Ilex – Maté Leaf (Mate folium)
|Latin name of the genus:||Ilex|
|Latin name of herbal substance:||Mate folium|
|Botanical name of plant:||Ilex paraguariensis st. hilaire|
|English common name of herbal substance:||Maté leaf|
Latin name of the genus: Ilex
Latin name of herbal substance: Mate folium
Botanical name of plant: Ilex paraguariensis St. Hilaire
English common name of herbal substance: Maté Leaf
- 1. Introduction
- 2. Historical data on medicinal use
- 3. Non-Clinical Data
- 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- Assessor’s overall conclusions on pharmacology
- 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- Assessor’s overall conclusions on pharmacokinetics
- 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- Assessor’s overall conclusions on toxicology
- 4. Clinical Data
- 4.1. Clinical Pharmacology
- 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- Assessor’s overall conclusions on pharmacodynamics
- 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- Assessor’s overall conclusions on pharmacokinetics
- 4.2. Clinical Efficacy
- 4.2.1. Dose response studies
- 4.2.2. Clinical studies (case studies and clinical trials)
- 4.2.3. Clinical studies in special populations (e.g. elderly and children)
- 4.3. Overall conclusions on clinical pharmacology and efficacy
- 5. Clinical Safety/Pharmacovigilance
- 5.1.Overview of toxicological/safety data from clinical trials in humans
- 5.2.Patient exposure
- 5.3. Adverse events and serious adverse events and deaths
- 5.3.1. Serious adverse events and deaths
- 5.4. Laboratory findings
- 5.5. Safety in special populations and situations
- 5.5.1. Intrinsic (including elderly and children) /extrinsic factors
- 5.5.2. Drug interactions
- 5.5.3. Use in pregnancy and lactation
- 5.5.4. Overdose
- 5.5.5. Drug abuse
- 5.5.6. Withdrawal and rebound
- 5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
- 5.6. Assessor’s overall conclusions on clinical safety
- 6. Overall conclusions
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Maté folium is
–the whole or cut dried,
–the whole or cut dried and roasted leaves of Ilex paraguariensis St. H., Aquifoliaceae [DAC 2004 M- 065]. Due to its polycyclic aromatic hydrocarbons (PAH) content, this substance is excluded from the HMPC monograph. See below and section 3.3.
Ilex paraguariensis (Aquifoliaceae) is a species of holly native to subtropical South America in Argentina, Eastern Paraguay, Western Uruguay and South Brazil.
The plant is a shrub or small tree growing up to 15 – 20 meters. The leaves are evergreen,
Soon after harvesting the leaves are briefly toasted at 300°C for about 1 min to avoid fermentation (inactivation of phenoloxydase) [Knöss 2005]. This procedure is called “sapeco”. So called “Green Maté” is yielded after drying at 80
Compounds of Maté depend on the origin, harvest time (light condition), age and mass of leaves, drying method and on the adulterations with other Ilex species [Athayde et al. 2000, Scherer et al. 2002, Ohem 1990, Ohem and Hölz 1988, Ohem 1996, Heck and de Mejia 2007, Bastos et al. 2006a, 2006b, 2007].
Adulterants are Ilex dumosa, I. theezans, I. brevicuspis, I. conocarpa, I. microdonta, I. argentina and
I. pseudobuxus. They contain little or none of the compounds of I. paraguariensis. Adulterations are problematic for quality due to their different concentration of xanthins and saponins [Heck and de Mejia 2007].
The drug contains purines like caffeine (0.5
Further constituents are phenolic compounds like chlorogenic acid (2.8%), caffeic acid (0.023%), mono- and dicaffeoyl quinic acid
The content of saponins varies from 5 to 10 %. All are desmosides of ursolic acid and oleanolic acid [Schneider et al. 2006, Schenkel and Montanha 1996, Gosmann and Schenkel 1989, Gosmann et al. 1995].
The amount of volatile compounds depends on the drying procedure (about 0.01
Other compounds are carotine
After drying process two compounds are formed: caffeoylshikimic acid and dicaffeoylshikimic acid. In relation to the moisture of the leaves, the caffeine and the
Additionally, PAH were detected in prepared Maté. A total content of 0.6 to 2.3 µg/L, with naphthalene, acenaphthene and phenanthrene having the highest concentration, were found by Zuin et al. 2005. Other authors reported smaller amount [Rojo de Camargo et al, 2002, Kamangar et al. 2008]. It is highly propable that PAH develop during the roasting process over wood fire. Because of that, the roasted leaves according the DAC monograph
Comminuted herbal substance [according DAC Mate viride, 2004,
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
There are combination medicinal products with anise, fennel, rosemary, coriander, senna leaf and fruit, motherwort herba and hawthorn on the German market. Indications are laxative and traditional use as a support in case of
There is one combination medicinal product with Salix alba, Valeriana officinalis, Cola nitida and Juniperus communis. There is a lack of information about indication and posology.
For combination products there are no information about the amount/content of the partners. Therefore a recommendation of a plausible dosage is not possible and so the combinations are not addressed.
1.2. Information about products on the market in the Member States
Regulatory status overview
MA: Marketing Authorisation TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
1.3. Search and assessment methodology
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Maté and its herbal preparations have been well known as stimulants in Europe for decades. Literature data support the traditional use of Maté as a medicinal product for traditional use. Several monographs have described Maté as a medicinal product for the treatment of mental and physical tiredness (e.g. Commission E monograph) and as a diuretic agent.
The requested status overview showed that only a few marketing authorisations for Maté containing products exist in Europe. But many products containing Maté are marketed as combination or as food supplement.
