Medicinal plants for the “ nerves ” : a review of ethnobotanical studies carried out in South Brazil

Among the medicinal purposes for which plants have been used is the treatment of “nerves”. Th e objective of this study was to search for species of plants used in the state of Rio Grande do Sul (South Brazil) for the relief of symptoms related to central nervous system (CNS) disorders. Twenty-seven ethnobotanical studies were compiled, in which a total of 94 species were cited. Th e fi ve most cited species were Cymbopogon citratus (81.5 %), Melissa offi cinalis (77.7 %), Aloysia citriodora (66.6 %), Matricaria chamomilla (62.9 %) and Passifl ora edulis (51.8 %). Scientifi c studies have corroborated the popular use of these plants as sedatives, but most studies are preclinical and very few have been clinical (M. chamomilla and M. offi cinalis), and these were mainly exploratory or were performed against placebo. In addition to effi cacy data, there are also indications of toxicity for M. chamomilla and P. edulis. In conclusion, there is a great diversity of plant species used in the treatment of symptoms related to CNS disorders, and they are most frequently used as a sedative. Data indicate that M. offi cinalis possesses clinical effi cacy in the treatment of symptoms associated with anxiety without signs of toxicity.


Introduction
Brazil is rich in ethnic and cultural diversity and holds valuable traditional knowledge associated with the use of herbal medicines (Brasil 2006).Such popular medicine is widespread in the South Region of the country, especially in rural areas where the population faces diffi culties in accessing primary care services (Souza et al. 2004) and uses alternative therapeutic resources including medicinal plants.Consumption is also favored by a widespread popular belief that medicinal plants and byproducts do not present adverse eff ects or toxicity, and thus are benefi cial and safe products for health (Mengue et al. 2001).However, there is also evidence that plants may be toxic and that in certain situations even plants considered safe may cause adverse (in some cases, serious) events or loss of effi cacy (Moreira et al. 2014;Lorenzo et al. 2015).Th us, knowledge about the use, pharmacological properties and toxicology of plants and products derived from them is fundamental to assure their safety and eff ectiveness (Rates 2001;Moreira et al. 2014;Lorenzo et al. 2015;Braga et al. 2017).Th e main objective of ethnobotanical research is to recover knowledge and the use of medicinal plants in communities (Rodrigues et al. 2011).Besides being important for the acquisition of knowledge of the fl ora and for preserving the cultural identity of communities, such studies also provide important elements for the rational and sustainable use of these resources, including the development of herbal medicines and the discovery of bioactive molecules, with consequent drug development (Rates 2001;Braga et al. 2017).In fact, many drugs used in current therapy were originally obtained or developed from plant products (Cragg & Newman 2013).
Previous compilations of ethnobotanical surveys conducted in the Brazilian state of Rio Grande do Sul focused on plants used for the treatment of diabetes (Trojan-Rodrigues et al. 2012) and pain (Stolz et al. 2014) and demonstrated that the use of medicinal plants is a widespread practice in the state.Neverthless, no compilation has been performed for plants used for the relief of symptoms related to central nervous system (CNS) disorders cited in ethnobotanical surveys in Rio Grande do Sul.Such plants are popularly denominated as medicinal plants for the "nerves".
Knowledge of the use of plants in popular medicine for treating CNS disorders is relevant, given the epidemiology of these diseases and the difficulty in establishing effective and safe pharmacological therapies.About 5.8 % of the Brazilian population lives with depression, and it has the greatest prevalence of anxiety disorders among countries of the world, with about 9.3 % of the population (WHO 2017).
