COMMUNITY HERBAL MONOGRAPH ON
MENTHA X PIPERITA
L., 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:
Mentha x piperita
L
.,
folium
(dried peppermint leaf)
ii) Herbal preparations:
A)
Comminuted herbal substance for tea
preparation
B)
Tincture (1:5; ethanol 45 % (v/v))
C) Tincture (1:5; ethanol 70 % (v/v))
Well-established use
Traditional use
Herbal substance for infusion or other herbal
preparation in liquid or solid dosage forms for oral
use
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The declaration of the active substance(s) for an individual finished product should be done in accordance with
relevant herbal quality guidance.
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Well-established use
Traditional use
Traditional herbal medicinal product for the
symptomatic relief of digestive disorders such as
dyspepsia and flatulence.
The product is a traditional herbal medicinal
product for use in specified indication exclusively
based upon long-standing use.
4.2 Posology and method of administration
Well-established use
Traditional use
Posology
Adults, elderly
Daily dose
Herbal tea: 4.5 - 9 g of the herbal substance,
divided in three single doses.
Tincture: 6-9 ml, divided in three single doses.
Children between 4 and 12 years of age,
adolescents between 12 and 16 years of age
Daily dose
Herbal tea only:
Children between 4 and 12 years of
age
3-5 g
Adolescents between 12 and 16
years of age
3-6 g
To be divided in three single doses.
The use in children under 4 years of age is not
recommended (see section 4.4 ‘Special warnings
and precautions for use’).
Duration of use
If the symptoms persist for more than 2 weeks
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted (see section 4.4 ‘Special warnings and
precautions for use’).
Method of administration
Oral use.
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4.3 Contraindications
Well-established use
Traditional use
Hypersensitivity to peppermint leaf preparations
or to menthol.
4.4 Special warnings and precautions for use
Well-established use
Traditional use
Patients with gastro-oesophageal reflux
(heartburn) should avoid peppermint leaf
preparations, because heartburn may increase.
Patients with gallstones and any other biliary
disorders should be cautious using peppermint leaf
preparations.
The use in children under 4 years of age is not
recommended as there is no experience available.
If symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
practitioner should be consulted.
For tinctures containing ethanol the appropriate
labelling for ethanol, taken from the ‘Guideline on
excipients in the label and package leaflet of
medicinal products for human use’, must be
included.
4.5 Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
None reported.
4.6 Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
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4.8 Undesirable effects
Well-established use
Traditional use
The gastro-oesophageal reflux may worsen and
heartburn may increase.
See also section 4.4 Special warnings and
precautions of use.
4.9 Overdose
Well-established use
Traditional use
No case of overdose has been reported.
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.
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
necessary for the safe use of the product.
Adequate tests on reproductive toxicity,
genotoxicity and carcinogenicity have not been
performed.
6.
Well-established use
Traditional use
Not applicable.
7.
4 September 2008
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Assessment Report
ASSESSMENT REPORT
FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS
THEREOF WITH TRADITIONAL USE
Mentha x piperita
L., folium
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
AMENDED
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
Whole or cut dried leaf of
Mentha x piperita
L.
Herbal preparation(s)
Infusion
Tinctures
Pharmaceutical forms
Solid and liquid dosage forms
Rapporteurs
Dr Helena Pinto Ferreira
Dr Ana Paula Martins
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1
INTRODUCTION
Peppermint is a perennial plant native to Europe, highly aromatic that may grow as tall as three feet.
The ancient Egyptians, Greeks and Romans knew it as flavouring for food and as medicine. It was first
cultivated in England commercially around 1750 while its aerial parts have been widely used for their
medicinal effects.
Peppermint is widely known to relieve digestive ailments, being a popular remedy for at least two
centuries.
Mentha x piperita
L. is believed to be a hybrid of spearmint (
Mentha spicata
L.) and water
mint (
Mentha aquatica
L.)(Murray et al, 1972), belonging to Labiatae family. The essential oil is
obtained from the fresh leaves of
Mentha piperita
L
.
by steam distillation and
.
it is widely used all
over the world for flavouring, cosmetic and medicinal purposes.
At the herbarium of the English botanist John Ray (1628-1705) it can be found one of the oldest
specimens of peppermint. In 1721,
Mentha piperita
became the official item of Materia Medica in the
London Pharmacopoeia as
Mentha piperitis sapore
(Fluckiger 1879, Herbalgram, American Botanical
Council, 1996).
The data researched is able to demonstrate the traditional basis of the plant and its products, as it
effective use in several clinical situations.
1.1
Description of the traditional herbal substance(s), herbal preparation(s) or
combinations thereof
Whole or cut dried leaf of
Mentha piperita
L.
