Community herbal monograph on
Ilex paraguariensis
St.
Hilaire, folium
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
i) Herbal substance
Not applicable.
ii) Herbal preparations
Comminuted herbal substance
Well-established use
Traditional use
Comminuted herbal substance as herbal tea for
oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Indication 1)
Traditional herbal medicinal product for symptoms
of fatigue and sensation of weakness.
Indication 2)
Traditional herbal medicinal product to increase
the amount of urine to achieve flushing of the
1 The material complies with DAC 2004 M- 066 and with Pharmacopée française, 10ème édition MATE VERT, janvier 1994.
2 The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
3 The content of polycyclic aromatic hydrocarbons (PAH) should be adequately controlled.
Community herbal monograph on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580539/2008
Page 2/6
Well-established use
Traditional use
urinary tract as an adjuvant in minor urinary
complaints.
The product is a traditional herbal medicinal
product for use in specified indications exclusively
based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults
Indication 1)
Daily dose:
Comminuted herbal substance as herbal tea:
2-4 g corresponding to 1 g herbal substance
3 times per day.
Indication 2)
Daily dose:
Comminuted herbal substance as herbal tea:
2.5-5 g corresponding to 2.5 g herbal substance
1 to 2 times per day.
The use in children and adolescents under 18
years of age is not recommended (see section 4.4
‘Special warning and precautions for use’).
Duration of use
Indication 1)
If the symptoms persist longer than 1 week
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Indication 2)
If the symptoms persist longer than 2 weeks
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Method of administration
Oral use.
Community herbal monograph on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580539/2008
Page 3/6
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance(s).
Gastric and duodenal ulcers, cardiovascular
disorders such as hypertension and arrhythmia,
hyperthyroidism.
Conditions where a reduced fluid intake is
recommended, e.g. obstruction of the urinary
tract.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
Indications 1) and 2)
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.
Indication 2)
If complaints or symptoms such as fever, dysuria,
spasms or blood in urine occur during the use of
the medicinal product, a doctor or a qualified
health care practitioner should be consulted.
4.5.
Interactions with other medicinal products and other forms of
interaction
Well-established use
Traditional use
Persons taking MAO-inhibitor drugs should use
mate with caution.
Caffeine containing preparations reduce sedative
action and increase side effects caused by
sympathomimetic drugs.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
There are no or limited data from use during
pregnancy and lactation.
Use should be avoided during pregnancy and
Community herbal monograph on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580539/2008
Page 4/6
Well-established use
Traditional use
lactation.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
4.8.
Undesirable effects
Well-established use
Traditional use
None known.
If adverse reactions occur, a doctor or a qualified
health care practitioner should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c (1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
Caffeine crosses the placenta and is distributed in
breast milk.
5.3.
Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
Community herbal monograph on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580539/2008
Page 5/6
Well-established use
Traditional use
necessary for the safe use of the product.
Adequate tests on reproductive toxicity,
genotoxicity and carcinogenicity have not been
performed.
Well-established use
Traditional use
Not applicable.
6 May 2010
Community herbal monograph on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580539/2008
Page 6/6
Assessment Report
......................... 2
......................... 4
ations thereof .4
...................... 6
...................... 7
......... .......................... 7
...................... 7
/preparations ... 7
f relevant
...................... 9
............................ 9
ance(s), herbal
...................... 9
.................... 13
herbal
.................... 14
.................... 14
e(s)/herbal
.................... 14
18
....................... 19
.................... 19
s)/preparation(s)
.................... 19
.................... 20
/preparation(s)
.................... 21
.................... 22
.................... 22
22
.................... 22
.................... 22
.................... 22
....................... 23
.................... 23
.................... 23
5.3. Adverse events and serious adverse events and deaths ......................................... 23
5.3.1. Serious adverse events and deaths .................................................................. 28
5.4. Laboratory findings .......................................................................................... 29
5.5. Safety in special populations and situations ......................................................... 29
5.5.1. Intrinsic (including elderly and children) /extrinsic factors ................................... 29
5.5.2. Drug interactions........................................................................................... 29
5.5.3. Use in pregnancy and lactation........................................................................ 30
5.5.4. Overdose ..................................................................................................... 33
5.5.5. Drug abuse................................................................................................... 33
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
....................................................
..................
.
3. Non-Clinical Data
...................................................................................
Assessor’s overall conclusions on toxicology
...............................................................
..............................................................................................
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 2/35
4. Clinical Data
.................... 33
tal ability...... 34
.................... 34
35
Annex .................................................................................................................................. 35
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 3/35
1. Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
thereof
Herbal substance(s)
Maté folium is
- the whole or cut dried, non-roasted leaves of
Ilex paraguariensis
St.Hilaire
, Aquifoliac
M-066; Pharmacopée française, 1994
eae
[DAC 2004
– Mate vert]
- the whole or cut dried and roasted leaves of
Ilex paraguariensis
St. H.
, Aq
065]. Due to its polycyclic aromatic hydrocarbons (P
HMPC monograph. See below and section 3.3.
uifoliaceae
[DAC 2004 M-
AH) content, this substance is excluded from the
Ilex paraguariensis
(Aquifoliaceae) is a species of holly native to subtropical South Ame
Argentina, Eastern Paraguay, Western Uruguay
rica in
and South Brazil.
The plant is a shrub or small tree growing up to 15 - 20 meters. The leaves are
[Blaschek
et al.
2007] long and 3-9 cm [Blaschek
et al.
2007, Frohne 1999] wide,
margin. Plants are flowering from September to December. Small white unisex flow
and sepals. Plants produce red stone fruits with 4-8 seeds.
evergreen, 6-20 cm
with a serrated
ers with 4-5 petals
d fermentation
So called “Green
elded after drying at 80 -100°C/about 24 h, powdering and removing twigs. Sometimes, a
vary from one
ch of the steps.
nd mass of leaves,
drying method and on the adulterations with other Ilex species [Athayde
et al.
2000, Scherer
et al.
et al.
2006a,
2002, Ohem 1990, Ohem and Hölz 1988, Ohem 1996
,
Heck and de Mejia 2007, Bastos
2006b, 2007].
Adulterants are
Ilex dumosa, I. theezans, I. brevicuspis, I. conocarpa, I. microdonta, I. ar
I. pseudobuxus
. They contain little or none of the compounds of
I. paraguarie
proble
Mejia 2007].
12-0.7% [Scherer
et
ne [Haaf 2004] or
ne (0.1-0.4% [Ohem 1996, Mazzafera 1994]). Other investigations yielded
higher amounts of caffeine 0.1 to 2.7% and higher or smaller amounts of theobromine 0.6-2.17%
[Haaf 2004, Scherer
et al.
2002, Schneider
et al.
2006]. According the DAC 2004, the unroasted
leaves contain a minimum of 0.6% caffeine and the roasted leaves contain a minimum of 0.4%
caffeine.
Further constituents are phenolic compounds like chlorogenic acid (2.8%), caffeic acid (0.023%),
mono- and dicaffeoyl quinic acid (10-20 %) [Haaf 2004, Ohem 1996] and three isomeric
dicaffeoylquinic acids: 3,5-dicaffeoylquinic acids (3.04%), 4,5-dicaffeolquinic acid (2.89%) and 3.4-
dicaffeoylquinic acid (0.855%) and flavonoids like quercetin (0.003%), rutine (0.06%), and kaempferol
(0.0012%) [Blaschek
et al.
2007].
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 4/35
combinations
Soon after harvesting the leaves are briefly toasted at 300°C for about 1 min to avoi
(inactivation of phenoloxydase) [Knöss 2005]. This procedure is called “sapeco”.
Maté” is yi
further roasting produces “roasted Maté”, in Brazil known as “chá mate”. The conditions
processing plant to another. Quality of the product will depend on variations in ea
Compounds of Maté depend on the origin, harvest time (light condition), age a
gentina
and
nsis
. Adulterations are
matic for quality due to their different concentration of xanthins and saponins [Heck and de
The drug contains purines like caffeine (0.5 -2.5% [Haaf 2004]), theobromine (0.
al.
2002, Filip
et al.
1998, Vasquez and Moyna 1986, Reginatto
et al.
1999]) and no
small amounts of theophylli
The content of saponins varies from 5 to 10 %. All are desmosides of ursolic acid and ol
[Schnei
1995].
The amount of volatile compounds depends on the drying procedure (about 0.0
al.
2007]). Predominant aroma components of Maté tea include amon
eugenol and geranial. Aroma components are produced by degradation reactions o
manufacture of the dried leaves [Lozano
et al.
2007, Kawakami and Kobayashi 19
1 -0.78% [Blaschek
et
g others geraniol, linalool,
ccurring during
91].
) [Knöss
et al.
1998]
d copper [Filip
et al.
nce of Mg, Al, Si, P,
l, K, Ca, Ti, Mn, Fe, Cu, Zn, and Rb at different concentrations was reported, which accounts for
about 3.4% of the total mass. Preparing the infusion yields a loss of about 90% of K and Cl, 50% of
Mg and P, and 20% of Mn, Fe, Cu, Zn, and Rb in the leaves. Water temperature favours the extracti
of K and Cl, while the concentration of other elements remains practically constant [
2007].
on
Giulian
et al.
After drying process two compounds are formed: caffeoylshikimic acid and dicaffeoy
relation to the moisture of the leaves, the caffeine and the 5-caffeoylquinic acid content varied. Caffe
acid was present in 45% of the infusion from dried leaves whereas quercetin, m
were not detected in the extract [Bastos
et al.
2007, 2006a].
lshikimic acid. In
ic
yricetin and kaempferol
ere detected in prepared Maté. A total content of 0.6 to 2.3 µg/L, with naphthalene,
tration, were found by Zuin
et al.
2005.
gar
et al.
2008]. It is
ause of that, the
the DAC monograph M-065 are excluded from the HMPC monograph.
Herbal preparation(s)
Comminuted herbal substance [according DAC Mate viride, 2004, M-066]
nd/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.
er, senna leaf and fruit,
ort herba and hawthorn on the German market. Indications are laxative and traditional use as
a support in case of cardio-vascular disorder caused by strain on the nerves. During the 80s and 90s
products containing Maté have been used medically.
SE:
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.
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 5/35
eanolic acid
der
et al.
2006, Schenkel and Montanha 1996, Gosmann and Schenkel 1989, Gosmann
et al.
Other compounds are carotine (0.004-0.023 mg/g), ascorbic acid (0.2 -2.0 mg/g
and mineral salts, like manganese, sodium, potassium, magnesium, iron, zinc an
2000, 2001, Blaschek
et al.
2007, Dickel
et al.
2007, Garcia
et al.
1997]. The prese
S, C
Additionally, PAH w
acenaphthene and phenanthrene having the highest concen
Other authors reported smaller amount [Rojo de Camargo et al, 2002, Kaman
highly propable that PAH develop during the roasting process over wood fire. Bec
roasted leaves according
Combinations of herbal substance(s) a
DE:
There are combination medicinal products with anise, fennel, rosemary, coriand
motherw
1.2. Information about products on the market in the Member States
Regulato y status over
r
view
Member
State Regulat ry St
o
atus
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: Not known
Belgium
MA
TRAD
Other TRAD
Other Specify:
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify: Not known
Denmark
MA
TRAD
Other TRAD
Other Specify: food supp.
Estonia
MA
TRAD
Other TRAD
Other Specify: food supp.
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Speci
fy: 2 medi
cinal products on
the market
Germany
MA
TRAD
Other TRAD
Other Specify: as combination and as
food, traditional use of
medicinal products in
the past
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify: as combination
Iceland
MA
TRAD
Other TRAD
Other Specify: Not known
Ireland
MA
TRAD
Other TRAD
Other Specify:
Italy
MA
TRAD
Other TRAD
Other Specify: Not known
Latvia
MA
TRAD
Other TRAD
Other Specify: food supp.
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify: Not known
Norway
MA
TRAD
Other TRAD
Other Specify: Herb itself is not
sified as a medicinal
duct
clas
pro
Poland
MA
TRAD
Other TRAD
Other Specify: Not known
Portugal
MA
TRAD
Other TRAD
Other Specify: Not known
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: Not known
Slovenia
MA
TRAD
Other TRAD
Other Specify: food supp.
Spain
MA
TRAD
Other TRAD
Other Specify: Herbal tea as food supp.