There are different pharmacological treatments for depressive disorders and anxiety.However, the available therapeutic arsenal has important limitations: benzodiazepine anxiolytics cause dependence and develop tolerance (Rates & Salles 2012;Murrough et al. 2015); antidepressants have low adherence due to adverse effects and long latency, about 30 uninterrupted days, to treatment efficacy.In addition, about 33 % of patients do not respond to antidepressants (Stahl 2014;Murrough et al. 2015).The contribution of plants to the development of drugs for the treatment of mental disorders can be exemplified by the species Rauwolfia serpentina, from which reserpine was isolated; although now in disuse, this drug was important in the early stages of the pharmacological treatment of schizophrenia.Species such as Hypericum perforatum and Piper methysticum, currently serve as raw material for the production of herbal medicines for the treatment of depression and anxiety, respectively.Valeriana officinalis, a species with millennial use, is recgonized by WHO as a sedative in replacement of benzodiazepines (WHO 2017).
Studies involving the use of plants to treat some CNS dysfunctions have been undertaken in different cultures, such as Andean (Lozada et al. 2006;Vidaurre et al. 2006;Bussmann et al. 2010), Mexican (Gutierrez et al. 2014), Spanish (Calvo & Cavero 2015) and Iranian (Saki et al. 2014) peoples.Many species of plants are used to treat some CNS dysfunctions in Brazil, as evidenced by the large number of herbal medicines registered by the National Health Surveillance Agency (ANVISA): about 146 used to treat mood disorders, approximately 80 simple herbal medicines, and 66 herbal compounds (Montezolli & Lopes 2015).
In this context, the objective of the present work was to compile plants used to treat symptoms related to mental disorders, such as depression and anxiety, mentioned in ethnobotanical studies carried out in the state of Rio Grande do Sul, and to perform a bibliographic survey of chemical, biological and toxicity data of the most cited species.for scientific data about chemical constitution, biological properties and evidence of toxicity.For this, clinical and preclinical studies were searched in the PubMed (http// www.pubmed.com),SciELO (http//www.SciELO.org/php/index.php),Scopus (https://www.scopus.com/home.uri)and Portal de Periódicos CAPES (http//www.periodicos.capes.gov.br).The scientific name of the plant was combined with the terms "depression", "sedative", "anxiety", "nervousness", "biological activity", "chemical composition" and "toxicity", as well as their corresponding words in Portuguese, and used as keywords in the searches.

Results and discussion
Twenty-seven ethnobotanical studies were assessed.The studies were performed in municipalities located in different physiographic regions of Rio Grande do Sul.The Depressão Central was the region with the greatest number of studies (07), which is likely due to its proximity to the most important universities.It should be noted that currently the Fortes's classification (Fortes 1959) is mainy of historical value.In fact, the diversity of climate, soil and landforms in Rio Grande de Sul generates distinct ecosystems included in two biomes: the Atlantic Forest and the Pampa.The Atlantic Forest biome is characterized by the predominance of forest vegetation.It originally encompassed about 37 % of the state of Rio Grande do Sul, occupying the northern half of the state, although only 7.5 % of the area of the biome in the state remains, with high a degree of fragmentation relative to the original vegetation cover (Brasil 2018a; Rio Grande do Sul 2018).The Pampa biome in Brazil is restricted to the southern half of Rio Grande do Sul, and encompasses over 63% of the state.This biome is characterized by the predominance of a set of lowland vegetation that extends through Uruguay and Argentina, and possesses a great diversity of fauna and flora that is still poorly known (Brasil 2018a;Rio Grande do Sul 2018).
Ninety-four plant species were indicated to treat CNS dysfunctions (Tab.1).Reports that provided only the genus or popular name were not considered.The families with the greatest number of species cited were Lamiaceae, with twenty-four species, Asteraceae, with thirteen species, and Rutaceae, with eight species.
Out of all the species cited (94), 73.4 % (69 species) were exotic and 26.6 % (25 species) were native to Rio Grande do Sul.This finding differs somewhat from that reported by Trojan- Rodrigues et al. (2012) and Stolz et al. (2014), who found parity in the popular use of native and exotic plants for treating diabetes and pain, respectively.The use of exotic species, which are frequently cultivated in domestic gardens, points to the influence of different cultures coming from several ethnic groups.European, Asian and African descendants have integrated with indigenous peoples in Brazil, which is responsible for originating the current tradition of popular use of medicinal plants in the country (Ceolin et al. 2009;Battisti et al. 2013;Löbler et al. 2014).