•
Herbal preparation(s)
1 2
Comminuted herbal substance for tea preparation
Tincture (1:5; ethanol 45% (V/V)
2.
TRADITIONAL MEDICINAL USE
-
It should be stated by means of a detailed description which herbal substance(s)/herbal
preparation(s) have been used and information should be provided for each preparation
separately.
2.1
Information on period of medicinal use in the Community regarding the specified
indication
Ellingwood, in 1902, in the book “Materia medica and Therapeutics – Chicago Medical Press:
recommends peppermint water (distillate) for “flatulent colic, gastrodynia, nausea, vomiting, intestine
spasmodic pain, hiccough, palpitation from indigestion, griping, cholera morbus, cholera infantum,
irritability of the stomach, diarrhoea with abdominal pain, nervous headache, painful gonorrhoea”.
In the Indian Materia Medica, leaves of
Mentha piperita
L. , in infusion, are used in cases of vomiting,
gastric colic, cholera, diarrhoea, flatulence, weak digestion, hiccup and palpitation of the heart
(Nadkarni’s – reprint of third edition – 1982)
2
According to “Note for guidance on Specifications: Test procedures and acceptance criteria for herbal drugs, herbal
preparations and herbal medicinal products” (CHMP/QWP/2820/00)
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1
According to “Note for guidance on Quality of herbal medicinal products” (CPMP/QWP/2819/00)
2.2
Type of tradition, where relevant
European phytotherapy
Ayurvedic medicine
2.3
Bibliographic/expert evidence on the medicinal use
Peppermint leaves are traditionally used (Forster 1996) as
carminative herbal medicinal product
with
therapeutic indications for the symptomatic treatment of digestive disorders such as dyspepsia (e.g.
spastic complaints of the upper gastrointestinal tract), flatulence, gastritis, enteritis and also as
cholagogue.
On the British Herbal Compendium its action is carminative, spasmolytic and choleretic (Bradley
1992).
Described as having carminative, digestive and stimulant properties (Costa Aloísio, 1986), and used as
an infusion for indigestion, gastric colic and diarrhoea.
Used for dyspeptic ailments and respiratory infections, hepatobiliary disfunction (Proença da Cunha,
2003).
As a
general digestive aid
a tea of dried peppermint leaves is employed for internal oral use, such as
intestinal spasms (Bradley 1992, Schilcher 1997).
In folk medicine is used as an emmenagogue, vermifuge, lactation enhancer and sedative. Also used to
treat bronchitis, bacillary dysentery, diabetes, diarrhoea, dysmenorrhoea, fevers, hypertension,
jaundice, nausea, pain, and respiratory and urinary tract infections (WHO monographs)
2.3.1
Evidence regarding the indication/traditional use
According to
ESCOP
, 2nd edition:
-
Used in the symptomatic treatment of digestive disorders such as dyspepsia, flatulence and
gastritis
According to
British Herbal Compendium
:
-
Dyspepsia, flatulence, intestinal colic, biliary disorders (Bradley 1992).
Belgium
(
Circulaire No. 367 of July 1991
:
Mentha piperitae
L. herbe):
-
Traditionally used in the symptomatic treatment of digestive disorders, although its activity has
not been proved in accordance with the current evaluation criteria for medicines.
(
Circulaire No. 450 of 1994
:
Mentha piperitae
L. herbe):
-
Traditionally used in the symptomatic treatment of digestive disorders, after any serious
pathological condition has been excluded.
France
(
Bulletin officielle No. 90/22 bis
: Menthe; feuille, sommité fleurie) :
Information for medical profession
-
030. Traditionally used topically as a soothing and antipruriginous application for
dermatological ailments, as a protective treatment for cracks, grazes, chapped skin and against
insect bites
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-
041. Traditionally used in the symptomatic treatment of digestive disorders such as: epigastric
distension; sluggishness of the digestion; belching; flatulence.
-
043. Traditionally used s adjuvant treatment for the painful component of spasmodic colitis.
-
045. Traditionally used to promote renal and digestive elimination functions.
-
122. Traditionally used in cases of nasal congestion and of common cold.
-
142. Traditionally used topically (mouth and throat washes, pastilles) as an anodyne for
affections of the buccal cavity and/or orofaringe.
-
144. Traditionally used topically in mouth washes, for oral hygiene.
Germany
(C
ommission E monograph published 30.11.85, amended 13.3.90 and 1.9.90
):
-
Spastic complaints of the gastrointestinal tract as well as gallbladder and bile ducts.
Standarddzulassung Nº. 1499.99.99 published 3.12.82 for a standard medicinal tea:
Pfefferminzblätter.
-
Gastro-intestinal and gall-bladder ailments.
