Anxiety: A Systematic Review of Neurobiology, Traditional Pharmaceuticals and Novel Alternatives...

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Anxiety: A Systematic Review of Neurobiology, Traditional Pharmaceuticals and Novel Alternatives from Medicinal Plants

Érica Aparecida Gelfuso1,§, Daiane Santos Rosa1,§, Ana Lúcia Fachin1, Márcia Renata Mortari2, Alexandra Olimpio Siqueira Cunha3 and Rene Oliveira Beleboni*,1

1Biotechnology Unity, University of Ribeirão Preto. Brazil

2Institute of Biological Sciences, Brasília University. Brazil

3Department of Physiology, University of São Paulo, Brazil

Abstract: Pathologic anxiety is a disproportional reaction of individuals to anticipation or misinterpretation of a potential danger, which affects individual social and personal life. Despite the advances already accomplished, further studies are still necessary in order to understand the mechanisms involved in anxiety. These may provide more effective and safer treatments to aid in the control of anxiety and improve patient quality of life. In this work, we review the current issue about anxiety disorders, covering general aspects such as basic epidemiology and classification, an overview of the pharmacological treatments employed and the current search for natural anxiolytics. Also, a compilation of data investigating the neurobiology that underlies anxiety disorders and a brief discussion evolving the most usual animal experimental models to study anxiety is presented.

Keywords: Anxiety, anxiolytics, botanicals, pharmacology, neurobiology, herbal medicines.

INTRODUCTION

Anxiety has been conceptualized as a significant physiological and behavioral response generated in order to avoid harm and elevate the chances of survival [1]. Thus, anxiety is an emotion that resulted from the evolutionary process and functions as an adaptive response to stress or stressful situations, facilitating survival to potential risks [2]. In this context, while fear is a response to a real threat; anxiety responses originated from the anticipation or misinterpretation of potential danger [3-6]. In some individuals, however, these anxiety responses may become persistent, uncontrollable, excessive and inappropriate, even after withdrawal of the stimulus, lacking any adaptive value, and negatively influencing the quality of everyday life.

Epidemiologic data from the World Health Organization (WHO) [7], show that at least one-third of the population in several countries experienced one episode of pathologic anxiety. In some countries such as Brazil, Canada, Holland and Turkey, anxiety is more prevalent than mood disorders and drug abuse. In Europe and USA, anxiety represents the major health problem in terms of healthcare costs, sick-leave from work, disabilities and premature mortality [8, 9]. The direct implications of these disorders are the reduction in work capacity and rise in labor absences that lead to direct and indirect social and economic costs. For example, the European Union estimated an impact of direct and indirect costs of 41 billion euros resulting from anxiety disorders [9].

*Address correspondence to this author at the Av. Constabile Romano, 2201, Biotechnology Unity, UNAERP; Ribeirão Preto- SP, 14096-900, Brazil; Tel: +55 (16) 3603-6892; Fax: +55 (16) 3603-7030. E-mails: [email protected], [email protected] §Authors with equal contribution to this work.

In addition, epidemiologic data show that groups with the highest probability of presenting any type of anxiety disorder are women, low-income individuals, young people, low educational level individuals (< 11 years of schooling), the unemployed, divorced and single [9].

Therefore, there is an indispensable need for studies focusing on understanding the pathophysiological aspects of anxiety and at the same time, aiming at the design of novel alternatives for the treatment of these disorders. This type of research would help, directly and indirectly to reduce the financial burden and would improve the life quality of affected people [9].

Based on these findings, several research studies have focused on aspects of the neurobiology of anxiety, the compilation of epidemiologic data and investigation of the potency and profile of traditional and alternative pharmaceuticals. Among the later, phytotherapics are increasingly being investigated.

Thus, the major aim of this article is to review some of the pathophysiological aspects of anxiety and to present the state-of-art of natural anxiolytics, also named “green anxiolytics”, in a comparative manner with synthetic analogues and traditional pharmaceuticals.

ANXIETY DISORDERS AND GENERIC CLASSIFICATION

Anxiety disorders exhibit a broad range of symptoms and various degrees of severity, and can cover a wide spectrum of nosological classifications. Furthermore, this spectrum may also vary with factors such as age of onset, the prevalence between men and women, and response to treatment [1]. Furthermore, many patients with an anxiety disorder also suffer from other psychiatric disorders (e.g.,

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2 CNS & Neurological Disorders - Drug Targets, 2013, Vol. 12, No. 8 Gelfuso et al.

60% with co-morbidity of depression) and/or physical or organic illnesses, further complicating the overall pattern of the syndrome [10, 11].

According to the American Psychiatric Association, anxiety disorders can be classified in different nosological categories (Diagnostic and Statistical Manual of Mental Disorders, (DSM-IV) 1994, 2000): generalized anxiety disorder (GAD); post-traumatic stress disorder (PTSD); obsessive-compulsive disorder (OCD); social anxiety or social phobia; specific phobias; agoraphobias with no history of panic; panic disorder with agoraphobia; panic disorder with no agoraphobia.

Previous works suggest that GAD is a hereditary disorder that afflicts around 5% of the population worldwide [12]. GAD refers to excessive and repetitive worry or tension about routine events that occur at least for six months, as for example worry about work performance [13-15]. Diagnostic criteria of GAD are based on the observation of three or more of the following symptoms, with at least one of them experienced in the last six months: tremors, fatigue, muscle tension, irritability, difficulty in concentration, sleep disturbances and restlessness [13-15].

PTSD patients experienced or witnessed an event that involved intense fear, impotence or horror, such as threatening of self-physical integrity or integrity of others. They remember and revive persistently the traumatic event in flashbacks, hallucinations or dreams [13, 16, 17]. In this case, individuals avoid thoughts, feelings, conversations, activities or places associated with the event, and may become unable to relate affectionately or to remember important aspects of the event, leading to social isolation and lack of future personal expectations [13, 16, 17]. People who suffer from PTSD frequently have sleep disturbances, irritability, difficulty in concentration, hypervigilance and frequent fright episodes [13, 16, 17]. Studies show that in only 7% of people suffering from PTSD is the disturbance long-lasting; that is, in most cases, patients will recover from the trauma in a period of one to four weeks [18].

OCD is a syndrome in which patients have a fixed idea, impulse or obsession, which causes intense anxiety and suffering, leading to a stereotyped and repetitive behavior or an uncontrolled urge like a ritual [13, 16]. These obsessions and behavioral alterations drastically interfere with the patient’s professional and personal life and they, in turn, recognize them as exaggerated and irrational [13, 16]. Most commonly observed obsessions are excessive worry about cleaning and symmetry, which are followed by repetitive washing and cleaning. In addition, patients with OCD frequently have doubts about their actions, so they tend to verify repeatedly things, such as locking the door or closing the car [16]. Besides the obsessions described above, mental compulsions like writing lists, prayers, marking dates and counting, although not noticed by nearby people, are recognized by physicians treating patients with OCD [19].

