COMMUNITY HERBAL MONOGRAPH ON
MENTHA x PIPERITA
L., AETHEROLEUM
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the marketing authorisation
application of Article 10(1)(a)(ii) of Directive
2001/83/EC as amended
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Mentha x piperita
L., aetheroleum (peppermint
oil)
Mentha x piperita
L., aetheroleum (peppermint
oil)
i) Herbal substance
not applicable
i) Herbal substance
not applicable
ii) Herbal preparation
ii) Herbal preparation
Essential oil obtained by steam distillation from
the fresh aerial parts of the flowering plant.
Essential oil obtained by steam distillation from
the fresh aerial parts of the flowering plant.
Well-established use
Traditional use
In gastro–resistant capsules (for oral use).
In liquid or semi-solid preparations
•
For cutaneous and transdermal use
•
For inhalation.
•
For oromucosal use
In liquid or semi-solid preparations (for cutaneous
use).
The pharmaceutical form should be described by
the European Pharmacopeia full standard term.
The pharmaceutical form should be described by
the European Pharmacopeia full standard term.
1
The material complies with the Ph. Eur. monograph (ref. 01/2005:0405)
2
The declaration of the active substance(s) for an individual finished product should be done in accordance with relevant
herbal quality guidance.
©
EMEA 2007
2/10
Well-established use
•
Oral use
1.
Herbal medicinal product for the
symptomatic relief of minor spasms of the
gastrointestinal tract, flatulence and
abdominal pain, especially in patients with
irritable bowel syndrome.
•
Cutaneous use
2.
Herbal medicinal product for the
symptomatic relief of mild tension type
headache.
Traditional use
Traditional herbal medicinal product
•
Cutaneous and transdermal use
1.
For the relief of symptoms in coughs and
colds
2.
For the symptomatic relief of localised
muscle pain
3.
For the symptomatic relief of localised
pruritic conditions in intact skin
•
Inhalation
4.
For the relief of symptoms in coughs and
colds
•
Oromucosal use
5.
For the relief of symptoms in coughs and
colds
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
Posology
•
Oral use
The use in children under 2 years of age is
contraindicated (see 4.3 Contraindications).
The use is not recommended in children under
8 years of age (see 4.4 Special warnings and
precautions for use).
The use is not recommended in children between
2 to 4 years of age (see 4.4 Special warnings and
precautions for use).
Adolescents over 12 years of age, adults,
elderly
0.2 - 0.4 ml in gastro-resistant capsules up to
three times daily.
•
Cutaneous and transdermal use
-
Indications 1, 2 and 3
Children between 8 to 12 years of age
0.2 ml in gastro resistant capsules, up to three
times daily.
•
Cutaneous use
Single dose
Children between 4 to 10 years of age
Semi-solid preparations 2 - 10%
Hydroethanolic preparations 2 - 4%
Children between 10 to 12 years of age,
adolescents between 12 to 16 years of age
Semi-solid preparations 5 - 15%
Hydroethanolic preparations 3 - 6%
up to three times daily
The use is not recommended in children and
adolescents under 18 years of age (see 4.4
Special warnings and precautions for use).
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Adults, elderly
In liquid or semi-solid preparations 10% in
ethanol, up to three times daily.
Adolescents over 16 years of age, adults
Semi-solid and oily preparations 5 - 20%
In aqueous-ethanol preparations 5 - 10%
In nasal ointments 1 - 5% essential oil.
•
Inhalation
-
Indication 4
Duration of use
•
Oral use
Adolescents over 12 years of age, adults
2 - 4 drops up to three times daily
•
Oromucosal use
-
Indication 5
The gastro-resistant capsules should be taken
until symptoms resolve, usually within one or
two weeks. At times when the symptoms are
more persistent, the intake of gastro-resistant
capsules can be continued for periods of no
longer than 3 months per course.
2 - 3 drops (0.08 - 0.12 ml), 3 - 4 times per day
(0.2 - 0.5 ml)
•
Cutaneous use
If symptoms persist or worsen after 2 weeks, a
physician should be consulted.
