Journal of Functional Foods 47 (2018) 457–468

Contents lists available at ScienceDirect

Journal of Functional Foods

journal homepage: www.elsevier.com/locate/jff

Health and technological aspects of methylxanthines and polyphenols from T

guarana: A review
Ádina L. Santana, Gabriela A. Macedo
Bioprocesses Laboratory/DEPAN/FEA (School of Food Engineering), University of Campinas, R. Monteiro Lobato, 80, Campinas, SP, Brazil

A R T I C LE I N FO A B S T R A C T

Keywords: Brazil is the major producer of guarana, a stimulant largely consumed worldwide. Interest in health benefits of
Paullinia cupana its consumption has increased the inclusion of guarana extracts in industry applications, providing dietary
Functional food supplements, medicines, cosmetics, and functional foods. Major bioactive constituents of guarana popularly
Bioactive compounds known are methylxanthines and catechins. Methylxanthines, particularly caffeine, are associated with im-
Emerging technologies
provement in cognitive function and energy-expenditure increasing. Catechins are phenolic constituents re-
ported with anticancer and antimicrobial effects. The application of combined processes to enhance the me-
thylxanthines and polyphenols profile and subsequent valorization of guarana waste fraction is an attractive
alternative for the obtaining of value-added products. In this context, this review provides a literature survey and
perspectives on health aspects and technological potential on the application of methylxanthines and poly-
phenols from guarana extracts for the development of functional foods with maximized bioactive constituents
and subsequently, health benefits.

1. Introduction
Guarana (Paullinia cupana Kunth var. sorbilis (Mart.) Ducke) fruit is
native to the Brazillian Amazon region known for its stimulant and
medicinal properties and used by indigenous communities (Schimpl, da
Silva, Gonçalves, & Mazzafera, 2013). The fruit of guarana is composed
of a red shell, presenting inside a seed partially covered by a white aril.
Only the seeds are consumed and commercialized.
Brazillian production of this crop in 2017 was estimated at
3.288.000 t, and cost variation between U$31.92/kg and U$50.42/kg
(CONAB, 2017). It is believed that around 70% of guarana production is
applied for the production of beverages, while 30% is applied for the
formulation of extracts, syrups, stick and powder. Few quantities are
exported (SEBRAE, 2016).
The seeds are applied mainly for its stimulant property and health
benefits attributed of its composition in terms of methylxanthines
(caffeine, theophylline and theobromine), from which are attributed
tonic and energetic properties. It also contains cathechin, epicathechin
and epicathechin gallate that are polyphenols that represent anti-
oxidant resources for human diet (Sousa et al., 2010).
The search in the Scopus database (Scopus, 2018) using the terms
“Paullinia cupana”, “phenolic compounds” and “caffeine” resulted on
112 documents, including 91 research articles, 16 review papers, 3
book chapters, 1 conference paper and 1 short survey, being the earliest
publication dating back to 1982. Considering Science Direct database
using the same terms, 76 documents were reported, including 12 review
articles, 31 research articles, 27 book chapters, 2 short communications
and 4 encyclopedia items (ScienceDirect, 2018).
Guarana seed processing involves fermentation, roasting and
grinding. These procedures may vary between large and small produ-
cers (Schimpl et al., 2013). Fermentation is applied to facilitate the
removing of the shells. Roasting of the seeds is performed, in order to
decrease moisture, which is a demand for the obtaining of extracts for
beverage industries. Grinding of the seeds promote a homogeneous
product, besides facilitate the obtaining of high-caffeine extracts
(Nazaré, 1997; Pereira, 2005). Fig. 1 summarizes the processing and
health attributes from guarana.
Nevertheless, information on the advantages on waste guarana
products from extraction procedures is scarce, except for utilization of
leaves as anticorrosive inhibitor (Faria Neto, 2017), and application of
waste seeds on the production of recycled paper (FAPEAM, 2012), en-
ergy (Lopes, Tannous, & Rueda-Ordóñez, 2016; Santos, 2015) and ex-
traction of pectic fraction for the obtaining of glycosides (Dalonso &
Petkowicz, 2012).
Bioprocessing, associated to emerging extraction technologies using
supercritical fluids is a reliable alternative to valorize waste materials.
The combination of these procedures consists on the transformation of
the solid matrix with the aid of microorganisms and uses of enzymes,
resulting on the improvement of quality and increasing of availability of
compounds of interest for further extraction procedures (Espinosa-

E-mail addresses: adina.santana@gmail.com (Á.L. Santana), macedoga@gmail.com (G.A. Macedo).