Social phobia is the most common anxiety disorder, the third more frequent psychiatric disturbance [20], and is characterized by the intense and persistent fear of social situations involving unknown people. Patients suffering from social phobia fear to be humiliated, judged or to act inadequately in public, so they feel extremely anxious or

even present panic attacks [13, 20]. Even though the individuals know that their fear is irrational, they keep avoiding social encounters or participate in them with intense suffering and anxiety. Most patients and nearby people do not understand that these symptoms characterize a psychiatric disorder, and they frequently feel ashamed to talk about their problem. Therefore, only 4 to 5.6% suffering from social phobia are correctly identified, diagnosed and treated [20].

Specific phobias are developed towards objects or specific situations, such as fear of animals, blood, flying, heights and injections, among others. Immediately upon the sight of a phobic stimulus, patients experience anxiety responses with phobic attack characteristics [13, 16, 21].

Among all anxiety disorders, agoraphobia and panic disorder are the most disabling, since they limit individual autonomy and often lead to social isolation [22]. Patients suffering from panic disorder experience fear of their own sensation of anxiety. The imminent threat sensation, like fear of dying, of having a heart attack, of going crazy, in addition to the fear of another attack generates a vicious cycle known as “fear of fear” [22, 23]. According to the National Institute of Mental Health, one-third of people with panic disorder develop agoraphobia, the fear of being in places from where it is difficult to escape or to get help in case of a panic attack [24-26].

Panic disorder is characterized by sudden attacks of intense terror that reach maximum state in 10 minutes, which are accompanied by autonomic sensations such as palpitations, sweating, weakness, shortness of breath or suffocating, nausea, fainting; or mental symptoms like confusion or fear of dying [13, 23, 25]. Agoraphobic patients avoid staying alone outside or even inside their homes, avoid crowds, closed places like supermarkets, movies, theaters, shopping centers, elevators and almost never or ever go on public transportation. In mild to moderate cases, they face these situations accompanied by their spouses or a close person; otherwise, they remain housebound [24, 25, 26].

According to American Psychiatry Association in DSM-IV, the criteria to diagnose panic and agoraphobia together is based on the observation that: (1) panic attacks are sudden, recurrent and unexpected; (2) the person fears novel attacks and its consequences for at least one month after the surge; (3) attacks are not related to the use of psychoactive substances or any other medical condition; (4) attacks might not be attributed to any other mental disorder [13, 23].

NEUROBIOLOGY OF ANXIETY

In general, the limbic system is responsible for emotional behavior. Based on the anatomy proposed by Paul Broca in 1877, James Papez in 1937 idealized a circuit widely known as the Papez Circuit, in which sensorial stimuli are sent from the cortex to the thalamus through the cingulate gyrus that also connects to the hippocampus. In the hippocampus, the information is processed and sent to the mammillary bodies in the hypothalamus through the fornix and from there back to the thalamus through the mamilothalamic tract [6, 27].

This basic circuitry was enlarged by Paul MacLean in 1949 that included the other areas of the hypothalamus,

Anxiety: A Systematic Review CNS & Neurological Disorders - Drug Targets, 2013, Vol. 12, No. 8 3

septum and the amygdaloid complex and gave the current name, limbic (from the Latin word limbo; border). Later, in 1958, Wallace Nauta showed that other encephalic structures, such as the periaqueductal gray matter (PAG), locus ceruleus, dorsal raphe nuclei, ventral tegmental area, dorsal tegmental nucleus reticular formation and the dorsal Gudden nucleus, also had connections to the limbic system [27]. Further analysis included also the pre-frontal cortex, which is responsible for several cognitive processes [6, 27].

Experiments using laboratory animals revealed that novel situations or the revival of an experience of real threat activate the amygdaloid complex and the septo-hippocampal system, which acts as the center of analysis of circumstances, comparing the actual experience with previously stored memories. In case of novel situations, this system activates the risk assessment behavior increasing alertness [28]. In real explicit, but distant danger, the PAG is thought to promote typical defense reactions such as freezing and fight or flight responses [5, 27, 28].

Communication among these structures is mediated by many neurotransmitters. Previous data show that anxiety states might be triggered by manipulation of neuropeptides, hormones from the hypothalamic-pituitary-adrenal axis (HPA), cholecystokinin, monoamines, steroids, such as cortisol, and the amino acids L-glutamate, -aminobutyric acid (GABA) and glycine [28].

During stressful situations or in the case of anticipatory anxiety, the most common response is activation of the HPA. Hypothalamic corticotropin-releasing hormone released in the hypophysary portal vessels stimulates the release of adrenocorticotrophic hormone in the anterior hypophysis [5, 28]. Adrenocorticotrophic hormone, in turn, acts on the cortex of adrenal gland stimulating the biosynthesis and release of cortisol into the blood stream [5, 28]. Cortisol functions as a signaling molecule that indicates stressful agents to the central nervous system (CNS). As a result, encephalic structures prepare the organism to fight or flight reactions, which can be divided in two stages; short-term and long-term. The short-term responses lead to activation of the sympathetic system and release of adrenaline that increases heart rate, level of alertness and changes perception [29]. The long-term stage includes activation of the HPA, resulting in mobilization of blood flow and energetic resources to the muscles, inhibition of the immunologic system and metabolic alterations. In the CNS, the excessive cortisol alters sleep patterns, causing insomnia, mood alterations and reduces the threshold for convulsive seizures [29].

Pathologic anxiety may also be caused by alterations in release and expression of receptors for the peptide cholecystokinin (CCK). There are two types of CCK; the CCK-A (alimentary) and CCK-B (brain), whose receptors are widely distributed in the CNS, mostly in limbic and cortical structures [30]. Experimental models of anxiety using rats exposed to environmental manipulations, such as social isolation, showed an increase in the expression of CCK-B receptors in limbic areas, as the frontal cortex. In addition, CCK-B antagonists exerted anxiolytic effects in animal models of anxiety, which corroborate with the hypothesis of their involvement in mechanisms underlying anxiety states [31].

The involvement of monoamines in mental disorders and consequently, anxiety, has been the subject of intense investigation. Stressor stimuli rapidly alter the release and/or uptake of noradrenaline, serotonin and dopamine. Each of these systems regulates the activity of specific neural structures, such as the locus coeruleus, which has most of the noradrenergic fibers in the CNS [32]. This rise in noradrenaline release in amygdala underlies most autonomic responses in anxiety, such as increase in heart rate. In the hippocampus, noradrenaline is thought to improve memory storage, indicating that this neurotransmitter has a fundamental role in conditioned fear and panic disorders [28, 32]. Release of dopamine in prefrontal cortex, in turn, correlates with hypervigilance states [28].

Serotonin (5-HT) is synthetized in the dorsal and medial Raphe nuclei whose fibers project to several structures of the encephalon, including the frontal cortex and limbic system structures such as the hippocampus, amygdaloid complex and PAG [28, 33, 34]. In conflict experiments with laboratory animals, inhibition of 5-HT release caused either by lesion or drug administration was anxiolytic, leading to the hypothesis that 5-HT is anxiogenic [35]. Nonetheless, microinjection of 5-HT agonists in the amygdala exerted anxiolytic effects in rodents submitted to the T-maze [34]. Therefore, the effects of 5-HT depend on the structure and type of stimulated receptors. Evidence shows that actions of 5-HT through the activation of PAG lead to the onset of defense behaviors and inhibition of panic-like responses. However, the role of 5-HT in anxiety remains to be fully elucidated [28, 33, 34]. Finally, some classical antidepressants inhibit the high-affinity enzyme, monoamine oxidase, present in the synaptic cleft of monoaminergic neurons that catabolizes monoamines. Therefore, the involvement of monoamines in anxiety is also supported by the fact that inhibitors of monoamine oxidase-B are used to treat some types of anxiety disorder such as social anxiety disorder [36].

