Khanum and Razack

Res Rev Biomed Biotech 1(2); 2010 ISSN 22297154 Research and Reviews in Biomedicine and Biotechnology Volume [1], Issue [2], 2010, 71-89 www.rrbb.in

Review article Anxiety- Herbal Treatment: A Review

Farhath Khanum* and Sakina Razack Biochemistry and Nutrition, Defence Food Research Laboratory, Mysore-570011, Karnataka, India
*Corresponding author email: farhathkhanum@gmail.com Article received on 19.09.2010; Revised article accepted on 16.12.2010 Copyright: 2010 rrbb.in

ABSTRACT Stress has become a part of the modern world and lifestyles. Persistent stress leads to anxiety. Anxiety is a general feeling of getting worried. In small quantities stress and anxiety are good as they can motivate and help one be more productive but people with persistent stress feel anxious quite often and anxiety interferes in their daily lives and is a matter of concern. Evidences suggest anxiety to be caused by dysfunction of one or more neurotransmitters and their receptors and has emerged to be a very important area of research. Plants have known to possess enormous potential to cure ailments from time immemorial. This review lists most widely used herbal anxiolytes and classifies them according their mechanisms of action. Keywords: Anxiety, Gamma Amino Butyric Acid, Herbal Anxiolytes, Neuropeptides, Serotonin.
INTRODUCTION:

Stress and anxiety are common psychiatric manifestations of the modern world and lifestyles. In small quantities, stress and anxiety are good; they can motivate and help one be more productive. However, too much stress, or a strong response to stress, is harmful. It can set up for general poor health as well as specific physical or psychological illnesses like infection, heart disease, or depression. Persistent and unrelenting stress often leads to anxiety and unhealthy behaviours. Anxiety is a Central Nervous System disorder [1-2]. Anxiety is a common emotional phenomenon in humans [3]. Anxiety is an emotional state, unpleasant in nature and is associated with uneasiness, discomfort and concern or fear about some defined or undefined future threat [4]. Anxiety is considered to be a normal reaction to stress and is characterized by www.rrbb.in

heart palpitations, fatigue, nausea and shortness of breath. Anxiety is the most common mental illness affecting one eighth of the total population and has become a very important area of research in psychopharmacology in the current decade [5] . Anxiety disorders are psychiatric disorders affecting nearly 25% of the adult population at some point in their life. The prevalence of anxiety disorders is 30.5% and 19.2% in women and men respectively. The prevalence of anxiety disorders is remarkably high in young people. Children aged 7 to 11 years reported a 15.4% prevalence rate of anxiety disorders. A survey has also stated that less than 14% of people with such psychiatric disorders receive treatment [6]. Anxiety can aggravate many physical and mental ailments and also impede recovery from any other problems.

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Khanum and Razack Classically, anxiety is distinguished into the state and the trait anxiety. State anxiety is anxiety a subject experiences at a particular moment and is increased by the presence of an anxiogenic stimulus. In contrast, trait anxiety does not vary from moment to moment and is considered to be an enduring feature of an individual [7-9]. FORMS OF ANXIETY DISORDERS Anxiety disorders comprise clinical conditions of Generalized Anxiety Disorder, Obsessive-compulsive Disorder, Panic Disorder, Post-traumatic Stress Disorder, Social Anxiety Disorder and Phobias. Generalized Anxiety Disorders : Generalized Anxiety Disorder involves a broad presentation of anxiety. It is characterized by long-lasting anxiety (for over 6 months) that is not focused on any one object or situation. Those suffering from this disorder experience non-specific persistent fear and worry and become overly concerned with everyday matters like health, work, money or family and experience these symptoms even when there are no signs of trouble in their life [4,10]. Obsessive-compulsive Disorder : This is a particularly important form of anxiety disorder which is characterized by obsessions i.e. recurrent thoughts that may not be about real-life problems and which the person fails to ignore or suppress. Compulsions are repetitive behaviours that the person feels driven to perform in response to an obsession. The compulsive behaviours attempt to reduce the distress from the obsessions. Panic Disorder : In this type of a disorder the person suffers from brief attacks of intense terror and apprehension which is often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty in breathing, lasting for a few minutes. The person also believes that he or she is seriously ill or about to die and this feeling can leave the person depressed or shaken for quite a while afterwards [4].

