International Journal of Biomedical Research

HERBAL DRUGS IN MIRROR OF ANXIETY DISORDER -A REVIEW Kamal M 1*, Jawaid T 2 1 Faculty of Pharmacy, Integral University, Lucknow (U. P.), India 2 Hygia Institute of Pharmaceutical Education and Research, Lucknow (U. P.), India Corresponding author*: [email protected] This article is available online at www.ssjournals.com

ABSTRACT Traditional Medicines derived from medicinal plants are used by about 60% of the world’s population. This review focuses on Herbal drugs used in the treatment of Anxiety disorder. Anxiety disorders, including generalized anxiety disorder (GAD), panic disorder, post- traumatic stress disorder (PTSD), and obsessive compulsive disorder (OCD), are the most prevalent behavioral disorders in the United States, affecting 17.2% of the population. The use of herbal supplements to treat anxiety has been increasing and the mechanisms of action of several are being elucidated. A list of medicinal plants with proven antianxiety effects used in treatment of Anxiety is compiled. These include, Citrus paradise, Cirsium rivulare, Drymaria cordata, Colocasia esculenta, Souroubea sympetala, Rollinia mucosa, Aethusa cynapium, Uncaria rhynchophylla, Cinnamomum cassia, Gastrodia elata, Apocynum venetum, Turnera aphrodisiaca, Scutellaria lateriflora, Valeriana officinalis, Galphimia glauca etc.

KEY WORDS: Herbal Drugs, Antianxiety, Anxiety

INTRODUCTION disorders in the United States, affecting 17.2% of the population. In the last few years there has been an

exponential growth in the field of herbal medicine and these drugs are gaining MEDICINAL PLANTS WITH popularity both in developing and ANTIANXIETY EFFECTS: developed countries because of their natural origin and less side effects. Many Citrus paradisi var.star ruby traditional medicines in use are derived (Grapefruit): from medicinal plants, minerals and [1] Citrus paradisi has been used traditionally organic matter . The current review to reduce stress and anxiety. The anti- focuses on herbal drug used in the anxiety activity of various extracts viz treatment of anxiety disorders, among the petroleum ether, chloroform, methanol most common mental disorders besides and water, of the leaves of Citrus paradisi depressive disorders with approximately var. star ruby using elevated plus maze one-eighth of the world population [2] (EPM) model in Swiss albino mice were affected at some point in their life . evaluated. Results show that methanol Anxiety disorders, including generalized extract at the dose of 100mg/kg of the anxiety disorder (GAD), panic disorder, leaves of Citrus paradisi var. star ruby post-traumatic stress disorder (PTSD), markedly increased the average time spent and obsessive compulsive disorder in the open arms of the EPM [3] (OCD), are the most prevalent behavioral .

