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Send Orders for Reprints to [email protected] Current Neuropharmacology, 2014, 12, 000-000 1 Herbal Medications that Target GABAergic Systems: A Review of the Psychopharmacological Evidence

Yuan Shia, Jing-Wen Donga, Jiang-He Zhaob, Li-Na Tanga and Jian-Jun Zhanga,* aState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China; bDepartment of Pharmacology, School of Marine, Shandong University, Weihai, P.R. China

Abstract: Insomnia is a common sleep disorder which is prevalent in women and the elderly. Current insomnia drugs mainly target the -aminobutyric acid (GABA) , receptor, histamine receptor, orexin, and serotonin receptor. GABAA receptor modulators are ordinarily used to manage insomnia, but they are known to affect sleep maintenance, including residual effects, tolerance, and dependence. In an effort to discover new drugs that relieve insomnia symptoms while avoiding side effects, numerous studies focusing on the neurotransmitter GABA and herbal medicines have been conducted. Traditional herbal medicines, such as methysticum and the seed of Zizyphus jujuba Mill var. spinosa, have been widely reported to improve sleep and other mental disorders. These herbal medicines have been applied for many years in folk medicine, and extracts of these medicines have been used to study their pharmacological actions and mechanisms. Although effective and relatively safe, natural plant products have some side effects, such as and skin reactions effects of Piper methysticum. In addition, there are insufficient evidences to certify the safety of most traditional herbal medicine. In this review, we provide an overview of the current state of knowledge regarding a variety of natural plant products that are commonly used to treat insomnia to facilitate future studies. Keywords: , insomnia, natural products, , -aminobutyric acid.

1. INTRODUCTION movement (REM) stage and several non-rapid eye movement (NREM) stages that follow a clearly defined Sleep is a crucially important process in the animal cyclical pattern [5, 6]. Several signaling molecules that play a kingdom. Sleep disorders affect a large portion of the general role in sleep have been identified. Various neurotransmitters, population worldwide, and insomnia is the most commonly including noradrenaline, acetylcholine, histamine, dopamine, reported sleep disorder. More than half of the American serotonin, and the neuropeptides orexin A and B (also population suffers from sleep disorders [1]. Because the referred to as hypocretins), promote wakefulness. By prevalence of insomnia increases with age, this problem is contrast, GABA and adenosine promote sleep [5]. GABA is potentially more serious in countries, such as China, that the major neurotransmitter that exerts inhibitory activity in contain an increasing elderly population. Insomnia is the (CNS), and more than 20% of all characterized by difficulty in initiating sleep and/or brain are GABAergic. Three pharmacologically maintaining sleep, non-restorative sleep or poor-quality sleep distinct classes of GABA receptors have been identified: [1, 2]. Sleep disturbances cause people to suffer from mental GABA receptors, GABA receptors, and GABA receptors. dysfunction and daytime sleepiness and can to various A B C The GABAA receptor, which was the first to be identified, health and socioeconomic issues. People who suffer from has a pentameric transmembrane structure that includes 19 insomnia for long time periods may also suffer from subunits (1-6, 1-3, 1-3, , , , , and 1-3). Different depression and experience a decreased quality of life [3]. subunit combinations produce subtypes with varying Sleep remains one of the most poorly understood locations and physiologies [7, 8]. GABAA receptors are biological processes. The function and molecular processes -gated chloride ion channels that are activated by underlying sleep remain elusive but are becoming clearer GABA and the , blocked by , after decades of research [4]. Mammalian sleep states are and coupled to the GABA, , , and characterized by altered brain activity during the rapid eye binding sites [9]. GABAA receptors are important therapeutic targets for the treatment of insomnia because they rapidly inhibit neurotransmission and participate in tonic inhibition [10]. GABA , the second identified receptor, *Address correspondence to this author at the State Key Laboratory of B Bioactive Substance and Function of Natural Medicines, Institute of Materia is a G-protein-coupled heterodimer composed of the subunits Medica, Chinese Academy of Medical Sciences and Peking Union Medical GABAB R1 and GABAB R2, and it plays a critical role in College, No. 1 Xian Nong Tan Street, Beijing 100050, P.R. China; synaptic transmission through the regulation of a meta- Tel/Fax: 86-10-63182392; E-mail: [email protected] botropic second messenger pathway that regulates Ca2+ or K+