Many patients with anxiety disorders, remarkably GAD and panic, have been treated with benzodiazepines (BDZ), since the short-term use of these drugs offer efficacy and safety [37]. BDZs target type-A GABA receptors, which is the most important inhibitory neurotransmitter in the CNS. A diminished GABAergic transmission is associated with the onset of convulsions and anxiety states, and a rise in GABA concentration in the synaptic cleft is anticonvulsant, neuroprotective and anxiolytic [6, 28, 38]. BDZs act as agonists of GABAA receptors, which are coupled to a chloride channel. The binding of GABA to GABAA promotes the opening of chloride channels, the hyperpolarization of neuronal membranes and, consequently, decreases frequency of action potentials, producing an overall depression of brain electrical activity, which is thought of as being anxiolytic [6, 27]. In addition, GABAergic neurons inhibit the release of 5-HT by neurons of dorsal Raphe nuclei, reducing the activation of amygdaloid complex, and so decrease anxiety and inhibit emotional memory processes [28].

In recent decades, the use of pharmacological functional magnetic resonance imaging (phMRI or pharmacological fMRI) has enabled the design of regional neural mechanisms of pharmacological treatment and also expanded the study of


neural networks involved in pathological anxiety [39, 40, 41]. This technique allows in vivo imaging of brain activity of humans and other animals and provides non-invasive assessment of drug-related changes in this activity [39, 40, 42]. Therefore, it can be useful as a biomarker for predicting anxiolytic function for existing and novel therapeutic agents [42, 43].

The primary and most commonly applied fMRI study is the blood oxygenation level-dependent contrast that detects brain responses which are inferred by physiological changes in hemodynamics and brain energy metabolism [40]. This approach permits to determine changes in specific brain areas and dose-dependent effects in both healthy patients and individuals diagnosed with social phobia and GAD after selective serotonin reuptake inhibitor (SSRI) treatment [42, 44-48]. These effects are particularly pronounced in the amygdaloid complex, which plays an essential role in the processing and consolidation of aversive emotional cues. fMRI studies carried out with healthy controls have reported acute administration of BDZ or pregabalin to attenuate activation of amygdaloid complex and insula during tests involving processing of emotional cues [49, 50]. Moreover, sub-chronic SSRI administration (eg, 3–30 days) has been associated with decreased amygdala, insula, and/or medial prefrontal cortex and anterior cingulate activation during anticipation and processing of emotional cues [42, 44, 48]. Therefore, attenuation of amygdaloid complex and insula activation during anticipatory or emotional processing may represent a common regional brain mechanism for anxiolytics across drug classes [50].

Finally, responses to stressors depend on previous experiences and how individuals cope with them. In general, the perception of a threating stimulus leads to sympathetic activation and autonomic symptoms, such as a rise in heart rate and blood pressure, sweating, xerostomy and breathing difficulty [28, 32]. The prolonged presence of the stimuli lead to later neuroendocrine, biochemical and behavioral manifestations, like activation of adrenals, catecholamine release and metabolic alterations, that prepare the individual to fight or flight reaction [28, 32]. Although adaptive, the persistent activation of these responses may cause hypertension and cardiac disorders, or even increase the risk of sudden death [28, 32]. Even later and slower responses include the persistent alteration of neuroendocrine axes that function as immunosuppressant: increased production of ketone bodies; appearance of gastric lesions; increase in urea, glycogen and fatty acids production; feeding disorders and increased susceptibility to myocardial necrosis.

ANIMAL MODELS OF ANXIETY DISORDERS

Studies with laboratory animals have provided an enormous amount of knowledge to the study of many aspects of anxiety disorders, such as neurobiology and pharmacology/treatment, in spite of certain limitations. The obvious ethical limitations of studies using humans, practicability and costing has made animal research very popular worldwide [5, 6, 51].

The use of animals to study some aspects of human anxiety disorders is possible because defense reactions are very preserved along evolution. According to Charles R.

Darwin in his book “The Expression of Emotions in Men and Other Animals”, defensive behaviors of humans share many aspects with other animals, and may trigger fear and anxiety behaviors [6, 27, 51, 52]. To corroborate this idea, modern molecular studies of genes related to defense behaviors show a high degree of homology among different species [6]. Thus, many animal models of anxiety were proposed in order to understand neural mechanisms of anxiety and consequently to select novel pharmacological targets and tools to be used in rational drug design.

The three most popular models used are the elevated plus maze, the light-dark choice test and the open field test. These models deal with innate fear of rodent from open, elevated and light environments. The conflict between the exploration of novel places and the fear of exposure to potential threat can be analyzed and pharmacologically manipulated in the above models. The higher the anxiety level, the less the animal will explore its novel environment [53, 54].

The horizontal or vertical explorations of the maze estimated by analysis of locomotion or rearing frequency, respectively, are considered parameters that allow the researcher to quantify anxiety responses. The open field test might be used not only to assess anti-anxiety effects of a given drug, but also to check if the drug induces neurological side effects, such as sedation and ataxia and thus alter behavioral responses in other anxiety tests like the elevated plus maze [55]. In addition, vertical exploration is frequently used as a measure of excitability, since the decrease in frequency of locomotion points to a depressive action over the CNS [56].

CLASSICAL PHARMACOLOGICAL TREATMENTS FOR ANXIETY

Over the past half century, and remarkably in the last decades, pharmacological treatments for pathologic anxiety have become more tolerable, available and numerous. In this period, research has provided a better understanding of the physiological and neurobiological mechanisms involved in pathologic anxiety, suggesting new approaches for treatment of this disorder [57]. In this respect, we briefly review the most important events leading to the modern pharmacology of anxiety disorders and discuss some aspects of their use.

The earliest modern psychopharmacological treatment of pathologic anxiety was the application of sedating medications, barbiturates and benzodiazepines, which exert their effects through GABA receptors [58]. Initially, barbiturates were the first anxiolytic drugs approved for treatment of the disorder. Drugs from this class available currently are derivatives of barbituric acid (2,4,6-trioxypyrimidine), with differences in the alkyl (CnH2n+1) and aryl (an aromatic ring, such as phenyl and benzyl) radicals linked to the C5. The general chemical structure of the barbiturates is shown in Fig. (1A). The classification of barbiturates is based on how quickly they act and how long they remain active; ultra-short duration (3 hours); short duration (12 hours) and long duration (24 hours). Barbiturates act on GABAA receptors by two different mechanisms: low concentrations increase GABA-induced chloride currents; high concentrations actually open the channels in the absence


of GABA, leading to the hypothesis that the receptor expresses both high- and low-affinity binding sites [59].