The following herbal preparation is on the European market since a period of 30 years and is included in the HMPC monograph on traditional use.
comminuted herbal substance (2 medicinal products on the French market; as food supplement since 1973 in Spain; and the German Commission E monograph from 05.05.1988)
2.2. Information on traditional/current indications and specified substances/preparations
Documentation of tradition in the European context:
Maté folium has an old tradition as a caffeine containing beverage. Due to caffeine, theobromine, flavonoids and saponins a stimulating and a diuretic effect are plausible. Maté tea is also marketed as a food supplement without any standardized regulations for classification.
Some monographs in European Pharmacopoeias or other accepted documents are established.
Monograph of the Commission E for herbal medicinal products (Federal Institute for drugs and medical devices) from 5.5.1988: indication: mental and physical tiredness, posology: 3 g drug/day, effects: analeptic, diuretic, positive inotropic, positive chronotropic, glycogenolytic, lipolytic.
Monographs of the Deutscher Arzneimittel Codex (DAC) 2004 “Mate folium toasted” and “Mate folium viride”; indication: mental and physical tiredness; posology: 3 g drug/day,
Diepenbrock (1960): Maté
List und Hörhammer (1976): Maté tea, indication: stimulant and stimulant on the bowel’s function, posology: single dose 1.0 g
British Herbal Pharmacopeia (1996): indications: physical and mental fatigue, headache, weight loss, nervous depression, rheumatic pain; posology:
In France maté leaves preparations are permitted for the treatment of asthenia, as a supportive adjunctive treatment in weight loss programs orally and topically, and to increase the renal excretion of water [Cahier de l’Agence No 3 1998]. Posology according Pharmacopée française 1989:
Based on the plausible effects and the described traditional use, from the above mentioned indications only the following indications are appropriate for a traditional use without the supervision of a medical practitioner for diagnostic purposes or for prescription or monitoring of treatment:
–Traditionally used for symptoms of fatigue and sensation of weakness.
–Traditional herbal medicinal product to increase the amount of urine to achieve flushing of the urinary tract as an adjuvant in minor urinary complaints.
In summary, the literature data mentioned an oral use in the following indications:
mental and physical fatigue
stimulant of bowel function
None of these indications are supported by sufficient pharmacological and clinical data (see sections 3 and 4). Thus a
Documentation of the tradition in other countries:
Maté was used as a beverage by ancient Indians in Brazil and Paraguay some hundred years ago, however Ilex paraguariensis was first cultivated by the Jesuit missionaries in the 17th century. As early as the 18th century Maté was brought to Portugal. Even then, its therapeutic effects as a stimulant were known.
At present consumption of Maté is common in parts of Brazil, Uruguay, Paraguay and Argentina. In those areas, the beverage largely has replaced coffee and tea. Due to its coffeine and theobromine content, it has traditionally used as a stimulant and diuretic. Due to its properties, in the last decades, the consumption of Maté has spread to many areas including the Middle East, Germany, and the United States. Michl and Haberler 1954 had already investigated the purine content of Maté in order to explain its effects. Already in 1883, Peckolt described the use of Maté. In the survey by Mendes and Carlini 2007 from 24 Brazilian books published between 1930 and 2003, Ilex paraguariensis is described as a
popular plant for treatment of weakness, muscular and mental fatigue, providing vitality, resistance and dynamics.
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
Posology and indications of the traditional herbal preparations of Maté folium
Comminuted herbal substance for herbal tea preparation
Range of posology:
From discussion of the MLWP reflecting the available data on indication and posology, the most common posology of 3 times daily a herbal tea prepared with 1 g herbal substance for the following indication on the stimulating activity was recommended: Traditional herbal medicinal product for symptoms of fatigue and sensation of weakness.
A second indication was derived addressing the traditional use as a diuretic:
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
[Alikaridis 1987]: A literature survey on chemical constituents of Ilex species is given. General and medicinal uses of the plant are also described. Due to its high methylxanthine content a stimulating and diuretic effect of Maté is postulated and plausible.
Ohem reported a diuretic effect of Maté due to its content of flavonoids, saponins, theobromine and caffeine in combination with chlorogenic acid [Ohem 1990, 1996]. There are no studies reported, which investigated the diuretic effect of Ilex paraguariensis preparations.
In vivo studies (caffeine):
[Lieberman et al. 2002]: This study examined whether moderate doses of caffeine would reduce adverse effects of sleep deprivation and exposure to severe environmental and operational stress on cognitive performance. 68 volunteers receive either 100, 200, or 300 mg caffeine or placebo in capsule form after 72 h of sleep deprivation and continuous exposure to other stressors. Caffeine, in a dose-
dependent manner, mitigated many adverse effects of exposure to multiple stressors. Caffeine (200 and 300 mg) significantly improved visual vigilance, choice reaction time, repeated acquisition, self- reported fatigue and sleepiness with the greatest effects on tests of vigilance, reaction time, and alertness. The greatest effects of caffeine were present 1 h
In order to characterize the antioxidant properties of Ilex paraguariensis infusions were analyzed by using different experimental models. The antioxidant capacity was in vitro evaluated by measuring the inhibition of
Lunceford et al. 2005 showed that polyphenol rich Mate extracts possess significant in vitro antiglycation activities (glycation means a nonenzymatic adduct formation between sugar dicarbonyls and proteins, that is one key molecular basis of diabetic complications due to hyperglycemia).
One in vivo study was performed by Colpo et al. 2007. Using two behavioral models, i.e., haloperidol- induced orofacial dyskinesia (evaluated measuring vacuous chewing movements, VCMs) and memory dysfunction, evaluated in a
Menini et al. 2007 demonstrated that Mate extracts (5
Schinella et al. 2005 demonstrated that Maté (10 g/250 ml) extract attenuates the myocardial dysfunction provoked by ischemia and reperfusion and that this cardioprotection involves a diminution of oxidative damage through a nitric
Baisch et al. 1998 studied the effect of aqueous Mate extract (30 g/130 ml) on precontracted mesenteric arterial bed. The injection of extract
Several in vivo studies were performed. Felippi et al. 2006 showed that consumption of Maté extract elevated cholesterol and
Görgen et al. 2005 showed that chronic ingestion of Mate extract significantly decreased ATP, ADP and AMP hydrolysis in blood serum. They concluded that due to the changes in balance of purine, Maté can be a drug target for the treatment of cardiovascular diseases.