1570-159X/14 $58.00+.00 ©2014 Bentham Science Publishers 2 Current Neuropharmacology, 2014, Vol. 12, No. 0 Shi et al. channels [11, 12]. The third receptor identified, GABAC, is a properties of these medicinal plants were described Cl ionophore comprising three subunits (1, 2, 3). It is in plant records during ancient times; one such example is more sensitive to GABA than the GABAA and GABAB the Compendium of Materia Medica [2, 21]. Herbal receptors [13]. GABAC receptor antagonists decrease total medications have been used both separately and in slow-wave sleep and paradoxical sleep [14]. combination. More than 29,000 prescriptions for herbal medications were received in Taiwan in 2002 [2]. Over the Sleep is regulated by the circadian rhythm and last two centuries, the scientific understanding of herbal homeostatic mechanisms, which are dominated by the CNS. plants has advanced significantly. Traditional pharmacognosy GABA is the primary inhibitory neurotransmitter in the research is often based on single active compounds that have CNS, and the GABA receptor is a target of the majority of been isolated from plant material [22]. sleep medications, including non-benzodiazepine “Z drugs” (, , , and ) and Herbal medicines typically contain complex mixtures of (BZDs), both of which target GABAergic compounds, and their mechanisms of action often remain signaling pathways [5, 15, 16]. Three generations of unclear. However, recent studies have shown that central have been developed based on GABAA receptor-mediated GABAergic neurotransmission changes when people or inhibitory processes. First- and second-generation hypnotics animals ingest the extracts of most herbal plants that are include and BZDs, respectively, third-generation reported to possess and sedative properties. The hypnotics include and . results of studies involving herbal plants published between All decrease waking, increase slow-wave sleep, and enhance 2000 and 2013 are addressed in this review. the intermediate stage of sleep, which is situated between slow-wave sleep and paradoxical sleep, at the expense of the 2. MATERIALS AND METHODS last sleep stage. Third-generation hypnotics are distinguished The authors conducted a computer-based search using from other drugs by a slight decrease in paradoxical sleep SCI Finder (Chemical Abstracts Service, CAS). An initial that occurs in the absence of increases in the intermediate search was performed using the terms “natural product”, stage of sleep during the first few hours after treatment [13, “herbal product”, and “sleep” in combination with the term 15, 16]. “GABA”. Following an examination of the retrieved Pharmacological treatments for insomnia that are literature, additional searches were conducted using the currently approved by the Food and Drug Administration terms “insomnia”, “sedative”, and “hypnotic” in combination (FDA) include GABA response modulators, melatonin with “GABA”, “natural products”, “herbal”, and “extract”. receptor , and histamine receptor antagonists. All papers that did not meet these criteria were excluded. Benzodiazepine receptor agonists (BZRAs), including BZD 3. RESULTS and non-BZD hypnotics, modulate GABA responses by activating the GABAA receptor and inducing an inward 3.1. Piper methysticum L.f. (Family: Piperaceae) chloride ion flux finally hyperpolarizes the membrane and reduces its action potential [8]. Barbiturates are effective but Piper methysticum originates in the Pacific Polynesian are associated with several safety concerns include low lethal Islands, and its extract, -kava, has been traditionally used as an herbal medicine to treat insomnia and anxiety in doses, residual sedation, tolerance, and dependence [17]. th BZRAs have essentially replaced barbiturates due to their the South Pacific since the 18 century. Its historic use, sufficient pharmacokinetic variability and substantially combined with modern scientific data demonstrating its improved therapeutic effects. However, BZDs have addictive safety and efficacy, led the German Commission E (expert properties and are associated with abuse liability, physical committee of the German Federal Institute for Drugs dependence, and tolerance, limiting their long-term use and Medical Devices) to approve the use of kava-kava [18]. Melatonin receptor agonists improve sleep onset preparations as nonprescription drugs for the treatment of with better safety, but the onset of efficacy occurs slowly anxiety disorders, stress, and restlessness in 1990 (Table 1). [19]. The first FDA-approved melatonin receptor agonist, There are eighteen isolated from kava-kava , is well tolerated, but it also has several adverse root extract, four chiral and two achiral enantiomers of effects, including headache, somnolence, nausea, and fatigue them perform most of the activaties including , [20]. The only selective H1 histamine receptor antagonist is (5,6-dehydrokawain), , low-dose , which is used to treat insomnia with 7,8-, kawain, and 7,8-dihydrokawain. It difficulty in sleep maintenance. Doxepin was proven safe also have been reported that administration of the and effective in clinical trials, with no abuse potential, but it alone did not exert the same pharmacologic activity as whole is associated with adverse events, including somnolence, kava-kava extract, some researchers suggested that this nausea, and upper respiratory tract infection [8]. Furthermore, may due to the modulation of transport and/or the efficacy and safety data for other drugs used to treat [24]. insomnia are inadequate. Because the previously mentioned Nevertheless, several cases of kava-kava-induced drugs cannot fulfill the needs of all insomnia patients, fulminant hepatic failure and acute hepatitis were reported in additional safe and effective drugs are needed to treat the year 2001 and 2002 [48-50], including which 11 hepatic insomnia. failure required liver transplants and eventually resulted in Herbal medicine has been used to treat insomnia in four deaths [50], liver biopsy and histologic examination worldwide countries for centuries. The anxiolytic and showed hepatocellular necrosis, inflammatory infiltration

Herbal Insomnia Medications that Target GABAergic Systems Current Neuropharmacology, 2014, Vol. 12, No. 0 3

Table 1. Herbal hypnotics: mechanisms of action and clinical applications.

Medicinal Mechanisms of Type of Major Sedative Constituents Herbal Medicine Common Names Parts Action Evidence* Compound Names Type of Compound

Kava, Kava Kava, Kawain, Dihydrokawain, Kava Pepper, Kava Modifies the Methysticin, Piper methysticum Shrub, Kava-Kava, Root GABA receptor 1, 2, 3 Dihydromethysticin, Lactones L.f. (Piperaceae) A Kawa Pepper, [23] Yangonin, and Yangona Pepper Desmethoxyyangonin [24]

Modifies the

GABAA receptor; Zizyphus jujuba Mill Plants, Chinese Activates the

var. spinosa Date, Common Seed GABAA receptor; 1, 2, 3 Sanjoinine A [25] Alkaloids (Rhamnaceae) Jujube Increases GABA synthesis by GAD activation [25]

All Heal, Common Valeriana , Garden Modifies the

officinalis L. Heliotrope, Garden Root GABAA receptor 1, 2 [26] Sesquiterpenoids (Caprifoliaceae) Valerian, Garden- [26] Heliotrope, Valerian

Modifies the Hypericum GABA - montbretii Spach — — A 1 Rutin and Quercitrin [27] Flavonids benzodiazepine (Hypericaceae) receptors [27]

Pinus massoniana Acicular Increases GABA Pine Needles 1 Volatile oil [29] Volatile oils Lamb. (Pinaceae) leaf levels [28]

Baikal Skullcap, Modifies the Chinese Skullcap, and baicalensis Georgi Root GABA receptor 1 Golden Root, A [30, 31] (Lamiaceae) [30] Helmet Flower

Atractylodes Modifies the Sesquiterpene macrocephala Koidz. — Rhizome GABA 1, 3 Atractylenolide II and III [32] A lactones (Compositae) receptor [32]

Increases GABA Ipomoea orizabensis release in the (Pelletan) Ledeb. Mexican scammony Root cortices of the 1 Convolvulin [33] Resin ex Steud. root brains of (Convolvulaceae) mice [33]

Ternstroemia lineata Calyx and Influences GABA DC. — 1 Jacaranone [34] Quinones Fruit release [34] (Pentaphylacaceae)

Rhus parviflora Modifies GABAA- Mesuaferrone B, Roxb. Tintidikah Fruit benzodiazepine 1 Rhusflavone, and Biflavonoids (Anacardiaceae) receptors [35] Agathisflavone [35]

Modifies Dimocarpus longan Longanae Arillus Fruit GABAergic 1, 3 extract [36] Unknown Lour. (Sapindaceae) systems [36]

Crassocephalum Blocks dopamine bauchiense (Hutch.) D-2 receptors and — Leaf 1 Alkaloid fraction [37] Alkaloids Milne-Redh. active GABAergic (Compositae) systems [37]

4 Current Neuropharmacology, 2014, Vol. 12, No. 0 Shi et al.

Table 1. contd….