Sweden
MA
TRAD
Other TRAD
Other Specify: 1 combination product
and 1 natural remedy
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 6/35
Member State Regulatory Status
Comments (not
mandatory field)
United Kingdom
MA
TRAD
Other TRAD
Other Specify: Not known
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’
and does not necessarily reflect the legal status of the
1.3.
Search and assessment methodology
2.
Historical data on medicinal use
2.1.
Information on period of medicina
l use in the Community
Maté and its herbal preparations have been well known as stimulants in Europe f
Literature data support the traditional use of Maté as a medicinal product for tradi
monographs have described Maté as a medicinal product for the treatment of men
tiredness (e.g. Commission E mon
or decades.
tional use. Several
tal and physical
ograph) and as a diuretic agent.
The requested status overview showed that only a few marketing authorisations fo
products exist in Europe. But many products containing Maté are marketed a
supplement.
The following herbal prepar
in the HMPC monograph on traditional use.
r Maté containing
s combination or as food
ation is on the European market since a period of 30 years and is included
comminuted herbal substance (2 medicinal products on the French market
since 1973 in Spain; and the German Commission E monograph from 05.05.198
; as food supplement
8)
2.2.
Information on traditional/current indications and
su
specified
bstances/preparations
Documentation of tradition in the European context:
, theobromine,
e plausible. Maté tea is also marketed as a
classification.
Some monographs in European Pharmacopoeias or other accepted documents are established.
DE:
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 –Gold-tea; indication: support of metabolism
List und Hörhammer (1976): Maté tea, indication: stimulant and stimulant on the bowel’s function,
posology: single dose 1.0 g
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 7/35
This regulatory overview is not legally binding
products in the MSs concerned.
Maté folium has an old tradition as a caffeine containing beverage. Due to caffeine
flavonoids and saponins a stimulating and a diuretic effect ar
food supplement without any standardized regulations for
cal and mental fatigue, headache, weight loss,
rvous depression, rheumatic pain; posology: 2-4 g/day
FR:
In France maté leaves preparations are permitted for the treatment of asthenia
adju
of water [Cahier d
g/day.
Assessor’s comment:
Based on the plausible effects and the described traditional use,
only the following indications are appropriate for a traditional use without the supe
practitioner for diagnostic purposes or for prescription
from the above mentioned indications
rvision of a medical
or monitoring of treatment:
Oral use:
- Traditionally used for symptoms of fatigue and sensation o
- Traditional herbal me
the urinar
f weakness.
dicinal product to increase the amount of urine to achieve flushing of
y tract as an adjuvant in minor urinary complaints.
In summary, the literature data mentioned an oral use in the following indications:
mental and ph
ysical fatigue
weight lo
ss
diuretic actions
antioxidant actions
antidiabetic actions
bile stimulant
cardioprotective actions
anti-inflammatory/rheumatic pain
stimu
lant of bowel function
None of these indications are supported by sufficient pharmacological and clinical data (see
and 4). Thus a well-established use cannot be supported.
sections 3
Documentation of the tradition in other countries:
ndred years ago,
7th 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
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 8/35
UK:
British Herbal Pharmacopeia (1996): indications: physi
ne
, as a supportive
nctive treatment in weight loss programs orally and topically, and to increase the renal excretion
e l’Agence No 3 1998]. Posology according Pharmacopée française 1989: 2.5-5
Maté was used as a beverage by ancient Indians in Brazil and Paraguay some hu
however
Ilex paraguariensis
was first cultivated by the Jesuit missionaries in the 1
popular pla
and dynamics.
nt for treatment of weakness, muscular and mental fatigue, providing vitality, resistance
2.3.
Specified strength/posology/route of administration/duration of use
Posology and indications of the tra
ditional herbal preparations of Maté folium
Comminut
ed herbal substan
ce for herbal tea preparation
ES:
as food supplement
Posology: 2-4
g/day
FR:
Indication: treatment of asthenia, as a supportive adjunctive treatment in weight loss
and to increase the renal excretion of water [Cahier de
programs orally and topically,
l’Agence No 3 1998].
sology: 2.5-5 g/day [Pharmacopée française 1989 “Tisanes”]
DE (Com E): Indication: mental and physical tiredness
Posology: 3 g /day
Assessor’s comment:
osology, the most
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.
rived addressing the traditional use as a diuretic: 1-2 times daily a herbal
tea infusion prepared with 2.5 g herbal substance for the following indication: Traditional herbal
nary tract as an
A second indication was de
medicinal product to increase the amount of urine to achieve flushing of the uri
adjuvant in minor urinary complaints.
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding th
substance(s), herbal preparation(s) an
e herbal
d relevant constituents thereof
Diuretic, anti-fatigue and stimulating effect:
[Alikaridis 1987]: A literature survey on chemical constituents of Ilex species is given.
medicinal uses of the plant are also described. Due to its high methylxanthine co
General and
ntent 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-
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 9/35
for relevant preparations and indications
Po
Range of posology: 2-5 g herbal substance
From discussion of the MLWP reflecting the available data on indication and p
common posology of 3 times
ssors. Caffeine (200
sition, self-
ue and sleepiness with the greatest effects on tests of vigilance, reaction time, and
alertness. The greatest effects of caffeine were present 1 h post-administration, but significant effects
persisted for 8 h.
Antioxidant effects:
In order to characterize the antioxidant properties of
Ilex paraguariensis
infusions
using different experimental models. The antioxidant capacity was
in vitro
eva
inhibition of luminal-induced chemiluminescence assay and the inhibition
substances formation in liposomes [Actis-Goretta
et al.
2002, Filip
et al.
2000]. O
peroxidase-like activity [Anesini
et al.
2006] or used the ferric thiocyanate me
2006b] or the TROLOX® (registered trade-mark of Hoffman-LaRoche, 6-hydroxy-2,
tetramethychroman-2-carboxylic acid) equivalent antioxidant capacity (TEAC)[Iva
Beside water extracts, organic extracts were investigated [Bastos
et al.
2007, Gugl
1995, Sari
et al.
2007, Schubert
et al.
extracts were analyzed by several authors [Bastos
et al.
2007, Bravo
et a
Carini
et al.
1998, Chandra and Gonzalez De Mejia 2004, Filip
et al.
2001, 2007, Iv
Rivelli
et al.
2007]. Comparative studies were performed with red and white
tea [Bixby
et al.
2005, Turkmen
et al.
2006].
were analyzed by
luated by measuring the
of 2,2’-thiobarbituric-reactive
thers examined the
thod [Bastos
et al.
5,7,8-
nova
et al.
2005].
iucci and Stahl
2007, Turkmen
et al.
2006]. Polyphenolic content of Mate
l.
2007, Bracesco
et al.
2003,
anova
et al.
2005,
wine, green tea and black
Lunceford
et al.
2005 showed that polyphenol rich Mate extracts possess significant
in vitro
n sugar dicarbonyls
hyperglycemia).
d Maté tea.
2
O
2
-induced
One
in vivo
study was performed by Co
induced orofacial dysk
dysfunction, evaluated in a water-maze task, were examined. Rats treated with Maté (50 g/l
libitum, 60 days) did not exhibit the increase in VCMs observed in
(p <0.001). In the water maze task, haloperidol treated animals displayed an
acquisition (p <0.05) compared to rats treated with vehicle. Maté prevented the ef
in this behavioural paradigm. The results indicate tha
probably related to the presence of polyphenols.
lpo
et al.
2007. Using two behavioral models, i.e., haloperidol-
inesia (evaluated measuring vacuous chewing movements, VCMs) and memory
, ad
control rats treated with haloperidol
impairment in memory
fects of haloperidol
t
Ilex paraguariensis
exhibits an antioxidant role
Cardioprotective actions:
al.
2007 demonstrated that Mate extracts (5 g /50-100 ml, 0.5 l/day) may prevent the loss
of cardioprotective function of high-density-lipoprotein affored by paraoxonase 1.
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 oxide-dependent mechanism.
Baisch
et al.
1998 studied the effect of aqueous Mate extract (30 g/130 ml) on precontracted
mesenteric arterial bed. The injection of extract (300-1050 µg) significantly inhibited, in a
concentration-dependent manner, the maximal contractile response induced by NG-nitro-L-arginine
methyl ester.
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 10/35
dependent manner, mitigated many adverse effects of exposure to multiple stre
and 300 mg) significantly improved visual vigilance, choice reaction time, repeated acqui
reported fatig
antiglycation activities (glycation means a nonenzymatic adduct formation betwee
and proteins, that is one key molecular basis of diabetic complications due to
Ramirez-Mares
et al.
2004 evaluated the chemopreventive activity of Ardisia tea an
Schinella
et al.
2000 showed that an aqueous extract (5 g/100 ml) of Maté inhibited the H
peroxidation of red blood cell membranes.
Menini
et
Several
in vivo
studies were performed. Felippi
et al.
2006 showed that consump
elevated cholesterol and low-density lipoprotei
viv
o endothelial function of atherosclerotic mice aorta.
tion of Maté extract
n (LDL) in hypercholesterolmic mice and improved
ex
Görgen
et al.
2005 showed that chronic ingestion
AMP hydrolysis in blood serum. They concluded that due to the changes in b
be a drug target for the treatment of cardiovascular diseases.
of Mate extract significantly decreased ATP, ADP and
alance of purine, Maté can
Mosimann
et al.
2002 studied whether Maté could reduce the progression of a
cholesterol-fed-rabbits. After 2 months of treatment, serum total cholesterol an
cholesterol-fed rabbits were approximate 20-fold higher. However, Maté extract d
serum lipid profile of control and cholesterol-fed rabbits (p>0
content was approximately 3-fold higher in hypercholesterolemic rabbits a
different between the two groups. Average aortic cholesterol content of Maté g
than that of chol
rteriosclerosis in
d triacylglycerol of
id not affect the
.05). Similarly, hepatic cholesterol
nd these levels were not
roup was 3-fold lower
esterol-fed rabbits (0.62 vs. 2.02 mg/g of tissue, p<0.05).
Mosimann
et al.
2006 showed that
Ilex paraguariensis
extract can inhibit the p
atheroscleros
antioxidant enzymes.
Stein
et al.
2005 showed that the chronic oral administration of
I. paraguariensis
e
rats fed hypercholesterolemic resulted in a significant reduction in serum levels of c
triglycerides.
xtract (110 g/l) in
holesterol and
Anti-obesity and weight loss actions:
Some reviews about the most popular plants, including
Ilex paraguariensis
, use
published [Dickel
et al.
2007, Pittler and Ernst 2004, Pittler
et al.
2005]. All
evidence for the most dietary supplements as aids in reducing body weight
d for weight loss were
authors concluded that the
is not convincing.
One
in vivo
study was performed by Pang
et al.
20
extract and its molecular mechanism in
investigated.
I. paraguariensis
extract (dry extract (5:1), ethanol 15%) supplementati
lowered body weight, visceral fat-pad weights, blood and hepatic lipid, glucose, in
levels of rats administered HFD. The results showed that
I. paraguariensis
extract c
protective effect against a HFD-induced obesity in rats, but supplementation of HFD wi
paraguariensis
extract did not affect the food efficiency ratio (FER= Body weight
experimental period/Food intake for the experimental period).
08. The anti-obesity effect of
Ilex paraguariensis
rats rendered obese by a high-fat diet (HFD) were
on significantly
sulin, and leptin
an have a
th
Ilex
gain for the
Chemopreventic and anticancerous actions:
med endothelial cells
is
) inhibit the growth
d to have novel cinnamate esters that inhibit
proteasome activity. Based upon the structures of the compounds isolated from Maté tea, synthetic
analogs of these compounds for proteasome activity were examined. Cinnamic acid amides had no
inhibitory activity against proteasomes, whereas cinnamate esters displayed the activity.
[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.
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 11/35
rogression of
is in cholesterol-fed rabbits, although it did not decrease the serum cholesterol and
[Arbiser
et al.
2005]: Natural product extracts were screened using ras-transfor
(SVR cells) as a bioassay, and found that extracts of Maté tea (
Ilex paraguayens
of endothelial cells. The extract was fractionated and foun
[Gonzalez de Mejia
et al.