Mosimann et al. 2002 studied whether Maté could reduce the progression of arteriosclerosis in
Mosimann et al. 2006 showed that Ilex paraguariensis extract can inhibit the progression of atherosclerosis in
Stein et al. 2005 showed that the chronic oral administration of I. paraguariensis extract (110 g/l) in rats fed hypercholesterolemic resulted in a significant reduction in serum levels of cholesterol and triglycerides.
Some reviews about the most popular plants, including Ilex paraguariensis, used for weight loss were published [Dickel et al. 2007, Pittler and Ernst 2004, Pittler et al. 2005]. All authors concluded that the evidence for the most dietary supplements as aids in reducing body weight is not convincing.
One in vivo study was performed by Pang et al. 2008. The
Chemopreventic and anticancerous actions:
[Arbiser et al. 2005]: Natural product extracts were screened using
[Gonzalez de Mejia and Ramirez 2004]: The objective was to evaluate the cytotoxicity of tea aqueous extracts and selected polyphenols on HepG2 cancer cells, and ornithin decarboxylase (ODC) and topoisomerase activities. Tested were epigallocatechin gallate, quercetin, gallic acid, green tea, Ardisia and Maté. Maté tea was the most active with 50% cell growth inhibition of 57 mg/ml, total growth inhibition of 74 mg/ml and 50% net cell killing of 83 mg/ml. The authors concluded that Ardisia and Maté teas may have public health potential as chemopreventive agents.
[Gonzalez de Mejia et al. 2005]: The objectives of this study were to determine the phenolic content of yerba mate tea products (MT) (Ilex paraguariensis) and evaluate their capacity to inhibit topoisomerase I (Topo I) and II (Topo II) activities and oral carcinoma cell proliferation. Total polyphenols of aqueous extracts of dried MT leaves were measured by the
Additionally investigations were conducted:
–the inhibition of the passive diffusion of cholic acid through dialysis membranes due to a Mate saponins [Ferreira et al. 1997],
–the antiparkinsonian activity of the hydroalcohol extract of Ilex paraguariensis [Milioli et al. 2007],
–the potential effects on diabetic complication [Gugliucci and Menini 2002, Wada et al. 1996,
–the bile stimulant actions of Maté [Gorzalczany et al. 2001] .
Assessor’s overall conclusions on pharmacology
Maté has a long tradition as a popular beverage with medicinal benefits: particularly, it has been used as a stimulant or a diuretic agent. However, in vivo studies with Maté were not performed to support these effects of Mate preparations. The traditional use of Maté for physical and mental tiredness can be explained by its content of a purine alkaloid: caffeine. The caffeine content of Maté is 0.5 – 2.5% of dried leaves. This is equal to
The pharmacological properties of caffeine are multiple: first of all it is known as a stimulant, including central nervous system stimulation, relaxation of smooth muscle and vasoconstriction. Its effect on cognitive function was supported by Lieberman et al. 2002. They examined the effects of 100- 300 mg caffeine.
Numerous in vitro studies and one in vivo study have been performed in order to examine the antioxidant capacity of Maté. It has been found that the consumption of Maté contributes to the antioxidant intake. It has been shown that the antioxidant activity positively correlates with the concentration of total polyphenols in particular caffeoylquinic derivatives. Its antioxidant effects may have potential health benefits such as lowering of human LDL, arthritis, inflammation, liver diseases and reduction of heart disease and cancer. Maté possesses a much higher antioxidant capacity than green tea and a slightly lower capacity than red wine. [Newell et al. 2007, Dralyuk et al. 2006].
Only a few in vitro and in vivo studies showed a possible effect on cardiovascular diseases. It has been demonstrated that Maté is capable of vasorelaxation of arterial beds in rats. It is also able to reduce ATP, ADP and AMP hydrolysis, which can help to balance the circulatory system. It has the ability to inhibit atherosclerosis and reduce serum concentrations of cholesterol and triglycerides, thus suggesting that Maté may be able to lower the risk for heart disease [Heck and de Mejia 2007].
Antiobesity and weight loss actions
Obesity and overweight are associated with diabetes, hypertension and other diseases that cause morbidity, mortality and high
Hypergylcemia may be a cause for diabetic complications due to dicarbonyls involved in advanced glycation end product formation. Oxidation has been linked to glycation and Maté extracts show a
Maté is also traditionally used in gastrointestinal disorders as eupeptic and choleretic agent. This effect may be attributed to a Maté induced increase in bile flow [Gorzalczany et al. 2001].
In the last decades, Maté has become very popular. Thus many areas of scientific interest on the metabolic effects of Maté are covered, but a complete assessment on clinical relevance is not possible, due to a lack of clinical investigations. In summary, the pharmacological data support the traditional indication as a stimulant and diuretic agent for more than 30 years.
Therefore, the following wording for the indications is suitable:
Traditional herbal medicinal product for symptoms of fatigue and sensation of weakness.
Traditional herbal medicinal product to increase the amount of urine to achieve flushing of the urinary tract as an adjuvant in minor urinary complaints.
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
No relevant data on the pharmacokinetics of Maté or Ilex paraguariensis preparations are available.
Ohem and Hölz 1990 cited that in vitro tests (resorption test according Koch) showed an increased transfer of caffeine in artificial blood, due to the presence of chlorogenic acids in Maté. Pharmacological studies showed that the lethal dose of caffeine was increased by
Interactions with other medicinal products
An August 11, 2005, United States patent application (documents #20050176777, #20030185908, and #20020054926) cites yerba mate extract as a monoamine oxidase (MAO) inhibitor; the maximum inhibition observed in vitro was
Assessor’s overall conclusions on pharmacokinetics
For the herbal substance or the herbal preparation no sufficient data are available. Therefore, no conclusion can be drawn.