Medicinal Mechanisms of Type of Major Sedative Constituents Herbal Medicine Common Names Parts Action Evidence* Compound Names Type of Compound

Florist`s Chrysanthemum, Chrysanthemum Increases Florist's Chrysanthemum, morifolium Ramat. Flower expression levels 1 Ethanol extract [38] Unknown Florist's Daisy, Florists' (Compositae) of GAD [38] Chrysanthemum, Mum

Mediates Dorstenia arifolia — Rhizome GABAergic 1 Methanol extract [39] Unknown Lam. (Moraceae) pathways [39]

Magnolia officinalis Bark of Modifies the and Rehder & E.H.Wilson Medicinal the root GABA receptor 1, 2 A [40, 41] (Magnoliaceae) and stem [40]

Common Licorice, Black Sugar, Common Licorice, Cultivated Licorice, Kahles S, Kahles S ssholz, Modifies GABA - Glycyrrhiza glabra L. Licorice, Licorice-Root, A Root BZD receptors 1 Glabrol [42] Flavonoids (Leguminosae) Licorice, Russian Licorice, [42] Spanish Juice, Spanish Licorice, Sweet Licorice, Sweet Wood, True Licorice

Ecklonia cava Modifies GABAA- , , Kjellman Paddle Weed — BZD receptors 1 , and (Lessoniaceae) [43] Triphlorethol-A [43]

Decreases the Melissa officinalis oil Melissa officinalis L. Whole level of GABA-T, [45, 46] Monoterpenaldehyde Balm, 1 (Lamiaceae) herb thereby increasing (citral a, citral b and s