2.3.2
Evidence regarding the specified strength
Tincture – (1:5 preparations, 45% ethanol) - (Bradley, 1992)
Tincture – (1:5 preparations, 70% ethanol) – (Erg.B.6, 1953, Commission E monographs, 1985)
1,5-9g of leaf – (ESCOP, Commission E)
2.3.3
Evidence regarding the specified posology
General use:
Infusion – usually prepared with one or two teaspoons (1, 5 to 3, 0 grams) of the dried leaves per 8
ounces of water (Bradley, 1992; Wichtl, 1989)
Tincture – (1:5 preparation, 45% ethanol) – 2 to 3 ml, three times daily (Bradley, 1992)
(
Kommission E monograph published 30.11.85, amended 13.3.90 and 1.9.90
):
-
5 – 15 g tincture/daily (1:5 preparations, 70% ethanol)
-
3 - 6 g of leaf
ESCOP
2
nd
Edition:
-
Adults
o
As an infusion, 1.5 – 3 g of the drug to 150 ml of water, three times daily
o
Tincture (1:5, 45% ethanol), 2-3 ml, three times daily
-
Elderly – the same as adults
-
Children from 4 years of age, daily dose as infusions only:
o
4-10 years, 3-5 g
o
10-16 years, 3-6 g
2.3.4
Evidence regarding the route of administration
See point 2.3.2
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2.3.5
Evidence regarding the duration of use
No restriction. If symptoms persist or worsen after 2 weeks, a doctor or a qualified health practitioner
should be consulted.
2.3.6
Assessor’s overall conclusion on the traditional medicinal use
Peppermint leaves are a very well known herbal medicinal product, widely used since a long time,
being a popular remedy inside and outside European countries, for its antispasmodic, choleretic and
carminative properties, as we can confirm in a large number of publications.
On the literature we can find references to several preparations such as tinctures, liquid extracts and
infusions, on single or combination products. The data about the 30 years of use for the tincture (1:5,
45% of ethanol) was not found, just the publication from Bradley from 1992, 16 years to now in
Europe. Being the one with the best explanation about the posology and accepted by the interested
parties, I propose to include it on the monograph.
2.4
Bibliographic review of safety data of the traditional herbal medicinal substances
2.4.1
Patient exposure
Peppermint leaves and extract can be used in cosmetic formulations as fragrance ingredients.
Peppermint water can be used as a flavouring agent or, also, as a fragrance component.
Menthol
In 1976, FAO/WHO Joint Expert Committee on Foods Additives established an ADI of 0, 2 mg/kg
body weight/day for menthol. In 2000, an ADI of 0-4mg/kg of body weight/day was allocated.
Pulegone and menthofuran
Maximum levels for pulegone in foodstuff and beverages to which flavourings or other food
ingredients with flavouring properties have been added: 25 mg/kg in foodstuff, 100 mg/kg in
beverages, with the exception of 250 mg/kg in peppermint or mint flavoured beverages and 350 mg/kg
in mint confectionery (Annex II of Directive 88/388/EEC). Pulegone may not be added as such to
foodstuff. Committee of Experts on Flavouring Substances (CEFS) of the Council of Europe (1997):
Menthofuran is the proximate hepatotoxin of pulegone. Tolerated daily intake (TDI) of menthofuran
and pulegone was set to 0.1 mg/kg bw, based on a no effect level (NOEL) of 20 mg/kg bw/d in the
28 days oral toxicity study in rats (Thorup et al. 1983 a,b) with a safety factor of 200. Menthofuran is
listed in the register of chemically defined flavouring substances laid down in Commission Decision
(1999/217/EC, 2002/113/EC).
USA: Pulegone and menthofuran have FEMA GRAS status and are listed among the authorized
synthetic flavouring substances. JECFA (Joint FAO/WHO Expert Committee on Food Additives,
2000): “No safety concern” was applied to (R)-(+)-pulegone and structurally related flavouring agents
including (R)-(+)-menthofuran.
Because of the toxicity of pulegone, the CIR expert Panel limited it to ≤ 1% in cosmetic grade. Recent
data reported that peppermint leaves are used in <0, 2% on formulations.
2.4.2
Adverse events
Peppermint teas contain only a low amount of menthol and menthone. In adults, the adverse reactions
are, in general, related with a high intake of menthol by other products, as confectionary or
pharmaceuticals.
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The normal and prolonged use of peppermint tea, rarely leads to adverse effects (ESCOP, 2
nd
ed), but
the gastro-oesophageal reflux may be worsened by taking it, as peppermint relaxes the lower
oesophageal sphincter. Due to this effect, it is not recommended to people with and gastrooesophageal
reflux.
Peppermint may stimulate the production of bile. In case of cholangitis, gallstones and other biliary
disorders, this product should be used with caution and under the supervision of a medical doctor.