Res Rev Biomed Biotech 1(2); 2010 Post-traumatic Stress Disorder: Post-traumatic stress disorder is an anxiety disorder which results from a traumatic experience. The symptoms include flashbacks or nightmares about what happened, hyper vigilance, startling easily, withdrawing from others, and avoiding situations that remind the person of the event. This disorder can continue for a sustained period of time with marked impairment in function. Social Anxiety Disorder : Is a marked and persistent fear of social or performance situations [4]. Phobias : A phobia is an unrealistic or exaggerated fear of a specific stimulus, such as heights, enclosed places or other situations. The phobic individual may experience full panic attacks when exposed to such stimuli. Phobias tend to be the most common form of anxiety disorder whereas panic disorders are fairly rare in the general population [11]. PHYSIOLOGY OF ANXIETY The human brain is the centre of human nervous system and is a highly complex organ. The part of the brain that triggers a response to danger is the Locus ceruleus and the area of the brain responsible for the acquisition and expression of fear conditioning is the Amygdala [12]. Once the neurotransmitters pick up over activity/hyperactivity in the locus ceruleus, the amygdala senses danger and instructs us to run from danger. Hence, once the amygdala gets activated it sends an alarm to the heart to beat faster, breathing to become rapid and in turn activates all the biological components of fight/flight response. The symptoms experienced during an anxiety attack include: Rapid heartbeat and rapid breathing Twitching or trembling Muscle tension Headaches Sweating Dry mouth and difficulty in swallowing and Abdominal pain 72

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Khanum and Razack Sometimes other symptoms accompany anxiety, such as: Blurred vision and Dizziness Diarrhoea or frequent need to urinate Irritability, including loss of temper Sleeping difficulties and nightmares Decreased concentration and Sexual problems. All these physical symptoms are felt when one is anxious or having a panic attack and are part of a system that is designed to keep one safe and do not cause any harm. They cause a problem only when they occur in response to situations where one is not physically threatened. ANXIETY - MECHANISM OF ACTION Anxiety is recognised as one of the most important emotional processes with firm neurobiological roots. The neurochemistry of anxiety although not well understood has emerged to be a major area of research leading to new approaches in the treatment of anxiety. Anxiety is caused due to too many or too few neurotransmitters in the brain. Brain synthesizes several neurotransmitters such as acetylcholine, adrenaline, dopamine,

Res Rev Biomed Biotech 1(2); 2010 endorphins, serotonin, gamma amino butyric acid, glutamate etc. Most information has come from studying the action of anxiety-reducing or anxiolytic drugs. The evidences suggest anxiety to be caused by dysfunction of one or more neurotransmitters and their receptors. The major thrusts of current work dealing with anxiety disorders have centered around the gamma amino butyric acid mechanisms, the serotonergic system, noradrenergic mechanisms and neuropeptides [10]. New evidences suggest a role for adenosine and cholecystokinin in the development of anxiety; drugs interactions with these neurotransmitters also may have anxiolytic effects. Gamma amino butyric acid (GABA) is one among the chief inhibitory neurotransmitters in the mammalian brain and an increasing wealth of information suggests that GABAergic mechanisms have a special role in the neurophysiology of anxiety [13]. GABA works to regulate the neuronal excitability and thereby serves as a brake on the neuronal circuitry during stress and is the brains natural stress reliever [14].

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Khanum and Razack GABA is formed by the decarboxylation of L-glutamate. Brain has three different types of GABA receptors GABAA, GABAB, GABAC. GABAA receptors are ligand-gated ion channels (ionotropic receptors) and

Res Rev Biomed Biotech 1(2); 2010 receptors are the seven GABAB transmembrane spanning G-protein coupled receptors (metabotropic receptors). The physiologic role of GABAC receptors is yet to be described.

Schematic representation of GABA receptor

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Khanum and Razack The GABAA receptors mediate fast inhibitory synaptic transmissions and regulate the neuronal excitability and are responsible for rapid mood changes (e.g. anxiety, panic and stress response). GABAA receptors are targets of sedating drugs such as benzodiazepines, barbiturates, neurosteroids and ethanol. Alteration of the influx of chloride ions within this receptor complex is associated with development of anxiety. All of the most commonly used anti-anxiety drugs (benzodiazepines, the barbiturates, and ethanol) selectively enhance only GABA mediated transmission[13], thereby elevating GABA levels. The GABAB receptors mediate slow inhibitory potentials and are known to play

Res Rev Biomed Biotech 1(2); 2010 an important role in memory, depressed mood and pain. The GABAB receptor ligand/agonists include baclofen, phenibut etc among others. Thus, these GABA agonists/analogues elevate GABA levels thereby exerting antianxiety, relaxing and anti-convulsant effects. Serotonin has long been viewed as a neurotransmitter involved in regulating emotional states. Of the 14 or so mammalian serotonin receptor subtypes that have been described, at least four have been implicated in anxiety in various animal models [15].

