Paullinia cupana: a multipurpose plant - a review

Leila Larisa Medeiros Marques Emilene Dias Fiuza Ferreira Mariana Nascimento de Paula Traudi Klein João Carlos Palazzo de Mello About the authors

Abstract

Seeds of guarana (Paullinia cupana Kunth, Sapindaceae) feature diverse pharmacological functions, for example, antimicrobial, antioxidant, anticarcinogenic, stimulating, and cognitive functions, as well as liver protection and weight loss. Many of these actions are probably due to the high content of methylxanthines and tannins in its seeds. In Brazil, the world's largest producer of guarana, the plant material is predominantly used in the soft drinks industry, although it is also used in the cosmetic and pharmaceutical industries. Although the Amazon region has the largest cropping area, the state of Bahia is the main guarana producer in Brazil (71%). This review focuses mainly on the possible pharmacological actions of guarana that have been investigated. Moreover, it discusses less-considered topics, such as the toxicology and quality control of seeds and extractives of guarana that will ultimately influence the safety of its use. In addition, it presents a detailed discussion of the methods used to prepare herbal drugs and their extracts, focusing on the importance of standardization and on the direct impact of preparatory factors, on the pharmacological properties of guarana extracts.

Keywords
Guarana; Pharmacological properties; Quality control; Standardization; Toxicology

Introduction

The guarana (Paullinia cupana Kunth, Sapindaceae) plant is associated with a remarkably wide range of pharmacological actions (Roncon et al., 2011Roncon, C.M., De Almeida, C.B., Klein, T., Mello, J.C.P., Audi, E.A., 2011. Anxiolytic effects of a semipurified constituent of guarana seeds on rats in the elevated T-maze test. Planta Med. 77, 236-241.; Bittencourt et al., 2013Bittencourt, L.S., Machado, D.C., Machado, M.M., Dos Santos, G.F.F., Algarve, T.D., Marinowic, D.R., Ribeiro, E.E., Soares, F.A.A., Barbisan, F., Athayde, M.L., Cruz, I.B.M., 2013. The protective effects of guarana extract (Paullinia cupana) on fibroblast NIH-3T3 cells exposed to sodium nitroprusside. Food Chem. Toxicol. 53, 119-125.; del Giglio et al., 2013del Giglio, A.B., Cubero, D.I.G., Lerner, T.G., Guariento, R.T., de Azevedo, R.G., Paiva, H., Goldman, C., Carelli, B., Cruz, F.M., Schindler, F., Pianowski, L., de Matos, L.L., del Giglio, A., 2013. Purified dry extract of Paullinia cupana (guarana) (PC-18) for chemotherapy-related fatigue in patients with solid tumors: an early discontinuation study. J. Diet. Suppl. 10, 325-334.; Portella et al., 2013Portella, R.L., Barcelos, R.P., Rosa, E.J.F., Ribeiros, E.E., Cruz, I.B.M., Suleiman, L., Soares, F.A.A., 2013. Guarana (Paullinia cupana Kunth) effects on LDL oxidation in elderly people: an in vitro and in vivo study. Lipids Health Dis. 12, 1-9.; Rangel et al., 2013Rangel, M.P., Mello, J.C.P., Audi, E.A., 2013. Evaluation of neurotransmitters involved in the anxiolytic and panicolytic effect of the aqueous fraction of Paullinia cupana (guarana) in elevated T maze. Rev. Bras. Farmacogn. 23, 358-365.; Bittencourt et al., 2014Bittencourt, L.S., Zeidán-Chuliá, F., Yatsu, F.K.J., Schnorr, C.E., Moresco, K.S., Kolling, E.A., Gelain, D.P., Bassani, V.L., Moreira, J.C.F., 2014. Guarana (Paullinia cupana Mart.) prevents β-amyloid aggregation, generation of advanced glycation-end products (AGEs), and acrolein-induced cytotoxicity on human neuronal-like cells. Phytother. Res. 28, 1615-1624.; Hertz et al., 2015Hertz, E., Cadoná, F.C., Machado, A.K., Azzolin, V., Holmrich, S., Assmann, C., Ledur, P., Ribeiro, E.E., Filho, O.C.d.S., Mânica-Cattani, M.F., Cruz, I.B.M.d., 2015. Effect of Paullinia cupana on MCF-7 breast cancer cell response to chemotherapeutic drugs. Mol. Clin. Oncol. 3, 37-43.; Machado et al., 2015Machado, A.K., Canodá, F.C., Azzolin, V.F., Dornelles, E.B., Barbisan, F., Ribeiro, E.E., Mânica-Cattani, M.F., Duarte, M.M.M.F., Saldanha, J.R.P., Cruz, I.B.M., 2015. Guarana (Paullinia cupana) improves the proliferation and oxidative metabolim of senescent adipocyte stem cells derived from human lipoaspirates. Food Res. Int. 67, 426-433.; Matsuura et al., 2015Matsuura, E., Godoy, J.S.R., Bonfim-Mendonça, P.S., Mello, J.C.P., Svidzinski, T.I.E., Gasparetto, A., Maciel, S.M., 2015. In vitro effect of Paullinia cupana (guarana) on hydrophobicity, biofilm formation, and adhesion of Candida albicans to polystyrene, composites, and buccal epithelial cells. Arch. Oral Biol. 60, 471-478.; Kober et al., 2016Kober, H., Tatsch, E., Torbitz, V.D., Cargnin, L.P., Sangoi, M.B., Bochi, G.V., da Silva, A.R.H., Barbisan, F., Ribeiro, E.E., da Cruz, I.B.M., Moresco, R.N., 2016. Genoprotective and hepatoprotective effects of guarana (Paullinia cupana Mart. var. sorbilis) on CCl4-induced liver damage in rats. Drug. Chem. Toxicol. 39, 48-52.). For hundreds of years, guarana has been grown and widely used by Brazilian Indians. Commonly, guarana seeds are used by simply dissolving the powder of the toasted and ground seed in water, either alone or in combination with other commercially available herbal drugs. Nowadays, it is commercially exploited, mainly by the soft drinks industry, although it is also highly valued by the cosmetic and pharmaceutical industries.

The pharmacological properties of guarana have been the main focus on two recent reviews (Hamerski et al., 2013Hamerski, L., Somner, G.V., Tamaio, N., 2013. Paullinia cupana Kunth (Sapindaceae): a review of its ethnopharmacology, phytochemistry and pharmacology. J. Med. Plants Res. 7, 2221-2229.; Schimpl et al., 2013Schimpl, F.C., da Silva, J.F., Goncalves, J.F., Mazzafera, P., 2013. Guarana: revisiting a highly caffeinated plant from the Amazon. J. Ethnopharmacol. 150, 14-31.). Although there has been a great deal of interest in studying caffeine from guarana including its benefits and harms (Nawrot et al., 2003Nawrot, P., Jordan, S., Eastwood, J., Rotstein, J., Hugenholtz, A., Feeley, M., 2003. Effects of caffeine on human health. Food Addit. Contam. A 20, 1-30.; Beck, 2005Beck, H.T., 2005. Caffeine, alcohol, and sweeteners. In: Prance, G.T. (Ed.), The Cultural History of Plants. Routledge, New York.; Nyska et al., 2005Nyska, A., Murphy, E., Foley, J.F., Collins, B.J., Petranka, J., Howden, R., Hanlon, P., Dunnick, J.K., 2005. Acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine. Toxicol. Sci. 83, 388-396.; Tfouni et al., 2007Tfouni, S.A.V., Camargo, M.C.R., Vitorino, S.H.P., Menegário, T.F., Toledo, M.C.F., 2007. Contribution of guarana powder (Paullinia cupana) as a source of caffeine in the diet. Rev. Nutrição 20, 63-68.), the most diverse pharmacological effects of guarana are associated with the tannins present in the plant seeds, which represent about 16% of the seed composition (Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.; Pelozo et al., 2008Pelozo, M.I.G., Cardoso, M.L.C., Mello, J.C.P., 2008. Spectrophotometric determination of tannins and caffeine in preparations from Paullinia cupana var. sorbilis. Braz. Arch. Biol. Technol. 51, 447-451.; Sousa et al., 2010Sousa, S.A., Alves, S.F., Paula, J.A.M.d., Fiuza, T.S., Paula, J.R., Bara, M.T.F., 2010. Determination of tannins and methylxanthines in powdered guarana (Paullinia cupana Kunth, Sapindaceae) by high performance liquid chromatography. Rev. Bras. Farmacogn. 20, 866-870.; Dalonso and Petkowicz, 2012Dalonso, N., Petkowicz, C.L.d.O., 2012. Guarana powder polysaccharides: characterisation and evaluation of the antioxidant activity of a pectic fraction. Food Chem. 134, 1804-1812.).

Ultimately, using the plant bioactives, either as pure compounds or as standardized extracts, requires extraction, pharmacological screening, isolation and characterization of the biological compound, as well as toxicological and clinical evaluation. Often, one or more of these primary steps is overlooked in most scientific papers. Furthermore, the varied preparatory methods used in the extraction and isolation, for instance, creates chemical diversity among the extracts or purified compounds, which affects their pharmacological properties (Marques et al., 2016Marques, L.L.M., Panizzon, G.P., Aguiar, B.A.A., Simionato, A.S., Cardozo-Filho, L., Andrade, G., Oliveira, A.G.d., Guedes, T.A., Mello, J.C.P., 2016. Guarana (Paullinia cupana) seeds: selective supercritical extraction of phenolic compounds. Food Chem. 212, 703-711.). Moreover, combining bioactives from various sources creates a variety of pharmacological effects that are still far from being exhausted.

The aim of this review is to present a state of the art assessment of guarana, particularly the chemical compounds that have been identified and characterized in its seeds. The main focus is to review the possible pharmacological actions of guarana, based on an exhaustive and intense appraisal of the relevant literature. In addition, it intends to introduce less-considered yet pivotal topics, such as toxicology and quality control of herbal drugs and extractives, as well as a broad discussion on the method of preparation of extracts and their standardization. In this context, we searched the Web of Science, Scopus, and PubMed databases, as well as the Brazilian scientific databases, such as Scielo.

History

The guarana plant has a well-established history that started before the conquest of America. It has been domesticated in interfluvial forests between the lower Tapajós River and the lower Madeira river in the Brazilian Amazon (Smith and Atroch, 2007Smith, N., Atroch, A.L., 2007. Guarana's journey from regional tonic to aphrodisiac and global energy drink. J. Evid. Based Complement. Altern. Med. 7, 279-282.). The Maués Indians in Brazil discovered and named the guarana fruit. They were the first consumers of the guarana beverage (Kuri, 2008Kuri, C.M.B., 2008. The guarana industry in Brazil. Int. Bus. Econ. Res. J. 7, 87-98.). The fruits of guarana are orange-red capsules that contain black seeds, partially covered by white arils (Fig. 1). The contrasting colors of the partially open fruit, creates the appearance of eyeballs, thus, giving credence to the legend (Fig. 1A) about the origin of the domestication of guarana. This myth, which is attributed to the Maués Indians, has it that a malevolent god attracted a beloved male child of the village into the jungle and killed him out of jealousy. The people of the village found the child dead, lying in the forest. A benevolent God consoles the village with a present in the form of guarana. He plucked out the left eye of the child and planted it in the forest, where it became the wild variety of guarana. The right eye was planted in the village, and it sprouted and produced fruits that resembled a child's eye (Beck, 2005Beck, H.T., 2005. Caffeine, alcohol, and sweeteners. In: Prance, G.T. (Ed.), The Cultural History of Plants. Routledge, New York.).

Fig. 1
Fruits and seeds of guarana. (A) Orange fruits with red capsules containing black seeds partially covered by white arils; (B) from bottom to top: newly-collected seeds partially covered by arils, dried and toasted powdered seeds; toasted, still undamaged seeds.

The first written description of guarana was made by a Jesuit missionary named Johannes Philippus Bettendorf (1625-1698), in 1669. As a missionary in the Amazon region, he observed that the Indians used to consume a drink made of guarana, which they reported as having diuretic properties and being effective against headaches, fevers, and cramps. In the mid-18th century, other reports described the use of guarana against diarrhea and its ability to mitigate the risks of heat stress (Henman, 1982Henman, A.R., 1982. Guarana (Paullinina cupana var. sorbilis): ecological and social perspectives on an economic plant of the central amazon basin. J. Ethnopharmacol. 6, 311-338.; Smith and Atroch, 2007Smith, N., Atroch, A.L., 2007. Guarana's journey from regional tonic to aphrodisiac and global energy drink. J. Evid. Based Complement. Altern. Med. 7, 279-282.). Ever since, many features of this plant have begun to be explored including an increasing amount of research on its chemical composition (Henman, 1982Henman, A.R., 1982. Guarana (Paullinina cupana var. sorbilis): ecological and social perspectives on an economic plant of the central amazon basin. J. Ethnopharmacol. 6, 311-338.). Due to the widespread use of guarana, mainly as a result of its stimulating effect on the central nervous system, it was officially described in the 1977 Brazilian Pharmacopoeia (Farmacopeia Brasileira, 1977Farmacopeia Brasileira, 1977. 3 ed. Atheneu, São Paulo.).

The first substance of guarana was isolated in 1826 and named guaranine, a tetramethylxanthine identical to caffeine. With further studies, researchers started to attribute the medicinal properties of guarana to several xanthines (caffeine, theophylline, and theobromine, for example) and the numerous tannins present in the plant (Henman, 1982Henman, A.R., 1982. Guarana (Paullinina cupana var. sorbilis): ecological and social perspectives on an economic plant of the central amazon basin. J. Ethnopharmacol. 6, 311-338.). The stimulating effects of guarana are apparently more lasting than the effects of coffee due to the tannins present in the guarana plant.

Cultivation and processing

Brazil is virtually the sole producer of guarana in the world. Guarana is originally from the Amazon, found primarily in the southeast region of the state of Amazonas, in the towns of Maués and Parintins (Machado, 1946Machado, O., 1946. Contribuição ao estudo das plantas medicinais do Brasil - o guarana (in Portuguese). Rodriguesia 9, 89-110.; Corrêa, 1984Corrêa, M.P., 1984. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. Ministério da Agricultura, Instituto Brasileiro de Desenvolvimento Florestal, Rio de Janeiro.) (Fig. 2). Guarana plants are abundant in the region of Maués, 250 km away from Manaus. They can also be found in small areas of the Venezuelan Amazon. In recent decades, the cultivation of guarana has been encouraged in other areas, particularly in the valleys of the rivers Purus and Tapajós (Amazonas), in the states of Pará, Acre, and Rondônia, in the cocoa-producing region of Bahia between the cities of Salvador and Ilhéus, in the Ribeira Valley in the state of São Paulo, and in the region of Alta Floresta, Mato Grosso (Henman, 1982Henman, A.R., 1982. Guarana (Paullinina cupana var. sorbilis): ecological and social perspectives on an economic plant of the central amazon basin. J. Ethnopharmacol. 6, 311-338.; Corrêa, 1984Corrêa, M.P., 1984. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. Ministério da Agricultura, Instituto Brasileiro de Desenvolvimento Florestal, Rio de Janeiro.; Duke, 1987Duke, J.A., 1987. Handbook of Medicinal Herbs, 2 ed. CRC Press LLC, Florida.; Suframa, 2003Suframa, 2003. Potencialidades estudo de viabilidade econômica: guarana. Superintendência da zona franca de Manaus - Suframa. Instituto superior de administração e economia ISAE/Fundação Getúlio Vargas (FGV), Manaus, Brazil, pp. 1–34.).

Fig. 2
The painted areas refer to the main Brazilian states envolved in guarana crop. The markings refer to the townships cities of Maués and Parintins, Amazonas state.

In 1974, the national guarana production, in Maués and other production areas of the state of Amazonas, was calculated at around 180-200 tons of dried seeds, while, in 1977, a study reported the production had increased to 300 tons of dried seeds (Nazaré and Figueiredo, 1982Nazaré, R.F.R., Figueiredo, F.J.C., 1982. Contribuição ao estudo do guarana. Embrapa Amazônia Oriental, Belém, p. 41.). In 2003, the production was estimated at approximately 4300 tons per year (Suframa, 2003Suframa, 2003. Potencialidades estudo de viabilidade econômica: guarana. Superintendência da zona franca de Manaus - Suframa. Instituto superior de administração e economia ISAE/Fundação Getúlio Vargas (FGV), Manaus, Brazil, pp. 1–34.). However, because of the significant economic exploitation, the production did not meet the demand, which posed risks of tampering.

Until the 1980s, the township of Maués was the undisputed leader in the production of guarana, representing 90% of the small farm production in Brazil. However, the expansion of the commercial use of the guarana seeds, in soft drinks and by pharmaceutical and cosmetic manufacturers, led thousands of farmers in southern Bahia, known as an area of cocoa cultivation, to grow the guarana plant (Table 1).

Table 1
Area, production, and yield in guarana crops in the year 2016.

Alta Floresta has an ideal hot and humid climate and soil properties for the cultivation of this fruit and is home to about 40 of the leading producers of guarana in Brazil. It is reported that in 2008, guarana plantations in the state of Mato Grosso, occupied approximately 89.6 ha, of which 46.8 ha were west of Alta Floresta town (Gouveia et al., 2012Gouveia, V.F., RossiI, A.P., Rossi, A.P., Rocha, V.d.F., Ribeiro, L.F.C., 2012. Profile of the producers of guarana (Paullinia cupana) of Alta Floresta-MT. Rev. Conexão UEPG 8, 300-312.).

According to data from the Brazilian Institute of Geography and Statistics (IBGE, 2017IBGE, 2017. Levantamento sistemático da produção agrícola. In: Coagro. Instituto Brasileiro d Geografia e Estatística-IBGE, Rio de Janeiro, pp. 1–113.), the plantations of guarana in Brazil occupied approximately 15,156 ha in 2016, with the state of Amazonas (8113 ha) and Bahia (6500 ha) the major contributors, together accounting for 96% of the cultivation area in Brazil, followed by 353 ha in Mato Grosso (Fig. 2). Although the state of Amazonas has the largest cultivated area, the largest production comes from Bahia (70%) because of its high yield (Table 1).

There has been increased interest in the guarana plant for its medicinal and stimulant properties by the food, pharmaceutical and cosmetic industries. Consequently, over the last decade, there has been a significant increase in the area of plantations. However, the average yield values, which consider the production by planted area, have remained constant (Table 2).

Table 2
Area, production and average yield of guarana in the Decade (2007-2016).

Guarana is widely used in the food industry in the form of syrups, extracts, and distillates, primarily as a flavoring agent and as a source of caffeine by soft drink manufacturers (Henman, 1982Henman, A.R., 1982. Guarana (Paullinina cupana var. sorbilis): ecological and social perspectives on an economic plant of the central amazon basin. J. Ethnopharmacol. 6, 311-338.; Duke, 1987Duke, J.A., 1987. Handbook of Medicinal Herbs, 2 ed. CRC Press LLC, Florida.). The greatest economic value of guarana is currently in the manufacture of beverages. The American Beverage Company (Ambev) alone uses 70% of the guarana seeds produced annually in Maués. The remaining production (30%) is destined for the phytochemical industry and exportation, mainly to Japan and the United States (Suframa, 2003Suframa, 2003. Potencialidades estudo de viabilidade econômica: guarana. Superintendência da zona franca de Manaus - Suframa. Instituto superior de administração e economia ISAE/Fundação Getúlio Vargas (FGV), Manaus, Brazil, pp. 1–34.). In 1972 the Law 5823, termed the Law of Juices, was enacted. This law established quantitative limits of guarana at 0.2-2 g l-1 soda and 1-10 g l-1 syrup (Homma, 2014Homma, A.K.O., 2014. Guaraná: passado, presente e futuro. In:Homma, A.K.O. (Ed.), Extrativismo vegetal na Amazônia: história, ecologia, economia e domesticação. Embrapa, Brasília, p. 472.). This led to a huge demand for the product because there was an increasing production of guarana soft drinks. The consistent increase in the demand for guarana has encouraged cultivation of guarana plants and agricultural techniques to improve production, rendering it are a promising market for farmers.