2.4.3
Serious events and deaths
Not known
2.4.3.1
Intrinsic (including elderly and children)/extrinsic factors
The oil of peppermint should be used with caution in infants and young children, as the nasal mucosa
is an autonomic reflexogen organ, which has a distance action to the heart, lungs and circulation and
may lead to sudden apnoea and glottal constriction. The children less than 2 years old present
particularly this reflex, so all the substances with a strong odour must be avoided. Peppermint oil must
be avoided at this range of age.
A cup of tea contains ca. 2.5 mg of menthol, which is as exciting as 5 drops (0.5 ml) of a 20 %
alcoholic solution of
Mentha
essential oil (Duband et al, 1992).
2.4.3.2
Drug-drug interactions and other interactions
Not reported.
2.4.3.3
Use in pregnancy and lactation
Data on the use during pregnancy and lactation is not available. Some references appoint
thatpeppermint may dry up milk secretions (Mills, 2005).
As a general precaution, the use is not recommended, unless medical advice proposed benefit is higher
than the potential risk.
2.4.3.4
An intoxication of a 9 years boy with a menthe (carvone) infusion prepared with 30 leaves is reported.
The symptoms were tachycardia and agitation, relieved after 24 hours (Augiseau et al, 1987).
This is not the case of
Mentha piperitae folium.
2.4.3.5
Drug abuse
Not applicable
2.4.3.6
Withdrawal and rebound
Not applicable
2.4.3.7
Effects on ability to drive or operate machinery
Not applicable
Contra indications (hypersensitivity and allergic potential to be both covered)
People with hypersensitivity to peppermint preparations should not take this medicinal product.
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Non-clinical safety data
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
(e.g. single/repeat dose toxicity, genotoxicity, carcinogenicity and reproductive and developmental
toxicity, local tolerance, other special studies)
Toxicity
A dry peppermint leaf extract was given to 12 mice as a single dose at 4000mg/kg body weight. None
of the animals died or showed macroscopic signs of toxicity over a 7-day period (Della Logia et al,
1990).
20g/L of
M. piperitae
tea were given to 48 rats during 30 days; serum iron and ferritin levels were
reduced (p<0.05), and increased unsaturated iron-binding capacity (p<0.01), on a study of Akdogan et
al. (2004a).
On another study, the biochemical and histopathological effects of
Mentha piperitae
L. and
Mentha
spicata
L on liver tissue of rats was investigated. Ast and Alt activities were increased, but not
statistically significant on the group with 20g/L of M. piperita tea, daily, during 30 days, In this group,
the histopathological evaluation there was minimal hepatocyte degeneration. The damage seems to be
dose dependent, according to the author (Akdogan et al., 2004b).
A similar study on the kidney of Wistar albino rats found no evidence of nephrotoxicity on the group
drinking 20g/L of
M. piperitae
tea, daily, during 30 days. The histopathological changes were
observed, slight on the group of
M. piperitae
compared with the group of
M. spicata
. They consist of
hydropic degeneration of tubular epithelial cells, epithelial cells with picnotic nuclei and eosinophilic
cytoplasm, enlargement of bowman capsules (Akdogan et al., 2003).
Peppermint oil, pulegone and menthofurane
Short-term toxicity studies demonstrated that peppermint oil (40 and 100 mg/kg b.w. day) and
pulegone (80 and 160mg/kg b.w.day) induced brain lesions in rats at oral doses.
The oral LD
50
of peppermint oil U.S.P. in fasted Wistar male rats after 24 h was found to be 4441±653
mg/kg. After 48h was 2426 mg/kg.
The interest in toxicity of pulegone, menthofuran and peppermint oil appears to have been provoked
by three reports in the literature. It was reported that pulegone, when given to rats for 28 days, caused
histopathological changes in the liver (vacuolisation) and the brain (“cystlike spaces”) (Thorup et al.
1983a,b; Olsen and Thorup, 1984). The histopathological changes were seen in rats receiving 80 and
160 mg/kg/day of pulegone. However, all haematological and clinical chemical parameters were
found to be within the normal range in all groups. There were neither obvious signs of clinical
symptoms due to encephalopathy. Based on these studies the NOEL (no effect level) of pulegone was
considered to be 20mg/kg bw/day. Later “confirmatory” studies by the same group, however, reported
that there were no significant histopathological changes in the liver or the brain. The “cyst-like
spaces” reported in the brain in the earlier studies were thus not confirmed and may have arisen from
inadequate tissue fixation procedures (Molck et al. 1998). In this study the clinical biochemical
examinations revealed increased plasma glucose, alkaline phosphatase and ALAT and a decreased
creatinine in the dosed group. In later studies the liver toxicity of pulegone has been confirmed and a
mechanism of action has been proposed based on its metabolism to menthofuran and other reactive
metabolites, which are the ultimate hepatotoxins (see SCF report on Public statement on the use of
HMP containing pulegone and menthofurane – EMEA/HMPC/138386/2005).