In addition to increasing GABAergic inhibitory transmission, recent findings indicate that barbiturates can also act as neuroprotective agents by inhibiting glutamate excitotoxicity via competitive block of glutamate AMPA ( -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. This blockade of glutamatergic transmission inhibits cationic influx into neurons and reduces the frequency of action potentials [60]. The main disadvantage of barbiturates is related to dosage, since the desired plasma concentration is closely related to the hypnotic dosage. Moreover, prolonged use of barbiturates induces physical and psychological dependency, pharmacological tolerance and abstinence syndrome in the case of withdrawal [61, 62]. In addition, barbiturates also induce untoward side effects that limit treatment, such as memory loss, irritability, sleep alterations and social and affective bluntness. Therefore, the use of barbiturates is limited to anesthesia and seizure control [61, 62].

BDZs were discovered in the early 1960s with the hope for safer and better psychiatric drugs, and subsequently became the most used class of drugs. As previously mentioned, BDZs are widely used as anxiolytics, and, are considered of low risk for physical dependency and death due their therapeutic profiles [63, 64]. The general structure of BDZs is shown in Fig. (1B). Chemical structures of BDZs contain a benzyl ring fused to a seven-member diazepinic ring. Modifications in the ring structure result in similar compounds that differentiate in pharmacokinetics parameters such as absorption, distribution and elimination [63, 64].

BDZs used as treatment of anxiety disorders have a rapid onset of effect and long half-lives. BDZs act as allosteric modulators of GABAA receptors at a specific binding site different from that of GABA. The high-affinity BDZ binding site is located in the extracellular part of the alpha-subunit, and BDZ binding cannot directly open the chloride channel [59]. Upon binding GABA and further chloride channel opening, BDZ binding induces a slight alteration in protein conformation not sufficient to open the pore, but to increase chloride conductance.

Although BDZs were developed as safer and more efficient drugs, they still induce many undesired side effects: decrease in psychomotor activity, diminishment of verbal learning, impairment of memory processes, development of pharmacological tolerance, potentiation of CNS depressors like alcohol, and finally development of dependency mostly after long-term treatment [64].

Until the discovery of antidepressants and inhibitors of catecholamine reuptake, most patients suffering of anxiety disorders received BDZs as first choice of treatment. Actually, the widely studied SSRIs, and to a growing degree, serotonin and norepinephrine reuptake inhibitors (SNRIs) (and for OCD, the mixed noradrenergic and serotonergic reuptake inhibitor tricyclic clomipramine), are considered the first-line pharmacological treatments for anxiety disorders [57, 65].

The SSRIs selectively block 5-HT reuptake through the pre-synaptic transporters, and each of the six available compounds has different indications according to the treated

disorder [65]. Interestingly, SSRIs have few side effects, and have low potential for abuse; they are also equally effective, safer in overdose, and more tolerable than the older tricyclic antidepressants [65, 66]. The chemical structure of fluoxetin, a SSRI, is shown in Fig. (1C).

Other antidepressants, such as tricyclic antidepressants (TCAs) or MAO inhibitors, are generally reserved as second- and third-line strategies due to tolerability issues. The use of TCAs started in 1950 as treatment for psychiatric disorders. The three-ring TCAs mode of action is through inhibition of 5-HT and adrenaline reuptake, and when given long-term, they down-regulate pre-synaptic alpha-2 receptors leading to increased noradrenaline release in the synaptic cleft [67, 68]. Many TCAs also act as antagonists at the muscarinic, 5-HT2, alpha-adrenaline and N-methyl-D-aspartic acid receptors, what explains the pronounced observed side effects. Recent studies of TCAs show that they have similar efficacy to SSRIs for panic disorder [67] and generalized anxiety disorder [68].

Although antidepressants are efficient in controlling many types of anxiety disorders, they also induce unwanted side effects, which may affect 30-50% of patients. Among these are xerostomy, nausea, sleepiness, dizziness, urinary retention, fatigue, sexual behavior alterations and weight gain, which occur less so with use of SSRIs [63, 66]. These effects can be minimized by starting at a low dose and increasing this gradually over two to four weeks [57]. It is noteworthy that TCAs are lethal in overdose and, compared to SSRIs, have a markedly broader, more problematic, and less tolerable side effect profile [57].

Also in relation to 5-HT, a drug class used to control anxiety are the azapirones [30]. These drugs act at the 5-HT1A receptor and have a safer profile than BDZs, since they do not affect motor activity or cause withdrawal syndromes and do not interact with alcohol or BDZs [55]. An example is the psychotropic drug buspirone, whose chemical structure is shown in Fig. (1D). Buspirone, like all members of the azapirones class, is an agonist of 5-HT1A and acts by two modes: competitively for post-synaptic receptors, or at pre-synaptic somatodendritic receptors decreasing neuronal firing rate [55, 69, 70]. The main disadvantages in their use are side effects, which include nausea, cephalea, dizziness and restlessness. In addition, the need to take the drug 3 times a day limits patient compliance. Finally, buspirone starts to exert its anxiolytic effect only two weeks after continuous usage. Therefore, although azapirones possess a safer pharmacological profile from the clinical point of view, these drugs do not overcome BDZs, especially in the treatment of patients previously under therapy with BDZs [70-72].

Other classes of pharmaceuticals are also used as anxiolytics. Example the antihistaminics, whose action is related to inhibition of histamine transmission, and the anticholinergics that inhibit muscarinic receptors. Histamine H1 receptors, which are widely expressed in limbic and non-limbic regions, are metabotropic receptors whose activation indirectly opens voltage-gated and store-operated calcium channels [73]. Activation of the histaminergic system is associated with neuronal plasticity, learning, memory and stress-fear behaviors. Hydroxyzine (Fig. 1E) is a non-selective antihistaminic that antagonizes H1 receptors and to


a minor extent muscarinic receptors and 5HT2 receptors, inhibiting sympathetic activation and suppressing some subcortical areas [74, 75]. The effectiveness of hydroxyzine for the treatment of GAD was recently reviewed [75]. According to these authors, hydroxyzine is an alternative to current standard treatments, with a safer profile, no dependency and low cost. The most commonly observed side effects associated with hydroxyzine therapy are transient sleepiness, difficulty in concentration, impairment of social interaction and irritability. Moreover, the anxiolytic dose is very close to the hypnotic dose [55, 76].

An alternative class of anxiolytics is the beta-blockers that antagonize the beta-type adrenaline receptor. The use of beta-blockers aims to attenuate somatic symptoms of anxiety induced by activation of the sympathetic system. Propanolol (Fig. 1F) was the initially developed to treat hypertension. At present there are many other beta-blockers and some may exhibit a degree of selectivity for beta1 adrenaline receptors [77]. When compared to BDZs, beta-blockers show some advantages such as reduction in cognitive impairments, no induction of dependency and do not cause sleepiness. However, they induce many side effects mostly cardiovascular, such as hypotension and dizziness, limiting their use by patients with cardiac insufficiencies. In addition, due to the beta2 blockade, in patients with asthma and chronic pulmonary obstructive disease, this class of drugs is highly contraindicated. Moreover, patients with diabetes should not take beta-blockers, since hypoglycemia induced tachycardia can be masked in patients using insulin or hypoglycemic oral drugs [78].