A limiting factor to production and expansion of guarana crops in Amazonas is anthracnose, a disease caused by the fungus Colletotrichum guaranicola Albuq. Several studies have assessed the genetic diversity of C. guaranicola (Duarte et al., 1995Duarte, M.L.R., Albuquerque, F.C., Corrêa, M.P.F., 1995. Variações morfológicas e fisiológicas em isolamentos de Colletotrichum guaranicola. Fitopatol. Bras. 20, 141-144.; Bentes and Matsuoka, 2002Bentes, J.L.S., Matsuoka, K., 2002. Histology of Colletotrichum guaranicola and Paullinia cupana var. sorbilis on resistant and susceptible clones. Fitopatol. Bras. 27, 71-77.; Bentes and Neto, 2011Bentes, J.L.S., Neto, P.Q.C., 2011. Variabilidade genética de Colletotrichum guaranicola usando marcadores AFLP. Acta Amaz. 41, 251-256.), providing useful information regarding disease management and crop improvement. Moreover, because of the presence of various types of lesions and the evolution of the disease in infected leaflets, a study was performed to clarify whether there were different population types of the pathogen. Consequently, eight types of pathogens were found in monosporic isolates in lesions formed in young leaflets of different guarana plants (Duarte et al., 1995Duarte, M.L.R., Albuquerque, F.C., Corrêa, M.P.F., 1995. Variações morfológicas e fisiológicas em isolamentos de Colletotrichum guaranicola. Fitopatol. Bras. 20, 141-144.). Genetic variability of twenty isolates obtained from infected plants in guarana crops was reported (2011).

Anthracnose can restructure endophytic bacterial communities by selecting certain strains in the phyllosphere of P. cupana (Bogas et al., 2015Bogas, A.C., Ferreira, A.J., Araujo, W.L., Astolfi, S., Kitajima, E.W., Lacava, P.T., Azevedo, J.L., 2015. Endophytic bacterial diversity in the phyllosphere of Amazon Paullinia cupana associated with asymptomatic and symptomatic anthracnose. SpringerPlus 4, 258.). The understanding of these interactions is important for the development of strategies for biocontrol of Colletotrichum. Silva et al. (2018)Silva, F.D., Liotti, R.G., Boleti, A.P.D., Reis, E.D., Passos, M.B.S., dos Santos, E.L., Sampaio, O.M., Januario, A.H., Branco, C.L.B., da Silva, G.F., de Mendonca, E.A.F., Soares, M.A., 2018. Diversity of cultivable fungal endophytes in Paullinia cupana (Mart.) Ducke and bioactivity of their secondary metabolites. PLoS ONE 13, http://dx.doi.org/10.1371/journal.pone.0195874.
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isolated and identified endophytic fungal communities from the roots and seeds of guarana genotypes susceptible and tolerant to anthracnose that grow in two sites of the Brazilian Amazonia forest. Another study (Silva et al., 2016Silva, M., Polonio, J.C., Quecine, M.C., de Almeida, T.T., Bogas, A.C., Pamphile, J.A., Pereira, J.O., Astolfi, S., Azevedo, J.L., 2016. Endophytic cultivable bacterial community obtained from the Paullinia cupana seed in Amazonas and Bahia regions and its antagonistic effects against Colletotrichum gloeosporioides. Microb. Pathog. 98, 16-22.) isolated endophytic bacteria from guarana seeds and tested the antagonistic activity of these bacteria against Colletotrichum gloeosporioides. The same authors suggested that these bacteria could be applied, in the future, to increase plant growth and disease resistance to anthracnose.

Additionally, varieties of guarana are being researched by the Brazilian Agricultural Research Corporation (Embrapa), to increase production and disease resistance. Varieties resistant to anthracnose (for example, cultivars BRS Marabitana and guarana BRS Saterê) were released in 2013. In the future, the production of guarana in the Amazon is expected to rise by up to 40%, without the need for increased forest deforestation. Also, a pulping machine has been developed for guarana fruits, eliminating the need for fermentation (Santos, 2014Santos, L.P., 2014. Sistema mecanizado de processamento pós-colheita de guaraná: nova tecnologia. In: Comunicado Técnico. Embrapa, Manaus, p. 12.).

An alternative to reduce the use of fertilizers is to provide plants with better soil nutrient absorption conditions. Arbuscular mycorrhizal fungi (AMF) fit in this context because they increase the root absorption area of the plants, allowing them to explore the soil more efficiently, thereby, rendering them less dependent on chemical fertilizers and, simultaneously, providing greater productive capacity from soil (Bona et al., 2017Bona, E., Cantamessa, S., Massa, N., Manassero, P., Marsano, F., Copetta, A., Lingua, G., D'Agostino, G., Gamalero, E., Berta, G., 2017. Arbuscular mycorrhizal fungi and plant growth-promoting pseudomonads improve yield, quality and nutritional value of tomato: a field study. Mycorrhiza 27, http://dx.doi.org/10.1007/s00572-016-0727-y.
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). Accordingly, the AMF are an important component of the microflora in natural ecosystems. A study performed by Oliveira and Oliveira (2005)Oliveira, A.N., Oliveira, L.A., 2005. Seasonal dynamics of arbuscular mycorrhizal fungi in plants of Theobroma grandiflorum Schum and Paullinia cupana Mart. of aN agroforestry system in Central Amazonia, Amazonas State, Brazil. Braz. J. Microbiol. 36, 262-270. reported the seasonal dynamics of AMF in plants of P. cupana. The maximum mycorrhizal colonization percentages and the highest numbers of spores were reached during February and May 2000 (rainy season). Rainfall, moisture content, and soil nutrient levels were significantly and positively correlated with colonization and with the number of spores. Soil moisture content was positively correlated with the number of spores.

The domestic industry and export demands for guarana, used for various purposes, along with factors, such as the development of new strains and modernization of machinery for the processing and knowledge of endophytic microorganisms, will gradually boost guarana cultivation.

Botanical characteristics

The official name currently accepted for guarana is P. cupana Kunth, Sapindaceae, according to The Plant List (2013)The Plant List, 2013. in: http://www.tropicos.org/Name/28600664 (Ed.), Paullinia cupana Kunth Published on the Internet; http://www.theplantlist.org/.
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Paullinia sorbilis Mart. is also accepted as a synonym (Funk et al., 2007Funk, V.A., Berry, P.E., Alexander, S.N., Hollowell, T.H., Kelloff, C.L., 2007. Checklist of the plants of the Guiana shield (Venezuela: Amazonas, Bolivar, Delta Amacuro; Guyana, Surinam, French Guiana). Contr. U.S. Natl. Herb. 55, 1-584.; Forzza, 2010Forzza, R.C., 2010. Lista de espécies Flora do Brasil. Jardim Botânico do Rio de Janeiro, Rio de Janeiro, Published on the Internet. http://floradobrasil.jbrj.gov.br/2010/ (accessed 16.06.18).
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). The scientific name comes from Christian Franz Paullini, a German botanist and physician who lived in the 18th century (1643-1712). He was the first to scientifically classify guarana, although the plant had already been cultivated for hundreds of years in the Brazilian Amazon (Kuri, 2008Kuri, C.M.B., 2008. The guarana industry in Brazil. Int. Bus. Econ. Res. J. 7, 87-98.).

The guarana plant is a lowland, tropical, woody, climbing shrub, which is adapted to a hot and humid climate (Lunguinho, 2007Lunguinho, L.G., 2007. Florescimento em guaranazeiro (Paullinia cupana var. sorbilis). Dissertação de Mestrado (Biotecnologia). Universidade Federal do Amazonas, Manaus, p. 86. http://200.129.163.131:8080/handle/tede/2244/ (accessed 19.08.18).
http://200.129.163.131:8080/handle/tede/...
). There are between 4 and 5 deep grooves in the main stem and the different branches. The branches are pilose at the end but glabrous at the base, measuring 4-8 mm in diameter. The skin is very dark and the woody body is simple. The leaves measure 40 cm in length and width and have partitions, in a distichous arrangement, pinnately compound, with 5 leaflets. The inflorescences are of two types including those whose branches develop in the axils of the leaves and those with branched peduncles, which develop in the tendrils (Corrêa, 1984Corrêa, M.P., 1984. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. Ministério da Agricultura, Instituto Brasileiro de Desenvolvimento Florestal, Rio de Janeiro.); the inflorescences may be longer than 30 cm (de Menezes-Júnior, 1942de Menezes-Júnior, J.B.F., 1942. Do exame microscópico do guarana em bromatologia. Rev. Inst. Adolfo Lutz 2, 45-68.). The flowers are partially single-sexed, zygomorphic and small, with an approximate length between 1.5 and 2 cm from the stem (Escobar et al., 1984Escobar, J.R., Correa, M.P.F., Aguilera, F.J.P., 1984. Estruturas florais, floração e técnicas para a polinização controlada do guaranazeiro. I. Simpósio Brasileiro do Guaraná – Anais. Embrapa-UEPAE, Manaus, p. 222.). The fruits are ellipsoidal or spherical, apiculate capsules that are red when ripe and measure 2-3 cm (Fig. 1). They have 1 or 2 egg-shaped seeds, of approximately 12 mm in length, with an abundant aril before maturity. The seed is unevenly convex on both sides, sometimes surmounted by a short, glabrous, glossy, brown-purple, or brown-black apical tip, and it features a wide hilum, which is surrounded by a fleshy, membranous and whitish aril. The embryo has no endosperm, has a short lower root-stem axis and thick, unequal, fleshy, firm, plano-convex cotyledons (de Menezes-Júnior, 1942de Menezes-Júnior, J.B.F., 1942. Do exame microscópico do guarana em bromatologia. Rev. Inst. Adolfo Lutz 2, 45-68.; Corrêa, 1984Corrêa, M.P., 1984. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. Ministério da Agricultura, Instituto Brasileiro de Desenvolvimento Florestal, Rio de Janeiro.).

Chemical aspects

Guarana is derived from the seeds of P. cupana, known for its stimulant properties. The seeds are the commercially useful part of the plant because of the large amounts of caffeine, theobromine, and theophylline, as well as the high concentration of tannins and other compounds, such as saponins, polysaccharides, proteins, fatty acids (Table 3) (Angelucci et al., 1978Angelucci, E., Tocchini, R.P., Lazarine, V.B., Prado, M.A.F., 1978. Caracterização química da semente de guarana (Paullinia cupana var. sorbilis Ducke). Bol. Inst. Tecnol. Alimentos 56, 183-192.; Henman, 1982Henman, A.R., 1982. Guarana (Paullinina cupana var. sorbilis): ecological and social perspectives on an economic plant of the central amazon basin. J. Ethnopharmacol. 6, 311-338.; Spoladore et al., 1987Spoladore, D.S., Boaventura, M.A.M., Sáes, L.A., 1987. Teor de cafeína em sementes matrizes do guaranazeiro. Bragantia 46, 425-429.; Baumann et al., 1995Baumann, T.W., Schulthess, B.H., Hänni, K., 1995. Guarana (Paullinia cupana) rewards seed dispersers without intoxicating them by caffeine. Phytochemistry 39, 1063-1070.; Nazaré, 1998Nazaré, R.F.R., 1998. Processamento de guarana em pó solúvel. Embrapa, Belém, PA, Brazil, p. 24.; Ushirobira et al., 2004Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Audi, E.A., Mello, J.C.P., 2004. Avaliação físico-química de sementes de guarana secas por diferentes métodos. Rev. Bras. Farmacogn. 14, 15-20.; Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.; Higgins et al., 2010Higgins, J.P., Tuttle, T.D., Higgins, C.L., 2010. Energy beverages: content and safety. Mayo Clin. Proc. 85, 1033-1041.; Schimpl et al., 2014Schimpl, F.C., Kiyota, E., Mayer, J.L., Goncalves, J.F., da Silva, J.F., Mazzafera, P., 2014. Molecular and biochemical characterization of caffeine synthase and purine alkaloid concentration in guarana fruit. Phytochemistry 105, 25-36.), and trace elements, such as manganese, rubidium, nickel and strontium (de Gois et al., 2016de Gois, J.S., Almeida, T.S., de Andrade, R.M., Toaldo, I.M., Bordignon-Luiz, M.T., Borges, D.L.G., 2016. Direct solid analysis for the determination of Mn, Ni, Rb and Sr in powdered stimulant plants using high-resolution continuum source atomic absorption spectrometry followed by chemometric classification based on elemental composition, polyphenol content and antioxidant activity. Microchem. J. 124, 283-289.). Although the concentration of caffeine can vary widely in the preparation of guarana, guarana provides about 50 mg caffeine per gram. The effects of ingestion of guarana are similar to those of caffeine. However, the duration of action may be considerably different due to possible interactions between the caffeine and saponins and tannins in guarana (Babu et al., 2008Babu, K.M., Church, R.J., Lewander, W., 2008. Energy drinks: the new eye-opener for adolescents. Clin. Ped. Emerg. Med. 9, 35-42.).

Table 3
Chemical composition of seeds of guarana (Paullinia cupana) and pharmacopoeial standards.

Table 3 shows the values chemical composition established by the Brazilian Pharmacopoeia (Anvisa, 2010Anvisa, 2010. Farmacopeia brasileira, vol. 2., 5 ed. Agência Nacional de Vigilância Sanitária, Brasília.) for guarana samples. The main chemical constituents of guarana (Box 1), caffeine, theobromine, and theophylline, are designated as methylxanthines. These compounds are often classified as purine alkaloids, as a result of their remarkable biological activity, restricted distribution, as well as the structural presence of heterocyclic nitrogen. However, because of their biogenetic origins (from purine bases rather than amino acids), in addition to their amphoteric nature, methylxanthines are more accurately classified as pseudo-alkaloids (Moraes et al., 2003Moraes, M.L.L., Micke, G.A., Fujyia, N.M., Tavares, M.F.M., 2003. Separação e análise de metilxantinas em extratos de guarana e erva mate por eletroforese capilar. Rev. Anal. 5, 44-50.).

Box 1
Identification of the main chemical constituents in samples of guarana.

Various methods to extract and analyze the methylxanthines in guarana seeds have been reported in the literature. A study conducted by Brenelli (2003)Brenelli, E.C.S., 2003. Caffeine extraction from stimulating beverages: a new approach for a classic organic chemistry experiment. Quim. Nova 26, 136-138. found less than 1.4% caffeine was extracted from samples of guarana powder using the Soxhlet extraction method. Other studies have found 4.8% (Saldaña et al., 2002Saldaña, M.D.A., Zetzl, C., Mohamed, R.S., Brunner, G., 2002. Extraction of methylxanthines from guaraná seeds, mate leaves, and cocoa beans using supercritical carbon dioxide and ethanol. J. Agric. Food Chem. 50, 4820-4826.) and 4.1% (Mehr et al., 1996Mehr, C.B., Biswal, R.N., Collins, J.L., 1996. Supercritical carbon dioxide extraction of caffeine from guarana. J. Supercrit. Fluids 9, 185-191.) caffeine in guarana seeds, by applying supercritical fluid extraction. Several procedures have also been described in the literature for the identification and quantification of these components (methylxanthines and total tannins) in guarana. The most common techniques used are spectrophotometry (Andrade et al., 1999Andrade, L., Schenkel, E.P., Bergold, A.M., 1999. Estudo da metodologia de análise de cafeína em sementes de guarana (Paullinia cupana). Rev. Bras. Farm. 80, 7-9.; Ushirobira et al., 2004Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Audi, E.A., Mello, J.C.P., 2004. Avaliação físico-química de sementes de guarana secas por diferentes métodos. Rev. Bras. Farmacogn. 14, 15-20.; Pelozo et al., 2008Pelozo, M.I.G., Cardoso, M.L.C., Mello, J.C.P., 2008. Spectrophotometric determination of tannins and caffeine in preparations from Paullinia cupana var. sorbilis. Braz. Arch. Biol. Technol. 51, 447-451.; Sousa et al., 2011Sousa, S.A., Pascoa, H., Conceição, E.C., Alves, S.F., Diniz, D.G.A., Paula, J.R., Bara, M.T.F., 2011. Dissolution test of herbal medicines containing Paullinia cupana: validation of methods for quantifcation and assessment of dissolution. Braz. J. Pharm. Sci. 47, 269-277.; Ribeiro and Coelho, 2012Ribeiro, B.D., Coelho, M.A.Z., 2012. Production of caffeine-rich guarana extracts using. Braz. J. Food Technol. 15, 261-270.; Roggia et al., 2016Roggia, I., Ziegler, S., Cruz, I.B.M., Ourique, A.F., Gomes, P., 2016. A derivative UV spectrophotometric method for the determination of methylxanthines and tannins in guarana bulk (Paullinia cupana) Int. J. Pharm. Sci. Res. 7, 2334-2342.), Raman spectroscopy (Edwards et al., 2005Edwards, H.G.M., Farwell, D.W., Oliveira, L.F.C., Alia, J.-M., Hyaric, M.L., Ameida, M.V., 2005. FT-Raman spectroscopic studies of guarana and some extracts. Anal. Chim. Acta 532, 177-186.), capillary electrophoresis (CZE) (Sombra et al., 2005Sombra, L.L., Gómez, M.R., Olsina, R., Luis, D., Martínez, L.D., Silva, M.F., 2005. Comparative study between capillary electrophoresis and high performance liquid chromatography in ‘guarana' based phytopharmaceuticals. J. Pharm. Biomed. Anal. 36, 989-994.; Kofink et al., 2007Kofink, M., Papagiannopoulos, M., Galensa, R., 2007. Enantioseparation of catechin and epicatechin in plant food by chiral capillary electrophoresis. Eur. Food Res. Technol. 225, 569-577.), high-performance liquid chromatography (HPLC) (Marx and Maia, 1990Marx, F., Maia, J.G., 1990. Analysis of guarana (Paullinia cupana var, sorbilis). III. Identification and determination of guaraná beverages by HPLC analysis of caffeine anda theophylline. Quim. Nova 13, 285-286.; Ushirobira et al., 2004Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Audi, E.A., Mello, J.C.P., 2004. Avaliação físico-química de sementes de guarana secas por diferentes métodos. Rev. Bras. Farmacogn. 14, 15-20.; Klein et al., 2012Klein, T., Longuini, R., Mello, J.C.P., 2012. Development of an analytical method using reversed-phase HPLC-PDA for a semipurified extract of Paullinia cupana var. sorbilis (guarana). Talanta 88, 502-506.), and ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry UPLC-MS (da Silva et al., 2017da Silva, G.S., Canuto, K.M., Ribeiro, P.R.V., de Brito, E.S., Nascimento, M.M., Zocolo, G.J., Coutinho, J.P., de Jesus, R.M., 2017. Chemical profiling of guarana seeds (Paullinia cupana) from different geographical origins using UPLC-QTOF-MS combined with chemometrics. Food Res. Int. 102, 700-709.).