Menthone
The oral toxicity of menthone was evaluated in an animal model. The decrease in plasma creatinine
and the increase in phosphatase alkaline and bilirrubin were dose dependent, after levels of 0, 200, 400
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and 800 mg/kg b. w. /day. The NOEL for menthone in this study was lower than 200 mg/kg b.w. /day.
A NOEL of 400 mg/kg b. w. /day was reported in a 28 day toxicity study in rats (FAO/WHO Expert
Committee on Food Additives, 2000).
Teratogenicity
Menthol
For maximum oral doses of 190, 220, 400, and 430 mg/kg/day, respectively, were not observed
teratogenic effects in mice, rats and hamsters (FAO/WHO expert on Food Additives, 2000).
Reproductive toxicity
The effects of
Mentha piperita
and
Mentha spicata
herbal teas on plasma total testosterone, luteinizing
hormone and follicle-stimulating hormone levels and testicular histologic features were evaluated. The
rats (200-250g) were randomized in four groups of 12 each. The experimental group was given 20g/L
M. piperita
tea, or 20g/L
M. spicata
tea or 40g/L
M. spicata
tea. The group control had commercial
drinking water. The follicle-stimulating hormone and luteinizing hormone had increased and total
levels of testosterone had decreased, comparing with the control group, being statistically significant.
The Johnsen testicular biopsy scores were different but not statistically significant (Akdogan et al.,
2003).
Genotoxicity
A chemopreventive action and a antigenotoxic effect was observed on an evaluation of aqueous
extracts of
Mentha pipe
ritae leaves, when is giving after an initiating dose of benzo[a]pyrene (0,5mg)
in newborn Swiss albino mice (Akdogan et al. 2004a, Samarth et al. 2006).
Six herbal infusions (
Matricaria chamomilla, Tilia cordata, Mentha piperitae, Mentha pulegium,
Uncaria tomentosa
and
valeriana officinalis
) were tested for antigenotoxicity, using the SMART test
in
Drasophila melanogaster
. Hydrogen peroxidase was used as an oxidative genotoxic agent.
The infusion of
M. pulegium
is desmutagenic in the SMART when assayed with hydrogen peroxide in
combined treatments. Both
M. perita
and
M. pulegium
infusions showed similar levels of anti-
genotoxicity (141 and 134%, respectively).
The authors conclude that the results of inhibition obtained for
M.
chamomilla
,
T. cordata
,
M.
piperita
,
M. pulegium
and
V. officinalis
surpassing 100% (ranging from 125 to 141%), can only be
explained by a synergism between their phenolic contents and the hydrogen peroxide due to the
known ability of phenols to scavenge reactive oxygen species such as those generated by hydrogen
peroxide (Romero-Jimenez 2005).
The oil of
Mentha piperitae
is the worst scenario. Peppermint oil was negative in two validated tests
of genotoxicity, the Ames test and the mouse lymphoma assay. Weak and inconsistent genotoxic
responses in other non-validated tests are probably toxicologically inconsequential. There is more
evidence for genotoxicity potential of menthol and there seems to be a discrepancy between
peppermint oil and its most important constituent menthol. However, the present evidence points to a
very weak or totally absent genotoxicity of peppermint oil.
Carcinogenicity
Chemopreventive action
In studies where some agents induced the carcinogenicity, peppermint showed a preventive and a
reduction effect.
A study was performed comparing a powdered tobacco mixture (15g) with and without 15g of
peppermint leaves, on the induction of morphological changes and tumors. These mixtures were
painted onto the cheek pouches of Syrian golden hamsters 3 times/week for 20 weeks. The non-mint
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tobacco mixture increased mucosal thickening (n=20/22 in non mint groups vs 9/15 in mint containing
group), leukoplasia (20/22 vs 3/15) and frank tumors (19/22 vs 0/15) in the oral cavity. 86.3% of the
animals on the group without peppermint present tumor bearing at week 30, while the group with
peppermint had 0% of tumors (Samman et al, 1998).
The results of the study performed by Sameena and Ashoc, on the papilloma-genesis of the skin
induced by 7,12-dimetylbenz (a) anthracene (DMBA) in mice, suggest that there is a
chemopreventive effect of peppermint on the development of skin papillomas, being most effective
during the promotional stage of carcinogenesis (Sameena et al., 2001).
An aqueous extract of
Mentha piperitae
leaves were evaluated by using 9-week medium term model
of benzo[
a
]pyrene-induced lung tumors in new born Swiss albino mice. The number of lung tumors
was reduced, after oral administration of
Mentha
extract, in an inhibition rate of 61, 26% in the
Mentha
treated group with respect to the reference group.