Duration of use
-
Indications 1, 4 and 5
Method of administration
Not to be used for more than 2 weeks.
-
Indications 2 and 3
•
Oral use
The capsule must be taken before meals.
It is not recommended to use the medicinal
product continuously for more than 3 months.
If the symptoms persist during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
•
Cutaneous use
The solution should be rubbed on the skin of
the forehead and temples, every 15 minutes.
Method of administration
•
Cutaneous and transdermal use
-
Indication 1
Application on the chest or on the back
-
Indications 2 and 3
Application on the affected area
•
Inhalation
The essential oil is added to hot water and the
vapour is inhaled. Alternatively, the essential
oil can be added on an appropriate
support/material and the vapour is inhaled.
•
Oromucosal use
In lozenges or oral spray.
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4.3 Contraindications
Well-established use
Traditional use
•
Oral use
Children under 2 years of age, because menthol
can induce reflex apnoea and laryngospasm.
Hypersensitivity to peppermint oil or menthol.
Patients with liver disease, cholangitis,
achlorhydria, gallstones and any other biliary
disorders.
Children with history of seizures (febrile or not).
Hypersensitivity to peppermint oil or menthol.
•
Cutaneous use
Hypersensitivity to peppermint oil or menthol.
4.4 Special warnings and precautions for use
Well-established use
Traditional use
•
Oral use
The use is not recommended in children under
8 years of age, as there is no sufficient
experience available.
The capsules should be swallowed whole, i.e.
not broken or chewed, because this would
release the peppermint oil prematurely,
possibly causing local irritation of the mouth
and oesophagus.
Patients, who already suffer from heartburn or
hiatal hernia have sometimes an exacerbation
of this symptom after taking peppermint oil.
Treatment should be discontinued in these
patients.
The use is not recommended in children between
2 to 4 years of age, as there is no sufficient
experience available.
•
Cutaneous and transdermal use
Eye contact with unwashed hands after the
application of peppermint oil, may potentially
cause irritation.
Peppermint oil should not be applied on broken
or irritated skin.
•
Oromucosal use
Patients, who already suffer from heartburn or
hiatal hernia have sometimes an exacerbation of
this symptom after taking peppermint oil.
Treatment should be discontinued in these
patients.
Peppermint oil should be used with caution in
inflamed and ulcerated conditions of the
gastrointestinal tract.
•
Cutaneous use
The use is not recommended in children and
adolescents under 18 years of age.
Eye contact with unwashed hands after the
application of peppermint oil may potentially
cause irritation.
4.5 Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
•
Oral use
None reported.
Use of food or antacids administered at the
same time could cause early release of capsule
content. Other medicinal products used to
decrease stomach acid, like histamine-2
blockers and proton pump inhibitors may cause
premature dissolution of the enteric coating and
should be avoided.
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4.6 Pregnancy and lactation
Well-established use
Traditional use
•
Oral use
Studies in animals have shown no teratogenic
effects.
It is unknown if peppermint constituents are
excreted in human breast milk. In the absence
of sufficient data, the use during pregnancy and
lactation is not recommended.
•
Cutaneous and transdermal use
•
Inhalation
•
Oromucosal use
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
•
Cutaneous use
Data on the use during pregnancy and lactation
is not available. As a general precaution, the
use is not recommended, unless medical advice
proposed benefit is higher than the potential
risk.
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
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
•
Oral use
Urine and stools with an odour to menthol were
observed; dysuria and inflammation of the
glans of the penis have been reported. The
frequency is not known.
•
Cutaneous and transdermal use
Hypersensitivity reactions such as skin rash,
contact dermatitis, and eye irritation have been
reported. These reactions are most of the time
mild and transient. The frequency is not known.
Irritation of the skin and mucosa of the nose is
possible, after local application. The frequency
is not known.
Allergic reactions to menthol were reported,
with headache, bradycardia, muscle tremor,
ataxia, anaphylactic shock and erythematous
skin rash. The frequency is not known.
•
Inhalation
Apnoea, broncho- and laryngoconstriction in
hypersensitive patients have been reported.