As above-mentioned, caffeine, a 1,3,7-trimethylxanthine, is found in large quantities in guarana seeds. The "Instituto Agronômico de São Paulo" (Agronomical Institute of São Paulo), in Brazil, conducted a study to characterize the caffeine content in the tegument, kernel, and seeds of forty mother plants of guarana. They found mean caffeine levels of 2.33% in the kernel, 1.09% in the tegument, and 2.15% in the integral seed (Spoladore et al., 1987Spoladore, D.S., Boaventura, M.A.M., Sáes, L.A., 1987. Teor de cafeína em sementes matrizes do guaranazeiro. Bragantia 46, 425-429.). The composition of various commercial samples of guarana seeds has been analyzed by gas chromatography (GC). A caffeine content ranging from 2.41 to 4.07% was documented (Pagliarussi et al., 2002Pagliarussi, R.S., Freitas, L.A.P., Bastos, J.K., 2002. A quantitative method for the analysis of xanthine alkaloids in Paullinia cupana (guarana) by capillary column gas chromatography. J. Sep. Sci. 25, 1-6.), which was below the minimum required concentration of caffeine (5%) by the Brazilian Pharmacopoeia (Anvisa, 2010Anvisa, 2010. Farmacopeia brasileira, vol. 2., 5 ed. Agência Nacional de Vigilância Sanitária, Brasília.). Conversely, studies using spectrophotometric methods reported 4.88-6.20% methylxanthines and 3.0-5.5% total tannins (Ushirobira et al., 2004Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Audi, E.A., Mello, J.C.P., 2004. Avaliação físico-química de sementes de guarana secas por diferentes métodos. Rev. Bras. Farmacogn. 14, 15-20.; Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.; Sousa et al., 2011Sousa, S.A., Pascoa, H., Conceição, E.C., Alves, S.F., Diniz, D.G.A., Paula, J.R., Bara, M.T.F., 2011. Dissolution test of herbal medicines containing Paullinia cupana: validation of methods for quantifcation and assessment of dissolution. Braz. J. Pharm. Sci. 47, 269-277.). This difference is probably due to a harvest performed without standardized procedures, at various times, a collection of immature fruits, and, mainly, different drying procedures. For example, different levels of methylxanthines and tannins associated with different methods of seed drying were shown (Ushirobira et al., 2004Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Audi, E.A., Mello, J.C.P., 2004. Avaliação físico-química de sementes de guarana secas por diferentes métodos. Rev. Bras. Farmacogn. 14, 15-20.).

Methylxanthines and catechins were identified in various preparations containing guarana including dried seeds, powders, tablets and capsules (Carlson and Thompson, 1998Carlson, M., Thompson, R.D., 1998. Liquid chromatographic determination of methylxanthines and catechins in herbal preparations containing guarana. J. AOAC Int. 81, 691-701.). The content of purine alkaloids in three samples of guarana and 39 commercial products was investigated (Meurer-Grimes et al., 1998Meurer-Grimes, B., Berkov, A., Beck, H., 1998. Theobromine, theophylline, and caffeine in 42 samples and products of Guarana (Paullinia cupana, Sapindaceae). Econ. Bot. 52, 293-301.). These authors found that the majority of the samples of guarana showed caffeine (2.95-5.12%) as the main alkaloid, with traces of theobromine and theophylline. Another study, with the objective of determining the caffeine levels in various brands of commercially available guarana powder, reported a wide variation in the levels of caffeine, ranging from 0.95 to 3.67% (Tfouni et al., 2007Tfouni, S.A.V., Camargo, M.C.R., Vitorino, S.H.P., Menegário, T.F., Toledo, M.C.F., 2007. Contribution of guarana powder (Paullinia cupana) as a source of caffeine in the diet. Rev. Nutrição 20, 63-68.). Sousa et al. (2010)Sousa, S.A., Alves, S.F., Paula, J.A.M.d., Fiuza, T.S., Paula, J.R., Bara, M.T.F., 2010. Determination of tannins and methylxanthines in powdered guarana (Paullinia cupana Kunth, Sapindaceae) by high performance liquid chromatography. Rev. Bras. Farmacogn. 20, 866-870. determined 3.95% caffeine and 0.87% tannins in guarana seeds. This variability among literature studies is possibly due to differences in the origin of the raw material, as well as genetic and environmental aspects, and the drying process that the raw materials have undergone.

The guarana derivatives by CZE and HPLC analysis were compared (Sombra et al., 2005Sombra, L.L., Gómez, M.R., Olsina, R., Luis, D., Martínez, L.D., Silva, M.F., 2005. Comparative study between capillary electrophoresis and high performance liquid chromatography in ‘guarana' based phytopharmaceuticals. J. Pharm. Biomed. Anal. 36, 989-994.). The caffeine results were similar to those of previous studies, ranging from 1.3 to 3.3%. Chiral CZE has been used to separate the enantiomers, catechin and ent-catechin, and epicatechin and ent-epicatechin, in guarana samples (Kofink et al., 2007Kofink, M., Papagiannopoulos, M., Galensa, R., 2007. Enantioseparation of catechin and epicatechin in plant food by chiral capillary electrophoresis. Eur. Food Res. Technol. 225, 569-577.).

A study on the composition of the fraction of tannins present in samples of guarana seeds showed that the total tannin content was considerably high, at around 12-14.1% of the dry matter, consisting mainly of condensed tannins, such as proanthocyanidins (10.7%), catechin (5.98%) and epicatechin (3.78%) (Marx, 1990Marx, F., 1990. Analysis of guarana seeds. II. Studies on the composition of the tannin fraction Z. Lebensm. Unters. Forsch. 190, 429-431.). In addition to the studies cited above, which have quantified the constituents in the herbal drugs, others have analyzed guarana seed extracts. A chemical evaluation of the semipurified extract of guarana seeds showed the presence of caffeine, catechin, epicatechin, and procyanidins B2, B3, and B4 (Ushirobira et al., 2007Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Nakamura, C.V., Dias Filho, B.P., Mello, J.C.P., 2007. Chemical and microbiological study of extract from seeds of guarana (Paullinia cupana var. sorbilis). Acta Farm. Bonaer. 26, 5-9.), as well as ent-epicatechin, and procyanidins A2 and C1 (Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.), by means of nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (Box 1).

Some of the constituents of the previous study (Ushirobira et al., 2007Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Nakamura, C.V., Dias Filho, B.P., Mello, J.C.P., 2007. Chemical and microbiological study of extract from seeds of guarana (Paullinia cupana var. sorbilis). Acta Farm. Bonaer. 26, 5-9.) were identified and quantified (Klein et al., 2012Klein, T., Longuini, R., Mello, J.C.P., 2012. Development of an analytical method using reversed-phase HPLC-PDA for a semipurified extract of Paullinia cupana var. sorbilis (guarana). Talanta 88, 502-506.). These authors reported that the semipurified guarana extract (mg/EPA) contained condensed tannins, such as 180.75 µg catechin, 278.875 µg epicatechin, and 300.875 µg caffeine. The method of micellar electrokinetic chromatography has been recently developed for separation and validation of EPA. It has proved to be efficient for the chiral separation of catechin, epicatechin, procyanidins B1, B2, and B4, as well as caffeine (Mello and Ito, 2012Mello, J.C.P., Ito, L.A., 2012. Aplicação da eletroforese capilar na análise de produtos naturais. In: Souza, G.H.B., Mello, J.C.P., Lopes, N.P. (Eds.), Revisões em Processos e Técnicas Avançadas de Isolamento e Determinação Estrutural Ativos de Plantas Medicinais. UFOP, Ouro Preto, pp. 209–242.).

Other studies, using both aqueous extracts (Barbosa and Mello, 2004Barbosa, G.D.A., Mello, J.C.P., 2004. Clinical evaluation of the guarana extract on the dental plaque control. Rev. Paul. Odontol. 26, 28-30.; Campos et al., 2011Campos, M.P.d.O., Riechelmann, R., Casa, L.B.A., Hassan, B.J., Casa, F.B.A., Giglio, A.D., 2011. Guarana (Paullinia cupana) improves fatigue in breast cancer patients undergoing systemic chemotherapy. J. Altern. Complement. Med. 17, 505-512.) and hydroalcoholic extracts (Lima et al., 2005Lima, W.P., Carnevali, J.L.C., Eder, R., Rosa, L.F.B.P.C., Bacchi, E.M., Seelaender, M.C.L., 2005. Lipid metabolism in trained rats: effect of guarana (Paullinia cupana Mart.) supplementation. Clin. Nutr. 24, 1019-1028.; Bittencourt et al., 2013Bittencourt, L.S., Machado, D.C., Machado, M.M., Dos Santos, G.F.F., Algarve, T.D., Marinowic, D.R., Ribeiro, E.E., Soares, F.A.A., Barbisan, F., Athayde, M.L., Cruz, I.B.M., 2013. The protective effects of guarana extract (Paullinia cupana) on fibroblast NIH-3T3 cells exposed to sodium nitroprusside. Food Chem. Toxicol. 53, 119-125.; Portella et al., 2013Portella, R.L., Barcelos, R.P., Rosa, E.J.F., Ribeiros, E.E., Cruz, I.B.M., Suleiman, L., Soares, F.A.A., 2013. Guarana (Paullinia cupana Kunth) effects on LDL oxidation in elderly people: an in vitro and in vivo study. Lipids Health Dis. 12, 1-9.) revealed quantities of constituents similar. The caffeine ranged from 1.2 to 7.97% and the tannins from 1.5 to 12%. These differences are probably due to genetic and environmental factors, as well as the extraction conditions.

Guarana seeds also contain acylglycerol and cyanolipids, a class of lipids found in some families, for example, Sapindaceae and Boraginaceae. The chemical composition of the total oil extracted from guarana seeds has indicated the presence of cyanolipids (3%) and acylglycerols (28%). NMR analysis indicated the presence of type I cyanolipids, cis-vaccenic acid (30.4%) and cis-11-eicosenoic acid (38.7%), as the main fatty acids. Paullinic acid (7.0%) was also an abundant component and oleic acid (37.4%) was the predominant fatty acid in the acyl chain of the acylglycerols (Avato et al., 2003Avato, P., Pesante, M.A., Fanizzi, F.P., Santos, C.A.M., 2003. Seed oil composition of Paullinia cupana var. sorbilis (Mart.) Ducke. Lipids 38, 773-780.). The presence of high molecular weight polysaccharides in samples of guarana was investigated (Dalonso and Petkowicz, 2012Dalonso, N., Petkowicz, C.L.d.O., 2012. Guarana powder polysaccharides: characterisation and evaluation of the antioxidant activity of a pectic fraction. Food Chem. 134, 1804-1812.). Pectin and a group of polysaccharides called hemicelluloses, such as xylans were identified in these samples.

Guarana methylxanthines have been extensively studied over the years. However, for many other classes of compounds, with possibly interesting pharmacological effects, investigations have been scarce. Examples include the saponins and the fatty acid types. Also, although tannins have been isolated from guarana, there is still much to be explored about this class of substances.

Pharmacological properties

Certain plant and herbal products, sold as food supplements, are popular medicines that are often perceived as safe, namely, non-toxic. This is not necessarily true, particularly if taken with prescription drugs, over-the-counter medicines or used in combination with other herbs. Moreover, they may have adverse side effects, such as stimulation and hallucinogenic properties (Carlini, 2003Carlini, E.A., 2003. Plants and the central nervous system. Pharmacol. Biochem. Behav. 75, 501-512.). Nevertheless, such products are readily available and have widespread use. A wide variety of dietary supplements for weight loss are marketed with claims of efficacy (Andersen and Fogh, 2001Andersen, T., Fogh, J., 2001. Weight loss and delayed gastric emptying following a South American herbal preparation in overweight patients. J. Hum. Nutr. Dietet. 14, 243-250.; Armstrong et al., 2001Armstrong, W.F., Johnson, P., Duhme, S., 2001. The effect of commercial thermogenic weight loss supplement on body composition and energy expenditure in obese adults. J. Exerc. Physiol. Online 4, 28-35.; Boozer et al., 2001Boozer, C.N., Nasser, J.A., Heymsfield, S.B., Wang, V., Chen, G., Solomon, J.L., 2001. An herbal supplement containing Ma Huang-guarana for weight loss: a randomized, double-blind trial. Int. J. Obes. 25, 316-324.; Opala et al., 2006Opala, T., Rzymski, P., Pischel, I., Wilczak, M., Wozniak, J., 2006. Efficacy of 12 weeks supplementation of a botanical extract-based weight loss formula on body weight, body composition and blood chemistry in healthy, overweight subjects-a randomised double-blind placebo-controlled clinical trial. Eur. J. Med. Res. 11, 343-350.; Onakpoya and Ernst, 2012Onakpoya, I., Ernst, E., 2012. Safety of guarana-containing weight loss supplements: a mini-review. J. Naturol. Complemen. Ther. 1, 45-50.). The lack of data on the toxicity and/or efficacy of many ingredients found in these products, even the predominant ingredients, is a cause for concern (Baghkhani and Jafari, 2002Baghkhani, L., Jafari, M., 2002. Cardiovascular adverse reactions associated with guarana: is there a causal effect?. J. Herb. Pharmacother. 2, 57-61.; Moaddeb et al., 2011Moaddeb, J., Tofade, T.S., Bevins, M.B., 2011. Hypertensive urgency associated with Xenadrine EFX use. J. Pharm. Pract. 24, 400-403.; Lude et al., 2016Lude, S., Vecchio, S., Sinno-Tellier, S., Dopter, A., Mustonen, H., Vucinic, S., Jonsson, B., Muller, D., Fruchtengarten, L.V., Hruby, K., Nascimento, E.D., Di Lorenzo, C., Restani, P., Kupferschmidt, H., Ceschi, A., 2016. Adverse effects of plant food supplements and plants consumed as food: results from the poisons centres-based plantLIBRA study. Phytother. Res. 30, 988-996.).

Guarana powder is a product easily available both in natural product stores and over the internet. It is either marketed alone or in combination with other herbal drugs, creating the likelihood of additive or synergistic effects (Spinella, 2001Spinella, M., 2001. Herbal medicines and epilepsy: the potential for benefit and adverse effects. Epilepsy Behav. 2, 524-532.). It is also included in a variety of energy drinks. The latter are easily found in gyms and supermarkets but they contain stimulants and/or additives. Guarana has also gained popularity because it is regarded as a "functional food". Guarana seeds, as above-mentioned, contain large amounts of caffeine (40-80 mg caffeine per gram guarana extract), as well as minor amounts of the related compounds, theobromine and theophylline (Henman, 1982Henman, A.R., 1982. Guarana (Paullinina cupana var. sorbilis): ecological and social perspectives on an economic plant of the central amazon basin. J. Ethnopharmacol. 6, 311-338.), which are stimulating substances (Mottram and Chester, 2015Mottram, D.R., Chester, N., 2015. Drugs in Sport, 6 ed. Taylor & Francis, New York, pp. 351.). The drink with the highest natural content of caffeine in the world is made from toasted guarana seeds, possessing at least 5% methylxanthines, expressed as caffeine (Prance and Nesbitt, 2005Prance, G.T., Nesbitt, M., 2005. The Cultural History of Plants. Routledge, New York; London.; Anvisa, 2010Anvisa, 2010. Farmacopeia brasileira, vol. 2., 5 ed. Agência Nacional de Vigilância Sanitária, Brasília.). Long-term intake of the various components of these energy drinks can result in significant changes in the cardiovascular system (Higgins et al., 2010Higgins, J.P., Tuttle, T.D., Higgins, C.L., 2010. Energy beverages: content and safety. Mayo Clin. Proc. 85, 1033-1041.), and even convulsions (Iyadurai and Chung, 2007Iyadurai, S.J., Chung, S.S., 2007. New-onset seizures in adults: possible association with consumption of popular energy drinks. Epilepsy Behav. 10, 504-508.). When guarana is added to energy drinks, it increases the amount of metabolized caffeine (McGuire, 2014McGuire, S., 2014. Institute of Medicine. 2014. Caffeine in food and dietary supplements: examining safety-workshop summary. Washington, DC: The National Academies Press, 2014. Adv. Nutr. 5, 585-586.). A series of adverse events are associated with the consumption of guarana including irritability, heart palpitations, anxiety, disorders of the central nervous system and myoglobinuria (Galduróz and Carlini, 1994Galduróz, J.C.F., Carlini, E.A., 1994. Acute effects of the Paullinia cupana, "guarana" on the cognition of normal volunteers. São Paulo Med. J. 112, 607-611.; Donadio et al., 2000Donadio, V., Bonsi, P., Zele, I., Monari, L., Liguori, R., Vetrugno, R., Albani, F., Montagna, P., 2000. Myoglobinuria after ingestion of extracts of guarana, Ginkgo biloba and kava. Neurol. Sci. 21, 124.; Haller et al., 2005Haller, C.A., Jacob, P., Benowitz, N.L., 2005. Short-term metabolic and hemodynamic effects of ephedra and guarana combinations. Clin. Pharmacol. Ther. 77, 560-571.; Pittler et al., 2005Pittler, M.H., Schimidt, K., Ernst, E., 2005. Adverse events of herbal food supplements for body weight reduction: systematic review. Obes. Rev. 6, 93-111.; Sharpe et al., 2006Sharpe, P.A., Granner, M.L., Conway, J.M., 2006. Availability of weight-loss supplements: results of an audit of retail outlets in a southeastern city. J. Am. Diet. Assoc. 106, 2045-2051.; Richardson et al., 2007Richardson, W.H., Slone, C.M., Michels, J.E., 2007. Herbal drugs of abuse: an emerging problem. Emerg. Med. Clin. North Am. 25, 435-457.). Guarana can also exacerbate epileptic seizures, lowering the seizure threshold or increasing the duration of seizures (Spinella, 2001Spinella, M., 2001. Herbal medicines and epilepsy: the potential for benefit and adverse effects. Epilepsy Behav. 2, 524-532.). Despite these reports, when taken alone, guarana has few adverse effects and the majority of them are similar to those observed after the consumption of products containing a high caffeine content (Ravi Subbiah, 2005Ravi Subbiah, M.T., 2005. Guarana consumption: a review of health benefits and risks. Alternat. Complement. Ther. 11, 212-213.). The daily dose of caffeine recognized as safe for adults is 400 mg (Nawrot et al., 2003Nawrot, P., Jordan, S., Eastwood, J., Rotstein, J., Hugenholtz, A., Feeley, M., 2003. Effects of caffeine on human health. Food Addit. Contam. A 20, 1-30.).

Aphrodisiac effects in rabbits were reported after administration of a combination of commercially available plant extracts containing guarana (Antunes et al., 2001Antunes, E., Gordo, W.M., de Oliveira, J.F., Teixeira, C.E., Hyslop, S., De Nucci, G., 2001. The relaxation of isolated rabbit corpus cavernosum by the herbal medicine Catuama and its constituents. Phytother. Res. 15, 416-421.). In another study (de Aquino et al., 2016de Aquino, J.C., Souza, C.F.C., Santos, J.R.D., Joachim-Bravo, I.S., 2016. Adding guarana powder to medfly diets: an alternative for improving the sterile insect technique. Sci. Agric. 73, 294-298.), male Mediterranean fruit flies were fed diets containing guarana powder (3%). These flies are pests of global importance for horticulture that can be controlled by the sterile insect technique (SIT), which depends on the sexual performance of lab-reared males when they are released into the field. The experiments indicated that the males fed diets enriched with guarana showed greater success in mating, representing a new and viable option to increase the efficiency of SIT (de Aquino et al., 2016de Aquino, J.C., Souza, C.F.C., Santos, J.R.D., Joachim-Bravo, I.S., 2016. Adding guarana powder to medfly diets: an alternative for improving the sterile insect technique. Sci. Agric. 73, 294-298.).