2005]: The objectives of this study were to de
yerba mate tea products (MT) (
Ilex paraguariensis
) and evaluate their capacity to inhi
topoisomerase I (Topo I) and II (Topo II) activities and oral carcinoma cell prolif
polyphenols of aqueous extracts of dried MT leaves were measured by the Fo
chlorogenic (CH) and gallic (GA) acids as standards. Topoisomerase inhibition was d
clone-forming assay, which uses yeast (
Saccharomyces cerevisiae
) strains as
included dimethyl sulfoxide (1.66%); camptothecin (50 µg/mL), a Topo I inhibitor; and amsacri
µg/mL), a Topo II inhibitor. Cytotoxicity studies were conducted using a nontumor
keratinocyte cell line HaCaT and two human squamous cancer cell lines (SCC
found to be a rich source of phenolic compounds. Total polyphenol content of vari
available traditional MT products ranged from 236 to 490 mg equiv of CH/g of dry
were significantly different among products depending on their origin (P < 0.001)
topoisomerase II activity was observed against JN394t2-4 strain for Nobleza Gau
µg equiv of CH) in comparison to GA (IC
50
= 112 mM) and CH (IC
50
> 1500 mM).
anti-topoisomerase activity against Topo II but not against Topo I. In additito
dependent cytotoxicity against all squamous cell lines tested. In comparison t
HaCaT [28 µg equiv of (+)-catechin mL-1], the cell line SCC-61 [21 µg equiv
was the m
is rich in phenolic constituents and can inhibit oral cancer proliferation. The effe
proliferation may be mediated via inhibition of topoisomerase II. The lack of correl
polyphenol content and the inhibition of topoisomerases suggested that the effect
topoisomerase inhibition may be due to other still unidentified biologically activ
constituents.
termine the phenolic content of
bit
eration. Total
lin-Ciocalteu assay, using
etermined by a
a model. Controls
ne (100
igenic human
-61 and OSCC-3). MT was
ous commercially
leaves. Such levels
. Higher anti-
cha MT (IC
50
= 0.43
MT showed catalytic
n, MT exhibited dose-
o premalignant cell line
of (+)-catechin mL-1]
ost sensitive to MT, resulting in 50% inhibition of net cell growth. It was concluded that MT
ct on cancer cell
ation between
of MT on
e phytochemicals
e activity of tea
g a battery of in
allocatechin gallate
tea (AT,
Ardisia
toxicity, TPA-induced
inone reductase activities were evaluated
in vitro
using HepG2 cells. The topoisomerase
using the
Saccharomyces cerevisiae
yeast system. Results suggest
that MT, AT and GT are cytotoxic to the HepG2 cells, with MT demonstrating dominant cytotoxicity.
T, AT, EGCG, Q and GA, which
ion of topoisomerase II
chemopreventive activity of AT and MT extracts. The authors concluded
entive agents.
Topoisomerase II, but not topoisomerase I, was the cellular target of M
acted mainly as true catalytic inhibitors. The cytotoxic activity and the inhibit
may contribute to the overall
that Ardisia and Maté teas may thus share a public health potential as chemoprev
Other effects:
Additiona
lly investigations were conducted:
- the iron-binding capacity of fractions Mate extra
cts [Anghileri and Thouvenot 2000],
- 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 anti-inflammatory action of Maté ingestion [Matsunaga
et al.
2000, Lanzetti
et al.
2008],
- the potential effects on diabetic complication [Gugliucci and Menini 2002, Wada
et al.
1996, Hin-Pang
et al.
2007],
- the bile stimulant actions of Maté [Gorzalczany
et al.
2001] .
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 12/35
[Ramirez-Mares 2004]: The aim of this study was to evaluate the chemopreventiv
aqueous extracts (2.7 g/250 ml water) in comparison to selected polyphenols usin
vitro marker systems relevant for the prevention of cancer. The effects of (-) epig
(EGCG), quercetin (Q), gallic acid (GA), green tea (GT,
Camellia sinensis
), ardisia
compressa
) and Maté tea (MT,
Ilex paraguariensis
) extracts were tested. Cyto
ODC and qu
inhibitory activity was also tested,
Assessor’s overall conclusions on pharmacology
, it has been used
erformed to support
ental tiredness can be
s 0.5 – 2.5% of
g to the monograph
Maté of the Commission E [Blumenthal
et al.
1998]. Other reports have given an amount of 50-100 mg
to its content of
.
caffeine in a 6 oz (177 ml) Mate infusion. Ohem 1996 reported a diuretic effect due
flavonoids, saponins, theobromine and caffeine in combination with chlorogenic acid
The p
central nervou
cognitive function was supported by Lieberman
et al.
2002. They examined
caffeine.
Antioxidant effects
Numerous
in vitro
studies and one
in vivo
study have been performed in order to
antioxidant capacity of Maté. It has been found that the consumption of Maté
antioxidant intake. It has
concentration of total polyphenols in particular caffeoylquinic derivatives. Its antiox
have potential health benefits such as lowering of human LDL, arthritis, inflamma
and reduction of heart disease and cancer. Maté possesses a much higher antiox
green tea and a slightly lower capacity than red wine. [Newell
et al.
2007, D
examine the
contributes to the
been shown that the antioxidant activity positively correlates with the
idant effects may
tion, liver diseases
idant capacity than
ralyuk
et al.
2006].
Cardioprotective actions
Only a few
in vitro
and
in vivo
studies showed a possible effect on cardiovascul
demonstrated that Maté is capable of vasorelaxation of arterial beds in rats. It
ATP, ADP and AMP hydrolysis, which can help to balance the circulatory system. It
inhibit atherosclerosis and reduce serum concentrations of cholesterol and triglyceri
suggesting that Maté may be able to lower the risk for heart disease [Heck
ar diseases. It has been
is also able to reduce
has the ability to
des, thus
and de Mejia 2007].
Antiobesity and weight loss actions
morbidity, mortality and high health-care expenditure.
Ilex paraguariensis
prep
applications in modulating physiological processes which in
balance. These effects could be related to its stimulant and lipolytic activities of the caffeine content
and the saponine content since saponines are reported to interfere
et al.
2007]. The reviewed studies provide some encouraging data but no evid
reasonable doubt that any specific dietary supplement is effective for reducing body
an effect, only a few clinical studies were performed. See chapter 4.2.2.
with cholesterol metabolism [Dickel
ence beyond a
weight. To confirm
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
dose-dependent inhibition of dicarbonyl action [Heck and de Mejia 2007].
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.
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 13/35
Maté has a long tradition as a popular beverage with medicinal benefits: particularly
as a stimulant or a diuretic agent. However,
in vivo
studies with Maté were not p
these effects of Mate preparations. The traditional use of Maté for physical and m
explained by its content of a purine alkaloid: caffeine. The caffeine content of Maté i
dried leaves. This is equal to 15-75 mg caffeine in 3 g Maté / daily dose accordin
harmacological properties of caffeine are multiple: first of all it is known as a stimulant, including
s system stimulation, relaxation of smooth muscle and vasoconstriction. Its effect on
the effects of 100- 300 mg
Obesity and overweight are associated with diabetes, hypertension and other diseases that cause
arations may have
fluence gut motility, food intake and energy
Therefo
re, the following wording for the indications is suitable:
Oral use:
Traditional herbal medicinal product for symptoms of fatigue and sensation of wea
kness.
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
substance(s), herbal preparation(s) and relevant constitue
the herbal
nts thereof
No relevant data on the pharmacokinetics of Maté or
Ilex paraguariensis
preparati
ons are available.
Ohem and Hölz 1990 cited that
in vitro
tests (resorption test according Koch) showed an increased
e to the presence of chlorogenic acids in Maté. Pharmacological
cid, after intravenous
Interactions with other medicinal products
An August 11, 2005, United States patent application (documents #20050176777, #20030185908,
amine oxidase (MAO) inhibitor; the maximum
U.S. Army Center for
d Preventive Medicine that yerba mate can cause high blood pressure when used
ne). See also 5.5.2
Assessor’s overall conclusions on pharmacokinetics
or the herbal substance or the herbal preparation no sufficient
conclusion can be d
data are available. Therefore, no
rawn.
3.3.
Overview
ubstance(s)/herbal preparation(s) and consti
of available toxicological data regarding the herbal
s
tuents thereof
single dose toxi
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
re
city:
productive toxicity
no data for herbal or herbal substance or herbal preparation were available
Caffeine data:
[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 caffeine-exposed
pregnancies in multiple animal species. The sum of evidence indicates that caffeine is not a
reproductive toxicant, even at high dosages that produce pharmacological and mild toxic effects in the
parental animals. The NOEL for reproductive effects of caffeine is in the range of 80-100 mg/kg/day
dosage.
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 14/35
transfer of caffeine in artificial blood, du
studies showed that the lethal dose of caffeine was increased by n-chlorogenic a
administration. No details for the tests were given.
and #20020054926) cites yerba mate extract as a mono
inhibition observed
in vitro
was 40–50%. In addition, it has been noted by the
Health Promotion an
in conjunction with other MAO inhibitors (such as phenelzine and tranylcypromi
F
Assessor’s comment:
on concluded that a
moderate consumption of caffeine (<5-6 mg/kg/day) via caffeinated beverages does not cause an
increase in any reproductive risks.
[Momoi
et al.
2008]: Caffeine consumption during pregnancy is reported to increase the ri
growth restriction and spontaneous abortion. In the study, the hypothesis th
caffeine exposure affects in utero developing embryonic cardiovascular (CV) fu
without altering maternal hemodynamics was tested. Caffeine (10 mg/kg/day subcu
administered daily to pregnant CD-1 mice from embryonic days (EDs) 9.5 to 1
gestation. Maternal and embryonic CV functions were assessed at baseline and at peak maternal
serum caffeine concentration using high-resolution echocardiography on EDs 9.
sk of in utero
at modest maternal
nction and growth
taneous) was
8.5 of a 21-day
5, 11.5, 13.5, and 18.5.
id not influence maternal body weight gain, maternal CV function, or
embryo resorption. However, crown-rump length and body weight were reduced in maternal caffeine
yos by ED 18.5 (P < 0.05). The authors concluded that the results suggested that modest
on and growth.
Maternal caffeine exposure d
treated embr
maternal caffeine exposure has adverse effects on developing embryonic CV functi
carcinogenicity and genotoxicity
Maté data:
eous solutions
showed mutagenic
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.
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 15/35
This review of the animal studies on reproductive toxicity of caffeine consumpti
Leitao and Braga 1994 analyzed the mutagenic and genotoxic effects of mate aqu
(prepared from instant Maté powder 200 mg/l) in bacterial cells. Maté solutions
effects in the Ames test (TA 97, TA 98, TA100 and TA 102
Assessor’s comment:
The described tests were performed according the OECD Guideline for testing of ch
utilizes prokaryotic cells, which differ from mammalian cells in factors like uptake,
chrom
information on the mutagenic and carcinogenic potency of a substance in m
1997].
In vitro
meta
Therefore the bacteria strains were exposed to S9 rat liver microsomal fraction, thi
S9 rat liver microsomal fraction abolished the genotoxic activity of Maté, thiourea s
genotoxic effect.
bolic activation systems cannot entirely mimic the mammalian in vivo conditions.
ourea and dipyridyl.
uppressed the
Indeed epidemiological studies have shown that in regions where the consumption of Maté is high, the
n cell lines are lacking. Sewram
nfusion may be
Further studies were describ
ed by Fonseca
et al.
2000. See this chapter
in vivo
studies.
These findings are reasonable because a liver metabolism of Maté cannot already b
oesophageal region. A higher incidence of bladder and kidney cancer cannot be exp
results yielded after treatment with S9 rat liver microsomal fraction. Therefore, furt
mammalian cell lines are necessary.
e performed in the
lained by the
her studies with
nic potential of maté
s pesticides – in the
on. Peripheral blood was
ltures were treated
filtered in sterilized sartorius filter with a 0.22 mm pore membrane), distilled water
tal person, 3000
ultures) were scored
ion concentrations
50 μg/ml
001). The authors
concluded that there is no clastogenic or/and aneugenic basis underlying maté action in the cytokinesis
cronucleus assay.
(negative control), and 6 μg/ml bleomycin (positive control). For each experimen
binucleated cells (BN) from two independent cultures (1000 cells from replicate c
for the presence of micronuclei (MN). No statistical differences between maté infus
were observed: 1400 μg/ml (0.001 ± 0.002), 700 μg/ml (0.0006 ± 0.0015), 3
(0.002 ± 0.002), 175 μg/ml (0.002 ± 0.003) and negative control (0.001 ± 0.
block mi
their data and the
a form of instant
ueous extracts of maté,
used in human
consumption. Secondly, the data from the three investigations are related to different maté
commercial suppliers.