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Khanum and Razack Serotonin is synthesised from the conversion of L-tryptophan to 5hydroxytryptophan which then crosses the blood-brain barrier and is then broken down to 5-hydroxytryptamine (5-HT) commonly known as serotonin. It has been reported that reduced levels of serotonin can produce anxiolytic effects [16]. The brain serotonin receptors have been divided into a wide range of subtypes based on their pharmacological specificities, anatomical distribution and function [10]. One of the receptor subtypes implicated in anxiety is the serotonin 1A receptor subtype an autoreceptor located (5-HT1A), presynaptically on serotonin neurons. When stimulated, this receptor inhibits the synthesis and secretion of serotonin [10]. The 5-HT1A receptor agonist buspirone exhibits anxiolytic effects in animals and is useful in the treatment of generalized anxiety disorder but not in panic disorder. In contrast to benzodiazepines, buspirone has a delayed onset of action and must be administered for up to several weeks before a significant reduction in anxiety is observed and has no sedative, anticonvulsant or muscle-relaxant activity and no significant addiction liability [17, 10]. Other serotonin receptors potentially involved in anxiety include the 5-HT2A, 5HT2C and 5-HT3 receptors. Antagonists for 5-HT2A receptor like ritanserin exhibit anxiolytic effects in some animal models [1819] . Likewise, blockage of the 5-HT2C receptor produces anxiolytic effect in animals [20]. In humans 5-HT2A receptor agonist m-chlorophenyl piperazine (m CPP) has been shown to generate anxiety in control subjects and in patients with a wide variety of anxiety disorders [10]. The 5-HT3 receptor antagonist ondansetron has been reported to be anxiolytic in some animal models [21]. The selective serotonin reuptake inhibitors (SSRIs) have proven useful for panic and obsessive-compulsive disorder. Thus, the finding that a number of drugs that are useful in panic disorder are not useful in generalized anxiety disorder and vice versa

Res Rev Biomed Biotech 1(2); 2010 suggests that the fundamental mechanism of these processes are different [10]. Norepinephrine Elevated levels of norepineprine are helpful in situations of emergencies or in fight/flight response. However, continuously elevated levels even when not in situations of danger put the person in states of anxiety, fear, irritability etc. Thus, the role of catecholamines in anxiety is being studied using adrenergic receptor agonists and antagonists [10]. Neuropeptides - Neuropeptides have been implicated in the regulation of complex behaviour including anxiety related behaviours and psychopathology.[22-23] There is increasing evidence suggesting that neuropeptides including substance P, corticotropin-releasing factor, neuropeptides Y, vasopressin, oxytocin, somatostatin, cholecystokinin, galanin have relevance in anxiety [24-25]. Behavioural effects of these peptides also have been studied using molecular biology techniques, including the central administration of antisense sequences that block translation of peptides or peptide receptor proteins, over expression of peptides in intact animals and generation of knockout mice lacking particular peptides or peptide receptors [10]. MANAGEMENT OF ANXIETY Management of anxiety disorders varies and depends on the nature of the disorder and individual patient characteristics [26]. The treatment involves: 1. Medications 2. Psychological treatment 3. Alternative therapy Medication: includes Selective Serotonin Reuptake Inhibitors (SSRIs) which may be the first choice of medication for generalised social phobia. These drugs elevate the level of neurotransmitter serotonin, among other effects. Ex. Fluoxetine, sertraline, paroxetine, citalopram etc. Other medications commonly prescribed for anxiety disorders include Benzodiazepines

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Khanum and Razack (ex: diazepam, chlordiazepoxide etc.) which facilitate inhibitory GABA transmission. Monoamine Oxidase Inhibitors (MAOIs) (Phenelzine, Moclobemide) that prevent the breakdown of serotonin and noradrenalin. Beta-blockers like propranolol, atenolol which reduce the ability to produce adrenaline. The common limitations of anxiety medications or drug therapy include comorbid psychiatric disorders and increase in dose leading to unbearable side-effects [2728] , such as allergic reactions, drowsiness, coordination problems, fatigue, mental confusion, nausea and addiction liability among others. Psychological treatment: Cognitive-Behavioural therapy and Exposure therapy are effectively used to treat anxiety disorders. Cognitive therapy focuses on changing patterns of thinking and beliefs that are associated with, and trigger, anxiety. The most important component of behaviour therapy is exposure. Exposure therapy includes confronting your fears to desensitise yourself to such dangers/fears that can trigger anxiety. Alternative treatments: Meditation beneficial to patients with phobias and panic disorders. Hydrotherapy promotes general relaxation of the nervous system. Exercise a natural stress buster and anxiety reliever. Relaxation techniques (Yoga) include progressive muscle relaxation and controlled breathing which when practised regularly attenuate anxiety. Biofeedback an effective method that uses sensors that measure physiological functions like heart rate, breathing and muscle tension and help to recognise the bodys anxiety response and learn how to control them using relaxation techniques. Hypnotherapy is sometimes used in combination with cognitive-behavioural therapy. The hypnotherapist applies different therapeutic approaches to help you