Mentha
extract reduced the frequency of BP
induced chromosomal aberrations and micronuclei in bone marrow cells and decreased the levels of
lipoperoxides and increased sulphydryl groups in liver and lung (Samarth et al, 2006). .
The effects of peppermint extracts against sub-lethal and lethal doses of gamma radiation in Swiss
albino mice were tested in several studies. Pretreatment with an aqueous extract of peppermint prior to
the radiation (whole body), 1g/kg administered 3 days before the irradiation with 8 Gy, increased the
hematological parameters. The survival rate was also better on the pretreatment group compared with
the irradiated control, 10 days post-irradiation (Samarth et al., 2004).
The serum alkaline phosphatase was increased and the acid phosphatase decreased, using the same
protocol, compared with the control, after irradiation, returning to normal after 5 days (Samarth at al.,
2002).
The intestinal mucosa of mice suffered increased villus heigh, total number of mitotic cells, and
decreased the number of goblet and dead cells after taking 1g/Kg peppermint extract, within 20 days
post-irradiation at 8 Gy (Mckay, 2006).
2.4.4
Assessor’s overall conclusions on safe use
On the studies performed were observed antimutagenic, anti-genotoxic and chemopreventive effects,
after the induction of several agents.
Toxicity tests in animals have not given cause for concern, with the recommended dosage range.
3
Pharmacological properties
3
3.1
Overview of pharmacological effects of herbal substance(s), herbal preparation(s)
and relevant constituents thereof on the basis of long-standing use and experience
Composition
The chemical components of peppermint leaves vary with plant maturity, variety, geographical region
and processing conditions. The fatty acid composition of the non-polar lipid fraction of peppermint
leaves is dominated by palmitic (16:0), linoleic (18:2) and linolenic (18:3) acids (Mackay, 2006).
The main active component is the essential oil. Its major constituents are menthol (30-55%) and
menthone (14-32%). Other monoterpenes present are limonene (1-5%), cineole (3, 5-14%),
menthofuran (1-9%), isomenthone (1,5-10%), menthyl acetate (2,8-10%), pulegone (until 4%),
carvone (until 1%) with a ratio of cineole content to limonene content greater than 2.
3
Not required as per Article 16c(1)(a)(ii) of Directive 2001/83/EC as amended
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Various flavonoids are present including luteolin and its 7-glycoside, rutin, hesperidin, eriocitrin and
highly oxygenated flavones. Other constituents include phenolic acids and small amounts of
triterpenes (ESCOP 2003, Julien et al 1984, Litvinenko et al 1975, Croteau, Loomis 1973).
Eriocitrin, with a concentration range of 6.6-15.0%, is the dominant flavonoid glycoside, accompanied
by luteolin 7-
0
-rutinoside, hesperidin and rosmarinic acid, on a study of 40 clones of
Mentha piperita
(Nair B., 2001).
About 75% of the polyphenolic compounds present in the leaves are extracted in an infusion (Mackay,
Blumberg 2006).
The leaves contain 1.2 – 3.9% (v/w) essential oil (Blumenthal
et al
.). The cut drug contains not less
than 9 mg/kg of essential oil (ESCOP).
An infusion of dried leaves is reported to contain 21% of the original oil (25mg/L) (Duband et al,
1992).
a.
In vitro
studies
Antioxidant
The antioxidant capacity of peppermint has been determined using of different assay methods. Among
some medicinal herbs,
Mentha piperitae
leaves showed a high oxygen radical absorbance capacity
(ESCOP).
Antimicrobial
A significant antiviral activity was reported in aqueous extracts of peppermint leaves towards
Influenza A, Newcastle disease virus, Herpes simplex virus and Vaccinia virus, in egg and cell culture
systems (Herrmann, Kucera, 1967). The antibacterial and fungicidal activity was demonstrated in
several studies, especially with peppermint oil.
The inhibition of the growth of
Salmonella typhimurium
,
Staphylococcus aureus
and
Vibrio
parahaemolyticus
were achieved with addition of ground leaves to the agar medium at concentrations
of 0,1-2,0% (w/v) (Aktug, Karapinar, 1986)
On another study was observed the reduction of the number of plaques of the rinderpest virus with
aqueous and ethanol extracts of the leaves of
Mentha piperita
, at concentrations of 4-8mg/ml (Alwan
AH et al, 1988).
Antispasmodic
Among other studies, alcoholic extracts of Peppermint leaf have antispasmodic effects on the isolated
guinea pig ileum. 2.5 and 10.0 ml/litre of a Peppermint leaf extract (1:3.5, ethanol 31% w/w) were
tested using acetylcholine and histamine as spasmodic agents. Both doses produced a significant
increase of the ED
50
, for acetylcholine and histamine-induced contractions and a significant decrease
of the maximum possible contractility. The effect obtained with 10.0 ml/litre corresponded to that of
0.13 mg atropine (effective dose of atropine in the treatment of abdominal spasms: 0.5 - 1.0 mg)
(Forster et al, 1980, 1983).