In vivo
:
[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
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 16/35
emicals. The test
metabolism,
osome structure and DNA repair processes. The test therefore does not/could not provide direct
ammals [OECD Guideline,
incidence of esophageal tumors is higher. But experiments using huma
et al.
2003 and Castellsague
et al.
2000 showed that the high temperature of the i
responsible for this finding. Their findings are supported by Islami
et al.
2009.
[Vargas-Alves 2008a]: The present study evaluates the clastogenic and/or aneuge
(
Ilex paraguariensis
) – previously tested for the presence of 48 organophosphorou
culture of human lymphocytes in the absence of exogenous metabolic activati
obtained once from three healthy female donors for lymphocyte cell cultures. The cu
with maté infusion (
Furthermore, the same authors focused on the reasons of discrepancies between
mutagenic response previously reported. First of all, Leitao and Braga (1994) used
Mate beverage, Fonseca
et al.
(2000), as reported below, tested lyophilized aq
on the contrary their group used a maté infusion, which is similar to the way it is
intervention, the liver, kidney and bladder cells were isolated and the DNA damage
was investigated by the COMET assay. The DNA repair process was also investigat
protect the cells from damage by the same methodology. The data showed that m
genotoxic in liver, kidney and bladder cells. The regular ingestion of mate tea increa
of DNA to H
2
O
2
-induced DNA strand breaks and improved the DNA repair after H
2
cells, irrespective of the dose ingested. Due to t
protect against DN
antioxidant activity of the mate tea's bioactive compounds.
induced by H
2
O
2
ed for its potential to
ate tea is not
sed the resistance
O
2
challenge in liver
hese results the authors suggested that mate tea could
A damage and enhance the DNA repair activity. Protection may be afforded by the
Assessor’s comment:
According to the authors, the da
and bladder cells. The COMET assay has not been validated and consequently it is
specifically and reliably it could differentiate between genotoxicants and non-gen
sensitive to artefacts and false positives.
ta presented showed that Maté tea is not genotoxic in liver, kidney
not known how
otoxicants. It is also
alterations as well
nking” rats. In the
ad ingested Maté on a daily
weeks were analyzed. Following sacrifice, the tongue was removed for anatomical-
athological and
esses were observed
in the samples of
cal
pathological and immunohistochemical evaluation. Results: In the anatomical-p
immunohistochemical examination, no alterations compatible with neoplasic proc
in the 75 pieces analyzed. The authors concluded that associations were not found
tongue from “Maté drinking” rats in the anatomical-pathological and immunohistochemi
examinations.
[Fonseca
et al.
2000]: Aqueous extracts of
Ilex paraguarariensis
(Mate-chimarrão; 200 g/l
analyzed for the presence of genotoxic, mutagenic, and clastogenic activities thr
based on the induction of the SOS functions (functions for repairing damage
as in human lymphocytes in vitro and in mammalian cells
in vivo
. The extrac
genotoxic, as assessed by lysogenic induction
Salmonella typhimurium
. The addition of S9 microsomal fraction, catalase, thiourea, or d
counteracted the genotoxic activity of Maté-chimarrão, suggesting that oxygen r
essential role in the genotoxicity of Maté-chimarrão extracts. The extracts were no
(bone marrow cells of rats) in the performed experimental conditions, but the au
increased frequency of chromosomal aberrations in Maté-chimarrão-treated huma
lymphocytes. The results supported that a high consumption of Maté-chimarrão
carcinogenes
)) were
ough bacterial trials
d microbial DNA.), as well
ts of Maté-chimarrão were
in
E. coli
, and they also induced mutagenesis in
ipyridyl
eactive species play an
t clastogenic
in vivo
thors observed an
n peripheral
can potentiate
is in the human oropharynx and esophagus.
[Pereira-Jotz
et al.
2006]:
To make a histological comparison between the aerodigestive tracts of a
group.
Seventy-five adult Wistar rats were tested, 60 rats drinking Maté at room temperature and 15 rats
drinking water (control group), during a period of 5 months. The histology of the aerodigestive tracts
of these animals was analyzed. Results: There was a significant difference (p=0.02) between those
that were given Maté and the control group. The authors concluded that there is evidence to suggest
that the consumption of Maté affects the upper aerodigestive tract in the animals studied, but not
inducing cancer.
PAH-content:
[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
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 17/35
[Vargas-Alves
et al.
2008b]: The aim of the study was to evaluate the pathological
as the immunohistochemical expression in samples from the tongues of “Maté dri
study, 75 adult Wistar, aged 5 months (weighing over 300 g each) that h
basis for 9
group of rats submitted to the consumption of erva-Maté
Ilex paraguariensis
, with a control
concentrations of 21 individual PAHs were measured in dry leaves of eight comme
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
Infusions were made by adding water to the leaves (5 g/30ml water; 80 °C or 5 °C
removing the resulting infusion after 5 min, and then adding more water to the rem
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.
concentrations ranged from 8.03 to 53.3 ng/g dry leaves. For the Maté infusions p
water and brand 1, 37% (1,092 of 2,906 ng) of the total measured PAHs an
of the benzo[a]pyrene content were released in
other hot and cold infusions. Conclusion: Very high concentrations of carcinogen
yerba Maté leaves and in hot and cold Maté infusions. Results support the hypoth
carcinogenicity of Maté may be related to its PAH content.
rcial brands of yerba
the surrogates.
, 5 minutes),
aining leaves. This
Benzo[a]pyrene
repared using hot
d 50% (25.1ng of 50 ng)
to the 12 infusions. Similar results were obtained for
ic PAHs were found in
esis that the
[Rojo de Camargo and Toledo 2002]: In order to estimate the contribution of Maté tea (ch
roasted mate) and regular coffee as a source of PAHs in the diet of the population
Brazil, different batches and brands of these products, totaling 18 samples, were anal
The consumption data were obtained from a dietary survey (frequency recall), whi
Campinas in 1993. PAH levels in the products were determined by high performa
chromatography with fluorescence detection (HPLC-FLD). Different PAHs w
of coffee, at levels varying with the brands and
PAH content in coffee was 10.12 μg/kg, while Maté tea showed a relatively lower le
contamination (S=0.70 μg/kg). Considering the per capita average daily consumpti
69.79 g of Maté tea and 86.77 g of coffee, one can assume that Maté tea and
approximately 0.05 μg and 0.88 μg of total PAHs, respectively, to the dietary
á mate;
of Campinas, SP,
ysed for PAH.
ch took place in
nce liquid
ere detected in all samples
the beverage preparation technique. The mean total
vel of
on estimates of
coffee contribute with
intake of these
contaminants by the studied population (n=600).
[Zuin
et al.
2005]: A simple procedure based on stir bar sorptive extraction (SBSE) and HPLC-FLD is
ves (
Ilex
a samples found by
, showing good
0.64 – 1.23 µg/l.
Assessor’s overall conclusions on toxicology
7, TA 98,
tor 3.5 to 5.6) and
; WP2s(λ)strain)
bone marrow cells of rats)
mate-chimarrão-
thout
lyophilization) showed no clastogenic or/and aneugenic basis underlying maté action in human
lymphocytes in the cytokinesis-block in the micronucleus assay [Vargas-Alves
et al.
2008a]. So it can
be presumed that a hot-water infusion is not comparable to the tested lyophilized extracts.
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
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 18/35
presented for the determination of 15 PAHs in herbal tea prepared with Maté lea
paraguariensis
St. Hil.; 1 g/100 ml water). The results of the commercial Maté te
the SBSE approach were compared with those obtained by liquid-liquid extraction
agreement. Mean values of 15 PAH were given. Total PAH content ranged from
Maté extracts (lyophilizied and resolved) showed mutagenic effects in the Ames test (TA 9
TA100 and TA 102 strains) at concentrations of 20 to 50 mg/plate (mutagenic fac
genotoxic activity in the induce test (phage induction in a lysogenic strain of
E. coli
[Leitao and Braga 1994]. The same extracts were not clastogenic
in vivo
(
but the authors observed an increased frequency of chromosomal aberrations in
treated human peripheral lymphocytes [Fonseca
et al.
2000]. A hot-water extract of Maté (wi
during the processing of Maté, as Maté is commonly dried over a smoky wood fir
2007]. The amount that is extracted by preparation of the infusion is 0.22 – 1.88 % of the anal
PAH content, thus a limitation is not necessary [Kamangar
et al.
2008, Blaschek
et al.
e [Heck and de Mejia
yzed
2007].
In comparison, total PAH conte
higher [Blaschek
et al.
2007]. Coffee is a worldwide consumed beverage and it is n
carcinogenic to humans due to its PAH.
nt in coffee is higher than in Maté, but the benzo[a]pyrene content is
ot classified as a
The international Agency of resear
group 2A. That means Maté is not classifiable as to its carcinogenicity to humans and Hot Maté
drinking is probably carcinoge
ch on cancer (IARC) listed in 1991 Maté in group 3 and Hot Maté in
nic to humans. These classifications were concluded on basis of the
known experimental data in the year 1991.
Roasted Maté leaves propabl
not included in the HMPC monograph.
y contain more PAH than dried leaves. Because of that, roasted leaves are
4.
Clinical Data
For the most studies cited, a detailed description of the used herbal su
was not available.
bstance(s)/herbal preparation(s)
4.1. Clinical Pharmacol
ogy
4.1.1.
Overview of pharmacodynamic data regarding the herb
substance(s)/preparation(s) including data on relevant const
al
ituents
Antioxidant effects:
ed human subjects
mined. Intake of water extracts of
Ilex
bit copper-induced autoxidation of LDL in whole plasma as shown by the end-term
production of thiobarbituric acid reactive substances (TBARS), and as a consequence are able to impair
lity and fragmentation
of apoB. When LDL was isolated from plasma prior to oxidation no significant differences in lag-time,
cluded that antioxidants in
to inhibit copper-induced
the appearance of Schiff base induced fluorescence, higher electrophoretic mobi
slope or maximum rate of oxidation could be detected. The authors then con
Ilex paraguariensis
are absorbed and reach sufficient high levels in plasma
LDL autoxidation by increasing aqueous-phase antioxidant capacity.
Assessor’s comment:
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.
Anti-obesity and weight loss:
[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
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 19/35
[Gugliucci 1996]: First the oxidability of LDL in whole plasma from 3 healthy fast
before and after intake of
Ilex paraguariensis
were exa
paraguariensis
inhi
rformed. Methods:
ng YGD
re and after 10
ch meal for 10 days in
healthy overweight
f YGD capsules
ght. Body weight
2 months. Results:
e of 58 ±15 min
0.8 ± 0.05 kg after
5.1 ± 0.5 kg after
atment with YGD
and 72.5 kg at the end
delayed gastric emptying, reduced
ed gastric fullness and induced significant weight loss over 45 days in overweight
n an uncontrolled
he group as a whole. The herbal
preparation is thus shown to be one that significantly modulates gastric emptying.
Assessor’s comment:
The study was performed with a preparation that contained not only Maté, but also Guaran
Damiana. Therefore the effects cannot only be attributed to Maté consumption.
a and
[Martinet
et al.
1999]: In this study the effects of oral administration of 12 plant p
anti-obesity action, in non-obese women and men were investigated. Six subjects took the Maté dry
reparations with
extract: 5 caps with 0.3 g lyophilised hot water extract (21.4%) from herb of Maté totalizing 1.5 g dry
crease in energy
change in respiratory
ensis
) extract, where a
ults suggested the
bly for the maté
of Maté for subjects on a low-calorie diet
dy mass index BMI
n exercising therapy
roups were not
e tonus were
better in Maté group. Cholesterol and triacylglycerides level decreased more in Maté group. Heart rate
up.
and arterial blood pressure showed a higher tendency to normal values in Maté gro
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 weight-loss. Obese men and
women consuming Maté have shown a decrease in respiratory quotient, indicating an increase in fat
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 20/35
and 45 days and weight maintenance over 12 months, the following tests were pe
Gastric emptying was observed using ultrasound scanning in seven healthy volunteers followi
and placebo capsules taken with 420 ml apple juice. Body weight was observed befo
days of treatment with three YGD capsules or three placebo capsules before ea
44 healthy overweight patients attending a primary health care centre. Forty-seven
patients entered a double-blind placebo-controlled parallel trial of three capsules o
before each main meal for 45 days compared with three placebo capsules on body wei
was monitored in 22 patients who continued active (YGD capsules) treatment for 1
The herbal preparation YGD was followed by a prolonged gastric emptying tim
compared to 38±7.6 min after placebo (P = 0.025). Body weight reductions were
YGD capsules compared to 0.3 ± 0.03 kg after placebo capsules over 10 days, and
YGD capsules compared to 0.3 ± 0.08 kg after placebo over 45 days. Active tre
capsules resulted in weight maintenance of the group (73 kg at the beginning
of 12 months). The herbal preparation, YGD capsules, significantly
the time to perceiv
patients treated in a primary health care context. Maintenance treatment given i
context resulted in no further weight loss, nor weight regain in t
extract. Six subjects took solid placebo caps in double- blind-study. No significant in
expenditure has been noted after treatment with any of these preparations. No
quotient (RQ) was shown, except after treatment with maté (
Ilex paraguari
drop in RQ was observed, indicating a rise in the proportion of fat oxidized. The res
poor potential of these plant preparations in the treatment of obesity, except possi
extract.