Regarding plant habit, 50.0 % (47 species) of the species were herbaceous, 21.3 % (20 species) arboreal, 19.1 % (18 species) shrubby and 9.6 % (nine species) climbing.About 60 % of the cited species had their leaves used while 17 % had the flowers or inflorescences used.These data are in agreement with other ethnobotanical studies of medicinal plants, which also found the flora to be mostly of herbaceous habit, a common occurrence for the Atlantic Forest biome.The commonality of the herbaceous habit may be related to the traditional practice of cultivation in backyards, since small plants are more easily cultivated in these smaller areas and backyard cultivation facilitates access to plants (Medeiros et al. 2004;Pinto et al. 2006;Giraldi & Hanazaki 2010).The use of leaves is predominant in Rio Grande do Sul since they are abundantly availability in the typical vegetation of southern Brazil, while the use of other plant parts is more characteristic of other regions, such as the Cerrado and Caatinga biomes, where the availability of leaves is more limited (Baldauf et al. 2009).The form of preparation cited for treating CNS dysfunctions for all species was tea (including decoction and infusion), although several speices were cited for other uses including as food and as a conndiment.Tea was also the predominant form of preparation cited in research on general medical use (Trojan-Rodrigues et al. 2012;Stolz et al. 2014).
Five species were cited in more than half of the studies surveyed: Cymbopogon citratus, with a 81.5 % citation frequency; Melissa officinalis, with 77.7 %; Aloysia citriodora, with 66.6 %; Matricaria chamomilla, with 62.9 %, and Passiflora edulis, with 51.8 %.Of these, only P. edulis is native to the study area.The use indicated for these five most cited species was as a sedative.Cymbopogon citratus, M. officinalis and M. chamomilla have been used as sedatives in other regions of Brazil, such as the states of Mato Grosso (Bieski et al. 2012), Minas Gerais (Costa & Mayworm 2011), Rio de Janeiro (Medeiros et al. 2004), and Rondônia (Santos et al. 2008).Indigenous peoples of Tocantins (Rodrigues & Carlini 2006) and quilombolas communities of Mato Grosso (Rodrigues & Carlini 2003) use C. citratus as a sedative.Indigenous communities living in cerrado savannahs and/or Pantanal wetlands use M. officinalis "to calm nervs" (Rodrigues & Carlini 2006).C. citratus, M. officinalis, M. chamomilla and P. edulis are used for the tratament of "nervios", anxiety and depression in Mexico (Gutiérrez et al. 2014), while M. officinalis and M. chamomilla are used for psychosomatic disorders in Peru (Bussmann et al. 2010).

Graphic Proof
drugs (Brasil 2011;2016).Citral is the main chemical constituent of the volatile oil of the plant, accounting for at least 60 % of its composition (Brasil 2010).Studies have suggested that the anxiolytic effect of the essential oil of this species is mediated by the GABAA receptor-benzodiazepine complex (Costa et al. 2011).
Melissa officinalis has been historically used as an anxiolytic (Wong et al. 1998).It is indicated in the Formulário de Fitoterápicos da Farmacopéia Brasileira as an antispasmodic, anxiolytic and mild sedative, with the warning that it should not be used in cases of hypothyroidism and used with caution with people with hypotension (Brasil 2011;2018b).According to the Brazilian Pharmacopoeia, M. officinalis must possess at least 4.0 % of total hydroxycinnamic derivatives, at least 2.0 % of rosmarinic acid and at least 0.6 % of volatile oil (Brasil 2010).Citral, geranial, neral and β-caryophyllene have been suggested as the main compounds responsible for actions of M. officinalis on the CNS (Tagashira & Ohtake 1998;Wake et al. 2000;Vale et al. 2002).