Flavonoids isolated from Peppermint leaf and dissolved in water, so that 1 ml corresponded to
approximately 0.5 g of dried leaf, inhibited muscular contraction of the guinea pig ileum induced by
barium chloride (Lallement-Guilbert et al, 1970).
Aqueous extracts of
Mentha piperitae
showed a significant, dose dependent relaxation effect on
isolated rabbit duodenum (Mahmood et al, 2003), being the dried leaf extract more effective than the
fresh one.
The mode of action on gastric motility of a combination (Iberogast ®) and its individual components
(hydroethanolic herbal extracts from
Iberis amara totalis
,
Menthae piperitae folium
– 1:2.5-3.5,
Matricariae flos, Liquorice root, Angelica radix, Carvi fructus, Cardus marianus fructus, Melissae
folium
and
Chelidonium herba
) was studied. Peppermint leaf extract did not show consistent responses
in the proximal stomach, inducing relaxation and contraction (Schemann et al, 2006).
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On another study in vitro model, was used the same product and some of its isolated compounds. The
study was performed to test their activity on histamine-induced contractions and spontaneous motility,
of intestinal samples from guinea pig.
Mentha piperita
leaves, as
Iberis amara
,
Melissa folium
had
significant effects on decreasing the contraction amplitude (Heinle et al, 2006 ).
b.
In vivo
studies
Gastrointestinal action
In experiments with cannulated dogs Peppermint tea (0.4 g/kg body weight) increased the secretion of
bile. Flavonoids, as well as the essential oil, seemed to contribute to this action (Steinegger et al 1992,
Pasechnik 1967).
Mixed flavonoids from Peppermint leaf (optimum dose 2 mg/kg,), showed choleretic activity in dogs.
Flavomentin, a flavonoid preparation from Peppermint leaf, stimulated bile secretion and the synthesis
of bile acids in dogs at doses of 0.5-6 mg/kg (optimum 2 mg/kg) (Pasechnik 1967).
In experiments with cannulated rats, intravenous injection of 0.5 ml of a Peppermint tea (1:5) per rat
or a flavonoid preparation (dosage corresponding to 3.3 g of Peppermint leaf per kg) proved effective
in increasing the amount of bile acids (Lallement-Guilbert et al, 1970).
The carminative action is due to a reduction in tonus of the oesophageal sphincter by Peppermint leaf
extracts, enabling release of entrapped air (ESCOP).
In the large intestine of pigs, peppermint extract and L-methionine reduced the production of volatile
sulphur compounds by the metabolism of intestinal bacteria (ESCOP). In another study (Ando et al,
2003), Holstein steers fed with peppermint, there were lower concentrations in the rumen of ammonia
nitrogen and reduction of the numbers of protozoa.
On the article (Mckay and Blumberg, 2006) where the bioactivity of peppermint was reported, a study
of female Wistar rats demonstrated modulatory effects of peppermint tea on selected hepatic phase I
metabolising enzymes. The pre-treatment with a 2% solution for 4 weeks (
n
= 5), the activities of
cytochrome P450 isoforms CYP1A2 (24%) and CYP2E (48%) were significantly reduced, compared
with a control group.
The potential antiulcerogenic, antisecretory and cytoprotective activity of the combination (Iberogast
®) and its individual components (hydroethanolic herbal extracts from
Iberis amara
totalis,
Menthae
piperitae
folium [containing 0,44 menthol and menthone]
Matricariae
flos, Liquorice root, Angelica
radix, Carvi fructus, Cardus marianus fructus,
Melissae
folium and
Chelidonium
herba) were tested in
male Wistar rats. A modified formulation of the combination was also tested, taking out three
components. Gastric ulcers were induced acutely by indometacin and cimetidine was used as a
reference anti-ulcerogenic. The parameters used were the free acidity, mucin and pepsin
concentrations in the gastric juice, and the prostaglandin and leukotriene levels in the gastric mucosa.
The stomach was histologically examined. Both preparations and their individual components protect
the stomach from the ulcerative damage caused by indomethacin, inhibiting the release of aggressive
factors like acid and leukotrienes, promoting the production of mucin and prostaglandins. This effect
could be attributed, according to the authors, to the presence of flavonoids (Khayal et al, 2001).