The frequency is not known.
Heartburn, perianal burning, blurred vision,
nausea and vomiting were reported. The
frequency is not known.
•
Cutaneous use
Hypersensitivity reactions such as skin rash,
contact dermatitis, and eye irritation have been
reported. These reactions are the most of the
time mild and transient.
If other adverse reactions not mentioned above
occur, a doctor or a pharmacist should be
consulted.
•
Oromucosal use
Contact sensitivity to menthol and peppermint
oil in patients presenting with intra-oral
symptoms in association with burning mouth
syndrome, recurrent oral ulceration or a
lichenoid reaction, were reported. The
frequency is not known.
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Allergic reactions to menthol were reported,
with headache, bradycardia, muscle tremor,
ataxia, anaphylactic shock and erythematous
skin rash. The frequency is not known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
professional should be consulted.
4.9 Overdose
Well-established use
•
Oral use
Overdose may cause severe gastro-intestinal
symptoms, diarrhoea, rectal ulceration,
epileptic convulsions, loss of consciousness,
apnoea, nausea, disturbances in cardiac
rhythms, ataxia and other CNS problems,
probably due to the presence of menthol.
In the event of overdose, the stomach should be
emptied by gastric lavage. Observation should
be carried out with symptomatic treatment if
necessary.
Traditional use
•
Cutaneous and transdermal use
No case of overdose has been reported.
•
Inhalation
Inhalation of large doses of menthol may lead
to dizziness, confusion, muscle weakness,
nausea and double vision.
•
Oromucosal use
Overdose may cause severe gastro-intestinal
symptoms, diarrhoea, rectal ulceration,
epileptic convulsions, loss of consciousness,
apnoea, nausea, disturbances in cardiac
rhythms, ataxia and other CNS problems,
probably due to the presence of menthol.
In the event of overdose, the stomach should
be emptied by gastric lavage. Observation
should be carried out with symptomatic
treatment if necessary.
5.1 Pharmacodynamic properties
Well-established use
Traditional use
•
Oral use
Pharmacotherapeutic group:
Other drugs for
functional bowel disorders
ATC code:
AO3AX
In vitro
studies
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
The principal pharmacodynamic effect of
peppermint oil relevant to the gastrointestinal
tract is a dose-related antispasmodic effect on
the smooth musculature, due to the interference
of menthol with the movement of calcium
across the cell membrane.
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Peppermint oil showed antifoaming and
carminative activity
in vitro.
Reductions in
gastric and intestinal foam volume were
observed
in
vitro
studies with peppermint oil.
In vivo
studies
In several studies in healthy subjects or
patients, who underwent exposure to
peppermint oil either by topical intraluminal
(stomach or colon) or oral administration by
single doses, result in effects, indicating a
substantial spasmolytic action of peppermint
oil on the smooth muscles of the
gastrointestinal tract.
The enteric coating delays the release of the
product until it reaches the distal small bowel,
exerting local effects of colonic relaxation.
Peppermint appears to enhance production of
bile. The choleretic and antifoaming effects of
peppermint oil play an additional role to the
antispasmodic action, decreasing the
abdominal distension, as the discomfort and
abdominal pain.
•
Cutaneous use
Pharmacotherapeutic group:
Other local
anesthetics
ATC code:
N01BX
The topical application of peppermint oil,
produces a prolonged cold sensation at the
local of application, by the stimulation of the
cold-sensitive receptors, giving an analgesic
effect.
The application to the forehead showed on the
EMG activity, a significant reduction of the
M temporalis wave, as a pronounced increase
in blood flow through the capillaries of the skin
5.2 Pharmacokinetic properties
Well-established use
Traditional use
•
Oral use
Menthol and other terpene constituents of
peppermint oil are fat soluble and rapidly
absorbed at the proximal small intestinal tract.
To some extent, they are excreted in the form
of glucoronide. The peak menthol urinary
excretion levels were lower and secretion
delayed with the modified-release preparations,
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended
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than with the immediate release preparations.