Guarana was placed alongside the plants with psychoanaleptic activity (stimulants), with emphasis on anorexigenic or weight reduction properties. Although the consumption of guarana can induce changes in lipid metabolism, these effects have been associated with the methylxanthine content of the extract (Lima et al., 2005Lima, W.P., Carnevali, J.L.C., Eder, R., Rosa, L.F.B.P.C., Bacchi, E.M., Seelaender, M.C.L., 2005. Lipid metabolism in trained rats: effect of guarana (Paullinia cupana Mart.) supplementation. Clin. Nutr. 24, 1019-1028.). Guaraná showed anti-adipogenic potential due to its ability to modulate miRNAs and genes related to this process (Lima et al., 2017Lima, N.D., Numata, E.D., Mesquita, L.M.D., Dias, P.H., Vilegas, W., Gambero, A., Ribeiro, M.L., 2017. Modulatory effects of guarana (Paullinia cupana) on adipogenesis. Nutrients 9, http://dx.doi.org/10.3390/nu9060635.
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) or an increase in energetic metabolism and stimulation of mitochondrial biogenesis, contributing to control of weight gain, even when associated with high-fat diet (Lima et al., 2018Lima, N.D., Teixeira, L., Gambero, A., Ribeiro, M.L., 2018. Guarana (Paullinia cupana) stimulates mitochondrial biogenesis in mice fed high-fat diet. Nutrients 10, http://dx.doi.org/10.3390/nu10020165.
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).

Preparations containing guarana in association with other herbal drugs, are widely used for weight loss in humans (Andersen and Fogh, 2001Andersen, T., Fogh, J., 2001. Weight loss and delayed gastric emptying following a South American herbal preparation in overweight patients. J. Hum. Nutr. Dietet. 14, 243-250.; Boozer et al., 2001Boozer, C.N., Nasser, J.A., Heymsfield, S.B., Wang, V., Chen, G., Solomon, J.L., 2001. An herbal supplement containing Ma Huang-guarana for weight loss: a randomized, double-blind trial. Int. J. Obes. 25, 316-324.; Bérubé-Parent et al., 2005Bérubé-Parent, S., Pelletier, C., Doré, J., Tremblay, A., 2005. Effects of encapsulated green tea and guarana extracts containing a mixture of epigallocatechin-3-gallate and caffeine on 24 h energy expenditure and fat oxidation in men. Br. J. Nutr. 94, 432-436.; Opala et al., 2006Opala, T., Rzymski, P., Pischel, I., Wilczak, M., Wozniak, J., 2006. Efficacy of 12 weeks supplementation of a botanical extract-based weight loss formula on body weight, body composition and blood chemistry in healthy, overweight subjects-a randomised double-blind placebo-controlled clinical trial. Eur. J. Med. Res. 11, 343-350.; Ruxton et al., 2007Ruxton, C.H.S., Kirkwood, L., McMillan, B., John, D.S., Evans, C.E.L., 2007. Effectiveness of a herbal supplement (Zotrim™) for weight management. Brit. Food J. 109, 416-428.; Bulku et al., 2010Bulku, E., Zinkovsky, D., Patel, P., Javia, V., Lahoti, T., Khodos, I., Stohs, S.J., Ray, S.D., 2010. A novel dietary supplement containing multiple phytochemicals and vitamins elevates hepatorenal and cardiac antioxidant enzymes in the absence of significant serum chemistry and genomic changes. Oxid. Med. Cell. Longev. 3, 129-144.), with positive results. As a result of its methylxanthine content, the guarana extract can block adenosine and phosphodiesterase inhibitors, thereby, increasing noradrenaline activity (Carlini, 2003Carlini, E.A., 2003. Plants and the central nervous system. Pharmacol. Biochem. Behav. 75, 501-512.). Considering the effects of caffeine on blood pressure elevation, guarana should be avoided by hypertensive individuals. It is also strongly recommended that the combination of guarana and supplements containing ephedra, such as Ma Hung and products with ephedrine alkaloids, should be avoided because it can increase the risk of myocardial infarction and sudden death (Boozer et al., 2001Boozer, C.N., Nasser, J.A., Heymsfield, S.B., Wang, V., Chen, G., Solomon, J.L., 2001. An herbal supplement containing Ma Huang-guarana for weight loss: a randomized, double-blind trial. Int. J. Obes. 25, 316-324.; Nyska et al., 2005Nyska, A., Murphy, E., Foley, J.F., Collins, B.J., Petranka, J., Howden, R., Hanlon, P., Dunnick, J.K., 2005. Acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine. Toxicol. Sci. 83, 388-396.). Also, antiarrhythmic medications, such as amiodarone, should not be consumed with guarana because such an association may decrease plasma amiodarone concentration, particularly in the heart (Rodrigues et al., 2012Rodrigues, M., Alves, G., Lourenco, N., Falcao, A., 2012. Herb-drug interaction of Paullinia cupana (guarana) seed extract on the pharmacokinetics of amiodarone in rats. Evid. Based Complement. Alternat. Med., http://dx.doi.org/10.1155/2012/428560.
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).

Literature studies have associated guarana with an impressive array of pharmacological functions (Box 2). For instance, guarana has gastroprotective properties and offers much better therapeutic benefits than caffeine in gastrointestinal disorders (Campos et al., 2003Campos, A.R., Barros, A.I.S., Santos, F.A., Rao, V.S.N., 2003. Guarana (Paullinia cupana Mart.) offers protection against gastric lesions induced by ethanol and indomethacin in rats. Phytother. Res. 17, 1199-1202.). A hepatoprotective effect of guarana powder seeds was demonstrated in rats (Kober et al., 2016Kober, H., Tatsch, E., Torbitz, V.D., Cargnin, L.P., Sangoi, M.B., Bochi, G.V., da Silva, A.R.H., Barbisan, F., Ribeiro, E.E., da Cruz, I.B.M., Moresco, R.N., 2016. Genoprotective and hepatoprotective effects of guarana (Paullinia cupana Mart. var. sorbilis) on CCl4-induced liver damage in rats. Drug. Chem. Toxicol. 39, 48-52.). Other studies have highlighted the cytoprotective effects of guarana (de Oliveira et al., 2002de Oliveira, J.F., Avila, A.S., Braga, A.C., de Oliveira, M.B., Boasquevisque, E.M., Jales, R.L., Cardoso, V.N., Bernardo-Filho, M., 2002. Effect of extract of medicinal plants on the labeling of blood elements with Technetium-99m and on the morphology of red blood cells: I - a study with Paullinia cupana. Fitoterapia 73, 305-312.; Freitas et al., 2007Freitas, R.S., Moreno, S.R.F., Lima-Filho, G.L., Fonseca, A.S., Bernardo-Filho, M., 2007. Effect of a commercial extract of Paullinia cupana (guarana) on the binding of 99mTc-DMSA on blood constituents: an in vivo study. Appl. Radiat. Isot. 65, 528-533.; Leite et al., 2011Leite, R.P., Wada, R.S., Monteiro, J.C., Predes, F.S., Dolder, H., 2011. Protective effect of guarana (Paullinia cupana var. sorbilis) pre-treatment on cadmium-induced damages in adult Wistar testis. Biol. Trace Elem. Res. 141, 262-274., 2013Leite, R.P., Predes, F.S., Monteiro, J.C., Freitas, K.M., Wada, R.S., Dolder, H., 2013. Advantage of guarana (Paullinia cupana Mart.) supplementation on cadmium-induced damages in testis of adult wistar rats. Toxicol. Pathol. 41, 73-79.; Oliveira et al., 2011Oliveira, D.M., Barreto, G., Galeano, P., Romero, J.I., Holubiec, M.I., Badorrey, M.S., Capani, F., Alvarez, L.D.G., 2011. Paullinia cupana Mart. var. sorbilis protects human dopaminergic neuroblastoma SH-SY5Y cell line against rotenone-induced cytotoxicity. Hum. Exp. Toxicol. 30, 1382-1391.; Bonadiman et al., 2017Bonadiman, B.D.R., Cadona, F.C., Assmann, C.E., Weis, G.C.C., Alves, A.D., Durte, M.F., Chaves, C.M., Chaves, C.D., Motta, K.M.D., Ribeiro, E.E., Bagatini, M.D., da Cruz, I.B.M., 2017. Guarana (Paullinia cupana): cytoprotective effects on age-related eye dysfunction. J. Funct. Food. 36, 375-386.) including neuroprotection (Bittencourt et al., 2014Bittencourt, L.S., Zeidán-Chuliá, F., Yatsu, F.K.J., Schnorr, C.E., Moresco, K.S., Kolling, E.A., Gelain, D.P., Bassani, V.L., Moreira, J.C.F., 2014. Guarana (Paullinia cupana Mart.) prevents β-amyloid aggregation, generation of advanced glycation-end products (AGEs), and acrolein-induced cytotoxicity on human neuronal-like cells. Phytother. Res. 28, 1615-1624.) and acetylcholinesterase inhibition (Trevisan and Macedo, 2003Trevisan, M.T.S., Macedo, F.V.V., 2003. Screening for acetylcholinesterase inhibitors from plants to treat Alzheimer's disease. Quim. Nova 26, 301-304.). Consequently, guarana has been suggested as a promising source of phytochemicals that can be used as an adjuvant therapy in the management of cognitive disorders, such as Alzheimer's disease (Bittencourt et al., 2014Bittencourt, L.S., Zeidán-Chuliá, F., Yatsu, F.K.J., Schnorr, C.E., Moresco, K.S., Kolling, E.A., Gelain, D.P., Bassani, V.L., Moreira, J.C.F., 2014. Guarana (Paullinia cupana Mart.) prevents β-amyloid aggregation, generation of advanced glycation-end products (AGEs), and acrolein-induced cytotoxicity on human neuronal-like cells. Phytother. Res. 28, 1615-1624.; Ruchel et al., 2017Ruchel, J.B., Braun, J.B.S., Adefegha, S.A., Manzoni, A.G., Abdalla, F.H., de Oliveira, J.S., Trelles, K., Signor, C., Lopes, S.T.A., da Silva, C.B., Castilhos, L.G., Rubin, M.A., Leal, D.B.R., 2017. Guarana (Paullinia cupana) ameliorates memory impairment and modulates acetylcholinesterase activity in Poloxamer-407-induced hyperlipidemia in rat brain. Physiol. Behav. 168, 11-19.), although this disease has multiple etiologies. Although some authors (Mingori et al., 2017Mingori, M.R., Heimfarth, L., Ferreira, C.F., Gomes, H.M., Moresco, K.S., Delgado, J., Roncato, S., Zeidan-Chulia, F., Gelain, D.P., Moreira, J.C.F., 2017. Effect of Paullinia cupana Mart. commercial extract during the aging of middle age Wistar rats: differential effects on the hippocampus and striatum. Neurochem. Res. 42, 2257-2273.) suggest that ingestion of guarana powder (21 mg of guarana powder (body weight, kg/day)) in middle-aged male Wistar rats does not improve cognitive development, they claim that this treatment can modify the machinery of oxidative stress and the neurodegenerative-signaling pathway by inhibiting pro-survival in the hippocampus and striatum. These results may contribute to the development of unfavorable microenvironments in the brain and neurodegenerative disorders.

Box 2
Pharmacological activities of the seeds of P. cupana or their associations described in the literature.

Additionally, the aqueous solution of guarana seed powder has shown antigenotoxic activity in animals chemically treated to induce DNA damage (Fukumasu et al., 2006aFukumasu, H., Avanzo, J.L., Heidor, R., Silva, T.C., Atroch, A., Moreno, F.S., Dagli, M.L.Z., 2006. Protective effects of guarana (Paullinia cupana Mart. var. sorbilis) against DEN-induced DNA damage on mouse liver. Food Chem. Toxicol. 44, 862-867.; Kober et al., 2016Kober, H., Tatsch, E., Torbitz, V.D., Cargnin, L.P., Sangoi, M.B., Bochi, G.V., da Silva, A.R.H., Barbisan, F., Ribeiro, E.E., da Cruz, I.B.M., Moresco, R.N., 2016. Genoprotective and hepatoprotective effects of guarana (Paullinia cupana Mart. var. sorbilis) on CCl4-induced liver damage in rats. Drug. Chem. Toxicol. 39, 48-52.).

The dry extract of guarana (ESG) has been used in topical formulations for the prevention and treatment of gynoid lipodystrophy because it increases the number of blood vessels in the dermis when used at 50% (Chorilli et al., 2004Chorilli, M., Ribeiro, M.C.A.P., Pires-de-Campos, M.S.M., Leonardi, G.R., Polacow, M.L.O., 2004. Emulsion effect containing dry extract of guarana over the blood vessels of the papillary dermis of rats. Saúde Rev. 6, 7-12.). The simultaneous transdermal delivery of the main substances present in guarana extracts was established, with penetration rates being highly dependent on the concentration and the vehicle (Heard et al., 2006Heard, C.M., Johnson, S., Moss, G., Thomas, C.P., 2006. In vitro transdermal delivery of caffeine, theobromine, theophylline and catechin from extract of Guarana, Paullinia cupana. Int. J. Pharm. 317, 26-31.).

Studies in our group have shown that the crude and semipurified extracts of guarana have antidepressant effects in chronic treatment that are comparable to the antidepressant, imipramine (Audi and Mello, 2000Audi, E.A., Mello, J.C.P., 2000. Efeito antidepressivo do extrato da droga vegetal guarana (Paullinia cupana var. sorbilis (Martius) Ducke), PI 0006638-9 (Patent). Universidade Estadual de Maringá, Brasil.). These effects cannot be linked to the methylxanthines because the results found with this substance alone are different from those found in the administration of the extracts (Otobone et al., 2007Otobone, F.J., Sanches, A.C.C., Magae, R.L., Martins, J.V.C., Sela, V.R., Mello, J.C.P., Audi, E.A., 2007. Effect off liophilized extracts from guarana seeds [Paullinia cupana var. sorbilis (Mart.) Ducke] on behavioral profiles in rats. Phytother. Res. 21, 531-535.). Thus, some condensed tannins, which were isolated from the semipurified fraction, could be responsible for this activity because they can cross the blood-brain barrier and thereby act on the central nervous system (Youdim et al., 2004Youdim, K.A., Shukitt-Hale, B., Joseph, J.A., 2004. Flavonoids and the brain: interactions at the blood-brain barrier and their physiological effects on the central nervous system. Free Radic. Biol. Med. 37, 1683-1693.). It is suggested that a mechanism other than the adenosine receptor antagonist, cyclopentyl adenosine (CPA), is involved in the antidepressant activity of guarana, because it is due to caffeine, rather than guarana (Campos et al., 2005Campos, A.R., Barros, A.I.S., Albuquerque, F.A.A., Leal, L.K.A.M., Rao, V.S.N., 2005. Acute effects of guarana (Paullinia cupana Mart.) on mouse behaviour in forced swimming and open field tests. Phytother. Res. 19, 441-443.).

The efficacy of guarana extract against chemotherapy-induced fatigue and depression symptoms in patients with solid tumors (Miranda et al., 2008Miranda, V.C., Trufelli, D.C., Fêde, A.B.S., Martins, F.D., Saad, L.S., Oliveira, V., Trindade, T.Z.C., Riechelmann, R., Giglio, A.D., 2008. Guarana (Paullinia cupana) for chemotherapy-related fatigue. Einstein 6, 195-199.) and at post-radiation (Miranda et al., 2009Miranda, V.C., Trufelli, D.C., Santos, J., Campos, M.P., Nobuo, M., Miranda, M.C., Schlinder, F., Riechelmann, R., Giglio, A.D., 2009. Effectiveness of guarana (Paullinia cupana) for postradiation fatigue and depression: results of a pilot double-blind randomized study. J. Altern. Complement. Med. 15, 431-433.), revealed that in both cases, the patients showed no significant difference in the effects of fatigue and depression compared to the control group. However, in two other studies conducted by different research groups, the standardized guarana extract proved to be effective, with low toxicity, in the treatment of chemotherapy-related fatigue in patients with breast cancer (Campos et al., 2011Campos, M.P.d.O., Riechelmann, R., Casa, L.B.A., Hassan, B.J., Casa, F.B.A., Giglio, A.D., 2011. Guarana (Paullinia cupana) improves fatigue in breast cancer patients undergoing systemic chemotherapy. J. Altern. Complement. Med. 17, 505-512.) and in patients with solid tumors (del Giglio et al., 2013del Giglio, A.B., Cubero, D.I.G., Lerner, T.G., Guariento, R.T., de Azevedo, R.G., Paiva, H., Goldman, C., Carelli, B., Cruz, F.M., Schindler, F., Pianowski, L., de Matos, L.L., del Giglio, A., 2013. Purified dry extract of Paullinia cupana (guarana) (PC-18) for chemotherapy-related fatigue in patients with solid tumors: an early discontinuation study. J. Diet. Suppl. 10, 325-334.).

Guarana contains various substances, for example, methylxanthines and polyphenols with chemopreventive and antineoplastic properties. Thus, guarana may act as a chemopreventive agent in carcinogenesis, demonstrating a potentially valuable health benefit. It can reduce cellular expansion of neoplastic cells, decrease the incidence and multiplicity of macroscopic lesions, and reduce the proliferation of tumor cells and increase tumor cell apoptosis, consequently, reducing the area of the tumor (Fukumasu et al., 2006bFukumasu, H., Silva, T.C.d., Avanzo, J.L., Lima, C.E.d., Mackwiak, I.I., Atroch, A., Spinosa, H.d.S., Moreno, F.S., Dagli, M.L.Z., 2006. Chemopreventive effects of Paullinia cupana Mart. var. sorbilis, the guarana, on mouse hepatocarcinogenesis. Cancer Lett. 233, 158-164., 2008Fukumasu, H., Avanzo, J.L., Nagamine, M.K., Barbuto, J.A., Rao, K.V., Dagli, M.L.Z., 2008. Paullinia cupana Mart var. sorbilis, guarana, reduces cell proliferation and increases apoptosis of B16/F10 melanoma lung metastases in mice Braz. J. Med. Biol. Res. 41, 305-310., 2011Fukumasu, H., Latorre, A.O., Zaidan-Dagli, M.L., 2011. Paullinia cupana Mart. var. sorbilis, guarana, increases survival of Ehrlich ascites carcinoma (EAC) bearing mice by decreasing cyclin-D1 expression and inducing a G0/G1cell cycle arrest in EAC cells. Phytother. Res. 25, 11-16.; Mingori et al., 2017Mingori, M.R., Heimfarth, L., Ferreira, C.F., Gomes, H.M., Moresco, K.S., Delgado, J., Roncato, S., Zeidan-Chulia, F., Gelain, D.P., Moreira, J.C.F., 2017. Effect of Paullinia cupana Mart. commercial extract during the aging of middle age Wistar rats: differential effects on the hippocampus and striatum. Neurochem. Res. 42, 2257-2273.).