GABA levels [44] citronellal [47]) *1: Experimental evidence of sedative activity, 2: Human clinical data, 3: Traditional medical systems and pharmacopoeia-endorsed use. and bile duct proliferation consistent with chemical hepatitis of other drugs used to treat anxiety. Therefore, novel [48]. Kava-kava were banned throughout the European enzymatic, analytical, toxicological, ethnobotanical, and Union and Canada by January 2003, and the use of these clinical studies are needed. extracts was subject to caution and advisories by the FDA A double-blind, randomized, placebo-controlled study of [48]. kava-kava for the treatment of generalized anxiety disorder Kava-kava extract toxicity appears to be idiosyncratic. was performed in April 2013. Importantly, GABA was While the hepatotoxic features of commonly used herbal analyzed as a potential pharmacogenetic marker of response products, including kava-kava, have been studied [51], the in this trial, specific GABA transporter polymorphisms underlying mechanisms remain uncharacterized. Possible appear to potentially modify anxiolytic response to kava- mechanisms for hepatotoxicity include inhibition kava, a significant reduction in anxiety was observed in the of cytochrome P450, reduction in liver content kava-kava group. What’s remarkable important is that and, more remotely, inhibition of cyclooxygenase standardized kava-kava was well tolerated and showed no activity. In particular, no clear evidence supports a causative obvious hepatotoxicity. In this study, no significant adverse role for the kavalactone and non-kavalactone constituents effects or liver function impairment were observed [53, 54]. isolated from kava-kava, including and This is consistent to the point that the risk-to-benefit ratio of B, in hepatotoxicity. Thus the possibility of kava-kava extracts is superior to that of other drugs that are direct toxicity of kava-kava extracts is precious little under used to treat anxiety. According to a previous analysis, the rate any analysis, yet the potential for drug interactions and/or the of incidence is 0.3 cases per one million daily doses of kava- potentiation of the toxicity of other compounds may play the kava, which is quite favorable with the benzodiazopenes, main role [52]. Presently, kava-kava toxicity appears to be including which hepatic adverse effects rate per million daily “idiosyncratic”. The risk-to-benefit ratio of kava-kava doses is 0.90 for , 1.23 for , and 2.12 extracts, nevertheless, remains high in comparison with that for . Similarly, the hepatotoxicity rate of nonsteroidal Herbal Insomnia Medications that Target GABAergic Systems Current Neuropharmacology, 2014, Vol. 12, No. 0 5 anti-inflammatory drugs was 3%–5% (acetylsalicylic acid), widely reported to be an effective treatment for insomnia, of which 3% again are potentially life-threatening [24]. but it is often present as Suan Zao Ren Tang or as a Acetaminophen-containing products also brought 258 component of some listed drugs. Single-component drugs cases of acute liver failure in the period 1998–2000 in US have not yet been developed. [55]. A recent pharmacologic study measured the electro- encephalograms (EEGs) and electromyograms (EMGs) of 3.3. Valeriana officinalis L. (Family: Caprifoliaceae) rats with electrodes implanted in their frontal cortices and Valerian (Valeriana officinalis) is widely used as a dorsal neck. When kava-kava extract was administered at a sedative and an anti-anxiety drug in folk medicine. Valerian dose of 300 mg/kg, the sleep latency of sleep-disturbed rats root is most commonly used for its sedative and hypnotic was remarkably shortened; no effects were observed on the properties in patients with insomnia. It is native to Europe total duration of wakefulness and NREM sleep [23]. Besides, and Asia and has been naturalized in eastern North America. J. Sarris et al. found that the aqueous kava-kava preparation Valerian contains over 150 chemical constituents, many of produced significant anxiolytic and antidepressant effects which are physiologically active, including alkaloids (e.g., while take no safety concerns, which implied that aqueous actinidine, which affects GABAergic metabolism), terpenes, rootstock extracts of kava-kava may be a new break point for organic acids and their derivatives (e.g., valeric acid and the management of anxiety [48]. valerenic acid; both affect the CNS), valepotriates (e.g., These latest studies demonstrate that kava-kava is an valepotriates and valeranone, which affect smooth muscle), effective and safety-promising anti-anxiety therapy and and [61]. In an effort to reveal the underlying GABA may be the active target of kava-kava. In general, mechanism of action of valerian, another study investigated kava-kava continues to have potential value for the treatment the modulation of GABAA receptors using valerian extracts of sleep disorders. It should be stressed again that even the of different polarities and sesquiterpenic acid contents in safest of the preferred prescription drugs appear to exhibit a Xenopus laevis oocytes expressing GABAA receptors hepatic adverse event rate at least three times that of the composed of the 1, 2, and 2S subunits. The results of kavalactones, thus research on the toxicity of kava-kava this study revealed that the extent of GABAA receptor would be of significant interest and impact. Further studies modulation by valerian extracts is related to the valerenic should focus on the identification of additional hepatotoxic acid content and one possible mechanism for the sedative constituents, with particular consideration given to possible and sleep-inducing effects of V. officinalis L. is stimulation adulterants and impurities, such as ochratoxin A- and of the GABAA receptor [26]. Moreover, another study sought aflatoxin (AF)-producing varieties of Aspergillus [56]. to identify the mechanism underlying the effects of valerian extracts on postsynaptic potentials (PSPs) in cortical 3.2. Zizyphus jujuba Mill var. spinosa (Family: Rhamnaceae) neurons. Treatment with an extract of macerated valerian roots in ethyl acetate (EA-E) at a concentration of 10 mg/mL Zizyphi spinosi semen (ZSS), the maturate seed of increased PSPs. PSP induction was completely blocked by Zizyphus jujuba Mill var. spinosa, is a historic classic herbal treatment with the GABAA receptor antagonist picrotoxin medication widely used in treating insomnia in Asian (100 m) [62]. However, the general mechanism of action of countries. There are three main types of ingredients in ZSS valerian (and particularly the mechanism underlying its mild that also display lipid oxidation resistance properties: sedative effects) remains unknown. , alkaloids, and flavonoids [57]. The underlying mechanism of ZSS remains unclear although numerous Ziegler G et al. reported that 600 mg/die valerian extract studies have been conducted over the past years. One of the LI 156 was at least as efficacious as a treatment with 10 major alkaloid compounds, sanjoinine A, enhances mg/die oxazepam in the treatment of non-organic insomnia -induced sleeping behaviors, which are more [63]. Many other studies also demonstrated that valerian is commonly referred to as hypnotic effects. As Ma Yuan et al. efficient in treating mild psychophysiological insomnia [63, reported, sanjoinine A behaves similarly to other GABAA 64]. But the clinical studies of valerian on improving sleep receptor agonists in a dose-dependent manner and increases quality reported have been turned out to be more negative chloride influx in primary cultured cerebellar granule cells, than positive [65]. Also in a meta-analysis of 18 reported thereby modifying GABAergic systems [25]. In another randomized clinical trials, analysis had been done to describe study by Ma Yuan et al., over-expression of the - and - the effectiveness of valerian on insomnia, the results showed subunits of the GABAA receptor and that there are only 0.70 min difference in LT between the decarboxylase (GAD65/67) in cultured cerebellar granule valerian and placebo