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Cirsium rivulare (Ornamental thistle): might contribute to its anxiolytic activity [6]. Cirsium rivulare (Asteraceae) is a herbaceous perennial plant occurring in Souroubea sympetala: Central Europe. It has been traditionally used in Polish folk medicine to treat Souroubea sympetala Gilg anxiety. Methanolic extracts from flowers (Marcgraviaceae) is a traditional anti- and leaves of Cirsium rivulare containing anxiety plant. SCE (supercritical carbon flavonoid compounds linarin, dioxide extraction) can be used to pectolinarin, apigenin, hispidulin, their generate a betulinic acid-enriched extract glycosides and a newly isolated with significant anxiolysis in vivo [7]. compound isokaemferide 7-O-(6''- methylglucuronide) were studied for Rollinia mucosa (Wild sugar apple): anxiolytic and pro-cognitive properties. The flavonoids from Cirsium rivulare Rollinia mucosa (Jacq.) Baill. leaves posses anxiolytic properties [4]. (Annonaceae) extract induced anxiolytic- like actions similar to those induced by Drymaria cordata (Tropical chickweed): diazepam in the avoidance exploratory behavior paradigm. Its significant activity Drymaria cordata hydroethanolic extract was shown at doses from 1.62 to 6.25 (DCHE) at 25, 50 and 100 mg/kg (p.o.) mg/kg [8]. was administered to study anxiolytic effect. Different models for anxiolytic Aethusa cynapium (Dog Poison): activity viz. Hole board, Open field, Elevated plus maze, Light/dark Aethusa cynapium L. (Apiaceae)is exploration model were used. The commonly called Fool’s parsley, dog’s presence of phytochemicals viz. parsley or lesser hemlock. Bioactivity triterpenes, diterpenes, steroids and guided fractionation of the anxiolytic tannins might contribute to its anxiolytic methanol extract of A. cynapium has led activity [5]. to the isolation of a novel unsaturated fatty acid. This new fatty acid-trideca- Colocasia esculenta (Arvi): 7,9,11-trienoic acid, isolated from A. cynapium was found to be responsible for Colocasia esculenta Linn. (Araceae), the antianxiety activity of the plant [9]. commonly known as elephant ear (English), possesses diverse Uncaria rhynchophylla: pharmacological activities. The neuropharmacological activities of The aqueous extract of hooks with stem of hydroalcoholic extract of leaves of Uncaria rhynchophylla were characterized Colocasia esculenta were evaluated. The for the anxiolytic like effects using the anxiolytic activity of HECE (100, 200, elevated plus maze (EPM) and the hole- and 400 mg/kg) per os (p.o.) was board apparatus in rats and mice. Single characterized by increased time spent and or repeated treatments of the aqueous number of entries in open arms in the extract of Uncaria rhynchophylla (200 EPM paradigm as compared to control mg/kg/day, p.o.) for 7 days significantly group (p < 0.001). The presence of increased the time-spent and entries into flavonoids, beta-sitosterol, and steroids open arms of the EPM, and reduced the IJBR 2 [1] [2011]62‐72

Kamal et al Review Article time-spent and entries into the closed Turnera aphrodisiaca (Damiana): arms versus saline controls (P<0.05) [10]. Apigenin, a bioactive principle of Turnera Cinnamomum cassia (Dalchini): aphrodisiaca Ward (Turneraceae) was evaluated for antianxiety activity at a dose The anxiolytic-like effects of a 50% EtOH of 2 mg/kg using well established models extract of Cinnamomum cassia (C. cassia) of anxiety, the hole board test, light/dark were determined. A single treatment with test and mirrored chamber test. C. cassia (750 mg/kg, p.o.) significantly Observations confirmed the anxiolytic increased the number of entries into and activity of apigenin. Maximum activity the time spent in the open arms of the was observed 30 min after the EPM compared with the controls [11]. administration of 10 mg/kg dose of apigenin [15]. Gastrodia elata: Scutellaria lateriflora L. (Scullcap): The anxiolytic-like effects of the aqueous extract of the rhizome of Gastrodia elata The phytochemistry and biological along with its phenolic constituents, 4- activity of Scutellaria lateriflora L. hydroxybenzyl alcohol (HA) and 4- (American skullcap) which has been hyroxybenzaldehyde (HD), using an traditionally used as a sedative and to treat elevated plus maze (EPM) in mice were various nervous disorders such as anxiety characterized. A single treatment of the was studied. The identification and aqueous G. elata extract significantly quantification of the flavonoid, baicalin in increased the percentage of time spent and a 50% EtOH extract (40 mg/g) and its arm entries into the open arms of the EPM aglycone baicalein in a 95% EtOH extract versus the saline controls. Among the (33 mg/g), as well as the amino acids phenolic constituents of G. elata, HA and GABA in H2O and EtOH extracts (~1.6 HD significantly increased the percentage mg/g) and glutamine in a H2O extract (31 of time spent and arm entries into the mg/g), was performed using HPLC. These open arms of the EPM versus saline compounds may play a role in anxiolytic controls (p<0.05) [12]. activity since baicalin and baicalein are known to bind to the benzodiazepine site Apocynum venetum L.: of the GABAA receptor and since GABA is the main inhibitory neurotransmitter [16]. O. Grundmann et al. evaluated the anxiolytic activity of an aqueous extract of Apocynum venetum L. (Apocynaceae) Valeriana officinalis (Tobacco Root): and bioguided its fractionation using the elevated plus maze (EPM) in mice as a Valerian root (Valeriana officinalis) is a model of anxiety. A single treatment of popular and widely available herbal AV extract markedly increased the supplement, primarily used to treat percentage time spent on the open arms of insomnia and anxiety. Neurobiological the EPM in two distinct concentration research has begun to show that the herb, ranges of 22.5–30 and 100–125 mg/kg with its active valerenic acid, interacts p.o., respectively, indicating a putative with the GABAA-ergic system, a anxiolytic-like activity [13-14]. mechanism of action similar to the benzodiazepine drugs. Results showed IJBR 2 [1] [2011]62‐72