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
single dose toxicity:
no data for herbal or herbal substance or herbal preparation were available
repeat dose toxicity:
no data for herbal or herbal substance or herbal preparation were available
no data for herbal or herbal substance or herbal preparation were available
[Christian and Brent 2001]: This document provides an extensive and critical literature review of the effects of caffeine on reproduction, pregnancy and development of the offspring of
This review of the animal studies on reproductive toxicity of caffeine consumption concluded that a moderate consumption of caffeine
[Momoi et al. 2008]: Caffeine consumption during pregnancy is reported to increase the risk of in utero growth restriction and spontaneous abortion. In the study, the hypothesis that modest maternal caffeine exposure affects in utero developing embryonic cardiovascular (CV) function and growth without altering maternal hemodynamics was tested. Caffeine (10 mg/kg/day subcutaneous) was administered daily to pregnant
carcinogenicity and genotoxicity
Leitao and Braga 1994 analyzed the mutagenic and genotoxic effects of mate aqueous solutions (prepared from instant Maté powder 200 mg/l) in bacterial cells. Maté solutions showed mutagenic effects in the Ames test (TA 97, TA 98, TA100 and TA 102 strains) at concentrations of 20 to
50 mg/plate (mutagenic factor 3.5 to 5.6) and genotoxic activity in the induce test (phage induction in a lysogenic strain of Escherichia coli; WP2s(λ)strain) with a maximal phage induction at concentrations of 10 to 20 mg/plate. Above these concentrations the mate solutions were cytotoxic. Addition of catalase (5U/ml), S9 rat liver microsomal fraction (20 µl/ml), thiourea (100 µM) or dipyridyl (10 µM) completely inhibited the lysogenic induction produced by Maté. The authors concluded that oxygen reactive species present in Maté play an essential role in its genotoxicity.
The described tests were performed according the OECD Guideline for testing of chemicals. The test utilizes prokaryotic cells, which differ from mammalian cells in factors like uptake, metabolism, chromosome structure and DNA repair processes. The test therefore does not/could not provide direct information on the mutagenic and carcinogenic potency of a substance in mammals [OECD Guideline, 1997].
In vitro metabolic activation systems cannot entirely mimic the mammalian in vivo conditions. Therefore the bacteria strains were exposed to S9 rat liver microsomal fraction, thiourea and dipyridyl. S9 rat liver microsomal fraction abolished the genotoxic activity of Maté, thiourea suppressed the genotoxic effect.
Indeed epidemiological studies have shown that in regions where the consumption of Maté is high, the incidence of esophageal tumors is higher. But experiments using human cell lines are lacking. Sewram et al. 2003 and Castellsague et al. 2000 showed that the high temperature of the infusion may be responsible for this finding. Their findings are supported by Islami et al. 2009.
Further studies were described by Fonseca et al. 2000. See this chapter in vivo studies.
These findings are reasonable because a liver metabolism of Maté cannot already be performed in the oesophageal region. A higher incidence of bladder and kidney cancer cannot be explained by the results yielded after treatment with S9 rat liver microsomal fraction. Therefore, further studies with mammalian cell lines are necessary.
(0.002 ± 0.002), 175 μg/ml (0.002 ± 0.003) and negative control (0.001 ± 0.001). The authors concluded that there is no clastogenic or/and aneugenic basis underlying maté action in the cytokinesis block micronucleus assay.
Furthermore, the same authors focused on the reasons of discrepancies between their data and the mutagenic response previously reported. First of all, Leitao and Braga (1994) used a form of instant Mate beverage, Fonseca et al. (2000), as reported below, tested lyophilized aqueous extracts of maté, on the contrary their group used a maté infusion, which is similar to the way it is used in human consumption. Secondly, the data from the three investigations are related to different maté commercial suppliers.
[Miranda et al. 2008]: Yerba mate (Ilex paraguariensis) is rich in several bioactive compounds that can act as free radical scavengers. Since oxidative DNA damage is involved in various pathological states such as cancer, the aim of this study was to evaluate the antioxidant activity of mate tea as well as the ability to influence DNA repair in male Swiss mice. Forty animals were randomly assigned to four groups. The animals received three different doses of mate tea aqueous extract (350 mg/g phenolic compounds; prepared by dissolving instant mate tea), 0.5, 1.0 or 2.0 g/kg, for 60 days. After
intervention, the liver, kidney and bladder cells were isolated and the DNA damage induced by H2O2 was investigated by the COMET assay. The DNA repair process was also investigated for its potential to protect the cells from damage by the same methodology. The data showed that mate tea is not genotoxic in liver, kidney and bladder cells. The regular ingestion of mate tea increased the resistance of DNA to
According to the authors, the data presented showed that Maté tea is not genotoxic in liver, kidney and bladder cells. The COMET assay has not been validated and consequently it is not known how specifically and reliably it could differentiate between genotoxicants and
[Fonseca et al. 2000]: Aqueous extracts of Ilex paraguarariensis
[Kamangar et al. 2008]: This study was conducted to determine whether drinking Maté could lead to substantial exposure to PAH, including known carcinogens, such as benzo[a]pyrene. Methods: The
concentrations of 21 individual PAHs were measured in dry leaves of eight commercial brands of yerba Maté from Barzil (roasted) and in infusions made with hot (80°C) or cold (5°C) water. Measurements were done using gas chromatography/mass spectrometry, with deuterated PAHs as the surrogates. Infusions were made by adding water to the leaves (5 g/30ml water; 80 °C or 5 °C, 5 minutes), removing the resulting infusion after 5 min, and then adding more water to the remaining leaves. This process was repeated 12 times for each infusion temperature. Results: The total concentrations of the 21 PAHs in different brands of yerba Maté ranged from 536 to 2,906 ng/g dry leaves. Benzo[a]pyrene concentrations ranged from 8.03 to 53.3 ng/g dry leaves. For the Maté infusions prepared using hot water and brand 1, 37% (1,092 of 2,906 ng) of the total measured PAHs and 50% (25.1ng of 50 ng) of the benzo[a]pyrene content were released into the 12 infusions. Similar results were obtained for other hot and cold infusions. Conclusion: Very high concentrations of carcinogenic PAHs were found in yerba Maté leaves and in hot and cold Maté infusions. Results support the hypothesis that the carcinogenicity of Maté may be related to its PAH content.