groups [66]. Therefore, it seems cells was observed after sanjoinine A (5.0 μM) treatment difficult to develop valerian into a specific medicine for [58]. Furthermore, ZSS is one of the ingredients in Suan Zao insomnia, in our concern mild psychophysiological insomnia Ren Tang, which exhibits binding affinity for the serotonin may be the most suitable indication for valerian clinical (5-hydroxytryptamine, 5-HT) 5-HT1A and 5-HT2 receptors applications. and GABA receptors. Serotonergic activation was reported 3.4. Hypericum montbretii Spach (Family: Hypericaceae) following treatment with Suan Zao Ren Tang [59], but the exact chemical constituents responsible are unclear. Hypericum grows in temperate and subtropical regions of Research regarding the effects of Sansohnin-to on sodium the Northern Hemisphere; and the family Hypericaceae pentobarbital-induced sleep duration revealed that the comprises over 400 species. In the past few years, various underlying mechanism of action of Sansohnin-to is related to Hypericum species have been widely studied for their stress-induced functional changes in the CNS [60]. ZSS is pharmacological activity in the CNS. Moreover, Hypericum 6 Current Neuropharmacology, 2014, Vol. 12, No. 0 Shi et al. is used as a treatment for , nicotine, and caffeine have certain effects on nervous system [73]. However, addiction, and it is accepted as an anxiolytic, antidepressant studies so far only concerned on the extraction and analyzed [67] and sedative [68]. The main chemical components of H. the volatile component of pine needles with a limited montbretii extracts are and flavonoids, number of studies in China, sedative and hypnotic effects of including rutin, hyperoside, -7-O-glucoside, quercitrin, the volatile oils and the mechanisms are unclear, which may , and vitexin [69]. Özgür Devrim Can et al. used lead to the breakthrough point for further study if we can different behavioral methods, including the activity cage test separate a active volatile component responsible for the and Hxb-induced sleep, to investigate the sedative activity of sedative and hypnotic effect. As a widely distributed and a methanol extract of H. montbretii containing rutin (1519 easily achieved herbal medication with mild nature, we ppm) and quercitrin (784 ppm). This H. montbretii extract believe there is a huge potential for pine needles in insomnia possessed sedative and anticonvulsant activities mediated via treatment, or as a supplement of prescription medicine, to the GABAA-benzodiazepine (GABAA-BZD) receptor complex say the least. Therefore, for the sake of prospective use in in the CNS of mice [27]. E. Ernst et al. evaluated the adverse clinical, further research may focus on the sedative effects drug reactions (ARDs) of Hypericum perforatum only to find and side effects of pine needles. that the most common adverse effects were gastrointestinal 3.6. Georgi (Family: Lamiaceae) symptoms, Hypericum perforatum showed an excellent tolerance with an incidence of adverse reactions similar to Scutellaria baicalensis is a traditional Chinese medicinal the placebo. A potential serious adverse effect may be herb, especially its dried roots, Scutellariae Radix, which has photosensitivity which appears to occur extremely rarely been documented to possess therapeutic effects for hundreds [70]. Hypericum perforatum may present pharmacokinetic of years. Its main active components of anti-inflammatory interactions with anticancer drugs in the findings of are baicalin, baicalein, and [74]. It has been widely Sparreboom A et al. [71] and may confound cancer care. used in China and other Asian countries for its anti- However, studies are far more needed of Hypericum for its inflammatory, anti-pyretic, anti-bacterial, anti-hypertensive, general clinical use, current studies are limited and more anti-allergic and sedating effects [30]. Recently, several researches concerned on the active ingredient and studies have demonstrated the effectiveness of Scutellariae mechanistic are needed. Radix in insomnia treatment, nevertheless, the clinical practice focus on the CNS regulation function of Scutellaria 3.5. Pinus massoniana Lamb. (Family: Pinaceae) baicalensis is limited [30]. Pine needles are needle-like leaves of Pinus massoniana Baicalein (BA) is one of the primary flavonoids in S. Lamb. Pine needles are traditionally used as insecticides, antipruritics, and , and they are also used as tea in baicalensis. One report demonstrated that the baicalin, the of the aglycone baicalein, decreased slow wave China, where a majority of the research on compounds from sleep (SWS) during the first 2 h of the light period but this plant has been performed. Chinese researchers Zhao G Z did not affect rapid eye movement sleep (REMS) after et al. studied the effects of different pine needle extracts on intracerebroventricular administration. Baicalin-mediated neurotransmitters and determined the levels of GABA and blockade of IL-1 enhanced SWS, suggesting that IL-1 glutamic acid in hippocampal slices of treated mice by HPLC. They observed significant increases in sodium receptor antagonism is involved in the ability of baicalin to reduce SWS during the light period. However, IL-1 pentobarbital-induced sleep duration and levels of GABA, concentrations during the light period were not altered indicating that pine needle extracts confer sedative and following baicalin administration. By contrast, baicalin hypnotic effects [28]. The Chinese Materia Medica states that increased both SWS and REMS during 8–10 hours of the the volatile oil of pine needles could improve sleep quality in dark (active) period when baicalin was administered at the mice when administered with pentobarbital sodium. Deng Y et al. observed sedation after treatment with volatile oil in beginning of the dark period, and this effect can be blocked by the GABA receptor antagonist bicuculline. Taken together, the shaking cage test and dynamic time testhowever A these results demonstrated that baicalin exhibits biphasic components of pine needles are extremely complex and effects on sleep-wake regulation (decreases in SWS during diversiform than other herbal medications that increased the the light period and increases in SWS and REMS during the difficulty in studying its underlying mechanism. Moreover, dark period) and the inhibition of IL-1 action together with the volatile oil has a significant synergistic effect with pentobarbital sodium [29]. The main chemical components enhancement of GABAA receptor activity may mediate the effects of baicalin during the light and dark periods, respectively of pine needles are volatile componentsincluding -ocimene [30]. Besides baicalein, wogonin (monoflavonoid, 5,7- (29.3%), sabinene (10.9%), -myrcene (9.6%), - dihydroxy-8-methoxyflavone), a benzodiazepine receptor (8.0%), -cadinene (7.3%), -terpinolene (4.9%), 2-hexanal ligand isolated from Scutellaria baicalensis Georgi had been (4.5%), and -pinene (4.3%), of which had antibacterial tested by Kwok Min Hui et al. as an alternative for BZDs, effects in vitro [72]. Latest research taken by LI Hong- yu et al. in the year 2012 isolated 6 aroma chemical components their study showed wogonin can exert GABA activation effect include enhancing the GABA-activated current in rat of pine needles including , dihydroactinidiolide, 2- dorsal root ganglion neurons and expressing recombinant rat isopropyl-5-methyl-2- hexenal, -curcumene, oleanitrile and GABA receptors in Xenopus laevis oocytes, and these (Z)-13-docosenamide including which vanillin and A enhancement can partially be reversed by benzodiazepine dihydroactinidiolide were the main components, and were site antagonist anexate (Ro15-1788) [75]. Wogonin was also isolated from the P.massoniana for the first time. Vanillin has been used in treatment and was demonstrated to proved to initiate little side-effects compared with BZDs although the underlying mechanisms are still unclear. Herbal Insomnia Medications that Target GABAergic Systems Current Neuropharmacology, 2014, Vol. 12, No. 0 7

