sleep time rapidly relieved -stress problems -↑subjective and deeper jective sleep second cycle ing insomnia were REM latency, -↑sleep time achieved with kava Significantly mood and sub NREM sleep in severity of the result -↓ wakefulness, on inducing sleep but were then maintained -↓Total stress severity -↓Total good effect on quality good effect -valerian: no sig effect -no difference in -no difference cognitive perfor - 3days night) nights between medication 6 weeks for (reference nd od of 2weeks 2 consecutive washout peri each drug with each - - nia poor subjects suffering ( 23-65y) and males 20 healthy 42 healthy 24 patients female 50.2 sleep within the previous 48.2) having (Mean age of duced insom 2weeks period from stress-in - weeks (n=19) (n=22) ly(n=20 -placebo -2ml of the followed by 2 water and then honey-flavored with kava 120 mg formulation was daily(n=24) This was administered oral then, 5 having dropped weeks off treatment andweeks off First treated for 6 weeks 3 tablets twice a day out, 19 received valerian dissolved in 50 mL of dissolved in 50 mL 600mg daily for another 6 3 0 - - trial, study trolled not dou ble-blind crossover cross-over randomized randomized, placebo-con Double-blind Double-blind, - Dor flower John’s John’s balance: 60mg St. Neurapas valerian+ H. lupulus, mg of fresh dissolved in 61% ethanol wort+28mg V. officinalis; V. measan®:460 rec. tinct. 1:12 Tinct. 1:10 and Tinct. 35mg passion radix (root) rec. strobulus (fruit) - - - er) nalis Wort) lupulus officinali Humulus Valeriana Valeriana Incarnata (St. Johns + V. offici V. + officinali + / Valeriana / Valeriana perforatun Hypericum + Passiflora ticum (kava) (passionflow Piper methys Piper

14 GMJ.2019;8:e1085 GMJ.2019;8:e10852 GMJ.2019;8:e136215 www.gmj.ir www.gmj.ir www.gmj.ir Honey/PVAFeizi Fwith, et al.Erythromycin for Wound Healing Review of MovassaghiHerbs for Insomnia S, et al. Review of Herbs for Insomnia Feizi F, et al.

should consider publications with no language to establish the safety and efficacy of herbal limitation and cover gray literature apart from medicines for treating insomnia in short- and easily accessible international databases. The long-term studies, for the wider application of strength of the current systematic review was herbal medicines for sleep disorders. Without to summarize the effects of medicinal herbs these studies, they may potentially result in on insomnia management, derived from both ineffective agents being used for treating in- animal and human studies. somnia. Therefore, unless serious mechanistic studies are undertaken to elucidate the mech- Conclusion anisms of action, there will be hesitation re- garding the usage of medicinal herbs for treat- Of the ten clinical trials, seven had high qual- ing neurological disorders such as insomnia. ity methodology (score>3). However, due to the limited studies for each medicinal herb, Acknowledgment it is not possible to draw a fixed conclusion about the efficacy of herbs on insomnia. Fur- The authors express their special thanks to Dr. ther clinical trials are needed to clarify the Mahdi Rezayat, Dr. Sepideh Arbabi Bidgoli, positive effects of each medicinal plant on and Dr. Gholamreza Amin for their generous sleep quality and quantity. The discrepan- comments and support. cy in studies which evaluated the same herb might be due to differences in study partici- Conflict of Interest pants, study design, and dosage and duration of the intervention. Concurrently, it is critical None declared.

References

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