Matricaria chamomilla is among the most important medicinal plants native to southern and eastern Europe (Singh et al. 2011;Telesinski et al. 2013).Singh & Aishwarya (2017) recently published a review on the biological properties of this species.It is indicated in the Formulário de Fitoterápicos da Farmacopéia Brasileira as antispasmodic, anxiolytic and mild sedative.The formulary also includes information on occasional allergic reactions and possible occurrence of nervous excitement and insomnia in cases of overdose, and that its use should be avoided with people that are allergic or hypersensitive to chamomile or plants of the family Asteraceae (Brasil 2011).Camazulene, coumarin and trans-caryophyllene have been suggested as the compounds responsible for the effects of M. chamomilla on the CNS (Hajjaj et al. 2013;Keefe et al. 2016;Mao et al. 2016).
Passiflora edulis is indicated in the Formulário de Fitoterápicos da Farmacopéia Brasileira as an anxiolytic and mild sedative, with the warning that its use may cause somnolence and that it should not be used chronically or concomitantly with other sedatives and depressants of the nervous system (Brasil 2011;2018b).
Aloysia citriodora is traditionally used in France as a sedative and muscle relaxant for newborns (Makram et al. 2015).This species is native to South America and has been cultivated into Europe since 1784 (Pio Corrêa 1931).According to Ragone et al. (2010), the effect of this plant is similar to the effect of benzodiazepines.Citral is its main constituent (Ponce-Monter et al. 2010).
Scientific studies on the efficacy of the five most frequently mentioned species (Tab.2) are mostly preclinical; that is, they were carried out with non-human animal models (rodents, fish, crustaceans), or were cellular or biochemical tests.Among the activities demonstrated by these studies, we highlight antimicrobial, antioxidant and anti-inflammatory properties and depressant of central nervous system (mainly, sedative effect).Clinical studies (i.e., on humans) were found only for Matricaria chamomilla and Melissa officinalis.Several clinical trials have suggested a modest beneficial action by M. chamomilla in relieving symptoms of anxiety (Amsterdam et al. 2009;2012;Zick et al. 2011;Keefe et al. 2016;Mao et al. 2016).A randomized double-blind clinical study of M. officinalis found indications of positive action for agitation and cognitive impairment in Alzheimer's patients (Akhondzadeh et al. 2003).Two other studies found positive action for anxiety.One, an open prospective study, indicated efficacy for insomnia and symptoms associated with stress and anxiety (Cases et al. 2011), while the other, a double-blind randomized placebo study, demonstrated efficacy in relieving anxiety-related heart palpitations (Alijaniha et al. 2015).
Indications regarding safety were found for two of the five most cited plants.Studies were found that reported genotoxicity of Matricaria chamomilla (Vieira et al. 2009;Delarmelina et al. 2012) and hepatobiliary and pancreatic (in rodents and humans) toxicity of Passiflora edulis (Maluf et al. 1991).These findings are matter for some concern, and indicate a need for additional research including long-term studies to establish the safety of these plants.