Previous studies suggest us the sedative and hypnotic GABA in the mouse brain cortex. IT-EM (20, 40, or 80 effects of Scutellaria baicalensis may apply to activation mg/kg, i.p.) prolonged the duration of loss of righting reflex GABA system, whereas the elucidation of the active induced by pentobarbital sodium (30 mg/kg) compared to the ingredients awaits further research. Later studies should also control group (P < 0.05). IT-EM (2.5 μg/mL) induced a be focus on verifying the effect and mechanism of baicalein time-dependent increase in GABA content in mouse brain and baicalin. cortex slices [33]. Taken together, these pharmacological results demonstrate that IT-EM produces sedative effect. 3.7. Atractylodes macrocephala Koidz. (Family: Compositae) Because IT-EM does not affect the release of glutamic acid, Atractylodes macrocephala is an essential ingredient in this sedative effect might be specifically mediated by the common Chinese herbal formula Jia-Wey-Shiau-Yau-San. increased GABA levels [33]. However, there is insufficient LC Chen et al. performed a 4-year-long clinical observation evidence to link IT-EM activity to GABA, which represents survey on outpatients with primary insomnia from January an area of future research. IT-EM also displays vasodilatory 2003 to December 2006, in which 6860 patients were treated and toxic effects toward tumor cells, and thus the balance by Chinese herbal medicines, and Jia-Wey-Shiau-Yau-San between treating insomnia and inducing toxicity must be turned out to be the second most widely used herbal formula considered when determining the dosage. If further research in the treatment of insomnia meanwhile Atractylodes findings can convince us with a safe dosage of treatment macrocephala is the second widely used herb items. But due without causing cytotoxicity, Ipomoea tyrianthina may turn to the constitute of herbal formulae is of great complexity, it to be a promising herbal medication to treat insomnia is difficult to identify the active ingredient clearly [76]. In without serve side effects.  addition, it has long been used as a digestive agent and may 3.9. Ternstroemia lineata DC. (Family: Pentaphylacaceae) stimulate immune responses [77]. Atractylol, atractylon, and butenolide A, B are the active ingredients of Atractylodes Ternstroemia pringlei (a synonym of Ternstroemia macrocephala [78]. In 2012, Singhuber et al. reported that lineata DC.), which is traditionally used as a tranquilizer and positive allosteric modulation of GABA-induced chloride to diminish insomnia and fear in Mexico, is widely currents (IGABA) might be partially responsible for the employed and commercially exploited [34]. In 2010, Lozada traditional ethnopharmacological use of A. macrocephala et al. reported that i.p. administration of organic and aqueous herbal drug as a sedative. In this study, two microelectrode extracts of T. pringlei calyx and fruits, in which the active voltage clamps were placed on recombinant 122S GABAA ingredient was established as jacaranone (1), resulted in receptors expressed in X. laevis oocytes, and the ability to dose-dependent decreases in the number of rearings in the modulate IGABA was measured. The petroleum ether extract of exploratory cylinder model in mice and GABA release at A. macrocephala rhizomes displayed strong IGABA potentiation, ratios of 217 and 179 pmol/ in GABA release and atractylenolide II and III, the primary components experiments using mouse brain slices in vitro. Moreover, the isolated from A. macrocephala, were apparently responsible sedative effects of these extracts were as follows (ED50): for the observed positive modulation of IGABA (166 ± 12%, n aqueous (77.58 mg/kg) > methanol (232.80 mg/kg) > = 3 and 155 ± 12%, n = 3) in vitro, And these effects were (345.93 mg/kg) > hexane (446.68 mg/kg). independent of the benzodiazepine binding site [32]. The sedative compound jacaranone was isolated from the MeOH crude extract, and its efficacy was clearly Despite the vitro and clinical observation studies showed demonstrated in a dose-dependent response analysis (ED = great efficiency of A. macrocephala on insomnia and GABA 50 25 mg/kg mouse weight). However, none of the extracts modulation, further studies are still needed to clarify the derived from Ternstroemia pringlei displayed anxiolytic therapeutic potential of A. macrocephala in human and its activity when tested in the elevated plus-maze model [34]. In molecular mechanism. For clinical application, clinical trials 2008, Balderas et al. tested the sedative effect of an aqueous concerning adverse effects and drug interactions are also extract of the dried fruits of Ternstroemia pringlei (rose) in needed. synergy with 6 CNS drugs and found that the 3.8. Ipomoea tyrianthina (Pelletan) Ledeb. ex Steud (Family: aqueous extract can induce a sedative effect in a dose- Convolvulaceae) dependent manner and potentiate the sedative effect of , diazepam, , or Ipomoea tyrianthina has been used as a mild purgative in pentobarbital and produce an attenuation of the sedative traditional Mexican medicine to treat nervous disorders and effect of ethanol. They believe that this plant has hard non- as an anti-tumor agent due to its characteristic resin predictive interactions with CNS depressant drugs; thereafter glycosides. In the year 2008, I León-Rivera et al. found the combination of this plant with CNS depressant drugs four new partially acylated tetrasaccharides of 11-hydro- should be avoided [80]. However, other researchers have xyhexadecanoic acid (14) which were isolated from a reported different issues, such as super-additive interactions, methanolic extract of Ipomoea tyrianthina showed which imply us further studies are still needed to confirm the antimycobacterial activity and exerted the potentiation of drug interactions and other side effects of Ternstroemia hypnosis induced by pentobarbital, protected against seizures pringlei before it becomes an recommended treatment for induced by pentylenetetrazole, and released GABA and insomnia. glutamic acid [79]. In 2011, León-Rivera et al. reported that convolvulin (IT-EM), an ether-insoluble resin glycoside 3.10. Rhus parviflora Roxb. (Family: Anacardiaceae) isolated from the root of I. tyrianthina can increase the In southern Asia (Ayurveda), Rhus parviflora is used to hypnotic effect induced by pentobarbital and the release of treat Vta vikra, which causes neurological complications. 8 Current Neuropharmacology, 2014, Vol. 12, No. 0 Shi et al.