Antiallergic action
A study was performed to clarify the effects of extracts of the leaves and stems of
Mentha piperita
L.
on experimental allergic rhinitis. The extraction process includes the removal of essential oil, fat,
followed by fractionation. This 50% ethanol extract had an effect, which was dose-dependent, on the
inhibition of histamine release from rat peritoneal mast cells. The compound 48/80 induced this
reaction and the inhibition was observed at a concentration of 3µg/ml. The water, 50% ethanol eluate,
separated by column Chromatography also shows a similar effect at a dose of 1µg/ml. The oral
administration of 50% EtOH inhibited sneezing and nasal rubbing induced by antigen-antibody
reaction. The repeated administration was more effective than a single administration (Inoue et al,
2001).
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Following these results, the same authors studied the antiallergic effect of the flavonoid glycosides
obtained from
Mentha piperita
L. Among the flavonoids isolated from the aerial part of M. piperita L.,
luteolin-7-0-rutinoside showed a dose-related inhibitory effect of an antigen induced nasal response at
doses of 100 and 300 mg/kg
NCS action
An aqueous extract of Peppermint leaf (50 g of dried leaf infused for 10 min in 500 ml hot water, then
spray-dried) administered orally in 2 single doses of 300 mg/kg and 1000 mg/kg in 16 mice showed a
weak sedative action in several tests: hexobarbital-induced sleep, exploratory behaviour, spontaneous
motility and motor coordination.
The peppermint extract, at a dose of 1000 mg/kg causes in rats, in the behavioural tests, a biphasic
effect with initial stimulation, followed by depression. It seems that the effect observed is due to the
oil contained in the extract. At a lower dose, 300mg/kg, the excitatory response is too weak and
transient, and only the depressive effect is recorded
The same Peppermint leaf extract, administered in the same two doses, showed a weak diuretic effect
in mice (Della Logia et al, 1990).
Diuretic action
The effect of peppermint on diuresis is weak. The effective dose is about 30 times higher than that of
aminophylline. At 1000 mg/kg oliguria was observed (Della logia et al, 1990).
c. Clinical studies
(in combinations)
Controlled studies
The efficacy and safety of the STW 5-II for the treatment of functional dyspepsia was assessed on a
double blind, randomized, placebo controlled, multicentre trial, for 4 week treatment blocks. STW 5-II
is a herbal combination of fresh plant extract ( 1:2, 50% v/v ethanol)of
Iberis amara totalis
and
extracts (1:3, 30% v/v ethanol) of matricaria flower (
Matricarae flos
, 30ml), peppermint leaves
(
Menthae piperitae
folium
, 30ml), caraway (C
arvi fructus
, 20 ml), licorice root (
Liquiritiae radix
,
10ml) and lemon balm (
Melissa folium
, 15 ml). 120 patients with recurrent and persistent dyspepsia
for 6 months (Rome I criteria) were recruited in hospitals and private practice by gastroenterologists.
The primary outcome measure was the improvement of a standardized gastrointestinal score (GIS),
which decreased in patients on the active treatment compared to placebo (p<0,001). Symptoms
improved on the next 4 weeks, also for the patients who switched to the active treatment, and got
worse on those who switched to placebo (Madisch et al, 2004).
Meta-analysis
Six randomized-controlled trials of STW 5(Iberogast) were identified for functional dyspepsia. Three
of them were placebo-controlled studies, met the inclusion criteria, and were included for this study.
One reference –controlled study supported the safety analysis. According to the authors, STW 5
demonstrated to be a valid therapeutic option for functional dyspepsia, considering efficacy and safety
(Melzer et al, 2004).
3.2
ASSESSOR’S OVERALL CONCLUSIONS
Mentha piperita
leaves is a well known and a traditional herbal medicinal product used for centuries in
the European countries.
There is enough literature to demonstrate its use for medicinal purposes
,
for the symptomatic
treatment of digestive disorders.
The pharmacological studies in vitro and in vivo showed antispasmodic effects of the smooth muscle
of the digestive tract, choleretic activity, and reduction in tonus of the oesophageal sphincter enabling
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the release of the entrapped air. Other studies indicate that there is a dose dependent analgesic and
anti-inflammatory action.
There are no clinical studies on the efficacy of
Menthae piperitae folium
alone, but just in combination
with other plants, given no reason for the inclusion on the well-established use.
The clinical studies of the essential oil, have demonstrated efficacy for the symptomatic relief of
minor spasms of the gastrointestinal tract, flatulence and abdominal pain,
These results support the therapeutic indication for the long-standing use of
Menthae piperitae folium
in digestive disorders, on the doses and preparations recommended and used traditionally:
-
Symptomatic relief of digestive disorders such as dyspepsia and flatulence.
ANNEXES
COMMUNITY HERBAL MONOGRAPH ON
MENTHA X PIPERITA
L., FOLIUM
LITERATURE REFERENCES
©
EMEA 2008
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Source: European Medicines Agency
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