In one clinical study with peppermint oil and
one clinical study with menthol, some
inhibition of CYP3A4 activity has been
described. Further investigations are necessary.
•
Cutaneous use
The systemic absorption after dermal
application was examined and concentration
time profiles were erratic and variable and the
half-lives relatively shorts.
5.3 Preclinical safety data
Well-established use
Traditional use
Peppermint oil was negative in two validated tests
of genotoxicity, the Ames test and the mouse
lymphoma assay. 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.
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.
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.
The highest recommended daily dose in EU is
1.2 ml peppermint oil i.e. 1,080 mg peppermint
oil, which contains maximum 140 mg pulegone +
menthofuran (Ph Eur). For a 60 kg person this
would correspond to a daily intake of 2.3 mg/kg
bw. No cases of liver damage caused by
peppermint oil or mint oil were reported under that
posology
(see SCF report referred to in the HMPC
‘Public statement on the use of herbal medicinal
products containing pulegone and menthofurane’
(EMEA/HMPC/138386/2005)).
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 and 800 mg/kg bw/day. The non-
observable-effect-level (NOEL) for menthone in
this study was lower than 200 mg/kg bw/day. A
NOEL of 400 mg/kg bw/day was reported in a
28 day toxicity study in rats.
In 2000, the FAO/WHO Joint Expert Committee
on Foods Additives established an acceptable daily
intake (ADI) of 0 - 4 mg/kg bw/day for menthol.
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Well-established use
Traditional use
Not applicable.
Not applicable.
31 October 2007
©
EMEA 2007
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Assessment Report
I.
REGULATORY STATUS OVERVIEW
MA: Marketing Authorisation;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ’Not Known’
Member State Regulatory Status
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify:
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify:
Italy
MA
TRAD
Other TRAD
Other Specify:
Food supplements
Latvia
MA
TRAD
Other TRAD
Other Specify:
Natural products
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:
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
©
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II.
ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL
PREPARATION(S) OR COMBINATIONS THEREOF WITH
WELL-ESTABLISHED USE
Mentha x piperita
L., aetheroleum
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
Mentha x piperita
L., aetheroleum
Herbal preparation(s)
Menthae piperitae aetheroleum
Pharmaceutical forms
Liquid dosage forms
Rapporteur
Dr Helena Pinto Ferreira
Dr Ana Paula Martins
©
EMEA 2008
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1
INTRODUCTION
Peppermint is believed to be a hybrid of spearmint (
Mentha spicata
L
.)
and water mint (
Mentha
aquatica
L
.)
(Murray, Lincoln and Marble, 1972).
It has been a popular domestic remedy for at least two centuries. The essential oil is obtained from the
fresh leaves of
Mentha piperita L.
by steam distillation and its most active product available in most
parts of the world for flavouring, cosmetic and medicinal uses.
The English Dictionary of Medicinal and Surgical Knowledge, in 1800, already considered
peppermint oil as “an aromatic stimulant to allay nausea, relieve spasmodic pain to the stomach and
the bowels, expel flatus or cover the taste or the quality of gripping effects of other medicine”
The activity of peppermint oil and of its major constituent, menthol, have been subject to a series of
pharmacological and clinical studies. Several medicinal products have been authorized for the relief of
digestive disorders, to reduce spasms of the smooth muscles, for neuralgic pains and for colds and
coughs, given orally or topically.
This monograph gives the result of the literature available on the efficacy and safety of peppermint oil,
for well-established use.
1.1
Description of the herbal substance(s), herbal preparation(s) or combinations
thereof
Mentha x piperita
L., aetheroleum
Herbal preparation(s)
1 2
:
Menthae piperitae aetheroleum
1.2
Information on period of medicinal use in the Community regarding the specified
indication
2
NON-CLINICAL DATA
For all studies cited, 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
Pharmacology
2.1.1
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
1
According to “Note for guidance on Quality of herbal medicinal products” (CPMP/QWP/2819/00…)
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)
3
According to the Guideline on the clinical assessment of fixed combinations of herbal substances/herbal preparations
(EMEA/HMPC/166326/2005)
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Major chemical constituents
The 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.