R. parviflora is an important part of the traditional medicinal and its advantages may lead to a novel therapy pathway for system in these countries and is referred to as Tintidikah. R. insomnia and bring us with new thoughts. parviflora is also used to treat stomach disorders. In the past 3.12. Crassocephalum bauchiense (Hutch.) Milne-Redh. year, the methanol extract of R. parviflora fruit (RPME) was (Family: Compositae) shown to exhibit significant GABAA-BZD receptor binding capacity by Shrestha et al. in a search for natural products Crassocephalum bauchiense (Hutch.) Milne-Redh that enhance sleep quality. There was a dose-dependent (Compositae) is a medicinal herb that has been reported to decrease in sleep latency and an increase in sleep duration in confer beneficial effects such as analgesia and antibacterial mice treated with pentobarbital and RPME (125, 250, 500, in the Cameroonian traditional system of medicine. It and 1000 mg/kg) orally. Moreover, the hypnotic effect contains alkaloids and is consumed to treat insomnia, of RPME was completely inhibited by 3H-Ro15-1788 dementia, and psychotic disorders [81]. The aqueous extract . In addition, the biflavonoids mesuaferrone B, (20, 40, 80 and 160 mg/kg, p.o.) and the alkaloid fraction (5, rhusflavone, and agathisflavone, which were isolated from 10, 20 and 40 mg/kg, p.o.) of C. bauchiense inhibit novelty- the ethyl acetate fraction, competitively blocked flumazenil induced rearing behavior in a dose-dependent manner, binding with Ki values of 0.280, 0.045, and 0.091 μM. It was decrease -induced stereotypy and fighting, proposed that the conjugated ketone and C6-C8 biflavonoid and significantly decrease body temperature. Sodium linkage in rhusflavone decreased sleep latency and increased pentobarbital-induced sleep duration was prolonged by the sleep duration by activating the BZD-site of GABAA [35]. aqueous extract, and this effect was blocked by N-methyl-- However, these finding were only clinical manifestations carboline-3-carboxamide, a partial inverse agonist of the without theory supporting, this hypothesis awaits confirmation benzodiazepine site of the GABAA receptor complex, and in molecular biology studies to identify the target of flumazenil, a specific antagonist of the benzodiazepine site rhusflavone. Also drug interactions and side effects need to of the GABAA receptor complex. However, bicuculline, be tested before it become a candidate for further preclinical which is a light-sensitive competitive antagonist of the studies of herbal medicine aimed at the treatment of GABAA receptor complex, was unable to inhibit the activity insomnia since most of the patients may take more than only of the aqueous extract of C. bauchiense. In biochemical one species of hypnotics. experiments, the concentration of inhibitory GABA was significantly increased in the brains of animals treated with 3.11. Dimocarpus longan Lour. (Family: Sapindaceae) the aqueous extract of C. bauchiense and sodium valproate. Dimocarpus longan is a popular fruit in many subtropical These results suggest that the aqueous extract and alkaloid countries due to its delicious taste, particularly in China and fraction prepared from C. bauchiense leaves possess South Asia. Moreover, its pulp and fresh Longanae Arillus antipsychotic and sedative properties in rodents, which are have been consumed in Asia for many years to treat anxiety mediated by the blockade of dopamine D-2 receptors and and insomnia. Yuan Ma et al. investigated the sedative/ GABAergic activation [37]. The results of another study hypnotic effects of a standardized methanol extract of seeking to determine the toxicity of C. bauchiense extracts Longanae Arillus (MELA) on pentobarbital-induced sleep demonstrated that it is safe for the treatment of bacterial behavior and whether the underlying mechanisms involve infection [82]. However, all these studies lacked the analysis GABAergic systems. They reported that MELA prolonged of composition, so the specific composition of the C. pentobarbital-induced sleep duration and reduced bauchiense extract is eager to be estimated for future pentobarbital-induced sleep latency in a similar fashion as research. Thus, safety and composition studies represent the muscimol, a GABAA receptor agonist. MELA increased both next phase of C. bauchiense research. the rate of sleep and sleep duration when administered with 3.13. Chrysanthemum morifolium Ramat. (Family: pentobarbital at a sub-hypnotic dosage, and it displayed synergic effects with muscimol in potentiating pentobarbital- Compositae) induced sleep onset and enhancing pentobarbital-induced The flowers of Chrysanthemum morifolium Ramat (FC) sleep duration. However, treatment with MELA alone did have been used in Asian countries for hundreds of years as a not induce sleep at the higher doses used in this experiment. medicinal herbal tea. Its main components are volatile oils In addition, both MELA and pentobarbital increased chloride (e.g., , camphor, and Chrysanthenone), flavonoids influx in primary cultured cerebellar granule cells. MELA (e.g., diosmetin and ), and amino acids (e.g., aspartic increased the expression of the GABAA receptor -subunit acid and glutamic acid) [83]. In China and some other Asia but did not affect the expression of the - and -subunits and countries like Korea, dried FC in herbal tea has traditionally glutamic acid decarboxylase in primary cultured cerebellar been used to treat insomnia. Some other studies have also granule cells, thus differing from the effects induced by been described additional biological features of FC include pentobarbital. In conclusion, although MELA itself does not , cardiovascular-protective, anti-tumorigenic, and induce sleep, its synergistic effect with pentobarbital anti-inflammatory properties. As Kim J W et al. reported in enhances the sleep behaviors induced by pentobarbital by 2011, administration of an ethanol extract of Chrysanthemum modifying GABAergic systems [36]. Further evidence is morifolium flowers (EFC) prolonged pentobarbital-induced needed to confirm how MELA affects GABAergic systems sleep duration at doses of 50 and 100 mg/kg without and find the answer why MELA alone did not induce sleep affecting sleep latency. However, treatment with EFC at the higher doses. In addition, the difference between the increased the rate of sleep onset and sleep duration induced active ingredients of Dimocarpus longan with other by a subhypnotic dose of pentobarbital (28 mg/kg, i.p.), and hypnotics should be revealed. The underlying mechanism the effects of 100 mg/kg EFC were similar to those of Herbal Insomnia Medications that Target GABAergic Systems Current Neuropharmacology, 2014, Vol. 12, No. 0 9 muscimol. Furthermore, EFC treatment (100 mg/kg) pentobarbital-induced sleep duration in a dose-dependent increased the expression of GAD without influence the manner, and treatment with honokiol (20 or 50 μM) - levels of the 1-, 2-, and 2-subunits of GABAA receptor. increased the [Cl ] concentration to 36.9 or 43.9 mM in The treatment of granule cells with EFC (1–4 μg/mL) primary cultured cerebellar neurons. Additional treatment of significantly increased chloride ion influx. These results primary cultured cerebellar granule cells showed selective  suggest that EFC may induce Cl channel opening in GABAA GABAA receptor -subunit expression increase, on the other receptors [38]. It would be economically advantageous if this hand, chronic honokiol treatment did not affect GAD ornamental plant could be used in medicine, but further abundance. These results suggest that honokiol potentiates - studies are needed to confirm that there is no difference pentobarbital-induced sleep through GABAA receptor Cl between EFC and currently available drugs. Besides, how to channel activation [40]. In 2012, Wei-Min Qu et al. reported make the extraction of the active ingredients efficient enough that i.p. honokiol (10 or 20 mg/kg) significantly shortened to become a medication may be the most important hurdle the sleep latency to NREM sleep and promoted NREM sleep for FC before applying in pharmaceutical industry. by modulating the benzodiazepine site on the GABAA receptor in mice. Unlike other commonly used sedative- 3.14. Dorstenia arifolia Lam. (Family: Moraceae) hypnotic drugs, honokiol did not affect the amount of REM Dorstenia arifolia has been used for years as a folk sleep or the electroencephalogram power density of either medicine to produce hypnotic, sedative, and anxiolytic NREM or REM sleep. Moreover, honokiol induced a type of effects; however, its pharmacological properties have not NREM sleep similar to physiological NREM sleep and may been studied. The smoke of its rhizome can induce a be suitable for the treatment of insomnia [86]. Magnolol lethargic sensation. D. arifolia extracts have been reported to significantly shortened sleep latency and increased the contain triterpenes esterified by fatty acids, unesterified amount of NREM and REM sleep after 3 h following its triterpenes, triterpenes esterified by acetic acid, and administration, and it also increased the number of NREM furanocoumarin [84]. Gisele Z S et al. reported a significant and REM sleep episodes. Immunohistochemical analyses decrease in the locomotor activity of mice after i.p. revealed that magnolol increased c-Fos expression in the administration of a methanol extract (ME) of the D. arifolia neurons of the ventrolateral preoptic nucleus (VLPO), a rhizome (10 and 50 mg/kg). and this ME-induced sedation group of neurons in the hypothalamus that release the can be blocked by flumazenil (10 mg/kg), an antagonist of inhibitory neurotransmitter GABA during sleep, and GABAA receptor. In addition, pentobarbital-induced sleep decreased c-Fos expression in the arousal tuberomammillary duration significantly increased after treatment with ME (50 nucleus, which is a dominant arousal regulation area located mg/kg). Furthermore, ME promoted - in the caudolateral hypothalamus. Magnolol-induced sleep- induced seizure protection and decreased mortality in a dose- promoting effects and changes in c-Fos expression were dependent manner compared to the control groups. To sum reversed by flumazenil, an antagonist of the benzodiazepine up, it is likely that the sedative activity of ME is mediated by site on the GABAA receptor. These results indicate that the GABAergic pathway, as GABAergic transmission produces magnolol increases NREM and REM sleep via the GABAA profound sedation in mice [39]. Studies of D. arifolia have receptor [41]. been limited, and further exploration is warranted. Several M. officinalis bark extracts have been approved 3.15. Rehder & E.H.Wilson (Family: for use, and their efficacy for the treatment of insomnia has Magnoliaceae) been confirmed; especially honokiol and magnolol as we mentioned, it seems to have a great future for M. officinalis Decoctions of Magnolia officinalis bark are prescribed as in insomnia treatment. Further studies may focus on isolation a drug in Hangekouboku-to, Saiboku-to and other traditional of other active ingredients and reveal its sedative-hypnotic Chinese medicine. They are primarily used to treat clinical mechanism more deeply. In addition, adverse reactions and depression and anxiety-related disorders, such as anxiety drug interactions should also be evaluated. neurosis and anxiety hysteria. M. officinalis bark extracts and several of its active constituents, such as honokiol and 3.16. Glycyrrhiza glabra L. (Family: Leguminosae) magnonol, have been studied in various mouse models. Their Licorice root (Glycyrrhiza glabra, GG) is one of the most activities were compared with diazepam (a classic frequently used natural medicines in the world and has been benzodiazepine anxiolytic that has been used to treat anxiety described as “the grandfather of herbs”. Licorice root has disorders since the 1960s) [85]. A proprietary patented blend been used medicinally in both Western and Eastern countries of the extract from the bark of Magnolia officinalis Rehder for more than 4,000 years. GG extract is extensively used in & Wilson [Magnoliaceae] together with the extract of the the US, and it is considered generally safe for use in foods bark of Phellodendron amurense Rupr [Rutaceae] has been by the FDA [42]. GG is also used as an ingredient in Suan produced and named Relora® (US Patent Nos. 6,582,735 Zao Ren Tang, which is a well-known traditional Chinese and 6,814,987) to help alleviate symptoms associated with remedy for insomnia [76]. In addition, a root component stress, such as nervous tension, irritability, concentration (glycyrrhizin) is generally regarded as the major biologically difficulties, and occasional sleeplessness [85]. active component of GG [87]. Honokiol and magnolol (6, 6, 7, 12-tetramethoxy-2, 2- Cho S et al. reported dose-dependent pentobarbital- dimethyl-1--berbaman, C H O ) are two major bioactive 18 18 2 induced sleep potentiation and an increase in the amount of constituents of M. officinalis bark which proved to be NREM sleep in mice, without a decrease in delta activity, efficient in sedative and hypnotic. Honokiol increased after GG ethanol extract (GGE) administration. The 10 Current Neuropharmacology, 2014, Vol. 12, No. 0 Shi et al.