https://doi.org/10.1016/j.jff.2018.05.048
Received 17 March 2018; Received in revised form 25 May 2018; Accepted 26 May 2018
Available online 14 June 2018
1756-4646/ © 2018 Elsevier Ltd. All rights reserved.
Á.L. Santana, G.A. Macedo
Fig. 1. Technological and health aspects attributed to guarana.
Pardo, Nakajima, Macedo, Macedo, & Martínez, 2017).
In this review we investigate aspects that justify the inclusion of
methylxhanthines and polyphenols from guarana in human diet and in
industry, considering the quality of these phytochemicals, effects in
human health, extraction procedures and patent survey.
2. Guarana (Paullinia cupana)
2.1. Chemical composition
In a general aspect, the composition of guarana seeds is estimated at
around 2–6% of caffeine, 60% starch (Schimpl et al., 2013), 15% pro-
tein, 0.16% lipids (Hamerski, Somner, & Tamaio, 2013), besides 14%
phenolic constituents, from which 13% tannins and 5.72% condensed
tannins were identified (Fukumasu et al., 2006).
2.1.1. Methylxanthines
Methylxanthines are consumed by almost everybody in almost
every area of the world. Caffeine, theophylline and theobromine are the
most well‐known members of this family of compounds (Oñatibia-
Astibia, Franco, & Martínez-Pinilla, 2017).
These constituents have been described to exert multiple physiolo-
gical effects in the human body, including in the nervous, respiratory
and cardiac systems. They stimulate the skeletal muscle and promote
diuresis. Male fertility is another field in which these compounds may
have positive outcomes. Methylxanthines can stimulate lipolysis and
inhibit adipogenesis through several molecular mechanisms, thus con-
tributing to fat depletion and weight loss towards the management of
obesity (Carrageta et al., 2018).
The caffeine content in guarana is significantly greater (about 4
times) than that of Coffea sp., and is 30 times higher that of cocoa and
10 times that of yerba tea, other popular stimulant drinks (Edwards
et al., 2005).
In the seeds of guarana, caffeine is the main methylxanthine and is
located mainly in the cotyledons (4.3%) and testa (1.5%), while the
pericarp contains a significantly smaller amount of methylxanthines,
mainly theobromine (Baumann, Schulthess, & Hänni, 1995).
The effects on health of methylxanthines have generated much
controversy, with some adverse reactions like atered heart rate, in-
creased blood pressure, nervousness, reduced fertility, and insomnia
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Journal of Functional Foods 47 (2018) 457–468
being associated with the consumption of these alkaloids (Yahia, 2017).
Theobromine has an effect similar to, but lesser than, that of caf-
feine in the human nervous system, making it a lesser homologue.
Theobromine is an isomer of theophylline, as well as paraxanthine
(Barcz et al., 1998). Some health effects like inhibition of nucleation
and crystal growth of uric acid (Grases et al., 2014) and anti-carcino-
genic activity (Sanphui & Nangia, 2014) have been attributed to theo-
bromine.
Recently antitumor effect of theophylline was reported in rectal
cancer in vitro assays because of inhibition of chitinase-3-like-1 protein
(YKL-40), a member of the mammalian chitinase-like glycoproteins,
which serves a key role in the pathogenesis of rectal cancer (Peng et al.,
2018).
2.1.2. Polyphenols
Polyphenols, or phenolic compounds, are divided into several
classes, i.e. phenolic acids (hydroxybenzoic acids and hydroxycinnamic
acids), flavonoids (flavonols, flavones, flavanols, flavanones, iso-
flavones, proanthocyanidins), stilbenes, and lignans (Brahem, Eder,
Renard, Loonis, & Le Bourvellec, 2017).
Most of health effects of guarana are related to its high antioxidant
potential, which is attributed to the presence of tannins, its character-
istics polyphenols (Peixoto et al., 2017).
Tannins are a group of phenolic compounds containing sufficient
hydroxyls and other suitable groups such as carboxyls, to give them the
ability to form strong complexes with various macromolecules. Based
on the specific structural characteristics and chemical properties of
tannins they can be divided into the flavonoid-derived condensed tan-
nins, and hydrolysable tannins (Abdi et al., 2018).
Hydrolysable tannin molecule contains a carbohydrate (generally D-
glucose) as a central core. The hydroxyl groups of these carbohydrates
are esterified with phenolic groups such as gallic acid or ellagic acid.
The hydrolysable tannin occur mainly in fruit pods and plant galls and
unlike condensed tannins their degradation products are absorbed from
the small intestine of animals (Min, Barry, Attwood, & McNabb, 2003).
Condensed tannins, also known as proanthocyanidins, are a class of
plant secondary metabolites, which are formed by the polymerization
of monomeric flavan-3-ols; that is, catechins, epicatechins, procyani-
dins and their derivatives (Sato & Matsui, 2012; Solaiman & Senoo,
2018).
Á.L. Santana, G.A. Macedo Journal of Functional Foods 47 (2018) 457–468

Table 1
Methodologies commonly used to investigate methylxanthines and catechins profile in guarana products.
Compound Product Yield of phytochemicals (%) Method of analysis Reference

Methylxanthines
Caffeine
Aril 1.64 HPLC Baumann et al. (1995)
Commercial powder 0.91–3.75 HPLC Belliardo, Martelli, and Valle (1985)
Extract 2–2.6 Capillary column GC Pagliarussi, Bastos, and Freitas (2006)
Pericarp 0.02 HPLC Weckerle, Stutz, and Baumann (2003)
Seeds 4.28 HPLC Baumann et al. (1995)
Seeds 1.81–2.95 Gravimetric Spoladore, Boaventura, and Saes (1987)

Theobromine
Aril 0 HPLC Baumann et al. (1995)
Pericarp 0.203 HPLC Weckerle et al. (2003)
Seeds 0.017 HPLC Yonekura et al. (2016)

Theophylline
Aril 0 HPLC Baumann et al. (1995)
Pericarp 0.001 HPLC Weckerle et al. (2003)
Seed 0.007 HPLC Baumann et al. (1995)

Polyphenols
Catechin
Seeds 30 HPLC-ECD Yonekura et al. (2016)
Epicatechin
Seeds 2.02 HPLC-ECD Yonekura et al. (2016)
Epicatechin gallate
Extracts 0.1–0.4 HPLC Majhenič et al. (2007)
Procyanidin B1
Seeds 0.372 HPLC-ECD Yonekura et al. (2016)
Procyanidin B2
Seeds 0.337 HPLC-ECD Yonekura et al. (2016)