A study conducted to monitor the acute effects of guarana powder (2.10% caffeine; 16% tannin) on cognition, anxiety and sleep in normal volunteers had negative results, suggesting the need for studies with chronic treatments (Galduróz and Carlini, 1994Galduróz, J.C.F., Carlini, E.A., 1994. Acute effects of the Paullinia cupana, "guarana" on the cognition of normal volunteers. São Paulo Med. J. 112, 607-611.). In another study that assessed the chronic administration of guarana on cognition in 15 normal elderly volunteers, no significant changes were observed (Galduróz and Carlini, 1996Galduróz, J.C.F., Carlini, E.A., 1996. The effects of long-term administration of guarana on the cognition of normal, elderly volunteers. São Paulo Med. J. 114, 1073-1078.). However, the authors explained the negative results could have been due to the insufficient treatment duration (150 d) or, moreover, that the tests used were not sensitive enough to detect the expected cognitive alterations (Galduróz and Carlini, 1996Galduróz, J.C.F., Carlini, E.A., 1996. The effects of long-term administration of guarana on the cognition of normal, elderly volunteers. São Paulo Med. J. 114, 1073-1078.).

Guarana has been used for a long time by the Indians as a stimulant and this effect is greatly associated with the presence of a large amount of caffeine in guarana seeds as above-mentioned. The psychoactive properties of the guarana extract were first observed by Kennedy et al. (2004)Kennedy, D.O., Haskell, C.F., Wesnes, K.A., Scholey, A.B., 2004. Improved cognitive performance in human volunteers following administration of guarana (Paullinia cupana) extract: comparison and interaction with Panax ginseng. Pharmacol. Biochem. Behav. 79, 401-411.. The results showed that doses of guarana (75 mg) and ginseng alone, or the combination of the two plants, led to an improvement in cognitive performance in humans. Nevertheless, in a study by the same research group, the effects of various doses of guarana (37.5, 75, 150, and 300 mg) were evaluated for the first time in humans and the same result was found, mainly at the lower doses, at a maximum of 4.5-8.4 mg caffeine (Haskell et al., 2007Haskell, C.F., Kennedy, D.O., Wesnes, K.A., Milne, A.L., Scholey, A.B., 2007. A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans. J. Psychopharmacol. 21, 65-70.). Both studies used a hydroalcoholic extract of guarana prepared by exhaustive percolation (Kennedy et al., 2004Kennedy, D.O., Haskell, C.F., Wesnes, K.A., Scholey, A.B., 2004. Improved cognitive performance in human volunteers following administration of guarana (Paullinia cupana) extract: comparison and interaction with Panax ginseng. Pharmacol. Biochem. Behav. 79, 401-411.; Haskell et al., 2007Haskell, C.F., Kennedy, D.O., Wesnes, K.A., Milne, A.L., Scholey, A.B., 2007. A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans. J. Psychopharmacol. 21, 65-70.). The authors suggested that the improvement in cognitive performance promoted by the standardized guarana extract could not be attributed solely to the caffeine content (11-12%) because at the lower doses, the level of caffeine was not considered to be sufficient to produce positive effects (Kennedy et al., 2004Kennedy, D.O., Haskell, C.F., Wesnes, K.A., Scholey, A.B., 2004. Improved cognitive performance in human volunteers following administration of guarana (Paullinia cupana) extract: comparison and interaction with Panax ginseng. Pharmacol. Biochem. Behav. 79, 401-411.; Haskell et al., 2007Haskell, C.F., Kennedy, D.O., Wesnes, K.A., Milne, A.L., Scholey, A.B., 2007. A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans. J. Psychopharmacol. 21, 65-70.). Improvement in cognitive performance was also obtained by investigating the influence of mouth rinsing of guarana and ginseng (0.4 g 25 ml-1) (Pomportes et al., 2017Pomportes, L., Brisswalter, J., Casini, L., Hays, A., Davranche, K., 2017. Cognitive performance enhancement induced by caffeine, carbohydrate and guarana mouth rinsing during submaximal exercise. Nutrients 9, http://dx.doi.org/10.3390/nu9060589.
http://dx.doi.org/10.3390/nu9060589...
).

Another study also showed positive results at a low dose (0.3 mg guarana ml-1), which contained 6.2 µg ml-1 caffeine (a quantity around 16 times lower than the caffeine used as a reference drug) (Espinola et al., 1997Espinola, E.B., Dias, R.F., Mattei, R., Carlini, E.A., 1997. Pharmacological activity of guaraná (Paullinia cupana Mart.) in laboratory animals. J. Ethnopharmacol. 55, 223-229.). Better results were found for cognitive capacity, including stability in the parasympathetic modulation in individuals who consumed a vitamin-mineral-guarana extract supplement, compared with the equivalent dose of caffeine (100 mg) alone (Pomportes et al., 2015aPomportes, L., Davranche, K., Brisswalter, I., Hays, A., Brisswalter, J., 2015. Heart rate variability and cognitive function following a multi-vitamin and mineral supplementation with added guarana (Paullinia cupana). Nutrients 7, 196-208.). In summary, evidence suggests that various components, such as flavonoids (Scholey and Haskell, 2008Scholey, A., Haskell, C., 2008. Neurocognitive effects of guarana plant extract. Drugs Fut. 33, 869.), saponins, and tannins (Espinola et al., 1997Espinola, E.B., Dias, R.F., Mattei, R., Carlini, E.A., 1997. Pharmacological activity of guaraná (Paullinia cupana Mart.) in laboratory animals. J. Ethnopharmacol. 55, 223-229.; Mattei et al., 1998Mattei, R., Dias, R.F., Espinola, E.B., Carlini, E.A., Barros, S.B.M., 1998. Guarana (Paullinia cupana): toxic behavioral effects in laboratory animals and antioxidant activity in vitro. J. Ethnopharmacol. 60, 111-116.; Otobone et al., 2005Otobone, F.J., Sanches, A.C., Nagae, R.L., Martins, J.V.C., Obici, S., Mello, J.C.P., Audi, E.A., 2005. Effect of crude extract and its semi purifies constituents from guarana seeds (Paullinia cupana var. sorbilis (Mart.)) Lucke on cognitive performance in morris water maze in rats. Braz. Arch. Biol. Technol. 48, 723-728.) can contribute to this psychoactive effect. This effect can also be attributed to the synergetic interactions between these various substances and/or other psychoactive substances present in the guarana extract. It is suggested that the biological activities of guarana go beyond the extensively reported central nervous system stimulation (Peixoto et al., 2017Peixoto, H., Roxo, M., Röhrig, T., Richling, E., Wang, X., Wink, M., 2017. Anti-aging and antioxidant potential of Paullinia cupana var. sorbilis: findings in Caenorhabditis elegans indicate a new utilization for roasted seeds of guarana. Medicines 4, http://dx.doi.org/10.3390/medicines4030061.
http://dx.doi.org/10.3390/medicines40300...
).

Recent studies by our group (Audi et al., 2010Audi, E.A., Roncon, C.M., Almeida, C.B., Mello, J.C.P., 2010. P.1.d.002 Effect of semi-purified constituent from guarana seeds on performance of rats in elevated T maze. Eur. Neuropsychopharmacol. 20, S274-S275.; Roncon et al., 2011Roncon, C.M., De Almeida, C.B., Klein, T., Mello, J.C.P., Audi, E.A., 2011. Anxiolytic effects of a semipurified constituent of guarana seeds on rats in the elevated T-maze test. Planta Med. 77, 236-241.; Rangel et al., 2013Rangel, M.P., Mello, J.C.P., Audi, E.A., 2013. Evaluation of neurotransmitters involved in the anxiolytic and panicolytic effect of the aqueous fraction of Paullinia cupana (guarana) in elevated T maze. Rev. Bras. Farmacogn. 23, 358-365.) showed that the semipurified guarana extract has both anxiolytic and panicolytic effects. The serotonergic, dopaminergic and glutamatergic neurotransmitters are involved in the anxiolytic effect, whereas serotonergic and dopaminergic neurotransmitters are involved in the panicolytic effect (Rangel et al., 2013Rangel, M.P., Mello, J.C.P., Audi, E.A., 2013. Evaluation of neurotransmitters involved in the anxiolytic and panicolytic effect of the aqueous fraction of Paullinia cupana (guarana) in elevated T maze. Rev. Bras. Farmacogn. 23, 358-365.).

There is great interest in the substitution of synthetic antioxidants by natural counterparts in food, encouraging a search for natural sources of antioxidants. This extends to other perishable goods, such as cosmetics, pharmaceutical products, and plastics. In addition, other biological properties are associated with antioxidants, for example, anticarcinogenicity, antimutagenicity, antiallergenicity, and anti-aging activities (Moure et al., 2001Moure, A., Cruz, J.M., Franco, D., Domínguez, J.M., Sineiro, J., Domínguez, H., Núnez, M.J., Parajó, J.C., 2001. Natural antioxidants from residual sources - review. Food Chem. 72, 145-171.). Several studies have shown that guarana has antioxidant activities (Mattei et al., 1998Mattei, R., Dias, R.F., Espinola, E.B., Carlini, E.A., Barros, S.B.M., 1998. Guarana (Paullinia cupana): toxic behavioral effects in laboratory animals and antioxidant activity in vitro. J. Ethnopharmacol. 60, 111-116.; Basile et al., 2005Basile, A., Ferrara, L., Del Pezzo, M., Mele, G., Sorbo, S., Bassi, P., Montesano, D., 2005. Antibacterial and antioxidant activities of ethanol extract from Paullinia cupana Mart. J. Ethnopharmacol. 102, 32-36.; Majhenic et al., 2007Majhenic, L., Skerget, M., Knez, Z., 2007. Antioxidant and antimicrobial activity of guarana seed extracts. Food Chem. 104, 1258-1268.; Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.; Dalonso and Petkowicz, 2012Dalonso, N., Petkowicz, C.L.d.O., 2012. Guarana powder polysaccharides: characterisation and evaluation of the antioxidant activity of a pectic fraction. Food Chem. 134, 1804-1812.; Bittencourt et al., 2013Bittencourt, L.S., Machado, D.C., Machado, M.M., Dos Santos, G.F.F., Algarve, T.D., Marinowic, D.R., Ribeiro, E.E., Soares, F.A.A., Barbisan, F., Athayde, M.L., Cruz, I.B.M., 2013. The protective effects of guarana extract (Paullinia cupana) on fibroblast NIH-3T3 cells exposed to sodium nitroprusside. Food Chem. Toxicol. 53, 119-125.; Portella et al., 2013Portella, R.L., Barcelos, R.P., Rosa, E.J.F., Ribeiros, E.E., Cruz, I.B.M., Suleiman, L., Soares, F.A.A., 2013. Guarana (Paullinia cupana Kunth) effects on LDL oxidation in elderly people: an in vitro and in vivo study. Lipids Health Dis. 12, 1-9.), which have been largely attributed to the polyphenols (particularly tannins). However, the polysaccharides in guarana powder have also shown antioxidant activity in vitro (Dalonso and Petkowicz, 2012Dalonso, N., Petkowicz, C.L.d.O., 2012. Guarana powder polysaccharides: characterisation and evaluation of the antioxidant activity of a pectic fraction. Food Chem. 134, 1804-1812.). The antioxidant effect is reported to be dose-dependent and present even at low concentrations in animals (1.2 µg ml-1) (Mattei et al., 1998Mattei, R., Dias, R.F., Espinola, E.B., Carlini, E.A., Barros, S.B.M., 1998. Guarana (Paullinia cupana): toxic behavioral effects in laboratory animals and antioxidant activity in vitro. J. Ethnopharmacol. 60, 111-116.; Basile et al., 2005Basile, A., Ferrara, L., Del Pezzo, M., Mele, G., Sorbo, S., Bassi, P., Montesano, D., 2005. Antibacterial and antioxidant activities of ethanol extract from Paullinia cupana Mart. J. Ethnopharmacol. 102, 32-36.). In another study testing crude and semipurified guarana extracts, it was found higher content of polyphenols, lower IC50 0 value and higher relative antioxidant capacity (RAC) for the semipurified extract (Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.).

Another promising feature of guarana is its antimicrobial activity, with possible use in industry product conservation or, for example, to prevent diseases caused by microorganisms. The aqueous extract of guarana, in the form of mouthwashes, has been evaluated in human individuals free of cavities and periodontal diseases. The antiplaque activity, determined according to the method of Greene and Vermillion (1964)Greene, J.C., Vermillion, J.R., 1964. The simplified oral hygiene index. J. Am. Dent. Assoc. 68, 7-13. through the Simplified Oral Hygiene Index, revealed the guarana extract was statistically efficient compared to the positive control and, therefore, a potential alternative in the control of dental plaque (Barbosa and Mello, 2004Barbosa, G.D.A., Mello, J.C.P., 2004. Clinical evaluation of the guarana extract on the dental plaque control. Rev. Paul. Odontol. 26, 28-30.). The in vitro antibacterial activity of a semipurified guarana extract against Streptococcus mutans, a bacterial species associated with cariogenic activity was demonstrated (Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.). The antibacterial activity against S. mutans was directly proportional to the polyphenol content present in the extract.

Guarana extracts have also displayed activity against several strains of bacteria and fungi (Pseudomonas aeruginosa, Proteus mirabilis, Proteus vulgaris, Escherichia coli, Bacillus cereus, Pseudomonas fluorescens, Aspergillus niger, Trichoderma viride and Penicillium cyclopium) (Basile et al., 2005Basile, A., Ferrara, L., Del Pezzo, M., Mele, G., Sorbo, S., Bassi, P., Montesano, D., 2005. Antibacterial and antioxidant activities of ethanol extract from Paullinia cupana Mart. J. Ethnopharmacol. 102, 32-36.; Majhenic et al., 2007Majhenic, L., Skerget, M., Knez, Z., 2007. Antioxidant and antimicrobial activity of guarana seed extracts. Food Chem. 104, 1258-1268.). According to the results, the alcoholic extracts possessed greater antimicrobial activity than aqueous extracts of guarana seeds, which had little or no antimicrobial activity against the microorganisms tested (Majhenic et al., 2007Majhenic, L., Skerget, M., Knez, Z., 2007. Antioxidant and antimicrobial activity of guarana seed extracts. Food Chem. 104, 1258-1268.). Crude, semipurified fractions of guarana (up to 1000 mg ml-1) were tested against strains of Staphylococcus aureus, Bacillus subtilis, E. coli and P. aeruginosa, but no activity of these fractions against these organisms was obtained (Ushirobira et al., 2007Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Nakamura, C.V., Dias Filho, B.P., Mello, J.C.P., 2007. Chemical and microbiological study of extract from seeds of guarana (Paullinia cupana var. sorbilis). Acta Farm. Bonaer. 26, 5-9.). In contrast, extracts of guarana seeds obtained by supercritical technology, using 40% cosolvent, showed antibacterial activity against a methicillin-resistant strain of S. aureus (Marques et al., 2016Marques, L.L.M., Panizzon, G.P., Aguiar, B.A.A., Simionato, A.S., Cardozo-Filho, L., Andrade, G., Oliveira, A.G.d., Guedes, T.A., Mello, J.C.P., 2016. Guarana (Paullinia cupana) seeds: selective supercritical extraction of phenolic compounds. Food Chem. 212, 703-711.). These conflicting results may be due to the form of preparation of the extract, method of seed drying, location the raw material was collected from, among other factors, as will be discussed later.

Some drug interactions have been attributed to guarana, such as potentiation of the action of chemotherapy drugs, causing an antiproliferative effect (Hertz et al., 2015Hertz, E., Cadoná, F.C., Machado, A.K., Azzolin, V., Holmrich, S., Assmann, C., Ledur, P., Ribeiro, E.E., Filho, O.C.d.S., Mânica-Cattani, M.F., Cruz, I.B.M.d., 2015. Effect of Paullinia cupana on MCF-7 breast cancer cell response to chemotherapeutic drugs. Mol. Clin. Oncol. 3, 37-43.). When administered with anticoagulants, guarana may inhibit platelet aggregation by increasing the risk of bleeding (Nicoletti et al., 2007Nicoletti, M.A., Oliveira-Junior, M.A., Bertasso, C.C., Coporossi, P.Y., Tavares, A.P.L., 2007. Principais interações no uso de medicamentos fitoterápicos. Infarma 19, 32-40.). Conversely, guarana extract can be potentially useful in the prevention of diseases, such as thrombosis and other vascular problems, and there are studies demonstrating its antagonist action on platelets (Bydlowski et al., 1988Bydlowski, S.P., Yunker, R.L., Subbiah, M.T., 1988. A novel property of an aqueous guarana extract (Paullinia cupana): inhibition of platelet aggregation in vitro and in vivo. Braz. J. Med. Biol. Res. 21, 535-538., 1991Bydlowski, S.P., D'Amico, E.A., Chamone, D.A.F., 1991. An aqueous extract of guarana (Paullinia cupana) decreases platelet thromboxane synthesis. Braz. J. Med. Biol. Res. 24, 421-424.; Ushirobira et al., 2007Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Nakamura, C.V., Dias Filho, B.P., Mello, J.C.P., 2007. Chemical and microbiological study of extract from seeds of guarana (Paullinia cupana var. sorbilis). Acta Farm. Bonaer. 26, 5-9.).

Guarana has also been used for its adaptogenic effect and, therefore, it is very useful in cases of drug addiction, particularly to relieve the hangover from the abuse of alcoholic beverages (Carlini et al., 2006Carlini, E.A., Rodrigues, E., Mendes, F.R., Tabach, R., Gianfratti, B., 2006. Treatment of drug dependence with brazilian herbal medicines. Rev. Bra. Farmacogn. 16, 690-695.).

All previously cited researchers used guarana seeds for their studies. However, a moderate antiplasmodial activity of chloroform extracts of branches and fruits of guarana have been shown (Lima et al., 2015Lima, R.B.S., Silva, L., Melo, M.R.S., Costa, J.S., Picanco, N.S., Lima, E.S., Vasconcellos, M.C., Boleti, A.P.A., Santos, J.M.P., Amorim, R.C.N., Chaves, F.C.M., Coutinho, J.P., Tadei, W.P., Krettli, A.U., Pohlit, A.M., 2015. In vitro and in vivo anti-malarial activity of plants from the Brazilian Amazon. Malar. J. 14, http://dx.doi.org/10.1186/s12936-015-0999-2.
http://dx.doi.org/10.1186/s12936-015-099...
). In this study, the methanolic extracts and aqueous extracts of the same plant parts and also chloroform, methanolic and aqueous extracts of the leaf, did not show antiplasmodial activity.

The reports show that guarana displays countless health benefits in cognitive disorders, such as depression and panic disorder or Alzheimer. Also, it is very promising as an antibacterial for oral diseases, such as plaque and periodontal diseases, and against bacterial species associated with cariogenic activity. Thus, the pharmacological activities should be fully explored with in-depth in vitro and in vivo tests, and, ultimately, clinical trials to prove these activities in humans.

Toxicity

Herbal drugs used in the preparation of medications for therapeutic purposes are foreign to the human body. Therefore, like any foreign substance, the products of their biotransformation may lead to reactions in the human body. For this reason, popular and even traditional use, are insufficient to validate herbal drugs as effective and safe medications. Safety should be assessed with pre-clinical and clinical pharmacological and toxicological studies (Lapa et al., 2010Lapa, A.J., Souccar, C., Lima-Landman, M.T., Godinho, R.O., Lima, T.C.M., 2010. Farmacologia e toxicologia de produtos naturais (in Portuguese). In: Simões, C.M.O., Schenkel, E.P., Gosmann, G., Mello, J.C.P., Mentz, L.A., Petrovick, P.R. (Eds.), Farmacognosia: da planta ao medicamento. UFRGS/UFSC, Porto Alegre, Florianópolis, pp. 247–262.). Preclinical toxicological studies are conducted according to the internationally accepted protocols, although legal requirements vary from country to country.