GABAA-BZD receptor antagonist flumazenil inhibited the sedative in a way [44]. But a huge number of researches hypnotic effect of GGE. Moreover, the ability of glabrol, including animal model analysis and molecular biology which was isolated from the -rich fraction of GGE, studies are still need to be done to certitude its sedative 3 to inhibit [ H]-flumazenil binding to the GABAA-BZD effect before reality use. receptors in rat cerebral cortical membranes with a binding affinity (Ki) of 1.63 μM suggests a possible mechanism of 4. DISCUSSION action. The molecular structures and pharmacophore models Sedative-hypnotic drugs are the most common treatments of glabrol also indicate that the isoprenyl groups of glabrol for insomnia, of which the most commonly used are BZDs are critical for binding to GABAA-BZD receptors. Glabrol and non-benzodiazepines. However, adverse effects such as increases sleep duration and decreases sleep latency in a dependence, impairment of memory or movement, and dose-dependent manner (5, 10, 25, and 50 mg/kg). In residual effects have limited the prescription of these drugs addition, its hypnotic effect can be blocked by flumazenil. [90]. Herbal medications have been widely used to treat These results imply that allosteric modulation of GABAA- insomnia worldwide for thousands of years. Increasing BZD receptors may be responsible for the sleep-inducing preclinical and clinical studies indicate the complex activity of GGE and its flavonoid glabrol [42]. mechanisms by which herbal medicines treat sleep disorders and anxiety, such as that Humulus lupulus prolonged In consideration of its safety and abundance using pentobarbital induced sleeping time and valerian improved experience, it’s reasonable to identify Licorice root has an ambitious application prospect. However, there are still sleep latency and quality in patients with sleep disorders. The mechanisms of herbal insomnia medications that target several problems need to be solved besides the drug safety: GABAergic systems include: (1) modifying GABA receptors, the GABA agonist-like effect of GGE remains unclear, and A A the most common sites of action of the discussed herbal its elucidation awaits further study. Furthermore, how to medications, as shown for kava-kava; (2) increasing GABA draw the largest biological activity of Licorice root is also a synthesis by activating GAD, as shown for Zizyphus jujuba; challenge for researchers. and (3) influencing GABA release, such as Ternstroemia 3.17. Kjellman (Family: Lessoniaceae) lineata. Ecklonia cava Kjellman, an edible brown seaweed, is Although herbal medications show their effectiveness to found in the coastal areas of Japan and Korea. The main some extent, several aspects of the of active chemical components of E. cava are phlorotannins herbal medicines must be resolved, including poor in vivo (e.g., eckol and [88]). Cho et al. reported that evidence of pharmacodynamics of human studies, lack of treatment with an ethanol extract of E. cava Kjellman (ECK- bioequivalence between plant extracts, difficulty in E) significantly potentiated pentobarbital-induced sleep in evaluating efficacy in clinical trials, and the production of mice. In the four solvent fractions that were isolated from standardized extracts, as various factors contribute to the ECK-E, the hypnotic activity was proportional to the total composition of herbal preparations [91]. Herbal medications content of and phlorotannins, which are known as are also associated with a certain of adverse reactions and seaweed . The major phlorotannins of the ethyl drug interactions such as allergic reactions of Humulus acetate (EtOAc) fraction that demonstrated the highest lupulus and the withdrawal symptoms at large doses of activity were eckol, eckstolonol, dieckol, and triphlorethol- valerian [61, 92], the scaly skin rash called “kava A, and their Ki (binding affinity, l M) values for [3H]- dermopathy” and hepatic damage after long-term use of flumazenil binding were 1.070, 1.491, 3.072, and 4.419 kava-kava were also reported [24]. The most serious respectively. The hypnotic effects of the ECK-E and the hepatotoxicity might be concerned with pharmacogenomics EtOAc fractions were fully inhibited by flumazenil, a effects and bile duct inflammation [52]. Honokiol has central specific GABAA–BZD receptor antagonist [43]. Furthermore, depressant and muscle relaxant effects which may lead to the ECK enzymatic extract displayed significant sleep- behavioral side effects at high concentrate, but this is nearly inducing (> 500 mg/kg) effects on pentobarbital-induced impossible because it’s unlikely to reach the purity required sleep in mice [89]. These results suggest that ECK-derived to initiate the side effects via inartificial magnolia bark [93]. phlorotannins induces sleep through positive allosteric The hypnotic effects of Zizyphus jujuba involve the modulation of the GABAA–BZD receptor. activation of GABAA receptors, serotonin receptor binding, and increased GAD expression levels, which yield positive 3.18. Melissa officinalis L. (Family: Lamiaceae) results, making Zizyphus jujuba a promising herbal Lemon balm (Melissa officinalis L.), which belongs to medication to treat insomnia without serious adverse effects the family Lamiaceae, is planted widely in central and [94]. Also, a research concerned on anticancer agents southern Europe, Asia, and tropical countries, such as Brazil reported that kava-kava and Hypericum perforatum may [45]. M. officinalis regulates a number of behavioral participate in potential pharmacokinetic interactions with measures, such as disturbed sleep and reduced excitability anticancer drugs because of their potential to significantly and anxiety. M. officinalis oil can also be used to treat modulate the activity of drug-metabolizing (notably herpetic infections, spasms, and antimicrobial infections due cytochrome P450 isozymes) and/or the drug transporter P- to its antitumor and antioxidant properties [45, 46]. M. glycoprotein [71]. But to our point of view, cancer patients officinalis can greatly influence GABA metabolism by may not pay so much attention to herbal insomnia decreasing the level of GABA-T thereby increasing GABA medication even they are troubled by sleeplessness. levels, which indicate that M. officinalis could acts as a Herbal Insomnia Medications that Target GABAergic Systems Current Neuropharmacology, 2014, Vol. 12, No. 0 11

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Received: March 03, 2013 Revised: November 02, 2013 Accepted: December 24, 2013