Res Rev Biomed Biotech 1(2); 2010 confront your fears while in a state of deep relaxation. Acupuncture used in traditional Chinese medicine, helps alleviate anxiety [4]. ANIMAL MODELS OF ANXIETY Serotonin receptor 1A Knock-out mice: Low levels of serotonin 1A (5-HT1A) have been repeated found in mood and anxiety disorders. Mice lacking in serotonin receptor 1A (5-HT1A KO) have been developed by three independent research groups in three different genetic background mice (C57BL/6J, 129/SV and SwissWebster; [29-31]. It was found that all mice independent of the genetic background showed an anxious phenotype compared to their corresponding wild-type mice. The autonomic changes associated with anxiety have also been found pronounced in these KO mice. Thus, indicating that the 5-HT1A receptor knock-out mice represent a genetic animal model for anxiety. However, straindependent variability within the core phenotype restricts the use of these KO mice. Apart from the receptor KO mice, there are groups of researchers who have selectively bred high anxiety breeds (HAB) and low anxiety breeds (LAB) of mice [32]. A number of psychogenetically selected rat models such as Maudsley reactive and nonreactive strain, Ronan high and low avoidance rat lines, Tsukuba strains and high/low anxiety-related behaviour (HAB/LAB) rat lines have been developed [32, 3, 33] . Co-transmission: Different neurotransmitters can be released from a single nerve terminal, including neuropeptides and small molecule neurotransmitters. Neuropeptides, acting as neurotransmitters can also act as cotransmitters and as co-transmitters they are known to activate specific pre or postsynaptic receptors that can alter the responsiveness of the neuronal membrane to the action of other neurotransmitters like noradrenaline, serotonin etc. Neurotransmitters like serotonin, noradrenaline and dopamine are known to

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Khanum and Razack control many of our mental states sometimes acting on their own or at other times together. These and other neurotransmitters have been implicated to play a major role in mental illnesses and diseases related to the brain. Oxidative stress and anxiety: Oxidative stress has been implicated in the aetiology of many pathological conditions including anxiety [34-35]. Brain is prone to oxidative stress due to high consumption of oxygen, its lipid rich constitution and modest antioxidant defences [36-37]. Hovatta et al.[146] in 2005 identified that the expression of glutathione reductase 1 and glyoxalase 1 (genes involved in antioxidative metabolism) is correlated to anxiety-related phenotypes. They also found that the activity of these enzymes is highest in the most anxious mice and lowest in the least anxious strains. Genetic manipulation studies using lentivirus-mediated gene transfer showed that local overexpression of glutathione reductase 1 and glyoxalase 1 in the cingulated cortex of murine brain results in an increase of anxiety-like behaviour, whereas inhibition of glyoxalase 1 expression produces low-anxiety mice. Thus, it was hypothesised that glyoxalase1 and glutathione reductase 1 regulate anxiety in mice. Another group of researchers generated HAB-M (high anxiety-related behaviour mouse) and LAB-M (low anxiety-related behaviour mouse) CD1 mouse lines as models of extremes in trait anxiety and used comparative proteomics to identify anxiety related protein markers and also reported differences in expression of glyoxalase 1 between HAB-M and LAB-M animals[38]. TEST FOR ANXIETYStudies related to the Central Nervous System and brain is accomplished using animals as experimental models. Animal models form the backbone of preclinical research on the neurobiology of psychiatric disorders, and are employed as screening tools in the search for novel therapeutic agents.[39] Rodents especially mice have

Res Rev Biomed Biotech 1(2); 2010 proven to be helpful in research as mice and humans share more than 90% of their genes in common. Furthermore, animal models are particularly helpful in situations when the impact of stress cannot be studied in humans because of ethical and other reasons [40] . A variety of tests for anxiety have been developed of which the commonly used ones include Elevated plus maze, Elevated zero maze, Light/Dark test, Vogels conflict test etc. Elevated plus Maze (EPM) The Elevated plus maze is a simple method for assessing anxiety responses of rodents. The EPM has four arms (two open and two enclosed) that are arranged to form a plus shape and elevated 40-70 cm from the floor. The model is based on rodents aversion of open spaces. The assessment of anxiety behavior of rodents is done by using the ratio of time spent on the open arms to the time spent on the enclosed arms. The elevated plus maze relies upon rodents proclivity towards dark (enclosed spaces) and an unconditioned fear of heights (open spaces). Elevated zero maze Elevated zero maze, a modification of the EPM comprises an elevated annular platform with two enclosed and two open quadrants, mounted on a base that raises the maze above the floor. The Elevated Zero Maze does not have a centre compartment thereby allowing uninterrupted exploration of the open and enclosed spaces and eliminating any ambiguity in interpretation of the time spent in a centre compartment. Light/Dark test The light/dark test in mice is based on the innate aversion to brightly illuminated areas and the spontaneous exploratory activity of mice. The apparatus comprises of a light (brightly lit) and a dark compartment separated with a partition. The distance traveled in each chamber, the total number of transitions, the time spent in each chamber and the latency to enter the light chamber are noted. The anxiolytic compounds are known to increase the total duration of time spent in the light