Due to their ability to modulate the activity of multiple targets in-
volved in carcinogenesis through direct interaction or modulation of
gene expression, polyphenols can be employed to inhibit the growth of
cancer cells. However, the main problem related to the use of poly-
phenols as anticancer agents is their poor bioavailability, which might
hinder the in vivo effects of the single compound (Fantini et al., 2015).
Besides poor bioavailability other most important obstacles hin-
dering the success of therapy based on those compounds are low
membrane permeability, physiological instability, oxidative degrada-
tion, and metabolic transformations (Lewandowska, Fichna, & Gorlach,
2016).
2.1.3. Methods for determination of methylxanthines and polyphenols
The quantification of methylxanthines and polyphenols is becoming
increasingly important considering the health effects of these com-
pounds and their widespread consumption of the public. In this context,
the analytical methodologies used for the detection of these con-
stituents include from tedious with inflated results, like gravimetric, to
low-time costing and precise methods.
Analytical methods used to determine these compounds on guarana
seeds (Table 1) include UV–Visible spectrophotometry, gas chromato-
graphy (GC), high performance liquid chromatography (HPLC), ion
chromatography, reversed phase HPLC- PDA, HPLC-electrochemical
detection, HPLC-ECD (Gerald, Arthur, & Adedayo, 2014). The HPLC
approach have been mostly applied to quantify methylxanthines and
polyphenols from guarana products (Table 1).
Total polyphenols using Folin-Ciocalteu reagent using a gallic acid
standard curve (Singleton, Orthofer, & Lamuela-Raventos, 1999) is an
alternative extensively used to estimate the phenolic composition of
several plant extracts, like turmeric (Santana, Osorio-Tobón, Cárdenas-
Toro, Steel, & Meireles, 2017), grape (Martins, Roberto, Blumberg,
Chen, & Macedo, 2016) and annatto (Torres, Santos, & Meireles, 2015),
mainly in cases in absence of advanced techniques for the quantifica-
tion of specific phenolic species of studied extract. Folin-Ciocalteu react
with all reducing species in a solution (Carocho & Ferreira, 2013). In a
mixture with the diluted extract and aqueous sodium carbonate
solution, it reacts with all phenolic species in solution, resulting in a
blue coloration, which absorbance can be analyzed by spectro-
photometer or a 96-well plate reader.
With its advantages of simplicity, economy, easy operation and re-
quired for only small amounts of solvent, thin-layer chromatography
(TLC) is a qualitative approach used widely in various fields to identify,
separate or purify mixtures of chemical and biological compounds
(Albuquerque, Santana, & Meireles, 2015).
The TLC, and its refined version, high-performance thin-layer
chromatography (HPTLC) have been applied to determine methyl-
xanthines and polyphenols from several plant-based products. For in-
stance, HPTLC have been used to investigate methylxanthines in bev-
erages formulated with Mate (Oellig, Schunck, & Schwack, 2018)and
polyphenols profile of plant extracts. In addition, TLC have been used to
fingerprint isolated caffeine from commercial guarana powder (El
Seoud et al., 2018).
Recently TLC detected terpenic phenolics in annatto (Johner,
Santana, & Meireles, 2017) and catechins in green tea extracts (Braz,
Wolf, Lopes, & Mello, 2012) using spray reagents appropriated to
identify these constituents.
2.1.4. Methods for determination of antioxidant activity
Antioxidants are a group of substances, which significantly inhibit
oxidation and reduce oxidative stress caused by increased levels of re-
active oxygen species and free radicals that can initiate chain reactions
in the cell, resulting in death or damage to the cell (Pathak et al., 2017).
The oxidative damage created by free radical generation is a critical
etiological factor implicated in several chronic human diseases such as
diabetes mellitus, cancer, atherosclerosis, arthritis and neurodegen-
erative diseases and also in the aging process. In treatment of these
diseases antioxidant therapy has gained an enormous importance
(Inbathamizh, Ponnu, & Mary, 2013).
Methods and tools used for measuring antioxidants activity have
advanced remarkably during the last few decades. Early methods
measure the efficacy of antioxidants against the formation of particular
species of oxidation products and therefore are based on lipid oxidation