The crude aqueous extract of the aerial parts presented an inhibitory effect on intestinal fluid accumulation and antidiarrheal action when applied in rabbits (in vivo), antispasmodic activity in isolated rabbit jejunum (in vitro) (Mehmood et al. 2015), anxiolytic and protective action in the gastric system against ethanol-induced ulceration (in vivo, in rats) (Al-Hashem 2010).The hydroalcoholic extract of aerial parts, tested in vitro in blood plasma and lung tissue and in vivo in rats, presented beneficial antioxidant action in lung lesions in cases of paraquat poisoning (Ranjbar et al. 2014); protected from oxidative damage caused by Paraquat poisoning (in vivo, in rats) (Tavakol et al. 2015); presented evidence of antidepressant effect in humans with anxiety associated with depression (Amsterdam et al. 2012).A standardized German camomile extract containing 1.2 % of apigenin presented an anxiolytic effect in humans with Generalized Anxiety Disorder (Amsterdam et al. 2009).The metabolic extract showed a neuroprotective activity against tetrafluoroaluminate (AlF ind) -induced oxidative stress (Ranpariya et al. 2011), and cerebral ischemia in rats (Chandrashekhar et al. 2010), antiallergic activity (in vitro) (Chandrashekhar et al. 2011).The essential oil of the flower showed antioxidant and antigenotoxic activity in spermatogonia of rats in vitro (Hernández-Ceruelos et al. 2010); (Aspergillus flavus, A. fumigatus, A. niger, Trichoderma harzianum and Fusarium oxysporum) (Jamalian et al. 2012).The essential oil of the aerial parts presented anxiolytic, sedative and muscle relaxant effects in mice and rats (Hajjaj et al. 2013).Infusion of the floral chapters showed anti-inflammatory activity against phlebitis (tested in humans) (Reis et al. 2011).Conjugated polysaccharide, isolated from dried flowers polyphenols have antioxidant properties blood (in vitro) (Kolodziejczyk-Czepas et al. 2015) and antiplatelet activity (in vivo, in mice) (Bijak et al. 2013).
Tincture (64 % alcohol) of Matricaria chamomilla (at a concentration of 20 mg / ml) caused an increase of micronuclei in the bone marrow cells of rodent (in vivo) the mutagenicity cases above-clinical dosage (400 ul / d) (Delarmelina et al. 2012).

Melissa officinalis
L.
The aqueous extract showed anti-inflammatory action in rats (in vivo) (Müzell 2006), and antioxidant properties (in rats, in vivo) (Martins et al. 2012).The lyophilized aqueous extract of the leaves reduced the frequency of palpitation episodes and anxiety in humans (Alijaniha et al. 2015).The ethanolic extract presented antidepressive property (in rats, in vivo) (Taiwo et al. 2012) and beneficial effect on agitation, cognitive function and mood healthy individuals and in Alzheimer's patients (Akhondzadeh et al. 2003;Kennedy et al. 2002;Wake et al. 2000).The hydroalcoholic extract of the leaves diminished the effects related to stress, such as anxiety, insomnia in humans (Cases et al. 2011), and presented antinociceptive effect and sedative action in rats (in vivo) (Soulimani et al. 1991).
The essential oil of leaves of M. officinalis showed anti-inflammatory activity in rats (in vivo) (Bounihi et al. 2013); antibacterial and antifungal activity in a multidrug resistant strain of Shigella sonei and in Trichophyton species, respectively (Mimica-Dukic et al. 2004); antioxidant and antitumor (in human and rat tumor cell lines) (Sousa et al. 2004); inhibitor of gastrointestinal spasms, in ileum isolated from rats (Sadraei et al. 2003); antiviral (herpes virus) (in vitro, in monkey kidney cells) (Schnitzler et al. 2008).Volatile essential oil compounds and plant extracts showed antiviral activity against herpes simplex virus type two (HSV-2) (in vitro) (Allahverdiyev et al. 2004;Wölbling & Leonhardt 1994).
No toxicity data were found.
The hydroalcoholic extract of the leaves presented an antioxidant effect in rats (in vitro, in vivo and ex vivo) (Rudnicki 2005), cicatrizant in rat bladders (in vitro) (Gonçalves Filho et al. 2006) and positively influenced the cicatrization of anastomoses in rats (Bezerra et al. 2006).It was found that the extracts present a significant effect on the central nervous system (in preclinical studies with rodents and clinicians) (Maluf et al. 1991).The methanolic extract of the leaves presented a diuretic effect in rats (in vivo) (Armas et al. 2009).The methanolic extract of passion fruit peels showed antioxidant activity (Zeraik et al. 2012).Peel flour has been shown to reduce total cholesterol and LDL cholesterol levels, but did not alter HDL cholesterol levels (in humans) (Ramos et al. 2007).The extract obtained from leaves by percolation showed to be depressant of the central nervous system in mice (Bruschi et al. 2002).Bark flour presented positive action on glycemic control in patients with Type 2 Diabetes Mellitus (Janebro et al. 2008).Hydroalcoholic and aqueous extracts of the leaves had anxiolytic effect in the high cross labyrinth in rats (Petry et al. 2001;De-Paris et al. 2002).