The last class of drugs used in to treat anxiety disorders is the atypical antipsychotics, members of the second generation of antipsychotics such as clozapine, shown in Fig. (1G). Atypical antipsychotic actions are due to the blockade of dopamine D2 and serotonin 5-HT2 receptors. This class of drugs induces less extrapyramidal effects than classical antipsychotics due to their antagonism over 5HT2 receptors or quick dissociation from D2 receptors [79]. Regarding treatment of anxiety disorders, atypical antipsychotics have been used as co-adjutants with SSRIs and other antidepressants, and data indicate that they might control anxiety states in patients refractory to medication [65]. Nevertheless, the benefits of using anti-psychotics as anxiolytics should be investigated further, since the existing trials comprised small patient numbers and there is no clear distinction of anti-depressive and anxiolytic activity. In addition, there is a degree of concern over side effects induced by long-term atypical antipsychotic treatment, most commonly related to sleepiness, cognitive impairment, late dyskinesia and catatonia [63, 80, 81].

Despite the widespread availability of psycho- and pharmacotherapies and the increasing consumption of anxiolytic drugs, there is still a great need for studies to identify novel alternatives with better pharmacological profile than the current therapeutic arsenal. Moreover, multidisciplinary studies on basic mechanisms underlying anxiety disorders should contribute to the identification of new targets and the design of novel drugs. Therefore, there is an urgent need to develop broadly acting, more effective anxiolytics with a rapid onset of action, that are better tolerated and with limited abuse potential. In this regard,

medicinal plants, which appear as sources of neuroactive molecules, are still poorly explored by pharmaceutical industry.

THE PERSPECTIVE OF MEDICINAL PLANTS IN THE TREATMENT OF ANXIETY

Natural products have been long used for the treatment of several pathologies as single medicines or as a complement to traditional therapeutics. The use of natural drugs and medicines has been more popular among Eastern civilizations, but has also experienced a marked increase in consumption within Western societies particularly in the last decades as, for example in the USA, where up to one-third of the population make use of those products [82, 83]. In fact, a great amount of the ethnopharmacological knowledge afforded by folk medicine, combined with chemical and taxonomic data reported by different basic and applied research groups, may be used by the pharmaceutical industry to produce novel drugs or phytotherapics. This appraisal is aimed at the production of more efficient, cheaper and possibly safer drugs that could replace synthetic drugs or be used as adjuvant in the treatment of many diseases [84-86]. Indeed, the world commerce of phytotherapics continues to increase, with investments of 14 to 22 billion dollars per year, even though more than 80% of world biodiversity is completely unexplored [87]. Recent findings showed that 847 of the novel drugs approved between 1981 and 2006 originated from natural sources, or were derived from the semi-synthesis or complete synthesis using natural products as probes [68, 89]. Considering the increased popularization in the use of phytotherapics, it is imperative that clinicians and pharmacologists recognize the limitations and potentialities of herbal medicines, to avoid either an unreasonable enthusiasm or reluctant judgment about their potential benefit [83, 89].

Anxiety and other mood disorders are one the most common motivations to search for alternative therapies [90, 91]. In fact, Eisenberg and collaborators [92] estimated that about 43% of patients with anxiety disorder make use of some complementary treatment. According to Astin [93], treatment with herbal medicines appear to be the preferential one [91]. Ethnopharmacological knowledge associated with pharmacological investigation of plant sources has led to the identification of a variety of species with neuroactive compounds effective in many animal models of neurological and mental disorders. Although reduced in number and considering the immense potential for biodiversity of components, many studies are currently being carried out to investigate the general actions, as well as neuronal site of action of these plant molecules, including those identified as potential targets for treatment of anxiety disorders [84, 94, 95].

Among the plants used to treat anxiety disorders worldwide, it is worth to mention the species Piper methysticum G. Forst. (Kava Kava) (Piperaceae), Passiflora incarnata L. (Passionflower) (Passifloraceae), Passiflora edulis Sims (Passifloraceae), Valeriana officinalis L. (Valerianaceae), Ginkgo biloba L. (Ginkgoaceae), Galphimia glauca Cav. (Malphigiaceae), Matricaria recutita L. (Asteraceae), Melissa officinalis (Lamiaceae), Scutellaria


lateriflora L. (Lamiaceae) and Camellia sinensis L. – (Theaceae) [30, 96, 97].

P. incarnata L. (Passionflower) and P. methysticum (Kava Kava) deserve special interest, due to the incidence of their usage worldwide and positive outcome of clinical trials performed to date. One of the most important clinical trials using Passiionflower was performed by Akhondzadeh and collaborators [98], in which patients diagnosed with GAD were submitted to a double-blind, and placebo-controlled assay to compare the effectiveness of a Passiionflower extract (45 drops/day; n=18) to the BZD oxazepam (30 mg/day; n=18) during a period of 4 weeks. No significant differences were observed between treatments using Passiionflower and oxazepam in ameliorating GAD symptoms. Total side effects did not differ between the two groups; however, patients treated with Passiionflower claimed to have a lower impairment of job tasks specially related to cognitive performance, despite a more rapid onset of action claimed for the BZD group (See also 83; 99).

For Kava Kava, Lakhan and Vieira [99] critically reviewed 11 clinical trials, most of them evidencing a positive correlation between the uses of Kava Kava extracts and amelioration of symptoms of different types of anxiety,

including GAD. Although positive evidence of efficacy for different preparations with Kava Kava, the safe use of different herbal preparations of Kava Kava merits discussion, mainly considering the banishment of Kava Kava use in some countries, such as the United Kingston, in the beginning of last decade, due to potential liver toxicity. However, it should be emphasized that liver injury appears to be a rare side-effect, at least up to 400 mg/day [99]. Further studies are needed to confirm the positive evidence for use of Passionflower and Kava Kava extracts in the treatment of anxiety, along with assessment of safety.

M. officinalis is another plant that deserves interest. Experimental evidence supports the acute and chronic use of this plant for the treatment of anxiety, together with its relative safety of use. Further studies on chronic use should be carried out, particularly in terms of a placebo-controlled investigation. Healthy volunteers (n=18) participating in an acute, double-blind, placebo-controlled study received doses of a commercial preparation of M. officinalis (Pharmaton SA; Lugano, Switzerland) (300 mg or 600 mg) or placebo on separate days with a 7-day washout period between them. According to the Defined Intensity Stressor Simulation Battery, the higher dose significantly reduced laboratory-induced stress, and also the lower dose increased the

Fig. (1). General chemical structures: Barbiturates (A); BZDs (B); Fluoxetine (C); Buspirone (D); Hydroxyzine (E); Propranolol (F); Clozapine (G).


mathematical processing speed without loss of accuracy. No adverse side effects were observed [100]. In a chronic treatment regimen, Cases and collaborators [101] reported the anxiolytic properties of another standardized formulation (CyracosR; Naturex, SA, France) (600 mg/day) for male and female volunteers (DSM-IV-TR) diagnosed with anxiety and sleep disturbances. Besides the relative safety of the phytotherapic product, the authors showed in an open-label 15-day study its effectiveness against mild-to-moderate anxiety and insomnia. However, interpretation of results is limited, as no placebo group or a group treated with a conventional drug for anxiety was used [101].