[Rojo de Camargo and Toledo 2002]: In order to estimate the contribution of Maté tea (chá mate; roasted mate) and regular coffee as a source of PAHs in the diet of the population of Campinas, SP, Brazil, different batches and brands of these products, totaling 18 samples, were analysed for PAH. The consumption data were obtained from a dietary survey (frequency recall), which took place in Campinas in 1993. PAH levels in the products were determined by high performance liquid chromatography with fluorescence detection
[Zuin et al. 2005]: A simple procedure based on stir bar sorptive extraction (SBSE) and
Assessor’s overall conclusions on toxicology
Maté extracts (lyophilizied and resolved) showed mutagenic effects in the Ames test (TA 97, TA 98, TA100 and TA 102 strains) at concentrations of 20 to 50 mg/plate (mutagenic factor 3.5 to 5.6) and genotoxic activity in the induce test (phage induction in a lysogenic strain of E. coli; WP2s(λ)strain) [Leitao and Braga 1994]. The same extracts were not clastogenic in vivo (bone marrow cells of rats) but the authors observed an increased frequency of chromosomal aberrations in
Several in vitro and in vivo studies have been conducted on the anticancer properties of Maté. These may be attributed to its antioxidant effects and to the proteasome inhibition induced by Maté. Compounds that may be responsible are 3,5 dicaffeoylquinic acid, rutin and quercetin. On the other hand there are several epidemiological studies that suggested an association between Maté consumption and an increased risk of developing esophageal, lung and bladder cancer. Compounds that may contribute to the development of cancer are PAH. It is highly probable that PAH develop
during the processing of Maté, as Maté is commonly dried over a smoky wood fire [Heck and de Mejia 2007]. The amount that is extracted by preparation of the infusion is 0.22 – 1.88 % of the analyzed PAH content, thus a limitation is not necessary [Kamangar et al. 2008, Blaschek et al.2007].
In comparison, total PAH content in coffee is higher than in Maté, but the benzo[a]pyrene content is higher [Blaschek et al. 2007]. Coffee is a worldwide consumed beverage and it is not classified as a carcinogenic to humans due to its PAH.
The international Agency of research on cancer (IARC) listed in 1991 Maté in group 3 and Hot Maté in group 2A. That means Maté is not classifiable as to its carcinogenicity to humans and Hot Maté drinking is probably carcinogenic to humans. These classifications were concluded on basis of the known experimental data in the year 1991.
Roasted Maté leaves propably contain more PAH than dried leaves. Because of that, roasted leaves are not included in the HMPC monograph.
4. Clinical Data
For the most studies cited, a detailed description of the used herbal substance(s)/herbal preparation(s) was not available.
4.1. Clinical Pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
[Gugliucci 1996]: First the oxidability of LDL in whole plasma from 3 healthy fasted human subjects before and after intake of Ilex paraguariensis were examined. Intake of water extracts of Ilex paraguariensis inhibit
The number of volunteers was only 3 and there is a lack of information on the concentration of the preparation of water extract.
[Pasqualotto et al. 2006]: The objective of this study was to evaluate and compare the seminal antioxidant enzymatic activity (SOD and catalase levels) among fertile and infertile men who consumed Maté. Maté intake was correlated with SOD levels (r=0.268; P=0.04) and catalase levels (r=0.311; P=0.01). Patients who drank more than 300 ml of Maté per day had higher SOD and catalase compared to men who did not drank Maté.
[Andersen and Fogh 2001]: To determine the effect of a herbal preparation `YGD’ containing Yerbe Mate, Guarana (seeds of Paullinia cupana) and Damiana (leaves of Turnera diffusa var. aphrodisiaca) on gastric emptying and to determine the effect of the same preparation on weight loss over 10 days
and 45 days and weight maintenance over 12 months, the following tests were performed. Methods: Gastric emptying was observed using ultrasound scanning in seven healthy volunteers following YGD and placebo capsules taken with 420 ml apple juice. Body weight was observed before and after 10 days of treatment with three YGD capsules or three placebo capsules before each meal for 10 days in 44 healthy overweight patients attending a primary health care centre.
The study was performed with a preparation that contained not only Maté, but also Guarana and Damiana. Therefore the effects cannot only be attributed to Maté consumption.
[Martinet et al. 1999]: In this study the effects of oral administration of 12 plant preparations with
[De Pasquale 1991]: A controlled
Assessor’s overall conclusions on pharmacodynamics
Clinical studies on antioxidative effects are rare. Only one study has been shown that Maté inhibits the LDL oxidation by inhibiting lipid peroxidation [Gugliucci et al. 1996]. It has been shown that this mechanism is possible, but it is speculation whether this is possible in vivo. The described study involved only 3 volunteers and there is no information about the used Maté preparation (e.g. concentration and amount).
Only a few clinical studies were performed to confirm an effect of Maté on
oxidation [Martinet et al. 1999]. A decrease in weight, after Maté consumption, has only been shown for combinations of Maté with Damiana and Guarana or Maté with Green tea, Asparagus, Black tea Guarana and Kidney beans [Andersen and Fogh 2001, Opala et al. 2006]. Further studies are necessary.