Antispasmodic action on the smooth muscle
Peppermint oil as a 1 % emulsion exhibited relaxant effects on tracheal smooth muscle of the guinea
pig: the I
50
was 83-91 mg/L.
Peppermint oil emulsified with tween, 1% in aqueous solution, relaxed chemically contracted guinea
pig taenia coli (I
50
: 22.1 μg/mL) and inhibited spontaneous activity in the guinea pig colon (I
50
: 25.9
μg/mL) and rabbit jejunum (I
50
: 15.2 μg/mL). Using whole cell clamp configuration in these jejunal
muscle cells, the potential –dependent calcium currents were inhibited in a dose-dependent manner by
peppermint oil. Peppermint oil reduced the peak current amplitude and increased the rate of current
decay, indicating a reduction of calcium influx similar to that caused by dihydropyridine calcium
antagonists. Peppermint oil demonstrated to inhibit non-competitively 5 –hidroxitriptamine (serotonin)
and the substance P induced smooth muscle contraction (Hills JM et al, 1991).
Both menthol and peppermint oil inhibited specific [3H] nitrendipine and [3H] PN 200-110 binding to
smooth and cardiac muscle and neuronal preparations with potencies comparable to, but slightly lower
than, those measured in the pharmacological and 45Ca2+ uptake experiments. Binding of menthol and
peppermint oil, studied at 78 micrograms ml-1, was competitive against [3H] nitrendipine in both
smooth muscle and synaptosome preparations. The data indicate that both menthol and peppermint oil
exert Ca2+ channel blocking properties which may underlie their use in irritable bowel syndrome. The
authors conclude that Ca2+ channel antagonism may not be the only pharmacological effect of
menthol and peppermint oil contributing to intestinal smooth muscle relaxation
(
Hawthorn M
et al, 1988).
Another study made experiments on male guinea pigs concerning the pharmacological activity of
essential oils on Oddi`s sphincter. Oddi`s sphincter prolapses through i.v. injection of
Mentha piperita
L.
(
Anon, 1990).
Peppermint oil appears to enhance production of bile. In experiments where bile flowed out of a
cannula from an anaesthetized dog, an infusion of peppermint leaves (0.4 g/kg) enhanced bile
production. Menthol also produced an enhancement of bile production: 0.06 g/kg in 1 dog and 0.1-1.0
g/kg in rats.
In others experimental studies in animals, menthol and peppermint oil induced a marked and dose
related choleresis (Siegers C., Guo Z., Pentz R, 1991).
Ant carminative activity
Peppermint oil showed antifoaming and carminative activity in vitro. Reductions in gastric and
intestinal foam volume were observed in vitro studies with peppermint oil. The carminative effect
results from a combination of actions. Antifoaming activity associated to the relaxation of the
oesophageal sphincter may release the gastric gas. The antimicrobial
activity
helps to reduce the
intestinal gas
(Harries N., James K., Pugh W, 1978)
Analgesic action
To characterize the effects of peppermint and caraway oil individually and in combination on the
visceral nociception in a rat model of post-inflammatory hyperalgesia, a study was performed. 28 male
Lewis rats were randomized to treatment with a rectal administration of trinitrobenzene sulphonic acid
(TNBS)/ethanol or physiological saline solution. After 14 days of treatment with peppermint and/or
caraway oil, a reduced visceromotor response was found of up to 50 % compared to placebo.
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Individually both oils had no significantly effect on post-inflammatory visceral hyperalgesia (Adam B
et al, 2006).
Studies have demonstrated that rodents who lay down in bedding that was soaked in peppermint oil
show a pain relief response compared with those who lay in control bedding.