Concerning Valeriana officinalis, Pakseresht et al. [102] performed a placebo-controlled and double-blind pilot trial to investigate its effects in the treatment of OCD. Limitations of sample size and study duration (8-weeks) notwithstanding, the authors reported that V. officinalis (750 mg/day) was effective against OCD compared to placebo group, rating symptom severity by the Yale-Brown Obsessive-Compulsive Scale. No significant differences were observed between experimental and control groups regarding side effects. However, no conventional drug was employed as control for comparison of effectiveness or safety in relation to placebo or treated groups [102]. In contrast, Andreatini et al. [103] reported that placebo, diazepam and the experimental group (treated with a mix of valepotriates constituted by 80% dihydrovaltrate, 15% valtrate and 5% acevaltrate -BYK-Gulden, Lomberg, Germany) had similar performances in relation to baseline or baseline change on scores of the most important parameters for detection of ameliorating GAD symptoms. Although the potential anxiolytic effect of valepotriates was not completely rules out, and considering limitations of sample size and study duration (4-weeks), no strong and conclusive evidence for V. officinalis anxiolytic effect was confirmed in this pilot trial. No side effects of note were registered for V. officinalis [103]. Although well-tolerated, the limitation on studies performed with humans and, to some degree the contradictory results, current information is insufficient to warrant an indication of V. officinalis for clinical treatment of anxiety [see also 104, 105].

Hipericum perforatum (St John’s wort) is popularly known for its antidepressant properties and has been mostly studied for this reason. As with V. officinalis and is spite of the promising potential for treatment of anxiety, there is no strong evidence for efficacy in human anxiety. Contradictory results were obtained using St John’s wort in the treatment of OCD patients [106, 107]. Even though there was a positive interpretation of experimental results using St John’s wort for treating GAD [108], Kobak et al. [109, 110] performing a double-blind, randomized trial with H. perforatum reported negative results for treatment of same type of anxiety (GAD) and social anxiety disorder. Although apparently safe for humans, St John’s wort requires further study to justify treatment of different types of anxiety.

The association of different plant extracts in a single herbal medicine is a common practice of general phytotherapy. This practice, in most of cases, should be better investigated to clearly demonstrate advantages and/or disadvantages in terms of a positive/negative synergism or

even unneeded costs or increased side effects. The same can be said for botanicals in phytoformulations intended to complement conventional drugs or medications for treating anxiety. Additionally, the correct adjustment of dosage/con-centration of each plant extract constituent of an effective formulation or even the adjustment of effective and safe doses of plant association in relation to isolated counterparts in therapeutic use must be better investigated. Concerning the association of plant extracts, since M. officinalis and V. officinalis share similar medical indications and have been used at times in association, Kennedy et al. [111] in a double-blind, randomized assay (n=24; health volunteers), investigated the effect of the combination of those plant extracts using a standardized medicine (Songha Night TM, Pharmaton Natural Health Products: 120 mg of V. officinalis plus 80 mg of M. officinalis, in tablet) on modulation of mood and anxiety. Regarding anxiety, results indicated that the plant association induced a dual response during laboratory-induced stress, in which response to anxiety varied according to the dose used in a placebo-controlled condition. Indeed, the lower dose of association (600 mg) used produced anxiolytic effects, while the higher dose (1800 mg) produced a slight but significant opposite effect in one session of anxiety parameters measurement [111].

The type of plant extract and plant part used to investigate the anxiolytic properties of herbal sources are generally variable, though some restriction is perceived when the suggested mode of anxiolytic action of plant extracts or constituents has already been described, in which the most prevalent investigations focus on monoaminergic and GABAergic neurotransmitter systems. This observed restriction seems to be mostly caused by the existing knowledge of traditional pharmacological targets for conventional anxiolytic drugs, rather than by a deep neurobiological investigation based on brain biochemical alterations underlying anxiety disorders. Commonly used plant extracts are either aqueous or hydroalcoholic, although percolation with n-hexane has also been employed, with choice obviously depending on the active compound to be extracted. Several phytochemical classes of compounds have been isolated from plants, and the flavonoids deserve special attention among the phenolic compounds with anxiolytic properties. Indeed, numerous flavonoids such as apigenin, wogonin and chrysin are reported to be anxiolytic, at least in animal models [112-115]. The main mode of action for these compounds appears to be correlated to GABAA receptor modulation, since the anxiolytic activity of flavonoids is abolished by antagonists of BZD sites in GABAA receptors. Unlike BZD compounds, flavonoids do not induce sedation at doses used to promote their anxiolytic effects [116, 117].

Despite the huge biotechnological and pharmaceutical potential of herbal medicines for treatment of anxiety disorders and other ailments, their major restrictions should be seriously discussed by the scientific community and consumers. Regarding the production and commercialization of phytotherapics, including the anxiolytic ones, their main problem is lack of quality control in formulations, particularly technical standardization and replication of therapeutic effects of drugs from distinct series. Over the past few years this issue has improved, due to conscientious efforts by national health agencies worldwide. Therefore, complete phytochemical analysis of natural products is


Table 1. Medicinal Plants with Anxiolytic Effects

Family/Plant Species Type of Extract and

Plant Part Used

Possible Anxiolytic

Compound(s) Likely Mode of Action

Effects of Extract in Human

Beings for Anxiety Ref.

Amaryllidaceae/ Hippeastrum vittatum

Ethanolic extract of fresh bulbs.

Montanin alkaloid.

It is suggested an action on GABAergic neurotransmission,

particularly on GABAA receptors.

No data found. [118]

Apiaceae/ Panax ginseng

Aqueous extract of root powder.

Probably Ginsenoside Rb1.

Based on scientific literature it is suggested actions on BDZs or 5-

HT1A receptors.

No human trial found for only P. gingeng against anxiety.

Gincosan, a combination of Ginkgo biloba and Panax

ginseng, had no effect on ratings of bodily symptoms of somatic

anxiety.

[105, 119, 120, 121]

Apocynaceae/ Apocynum venetum

Ethanolic leaves extract.

Probably mediated by the kaempferol and

other synergistic compounds.

GABAergic system and to a lower extent 5-HT1A, needs more

research. No data found. [55, 122]

Araliaceae/ Panax quinquefolium

Primary extraction of roots in ethanol 70%.

Saponins. GABAergic and cholinergic system, needs more research.


Asteraceae/ Sphaeranthus indicus

Hydroalcoholic extract of the

flowering plant.

In the extract there are proteins, carbohydrates,

steroids, saponins, tannins, flavonoids,

coumarin, triterpenes and essential oils.

Not mentioned. No data found [124]

Burseraceae/ Protium heptaphyllum

Extract of stem bark resin.

Isometric triterpenes mixed alpha and beta-

amyrins.

Probable action over GABAA receptors.

No data found [125]

Fabaceae/ Cinnamomum cassia

Hydroalcoholic extract of stem bark.

Not exactly mentioned Interacts with 5-HT1A and GABAA receptors


Ginkgoaceae/ Ginkgo biloba

Special extract EGb 761® of leaves.

Flavone glycosides and terpenes lactones

(ginkgolide, bilobalide). Not exactly mentioned.