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that there was a significant reduction in III increased the number of entries in the anxious behavior when valerian extract or open arms of the EPM test as compared valerenic acid exposed subjects were with control. Riparin III potentiated the compared to the ethanol control group. barbiturate-induced sleeping time and The evidence supports Valeriana presented antidepressant- and anxiolytic- officinalis as a potential alternative to the like effects [20]. traditional anxiolytics as measured by the elevated plus maze [17]. Calotropis gigantea:

Galphimia glauca (Gold shower): Alcoholic extract of peeled roots of Calotropis gigantea R.Br. An infusion prepared with aerial parts (Asclepiadaceae) was tested orally in from Galphimia glauca has been widely albino rats at the dose level of 250 and used in Mexican traditional medicine as a 500 mg/kg bodyweight for CNS activity. remedy for nervous excitement. the The extract treated rats spent more time in anxiolytic like effects of G. glauca the open arm of EPM showing its methanolic extract (standardized on GB antianxiety activity [21]. content, 8.3 mg/g) were assayed by using the elevated plus-maze, on ICR albino Piper methysticum G. Forster: mice. This extract, administered orally, three times (24, 18 and 1 h before the Kava-Kava, a drug derived from a test), and in different doses (125, 250, traditional psychoactive beverage used in 500, 1000 and 2000 mg/kg) was able to the South Pacific, is known for increase significantly (po0:05) the number tranquilizing and anxiolytic effects. of entries, as well as the time spent in the Extracts made from the roots of the Kava open arms of the elevated plus-maze, plant (Piper methysticum G. Forster) have indicating an anxiolytic-like effect [18]. anxiolytic and mild sedative effects in man. Kava kava extract (120–240 mg/kg Morinda citrifolia (Mulberry): po) affected the behaviour measured in the X-maze test, inducing an anxiolytic Noni (Morinda citrifolia) is increasing in like behaviour similar to diazepam (15 worldwide popularity as a food or dietary mg/kg po) [22]. supplement with versatile health benefits. Noni fruit indicate the presence of Passiflora incarnata: competitive ligand(s), which may bind to the GABAA receptor as an agonist, and The petroleum ether, chloroform, thus induce its anxiolytic and sedative methanol, and water extracts of Passiflora [19] effects . incarnata whole plant have been evaluated for their anxiolytic activity Aniba riparia: using the elevated plus-maze model in mice. The methanol extracts of leaves, Methyl ethers of N-(2,6- stems, flowers, and whole plant exhibited dihydroxybenzoyl) tyramine (riparin III) anxiolytic effects at 100, 125, 200 and isolated from the unripe fruit of Aniba 300 mg/kg, respectively [23]. riparia was administered intraperitoneally to male mice at single doses of 25 and 50 mg/kg. . At the dose of 50 mg/kg, riparin IJBR 2 [1] [2011]62‐72