459
Á.L. Santana, G.A. Macedo
measurement (Shahidi & Zhong, 2015). However, there is not one
method that can provide unequivocal results and the best solution is to
use various methods instead of a one-dimension approach (Carocho &
Ferreira, 2013).
Considering in vivo and in vitro methods of antioxidant evaluation,
literature reported that 19 in vitro and 10 in vivo methods are being used
nowadays, from which DPPH (2,2-diphenyl-1-picryl-hydrazyl) radical
scavenging activity was the most in vitro test used, while the lipid
peroxidation inhibition was found as the mostly used in vivo assay
(Alam, Bristi, & Rafiquzzaman, 2013).
Antioxidant capacity of guarana extracts has been mostly studied
using the DPPH (Bonilla & Sobral, 2017; Dalonso & Petkowicz, 2012;
Majhenič, Škerget, & Knez, 2007; Peixoto et al., 2017; Yamaguti-Sasaki
et al., 2007) and thiobarbituric acid, TBA (Basile et al., 2005; Mattei,
Dias, Espı́nola, Carlini, & Barros, 1998) approaches.
The DPPH method is based on the capture of DPPH free radical by
antioxidant constituents (Brand-Williams, Cuvelier, & Berset, 1995).
Antioxidant efficiency is measured at ambient temperature and thus
eliminates the risk of thermal degradation of the molecules tested.
However, the reactional mechanism between the antioxidant and DPPH
depends on the structural conformation of the antioxidant (Bondet,
Brand-Williams, & Berset, 1997).
The thiobarbituric acid (TBA) assay is the most commonly used
assay to study lipid oxidation. Addition of iron or copper salts to bio-
logical molecules causes site-specific formation of oxygen-derived free
radicals such as peroxyl radical (ROO%) and hydroperoxyl radical
(HOO%) which can trigger lipid peroxidation chain reactions. This re-
action occurs by abstracting a hydrogen atom from a side chain me-
thylene carbon of polyunsaturated fatty acids and transforms it into
lipid hydroperoxides (Pai Kotebagilu, Reddy Palvai, & Urooj, 2015).
Lipid oxidation is an autocatalytic process, which is common con-
sequence of cell death. This process is problematic in food systems,
where oxidative rancidity causes nutritional loss and development of
toxic compound. Considering health aspects, lipid oxidation may cause
peroxidative tissue damage in inflammation, cancer and toxicity of
xenobiotics and aging (Alam et al., 2013; Ghani, Barril, Bedgood, &
Prenzler, 2017).
2.2. Impact in human health
2.2.1. Cytotoxic effects
Chemical structure of fatty acids from guarana is predominantly
unsaturated (76:24, unsaturated/saturated), which is susceptible to
oxidation. Lipid oxidation affect cellular membrane integrity in terms of
unsaturated fatty acids degradation. As a consequence, undesirable
toxic effects to human health may occur, such as premature aging and
arteriosclerosis (Silva, Rovellini, Fusari, & Venturini, 2015).
In addition, processing conditions used in guarana seed roasting
may result in the presence of polycyclic aromatic hydrocarbons (PAHs)
that represent an important group of chemical carcinogens formed
during incomplete combustion of organic matter. In some cases after
roasting the seeds are submitted to a smoking step, which can originate
PAHs (Camargo, Tfouni, Vitorino, Menegário, & Toledo, 2006).
A recent study detected 16 PAHs in 10 commercial guarana powder
samples. Naphthalene and phenanthrene were the PAHs found in the
commercial guaraná powder samples and only naphthalene in the
guaraná seeds, which may have originated from the frequent forest fires
which occur in the Amazon region, suggesting that PAHs associated
with particulate matter may be deposited on the surface of the vege-
tables, as well as during their processing (Veiga et al., 2014).
Besides of this, some of the guarana processing stages are suscep-
tible to fungal contamination, favoring the production of mycotoxin
ochratoxin A (OTA), which has nephotoxic effect (Martins, Kluczkovski,
Santos, Fernandes, & Scussel, 2014).
In addition, investigators targeted to determining health risks as-
sociated with guarana consumption in animals and humans have
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Journal of Functional Foods 47 (2018) 457–468
uncovered toxic effects, mostly when the herb is combined with other
nutritional supplements, like ginseng (Subbiah, 2005).
Literature presents controversy regarding the effects of guarana on
cellular tissues (Onakpoya & Ernst, 2012). This is probably due because
most of dietary antioxidants can behave as prooxidants; it all depends
on their concentration and the nature of neighbouring molecules
(Carocho & Ferreira, 2013).
Cytotoxic effects were observed in aqueous extracts formulated with
guarana (3.125–50 mg/mL), caffeine (0.125–2 mg/mL) and taurine
(1–16 mg/mL) applied on human neuroblastomaderived SH-SY5Y cells.
Excessive removal of intracellular reactive oxygen species, to non-
physiological levels (or “antioxidative stress”), could be a cause of in
vitro toxicity induced by these drugs (Zeidán-Chuliá et al., 2013).
According to previous investigation on the cytotoxicity of aqueous
guarana extract (10, 20, 30, and 40 mg/mL) applied on Chinese ham-
ster ovarian (CHO) and bacterial cells, concentration of guarana is of
critical importance in its cytotoxic activity and high doses could be
harmful to human health (Maria, Lopez, Diaz, Muñoz-Mingarro, &
Pozuelo, 1998).
2.2.2. Antimicrobial effects
Extracts of cocoa (Todorovic, Milenkovic, Vidovic, Todorovic, &
Sobajic, 2017) and tea (Nibir, Sumit, Akhand, Ahsan, & Hossain, 2017)
have been studied in terms of antimicrobial effect against various pa-
thogenic bacteria. Antimicrobial effects of the studied extracts were
correlated to the polyphenols content, similarly to guarana, despite of
controversy of results available in literature.
Highest antifungal activity of aqueous and alcoholic extracts against
A. niger. However, only alcoholic extracts exhibited strong antibacterial
activities (> 80%) against P. fluorescens and B. cereus. Authors reported
that water is not a suitable solvent for extraction of antibacterial sub-
stances when compared to other solvents, like methanol and ethanol
(Majhenič et al., 2007).
Extracts of guarana obtained with supercritical fluid showed strong
antimicrobial activity against strains of S. aureus MRSA N315 due to
collateral sensitivity effect in resistant bacterial strains. Collateral drug
sensitivity networks may further serve as basis for designing treatments
in which multiple antibiotics are cycled over time (Marques et al.,
2016).
Ethanolic extracts proved to be inhibit effectively both Gram posi-
tive and Gram negative bacteria, particularly P. aeruginosa, P. vulgaris,
P. mirabilis and E. coli (Basile et al., 2005). Furthermore, in vitro as-
sessment of the antibacterial potential of the extracts against S. mutans
showed that these products could be used in the prevention of bacterial
dental plaque (Yamaguti-Sasaki et al., 2007).
Nevertheless, Carvalho et al. (2016) found bacteriostatic activity
with minimum inhibitory concentration (MIC) of 250 μg/mL and no
bactericidal activity, with minimal bactericidal concentration
(MBC > 250 μg/mL) of guarana extracts against S. aureus and S. epi-
dermidis. These information were in accordance with those found
elsewhere against S. aureus, E. coli, P. aeruginosa and B. subtilis
(Antonelli-Ushirobira et al., 2007; Bonilla & Sobral, 2017).
2.2.3. Evaluation of guarana effects: Ex vivo assays
The effects of guarana extract on body weight control, food intake,
increasing of energy expenditure are associated to its ability to mod-
ulate micro-RNAs and genes related to adipogenesis process (da Costa
Krewer et al., 2011; Portella et al., 2013). Body weight reduction was
attributed to the enhancement of thermogenesis and mitochondrial
biogenesis (Lima, Caria, Gambero, & Ribeiro, 2018; Lima, Teixeira,
Gambero, & Ribeiro, 2018).
In addition, guarana may also influence glucose metabolism by in-
hibiting carbohydrate digestion. The compounds present in guarana
may be able to neutralize free radicals by hydrogen or electron dona-
tion, acting as a chelating agent, and/or denaturing proteins (Silva,
Sampaio, Freitas, & Torres, 2017).
Á.L. Santana, G.A. Macedo
Table 2
Health effects of guarana: studies reported with ex vitro assays.
Health effect Cell type
Reduction in LDL oxidation Low density lipoprotein (LDL) obtained from human
voluntary donors
Reduction in cell mortality, lipid peroxidation, DNA Embryonic fibroblast culture (NIH-3T3) cells
damage and cell oxidative stress
Prevention in protein glycation Human neuroblatoma cell line (SH‐SY5Y)
Antiproliferative Human cancer colorectal HT-29 cell line American
Anti-toxicity Type Culture Collection (ATCC®)
Cytoprotective Adult human retinal pigment epithelial cells ARPE-
19 (ATCC CRL-2302TM)
Anti-adipogenic 3T3-L1 cell line
The effects of guarana extracts applied to ex vivo assays using var-
ious concentrations are reviewed in Table 2.
2.2.4. Evaluation of guarana effects: In vivo assays applied to animals
Methylxanthines are attributed to the therapeutic potential of
guarana on memory and anxiogenic-like behavior, because of the ca-
pacity of these compounds, mainly caffeine to increase acetylcholine
release into synapses, thereby directly modulating the activity of acet-
ylcholinesterase (AChE), which may reduce memory impairment in the
brains of rats with induced hyperlipidemia. Hyperlipidemia is abnor-
mally elevated levels of any or all lipids or lipoproteins in the blood
(Ruchel et al., 2017).
Anxiolytic and panicolytic effect of aqueous extracts (8 mg/kg) on
rodents were reported. The administration of this low concentration of
extract contributed to the serotonergic, dopaminergic and glutama-
tergic neurotransmission systems, which are involved on the anxyolitic
effect, and to the serotonergic and dopaminergic neurotransmission
systems, which are involved in the panicolytic effect (Rangel, de Mello,
& Audi, 2013).
Anti-aging activity of aqueous extract in the model system
Caenorhabditis elegans were attributed to the high antioxidant activity of
guarana (Peixoto et al., 2017).
The extract of guarana (30, 150 and 300 mg/kg) applied in
HanUnib: WH (Wistar) and Unib:SW (Swiss) rodents resulted in re-
duction in weight (for all concentrations) and biochemical changes
(150 and 300 mg/kg) in terms of increasing in alkaline phosphatase and
blood urea concentration, probably because of toxicity of extracts at
higher doses (Antonelli-Ushirobira et al., 2010).
Crude and aqueous fractionated extracts of guarana seeds exhibited
significant nootropic effect in Wistar rodents (Otobone et al., 2005).
Nootropics are also known as smart drugs and cognitive enhancers.
However, the data found previously contrast to those reported by