[De Pasquale 1991]: A controlled double-blind clinical trial
was performed to confirm the weight loss properties of Maté. 30 subjects with a bo
>20 received, beside Maté-tablets or Maté instant tea, a low calorie diet and a
(physical activity) for 45 days. The averages of weight loss between the two g
significantly different. Positive effects like less hungry feeling, diuresis, psycho- and muscl
y been shown
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 well-established use of Maté c
demonstrated.
annot be
Long-standing use of Maté preparations establish the traditional use o
symptoms of fatigue and sensation of weakness and as a diuretic agent.
f
Ilex paraguariensis
leaves for
4.1.2. Overview of pharmacokinetic data re
substanc
garding the herbal
e(s)/preparation(s) including data on relevant constituents
No data for the herbal substance or herbal preparations are available.
Caffeine data:
Deutscher Arzneimittel Codex: German Commission B monograph caffeine 1989, 2
xanthine derivate that exerts its physiological effects in large part through antagoni
adenosine receptors. Caffeine shows an absorption half-life of 2-13 min and
oral or parenteral administration. Absorption of methylxanthines relates more to
water solubility. After administration of 5 mg/kg a lag time of 5-9 min, maximum pl
C
max
within 30-40 min and 9-10 µg/ml was measured. Protein binding is low (30-40
of distribution amounts to 0.52-1.06 l/kg. Caffeine rapidly distributed to all body
breast milk, crosses the placenta and blood-br
metabolized to paraxanthine, about 6-10% to theobromine and about 3-4% to
compounds are further demethylated to monoethylxanthines and than to methyl
half-life lies between 4.1 and 5.7 h, but it varied widely among individuals. Caffein
have a renal elimination. 48-h urine contained 86% of the administered dose. In neonates,
of caffeine yielded values of 65-130 h. Decreases to adult values by 4 to 9 mont
inversely proportional to gestational/post-conceptual age.
004]: Caffeine is a
sm of central
is readily absorbed after
lipophilicity than to
asma concentration
%) and the volume
compartments, also in
ain barrier. In adults, about 70% of the dose is
theophylline. These
uric acids. Plasma
e and its metabolites
the half-life
hs post-term and is
encephalographic
t, caffeine-related
bits were observed
ne
2
), maximum time
ents, determined by
ter half-life values
ince the elimination
ne clearance
observed overnight, when smoking was resumed in the control group, may indicate a short delay for
the induction of hepatic cytochrome, reported here for the first time. Electrophysiological responses to
caffeine, including vigilance and cortical activity, were assessed by ambulatory electroencephalographic
(EEG) recorded during a period of 6 h before and after caffeine consumption. Following caffeine intake,
the caffeine-intolerant subjects presented an increase in vigilance levels with faster peak alpha, beta
frequency and lower delta and theta power when compared to tolerant subjects. Pharmacokinetic
parameters and EEG data showed significant differences between sleep-sensitive and control subjects.
These variations may be explained by cigarette smoking and the higher caffeine intake observed in the
subjects of the control groups while caffeine sleep-sensitive subjects have a significantly lower caffeine
intake, as already reported in previous studies on patients with sleep disturbances.
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 21/35
oxidation [Martinet
et al.
1999]. A decrease in weight, after Maté consumption, has onl
for combinations of Maté with Damiana and Guarana or Maté with Green tea, Asparagus,
[
[Bchir
et al
. 2006]: The present study investigated pharmacokinetic and electro
responses to caffeine (140 mg) in 2 groups of healthy volunteers reporting, or no
sleep disturbances. Significant differences in caffeine consumption and smoking ha
between the 2 groups. Plasma samples were taken from each subject before (
T0
) and after caffei
romine (TB) and
h compound
lue (2.07 and 2.20
kg-1, respectively).
and 4.14 ml min-1
ectively). The half-
and PX (4.1
ibution at steady state of TP (0.44 l kg-1) was lower than
that of the other methylxanthines (0.63-0.72 l kg-1). The unbound volume of distribution of TP (0.77 l
whereas the unbound volume of distribution of
kg-1) was however the same as that of TB (0.79 l kg-1)
PX (1.18 l kg-1) was similar to that of CA (1.06 l kg-1).
Assessor’s overa
ll conclusions on pharmacokinetics
Due to lack of data for Maté pre
parations, 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)
9 Persons received 1,200 kcal reduction diet for 28 days. Side-effects were
ven per week in 39
he trial. In the
f this trial 24% of the persons felt hungry, in the end only 6% did (p=0.07). In comparison
to the controlled group remarkable reductions of following symptoms were noticed: headache,
depression, pain, thirst and lack of concentration.
Assessor’s comment:
A reduction of tiredness and other side-effects of calorie reduction diets was observed, but a weight
the Maté posology is
tory.
There are a few studies that investigated the effect on weight loss of preparations that containing Maté
tea and Kidney beans
ount and contribution of
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
Not reported.
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 side-effects while being on a calorie-reduced diet, supported a reduction of tiredness. Also
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 22/35
[Lelo
et al.
1986]: The pharmacokinetics of caffeine (CA), paraxanthine (PX), theob
theophylline (TP) were studied in 6 healthy male volunteers after oral administration of eac
on separate occasions. The total plasma clearances of CA and PX were similar in va
ml min-1 kg-1, respectively) as were those for TP and TB (0.93 and 1.20 ml min-1
The unbound plasma clearances of CA and PX were also similar in magnitude (3.11
kg-1, respectively) as were those of TP and TB (1.61 and 1.39 ml min-1 kg-1, resp
lives of TP and TB (6.2 and 7.2 h, respectively) were significantly longer than those of CA
and 3.1 h, respectively). The volume of distr
[Matzkies 1989]: 7
measured daily. 100 g tea containing Maté leaves (20 g / 7 cups per day) were gi
persons. Thus the symptom of tiredness was reduced from 33% to 10% during t
beginning o
loss due to the consumption of Maté could not be detected. The information on
unsatisfac
beside other drugs like Guarana and Damiana or Asparagus, Green tea, Black
[Opala
et al.
2006, Ruxton 2004]. Due to the lack of information about the am
Maté, the effect of Maté cannot be assessed.
for the described diuretic, ant
effects, no clinical data are available.
i-inflammatory, bile stimulant cardio protective and chemoprotective
r 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
5.2.
Patient exposure
[Goldenberg 2002]: Maté consumption has been associated with an increased rate
oropharyngeal, esophageal, and laryngeal cancers. The purpose of this study w
literature and discuss the role of Maté consumption in the development of oral an
cancer and the potential carcinogenic mechanisms. A review of the relevant literatu
consumption with oral and oropharyngeal cancer and the carcinogenicity of
search was performed using Medline, library catalogues, OCLC first search and I
databases. Case control studies on Maté drinking populations and,
in vivo
and
in vi
carcinogenicity of Maté were reviewed. The populations reviewe
alcohol and tobacco products confounding the influence of Maté as an independent
evidence in the literature that Maté consumption is itself carcinogenic and pla
development of cancers of the oral cavity and oropharynx. The author conclude
exact mechanism of carcinogenesis is still unknown, available information sugg
should be considered one of the risk factors for oral and oropharyngeal cancer.
of oral,
as to review the
d oropharyngeal
re linking Maté
Maté was performed. The
SI web of science
tro
studies on the
d in many of these studies also used
risk factor. There is
ys a role in the
d that although the
ests that Maté drinking
nd discuss the role of
formed of the
ad and neck cancer and the proposed
vivo
and
in vitro
in many of these
é as an independent
in the literature suggests that maté consumption is carcinogenic and plays a role
in the development of cancers of the oral cavity, pharynx, larynx, and esophagus. Both chemical and
le information suggests that maté
thermal carcinogenesis mechanisms have been suggested. Availab
drinking is a risk factor for upper aerodigestive tract cancer.
h a moderate level
be required to
lternatively 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 case-control study involved 114 Argentinean case-control
pairs. Maté consumption was recorded for time of interview, and 20 and 40 years previously. Maté con
bombilla consumed 20 years ago was associated with bladder cancer in ever-smokers (odds ratio
(OR)=3.77, 95% confidence interval (CI): 1.17–12.1), but not in never-smokers. Maté cocido was not
associated with bladder cancer. These results are consistent with a previous study in Uruguay.
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 23/35
All reported studies in orde
[Goldenberg
et al.
2003]: The purpose of this study was to review the literature a
Maté consumption as a risk factor for head and neck cancers. The review was per
relevant literature linking maté consumption with he
carcinogenicity of maté. Case control studies on maté-drinking populations and
in
studies on the carcinogenicity of maté were reviewed. The populations included
studies also used alcohol and tobacco products, confounding the influence of mat
risk factor. Evidence
[Abnet 2007]: In this review, hot Maté is listed according the IARC as an agent wit
to influence the risk of developing cancer. It is concluded that further research will
disentangle the effect of Maté and the temperature at which it is consumed. A
[Castellsague
et al.
2000]: To estimate the effects of consuming hot beverages
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 participatin
based case-control studies of squamous-cell carcinoma of the esophagus condu
of South America were analyzed. After adjusting for the strong effects of tobacco an
consumption, both heavy Maté drinking (> 1 l/day) and self-reported very hot M
significantly associated with esophageal cancer risk in men and women. The magni
the association for Maté amount and, to a lesser extent, Maté temperature, were
than men. The joint effects of Maté amount and Maté temperature were more than
following a statistically significant synergistic interaction (p = 0.02) which was par
among heavy drinkers (> 1.50 l/day) of very hot Maté (OR = 4.14, 95% CI: 2.24-7.
light drinkers (<0.50 l/day) of cold, warm/hot Maté. Consumption of other very ho
tea and coffee with milk but not coffee alone, was also significantly associated wi
in the 2- to 4-fold ran
consumption of vegetables, fruits, cereals and tea. In contrast, frequent consumpt
fats and salt was associated with a moderately increased risk. This pooled analy
a carcinogenic effect of chronic thermal injury in the esophagus induced by the c
hot drinks, including Maté.
, including Maté (an
g in a series of 5 hospital-
cted in high-risk areas
d alcohol
até drinking were
tude and strength of
higher for women
multiplicative,
ticularly evident
67) compared to
t beverages, such as
th an increased risk,
ge. Statistically significant protective associations were identified for high
ion of meat, animal
sis added evidence for
onsumption of very
[De Stefani
et al.
1988]: A case-control study of oral and pharyngeal cancer involvin
108 cases and 286 controls was carried out in the University Hospital of Montevideo,
study was restricted to males and cases afflicted with lip, salivary gland an
were excluded. Point estimates of relative risk (RR) associated with smoking va
variables, nutritional items and ingestion of hot infusions of the herb
Ilex parag
obtained by
tobacco users and heavy drinkers of wine displayed an OR of 17.2. Maté exposure
dose-response, after adjustment for age, tobacco and alcohol intake, with a 5-fold i
heavy consumers. Joint exposure to black tobacco and wine displayed very high ri
significant interactions were observed. The results suggested that the high rates of
cancer could be explained by the multiplicative effect of black tobacco smoking, wi
Maté ingestion.
[De Stefani
et al.