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Rubus brasiliensis: isoorientin (20 mg/kg) resulted in anxiolytic like effects [27]. Hexanic ethanolic fraction of Rubus brasiliensis Martius (Roseceae), have Coriandrum sativum L. (Dhania): been evaluated for their anxiolytic activity using the elevated plus-maze model in Coriandrum sativum L. has been Wistar rats and Swiss mice. ). All the recommended for relief of anxiety and doses of the extract, 50, 100 and 150 insomnia in Iranian folk medicine. The mg/kg, administered per gavage (vo), 30 anxiolytic effect of aqueous extract (10, min before the behavioural evaluation, 25, 50, 100 mg/kg, i.p.) was examined in induced an anxiolytic effect expressed by: male albino mice using elevated plus- increased number of entries in and time maze as an animal model of anxiety. In spent in the open arms and percentage of the elevated plus-maze, aqueous extract at open arm entries; and decreased number 100 mg/kg showed an anxiolytic effect by of entries and time spent in the closed increasing the time spent on open arms arms [24-25]. and the percentage of open arm entries, compared to control group [28]. Aloysia polystachya (Griseb.): Cassia siamea: Hydro-ethanolic extract obtained from the aerial parts of Aloysia polystachya Cassia siamea, a plant used in Thai (Verbenaceae) have been evaluated for traditional medicine, and barakol, its their anxiolytic activity using the elevated active chemical, were studied on an plus-maze model in male mice. The elevated plus-maze compared with ethanolic extract significantly increased diazepam. An aqueous extract of C. the percentage of both entries (1.0 and siamea (1, 6, and 12 g/kg body wt., orally) 100.0 mg/kg) and the time spent (10.0 and produced a small increase in the 100.0 mg/kg) into the open arms of the percentage of the open: total number of elevated plus maze (EPM) [26]. arm entries and time, time spent on the end of the open arms, total number of arm Passiflora edulis f. flavicarpa: entries, and number of rears/min. Barakol at 25 and 50 mg/kg increased the Ethanolic extract (EE) of the aerial part of percentage of the open: total number of Passiflora edulis f. flavicarpa and its arm entries and time and number of rears fractions, viz. petrol ether extract (PEE), [29]. ethyl acetate extract (EAE), n-BuOH Scutellariae radix: extract (BE) and aqueous extract (AE), together with subfractions of BE, viz. Baicalein, one of the active principles of BEF-I, BEF-II, BEF-III, BEF-IV and the Chinese herbal drug, Huangqin isoorientin, have been evaluated for their (Scutellariae Radix), and its 7-glucuronide anxiolytic activity using the elevated plus- baicalin, have anxiolytic-like effects in a maze model in male mice. Single-dose Vogel conflict test. The results showed oral administration of EE (300 mg/kg and that both baicalein (10 mg/kg, i.p.) and 400 mg/kg), BE (125 mg/kg and baicalin (20 mg/kg, i.p.) significantly 200 mg/kg), AE (200 mg/kg and increased the number of shocks accepted 300 mg/kg), BEF-I (200 mg/kg), BEF-II in the Vogel lick-shock conflict paradigm (200 mg/kg), BEF-III (100 mg/kg), or over 9 min, as did a benzodiazepine IJBR 2 [1] [2011]62‐72

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receptor agonist, chlordiazepoxide (5.0 diazepam, significantly increased not only mg/kg, i.p.) and a 5-HT1A receptor the number of entrances (100% and 66%, agonist, 8-hydroxy-2(di-n- respectively) but also the time of propylamino)tetralin (0.5 mg/kg, i.p.) [30]. permanence in the open arms (104% and 199%, respectively), indicating that PIP Tilia americana var. mexicana: presents an anxiolytic activity [35].