Mingori et al. (2017), which chronic supplementation with guarana
extract (21 mg commercial powder/kg weight) was not effective against
oxidative stress and did not provide any cognitive benefit during the
6 months aging of the Wistar rodents.
Literature relates considering the impact of guarana extracts applied
in experiments with rodents are summarized in Table 3.
2.2.5. Evaluation of guarana effects: In vivo assays applied to humans
A recent investigation with head and neck cancer patients (degree
I–IV) reported guarana extract acted in some of the symptoms including
pain, which may be due to its anti-inflammatory effects. However, the
authors do not believe that guarana was directly beneficial for this
patient population (Martins, Ferreira, Arruda, & Giglio, 2015).
Literature reports nutritional supplement interventions have shown
some promise in improving cognitive function and mental health
(Parletta, Milte, & Meyer, 2013). Psychoactive effects of supplementa-
tion with multivitaminic/mineral and guarana was associated to the
caffeine content reported, i.e., 40 mg as equivalent to approximately
half a cup of fresh brewed coffee (Kennedy et al., 2008).
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Journal of Functional Foods 47 (2018) 457–468
Concentration of guarana extract Reference
applied (μg/mL)
0.05, 0.1, 0.5, 1 and 5 Portella et al. (2013)
500, 1500, 1000 and 20,000 Bittencourt et al. (2013)
10, 100, and 1000 Bittencourt et al. (2014)
100 Cadoná et al. (2016)
25, 30, 50, 100, 250 and 500 Bonadiman et al.
(2017)
50, 100, 150, 200 and 300 Lima et al. (2017)
In fact, caffeine it is the best known psychoactive stimulant resulting
in heightened alertness and arousal and improvement of cognitive
function (Kasımay Çakır et al., 2017).
Short-term safety and weight-loss promoting effects of herbal
combinations containing guarana has been evaluated in clinical trials.
Combination of ephedrine (alkaloid from Ma Huang) and caffeine (al-
kaloid from guarana) produced weight loss in overweight people be-
cause of thermogenesis promotion, resulting in the increasing of oxygen
consumption around 10% over several hours (Boozer et al., 2001). As
consequence, around 25–40% of weight loss was related to thermo-
genesis and 60–70% was from reduction of food intake in animals and
humans (Joshi & Adhikari, 2017).
Nevertheless, adverse effects cannot be ignored. Ephedrine admin-
istration causes the release of catecholamines (via a- and b-adreno-
ceptors), while caffeine has a-adrenergic-like properties (phosphodies-
terase enzyme inhibition), thus it impacts cardiovascular function
(Kalman, Incledon, Gaunaurd, Schwartz, & Krieger, 2002).
Cancer-related fatigue is the most prevalent cancer symptom, re-
ported in 50%-90% of patients and severely impacts quality of life and
functional capacity (Campos, Hassan, Riechelmann, & del Giglio,
2011). Hot flashes (HFs) are episodic sensations of heat, intense
sweating, and flushing that are often accompanied by palpitations and
anxiety (Giglio & Giglio, 2015). The administration of guarana extract
in breast cancer survivals contributed to the decreasing of HFs.
Nevertheless, the patients reported adverse effects like anorexia, in-
somnia, constipation, besides considered mild, and none warranted
discontinuation of the study (Oliveira et al., 2013).
Reviewed literature reports on the impact of guarana extracts in
human health are available in Table 4.
3. Obtaining of phytochemicals from guarana Seeds: Extraction
methods and bioprocessing
3.1. Extraction methods
Interest in the development of processes for the production or ex-
traction of bioactive compounds from natural sources has increased in
recent years due to the potential applications of these compounds in
food, chemical, and pharmaceutical industries (Martins et al., 2011).
Common plant extraction methods for pharmaceutical and food
processing are hydrodistillation, steam distillation, cold pressing, and
solvent extraction (Bergs et al., 2013). Emerging technologies like su-
percritical fluid extraction, pressurized liquid extraction, PLE (Santana,
Zabot, et al., 2017), ultrassound (Lopes de Menezes, Johann, Diório,
Pereira, & da Silva, 2018) and microwave (Pandey & Shrivastava, 2018)
assisted extraction are environmental-friendly alternatives that have
been used extensively for the effective obtaining of extracts from waste
plant matrices and recovery of phytochemicals.
The methods of extraction used for the obtaining of phytochemicals
from guarana seeds reported on literature are showed on Table 5.
Á.L. Santana, G.A. Macedo
Table 3
Health effects of guarana: in vivo studies reported with animals.
Health effects Animal lineages
Panicolytic HanUnib: WH (Wistar)
Antitumoral C57BI/6
Absence in fetal death and maldeformation ICR (Crj: CD-1)
Anti-adipogenic HanUnib: WH (Wistar) and
Unib:SW (Swiss)
Cognitive improvement HanUnib: WH (Wistar)
Anxiolytic HanUnib: WH (Wistar)
Panicolytic
Anti-proliferative BALBc
Anti-inflammatory effect; Increasing in HanUnib: WH (Wistar)
testosterone synthesis
Anti-adipogenic effect C57BL6J
Anti-adipogenic effect Unib:SW (Swiss)
Weight control HanUnib: WH (Wistar)
Anti-stress activity NI
Cognitive improvement HanUnib: WH (Wistar)
Nootropic
NI – Non-identified.
3.1.1. Solvent extraction
Solvents such as dimethyl chloride, water and chloroform have been
used for methylxanthines removal from natural plants. Nevertheless,
chemical solvents require several hours for a complete extraction and
carry with them the risk of toxic residue in the extracted products.
Water, although an excellent solvent of methylxanthines, is highly
nonselective and its use may result in the removal of other valuable
components from the extracted product (Saldaña, Zetzl, Mohamed, &
Brunner, 2002b).
Conventional methods for the obtaining of extracts from guarana is
solvent extraction by maceration of seeds using a hydroalcoholic solu-
tion formulated with approximately 50:50, ethanol:water (v/v), during
24 h, followed by subsequent centrifugation in order to separate extract
and waste seeds (Nazaré, 1997).
Extracts of guarana obtained by conventional methods present dark-
brown coloration with high levels of caffeine and tannins, and sub-
sequent high bitterness and astringency, a factor that limit the use of
extracts with high concentrations of tannins (Ribeiro, Coelho, &
Barreto, 2012). This is attributed to the caffeine-tannin complex, which
was indicated to occur through the non-methylated nitrogen atom in
the imidazole ring of caffeine, by hydrogen-bonding with a hydroxyl
group of the tannins (Edwards et al., 2005).
Some strategies were performed to reduce the caffeine-tannins
complex, such as the use of selective solvents for the extraction of
caffeine such as supercritical CO2 (Saldaña, Zetzl, Mohamed, &
Brunner, 2002a) or the exchange of caffeine by another component in
the complex, by which the condensed tannins would have greater af-
finity, like proteins (Huang et al., 2011) and proline-rich polymers
(Hagerman, 1989).
3.1.2. Supercritical fluid extraction (SFE)
Supercritical Fluid Extraction (SFE) using carbon dioxide (CO2) as
solvent is a clean technology based on solvent properties above its
critical point for the extraction or separation of compounds from a
complex matrix. The low critical temperature and pressure
(Tc = 31.05 °C, Pc = 7.38 MPa), nontoxicity, and low cost have ren-
dered supercritical CO2 a suitable solvent for food products (Brunner,
2005).
Although CO2 is an attractive alternative to conventional solvent
extraction of bioactive components from seeds, fruits, leaves, flowers,
rhizomes, etc., it does not extract efficiently polar solutes, and the use
of liquid cosolvents is applied in order to increase solvent power of
Journal of Functional Foods 47 (2018) 457–468
Dose of guarana extract administrated (mg/ Reference
kg body weight)
4, 8 and 16 Roncon, de Almeida, Klein, de Mello, and
Audi (2011)
2000 Fukumasu et al. (2008)
500 Gu et al. (2001)
30, 150 and 300 Antonelli-Ushirobira et al. (2010)
12.5, 25 and 50 Ruchel et al. (2017)
8 Rangel et al. (2013)
100, 1000 and 2000 Fukumasu et al. (2008)
2000 Leite, Wada, Monteiro, Predes, and Dolder
(2011)
1000 Lima, Caria, et al. (2018)
1000 Lima, Teixeira, et al. (2018)
821 Ventura, Rodrigues, Falcão, and Alves
(2018)
25, 50 and 100 Campos, Barros, Albuquerque, Leal, and
Rao (2005)
30 Otobone et al. (2005)
carbon dioxide towards polar molecules (Reverchon & De Marco,
2006).
The selection of the operating conditions depends on the specific
compound or compound family to be extracted. Literature reports low
solubility of methylxanthines in 100% supercritical CO2, however its
mixture with 5% and 10% ethanol resulted in 98% caffeine extracted
from ground seeds of guarana (Saldaña et al., 2002b).
Similarly to methylxanthines, it is necessary the use of a cosolvent
associated with supercritical CO2, because of low solubility of catechins
(Cháfer, Berna, Montón, & Muñoz, 2002). A recent study obtained
higher yield of catechin and epicatechin with SFE using a cosolvent
mixture composed of 40% ethanol:methanol (Marques et al., 2016).
3.1.3. Pressurized liquid extraction (PLE)
Pressurized liquid Extraction (PLE) enhances the extraction of solid
matrices with low time and solvent consumption, because of employ-
ment of high temperature and pressure conditions (Vazquez-Roig &
Picó, 2015).
Minimizing the extraction time avoids a possible thermal degrada-
tion. Therefore, PLE is widely used as an extraction technique to
identify components present at low concentrations and with photo-
sensitive and thermosensitive characteristics (Oliveira, Cornelio-
Santiago, Fukumasu, & Oliveira, 2018).
Solvating properties, viscosity, polarity, surface tension and diffu-
sivity of water change significantly with applied high pressure and
temperature, which result in striking improvement in the yield of
bioactive components such as phenolics (Çam, Dinç Işıklı, Yüksel,
Alaşalvar, & Başyiğit, 2018)
3.2. Bioprocessing
The food and bioprocessing industry is facing enormous challenges
for developing and implementing systems that can produce high
quality, safe foods as well as feeds while also being efficient, en-
vironmentally acceptable, and sustainable (Neethirajan & Jayas, 2011).
The use of enzymes in industries has long been recognized for its
effectiveness, both technologically and economically. It encompasses to
achieve high product yields, reduce by-product formation, and avoid
severe operational conditions. Hence, enzymes are also being used in
the extraction of important bioactive compounds. Enzyme-assisted ex-
traction technique uses specific enzymes to disrupt the cell wall of
source material to improve its extraction yield (Marathe, Jadhav,
462
 Á.L. Santana, G.A. Macedo