1991]: A case-control study of bladder cancer involving intervie
cases and 222 controls was carried out in Montevideo, Uruguay. The analysis was
for each sex. Point estimates of RR associated with smoking variables, ingestio
herb
Ilex paraguariensis
(maté), and selected dietary items were obtained by strat
regression analysis. Among men, smokers of black tobacco showed a RR 2.7 highe
smokers and maté exposure showed a significant dose-response, after adjustment for age,
social class, hospital, type of tobacco, smoking intensity, smoking duration, and
consumption, with a seven-fold increase in risk for heavy consumers. Joint exposu
and maté consumption showed a multiplicative effect. Women showed a similar incr
ws with 111 incident
conducted separately
n of infusions of the
ified and logistic
r than blond tobacco
residence,
vegetable
re to type of tobacco
ease in risk with
maté consumption. The results suggested that the high mortality rates of bladder cancer observed in
Uruguay could be explained by the combined effect of black tobacco smoking and maté ingestion.
[De Stefani
et al.
1996]: During the period from January 1988 to December 1994, a case-control study
that included 497 cases of lung cancer and 497 controls was carried out at
the Instituto de Oncologia,
Montevideo, Uruguay, to evaluate the
relationship between the drinking of Maté and the risk of lung
cancer in
men. Maté drinking has been associated with risk of most
upper-aerodigestive tract cancers.
After adjusting for major covariates,
including pack-years of cigarette smoking, the amount of Maté
was
associated with a 1.6-fold increase in risk for heavy drinkers, compared
with light drinkers, with a
significant dose-response pattern. When the
analysis was performed by cell type, small cell lung cancer
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 24/35
g interviews with
Uruguay. The
d nasopharyngeal cancer
riables, alcohol
uariensis
('Maté') were
logistic regression analysis. Dark tobacco smokers showed a RR 3.4 times higher than light
showed a significant
ncrease in risk for
sks and no
oropharyngeal
ne drinking and
showed a
significant increase in relative risk for Maté amount (OR, 2.9; 95%
duration (OR, 3.6; 95%
associated with Maté drinking.
CI, 1.3-6.2) and Maté
CI, 1.3-9.9). On the other hand, pulmonary adenocarcinoma
was not
ol study of diet and
ols was carried out in
ated with a 3.4
r the highest category of intake, with a significant dose-response pattern. Also,
barbecued meat, protein and heterocyclic amine intakes were associated with significant increases in
an increased risk of
risk of RCC. The consumption of the beverage known as 'Maté' was associated with
3.0 for heavy drinkers.
ngeal cancer and 290
e interviewed in the
gn, and
ns. Dark tobacco
ight (flue-
cured) tobacco smokers and 35 times that of non-smokers. Alcohol exposure displayed lesser effects
n 100 times higher).
splayed by hard
trolling for the
but its interaction with tobacco smoking resulted in very high risks (more tha
Among particular types of alcoholic beverages, red wine showed RRs similar to those di
liquor consumption. Maté was associated with a threefold increase in risk, after con
effects of age and tobacco and alcohol consumption.
[De Stefani
et al.
2007]. An additional case-control study in order to further explor
nonalcoholic beverages in bladder carcinogenesis. Methods: In the time period 199
incident cases with transitional cell carcinoma of the bladder and 501 patients treat
hospitals and in the same time period were frequency matched on age, sex, and resi
and controls were face-to-face in
intake of maté, coffee, tea, and soft drinks. Statistical analysis was carried out b
multiple logistic regression. Results: Ever maté drinking was positively associated
(OR 2.2, 95% CI 1.2–3.9) and the risk increased for increasing duration and amou
Both coffee and tea were strongly associated with bladder cancer risk (OR for coffee
CI 1.2–2.3; OR for tea drinking 2.3, 95% CI 1.5–3.4). These results were confirmed
analysis of never-smokers. The authors suggested that drinking of maté, coffee and
factors for bladder carcinoma in Uruguay.
e the role of
6–2000, 255
ed in the same
dence. Both cases
terviewed on occupation, tobacco smoking, alcohol drinking and
y unconditional
with bladder cancer
nt of maté drinking.
drinking 1.6, 95%
in a separate
tea may be risk
(ESCC) in Brazil
f 20.4/100,000/year
tobacco smoke and
stigate the degree and
hundred
ecruited, given a
standardized questionnaire, and asked to provide a urine sample for measurement of 1-hydroxypyrene
glucuronide (1-OHPG), a PAH metabolite). Urine 1-OHPG concentrations were measured using
immunoaffinity chromatography and synchronous fluorescence spectroscopy and urine cotinine was
measured using a dipstick test. The authors examined factors associated with 1-OHPG concentration
using Wilcoxon tests and multiple linear regression. Results: Urine 1-hydroxypyrene glucuronide (1-
OHPG) was successfully measured on 199 subjects. The median (interquartile range) of urine 1-OHPG
in the 199 participants was 2.09 pmol/ml (0.51, 5.84). Tobacco smoke exposure and maté drinking
were statistically significantly associated with higher urine 1-OHPG concentrations in the multivariate
linear regression model. Conclusion: Tobacco smoke and maté both contribute to high levels of
benzo[a]pyrene exposure in the people of Southern Brazil. This high PAH exposure may contribute to
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 25/35
[De Stefani
et al.
1998]: In the period January 1988-December 1995, a case-contr
renal cell carcinoma (RCC) risk involving 121 cases and 243 hospitalized contr
Montevideo, Uruguay. After adjusting for major covariates, red meat intake was associ
increase in risk fo
[De Stefani
et al.
1987]: One hundred seven patients afflicted with incident lary
controls with diseases considered not related to tobacco and alcohol exposure wer
University Hospital of Montevideo, Uruguay. The study followed a case-referent desi
epidemiologic analysis was carried out at the Louisiana State University, New Orlea
smoking was the strongest risk factor, with an RR 2.5 times higher than that showed by l
[Fagundes
et al.
2006]: The highest rates of esophageal squamous cell carcinoma
occur in Rio Grande do Sul, the most Southern state, which has incidence rates o
for men and 6.5/100,000/year for women. Exposure to carcinogenic PAHs through
other sources may increase the risk of ESCC. The aims of the study were to inve
sources of PAH exposure of the inhabitants of this region of Southern Brazil. Methods: Two
healthy adults (half smokers, half non smokers, half male and half female) were r
the high rates of ESCC observed in this population. The increased urine 1-OHP
associated with maté suggested that contaminants,
increased risk of ESCC previously reported for maté consumption.
G concentrations
not just thermal injury, may help explain the
[Munoz
et al.
1987]: Thermal injury resulting from drinking very hot beverages has
as a risk factor for oesophageal cancer, although no information is available on the
this injury in human or experimental animals. The drinking of hot maté tea is very c
moderately high incidence of oesophageal cancer in south-eastern areas of South A
investigated the prevalence of precancerous lesions of t
whom half were daily maté drinkers and the remainder were non-maté drinkers. Th
matched for age, smoking and alcohol intake. Maté drinkers were 2.2 times mor
develop histologically confirmed esophagitis than non-maté drinkers.
been incriminated
lesions caused by
ommon in areas of
merica. This study
he oesophagus in 60 unskilled male workers, of
ese 2 groups were
e likely (p = 0.046) to
[Munoz
et al.
1998]: The relationship between social class indicators, body ma
life-style habits (alcohol, coffee, maté and tea drinking) and colorectal cancer was
case-control study conducted between 1993 and 1997 in Cordoba, Argentina, a re
mortality area for colorectal cancer. Cases were 190 pati
histologically confirmed colorectal adenocarcinomas, and controls were 393 pa
hospital for a wide spectrum of acute, non-neoplastic disorders. The consumpti
tea was not significantly related to colorectal cancer, but the ORs were below un
coffee, 0.9 (0.6-1.5) for maté and 0.8 (0.6-1.2) for tea drinkers).
ss index (BMI), selected
investigated in a
latively high
ents below 80 years of age with incident,
tients admitted to
on of coffee, maté and
ity (0.9 (0.7-1.3) for
[Pintos
et al.
1994]: Maté drinkers have high risks of upper aerodigestive tract ca
conceivable that this high risk may be attributable to confounding by smoking
exposures. To test this hypothesis, the data from a case-control study of upper ae
cancers conducted in Southern Brazil were analyzed. The authors matched non
756) to cases (N = 378) on the basis of age, sex, and period of admission. They esti
of maté consumption by conditional logistic regression with adjustment for smoking
sociodemographics, and several dietary items, considered as confounders. The un
upper aerodigestive tract cancers was 2.1 [95% CI = 1.6-2.7]. Some excess risk p
adjustment for potential confounders (RR = 1.6; 95% CI = 1.2-2.2). Most of the
drinkers was for oral (RR = 1.9; 95% CI = 1.1-3.3) and laryngeal (RR = 2.2; 95%
cancers. There was no evidence of associations with coffee and tea drinking. The au
that the association of maté consumption with upper aerodigestive tract cancer risk
from insufficient control of confounding by critical exposures. Owing to its high p
South America, maté drinking may be linked to as many as 20% of all cases occ
ncers, but it is
alcohol, and other
rodigestive tract
cancer controls (N =
mated the effect
, alcohol,
adjusted RR for all
ersisted after
excess risk for maté
CI = 1.1-4.5)
thors concluded
is unlikely to result
revalence in Southern
urring in this region.
us cell carcinomas
ea Rio Grande do Sul,
CP and DNA
th p53 polymorphism)
r (n = 1) or intron border
mutations (n = 2) that cause splicing aberrations. They were preferentially found in exon 5 (36.7%)
and exon 8 (32.7%). Several mutations were located in the mutation hot spot codons 248, 273 and
282, mainly at CpG sites. Transition mutations were observed in 53.1% (among them 50% G > A),
transversion mutations in 34.7% (among them 47.1% G > T) and frameshifts in 12.2%, the latter 2
mainly in smokers and alcohol drinkers. Transitions were more prevalent in females than in males (p <
0.05). TP53 mutations, mainly transversions, were more frequently found in heavy smokers (p =
0.03), with the same tendency after chronic alcohol consumption. Comparison with the worldwide IARC
database disclosed differences in the TP53 mutation pattern of the Brazilian tumors, with a higher
accumulation of TP53 mutations in exon 8 and a higher prevalence of transition mutations. Mutations
at the reported hot spot codon 176 were missing. Although difficult because of the documented
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[Pütz
et al.
2002]: In an attempt to correlate the TP53 mutation pattern of squamo
of the esophagus (ESCC) and life style factors of patients from the high risk ar
Brazil, 135 ESCC were analyzed, after prescreening by p53 immunohistochemistry, by SS
sequencing of TP53, exon 5-9. Forty-nine somatic TP53 mutations (and 1 case wi
were identified as missense (n = 39), frameshift (n = 6), silent (n = 1), ambe
thesis is proposed
n this high risk area
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.
l cancer and
até drinking in
king, alcohol
cold or hot Maté
at which Maté was
or hot Maté, drinkers of
the strong effects of
s effect seemed to be
ch hot Maté is
se-response
ng for these and
the consumption of other food groups, diets rich in fats and red meats, especially beef, were
king does not
ature at which Maté is
ophageal cancer in this
associated with esophageal cancer risk. The authors concluded that cold Maté drin
increase the risk of esophageal cancer. This study identified the very hot temper
drunk, and not the amount or the duration, as an important risk factor for es
population.
[Sewram
et al.
2003]: A retrospective hospital-based case-control study was carrie
Oncology Institute of Montevideo, Uruguay, to investigate the role of maté consum
cancer risk. The study included 344 cases with squamous cell carcinoma of the esopha
controls recruited between January 1988 and August 2000. Maté consumption was
associated with an increased risk of developing esophageal cancer and showed a
with a RR of 2.84 [95% CI, 1.41–5.73] for those drinking more than 1 l/day of
nondrinkers. Subjects who self-reported drinking maté at a very hot tempera
increase in risk [OR, 1.87; 95% CI, 1.17–3.00] compared with those drinking warm to hot maté,
adjusting for cumulative consumption of maté. Maté amount and temperature were
independent effects and, although no departure from multiplicativity was ob
covariates, those drinking m
in risk (OR, 2.95; 95% CI, 1.30–6.74) compared with those drinking less than 0.
warm to hot temperature. Subjects with high cumulative exposure to maté in the presenc
alcohol and tobacco exposures presented a lower-risk estimate (OR, 1.52; 95% CI
whereas those with high cumulative exposures to maté, alcohol and tobacco presen
increase in esophageal cancer risk (OR, 7.10; 95% CI, 3.75–13.46). The population-attri
fraction as a result of maté consumption was calculated to be 53%, of which the so
and temperature was 14.8 and 12.6% respectively, and 14.9% was attributable
d out at the
ption in esophageal
gus and 469
significantly
clear dose response,
maté as compared with
ture had an almost 2-fold
after
observed to have
served between the two
ore than 1 l/day of maté at a very hot temperature had a 3-fold increase
5 l/day of maté at a
e of low
, 0.88–2.62),
ted a 7-fold
butable
le effect of amount
to high maté
consumption at high temperature.
