The Confrontation between Ethnopharmacology and Pharmacological Tests of Medicinal Plants Associated with Mental and Neurological Disorders

For neurological disorders, pharmacological tests have shown promising results in the reduction of side effects when using plants with known therapeutic effects in the treatment of some types of dementia. Therefore, the goals of this study are to gather data about the major medicinal plants used in the nervous system as described in ethnopharmacological surveys from South America and Brazil and to compare this data with the results from pharmacological tests on the active principles of those same plants found in the scientific literature. After collecting the data about each plant, their respective popular indication was compared with the results found through pharmacological tests. The discrepancy rate between the effects observed by ethnopharmacological and pharmacological methods in this study is greater than 50%. In conclusion, despite the importance of ethnopharmacological data, it is important to make comparisons with pharmacological tests for the same plants, since the pharmacological studies, although few, have shown a high rate of discrepancy in the results.


Introduction
The knowledge of medicinal plants for therapeutic purposes originated from indigenous tribal cultures [1][2][3][4] or ancient civilizations such as those once found in Iran, India, or China [1][2][3][5][6][7] and was passed from generation to generation mostly by means of oral tradition. Presently, knowledge is commonly limited to a village and rural areas or by families isolated from urban centers [8]. Most likely, original information of plants used for therapeutic purpose underwent modifications through time. This was due to their discovery by trial and error over many generations and the oral transmission of information rather than through writing.
A previous study associated culturally propagated therapeutic effects of different medicinal plants obtained by ethnopharmacological/ethnobotanical means with those found in laboratory tests, showing approximately 66% discrepancy in the results [9]. Trading and distribution mistakes [10], similarity of plant names for different species [11], presence of impurities during preparation from other plants, insects, and mushrooms [12], and unexpected reactions and interactions with the active compounds [13] are all examples of commonly encountered problems in the therapeutic use of medicinal plants.
It is not suggested that the medicinal use of plants should be banned, decreased, or hampered. However, there is a need for each procedure to be evaluated by government agencies, institutions, and specialists who understand the therapeutic use of biodiversity in societies with an increasing interest in alternative treatments [6,14,15] or in populations with limited or no access to other types of therapeutic resources. Medicinal plant-based therapy may offer benefits, 2 Evidence-Based Complementary and Alternative Medicine like decreased side effects [16][17][18], higher autonomy for individuals in caring for their own health [3], reduced or nonexistent costs, and easy access for social groups located in inaccessible areas or away from urban centers and for people in poor urban areas with limited or no access to a healthcare system [6,14,15,19,20]. Indeed, those groups rely on alternative therapeutic methods for their health care, especially those derived from local medicinal plants, which is a major issue in countries with higher income gaps.
Many ethnopharmacological surveys were performed in countries and regions representing the greatest biodiversity to identify plants used, with the aim of preserving the cultural heritage of the plant therapy [1-3, 5-7, 21, 22] and acquiring new active compounds for the pharmaceutical industry [8].
Brazil presents the largest biodiversity on the planet [23] and has a large amount of unexplored resources available for ethnopharmacological and herbal studies given that only 16% of Brazil's medicinal plants or just 8% of Brazilian national flora [24] has been evaluated for therapeutic potential [25]. This country represents around 47% of all territories of the South American continent.
Countries in South America present important data about medicinal plants, because of their specific locations in the Andean region, close/into the Amazon Forest [8] or the pampas. Indeed, the use of some medicinal plants was first found in the population in the Andes Ridge, in the pampas, Patagonia [10], or Brazilian's savanna (cerrado) [9]. Probably because of the large population or size, most of the studies in South America are found in Brazil, while ethnopharmacological studies are incipient in other countries in this continent [8,10].
However, quality or reliability of medicinal plant effects cannot be ensured if ethnobotanical studies do not provide laboratory verification of the effects when prescribing compounds derived from those medicinal plants. Healthcare professionals and patients should note that studies about the correspondence or discrepancy between ethnopharmacological knowledge and laboratory tests for the same plant are lacking [9] and must be done for each class of drug.
There is a growing evidence from in vitro, animal, and clinical studies reporting that medicinal plants might be beneficial for treating various mental and neurological disorders including Alzheimer disease, depression, anxiety, and insomnia [363][364][365][366]. For neurological disorders, in particular, pharmacological tests have shown promising results in the reduction of side effects when using plants with known therapeutic effects in the treatment of some types of dementia [18,22,[367][368][369][370][371][372]. Medicinal plants have been sought as an alternative therapy [18, [373][374][375] owing to the inefficacy of some industrial medications on certain diseases, such as degenerative ones. Examples are the use of Melissa officinalis, Salvia officinalis, Ginkgo biloba, and Huperzia serrata for treating the symptoms of Alzheimer disease [18, [373][374][375].
The problem is that, especially in developing and/or populated countries, people rely on medicinal plants as primary healthcare [376]. The situation is true for mental and neurological disorders. Patient complaints associated directly or indirectly with neurological or neuropsychiatric disorders, such as headache, insomnia, amnesia, anxiety, or depression, are very common [146,298,377,378], and the use of medicinal plants for these purposes is very frequent in populated countries such as Brazil, India, and China [1-3, 5-7, 22] but without support of adequate pharmacological tests.
Considering the errors in the use and sale of alternative medicines as a whole, we hypothesize that the same errors could happen with plants that act directly on the nervous system. Therefore, the goal of this study is to gather data about the major medicinal plants used in the neural system, as described in ethnopharmacological surveys from South America like in Brazil and compare this data with the results from pharmacological tests on the active principles of those same plants found in the scientific literature. Specifically, this study intends to present reliable data for the use of medicinal plants in primary healthcare and assisting conventional treatments of neurological disorders.