Table 4
Health effects of guarana: in vivo studies reported in humans.
Health effect Duration Subject condition Experimental intervention Control Adverse effects Reference
intervention

Anti-adipogenic 2 weeks Overweight patients (body mass index Beverage formulated by diluting 3 g of powdered NI NI Yonekura et al. (2016)
LDL cholesterol reduction between 25 and 30 kg/m2) guarana in 300 mL of water per day
Anti-adipogenic 8 weeks Overweight patients (body mass index Herbal supplement containing Ma-Huang (72 mg of Placebo Elevated blood pressure Boozer et al. (2001)
between 29 and 35 kg/m2) ephedrine/day) and Guarana (240 mg of caffeine/daily) Palpitation + chest pain
Irritability
Weight loss 2 weeks Overweight patients (body mass Herbal supplement containing Ma Huang (20 mg Placebo Dry mouth Kalman et al. (2002)
Fat loss index ≥ 25 kg/m2) ephedrine/day), guarana (200 mg caffeine/day) bitter Increased Thirst
orange (5 mg synephrine/daily) Headache
Insomnia
Reduction of cancer-related fatigue 3 weeks Breast cancer women receiving Dried guarana extract 100 mg/day Placebo NI Campos et al. (2010)
systematic chemotherapy
Weight control and appetite 4 weeks Advanced cancer patients with Dried guarana extract 100 mg/day NI Arthralgia Palma et al. (2016)
increasing in cancer-related decreased appetite and weight loss
anorexia
Pain relieving 3 weeks Patients with head and neck cancer Dried guarana extract 100 mg/day Placebo NI Martins et al. (2015)