[Vassallo
et al.
1985]: Esophageal cancer has constituted a major public health problem in Uruguay,
with age-adjusted death rates of 14.5/100,000 for males and of 3.8/100,000 for females. A case-
control study was undertaken to ascertain the possible association of the drinking Maté with cancer of
the esophagus, after controlling for well-known risk factors, such as alcohol and tobacco consumption.
Two hundred twenty-six patients with esophageal cancer and 469 controls (control:case = 2.1) were
interviewed at the time of admission or consultation at the Oncology Institute of Montevideo from 1979
through 1984. Males showed elevated risks of esophageal cancer associated with heavy tobacco (RR =
10.8) and alcohol (RR = 10.3) exposures. Among females, the independent effects of tobacco and
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coexposure to various life style risk factors in most patients of this series, the hypo
that besides smoking and alcohol drinking the commonly consumed hot Maté tea i
for ESCC is responsible for this different pattern of
[Rolon
et al.
1995]: A hospital-based case-control study, including 131 cases of esophagea
381 controls, was carried out in Paraguay to investigate the role of hot and cold M
esophageal cancer risk. Detailed information on Maté drinking and on tobacco smo
consumption, and dietary habits was obtained by interview. Amount and duration of
drinking were not associated with esophageal cancer risk. However, temperature
drunk was significantly associated with risk. As compared to drinkers of warm
very hot Maté had an increased risk for esophageal cancer even after adjusting for
alcohol and tobacco consumption (adjusted OR = 2.4; 95% CI = 1.3-4.3). Thi
mainly due to the temperature at which Maté cocido (one of the two ways in whi
prepared) was drunk (OR = 6.5; 95% CI = 3.2-12.2). As expected, very strong do
associations were found for alcohol consumption and cigarette smoking. After correcti
alcohol were non significant. Maté consumption (0.5 -1 l/day) had an independe
and females, with OR of 6.5 and 34.
response was evident in both sexes.
nt effect in both males
6, respectively, for heavy users. Moreover, a well-defined dose
[Victoria
et al.
1987]: There is a cluster of high-incidence areas of oesophageal can
South America, including Southern Brazil, Uruguay and parts of Argentina. This ca
investigated the hypothesis that this may be due to the drinking of maté, a traditi
at a very high temperature, and also studied the role of other known risk factor
tobacco. Cases (171) and age- and sex-matched controls (342) were recruited
State of Rio Grande do Sul in Southern Brazil. The crude OR for daily maté drinker
to those drinking less frequently than daily (p = 0.006). Other risk factors included the dri
cachaça (a sugar cane spirit), smoking, rural residence, low fruit consumption and hi
meats. After adjustment for these variables through conditional logistic regres
with daily maté drinking was reduced to 1.47 (90% CI = 0.87-2.50). Although th
provide evidence of
rates could be explained by relative risks of the magnitude observed. This is due t
approximately 70% of adult males and 50% of females are daily drinkers. In add
revealed that alcohol, tobacco smoking and rural residence are the
cancer in this popu
lation
[Spinella
et al.
2001]: Anecdotal, uncontrolled observations suggest that herbal st
ephedrine (ephedra or ma huang) and caffeine (cocoa, coffee, tea, maté, guarana, col
exacerbate seizures in people with epilepsy, e
imulants containing
a or kola) can
specially when taken in combination.
Assessor’s comment:
Data on Maté are insufficient. Therefore an effect of Maté on people suffering from
assessed. For a detailed comment on the risk of cancer/cancerogenic potential, se
epilepsy cannot be
e 5.6.
5.3.1.
Serious adverse events and deaths
ogical features similar
resident in Britain.
s confirmed at necropsy.
ine 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.
Assessor’s comment:
sumption was
ent’s sample of
Maté tea. Thus it could be assumed that the presence of pyrrolizidine alkaloids was caused by
adulterations [McGee
et al.
1976].
[Hsu
et al.
1995]: An outbreak of cholinergic poisoning occurred in New York City during a 3-day
period. Seven individuals from three families of South American origin were affected. Signs and
symptoms of illness included dry skin, hyperthermia, tachycardia, dilated pupils, agitation, and
hallucinations. Onset of illness in all cases was temporally associated with consumption of a tea that
was labelled "Paraguay Tea" and was purchased from a grocery store specializing in South American
foods. Paraguay tea, made from the leaves of the holly,
Ilex paraguariensis
, contains caffeine and
theophylline and is a popular beverage in South America. Samples of the tea analyzed with gas
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cer in south-eastern
se-control study
onal beverage drunk
s such as alcohol and
from hospitals in the
s was 1.92 relative
nking of
gh intake of
sion, the OR associated
e study failed to
a strong association between maté and esophageal cancer, the cluster of high
o the fact that
ition, this study
main risk factors for oesophageal
[McGee
et al.
1976]: Veno-occlusive disease of the liver with clinical and pathol
to those of the condition occurring in the Caribbean is described in a young woman
The diagnosis was made from liver biopsies and hepatic venography and wa
Small amounts of pyrrolizid
Only one case of veno-occlusive disease of the liver associated with Maté tea con
described. The small amounts of pyrrolizidine alkaloids were only recovered in the pati
ine. An investigation
a 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 con
contaminated with plants that contain belladonna alkaloids. During March 1994, the New York Ci
Department of Health investigated seven cases of anticholinergic poisoning in me
families; three of the seven ill persons required emergency treatment for
For all cases, mani
sumption of foods
ty
mbers of three
characteristic manifestations.
festations 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
,
cases.
which is native to South America. The report summarized the investigation of these
Assessor’s comment:
tributed the disease to an adulteration of the herbal tea. Adverse events due
to the content of caffeine can be sleeplessness, uneasiness, tachycardia and gastro-intestinal
contraindications result from these known adverse events including a
ovascular disorders such as hypertension
complaints. The following
benefit-risk assessment: gastric and duodenal ulcers, cardi
and arrhythmia, hyperthyroidism.
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 f
actors
No data for the herbal substance or herbal preparations are available.
Assessor’s comment:
Use in children and adolescents under 18 years of age is not recommended
sufficient. In general, an appearance of tiredness in children and adolescents shoul
a physician. A treatment with Maté containing preparations, without clarifying the causes,
seem to be adequate.
because data are not
d be investigated by
does not
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 40–50%. In addition, it has been noted by the U.S. Army Center for Health Promotion and
Preventive Medicine that yerba mate can cause high blood pressure when used in conjunction with
other MAO inhibitors (such as Nardil® and Parnate®).
[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, anti-depression therapy, eating disorders, withdrawal
syndromes, and the cessation of smoking.”
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chromatography contained belladonna alkaloids but neither caffeine nor theophyll
by the New York City Department of Health personnel determined that the te
In all cases, the authors at
Caffeine interactions:
[Thomson Microdex 2007]: Drug interactions and/or related problems of caffeine in
oxidase (MAO) inhibitors, including furazolidone, procarbazine and selegiline (larg
may produce dangerous c
side effects of caffe
mild increase in blood pressure).
Assessor’s comment:
e, the following is
ds ‘interactions with other medicinal products and other forms of interactions’
for inclusion in the HMPC monograph: “Persons taking MAO-inhibitor drugs should use Maté with
ons reduce sedative action and increase side effects caused
caution” and “Caffeine containing preparati
by sympathomimetic drugs”.
5.5.3.
Use in pregnancy and lactation
[Martin
et al.
2007]: The premature newborn of a mother who reported drinkin
pregnancy presented with increased jitteriness and irritability, high-pitched cry, h
limbs, and brisk tendon reflexes consistent with neonatal withdrawal syndrome.
caffeine and theobromine were detected in various maternal and neonatal biologic
(placenta, cord serum, neonatal urine, maternal and neonatal hair, meconium, a
demonstrating both acute and chronic prenatal and postnatal exposure to these me
contained in high amounts in homemade Maté. Symp
g Maté during
ypertonia in the
High concentrations of
al matrices
nd breast milk),
thylxanthines,
toms progressively disappeared at 84 hours of
ed at 24 days of
likely generated the
hylxanthines or
strongly
ption to a maximum
age, although intermittent irritability was still present when the infant was discharg
age. Fluctuating caffeine (and theobromine) content in different breast milk feeds
baby's irritability, due to either the physiological stimulatory effects of the met
postnatal withdrawal syndrome as the substances cleared from the body. The mother was
advised to initiate a considerable, progressive, constant reduction of Maté consum
of 2 cups a day for the duration of breastfeeding.
on preterm and small for
31 December 1993,
tas, Southern
rthweight was recorded
and gestational age at birth assessed using the Dubowitz score. All 5,189 single births were analyzed.
SGA and preterm birth was 8 and 9.1%, respectively. Maté intake at least once a
rude analyses showed
-consumers
6), whereas no statistical association was detected with
preterm births. After controlling for confounders, the significance of the association with SGA birth no
longer held and the lack of association with prematurity remained unchanged. Prevalence of daily Maté
drinking was high among pregnant women and, contrary to the hypothesis, no harmful effect on
intrauterine growth or duration of pregnancy was detected.
The prevalence of
week during the entire pregnancy period was reported by 68% of the mothers. C
a 30% increase in the risk of SGA among daily Maté drinkers compared with non
(prevalence ratio = 1.3; 95% CI 1.1–1.
Assessor’s comment:
The level of exposure to Maté drinking during pregnancy was obtained retrospectively. Only weekly
frequency but not the amount of Maté consumed was investigated. Non-Maté drinkers (references)
may have consumed caffeine from other sources.
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take: Monoamine
e amounts of caffeine
ardiac arrhythmias or serve hypertension because of the sympathomimetic
ine; concurrent use with small amounts of caffeine may produce tachycardia and
On the basis of the data available concerning drug interactions for Maté and caffein
recommended as regar
[Santos
et al.
2005]: To assess the effect of Maté drinking during pregnancy
gestational age (SGA) birth, a cross-sectional study was done. From 1 January to
in the first 24 h after delivery, all 5,304 mothers giving birth at the hospitals in Pelo
Brazil, were interviewed and several of their characteristics were gathered. Bi
[Matijasevich
et al.
2006]: The objective of this study was to examine the asso
intake during pregnancy and fetal mortality in Montevideo, the capital city of Urug
account several potential confounding factors. A population-based case-co
between 1 August 2002 and 31 December 2003. A total of 382 cases and 792 cont
Cases consisted of women hospitalised with a medically confirmed diagnosis of
antepartum fetal death, in all maternity hospitals during the study period. An
defined as a fetal death in which the attending doctor certified that the death occurred pri
onset of labour. Fetal deaths were included if they were of at least 20 weeks' gesta
weighed >350 g. Controls were women who had a live, vigorous and term adequate
age newborn. Multiple gestations and fetuses/newborns with evident congenital m
excluded. Only a small proportion of the mothers (8.1% of the cases and 9.5% of the control
consume caffeine during pregnancy. Among consumers, Maté drinking wa
caffeine in both cases and controls. After controlling for mother's and her partner's
of abortions and/or fetal deaths, vomiting/nausea during the first trimester of ge
attendance for prenatal care, the category of mean caffeine intake of > or = 3
significantly increased risk of fetal death (OR 2.33 [1.23; 4.
consumption durin
attend for prenatal care and women with a history of abortions and fetal death we
risk of fetal death. As Maté drinking is highly consumed among pregnant women
association found with fetal d
eath makes it a preventable risk factor.