In vivo and in vitro studies have been conducted to evaluate the possible toxicity of guarana extracts or their association with other plants (Box 3). Fluid extracts of guarana were used in association with other plants, to test the toxicity of these formulations in vivo, and demonstrated to be safe (Oliveira et al., 2005Oliveira, C.H., Moraes, M.E.A., Moraes, M.O., Bezerra, F.A.F., Abib, E., De Nucci, G., 2005. Clinical toxicology study of an herbal medicinal extract of Paullinia cupana, Trichilia catigua, Ptychopetalum olacoides and Zingiber oficinale (Catuama®) in healthy volunteers. Phytother. Res. 19, 54-57.; Mello et al., 2010Mello, J.R.B., Mello, F.B., Langeloh, A., 2010. Pre-clinic toxicity of a phytoterapic containing Anemopaegma mirandum, Cola nitida, Passiflora alata, Paullinia cupana, Ptychopetalum olacoides and thiamin chlorhydrate. Lat. Am. J. Pharm. 29, 1431-1435.). Namely, they did not present any observable toxic effects with a 28 or 30 days treatment, with rabbits and human being. Other in vivo and in vitro studies (Espinola et al., 1997Espinola, E.B., Dias, R.F., Mattei, R., Carlini, E.A., 1997. Pharmacological activity of guaraná (Paullinia cupana Mart.) in laboratory animals. J. Ethnopharmacol. 55, 223-229.; Mattei et al., 1998Mattei, R., Dias, R.F., Espinola, E.B., Carlini, E.A., Barros, S.B.M., 1998. Guarana (Paullinia cupana): toxic behavioral effects in laboratory animals and antioxidant activity in vitro. J. Ethnopharmacol. 60, 111-116.) have described absence or low toxicity to aqueous extracts of guarana, even after 23 months of treatment. The cytotoxicity of the aqueous extract of guarana at 10, 20, 30, and 40 mg ml-1 in Chinese hamster ovary (CHO) cells was investigated (Santa Maria et al., 1998Santa Maria, A., Lopez, A., Diaz, M.M., Munhoz-Mingarro, D., Pozuleo, J.M., 1998. Evaluation of the toxicity of guarana with in vitro bioassays. Ecotoxicol. Environ. Safe 39, 164-167.). At the lowest dose tested, the extract was harmless, but the authors warn that a prolonged use or high doses might be harmful to human health. In contrast, a semipurified fraction of guarana presented a possible toxic effect to the liver, with greater biological susceptibility in male rats at doses of 150 and 300 mg kg-1, after 90 d of treatment (Antonelli-Ushirobira et al., 2010Antonelli-Ushirobira, T.M., Kaneshima, E.N., Gabriel, M., Audi, E.A., Marques, L.C., Mello, J.C.P., 2010. Acute and subchronic toxicological evaluation of the semipurified extract of seeds of guarana (Paullinia cupana) in rodents. Food Chem. Toxicol. 48, 1817-1820.). In another study, human neuronal SH-SY5Y cells treated with guarana, developed signs of neurite and apoptotic degeneration (Zeidan-Chulia et al., 2013Zeidan-Chulia, F., Gelain, D.P., Kolling, E.A., Rybarczyk-Filho, J.L., Ambrosi, P., Terra, S.R., Pires, A.S., da Rocha, J.B., Behr, G.A., Moreira, J.C.F., 2013. Major components of energy drinks (caffeine, taurine, and guarana) exert cytotoxic effects on human neuronal SH-SY5Y cells by decreasing reactive oxygen species production. Oxid. Med. Cell Longev., http://dx.doi.org/10.1155/2013/791795.
http://dx.doi.org/10.1155/2013/791795...
). The authors suggested that excessive removal of intracellular reactive oxygen species to non-physiological levels could be a cause of guarana-induced in vitro toxicity. Moreover, the guarana extracts were considered to be genotoxic as assessed by lysogenic induction in E. coli (da Fonseca et al., 1994da Fonseca, C.A., Leal, J., Costa, S.S., Leitao, A.C., 1994. Genotoxic and mutagenic effects of guarana (Paullinia cupana) in prokaryotic organisms. Mutat. Res. 321, 165-173.). These extracts were also able to induce mutagenesis in Salmonella Typhimurium. This genotoxicity was attributed to the presence of a molecular complex formed by caffeine and flavonoid (catechin and epicatechin) in the presence of potassium.

Box 3
Toxicology of seeds of P. cupana or their associations described in the literature.

Therefore, in toxicity testing, it is important to determine the dose of the drug, bearing in mind the form of pharmaceutical preparation of its extract and to specify the amount administered, particularly in in vivo tests, where the weight of the animal is taken into account. The lack of standardization of these factors may raise doubt about the definition of a safe dose, administered both in acute or in chronic regimen.

In addition to the numerous health benefits and useful therapeutic indications for humans, guarana has demonstrated low toxicological potential, as evidenced by various in vitro and in vivo studies. Thus, it can be safely used by patients when in pharmaceutical formulations.

Quality control

The quality of herbal drugs is determined mainly by the content of the bioactives responsible for the therapeutic effects and by the absence of contaminants. Each stage of production, from cultivation to extraction of raw materials, have an impact on the quality and quantity of the active compounds present in plants (Carvalho et al., 2010Carvalho, L.M., Costa, J.A.M., Carnelossi, M.A.G., 2010. Qualidade em plantas medicinais. Embrapa, Aracaju.). The poor quality of the raw plant is a cause of concern to health care professionals and the scientific community because it may interfere with the efficacy and safety of the product (Boullata and Nace, 2000Boullata, J.I., Nace, A.M., 2000. Safety issues with herbal medicine. Pharmacotherapy 20, 257-269.).

The analysis of commercial samples shows that these medications often do not meet pharmacological specifications of quality. This is indicative of the need to implement quantitative techniques to control the physical and chemical quality of raw plant materials. Furthermore, pharmaceutical companies that purchase these products must have greater discretion for proper use, storage and manipulation of these products, while performing appropriate quality control (Bara et al., 2006Bara, M.T.F., Ribeiro, P.A.M., Arantes, M.C.B., Amorim, L.L.S.S., Paula, J.R., 2006. Determinação do teor do princípios ativos em matéria-primas vegetais. Rev. Bras. Farmacogn. 16, 211-215.).

After a medicinal plant is harvested, it may lose quality in subsequent stages of processing, which makes the drying process fundamental for the quality of the final product (Borgo et al., 2010Borgo, J., Xavier, C.A.G., Moura, D.J., Richter, M.F., Suyenaga, E.S., 2010. The Influence of drying processes on flavonoid level and the antioxidant activity of Baccharis articulata (Lam.) extracts. Rev. Bras. Farmacogn. 20, 12-17.). Guarana seeds can be dried by several distinct methods and the choice of a particular method strongly influences the quality of the product. If drying is not performed properly, it can enable the degradation of bioactives, allow the infestation and growth of microorganisms, compromising the content of active ingredients (Carvalho et al., 2010Carvalho, L.M., Costa, J.A.M., Carnelossi, M.A.G., 2010. Qualidade em plantas medicinais. Embrapa, Aracaju.). A physical chemical evaluation of guarana seeds submitted to different drying methods was conducted (Ushirobira et al., 2004Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Audi, E.A., Mello, J.C.P., 2004. Avaliação físico-química de sementes de guarana secas por diferentes métodos. Rev. Bras. Farmacogn. 14, 15-20.). These authors reported the highest content of methylxanthines obtained with seeds dried in a metal pot for 4 h, with the addition of water. In contrast, the highest content of total tannins was found under the same conditions, but without the addition of water. Another relevant point is the temperatures used in these drying processes. The temperature 120 ºC was determined as optimal for drying plant extracts using the fluidized bed drying technique (Pagliarussi et al., 2006Pagliarussi, R.S., Bastos, J.K., Freitas, L.A.P., 2006. Fluid bed drying of guarana (Paullinia cupana HBK) extract: effect of process factors on caffeine content. AAPS Pharm. Sci. Tech. 7, E1-E7.).

Some of the processing steps for guarana, such as its storage, are also fundamental in quality control of the final product. The incorrect storage of seeds can lead to loss of material whether for physical or biological reasons. One concern about the quality of natural products is the potential for contamination by fungi, with the risk of the presence of mycotoxins (Kneifel et al., 2001Kneifel, W., Czech, E., Kopp, B., 2001. Microbial contamination of medicinal plants - a review. Planta Med. 68, 5-15.). This makes a product unfit for consumption, even when in its original package (Carvalho et al., 2010Carvalho, L.M., Costa, J.A.M., Carnelossi, M.A.G., 2010. Qualidade em plantas medicinais. Embrapa, Aracaju.). Considering the increased use of herbal products as alternative medications, standards have to be established for herbal drugs to reduce risks to consumer health. Fungal contamination can occur in the process of planting and harvesting, as well as in the manipulation of seeds, if performed improperly (Kneifel et al., 2001Kneifel, W., Czech, E., Kopp, B., 2001. Microbial contamination of medicinal plants - a review. Planta Med. 68, 5-15.). This contamination can lead to deterioration and affect organoleptic characteristics.

There are no specification limits for fungal contamination of guarana in the Brazilian legislation, nor is there any mention of how it should be marketed or packaged. The Brazilian legislation (Anvisa, 2001Anvisa, 2001. RDC 12, Regulamento técnico sobre padrões microbiológicos para alimentos (in Portuguese). Agência Nacional de Vigilância Sanitária. Diário Oficial da União.) only establishes maximum limits for coliforms at 45 ºC (10 CFU g-1), Staphylococcus coagulase positive (500 CFU g-1) and Salmonella sp. (absence in 25 g) for guarana (powder, capsules, tablets or similar forms) alone, or in combination with other drugs.

The chemical composition of guarana (Table 3) is stamped by the package by its energy content. In this way, there may be contamination with fungal strains as a result of the high content of lipids and carbohydrates in guarana seeds. Additional factors, such as water activity, moisture, substrate composition, and insect-caused damage also influence fungal growth and mycotoxin production (Aquino et al., 2007Aquino, S., Gonçalez, E., Reis, T.A., Sabundjian, I.T., Trindade, R.A., Rossi, M.H., Corrêa, B., Villavicencio, A.L.C.H., 2007. Effect of γ-irradiation on mycoflora of guarana (Paullinia cupana). Radiat. Phys. Chem., 1470-1473.). The presence of mycotoxigenic strains in samples of guarana has been reported (Bugno et al., 2006Bugno, A., Almodovar, A.A.B., PereiraI, T.C., Pinto, T.J.A., Sabino, M., 2006. Occurrence of toxigenic fungi in herbal drugs. Braz. J. Microbiol. 37, 47-51.). In another study, it was found the presence of toxigenic strains in 2% of the samples analyzed and identified Aspergillus sp. and Penicillium sp., which are both mycotoxin-producing, affecting food safety (Martins et al., 2014Martins, M., Kluczkovski, A.M., Santos, A.C.S., Fernandes, O.C.C., Scussel, V.M., 2014. Evaluation of ochratoxin A and fungi in powdered guarana (Paullinia cupana Kunth), a caffeine rich product from Amazon forest. Afr. J. Microbiol. Res. 8, 545-550.). One strategy to decrease fungal contamination could be radiation by ionization (gamma rays) of these plant materials, avoiding the risk of contamination of consumers and manufacturers. This could be useful in attesting the sanitary quality of the product (Aquino et al., 2007Aquino, S., Gonçalez, E., Reis, T.A., Sabundjian, I.T., Trindade, R.A., Rossi, M.H., Corrêa, B., Villavicencio, A.L.C.H., 2007. Effect of γ-irradiation on mycoflora of guarana (Paullinia cupana). Radiat. Phys. Chem., 1470-1473.). A microbiological study by Aquino et al. (2007)Aquino, S., Gonçalez, E., Reis, T.A., Sabundjian, I.T., Trindade, R.A., Rossi, M.H., Corrêa, B., Villavicencio, A.L.C.H., 2007. Effect of γ-irradiation on mycoflora of guarana (Paullinia cupana). Radiat. Phys. Chem., 1470-1473., showed that 90% of the samples of powder guarana, purchased in open-air markets, showed fungal growth above the limit set by the World Health Organization (WHO) (1998)WHO, 1998. Quality Control Methods for Medicinal Plant Materials. World Health Organization, Geneva. which is 103 CFU g-1 in raw materials for internal use. The predominant flora was composed of Aspergillus (82%) and Penicillium (15%) (Aquino et al., 2007Aquino, S., Gonçalez, E., Reis, T.A., Sabundjian, I.T., Trindade, R.A., Rossi, M.H., Corrêa, B., Villavicencio, A.L.C.H., 2007. Effect of γ-irradiation on mycoflora of guarana (Paullinia cupana). Radiat. Phys. Chem., 1470-1473.). A total of 70% of the vegetal raw material from factories and pharmacies also exceeded the limit established by WHO (Aquino et al., 2007Aquino, S., Gonçalez, E., Reis, T.A., Sabundjian, I.T., Trindade, R.A., Rossi, M.H., Corrêa, B., Villavicencio, A.L.C.H., 2007. Effect of γ-irradiation on mycoflora of guarana (Paullinia cupana). Radiat. Phys. Chem., 1470-1473.). The treatment of these samples with 5 kGy of irradiation reduced 85% of the contamination, remaining within the limits established. With the highest dose (10 kGy), gamma irradiation completely eliminated the contamination of guarana (Aquino et al., 2007Aquino, S., Gonçalez, E., Reis, T.A., Sabundjian, I.T., Trindade, R.A., Rossi, M.H., Corrêa, B., Villavicencio, A.L.C.H., 2007. Effect of γ-irradiation on mycoflora of guarana (Paullinia cupana). Radiat. Phys. Chem., 1470-1473.).

Another type of contamination produced in the processing of guarana seeds that may affect their quality is polycyclic aromatic hydrocarbons (PAH). PAH are a family of compounds characterized by having two or more condensed aromatic rings (Box 4). They represent an important class of chemical formed during the incomplete combustion of organic material and are considered to be carcinogenic and genotoxic. They occur as contaminants in various types of food, mainly as a result of environmental pollution and some types of processes, such as smoking, drying and roasting. During the processing of guarana seeds, these substances could be formed as chemical contaminants. The presence of five PAH compounds was analyzed in thirteen brands of guarana powder selected (Camargo et al., 2006Camargo, M.C.R., Tfouni, S.A.V., Vitorino, S.H.P., Menegário, T.F., Toledo, M.C.F., 2006. Detemination of polycyclic aromatic hydrocarbons (PAHS) in guarana powder (Paullinia cupana). Cienc. Tecnol. Aliment. 26, 230-234.). At least 1 of the 5 contaminants was present in 81% of the samples, and in 35% of samples, all of the PAH were detected. This study (Camargo et al., 2006Camargo, M.C.R., Tfouni, S.A.V., Vitorino, S.H.P., Menegário, T.F., Toledo, M.C.F., 2006. Detemination of polycyclic aromatic hydrocarbons (PAHS) in guarana powder (Paullinia cupana). Cienc. Tecnol. Aliment. 26, 230-234.) showed a wide variation in the average levels of PAH (0.05-13.95 µg kg-1), among the evaluated brands. Another study reported the concentration of PAH found in various brands of guarana powder ranged from 0.39 to 1.60 µg kg-1 (Veiga et al., 2014Veiga, L.L.A., Amorim, H., Moraes, J., Silva, M.C., Raices, R.S.L., Quiterio, S.L., 2014. Quantification of polycyclic aromatic hydrocarbons in toasted guarana (Paullinia cupana) by high-performance liquid chromatography with a fluorescence detector. Food Chem. 152, 612-618.). These results indicate that this wide concentration range probably results from the various forms of guarana processing, leading to the presence of these contaminants in the final product. However, the quantities of PAHs found were below the values set by European legislation (EC 835/2011) for other food types, as there is no specific legislation in Brazil for the safe limit of these compounds in guarana.

Box 4
Chemical structures of polycyclic aromatic hydrocarbons that may be present as contaminants of guarana seeds, other sources and their effects on humans. Source: Pubchem. https://pubchem.ncbi.nlm.nih.gov/.

There is a need to implement analytical tests of quality control that are accurate, sensitive, reproducible, easy to implement, and low-cost, for both the analysis of a medicinal plant, as well as for the analysis of its extracts and derivatives. There are several physicochemical and analytical tests used to characterize a medicinal plant, for example, loss on drying, level of extractives, dry matter content, level of methylxanthines, total tannins, moisture, and ash. Thermal analysis, for example, thermogravimetry, is a potential tool for measuring technological parameters, in quality control, and in the analysis of moisture and ash contents (Araújo et al., 2006Araújo, A.A.S., Mercuri, L.P., Seixas, S.R.S., Storpirtis, S., Matos, J.R., 2006. Determination of humidity and ash content of guarana commercial samples using conventional method and thermal analysis. Rev. Cienc. Farm. Básica Apl. 42, 269-277.). Spectrophotometric methods have been used in samples of guarana seeds to determine methylxanthines and total tannins (Ushirobira et al., 2004Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Audi, E.A., Mello, J.C.P., 2004. Avaliação físico-química de sementes de guarana secas por diferentes métodos. Rev. Bras. Farmacogn. 14, 15-20.; Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.; Sousa et al., 2011Sousa, S.A., Pascoa, H., Conceição, E.C., Alves, S.F., Diniz, D.G.A., Paula, J.R., Bara, M.T.F., 2011. Dissolution test of herbal medicines containing Paullinia cupana: validation of methods for quantifcation and assessment of dissolution. Braz. J. Pharm. Sci. 47, 269-277.).

UV-visible spectrophotometry, chromatographic analysis by thin-layer chromatography, HPLC (Marx and Maia, 1990Marx, F., Maia, J.G., 1990. Analysis of guarana (Paullinia cupana var, sorbilis). III. Identification and determination of guaraná beverages by HPLC analysis of caffeine anda theophylline. Quim. Nova 13, 285-286.; Klein et al., 2012Klein, T., Longuini, R., Mello, J.C.P., 2012. Development of an analytical method using reversed-phase HPLC-PDA for a semipurified extract of Paullinia cupana var. sorbilis (guarana). Talanta 88, 502-506.; Machado et al., 2018Machado, K.N., Freitas, A.A.d., Cunha, L.H., Faraco, A.A.G., Pádua, R.M.d., Braga, F.C., Vianna-Soares, C.D., Castilho, R.O., 2018. A rapid simultaneous determination of methylxanthines and proanthocyanidins in Brazilian guaraná (Paullinia cupana Kunth.). Food Chem. 239, 180-188.), CZE (Sombra et al., 2005Sombra, L.L., Gómez, M.R., Olsina, R., Luis, D., Martínez, L.D., Silva, M.F., 2005. Comparative study between capillary electrophoresis and high performance liquid chromatography in ‘guarana' based phytopharmaceuticals. J. Pharm. Biomed. Anal. 36, 989-994.; Kofink et al., 2007Kofink, M., Papagiannopoulos, M., Galensa, R., 2007. Enantioseparation of catechin and epicatechin in plant food by chiral capillary electrophoresis. Eur. Food Res. Technol. 225, 569-577.), and micellar electrokinetic chromatography (Mello and Ito, 2012Mello, J.C.P., Ito, L.A., 2012. Aplicação da eletroforese capilar na análise de produtos naturais. In: Souza, G.H.B., Mello, J.C.P., Lopes, N.P. (Eds.), Revisões em Processos e Técnicas Avançadas de Isolamento e Determinação Estrutural Ativos de Plantas Medicinais. UFOP, Ouro Preto, pp. 209–242.) are techniques used in the separation of substances present in the guarana extract. This is an important step to establish a chromatographic profile of the extracts and consequently, their standardization.