Materials and Methods
This study was done through literature review of ethnopharmacological surveys on the medicinal plants used by groups in South America (with emphasis on Brazil) found in academic databases (MEDLINE, LILACS, Scopus, SciELO, Google Academic, and Elsevier). The terms searched were ethnobotanical studies, medicinal plants, ethnopharmacology, neural system, South America, and Brazil. The search was restricted to the most recent and classical articles/books written in Portuguese, English, or Spanish. After collecting the data about each plant, their respective popular indication was compared with the results found through pharmacological tests.
For the first phase, 55 ethnobotanical survey articles were selected and then the most commonly used plants by the population for treating neural system disorders were identified. A table was prepared with data regarding family, scientific name, part of the plant utilized, preparation method, indications, and comparison with pharmacological tests.
In the second phase, 181 articles in which pharmacological tests had been performed with the chosen plants were selected. Unfortunately, scientific tests for the proposed indication or toxicity for all the plants could not be found.

Costus brasiliensis
Schum./Cana-de-macaco Not found Calmative [67] Not found Not found * It is the popular name that was quoted. * * It was not mentioned how to prepare. * * * It is the portion used or how to prepare that was quoted.  (Table 1). Table 1 shows a list of the medicinal plants analyzed in this study. The pharmacological effects including "anticonvulsant" and "anxiolytic" were considered to correspond to "calmative" in medicinal effects cited by population since both effects are attributed to the same action in the neural system, that is, inhibitory action. Furthermore, the pharmacological effect "anti-inflammatory" was also considered to correspond to "analgesic" in medicinal effects cited by population since anti-inflammatory agents are effective in treating pain diseases.
Despite that, the frequency of effects observed by most pharmacological tests does not coincide with those reported for the same plants when analyzed by ethnopharmacological means, (i.e., antioxidant, anti-inflammatory, antibacterial, and antimicrobial), demonstrating a high discrepancy between proven and popularly mentioned effects (Figure 6). It is important to remember that results of pharmacological tests were not found for all the plants mentioned in the ethnopharmacological studies, although those represent a small minority (16.9%) ( Figure 5).
The discrepancy rate between the effects observed by ethnopharmacological and pharmacological methods in this study is in agreement with a previous study [9] and, in both cases, a disagreement of over 50% was found. This data indicates the need for better control in the use of medicinal plants as a whole, especially in countries with a large proportion of economically backward population where such therapy is most common, such as China, India, and Brazil. However, there are possibilities that scientific studies are not enough or they are missing to corroborate the ethnopharmacological activities.
Tables like the one produced in this study can be used as a basis for the indication of medications for health professionals working in the neural area who choose to substitute alternative therapies with conventional methods. The tables can be used to maintain the patient's health and help make these treatments more accessible to people of all economic levels [385], bring medical practice closer to the care of cultural groups [386], and expand the idea of wholeness in healthcare.
Performing pharmacological tests in the medicinal plants mentioned in ethnopharmacological studies will help avoid prescription errors based only on popular knowledge, which, despite the importance, exhibits extensive methodological shortcomings from its propagation through generations (see Introduction). Although the pharmacological tests cannot solve problems related to contamination during preparation and/or mistakes when identifying plants by unskilled people, performing those tests would decrease the problems caused by adverse effects and wrong prescriptions.
Neurological disorders present complex etiologies often with aggravating social influences, requiring special care when making prescriptions; many critically ill patients are secluded from society and require medical monitoring and medications derived from modern pharmaceutical technology since indications for complex etiologies like dementias were not addressed in the ethnopharmacological articles analyzed in this study. In conclusion, despite the importance of ethnopharmacological data, it is important to make comparisons with pharmacological tests for the same plants, since the pharmacological studies, although few, have shown a high rate of discrepancy in the results, nevertheless, to be important to cite that the scientific studies could not be enough, or are missing, to corroborate the ethnopharmacological activities. Tables containing the plants

Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this paper.