On another study in identified Helix neurons, the authors indicate a modulating action of external
menthol on Ca inactivation (
Hawthorn M
et al, 1988)
Virucidal, antimicrobial and antiplasmid action
The virucidal effect
in vitro
was assessed on a study, where the inhibitory activity against herpes
simplex (type 1 and type 2) was tested. A plaque reduction assay was used with RC-37 cells, where
the HSV-1 and 2 were grown. Peppermint oil was dissolved in ethanol (1% final concentration of
ethanol) and added to the cell culture medium, at the non-toxic concentration of 0, 01%. To determine
the antiviral action, cells were pre-treated with peppermint oil before the infection, viruses were
incubated with peppermint oil before infection and cells and viruses were incubated together during
adsorption or after penetration of the virus into the host cells. All these experiments were performed in
parallel with acyclovir to test the suitability of the assay and were compared to untreated controls.
Ethanol had no effect on virus titters and did not exhibit any toxic effect on the cells. At non-cytotoxic
concentration of the oil, 0, 01% peppermint oil, the titres of HSV-1 and 2 reduced 82% and 92%
respectively. Higher concentrations reduced virus titters for more than 90 %. The 50% inhibitory
concentration (IC
50
) of peppermint oil was determined at 0,002% and 0, 0008% for HSV-1 and 2. The
peppermint oil affected the virus before adsorption, exerting a direct effect on the virus. Not after
penetration into the host cell (Dresser et al, 2002).
Peppermint oil showed antimicrobial and antiplasmid activity, demonstrating a synergistic additive
interaction with oxytetracycline (Schelz Z, 2006).
Bronchomucotropic activity
Menthol
Menthol (1mg of menthol/kg added to the water vaporizer, corresponding to systemic absorption of
not over 20 μg/kg body weight) was given to rabbits anesthetised with urethane. It augmented the
soluble mucus content and lowered the specific gravity of respiratory tract fluid. The author concludes
that the bronchomucotropic effects were due to direct local stimulation of mucus secreting cells in the
respiratory tract. Inhalation of larger amounts of menthol depressed the volume output and mucus
content of respiratory tract fluid (Boyd., Sheppard , 1969).
On several old studies peppermint oil was reported to depress ciliary activity, but there are some other
studies where PO markedly stimulated it (Das, Rathor, Sinha, Santal, 1970) .
Using VapoRub vapours in a study, where animals were exposed continuously to 30 times the relative
peak clinical atmospheric concentrations of the product, no significant suppression of pulmonary
bactericidal activity was observed (Jakab, Green, 1975).
Interactions
Peppermint oil has demonstrated competitive antagonism at calcium channels in animals and in vitro.
On a theoretical point of view, the calcium channels blockers effectivity may be modified.
Peppermint oil was reported to inhibit cytochrome P450 3A (CYP3A) activity in rat and human liver
microsomes and to enhance the oral bioavailability of the CYP3A4 substrate felodipine in people
(Dresser et al, 2002).
A study compared the effects of peppermint oil with ketoconazole and D-alpha-tocopheryl poly
(ethylene glycol 1000) succinate (TPGS), on the inhibition of cyclosporine oral bioavailability in rats.
Peppermint oil (100mg/kg) tripled the mean cyclosporine maximum concentration. The author
©
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suggests that inhibition of cytochrome P450 3A is not the only mean by which peppermint oil
enhances cyclosporine bioavailability (Wacher et al, 2002).
Peppermint oil demonstrated to enhance 46-fold increase the penetration of 5-fluorouracil, in a study
using excised rat skin (Abdullah et al 1996
)
.
2.1.2
Assessor’s overall conclusions on pharmacology
Peppermint showed in vitro and in vivo studies, to have antispasmodic activity on the gastrointestinal
smooth muscle. The mechanism seems to be related to the reduction of the calcium influx and the
block of non-competitive contraction induced by 5-hidroxytriptamine.
Peppermint appears to have antiseptic properties in vitro and cholagogic action in vivo, but had no
significantly effect on post-inflammatory visceral hyperalgesia.
The bronchomucotropic effects were contradictory, with depressing and stimulatory action of mucus
secreting cells in the respiratory tract.
The competitive antagonism at calcium channels in animals and in vitro raises the possibility of
interaction with other calcium blockers.
The reversible inhibition of cytochrome P450 3A was reported in vitro and in vivo, requiring further
investigation.