A simple and rapid HPLC-PDA method was developed and validated for the simultaneous quantification of seven chemical markers in dry guaraná seed powder: theobromine, theophylline, caffeine, catechin, epicatechin, procyanidins A2 and B2 (Machado et al., 2018Machado, K.N., Freitas, A.A.d., Cunha, L.H., Faraco, A.A.G., Pádua, R.M.d., Braga, F.C., Vianna-Soares, C.D., Castilho, R.O., 2018. A rapid simultaneous determination of methylxanthines and proanthocyanidins in Brazilian guaraná (Paullinia cupana Kunth.). Food Chem. 239, 180-188.). The extraction method developed employed liquid-solid maceration using a solvent mixture of ethanol:water (8:2, v/v) with diluted acid (H3PO4 0.1% in water, v/v) with three successive extractions in 10 min each.

Preparation of extracts, standardization and pharmaceutical forms

The choice of extraction method is the most important part of the extraction process because the composition of bioactives will be heavily dependent on this step and, consequently, it will have an impact on the expected pharmacological action. This can occur in both alternative ("green") extractions, such as supercritical extractions (by microwave or ultrasound) and in conventional extractions, namely, liquid extractions based on organic solvents or mechanical pressing. Supercritical extraction, for example, can be selective, and can obtain more or less polar compounds, according to the cosolvent added to the system, or by defining other conditions of extraction, for example, temperature (Marques et al., 2016Marques, L.L.M., Panizzon, G.P., Aguiar, B.A.A., Simionato, A.S., Cardozo-Filho, L., Andrade, G., Oliveira, A.G.d., Guedes, T.A., Mello, J.C.P., 2016. Guarana (Paullinia cupana) seeds: selective supercritical extraction of phenolic compounds. Food Chem. 212, 703-711.). In addition, supercritical extracts of the same plant can show a greater concentration of phenolic compounds and antiradical activity than extracts resulting from solid extraction-liquid extraction (Pinelo et al., 2007Pinelo, M., Ruiz-Rodríguez, A., Sineiro, J., Señoráns, F.J., Reglero, G., Núnez, M.J., 2007. Supercritical fluid and solid-liquid extraction of phenolic antioxidants from grape pomace: a comparative study. Eur. Food Res. Technol. 226, 199-205.). They can even be more effective in extracting substances with antimicrobial activity compared with extracts obtained from methanolic extraction (Liu et al., 2007Liu, X., Zhao, M., Wang, J., Luo, W., 2007. Antimicrobial and antioxidant activity of emblica extracts obtained by supercritical carbon dioxide extraction and methanol extraction. J. Food Biochem. 33, 307-330.). A similar behavior occurs in conventional extractions, that is, they may present more or less pronounced biological activities, or even absence of activity, depending on the conditions of extraction used for the same plant (Kalia et al., 2008Kalia, K., Sharma, K., Singh, H.P., Singh, B., 2008. Effects of extraction methods on phenolic contents and antioxidant activity in aerial parts of Potentilla atrosanguinea Lodd. and quantification of its phenolic constituents by RP-HPLC. J. Agric. Food Chem. 56, 10129-10134.; Chiste et al., 2014Chiste, R.C., Benassi, M.D., Mercadante, A.Z., 2014. Efficiency of different solvents on the extraction of bioactive compounds from the Amazonian fruit Caryocar villosum and the effect on its antioxidant and colour properties. Phytochem. Anal. 25, 364-372.; Murugan and Parimelazhagan, 2014Murugan, R., Parimelazhagan, T., 2014. Comparative evaluation of different extraction methods for antioxidant and anti-inflammatory properties from Osbeckia parvifolia Arn. - an in vitro approach. J. King Saud Univ. Sci. 26, 267-275.; Bektas et al., 2016Bektas, E., Daferera, D., Sokmen, M., Serdar, G., Erturk, M., Polissiou, M.G., Sokmen, A., 2016. In vitro antimicrobial, antioxidant, and antiviral activities of the essential oil and various extracts from Thymus nummularis M. Bieb. Indian J. Tradit. Knowl. 15, 403-410.; Nguyen et al., 2016Nguyen, V.T., Pham, H.N.T., Bowyer, M.C., van Altena, I.A., Scarlett, C.J., 2016. Influence of solvents and novel extraction methods on bioactive compounds and antioxidant capacity of Phyllanthus amarus. Chem. Pap. 70, 556-566.). Therefore, it is still surprising that many studies do not consider these aspects in the preparation of herbal drugs and do not clarify how the relevant extract was prepared.

Some authors indicate the treatment dose based on guarana seed powder (Galduróz and Carlini, 1994Galduróz, J.C.F., Carlini, E.A., 1994. Acute effects of the Paullinia cupana, "guarana" on the cognition of normal volunteers. São Paulo Med. J. 112, 607-611., 1996Galduróz, J.C.F., Carlini, E.A., 1996. The effects of long-term administration of guarana on the cognition of normal, elderly volunteers. São Paulo Med. J. 114, 1073-1078.; Fukumasu et al., 2006bFukumasu, H., Silva, T.C.d., Avanzo, J.L., Lima, C.E.d., Mackwiak, I.I., Atroch, A., Spinosa, H.d.S., Moreno, F.S., Dagli, M.L.Z., 2006. Chemopreventive effects of Paullinia cupana Mart. var. sorbilis, the guarana, on mouse hepatocarcinogenesis. Cancer Lett. 233, 158-164.; Bulku et al., 2010Bulku, E., Zinkovsky, D., Patel, P., Javia, V., Lahoti, T., Khodos, I., Stohs, S.J., Ray, S.D., 2010. A novel dietary supplement containing multiple phytochemicals and vitamins elevates hepatorenal and cardiac antioxidant enzymes in the absence of significant serum chemistry and genomic changes. Oxid. Med. Cell. Longev. 3, 129-144.), often bought commercially and previously ground, in the form of capsules or tablets (Campos et al., 2011Campos, M.P.d.O., Riechelmann, R., Casa, L.B.A., Hassan, B.J., Casa, F.B.A., Giglio, A.D., 2011. Guarana (Paullinia cupana) improves fatigue in breast cancer patients undergoing systemic chemotherapy. J. Altern. Complement. Med. 17, 505-512.; Silvestrini et al., 2013Silvestrini, G.I., Marino, F., Cosentino, M., 2013. Effects of a commercial product containing guarana on psychological well-being, anxiety and mood: a single-blind, placebo-controlled study in healthy subjects. J. Negat. Results Biomed. 12, http://dx.doi.org/10.1186/1477-5751-12-9.
http://dx.doi.org/10.1186/1477-5751-12-9...
). In other studies, the treatment involves simple dilution of the powder in water or another solvent of the toasted and ground seed alone (Espinola et al., 1997Espinola, E.B., Dias, R.F., Mattei, R., Carlini, E.A., 1997. Pharmacological activity of guaraná (Paullinia cupana Mart.) in laboratory animals. J. Ethnopharmacol. 55, 223-229.; de Oliveira et al., 2002de Oliveira, J.F., Avila, A.S., Braga, A.C., de Oliveira, M.B., Boasquevisque, E.M., Jales, R.L., Cardoso, V.N., Bernardo-Filho, M., 2002. Effect of extract of medicinal plants on the labeling of blood elements with Technetium-99m and on the morphology of red blood cells: I - a study with Paullinia cupana. Fitoterapia 73, 305-312.; Fukumasu et al., 2006aFukumasu, H., Avanzo, J.L., Heidor, R., Silva, T.C., Atroch, A., Moreno, F.S., Dagli, M.L.Z., 2006. Protective effects of guarana (Paullinia cupana Mart. var. sorbilis) against DEN-induced DNA damage on mouse liver. Food Chem. Toxicol. 44, 862-867.; Freitas et al., 2007Freitas, R.S., Moreno, S.R.F., Lima-Filho, G.L., Fonseca, A.S., Bernardo-Filho, M., 2007. Effect of a commercial extract of Paullinia cupana (guarana) on the binding of 99mTc-DMSA on blood constituents: an in vivo study. Appl. Radiat. Isot. 65, 528-533.; Fukumasu et al., 2008Fukumasu, H., Avanzo, J.L., Nagamine, M.K., Barbuto, J.A., Rao, K.V., Dagli, M.L.Z., 2008. Paullinia cupana Mart var. sorbilis, guarana, reduces cell proliferation and increases apoptosis of B16/F10 melanoma lung metastases in mice Braz. J. Med. Biol. Res. 41, 305-310., 2011Fukumasu, H., Latorre, A.O., Zaidan-Dagli, M.L., 2011. Paullinia cupana Mart. var. sorbilis, guarana, increases survival of Ehrlich ascites carcinoma (EAC) bearing mice by decreasing cyclin-D1 expression and inducing a G0/G1cell cycle arrest in EAC cells. Phytother. Res. 25, 11-16.; Krewer et al., 2011Krewer, C.C., Ribeiro, E.E., Ribeiro, E.A.M., Moresco, R.N., da Rocha, M.I.U.M., Montagner, G.F.F.S., Machado, M.M., Viegas, K., Brito, E., da Cruz, I.B.M., 2011. Habitual intake of guarana and metabolic morbidities: an epidemiological study of an elderly Amazonian population. Phytother. Res. 25, 1367-1374.; Leite et al., 2011Leite, R.P., Wada, R.S., Monteiro, J.C., Predes, F.S., Dolder, H., 2011. Protective effect of guarana (Paullinia cupana var. sorbilis) pre-treatment on cadmium-induced damages in adult Wistar testis. Biol. Trace Elem. Res. 141, 262-274.; Oliveira et al., 2011Oliveira, D.M., Barreto, G., Galeano, P., Romero, J.I., Holubiec, M.I., Badorrey, M.S., Capani, F., Alvarez, L.D.G., 2011. Paullinia cupana Mart. var. sorbilis protects human dopaminergic neuroblastoma SH-SY5Y cell line against rotenone-induced cytotoxicity. Hum. Exp. Toxicol. 30, 1382-1391.; Leite et al., 2013Leite, R.P., Predes, F.S., Monteiro, J.C., Freitas, K.M., Wada, R.S., Dolder, H., 2013. Advantage of guarana (Paullinia cupana Mart.) supplementation on cadmium-induced damages in testis of adult wistar rats. Toxicol. Pathol. 41, 73-79.; Kober et al., 2016Kober, H., Tatsch, E., Torbitz, V.D., Cargnin, L.P., Sangoi, M.B., Bochi, G.V., da Silva, A.R.H., Barbisan, F., Ribeiro, E.E., da Cruz, I.B.M., Moresco, R.N., 2016. Genoprotective and hepatoprotective effects of guarana (Paullinia cupana Mart. var. sorbilis) on CCl4-induced liver damage in rats. Drug. Chem. Toxicol. 39, 48-52.; Yonekura et al., 2016Yonekura, L., Martins, C.A., Sampaio, G.R., Monteiro, M.P., Cesar, L.A.M., Mioto, B.M., Mori, C.S., Mendes, T.M.N., Ribeiro, M.L., Arcari, D.P., Torres, E., 2016. Bioavailability of catechins from guarana (Paullinia cupana) and its effect on antioxidant enzymes and other oxidative stress markers in healthy human subjects. Food Funct. 7, 2970-2978.). In addition, ground guarana seeds or their extracts may be used in association with other herbal drugs, usually in commercially available formulations (Antunes et al., 2001Antunes, E., Gordo, W.M., de Oliveira, J.F., Teixeira, C.E., Hyslop, S., De Nucci, G., 2001. The relaxation of isolated rabbit corpus cavernosum by the herbal medicine Catuama and its constituents. Phytother. Res. 15, 416-421.; Boozer et al., 2001Boozer, C.N., Nasser, J.A., Heymsfield, S.B., Wang, V., Chen, G., Solomon, J.L., 2001. An herbal supplement containing Ma Huang-guarana for weight loss: a randomized, double-blind trial. Int. J. Obes. 25, 316-324.; Campos et al., 2004Campos, M.M., Fernandes, E.S., Ferreira, J., Bortolanza, L.B., Santos, A.R., Calixto, J.B., 2004. Pharmacological and neurochemical evidence for antidepressant-like effects of the herbal product Catuama. Pharmacol. Biochem. Behav. 78, 757-764.; Bérubé-Parent et al., 2005Bérubé-Parent, S., Pelletier, C., Doré, J., Tremblay, A., 2005. Effects of encapsulated green tea and guarana extracts containing a mixture of epigallocatechin-3-gallate and caffeine on 24 h energy expenditure and fat oxidation in men. Br. J. Nutr. 94, 432-436.; Opala et al., 2006Opala, T., Rzymski, P., Pischel, I., Wilczak, M., Wozniak, J., 2006. Efficacy of 12 weeks supplementation of a botanical extract-based weight loss formula on body weight, body composition and blood chemistry in healthy, overweight subjects-a randomised double-blind placebo-controlled clinical trial. Eur. J. Med. Res. 11, 343-350.; Ruxton et al., 2007Ruxton, C.H.S., Kirkwood, L., McMillan, B., John, D.S., Evans, C.E.L., 2007. Effectiveness of a herbal supplement (Zotrim™) for weight management. Brit. Food J. 109, 416-428.; Kennedy et al., 2008Kennedy, D.O., Haskell, C.F., Robertson, B., Reay, J., Brewster-Maund, J.C., Luedemann, J., Maggini, S., Ruf, M., Zangara, A., Scholey, A.B., 2008. Improved cognitive performance and mental fatigue following a multi-vitamin and mineral supplement with added guarana (Paullinia cupana). Appetite 50, 506-513.; Bulku et al., 2010Bulku, E., Zinkovsky, D., Patel, P., Javia, V., Lahoti, T., Khodos, I., Stohs, S.J., Ray, S.D., 2010. A novel dietary supplement containing multiple phytochemicals and vitamins elevates hepatorenal and cardiac antioxidant enzymes in the absence of significant serum chemistry and genomic changes. Oxid. Med. Cell. Longev. 3, 129-144.; Pomportes et al., 2015aPomportes, L., Davranche, K., Brisswalter, I., Hays, A., Brisswalter, J., 2015. Heart rate variability and cognitive function following a multi-vitamin and mineral supplementation with added guarana (Paullinia cupana). Nutrients 7, 196-208., 2017Pomportes, L., Brisswalter, J., Casini, L., Hays, A., Davranche, K., 2017. Cognitive performance enhancement induced by caffeine, carbohydrate and guarana mouth rinsing during submaximal exercise. Nutrients 9, http://dx.doi.org/10.3390/nu9060589.
http://dx.doi.org/10.3390/nu9060589...
). Several studies have reported on an extract obtained using a controlled temperature, defined extraction time and standardized amount of solvent (Bydlowski et al., 1988Bydlowski, S.P., Yunker, R.L., Subbiah, M.T., 1988. A novel property of an aqueous guarana extract (Paullinia cupana): inhibition of platelet aggregation in vitro and in vivo. Braz. J. Med. Biol. Res. 21, 535-538.; Bydlowski et al., 1991Bydlowski, S.P., D'Amico, E.A., Chamone, D.A.F., 1991. An aqueous extract of guarana (Paullinia cupana) decreases platelet thromboxane synthesis. Braz. J. Med. Biol. Res. 24, 421-424.; Miura et al., 1998Miura, T., Tatara, M., Nakamura, K., Suzuki, I., 1998. Effect of guarana on exercise in normal and epinephrine-induced glycogenolytic mice. Biol. Pharm. Bull. 21, 646-648.; Barbosa and Mello, 2004Barbosa, G.D.A., Mello, J.C.P., 2004. Clinical evaluation of the guarana extract on the dental plaque control. Rev. Paul. Odontol. 26, 28-30.; Basile et al., 2005Basile, A., Ferrara, L., Del Pezzo, M., Mele, G., Sorbo, S., Bassi, P., Montesano, D., 2005. Antibacterial and antioxidant activities of ethanol extract from Paullinia cupana Mart. J. Ethnopharmacol. 102, 32-36.; Lima et al., 2005Lima, W.P., Carnevali, J.L.C., Eder, R., Rosa, L.F.B.P.C., Bacchi, E.M., Seelaender, M.C.L., 2005. Lipid metabolism in trained rats: effect of guarana (Paullinia cupana Mart.) supplementation. Clin. Nutr. 24, 1019-1028.; Haskell et al., 2007Haskell, C.F., Kennedy, D.O., Wesnes, K.A., Milne, A.L., Scholey, A.B., 2007. A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans. J. Psychopharmacol. 21, 65-70.; Jippo et al., 2009Jippo, T., Kobayashi, Y., Sato, H., Hattori, A., Takeuchi, H., Sugimoto, K., Shigekawa, M., 2009. Inhibitory effects of guarana seed extract on passive cutaneous anaphylaxis and mast cell degranulation. Biosci. Biotechnol. Biochem. 73, 2110-2112.; Portella et al., 2013Portella, R.L., Barcelos, R.P., Rosa, E.J.F., Ribeiros, E.E., Cruz, I.B.M., Suleiman, L., Soares, F.A.A., 2013. Guarana (Paullinia cupana Kunth) effects on LDL oxidation in elderly people: an in vitro and in vivo study. Lipids Health Dis. 12, 1-9.; Machado et al., 2015Machado, A.K., Canodá, F.C., Azzolin, V.F., Dornelles, E.B., Barbisan, F., Ribeiro, E.E., Mânica-Cattani, M.F., Duarte, M.M.M.F., Saldanha, J.R.P., Cruz, I.B.M., 2015. Guarana (Paullinia cupana) improves the proliferation and oxidative metabolim of senescent adipocyte stem cells derived from human lipoaspirates. Food Res. Int. 67, 426-433.). Other authors grind the intact seed and subsequently extract it with organic solvents and then semipurify these extracts, commonly by means of partitions with different solvents (Otobone et al., 2005Otobone, F.J., Sanches, A.C., Nagae, R.L., Martins, J.V.C., Obici, S., Mello, J.C.P., Audi, E.A., 2005. Effect of crude extract and its semi purifies constituents from guarana seeds (Paullinia cupana var. sorbilis (Mart.)) Lucke on cognitive performance in morris water maze in rats. Braz. Arch. Biol. Technol. 48, 723-728., 2007Otobone, F.J., Sanches, A.C.C., Magae, R.L., Martins, J.V.C., Sela, V.R., Mello, J.C.P., Audi, E.A., 2007. Effect off liophilized extracts from guarana seeds [Paullinia cupana var. sorbilis (Mart.) Ducke] on behavioral profiles in rats. Phytother. Res. 21, 531-535.; Antonelli-Ushirobira et al., 2007Antonelli-Ushirobira, T.M., Yamaguti, E., Uemura, L.M., Nakamura, C.V., Dias Filho, B.P., Mello, J.C.P., 2007. Chemical and microbiological study of extract from seeds of guarana (Paullinia cupana var. sorbilis). Lat. Am. J. Pharm. 26, 5-9.; Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.; Roncon et al., 2011Roncon, C.M., De Almeida, C.B., Klein, T., Mello, J.C.P., Audi, E.A., 2011. Anxiolytic effects of a semipurified constituent of guarana seeds on rats in the elevated T-maze test. Planta Med. 77, 236-241.; Dalonso and Petkowicz, 2012Dalonso, N., Petkowicz, C.L.d.O., 2012. Guarana powder polysaccharides: characterisation and evaluation of the antioxidant activity of a pectic fraction. Food Chem. 134, 1804-1812.; Rangel et al., 2013Rangel, M.P., Mello, J.C.P., Audi, E.A., 2013. Evaluation of neurotransmitters involved in the anxiolytic and panicolytic effect of the aqueous fraction of Paullinia cupana (guarana) in elevated T maze. Rev. Bras. Farmacogn. 23, 358-365.; Matsuura et al., 2015Matsuura, E., Godoy, J.S.R., Bonfim-Mendonça, P.S., Mello, J.C.P., Svidzinski, T.I.E., Gasparetto, A., Maciel, S.M., 2015. In vitro effect of Paullinia cupana (guarana) on hydrophobicity, biofilm formation, and adhesion of Candida albicans to polystyrene, composites, and buccal epithelial cells. Arch. Oral Biol. 60, 471-478.) or other types of extraction, for example, supercritical extraction (Mehr et al., 1996Mehr, C.B., Biswal, R.N., Collins, J.L., 1996. Supercritical carbon dioxide extraction of caffeine from guarana. J. Supercrit. Fluids 9, 185-191.; Saldaña et al., 2002Saldaña, M.D.A., Zetzl, C., Mohamed, R.S., Brunner, G., 2002. Extraction of methylxanthines from guaraná seeds, mate leaves, and cocoa beans using supercritical carbon dioxide and ethanol. J. Agric. Food Chem. 50, 4820-4826.; Marques et al., 2016Marques, L.L.M., Panizzon, G.P., Aguiar, B.A.A., Simionato, A.S., Cardozo-Filho, L., Andrade, G., Oliveira, A.G.d., Guedes, T.A., Mello, J.C.P., 2016. Guarana (Paullinia cupana) seeds: selective supercritical extraction of phenolic compounds. Food Chem. 212, 703-711.).