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Khanum and Razack compartment whereas the anxiogenic compounds work in the opposite way. Vogels conflict test The Vogel conflict test is based on the principle that the water deprived animal is placed in the test cage with a special conductive floor grid and a drinking bottle with an electrically conductive nipple. The animal licks are recorded and monitored by very low electrical currents applied to the nipple that are below the animal's perception level. After a specified number of licks an electric shock is applied to the nipple and the animal can escape the shock by withdrawing from the drinking tube/nipple. The number of shocks received after treatment with the anxiolytic drug is compared with the untreated animals. The anxiolytic drugs significantly increase the number of licks and therefore the number of shocks applied. Open field test It is generally used paradigm to assess/evaluate the locomotor, exploratory and anxiety-like behaviour in laboratory animals. The open field area/arena usually consists of brightly lit square or round area enclosed by walls with the animal usually being placed in the centre and its behaviour being recorded for a known period of time (3-15 minutes). It relies on the fact that the rodent when anxious stays close to the enclosed walls and measures the degree to which the rodent avoids the central area. Hole-board test A generally used paradigm to measure the exploratory behaviour of rodents and the potentiality of anxiolytics. The apparatus usually consists of a wooden chamber with 16 holes measuring about 3cm in diameter present on the floor which is elevated from the ground ensuring that the rats could peep through the holes and each rat is placed individually and the latency to the first head dip, the number of head dips, the total time

Res Rev Biomed Biotech 1(2); 2010 spent with the head dips, the number of rearings and the total number of defecations are noted. State-Trait Anxiety Inventory (STAI)STAI [9] is one of the most widely used selfreport measures of anxiety. A means for appraisal of anxiety in research & clinical settings with questionnaires. The scores obtained are directly related with anxiety i.e. higher the score (20-80) greater the anxiety. It helps practitioners differentiate between anxiety and depression. The STAI occurs in three forms. The STAI Form X is the first version of the STAI, the STAI Form Y differentiates between temporary or emotional state anxiety versus long standing personality trait anxiety in adults, and the third form is the STAI for children [41].
HERBAL ANXIOLYTES:

Plants are known to have enormous potential to cure ailments from time immemorial. Ayurveda and Unani are such inherited traditional systems of health and longevity that are based on herbal medicines. The World Health Organization has approved that traditional health and folk medicine systems have proved to be more effective in health problems worldwide [42]. Traditional medicines are used by about 60% of the world populations in rural areas in the developing countries and is gaining acceptance in the developed countries where modern medicines predominates [4]. However, the major hurdle in the uninhibited exploitation of herbal medicines into the regular practice of prescription is the lack of sufficient scientific data and better understanding of efficacy and safety of the herbal products [43]. A number of plants have been scrutinised for their anxiolytic effects. Table 1 gives a list of some of the widely studied plants for anxiolytic effects.

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Khanum and Razack Table 1: List of plants with anxiolytic properties

Plant name Abies pindrow Royle Family Pinaceae

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Active constituents The fresh leaves yield 0.25% oil which contains -pinene (14.7%), llimonene (10.6%), 3-carene (11.8%), dipentene (8.4%), l-bornyl acetate (15.7%) and l-codinene (9.9%).[44] The herb contains an alkaloid achilleine, isovaleric acid, salicylic acid, asparagines, sterols, flavonoids, tannins, choline and trigonelline and coumarins.[46] Flowers yield an essential oil azulene.[47] Presence of choline has been shown to impart hypotensive effect.[51]

Reference [45]

Achillea millefolium. L.