There is a report of improvement of cognitive ability for patients Generalized Anxiety Disorder

with decrease of Hamilton Anxiety Rating Scale total score

by use of EGb 761® extract

[113, 127]

Hypericaceae/ Hypericum perforatum

Metanolic extract of aerial parts (LI 160-Eurofarma, Italy).

Not exactly mentioned, however, the extraction

is standardized on a basis of hypericin

(0.3%) and hyperforin (3.3%), showing a low content of compounds previously known as

anxiolytics.

The plant extract inhibits 5-HT re-uptake and hyperforin inhibits GABA and glutamate re-uptakes.

Needs more research.

The published human trials do not support the use of Saint John´s

Wort in treating anxiety.

[107, 110, 128, 129]

Iridaceae/ Crocus sativus

Aqueous extract of powdered stigmas.

Safranal. BDZ site at the GABAA receptors. Needs more research.

No data found. [107, 110, 128-130]

Lamiaceae/ Lavandula angustifolia

Essential oil obtained by the steam distillation of

flowers.

Essential oil extract is rich in linalool and

linalyl acetate, however, needs more

research.

Probable actions over 5-HT receptors as well as GABAergic

and glutamatergic systems, however, more research is

required.

Promising evidence for oral lavender use is suggested for treatment of anxiety, however

further studies are needed. Additionally, Lavander Ayurvedic

oil-dripping treatment showed anxiolytic effects. Also

aromatherapy with an essential oil blend of rose otto and Lavandula

augustifolia is recommended as a complementary therapy for

anxiety.

[131, 132, 133, 134]


(Table 1) contd…..


Plant Part Used

Possible Anxiolytic




Lamiaceae/ Melissa officinalis

Industrial hydroalcoholic

extract of aerial parts (Cyracos®, Naturex

SA).

Rosmarinic acid, oleanolic acid and

ursolic acid.

Inhibits GABA-T enzyme, prolonging GABAergic activity

in the synaptic cleft.

Studies with standardized formulation containing M. officinalis have suggested a

significant reduction in laboratory-induced stress and the effectiveness of this plant against

mild-to-moderate anxiety and against insomnia.

[100, 101, 135, 136]

Lamiaceae/ Salvia divinorum

Isolated compound (Tocris Bioscience,

UK). Salvinorin A. Acts over -opioid receptors and

endocannabinoid system. No data found. [137]

Lamiaceae/Scutellaria baicalensis George

Root powder extracted in

dichloromethane leading to isolation of

a flavonoid.

Wogonin (flavonoid). Positive allosterism with BDZ site at the GABAA receptor.


Magnoliaceae/ Magnolia obovata

Isolated compound by extraction from

leaves using acetone and chloroform as solvents. (Korea

Research Institute of Bioscience and Biotechnology).

Obovatol (Lignan).

Modulate the expression of GABAA -subunit in the

amygdala and increases Cl- conductance through these

receptors.


Malphigiaceae/ Galphimia glauca

Extraction by percolation with n-hexane followed by methanol extraction using aerial parts of

plant.

Galphimine-B (GB). Possible action on serotoninergic system.

Capsules containing the dry extract of G. glauca standardized in content of galphimine-B has anxiolytic effect in patients with Generalized Anxiety Disorder.

[140, 141]

Orchidaceae/ Gastrodia elata

Aqueous extract of rizhome

Mostly phenolic compounds: 4-

hidroxybenzil alcohol (HA) and 4-

hydroxybenzaldehyde (HD).

Possible activation of 5-HT1A (HA) and GABA receptors

(HD). No data found. [142]

Papaveraceae/ Eschscholzia californica

Hydroalcoholic extract of aerial parts.

Not exactly mentioned. Possible involvement of BDZ site of GABAA receptors.

No human trial found for only Eschscholzia californica against

anxiety. A combination of

Crataegus oxyacantha and Eschscholtzia californica extracts and magnesium is reported to be

effective in treating mild to moderate anxiety disorders.

[143, 144]

Papilionaceae/ Erythrina mulungu

Flower hydroalcoholic

extract.

(+)- -hydroxy-erysotrine, erythravine and (+)-11 -hydroxy-erythravine alkaloids.

Not exactly mentioned. No data found. [145, 146]

Passifloraceae/ Passiflora incarnata

Hydroalcoholic extract of aerial parts (Commercial extract Passiflorae herba).

Not exactly mentioned, however phytochemical

analysis showed C-glycosides – flavonoids

as main compounds.

Not exactly mentioned.

The extract is effective as a premedication to suppress anxiety

in patients who will undergo spinal anesthesia and surgery. It´s also reported as effective for the treatment of generalized anxiety

disorder.

[98, 147-150]

Passifloraceae/ Passiflora

quadrangularis

Hydroalcoholic extract of leaves.

Under investigation, the it is suggested action for triterpenes and

steroids, however it is not rules out action for

alkaloids and flavonoids.

Not mentioned, however for other plants from the same

botanical genus is showed the presence of compounds able to

bind at BDZ receptors.

No data found [151]


(Table 1) contd…..


Plant Part Used

Possible Anxiolytic




Phytolaccaceae/ Petiveria alliacea

Ethanolic extract of the whole plant. Possibly flavonoids. Not exactly mentioned. No data found. [152]

Piperaceae/ Piper methysticum

Industrial acetonic rhizome extract

(WS®1490). Possibly lactones.

BDZ-like actions are suggested, however other studies suggest also inhibition of Na+ and Ca++

channels.

Aqueous Kava extract produced anxiolytic and antidepressant

activity in clinical trial, but these data are contradictory in the

literature. Kava is also reported to enhance cognitive functioning and to treat sleep disturbance associated with non-psyhcotic

anxiety disorders.

[128, 153-159]

Rhamnaceae/ Ziziphus

jujuba Ethanolic extract of

seeds. Not exactly mentioned.

It is suggested that a reduction in cerebral monoaminergic activity

is responsible for anxiolytic activity, however needs more

research.


Rosaceae/Rubus

brasiliensis

Infusion and ethanolic extract of

flowering plant

Not exactly mentioned, however it is supposed

to be at least one lipophilic compound

with low toxicity.

It is suggested an agonistic effect on BDZ receptor. No data found. [114, 115]

Rubiaceae/ Uncaria

rhynchophylla Aqueous extract of

hooks.

Not mentioned, but it is supposed a

participation for indolic alkaloids.

Possible involvement of 5-HT system; needs more research also

for investigation of the involvement of GABA receptors.


Rutaceae/ Casimiroa

edulis Hydroalcoholic extract of leaves. Not exactly mentioned.

Not investigated, however for the antidepressant activity of the

plant is suggested the involvement of

catecholaminergic system.

No data found [162]

Solanaceae/ Withania

somnifera

Commercialized ethanolic extract (Aswal, India).

Not exactly mentioned. It is suggested a modulation of

GABAergic system; needs more research.

Ashwagandha (W. somnifera) plus dietary counseling, deep

breathing relaxation techniques and a standard multi vitamin produced improvements in

patient´s anxiety. Ameliorating profile of Brief Psychiatric Rating Scale was showed in patients by

Andrade et al., 2000. Further studies are needed.

[129, 163, 164]

Theaceae/ Camellia

sinensis Aqueous extract of

leaves.

Not mentioned. Plant rich in phenolic

compounds.