Clinical data on pharmacodynamics are rare, thus a
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
No data for the herbal substance or herbal preparations are available.
[Deutscher Arzneimittel Codex: German Commission B monograph caffeine 1989, 2004]: Caffeine is a xanthine derivate that exerts its physiological effects in large part through antagonism of central adenosine receptors. Caffeine shows an absorption
[Bchir et al. 2006]: The present study investigated pharmacokinetic and electroencephalographic responses to caffeine (140 mg) in 2 groups of healthy volunteers reporting, or not,
[Lelo et al. 1986]: The pharmacokinetics of caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were studied in 6 healthy male volunteers after oral administration of each compound on separate occasions. The total plasma clearances of CA and PX were similar in value (2.07 and 2.20 ml
Assessor’s overall conclusions on pharmacokinetics
Due to lack of data for Maté preparations, no conclusions can be drawn.
4.2. Clinical Efficacy
4.2.1. Dose response studies
No data available.
4.2.2. Clinical studies (case studies and clinical trials)
[Matzkies 1989]: 79 Persons received 1,200 kcal reduction diet for 28 days.
A reduction of tiredness and other
There are a few studies that investigated the effect on weight loss of preparations that containing Maté beside other drugs like Guarana and Damiana or Asparagus, Green tea, Black tea and Kidney beans [Opala et al. 2006, Ruxton 2004]. Due to the lack of information about the amount and contribution of Maté, the effect of Maté cannot be assessed.
4.2.3. Clinical studies in special populations (e.g. elderly and children)
4.3. Overall conclusions on clinical pharmacology and efficacy
Although Maté has been used for symptoms of fatigue and sensation of weakness, clinical trials supporting this use are lacking. Only one study, performed by Matzkies 1989 in order to detect a reduction of
for the described diuretic,
All reported studies in order to detect the efficacy of Maté in reducing weight were performed with administration of a combination product. Because of that, the clinical relevance of Maté in weight management cannot be assessed.
5. Clinical Safety/Pharmacovigilance
5.1.Overview of toxicological/safety data from clinical trials in humans
[Goldenberg 2002]: Maté consumption has been associated with an increased rate of oral, oropharyngeal, esophageal, and laryngeal cancers. The purpose of this study was to review the literature and discuss the role of Maté consumption in the development of oral and oropharyngeal cancer and the potential carcinogenic mechanisms. A review of the relevant literature linking Maté consumption with oral and oropharyngeal cancer and the carcinogenicity of Maté was performed. The search was performed using Medline, library catalogues, OCLC first search and ISI web of science databases. Case control studies on Maté drinking populations and, in vivo and in vitro studies on the carcinogenicity of Maté were reviewed. The populations reviewed in many of these studies also used alcohol and tobacco products confounding the influence of Maté as an independent risk factor. There is evidence in the literature that Maté consumption is itself carcinogenic and plays a role in the development of cancers of the oral cavity and oropharynx. The author concluded that although the exact mechanism of carcinogenesis is still unknown, available information suggests that Maté drinking should be considered one of the risk factors for oral and oropharyngeal cancer.
[Goldenberg et al. 2003]: The purpose of this study was to review the literature and discuss the role of Maté consumption as a risk factor for head and neck cancers. The review was performed of the relevant literature linking maté consumption with head and neck cancer and the proposed carcinogenicity of maté. Case control studies on
[Abnet 2007]: In this review, hot Maté is listed according the IARC as an agent with a moderate level to influence the risk of developing cancer. It is concluded that further research will be required to disentangle the effect of Maté and the temperature at which it is consumed. Alternatively the author supposed that a contamination with PAH, which are introduced during preparation of the leaves, may be the carcinogenic agent.
5.3. Adverse events and serious adverse events and deaths
[Bates et al. 2007]: This bladder cancer
[Castellsague et al. 2000]: To estimate the effects of consuming hot beverages, including Maté (an infusion of the herb Ilex paraguayensis), tea, coffee and coffee with milk, and other food items on esophageal cancer risk, data from 830 cases and 1,779 controls participating in a series of 5 hospital- based
[De Stefani et al. 1988]: A
[De Stefani et al. 1991]: A
[De Stefani et al. 1996]: During the period from January 1988 to December 1994, a
showed a significant increase in relative risk for Maté amount (OR, 2.9; 95% CI,
[De Stefani et al. 1998]: In the period January
[De Stefani et al. 1987]: One hundred seven patients afflicted with incident laryngeal cancer and 290 controls with diseases considered not related to tobacco and alcohol exposure were interviewed in the University Hospital of Montevideo, Uruguay. The study followed a
[De Stefani et al. 2007]. An additional
[Fagundes et al. 2006]: The highest rates of esophageal squamous cell carcinoma (ESCC) in Brazil occur in Rio Grande do Sul, the most Southern state, which has incidence rates of 20.4/100,000/year for men and 6.5/100,000/year for women. Exposure to carcinogenic PAHs through tobacco smoke and other sources may increase the risk of ESCC. The aims of the study were to investigate the degree and sources of PAH exposure of the inhabitants of this region of Southern Brazil. Methods: Two hundred healthy adults (half smokers, half non smokers, half male and half female) were recruited, given a standardized questionnaire, and asked to provide a urine sample for measurement of
the high rates of ESCC observed in this population. The increased urine
[Munoz et al. 1987]: Thermal injury resulting from drinking very hot beverages has been incriminated as a risk factor for oesophageal cancer, although no information is available on the lesions caused by this injury in human or experimental animals. The drinking of hot maté tea is very common in areas of moderately high incidence of oesophageal cancer in
[Munoz et al. 1998]: The relationship between social class indicators, body mass index (BMI), selected
[Pintos et al. 1994]: Maté drinkers have high risks of upper aerodigestive tract cancers, but it is conceivable that this high risk may be attributable to confounding by smoking alcohol, and other exposures. To test this hypothesis, the data from a
[Pütz et al. 2002]: In an attempt to correlate the TP53 mutation pattern of squamous cell carcinomas of the esophagus (ESCC) and life style factors of patients from the high risk area Rio Grande do Sul, Brazil, 135 ESCC were analyzed, after prescreening by p53 immunohistochemistry, by SSCP and DNA sequencing of TP53, exon
coexposure to various life style risk factors in most patients of this series, the hypothesis is proposed that besides smoking and alcohol drinking the commonly consumed hot Maté tea in this high risk area for ESCC is responsible for this different pattern of TP53 mutations because of chronic hyperthermic irritation and inflammation in the esophagus with an endogenous formation of radicals or carcinogenic factors that lead to a higher prevalence of transition mutations.