Asteraceae

[48-50]

Aloysia polystachya Griseb & Moldenke Albizzia lebbeck. (L). Benth. Albizzia julibrissin Durazz Angelica sinensis Oliv. Diels. Aniba riparia Nees Mez. Annona cherimola Mill. Apocynum venetum. L. Azadirachta indica. A. Juss Bacopa Pennell monnieri. L

Verbenaceae Fabaceae Fabaceae Apiaceae Lauraceae Annonaceae Apocynaceae The leaves have been shown to contain caffeic acid, alkaloids, kaempferol and quercetin.[44] Two flavonol glycosides quercitrin and isoquercitrin. The essential oil contains lingustilide. Riparins (methyl ether of N-benzoyl tyramine) exert antianxiety effects. -cariophyllene, -selinene, -cubebene, and linalool The chemical constituents of the leaves and flowers include ionone glucosides named apocynoside I and II, several compounds have been isolated and include kaempferol, kaempferol 3-0-beta-D-glucoside, vanillic acid, baimaside, daucosterol. The chemical compounds isolated from Neem oil include nimbin, nimbinin, and nimbidin. The seeds contain a complex secondary metabolite azadirachtin. Major chemical constituents found in B.monnieri are saponins, triterpenes & dammoranes such as bacosides A, B & C, bacosaponines D, E & F.[63-64] The chemical constituents include diterpenes, fattyacids, isoflavones, lipids and phenolic compounds.

[52-53] [54-55] [56] [57] [58] [59] [60]

Meliaceae Scrophulariaceae Fabaceae

[61]

[62]

Caesalpinia Bonducella (Roxb). Casimiroa edulis Llave & Lex. Cannabis sativa L. Cecropia glazioui. Sneth. Centella Urban asiatica. (L)

[65] [66]

Rutaceae Cannabaceae Moraceae Apiaceae Cannabidiol an cannabinoid exerts anti-anxiety effects The essential oil includes triterpeniod saponins such as asiaticoside (got from fresh leaves, a glucoside), brahmoside and thankuniside, alkaloids (hydrocotyline, isolated from the dried plant) an some bitter principles.[69] The chemical constituents include 4-methulacetophenone, carotenoids, and essential oil containing monoterpenes sesquiterpenes, coumarins, caffeinel isoquinoline, alkaloids, flavonoids, triterpenoids and steroids.[51] The chemical constituents include monoterpenes, sesquiterpenes, flavonoids, caretenoids, alkaloids, coumarins and vitamin c.[51] The active constituents include tannins, resins, starch and the roots contain taraxerol and taraxerone. The phytoconstituents include linalool, linalyl acetate, thymol, caryphyllene, -pinene, borneol, limonene, -phellandrene, citranellol, 1, 8-cineole and geranyl acetate.[51] Berberine, atrorrhizine, palmatine, epiberberine, coptisine, and jatrorrhizine.

[67] [68] [70]

Citrus aurantium. Linn.

Rutaceae

[71]

Citrus sinensis L. Osbeck Clitoria ternatea. L. Coriandrum sativum L.

Rutaceae Fabaceae Apiaceae Ranunculaceae Amaryllidaceae

[72] [73] [74] [75]

Coptis chinensis Franch Crinum Andrews. giganteum

Crocus sativus L. (Saffron/kesar)

Iridaceae

Saffron contains more than 150 volatile and aroma yielding compounds. Among the non-volatile active compounds include carotenoids like zeaxanthine, lycopene and various and -carotenes. -crocin (a digentiobiose ester of carotenoid crocetin) imparts the golden yellow-orange colour. Safranal and picrocrocin give saffron much of its distinctive aroma.

[76]

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Davilla rugosa Poiret Echium amoenum Erythrina velutina Willd. Erythrina variegata L Erythrina mulungu Mart.ex.Benth. Eschscholzia californica cham. Euphoria longana Lamk. Euphorbia hirta L. Eurycoma Jack. longifolia Dilleniaceae Boraginaceae Fabaceae Fabaceae Fabaceae Papaveraceae Sapindaceae Euphorbiaceae Simaroubaceae

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[77] The chemical constituents include flavonoids, saponins, unsaturated terpeniods and sterols.[78] Erythrina plants produce alkaloids, flavonoids and terpenes.[81-81] The chemical constituents include alkaloids, flavonoids and terpenes. The leaves and stems contain the alkaloid erythrinaline. The seeds yield the alkaloid hypaphorine and a saponin-migarrhin.[51] Tetrahydroisoquinoline alkaloids erythravine and (+)-11-hydroxyerythravine.[85] The chemical constituents include alkaloids and flavone glycosides. The active principle is adenosine. The chemical constituents include flavonoids, polyphenols, tannins, alkanes, triterpenes and phytosterols.[89] [79-80] [83] [84] [86] [87] [88] [90] [91]

Euphorbia Linn.

neriifolia

Euphorbiaceae

The phytochemical constituents include a variety of triterpenes like nerifolione, euphol, euphorbol and others from latex, bark, root, whole plant and leaf. Anthocyanins like delphin and tulipanin and diterpenes were isolated from the bark and roots.[92] The phytochemical study showed the presence of steroidal saponins, reducing sugar, tannins, flavonoids in the crude leaf extract.[93]

[93]

Galphimia glauca Cav. Gastrodia elata Blume.