All of these methods of extraction or preparation of the samples are valid, provided that researchers perform quality control of herbal drugs and standardization of the extract by means of chromatographic or spectroscopic techniques (Ushirobira et al., 2004Ushirobira, T.M.A., Yamaguti, E., Uemura, L.M., Audi, E.A., Mello, J.C.P., 2004. Avaliação físico-química de sementes de guarana secas por diferentes métodos. Rev. Bras. Farmacogn. 14, 15-20.; Edwards et al., 2005Edwards, H.G.M., Farwell, D.W., Oliveira, L.F.C., Alia, J.-M., Hyaric, M.L., Ameida, M.V., 2005. FT-Raman spectroscopic studies of guarana and some extracts. Anal. Chim. Acta 532, 177-186.; Sombra et al., 2005Sombra, L.L., Gómez, M.R., Olsina, R., Luis, D., Martínez, L.D., Silva, M.F., 2005. Comparative study between capillary electrophoresis and high performance liquid chromatography in ‘guarana' based phytopharmaceuticals. J. Pharm. Biomed. Anal. 36, 989-994.; Kofink et al., 2007Kofink, M., Papagiannopoulos, M., Galensa, R., 2007. Enantioseparation of catechin and epicatechin in plant food by chiral capillary electrophoresis. Eur. Food Res. Technol. 225, 569-577.; Pelozo et al., 2008Pelozo, M.I.G., Cardoso, M.L.C., Mello, J.C.P., 2008. Spectrophotometric determination of tannins and caffeine in preparations from Paullinia cupana var. sorbilis. Braz. Arch. Biol. Technol. 51, 447-451.; Klein et al., 2012Klein, T., Longuini, R., Mello, J.C.P., 2012. Development of an analytical method using reversed-phase HPLC-PDA for a semipurified extract of Paullinia cupana var. sorbilis (guarana). Talanta 88, 502-506.; Roggia et al., 2016Roggia, I., Ziegler, S., Cruz, I.B.M., Ourique, A.F., Gomes, P., 2016. A derivative UV spectrophotometric method for the determination of methylxanthines and tannins in guarana bulk (Paullinia cupana) Int. J. Pharm. Sci. Res. 7, 2334-2342.; Mingori et al., 2017Mingori, M.R., Heimfarth, L., Ferreira, C.F., Gomes, H.M., Moresco, K.S., Delgado, J., Roncato, S., Zeidan-Chulia, F., Gelain, D.P., Moreira, J.C.F., 2017. Effect of Paullinia cupana Mart. commercial extract during the aging of middle age Wistar rats: differential effects on the hippocampus and striatum. Neurochem. Res. 42, 2257-2273.). However, most studies to date have not quoted if quality control of medications was performed. Often, there is also a lack of essential information about the process, for example, the type of extraction performed, the solvent used, temperature, time of extraction or other relevant and important information necessary for the standardization.

An efficient way that some authors have found to give greater reliability to their results, as well as provide specific information about the steps of extraction, is the standardization of analytical methods to evaluate and quantify the major components of their extracts (Kennedy et al., 2004Kennedy, D.O., Haskell, C.F., Wesnes, K.A., Scholey, A.B., 2004. Improved cognitive performance in human volunteers following administration of guarana (Paullinia cupana) extract: comparison and interaction with Panax ginseng. Pharmacol. Biochem. Behav. 79, 401-411.; Haskell et al., 2007Haskell, C.F., Kennedy, D.O., Wesnes, K.A., Milne, A.L., Scholey, A.B., 2007. A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans. J. Psychopharmacol. 21, 65-70.; Majhenic et al., 2007Majhenic, L., Skerget, M., Knez, Z., 2007. Antioxidant and antimicrobial activity of guarana seed extracts. Food Chem. 104, 1258-1268.; Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.; Campos et al., 2011Campos, M.P.d.O., Riechelmann, R., Casa, L.B.A., Hassan, B.J., Casa, F.B.A., Giglio, A.D., 2011. Guarana (Paullinia cupana) improves fatigue in breast cancer patients undergoing systemic chemotherapy. J. Altern. Complement. Med. 17, 505-512.; Fukumasu et al., 2011Fukumasu, H., Latorre, A.O., Zaidan-Dagli, M.L., 2011. Paullinia cupana Mart. var. sorbilis, guarana, increases survival of Ehrlich ascites carcinoma (EAC) bearing mice by decreasing cyclin-D1 expression and inducing a G0/G1cell cycle arrest in EAC cells. Phytother. Res. 25, 11-16.; Roncon et al., 2011Roncon, C.M., De Almeida, C.B., Klein, T., Mello, J.C.P., Audi, E.A., 2011. Anxiolytic effects of a semipurified constituent of guarana seeds on rats in the elevated T-maze test. Planta Med. 77, 236-241.; Bittencourt et al., 2013Bittencourt, L.S., Machado, D.C., Machado, M.M., Dos Santos, G.F.F., Algarve, T.D., Marinowic, D.R., Ribeiro, E.E., Soares, F.A.A., Barbisan, F., Athayde, M.L., Cruz, I.B.M., 2013. The protective effects of guarana extract (Paullinia cupana) on fibroblast NIH-3T3 cells exposed to sodium nitroprusside. Food Chem. Toxicol. 53, 119-125., 2014Bittencourt, L.S., Zeidán-Chuliá, F., Yatsu, F.K.J., Schnorr, C.E., Moresco, K.S., Kolling, E.A., Gelain, D.P., Bassani, V.L., Moreira, J.C.F., 2014. Guarana (Paullinia cupana Mart.) prevents β-amyloid aggregation, generation of advanced glycation-end products (AGEs), and acrolein-induced cytotoxicity on human neuronal-like cells. Phytother. Res. 28, 1615-1624.; Portella et al., 2013Portella, R.L., Barcelos, R.P., Rosa, E.J.F., Ribeiros, E.E., Cruz, I.B.M., Suleiman, L., Soares, F.A.A., 2013. Guarana (Paullinia cupana Kunth) effects on LDL oxidation in elderly people: an in vitro and in vivo study. Lipids Health Dis. 12, 1-9.; Hertz et al., 2015Hertz, E., Cadoná, F.C., Machado, A.K., Azzolin, V., Holmrich, S., Assmann, C., Ledur, P., Ribeiro, E.E., Filho, O.C.d.S., Mânica-Cattani, M.F., Cruz, I.B.M.d., 2015. Effect of Paullinia cupana on MCF-7 breast cancer cell response to chemotherapeutic drugs. Mol. Clin. Oncol. 3, 37-43.; Kober et al., 2016Kober, H., Tatsch, E., Torbitz, V.D., Cargnin, L.P., Sangoi, M.B., Bochi, G.V., da Silva, A.R.H., Barbisan, F., Ribeiro, E.E., da Cruz, I.B.M., Moresco, R.N., 2016. Genoprotective and hepatoprotective effects of guarana (Paullinia cupana Mart. var. sorbilis) on CCl4-induced liver damage in rats. Drug. Chem. Toxicol. 39, 48-52.), for example, by HPLC (Klein et al., 2012Klein, T., Longuini, R., Mello, J.C.P., 2012. Development of an analytical method using reversed-phase HPLC-PDA for a semipurified extract of Paullinia cupana var. sorbilis (guarana). Talanta 88, 502-506.; Cadona et al., 2016Cadona, F.C., Machado, A.K., Azzolin, V.F., Barbisan, F., Dornelles, E.B., Glanzner, W., Goncalves, P.B.D., Assmann, C.E., Ribeiro, E.E., da Cruz, I.B.M., 2016. Guarana caffeine-rich food increases oxaliplatin sensitivity of colorectal HT-29 cells by apoptosis pathway modulation. Anti-Cancer Agents Med. Chem. 16, 1055-1065.; Machado et al., 2018Machado, K.N., Freitas, A.A.d., Cunha, L.H., Faraco, A.A.G., Pádua, R.M.d., Braga, F.C., Vianna-Soares, C.D., Castilho, R.O., 2018. A rapid simultaneous determination of methylxanthines and proanthocyanidins in Brazilian guaraná (Paullinia cupana Kunth.). Food Chem. 239, 180-188.), CZE (Kofink et al., 2007Kofink, M., Papagiannopoulos, M., Galensa, R., 2007. Enantioseparation of catechin and epicatechin in plant food by chiral capillary electrophoresis. Eur. Food Res. Technol. 225, 569-577.), and NMR (Yamaguti-Sasaki et al., 2007Yamaguti-Sasaki, E., Ito, L.A., Canteli, V.C.D., Ushirobira, T.M.A., Ueda-Nakamura, T., Dias Filho, B.P., Nakamura, C.V., Mello, J.C.P., 2007. Antioxidant capacity and in vitro prevention of dental plaque formation by extracts and condensed tannins of Paullinia cupana. Molecules 12, 1950-1963.). The key substances present in the guarana plant can be used as chemical markers (Funasaki et al., 2016Funasaki, M., Barroso, H.D., Fernandes, V.L.A., Menezes, I.S., 2016. Amazon rainforest cosmetics: chemical approach for quality control. Quim. Nova 39, 194-209.). The intake of ultrafine guarana powder was used in overweight humans, by diluting this powder at the time of consumption (Yonekura et al., 2016Yonekura, L., Martins, C.A., Sampaio, G.R., Monteiro, M.P., Cesar, L.A.M., Mioto, B.M., Mori, C.S., Mendes, T.M.N., Ribeiro, M.L., Arcari, D.P., Torres, E., 2016. Bioavailability of catechins from guarana (Paullinia cupana) and its effect on antioxidant enzymes and other oxidative stress markers in healthy human subjects. Food Funct. 7, 2970-2978.). These authors searched the nutrients of the powder (proteins, lipids, carbohydrates, ashes, humidity, and calories) and phytochemical composition of guarana seeds (total polyphenols, catechins, proanthocyanidins, and methylxanthines) after extraction, and investigated the individual flavonoids by HPLC with an electrochemical detector.

Other authors have prepared dosage forms of these fractionated and standardized extracts. The development of a pharmaceutical form comprises several steps including studies on pre-formulation and formulation themselves, which consist of the physical, chemical, physicochemical, and biological characterization of all raw materials including the drug used in the preparation of the product, as well as the anatomical and physiological characterization of the route of administration and absorption and, finally, the preparation of the dosage form (Wanczinski et al., 2002Wanczinski, B.J., Felipe, D.F., Cardoso, M.L.C., Cavalcanti, O.A., 2002. Development of AAS 500 mg tablets influenced by direct compression (CD) process. Acta Sci. 24, 649-655.).

From a pharmaceutical technology perspective, the drying of plant extracts is a crucial step to developing a product suitable for industrial use and therapeutic application (Couto et al., 2013Couto, R.O., Martins, F.S., Chaul, L.T., Conceição, E.C., Freitas, L.A.P., Bara, M.T.F., Paula, J.R., 2013. Spray drying of Eugenia dysenterica extract: effects of in-process parameters on product quality. Rev. Bras. Farmacogn. 23, 115-123.). Spray drying is a promising approach for the development of phytopharmaceutical intermediate products. It is a method of preparation of microparticles that is widely used in the fields of pharmaceutics and biochemistry and in the food industry due to the wide availability of the equipment and ease of industrialization. A UV-vis method of validation was developed for the quantification of caffeine and total polyphenols using the granulated form of the extract of guarana seeds (Pelozo et al., 2008Pelozo, M.I.G., Cardoso, M.L.C., Mello, J.C.P., 2008. Spectrophotometric determination of tannins and caffeine in preparations from Paullinia cupana var. sorbilis. Braz. Arch. Biol. Technol. 51, 447-451.). The method showed a good performance in the quantification of caffeine and total polyphenols. Microspheres containing semipurified guarana extract were obtained by spray-drying, using a combination of maltodextrin and gum arabic, which provided a satisfactory encapsulation efficiency (80-110%) and product efficiency (55-60%), thus, demonstrating the viability of producing these microspheres by spray-drying (Klein et al., 2015Klein, T., Longhini, R., Bruschi, M.L., Mello, J.C.P., 2015. Microparticles containing guarana extract obtained by spray-drying technique: development and characterization. Rev. Bras. Farmacogn. 25, 292-300.).

In another study, the same group of researchers evaluated the technical feasibility of producing a semipurified extract of guarana in tablet form, using a process of direct compression (Klein et al., 2013Klein, T., Longhini, R., Bruschi, M.L., Mello, J.C.P., 2013. Development of tablets containing semipurifi ed extract of guarana (Paullinia cupana). Rev. Bras. Farmacogn. 23, 186-193.). Using method provided in pharmacopoeia, technological and physical-chemical assays were performed. They obtained tablets with quality features that meet pharmacological specifications and are suitable and safe for administration (Klein et al., 2013Klein, T., Longhini, R., Bruschi, M.L., Mello, J.C.P., 2013. Development of tablets containing semipurifi ed extract of guarana (Paullinia cupana). Rev. Bras. Farmacogn. 23, 186-193.). Although several authors are concerned about standardizing extracts to investigate their biological activity or pharmacological effect, there are still gaps to be filled regarding the form of preparation of the medicinal plant, in numerous studies which use guarana seeds.

The dissolution behavior of various herbal medicines in the form of capsules and pills containing guarana obtained from different locations was evaluated (Sousa et al., 2011Sousa, S.A., Pascoa, H., Conceição, E.C., Alves, S.F., Diniz, D.G.A., Paula, J.R., Bara, M.T.F., 2011. Dissolution test of herbal medicines containing Paullinia cupana: validation of methods for quantifcation and assessment of dissolution. Braz. J. Pharm. Sci. 47, 269-277.). These authors found that 100% of the herbal drugs examined, were in disagreement about the presence of 4 markers, showing that 60% had 3 markers (caffeine, catechin, and epicatechin), while 40% had just caffeine. Only the capsules had at least 80% of the markers. The fourth marker, theophylline, was not found in any of these herbal medicines. These results highlight the need for rigorous quality control, starting with the medicinal plant, thus, ensuring the therapeutic action of these drugs.

Some authors carefully report the implementation of quality control of the drug. However, values of caffeine and total tannins of guarana are discrepant from those already reported in the literature on the chemical composition of this medicinal plant (Table 3) or do not meet previously established pharmacopoeial standards (Galduróz and Carlini, 1994Galduróz, J.C.F., Carlini, E.A., 1994. Acute effects of the Paullinia cupana, "guarana" on the cognition of normal volunteers. São Paulo Med. J. 112, 607-611., 1996Galduróz, J.C.F., Carlini, E.A., 1996. The effects of long-term administration of guarana on the cognition of normal, elderly volunteers. São Paulo Med. J. 114, 1073-1078.; Espinola et al., 1997Espinola, E.B., Dias, R.F., Mattei, R., Carlini, E.A., 1997. Pharmacological activity of guaraná (Paullinia cupana Mart.) in laboratory animals. J. Ethnopharmacol. 55, 223-229.; Mattei et al., 1998Mattei, R., Dias, R.F., Espinola, E.B., Carlini, E.A., Barros, S.B.M., 1998. Guarana (Paullinia cupana): toxic behavioral effects in laboratory animals and antioxidant activity in vitro. J. Ethnopharmacol. 60, 111-116.; Oliveira et al., 2013Oliveira, S.S., Giglio, A.B., Lerner, T.G., Zanellato, R.M., Tiemi, L., Reifur, L., Santi, P.X., Giglio, A., 2013. Paullinia cupana for control of hot flashes in breast cancer patients: a pilot study. Einstein 11, 435-438.).

From this discussion, it is evident that studies are primarily focused on the results of the research; however, it is crucial that previous measures should be taken. The form of preparation of the extract can select a specific group of compounds and that can often provide conflicting results for the same pharmacological action being investigated. Many environmental factors have an impact on the synthesis of secondary metabolites, both for total contents and relative proportions. Some of these include UV radiation, water availability, seasonality, atmospheric composition, altitude, temperature, and soil composition (Gobbo-Neto and Lopes, 2007Gobbo-Neto, L., Lopes, N.P., 2007. Medicinal plants: factors of influence on the content of secondary metabolites. Quim. Nova 30, 374-381.). These factors, combined with the genetic factor and the form of extraction, increase the chance of an extract being unique.

Therefore, when there is a lack of standardization and even lack of concern about how the extract is obtained, questions arise as to the reliability of the results. When searching the same pharmacological effect, authors using the guarana extract can present variable results for numerous reasons, namely, the method itself or the test used to measure that effect. Additionally, the comparison of studies is often not feasible because the forms of preparation of the extract are distinct or often unknown.

Conclusions

Although guarana has been the focus of many scientific studies, there are still gaps to be filled. This literature review described the botanical characteristics, presented recent data on the cropping and production of guarana, and highlighted all the substances that have currently been identified in this plant. Studies that showed the full range of pharmacological actions already searched for guarana seeds were covered. In addition, the importance of quality control of herbal drugs was emphasized, followed by the required standardization of their extract, due to consequent impacts on pharmacological action.

It is known that the pharmacological activities of plants are due to the distinct and diverse compounds existing in their composition and their proportion can be changed depending on the way the extract is prepared. These differences will be resolved through quality control of the medicinal plant and the standardization of its extract. The quality control of herbal drugs is essential to ensure the pharmacological standard of quality of guarana by means of analysis required for this plant. Another crucial point is the standardization of the extract that will be used for both in vitro and in vivo tests, by identifying and quantifying the main compounds present in guarana seeds. With this data set and knowledge of the low potential for toxicity of the extract, the results and conclusions can have greater reliability concerning guarana, as well as provide a reference for future scientific studies.

Acknowledgments

The authors would like to thank CAPES, FINEP, INCT_IF, and CNPq for their financial support, and Admir Arantes for his technical support.

References

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    » http://dx.doi.org/10.1155/2013/791795

Publication Dates

  • Publication in this collection
    Jan-Feb 2019

History

  • Received
    18 July 2018
  • Accepted
    28 Aug 2018
  • Published
    19 Sept 2018
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