[Rolon et al. 1995]: A
[Sewram et al. 2003]: A retrospective
[Vassallo et al. 1985]: Esophageal cancer has constituted a major public health problem in Uruguay, with
alcohol were non significant. Maté consumption (0.5
[Victoria et al. 1987]: There is a cluster of
[Spinella et al. 2001]: Anecdotal, uncontrolled observations suggest that herbal stimulants containing ephedrine (ephedra or ma huang) and caffeine (cocoa, coffee, tea, maté, guarana, cola or kola) can exacerbate seizures in people with epilepsy, especially when taken in combination.
Data on Maté are insufficient. Therefore an effect of Maté on people suffering from epilepsy cannot be assessed. For a detailed comment on the risk of cancer/cancerogenic potential, see 5.6.
5.3.1. Serious adverse events and deaths
[McGee et al. 1976]:
Small amounts of pyrrolizidine alkaloids were recovered from a sample of Maté (Paraguay) tea, owned by the patient, to which she was addicted. It seems probable that the consumption of large amounts of this tea was the cause of the hepatic disease.
Only one case of
[Hsu et al. 1995]: An outbreak of cholinergic poisoning occurred in New York City during a
chromatography contained belladonna alkaloids but neither caffeine nor theophylline. An investigation by the New York City Department of Health personnel determined that the tea was from a single lot, imported by one distributor, and sold at one grocery store. Unsold inventories of the tea were quarantined, and no further cases of anticholinergic poisoning were reported.
[Meggs et al. 1995]: Inadvertent anticholinergic poisoning can result from consumption of foods contaminated with plants that contain belladonna alkaloids. During March 1994, the New York City Department of Health investigated seven cases of anticholinergic poisoning in members of three families; three of the seven ill persons required emergency treatment for characteristic manifestations. For all cases, manifestations occurred within 2 hours after drinking tea made from leaves purchased commercially and labelled as Paraguay tea, an herbal tea derived from the plant Ilex paraguariensis, which is native to South America. The report summarized the investigation of these cases.
In all cases, the authors attributed the disease to an adulteration of the herbal tea. Adverse events due to the content of caffeine can be sleeplessness, uneasiness, tachycardia and
5.4. Laboratory findings
No data for the herbal substance or herbal preparations are available.
5.5. Safety in special populations and situations
5.5.1. Intrinsic (including elderly and children) /extrinsic factors
No data for the herbal substance or herbal preparations are available.
Use in children and adolescents under 18 years of age is not recommended because data are not sufficient. In general, an appearance of tiredness in children and adolescents should be investigated by a physician. A treatment with Maté containing preparations, without clarifying the causes, does not seem to be adequate.
5.5.2. Drug interactions
No clinical data for the herbal substance or herbal preparations are available.
An August 11, 2005, United States patent application (documents #20050176777, #20030185908, and #20020054926) cites yerba mate extract as a MAO inhibitor; the maximal inhibition observed in vitro was
[U.S. patent 20030185908]: “The MAO inhibitors of the present invention are useful for a variety of therapeutic applications, such as the treatment of depression, disorders of attention and focus, mood and emotional disorders, Parkinson’s disease, extrapyramidal disorders, hypertension, substance abuse, smoking substitution,
[Thomson Microdex 2007]: Drug interactions and/or related problems of caffeine intake: Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine and selegiline (large amounts of caffeine may produce dangerous cardiac arrhythmias or serve hypertension because of the sympathomimetic side effects of caffeine; concurrent use with small amounts of caffeine may produce tachycardia and mild increase in blood pressure).
On the basis of the data available concerning drug interactions for Maté and caffeine, the following is recommended as regards ‘interactions with other medicinal products and other forms of interactions’ for inclusion in the HMPC monograph: “Persons taking
5.5.3. Use in pregnancy and lactation
[Martin et al. 2007]: The premature newborn of a mother who reported drinking Maté during pregnancy presented with increased jitteriness and irritability,
[Santos et al. 2005]: To assess the effect of Maté drinking during pregnancy on preterm and small for gestational age (SGA) birth, a
The level of exposure to Maté drinking during pregnancy was obtained retrospectively. Only weekly frequency but not the amount of Maté consumed was investigated.
[Matijasevich et al. 2006]: The objective of this study was to examine the association between caffeine intake during pregnancy and fetal mortality in Montevideo, the capital city of Uruguay, taking into account several potential confounding factors. A
The aim of the study was to examine the association between caffeine intake and fetal mortality. The caffeine amount of Maté was assumed at 0.17 mg/ml. The differences between the caffeine sources (coffee or Maté) were not examined.
Caffeine consumption during pregnancy:
[Ford et al. 1998]: To examine the association between maternal caffeine consumption during pregnancy and the risk of sudden infant death syndrome (SIDS). Methods: A nationwide
Conclusion: Caffeine intake has been associated with fetal harm and SIDS. Reducing heavy caffeine intake during pregnancy could be another way to lessen the risk of SIDS. The authors remarked that this needs confirmation by others.