It is suggested the involvement of monoaminergic system

(serotonin and dopamine), however more research is

required.


Tiliaceae/ Tilia

americana var mexicana

Methanolic extract of flowers and bracteas.

Flavonoids: tiliroside, rutine, quercetin,

qercitrin, and kaempferol. The first

listed compound is the main component of

active chromatographic fraction (F1C).

Not exactly mentioned, however and based on F1C fraction

constituents, especially kaempferol, it is suggested the

inhibition of MAO-A and MAO-B enzymes. Needs more

research.


Turneraceae/ Turnera aphrodisiaca

Methanolic extract of aerial parts. Apigenin flavonoid. Not mentioned. No data found. [167]

Valerianaceae/ Valeriana officinalis

Hydroalcoholic extract of the roots. Valerenic acid.

It is suggested the involvement of GABAergic system. It is

known a BDZ-like action over the GABAA receptor complex

for valerenic acid.

Anti-obsessive and anti-compulsive effects has been

suggested, however there is no conclusive evidence supporting

the use of V. officinalis in treatment of anxiety.

[102, 129, 168, 169]

Verbenaceae/ Aloysia polystachya

Hydroalcoholic extract of aerial parts.

Possibly thujone and carvone, however

needs more research.

It is suggested a mechanism different from those involving

GABAA receptors. No data. [170, 171]

Abbreviations: BZD: Benzodiazepines; GABA: -aminobutyric acid; 5-HT: Serotonin.


imperative to achieve high grades of quality. This will help to detect differences among plant extracts caused by biotic and abiotic factors that affect plant growth and development and the production of secondary metabolites. Correct taxonomic identification of the plant as well as microbiological quality control also represents a problem for the production of phytotherapics, even in large-scale industry in some countries. Quality control guidelines exist worldwide, and other regulations have been proposed to assure yet better quality control. Even so much remains to be done, especially when compared to the strict policies established by the US Food and Drug Administration and related agencies worldwide for traditional pharmaceutical products. Clinical efficacy and toxicity of many phytotherapics is also a concern. Among several compounds with anxiolytic potential, unequivocal clinical trials to fully characterize effectiveness and toxicological aspects are needed. The scientific literature in this field, we believe, is somewhat biased by the tendency to report positive results [91]. Moreover, many clinical trials lack adequate replication and carry methodological deficiencies, such as inaccuracies in heterogeneity and size of samples, consistency in quality of the phytotherapic used, period of follow up and recommended treatment dosage or even lack of a reliable placebo control group [83, 91].

Several plant extracts and isolated compounds have been investigated and tested in animal models of anxiety or even in clinical trials (Table 1). Due to the extensiveness of the subject; this synoptic table is not intended to fully cover all investigated species but rather give examples of the great diversity of plant families traditionally used, and whose pharmacological potential has been scientifically validated, at least in experimental animal models and in a few cases in humans.

FINAL REMARKS

This review was intended to set the stage for future discussions on anxiety disorders, some of its neural basic mechanisms and animal models applied to scientific investigations, together with traditional pharmacological treatments using crude plant extracts and neuroactive compounds isolated from plant extracts. These interconnected issues will hopefully lead to a better understanding of the complexity of anxiety disorders, and provide new possibilities toward an integrated approach for their treatment. To this end, a better understanding of the neural mechanisms of anxiety using animal models or other technical approaches could be crucial to reveal new molecular targets of natural or synthetic drugs whose mode of action is not still conceptually considered state of art.

Anxiety comprises a heterogeneous class of disorders that impose a huge personal, social and financial burden on society. Epidemiologic data show a high prevalence of anxiety disorders in many countries. However, these data might be underestimated, since in most cases patients suffering from anxiety are wrongly diagnosed or do not seek medical assistance. In addition, some countries lack precise epidemiological estimates of prevalence, treatment, and costs which might be underestimated. Therefore, it is of great importance to achieve a more realistic and complete impact

measurement of the damage caused by anxiety to general society.

Despite the variety of conventional anxiolytic drugs available there remains a need for innovative agents. Conventional drugs efficiently control, in most cases, many of the described anxiety states. However, some patients are untreated or do not tolerate the undesired side effects caused by chronic use of these medications, leading to yet additional social or personal problems and economic costs.

In this context, plant extracts appear to be a rich source of biological compounds that remain unexplored. In many cases their use is limited to folk medicine or, in some cases when industrially produced limited by lack of rigid quality control of production. Consequently, several studies have aimed to pharmacologically validate phytotherapics and develop innovative pharmaceutical products for use in the treatment of anxiety disorders. Yet, there is still a need for an overall enhancement of understanding and quality control of many optional remedies, especially considering aspects of production or usage as manufacturing, safety and effectiveness. Even taking into account these and other limitations like the insufficiency of robust clinical trials, it is important to identify negative and positive general potential/aspects related to herbal medicines or botanicals, especially to avoid either an unreasonable enthusiasm or an anticipatory negative judgment about their potential benefits.

In the same context, the precise neurobiological processes underlying anxiety disorders are continuously under investigation. Animal models play an important role in understanding the basic aspects and also in the testing of novel compounds. However, inconsistencies have been observed when comparing results obtained with animal models and clinical trials in humans. These models need to be constantly updated in order to reproduce the most important aspects of human anxiety disorders and function as predictors of anxiolytic therapy. This is a difficult goal, considering the heterogeneity of anxiety disorders and the complexity of human mental processes. Nevertheless, with improved techniques of molecular biology, imaging, pharmacology and physiology, it should become possible to overcome these difficulties and achieve safer and more efficient therapies for anxiety disorders.

In spite of the fact that many plants have been tested in animal models of anxiety and considering their anxiolytic activity attested to by folk and traditional use, very few compounds have actually come to market. Most reports on plant research are limited to validate extract activity in a given model or to investigate pharmacological targets focusing on isolated compounds. Thus, a novel concept for planning plant validation investigations for therapeutic purposes should be put in practice to advance and to accelerate the discovery of innovative anxiolytic drugs for treating anxiety disorders in man.

ABBREVIATIONS

AMPA = -amino-3-hydroxy-5-methyl-4- receptor I soxazoleprop-ionic acid receptors

5-HT = Serotonin

BDZ = Benzodiazepines


CCK = Cholecystokinin

CNS = Central Nervous System

DSM = Diagnostic and Statistical Manual of Mental Disorders

GABA = -aminobutyric acid

GABA-T = Gamma-aminobutyric Acid Transaminase

GAD = Generalized Anxiety Disorder

HPA = Hypothalamic-Pituitary-Adrenal

MAO = Monoamine Oxidase

OCD = Obsessive-Compulsive Disorder

PAG = Periaqueductal Gray Matter

phMRI or = Pharmacological Functional Magnetic pharmacological Resonance Imaging fMRI

PTSD = Post-traumatic Stress Disorder

SSRI = Selective Serotonin Reuptake Inhibitor

TCA = Tricyclic Antidepressant

WHO = World Health Organization

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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Received: February 6, 2013 Revised: June 30, 2013 Accepted: July 2, 2013

Anxiety: A Systematic Review of Neurobiology, Traditional Pharmaceuticals and Novel Alternatives...

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