Malpighiaceae Orchidaceae The phytochemical studies have revealed the presence of several phenolic compounds, including 4-hydroxybenzyl alcohol, 4hydroxybenzaldehyde, vanillin, vanillyl alcohol, -sitosterol and gastrodin.[95] The phytoconstituents include flavonoids, glycosides and terpenoids (ginkgolides, bilobalides). The phytochemical constituents include hypericin and other dianthrones, flavonoids, xanthones and hyperforin. The active constituent of the plant Elenoside, a lignin (-D-glucoside) got from the leaves. Xanthones, triterpenes and their biphenyl derivatives.[100-101]

[94] [5]

Ginkgo biloba L. Hypericum perforatum L. Ipomoea stans Cav. Justicia hyssopifolia Linn. Kielmeyera coriacea Mart. ex Saddi. Magnolia dealbata Zucc. Matricaria L. chamomilla

Ginkgoaceae Hyperiaceae Convulvulaceae Acanthaceae Clusiacea Magnoliaceae

[96] [97] [98] [99] [102] [103]

Asteraceae

Melissa officinalis L. Momordica Linn. Morus alba L. charantia

Lamiaceae Cucurbitaceae

Moraceae

Mitragyna Korth

speciosa

Rubiaceae

Nardostachys jatamansi DC.

Valerianaceae

The flowers possess 1-2% volatile oils containing alpha-bisabolol, alpha-bisabolol oxides A & B, and matricin (usually converted to chamazulene). Other active constituents include the bioflavonoids apigenin, luteolin, and quercetin. These active constituents contribute to the myriad health benefits of the plant. It contains rosmarinic acid, phenolic acids, triterpenes, monoterpene glycosides, flavonoids and the essential oil contains citronellal, citral, germacrene and caryophyllene. The phytoconstituents include alkaloids, steroids, triterpeniods, amino acids, and flavonoids, reducing sugar, tannins and saponins.[106] The phytoconstituents include flavonoids, tannins, triterpenes, anthocyanins, anthroquinones, phytosterols, sitosterols, benzofuran derivatives, morusimic acid, oleanolic acid, alkaloids, steroids, saponins and phenolic compounds.[107-108] The active constituents are mitragynine, mitraphylline, and 7hydroxymitragynine. The chemical 7-hydroxymitragynine is effective as a pain reliever. Mitragynine is also a pain reliever, but it is not as powerful as 7-hydroxymitragynine. Chemically, N. jatamansi contains sesquiterpinenoids like jatamansone, spirojatamol, patchouli alcohol, norseychelanone, jatamol A and B, lignins and neolignins, jatmansic acid, terpenic caumarins like oroselol and jatamansin. Reports on Nepeta species show that the main constituents of the oil are diastereomeric nepetalactones.

[104]

[105] [106]

[109]

[110] [111]

Nepeta persica Boiss.

Lamiaceae

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Nepeta cataria L. Pachyrrhizus erosus L.

Res Rev Biomed Biotech 1(2); 2010

The principal constituents of the oil are nepetalactone and nepetalic acid, nepetalic anhydride, -caryophyllene and an ether and ester. The phytoconstituents of the seed include rotinoids, flavonoids and phenylfuranocoumarin derivatives. The phytoconstituents include paeonolide, paeonol, paeonoside and paeoniflorin. Ginsenosides It constitutes an array of phytoconstituents some of which include betacarboline harmala alkaloids, coumarins, flavonoids and their glycosides, organic acids, phenolic compounds. Chrysin, a flavone is known to render the anxiolytic properties.

Lamiaceae Leguminosae Paeoniaceae Araliaceae.

[112-113] [114] [115-119]

Paeonia mountan Sims. Panax ginseng C. A. Meyer Passiflora Linn. incarnata

Passifloraceae Passifloraceae Passifloraceae Piperaceae

[120] [51, 13] [121]

Passiflora foetida L Passiflora edulis Sims. Piper methysticum G. Forster. Rauvolfia serpentina (L.) Benth. ex Kurz.

The active compounds include kava-lactones/kava-pyrones. It contains a variety of bioactive compounds including reserpine (the most important alkaloid present in the root, stem & leaves of the plant), ajmaline, deserpidine, rescinnamine, reserpinine, sarpagine, serpentinine. R.rosea contains a variety compounds including phenylpropanoids like rosavin, rosin, rosarin, phenylethanol derivatives like salidroside, tyrosol, flavonoids like rodiolin, rodionin, monoterpenes like rosiridol, triterpenes like daucosterol and phenolic acids like chlorogenic acids.