The aqueous extract of the leaves showed hepatobiliary and pancreatic toxicity in rodents and in humans (Maluf et al. 1991).
The essential oil extracted from the leaves presented microbicidal activity, microbicide on strains of Staphylococcus spp., Streptococcus mutans and Candida spp.(Almeida et al. 2013); anxiolytic and anticonvulsive effects in mice (Blanco et al. 2009;Costa et al. 2011); anti-inflammatory action in rats (in vivo); antifungal activity in Candida albicans strains (Silva et al. 2008), C. tropicalis and Aspergillus niger (in vitro) (Boukhatem et al. 2014), and antimalarial activity in mice (in vivo) (Tchoumbougnang et al. 2005).Polyphenols from C. citratus reduced the production of lipopolysaccharide-induced cytokines (LPS) in human and rat macrophages (in vitro) (Francisco et al. 2013).The fraction of tannins from the infusion of the leaves presented antioxidant activity (Costa et al. 2015), as well as the aqueous extract (in vivo, in rats) (Somparn et al. 2014).Aqueous extract prevented oxidative stress induced by H2O2 in male rats (Rahim et al. 2014).Leaf extract presented gastric protective activity on ethanol induced lesions in rats (Sagradas et al. 2015).
No toxicity data were found.
The aqueous extract of the leaves presented antispasmodic effect (tested in rat duodenum, in vitro) (Ragone et al. 2007); sedative and anxiolytic effects in rats and mice (in vivo and in vitro) (Ragone et al. 2010); antioxidant activity (Zamorano-Ponce et al. 2006;Portmann et al. 2012) and anti-inflammatory (in rats, in vitro and in vivo) (Ponce-Monter et al. 2010).The hexane extract from the leaves presented a spasmolytic and anti-inflammatory effect in fragments of the uterus of female rats (Ponce-Monter et al. 2010).The essential oil presented antioxidant and anesthetic activity in vivo in fish and shrimp larvae (Gressler et al. 2014;Parodi et al. 2014) and antibacterial against Staphylococcus aureus (Oliva et al. 2015), Escherichia coli, Klebsiella ozaenae, Enterobacter aerogenes, Proteus mirabilis, Staphylococcus aureus and Enterococcus sp.(Rojas et al. 2010).
No toxicity data were found.

Table 1 .
Medicinal plants used as antidepressants.tranquilizers or sedatives.mentioned in the ethnobotanical surveys carried out in Southern Brazil.Origin: E=exotic, N=native, Habit: C=climber, H=herb, S=shrub, T=tree.

Table 2 .
Chemical composition, biological activities and toxicity of medicinal species with CNS action cited in at least fourteen ethnobotanical surveys.

Table 2 .
Cont.therapeutic use: Matricaria chamomilla, Melissa officinalis, Cymbopogon citratus and Passiflora edulis.Scientific studies corroborate popular use as a sedative, but most studies are preclinical, with the few clinical studies (M.chamomilla and M. officinalis) being mainly exploratory and/or performed against placebo.Among the most cited species, M. chamomilla and P. edulis possess potential longterm toxicity.The present study finds M. officinalis to be the species with the best indications of clinical efficacy in the treatment of symptoms associated with anxiety, with an absence of toxicity data.Taken together, the results presented here evidence the need for further research on the plant species mentioned in ethnobotanical surveys carried out in the state of Rio Grande do Sul.