The ethnomedicinal use of Tilia Aloysia polystachya: americana var. mexicana inflorescences as sedative and anxiolytic is reinforced by Hydroalcoholic extract from leaves of examinating inflorescences used by Aloysia polystachya (Verbenaceae) were communities of the State of Michoacan, studied for their anxiolytic effect in the Mexico. A significant attenuation in the elevated plus maze. All doses injected anxiety-response in the plus-maze test (from 1.56 to 50 mg/kg) increased the were observed [31-32]. exploration of the EPM open arms in a similar way to that of diazepam (1 mg/kg, Casimiroa edulis: i.p.). The components of the hydroalcoholic extract of A. polystachya, Anxiolytic-like actions of an aqueous such as thujone and carvone among extract of the leaves of Casimiroa others, may have anxiolytic and (Rutaceae) were studied in male Wistar antidepressant-like properties [36]. rats in the elevated plus-maze test. Diazepam (Dz) (1.30 mg/kg; P<0.05) and Panax quinquefolium: Casimiroa edulis (25.0 mg/kg, P<0.05; 35.0 mg/kg, P<0.05) increased open arms Xiu-Yan Wei et al. had studied the exploration (i.e., anxiolytic-like action) anxiolytic effect of the saponins from [33]. Aniliaeea Panax quinquefolium L. (PQS) in male mice by using a number of Ziziphus jujube: experimental paradigms of anxiety and compared with that of the known Ethanolic extract of Ziziphus jujube were anxiolytic compound diazepam. Use of evaluated for anxiolytic effect. The SZJE the elevated plus-maze test revealed that at the dosage 0.5–1.0 g/kg increased the PQS (50 mg/kg, p.o.) and diazepam percentage of time-spent and the (2.5 mg/kg, p.o.) increased the percentage percentage of arm entries in the open arms of time and entries spent in open arms [37]. of the EPM and decreased the percentage of time-spent and the percentage of arm Scutellaria baicalensis: entries in the closed arms of the EPM [34]. Kwok Min Hui et al. evaluated the Piper tuberculatum: pharmacological properties of a naturally occurring monoflavonoid, 5,7-dihydroxy- Piplartine (PIP), an amide alkaloid 8-methoxyflavone or wogonin obtained isolated from the roots of Piper from Scutellaria baicalensis. Oral tuberculatum (Piperaceae), was studied administration of wogonin (7.5 to for their anxiolytic effect in the elevated 30 mg/kg) elicited an anxiolytic response plus maze. Results showed that PIP (50 that was similar to that elicited by and 100 mg/kg, i.p.), similarly to diazepam in the elevated plus-maze; a IJBR 2 [1] [2011]62‐72

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dose-dependent increase in open arm Paeonia moutan: entries and time spent in open arms was observed [38]. The anxiolytic-like effect of paeonol, a phenolic component from the root bark of Panax ginseng: Paeonia moutan, was studied by Xiao Juan Mi et al. As with 2 mg/kg diazepam, The putative anxiolytic activity of the paeonol (at 17.5 mg/kg) increased the white and red varieties of ginseng, the percentage of time spent on open arms in root of Panax ginseng, was investigated in the elevated plus maze and increased the rats and mice by S.K. Bhattacharya et al. time spent in the light area of the White and red varieties of ginseng (20 and light/dark box (at 8.75 and 17.5 mg/kg) 50 mg/kg) showed positive results when [42]. tested against several paradigms of experimental anxiety. Both were effective Celastrus paniculatus (Malkangani): in the open-field and elevated plus-maze tests [39]. The Celastrus oil, extracted from seeds of Celastrus paniculatus tested at 2 dose Protium heptaphyllum: levels (1 and 1.5 g/kg), exhibited significant anxiolytic activity [43]. G.F. Aragao et al.examined the anxiolytic and antidepressant effects of the mixture Albizzia lebbeck (Siras): of alpha and beta-amyrin (AMY), pentacyclic triterpenes isolated from the Albizzia lebbeck (Linn.) Benth. of family stem bark resin of Protium heptaphyllum. Mimosaceae is a medium to large sized In the open-field test, AMY at the doses tree distributed throughout India. The of 10, 25 and 50 mg/kg, after effect of saponin containing, n-butanolic intraperitoneal or oral administrations, fraction (BF), extracted from dried leaves significantly decreased the number of of Albizzia lebbeck, was studied on crossings, grooming, and rearing. In the cognitive behavior and anxiety in albino elevated-plus-maze test, AMY increased mice. The anxiolytic activity of BF (0, 10, the time of permanence and the number of 25, and 50 mg/kg) was assessed by entrances in the open arms [40]. studying its effect on the duration of occupancy in the closed arm. Animals Securidaca longepedunculata: treated with BF (25 mg/kg) spent more time in the open arm in a dose-dependent O.O. Adeyemi et al. investigated the manner [44]. anxiolytic activities of the aqueous root extract of Securidaca longepedunculata. Hypericum perforatum: The extract (100–400 mg/kg) produced a significant (P < 0.01) dose dependent H. perforatum is sometimes called prolongation of the cumulative time spent Common St John's wort family in the open arms of the elevated plus maze Clusiaceae.The total extract of H. [41]. perforatum increases the locomotor activity in the open field and exerts anxiolytic activity in the light–dark test, whereas the single components did not show any effect [45]. IJBR 2 [1] [2011]62‐72

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