463
(stages I-IV) subjected to
chemoradiation
Cognitive performance and mood 6 days Undergraduate and healthy volunteers Dried ethanolic extract of guarana: 37.5 mg, 75 mg, Placebo NI Haskell, Kennedy, Wesnes,
improvement 150 mg and 300 mg Milne, and Scholey (2007)
Reduction in hot flashes in breast 3 months Breast cancer survivals patients Guarana extract: 100 mg/day Placebo Anorexia Oliveira et al. (2013)
cancer survivals Insomnia
Nausea
Anxiety
Constipation
Headache
Antitumoral 3 weeks Breast cancer patients with various Guarana extract: 75 mg/day Placebo NI del Giglio et al. (2013)
Fatigue stabilization solid tumors treated with
chemotherapy
Reduction in mental fatigue 60 min of continuous Health young volunteers Multivitaminic/minerals complex containing 222.2 mg Placebo NI Kennedy et al. (2008)
performance of guarana
Cognitive performance and mood 5 days Health young volunteers Dried guarana extract: 75 mg/day and 200 mg/day of Placebo NI Kennedy, Haskell, Wesnes,
improvement Panax ginseng and Scholey (2004)

NI – Non-identified.
Journal of Functional Foods 47 (2018) 457–468
Á.L. Santana, G.A. Macedo Journal of Functional Foods 47 (2018) 457–468

Table 5
Extraction methods used for the obtaining of methylxanthines and polyphenols from guarana.
Method Conditions Yield in extract and bioactives Reference

Enzyme-assisted extraction Solvent: water Extract: 1.9–9.74% Ribeiro et al. (2012)

Solvent extraction
Supercritical fluid extraction
Supercritical fluid extraction
Supercritical fluid extraction
Enzymes: cellulose, hemicellulose, pectinase, α-amylase and amyloglucosidase Caffeine/total tannins ratio: 0.83–1.65
Temperature: 50 °C and 70 °C Caffeine:3.92–4.45 g/L
Extraction time: 60 min Total tannins: 2.7–4.72 g/L
Solvents: water, methanol, 35% acetone and 60% ethanol Extract: 11.7–24.8% Majhenič et al. (2007)
Temperature: 25 °C and boiling temperatures 100 °C (water), 62 °C (methanol), Caffeine: 120–250 mg/g
85 °C (acetone) 75 °C (ethanol) Catechin: 15–55 mg/g
Extraction time: 120 min Epicatechin: 11–55 mg/g
Epicatechin gallate: 1–9 mg/g
Solvent: CO2, methanol and ethanol Extract: 1.15–3.93% Marques et al. (2016)
Temperature: 40, 50 and 60 °C Caffeine: 35.66–67.88 g/100 g
Pressure: 100, 200 and 300 bar Catechin: 0.22–9.09 g/100 g
Extraction time: 20, 40 and 60 min Epicatechin:0.21–7.93 g/100 g
Solvent: CO2 Extract: NI Saldaña et al. (2002a)
Temperature: 40 and 70 °C Caffeine: 10–45 mg/g
Pressure: 100, 200 and 400 bar
Extraction time: 240 min
Solvents: CO2 and ethanol Extract: NI Saldaña et al. (2002b)
Temperature: 40, and 70 °C Caffeine: 10–35 mg/g
Pressure: 400 bar
Extraction time: 210 min

NI – Non-identified.