[122-125]

Apocynaceae.

Rhodiola rosea L.

Crassulaceae Rutaceae Rosaceae Santalaceae Lamiaceae Lamiaceae Lamiaceae

Ruta chalepensis L. Rubus brasiliensis Martius. Santalum album Salvia officinalis L. Scutellaria Georgi baicalensis

[126] [127] The phytoconstituents include sesquiterpenes like santalene, farnesene and alcohols like santalol. The active constituents are present in the essential oil, which contains cineole, borneol, and thujone. Wogonin-a monoflavanoid exerts anti-anxiety efffects. Flavonoids baicalin and its aglycone baicalein show anti-anxiety effects

[128] [129] [130] [131]

Scutellaria lateriflora L. Stachys lavundulifolia Vahl. Sceletium tortuosum (L.) N.E. Brown Sesbania grandiflora (L.) Poiret. Sphaeranthus indicus Linn. Tragia involucrata Linn. Turnera aphrodisiaca Ward. Tilia Americana L. Uncaria rhynchophylla (Miq.) Jacks Valeriana edulis ssp. procera Meyer Valeriana officinalis L.

Aizoaceae. Fabaceae Asteraceae Euphorbiaceae Turneraceae Malvaceae Rubiaceae. Valerianaceae

The major alkaloids include mesembrenol and tortuosamine. Triterpenes show anti-anxiety effects

mesembrine,

mesembrenone, [132] [133] [134]

Methyl chavicol, -ionone, d-cadinene, p-methoxy cinnamaldehyde have been identified as the major constituents. The leaves contain volatile oil, tannins, flavonoids, beta-sitosterol, damianin and glycosides. The active constituents include flavonoids, volatile oils, mucilaginous constituents and tannins.

[135] [136] [137] [138]

Valerianaceae Verbenaceae

The chemical constituents include alkaloids, lignans, glycosides, volatile & non-volatile constituents, aminoacids, caffeic acid, chlorogenic acid, beta-sitosterol, methyl 2-pyrrolketone, choline, tannins, gum and a resin. The main constituents are alkaloids and steroidal lactones. Among the various alkaloids withanine is the main constituent. The steroidal lactones are commonly called withanolides and are the most important bio-active components present in roots that account for the multiple medicinal properties of the herb. Two acyl steryl glucoside namely sitoindoside VII and sitoindoside VIII have been isolated from root. The glycowithanolides exhibited significant anxiolytic activity

[139-140] [141]

Vitex negundo Linn.

Withania somnifera (L.) Dunal

Solanaceae.

[142]

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Zingiber Roscoe. officinale

Res Rev Biomed Biotech 1(2); 2010

Sesquiterpenoids, monoterpenoids and nonvolatile phenylpropanoidderived compounds.

Zingiberaceae Rhamnaceae

[143] [144]

Ziziphus jujuba Mill.

Table 2: Lists the plants influencing GABAergic system

Plant name Annona cherimola Mill. Apocynum venetum. L Gastrodia elata Blume. Ipomoea stans Cav. Melissa officinalis L. Pachyrrhizus erosus L. Rauvolfia serpentina (L.) Benth. ex Kurz Rubus brasiliensis Martius. Scutellaria baicalensis Georgi Scutellaria lateriflora L. Sesbania grandiflora (L.) Poiret. Tragia involucrata Linn. Common name Cherimoya/Cherimolia/Custard apple Reference [59] [60] [5] [98] [105] [113] [145] [127] [129] [130] [132] [134]

Tumbavaqueros

Indian snakeroot or sarpagandha Baikal skullcap Skullcap Agati

Table 3: Lists the plants influencing the serotonergic system

Plant name Albizzia julibrissin Durazz. Gastrodia elata Blume. Sesbania grandiflora (L.) Poiret. Uncaria rhynchophylla (Miq.) Jacks Common name Persian silk tree or pink siris Agati Reference [56] [5] [132] [137]

CONCLUSION Thus, natural herbs/herbal mixtures that act synergistically promise to provide an effective remedy for anxiety. However, only very few among these have been proved to be effective anxiolytes with trials carried out on humans. Synthetic drugs and medications possess enormous side effects, so these herbs with a wide therapeutic applicability promise to alleviate anxiety with very few adverse effects. ACKNOWLEDGEMENT The work has been carried out for a project funded by Defense Research and Development Organization, India. Authors kindly acknowledge constant encouragement given by Director, DFRL. REFERENCES
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Sources of support: DRDO, India Conflict of interest: None declared

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