[Bracken et al. 2003]: Whether caffeine consumption during pregnancy represents a fetal hazard remains uncertain. The authors report on a large prospective study designed to examine this question. In
Caffeine crosses the placenta and achieves blood and tissue concentrations in the fetus that are similar to maternal concentrations. One case of a mother who reported drinking Maté during pregnancy was described. The premature newborn presented with increased jitter and irritability,
The Food Standards Agency has recommended that pregnant women should limit their caffeine intake to less than 300 mg of caffeine a day. A higher intake may be associated with fetal loss.
Caffeine is distributed into breast milk. Although the concentration of caffeine in breast milk is 1% of the mother’s plasma concentration, caffeine can accumulate in the infant, due to its increased
The study of Santos et al. 2005 showed no harmful effect, but they did not investigate the amount of Maté consumed. Additionally, the level of exposure to Maté drinking during pregnancy was obtained retrospectively and the
There is insufficient information on the excretion of Maté/metabolites in the milk. A risk to the suckling child cannot be excluded. Medicinal products containing Maté should not be used during breast- feeding.
Due to the caffeine content of Maté and the effects reported by Santos et al. 1998, 2005 and Martin et al. 2007, the following wording, from the appendix 3 of the EMA ‘Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling’ (EMEA/CHMP/203927/2005), is recommended for inclusion in the HMPC monograph: “There are no or limited data from use during pregnancy and lactation. The use should be avoided during pregnancy and lactation.”
No data for Maté preparations are available.
Caffeine data: single dose toxicity
[Hunnius et al. 2009]: lethal dose is about 10 g.
Caffeine data: repeat dose toxicity
[James and Crosbie 1987]: Conflicting results have been reported as to whether habitual caffeine use is associated with symptoms of poorer health. The aim of the study was to further examine the association between caffeine use and somatic and psychological symptomatology while controlling for potentially confounding influences such as concurrent substance use. Information was obtained on the somatic and psychological health, substance use, and biographic background of 96 individuals divided into 3
[Blaschek et al. 2007]: Caffeine may cause side effects like insomnia, anxiety, tremulousness, raised blood pressure, increase of stomach acid and gastroesophageal reflux.
5.5.5. Drug abuse
No data for Maté preparations are available.
Caffeine tolerance development
[Evans and Griffith 1992]:
5.5.6. Withdrawal and rebound
No data for Maté preparations are available.
It is well known that a caffeine withdrawal causes symptoms like headache.
5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
No studies on the effect of Maté on the ability to drive and use machines have been performed.
[Deutscher Arzneimittel Codex:
5.6. Assessor’s overall conclusions on clinical safety
There are numerous publications indicating both a chemoprotective potential of Maté tea (high content of antioxidants) and an increased risk for cancer of the mouth and pharynx, esophagus, bladder and kidney (see chapter 5.3). However, it has to be considered that an increased risk for oral and pharyngeal cancer is postulated in case of frequent intake of very hot liquids, as for example Maté tea (Ghadirian 1987, Islami et al. 2009). The performed case control studies are insufficient concerning the quality of the case report forms, the inclusion/exclusion criteria and diagnoses documented. Thus, valid epidemiological and mechanistic studies are missing to establish a causal relationship of Maté consumption and cancer of the bladder and kidney.
In conclusion at present, there is no evidence that Maté tea contains more potent genotoxic ingredients than other roasted, fried or smoked food. As compared to Maté tea, coffee and smoked food contain similar or even higher amounts of PAH. In consumers of coffee and smoked products of cheese, meat and fish, the formation of corresponding PAH metabolites is expected which is documented for the consumption of meat from the barbecue. Valid studies investigating how far the consumption of barbecued meat, smoked or roasted food could mean an additional cancer risk are not available. Based on the present scientific data, it can be assumed that considering the background exposure of an average food consumer, there is no relevant additional genotoxic or carcinogenic risk when consuming moderate amounts of Maté tea. For the risk assessment, also the postulated, possible chemoprotective effects due to the high rate of antioxidants have to be considered. Valid data, however, are not available at present.
On the basis of the
– “Gastric and duodenal ulcers, cardiovascular disorders such as hypertension and arrhythmia, hyperthyroidism.”
–“The use in children and adolescents under 18 years of age is not recommended due to lack of adequate data.”
–“Not recommended before bedtime as it may cause sleep disturbances.”
– “Persons taking
Pregnancy and lactation
– “There are no or limited data from use during pregnancy and lactation. The use should be avoided during pregnancy and lactation.”
As regards the indication as an adjuvant in minor urinary complaints, the following warning is
The contraindications (‘Hypersensitivity to the active substance(s)’ and ‘Conditions where a reduced fluid intake is recommended, e.g. obstruction of the urinary tract’ are also recommended.
Due to a possible caffeine tolerance development [Evans and Griffiths 1992], it is recommended to limit the duration of use to 1 week for the first indication (symptoms of fatigue and sensation of weakness) and to 2 weeks for the second indication (adjuvant in minor urinary complaints).
The Community herbal monograph also should indicate that adequate tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.
6. Overall conclusions
Maté tea is well known and used as a traditional herbal medicinal product for centuries in South America and for decades in European countries. Sufficient data are available to develop a Community monograph on the traditional use of Ilex paraguariensis St. Hilaire, folium (Maté leaves), provided the indications are suitable for
“Traditional herbal medicinal product for symptoms of fatigue and sensation of weakness.
Traditional herbal medicinal product to increase the amount of urine to achieve flushing of the urinary tract as an adjuvant in minor urinary complaints.”
Based on the present scientific data, it can be assumed that there is no relevant genotoxic or carcinogenic risk when consuming moderate amounts of Maté tea. Although several studies on the carcinogenicity of Maté were examined, due to a positive
For the risk assessment also the postulated, possible chemoprotective effects due to the high rate of antioxidants have to be considered. Valid data, however, are not available at present.