Bankar, & Singhal, 2017).
3.2.1. Solid state fermentation (SSF)
Solid state fermentation (SSF) is a bioprocess used by various in-
dustries for the production of metabolites of microorganisms from solid
substrates, which may be cereal bran, bark, fruit seeds, and related
materials. The SSF using food grade fungi could provide non-expensive
strategies for producing biologically active products and enhance the
value of plant-food wastes. The products generated are feed, fuel, food,
industrial chemicals and pharmaceutical products (Vazquez-Roig &
Picó, 2015). The main advantage of this method is the minimum pro-
duction of tailings and liquid effluents (Ghosh, 2016).
The action of enzymes such as α-amylase, laccase and β-glucosidase,
tannin acyl hydrolase, ellagitanin acyl hydrolase, among others, plays
an important role in the mobilization of bioactive phenolic compounds
during SSF (Martins et al., 2011).
For instance, biotransformation based on SSF and application of the
enzyme tannase resulted on modified polyphenols with improved li-
pogenic activity from citrus wastes (Nakajima, Madeira, Macedo, &
Macedo, 2016), with chemopreventive potential from green tea leaves
(Macedo et al., 2012) and increased antioxidant activity from grape
wastes (Martins et al., 2016). Furthermore, tannase-mediated bio-
transformation improved daidzein metabolites profile in soymilk (de
Queirós, Macedo, & Macedo, 2016).
In fact, the action of enzymes such as α-amylase, laccase and β-
glucosidase, tannin acyl hydrolase, ellagitanin acyl hydrolase, among
others, plays an important role in the mobilization of bioactive phenolic
compounds during SSF (Martins et al., 2011).
caffeine contents were obtained using 0.23% cellulase, 0.86% hemi-
cellulase and 1% α-amylase (Ribeiro et al., 2012).
4. Patent survey
According to Google Patent database (Google, 2018) 5,495 results
were found, by inserting the term ́́ guaraná́. Many of these documents
propose methods of extraction to intensify the obtaining of phyto-
chemicals (Rohde, Rohde, Schuler, & Handel, 2000; Turano, 2006).
In the year 2000, an enzyme-assisted extraction process of guarana
was patented by Japanese Coorporation Mie Kariyou Corp (Watanabe,
Yasuyuki, & Shige, 2000) resulting in extracts with 5% of caffeine and
13.4% of tannins.
Patent on the optimization on the obtaining of extracts with po-
tential application in studies with animals (Otobone et al., 2005; Rangel
et al., 2013) have been performed using solvent extraction with acetone
and water (7:3, v/v) by turbo extraction followed by evaporation of
organic solvent, with further freeze-drying and fractionation with ethyl-
acetate (Audi & Melo, 2000).
In addition, guarana extract formulation associated with other plant
extracts for appetite suppressing and weight loss (Gardiner & Heuer,
2006; RTC, 2004), cosmetics cellulite treating (Elson, 2005), and en-
ergy drinks (Maniga, 2014) have been patented.
Few patents were found on the use of guarana waste processing. A
method on the reusing of waste shells for the production of tea was
proposed (Ferreira, 2008). Process on recovery antioxidant from waste
streams of coffee beans, guarana, tea leaves and chocolate was pro-
posed in patent number EP2358209 A1 (Taylor, Szarek, & Ward, 2011).

3.2.2. Enzyme-assisted extraction 5. Current trends and future perspectives: Optimization of

Enzyme-assisted extraction (EAE) is also gaining a lot of attention as
an efficient procedure to enhance the release and recovery of bioactive
compounds from plants (Miron, Herrero, & Ibáñez, 2013). Enzymes are
ideal catalysts to assist in the extraction, modification or synthesis of
complex bioactive compounds of natural origin.
Enzymes such as cellulases, pectinases and hemicellulases are often
used to destruct the cell wall components of the plant cell, thereby
enhancing the recovery of value-added compounds. Proteases can be
used to hydrolyze proteins thereby increasing total free amino acids
(Poojary, Orlien, Passamonti, & Olsen, 2017).
Optmized conditions of EAE applied to guarana for the obtaining of
non-alcoholic guarana extracts with low tannin concentrations and high
bioactives obtaining and potential of guarana waste using
combined technologies
Low solubility, instability under conditions encountered in the
gastrointestinal tract (pH, enzymes, presence of other nutrients), in-
sufficient gastric residence time, and the difficulty for many poly-
phenols to diffuse across the cells through the lipid-bilayer cell mem-
branes in the intestine account for the low bioavailability of diet
polyphenols (Hu, Liu, Zhang, & Zeng, 2017).
Emerging technologies and process optimization on the obtaining of
polyphenols with enhanced bioavailability have been applied to over-
come these difficulties. Modified polyphenols with increased

464
Á.L. Santana, G.A. Macedo
Fig. 2. Future direction on recovery of methylxanthines and polyphenols from guarana wastes.
antioxidant potential one of the possible products produced via SSF
(Macedo, Battestin, Ribeiro, & Macedo, 2011).
Supercritical and compressed fluids-based particle formation tech-
niques have been used to enhance stability of bioactive ingredients with
the employment of biodegradable and biocompatible polymer as carrier
agents, which have been applied using the extracts from turmeric
(Santana & Meireles, 2017) and blackberry residues (Machado et al.,
2018).
In addition, PLE has been shown to be a highly efficient technique to
obtain extracts with higher yields in phenolic compounds. Solvents
ethanol, water and acetone applied at 40–100 °C and pressures of
10–30 MPa were used to enhance the obtaining of phenolic compounds
from the wastes of turmeric (Santana, Osorio-Tobón, et al., 2017), ju-
çara (Garcia-Mendoza et al., 2017), and passionfruit (Viganó et al.,
2016).
An urge to find clean technologies for sustainable development re-
sults in a strategy to valorize organic solid waste using combined pro-
cesses. In addition, integration of different processes are related to in-
crease the process efficiency and the improvement of quality of
products (Viganó, Machado, & Martínez, 2015).
The reuse of agro-industrial waste in integrated extraction and
bioprocessing techniques looks attractive because of their availability,
low cost, and characteristics that allow obtaining different methyl-
xanthines and phenolic compounds, besides being an environment
friendly alternative for their disposal.
In addition, integrated extraction and bioprocess techniques may
increase the applicability of guarana waste in terms of sensorial ac-
ceptance, because of reduced tannins content, responsible for the ad-
stringent flavor. Fig. 2 shows a schematic diagram reporting future
direction on reusing of guarana wastes.
6. Conclusion
Mehtylxanthines and polyphenols are widely distributed in nature
and recent interest on these compounds considering health and tech-
nological perspectives induced the wide range of research papers in-
vestigations on their potential health benefits and strategies to intensify
the obtaining of these constituents.
Most of guarana production is subjected to the formulation of car-
bonated beverages and energetic drinks. Literature survey provides
information on the beneficial effects of guarana on treatment of dis-
eases, despite controversial relates.
Nowadays there is a growing interest on the application of waste
465
Journal of Functional Foods 47 (2018) 457–468
plant matrices for the recovery of phytochemicals. These products may
be reused as substrates in solid-state fermentation, combined with
further extraction processes providing a green alternative for value-
addition.
Conflict of interest
The authors confirm that this article content has no conflict of in-
terest.
Acknowledgements
Ádina L. Santana thank CAPES (1764130) for her post-doctoral fi-
nancial support.
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