Assessor’s comment:
The aim of the study was to examine the association between caffeine intake and fe
caffeine amount of Maté was assumed at 0.17 mg/ml. The differences between th
(coffee or Maté) were not examined.
tal mortality. The
e caffeine sources
Caffeine consumption during pregnancy
:
egnancy was
study was performed.
at the same period of
d using conditional
ffeine intake was
uartiles; the baseline for comparison was less than 48 mg per day. The adjusted ORs for
CI, 0.85 to 1.95) for 48 to
to 2.89) for more
and the
2.93), and 2.62
g association of
he logistic scale in
which ORs increased by a factor of 1.22 (1.10 to 1.34) for each 100 mg of caffeine ingested daily
during pregnancy.
fetal loss associated with caffeine intake before pregnancy were 1.29 (95%
162 mg; 1.37 (95% CI, 0.92 to 2.04) for 163 to 321 mg; and 1.85 (95% CI, 1.18
than 321 mg. The same comparisons were made for caffeine intake during pregnancy,
respective adjusted ORs were 1.15 (95% CI, 0.82 to 1.63), 1.95 (95% CI, 1.29 to
(95% CI, 1.38 to 5.01). After controlling for confounding factors, there was a stron
caffeine intake during pregnancy and fetal loss, compatible with a linear trend on t
[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 case-control
study surveying parents of 393 SIDS victims and parents of 1,592 control infants. Caffeine
consumption in each of the first and third trimesters was estimated by questionnaire. Heavy caffeine
intake was defined as 400 mg/day or more (equivalent to 4 or more cups of coffee per day). Results:
Infants whose mothers had heavy caffeine consumption throughout their pregnancy had a significantly
increased risk for SIDS (OR 1.65; 95% CI 1.15 to 2.35) after adjusting for likely confounding factors.
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ciation between caffeine
uay, taking into
ntrol study was conducted
rols were recruited.
spontaneous
tepartum fetal death was
or to the
tional age or
-for-gestational-
alformations were
s) did not
s the most frequent source of
education, history
station and
00 mg/day showed a
41]) compared with no caffeine
g pregnancy. The study also found that less-educated women, mothers who did not
re at an increased
in Uruguay, the
[Infante-Rivard
et al.
1993]: To determine if caffeine intake before and during pr
associated with an increased risk for fetal loss, an incidence-density case-control
A total of 331 women with fetal loss and 993 controls with a normal pregnancy
pregnancy were investigated. Crude and adjusted ORs for fetal loss were estimate
logistic regression. A trend test for increasing caffeine intake was also used. Ca
divided into q
Conclusion: Caffeine intake has been associated with fetal harm and SIDS. Reduc
intake during pregnancy co
this needs confirmation by others.
ing heavy caffeine
uld be another way to lessen the risk of SIDS. The authors remarked that
[Bracken
et al.
2003]: Whether caffeine consumption during pregnancy repre
remains uncertain. The authors report on a large prospective study designed to exa
In 1996–2000, 2,291 mothers with singleton live births in Connecticut and Massachusetts
evaluated after their first prenatal visit and were questioned about caffeine cons
confounding factors. Urine samples were provided to analyze urinary caffeine, cotinine, and creati
levels. Mothers were followed throughout pregnancy to monitor changes in
outcomes were obtained from medical records. Self-reports of caffeine consumpt
third trimesters were not associated with intrauterine growth retardation, low birth wei
delivery. For every 1 mg/g creatinine increase in urinary caffeine, risk of intrauterine growth
retardation was essentially unchanged (OR = 0.96, 95% CI: 0.85, 1.08). In co
creatinine increase in urinary cotinine significantly increased risk (OR = 1.003, 95%
Mean birth weight was reduced by reported caffeine consumption (–
consumed daily, 95
did not increase risk for any perinatal outcome. This small decrease in birth weight,
maternal caffeine consumption, is unlikely to be clinically important except for wo
mg of caffeine daily (approximately six 10-ounce (1 ounce = 28.3 g) cups of cof
sents a fetal hazard
mine this question.
were
umption and important
nine
consumption. Pregnancy
ion in the first and
ght, or preterm
ntrast, a 0.005 mg/g
CI: 1.001, 1.005).
28 g per 100 mg of caffeine
% CI: –0.10, –0.46, p = 0.001) but not mean gestational age. Decaffeinated coffee
observed for
men consuming 600
fee).
Assessor’s comment:
Caffeine crosses the placenta and achieves blood and tissue concentrations in the fetus that are similar
ing pregnancy was
described. The premature newborn presented with increased jitter and irritability, high-pitched cry,
syndrome.
taneous abort and
hypertonia in the limbs, and brisk tendon reflexes consistent with neonatal withdrawal
Studies have shown that heavy caffeine consumption may increase the risk of spon
reduced birth weight.
The Food Standards Agency has recommended that pregnant women should limit
to less than 300 mg of caffeine a day. A higher intake may be associated with fetal
their caffeine intake
loss.
Caffeine is
the mother’s plasma concentration, caffeine can accumulate in the infant, due to its
The infants may show signs of caffeine stimulation such as hyperactivity and
feedi
ng mother drank caffeine-containing beverages.
The study of Santos
et al.
2005 showed no harmful effect, but they did not inv
Maté consumed. Additionally, the level of exposure to Maté drinking duri
retrospectively and the non-Maté drinkers (taken as references) may have consum
other sources.
estigate the amount of
ng pregnancy was obtained
ed caffeine from
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.”
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to maternal concentrations. One case of a mother who reported drinking Maté dur
distributed into breast milk. Although the concentration of caffeine in breast milk is 1% of
increased half-life.
wakefulness when breast-
5.5.4. Overdose
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 ha
is associated with symptoms of poorer health. The aim of the study was to further
association between caffeine use and somatic and psychological symptomatology w
potentially confounding influences such as concurrent substance use. Information was obtained on the
somatic and psychological health, substance use, and biographic background of 9
into 3 equal-sized groups matched on age an
specifically because of their habitually high caffeine intake. The other 2 groups con
subjects of psychiatric patients and university students w
bitual caffeine use
examine the
hile controlling for
6 individuals divided
d sex. One group consisted of subjects who were chosen
sisted of comparison
ho represented widely varying levels of
somatic and psychological health. The results indicated that, at high intake levels, caffeine may have
on somatic and psychological health.
detrimental effects
[Blaschek
et al.
2007]: Caffeine ma
blood pressure, increase of
y cause side effects like insomnia, anxiety, tremulousness, raised
stomach acid and gastroesophageal reflux.
5.5.5.
Drug abuse
No data for Maté preparations are available.
Caffeine tolerance development
[Evans and Griffith 1992]: Thirty-two healthy subjects with histories of moderat
abstained from dietary caffeine throughout the study. Subjects were strat
several factors including caffeine preference, which was assessed using a caffeine versus placebo
choice procedure. Subsequently, subjects received either caffeine (300 mg t.i.d.) or pl
t.i.d.) for 18 consecutive days, and thereafter were exposed again to a caffeine
procedure. The study documented tolerance development to the subjective effects
chronic dosing, administration of caffeine produced significant subjective effects in the chro
group but not in the chronic caffeine group. The study also provided indirect
e caffeine consumption
ified into 2 groups based on
acebo (placebo
versus placebo choice
of caffeine: after
nic placebo
evidence for tolerance
development: during chronic dosing, the chronic caffeine and placebo groups did not differ
nd subjective effect. When subjects were categorized into caffeine
choosers or non-choosers, caffeine choosers tended to report positive subjective effects of caffeine and
Non-choosers, in contrast, tended to report negative subjective
ng effects of caffeine as assessed by
caffeine versus placebo choice, possibly because the relatively short duration of caffeine abstinence in
the placebo condition was not sufficient to result in maximal withdrawal effects after termination of the
relatively high caffeine dose. This study provided the clearest evidence to that date of complete
tolerance development to a CNS effect of caffeine in humans.
meaningfully on ratings of mood a
negative subjective effects of placebo.
effects of caffeine. Chronic caffeine did not alter the reinforci
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.
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 33/35
5.5.7.
Effe
mental ability
cts on ability to drive or operate machinery or impairment of
No stud
ies on the effect of Maté on the ability to drive and use machines have been performed.
Caffeine:
e intended use of
caffeine does not affect the ability to drive or operate machinery. Caffeine did not compensate at all
es. In particular cases, an increased
the alcoholic involved ability to drive or to operate machin
resorption of alcohol may occur.
5.6.
Assessor’s overall conclusions on clinical safety
There are numerous publications indicating both a chemoprotective potential of Mat
of antioxidants) and an increased risk for cancer of the mouth and pharynx, esopha
kidney (see chapter 5.3). However, it has to be considered that an increase
pharyngeal cancer is postulated in case of frequent
(Ghadirian 1987, Islami
et al.
2009). The performed case control studies a
quality of the case report forms, the inclusion/exclusion criteria and diagnoses documente
epidemiological and mechanistic studies are missing to establish a causal r
consumption and cancer of the bladder and kidney.
é tea (high content
gus, bladder and
d risk for oral and
intake of very hot liquids, as for example Maté tea
re insufficient concerning the
d. Thus, valid
elationship of Maté
nt genotoxic
offee and smoked
oked products of
pected which is
documented for the consumption of meat from the barbecue. Valid studies investigating how far the
al cancer risk are not
fic data, it can be assumed that considering the background
n average food consumer, there is no relevant additional genotoxic or carcinogenic risk
so the postulated, possible
ive effects due to the high rate of antioxidants have to be considered. Valid data,
er, are not available at present.
consumption of barbecued meat, smoked or roasted food could mean an addition
available. Based on the present scienti
exposure of a
when consuming moderate amounts of Maté tea. For the risk assessment, al
chemoprotect
howev
On the basis of the above-mentioned data and a possible summation of caffei
following co
ne from foodstuff, the
nditions of useare recommended:
Contraindications
- “
Gastric and duodenal ulcers, cardiovascular disorders such as hypertension and
hyperthyroidism
.
”
arrhythmia,
Warnings
- “
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.”
Interactions
- “
Persons taking MAO-inhibitor drugs should use Maté with caution. Caffeine containing preparations
reduce sedatives action and increase side effects caused by sympathomimetic drugs
.
”
Pregnancy and lactation
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 34/35
[Deutscher Arzneimittel Codex: Caffeine-monograph Commission B 2004]: Th
In conclusion at present, there is no evidence that Maté tea contains more pote
ingredients than other roasted, fried or smoked food. As compared to Maté tea, c
food contain similar or even higher amounts of PAH. In consumers of coffee and sm
cheese, meat and fish, the formation of corresponding PAH metabolites is ex
- “
There are no or limited
during pregnancy and lactation.”
data from use during pregnancy and lactation. The use should be avoided
As regards the indication as an adjuvant in minor urinary complaints, the foll
recomm
during the use of the medicinal product, a doctor or qualified health care practitioner shoul
consulted.”
owing warning is
ended:
-
“If complaints or symptoms such as fever, dysuria, spasms or blood in urine occur
d be
The contraindications (‘Hypersensitivity to the active substance(s)’ and ‘Conditio
fluid intake is recommended, e.g. obstruction of the urinary tract’ are also recommended.
ns where a reduced
recommended to
indication (symptoms of fatigue and sensation of
weakness) and to 2 weeks for the second indication (adjuvant in minor urinary complaints).
The Community herbal monog
genotoxicity and carcinogenic
raph also should indicate that adequate tests on reproductive toxicity,
ity have not been performed.
6.
Overall conclusions
Maté tea is well known and used as a traditional herbal med
America and for decades in European countries. Sufficient data are availa
monograph on the traditional use of
Ilex paraguariensis
St. Hilaire
,
folium
(Maté le
indications are suitable for self-medicati
Commission E monograph and the Cahier de l’Agence No 3 and reflecting a
traditional herbal medicinal products. The following indications are agreed:
icinal product for centuries in South
ble to develop a Community
aves
), provided the
on. The indications were established, considering the
lso the requirements 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
tract as an adjuvant in minor urinary complaints.”
flushing of the urinary
Based on the present scientific data, it can be assumed that there is no relevant genotoxic or
ral studies on the
carcinogenicity of Maté were examined, due to a positive AMES-test and to the high incidence of
geal and renal cancer in Brazil, Argentina, Paraguay and Uruguay, at present it can be
concluded that there is no evidence that Maté tea contains more potent genotoxic ingredients than
d or smoked food. For the estimation of a potential risk, it has to be taken into
account that, in the above-mentioned countries, large quantities of Maté are consumed (average: 7
kg/inhabitant/year) and that it is usually consumed at very high temperature.
oesopha
other roasted, frie
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.
Annex
List of references
Assessment report on
Ilex paraguariensis
St. Hilaire, folium
EMA/HMPC/580545/2008
Page 35/35
Due to a possible caffeine tolerance development [Evans and Griffiths 1992], it is
limit the duration of use to 1 week for the first
carcinogenic risk when consuming moderate amounts of Maté tea. Although seve
Source: European Medicines Agency
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