Cyclosporine maximum concentration may increase, with the action of peppermint oil. Topically,
peppermint oil increased the penetration of 5-fluorouracil.
2.2
Pharmacokinetics
2.2.1
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
Dermal absorption
The absorption rate for Peppermint oil was measured after the application of eserine in a peppermint
oil vehicle, to a 2.2cm
2
shaved area on the abdomen of mice. The latent period between application
and the eserine-induced signs, gave the absorption rate of peppermint oil, which was of 58 minutes
(Final report on the Safety Assessment of Mentha Piperita, 2001)
Inhalation
Pulmonary absorption depends on various factors, like the kind of compound and the breathing
mechanics of the subjects. In one study, it was demonstrated that the release of compounds from water
into the headspace depended on water temperature.
Elimination half lives for inhalated menthol and camphor were 35, 5 and 39,9min respectively. This
indicates that there should be no accumulation during long-term application (Kohlert et al, 2000).
Oral absorption and metabolism
The major biliary metabolite is menthol glucuronide, which undergoes enterohepatic circulation.
Metabolism of l-menthol in rats was investigated both
in vivo
and
in vitro
. Metabolites isolated and
characterized from the urine of rats after oral administration (800 mg/kg of body weight/day) of l-
menthol were the following: p-menthane-3, 8-diol (II), p-menthane-3, 9-diol (III), 3, 8-oxy-p-
menthane-7-carboxylic acid (IV), and 3, 8-dihyroxy-p-menthane-7-carboxylic acid (V).
In vivo
, the
major urinary metabolites were compounds II and V. Repeated oral administration (800 mg/kg of
body weight/day) of l-menthol to rats for 3 days resulted in the increase of both liver microsomal
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cytochrome P-450 content and NADPH-cytochrome c reductase activity by nearly 80%. Further
treatment (for 7 days total) reduced their levels considerably, although the levels were still higher than
the control values. Both cytochrome b5 and NADH-cytochrome c reductase levels were not changed
during the 7 days of treatment. Rat liver microsomes readily converted l-menthol to p-menthane-3, 8-
diol (II) in the presence of NADPH and O2. This activity was significantly higher in microsomes
obtained from phenobarbital (PB)-induced rats than from control microsomal preparations, whereas 3-
methylcholanthrene (3-MC)-induced microsomes failed to convert l-menthol to compound II in the
presence of NADPH and O2. L-Menthol elicited a type I spectrum with control (Ks = 60.6 microM)
and PB-induced (Ks = 32.3 microM) microsomes whereas with 3MC-induced microsomes it produced
a reverse type I spectrum (
Hawthorn e
t al, 1988)..
One randomized 4-way crossover study was designed to determine the effect of peppermint oil and
ascorbylpalmitate on cytochrome P4503A4 (CYP3A4) activity in vitro and oral bioavailability of
felodipine in humans. The method was the study of the reversible mechanism-based inhibitions of
nifedipine oxidation in human liver microsomes. Oral administration of 10-mg extended-release tablet
of felodipine with grapefruit juice (300 mL), peppermint oil (600 mg), ascorbyl palmitate (500 mg), or
water, were given to 12 healthy volunteers, and determined the pharmacokinetics of felodipine and
dehydrofelodipine. The authors concluded that
Peppermint oil, menthol, menthyl acetate, and ascorbyl
palmitate were moderately potent
reversible inhibitors of in vitro CYP3A4 activity. Nevertheless
further investigation should be done (Dresser et al, 2002).
In one randomized, double blind, two way crossover study with eleven subjects, comparing the
kinetics and effects of a single oral dose of Felodipine ER tablet (Plendil 10 mg), with Menthol (test)
or placebo (reference), was studied the effect of menthol on the pharmacokinetics and
pharmacodynamics of Felodipine in healthy subjects. The results concluded that the pharmacokinetics
parameters of Felodipine and dehydrofelodipine were not markedly during the measurements
(Gelal, 2002).
Excretion
The urinary metabolites result from hydroxylation at the C-7 methyl group at C-8 and C-9 of the
isopropyl moiety, forming a series of mono- and dihydroxymenthols and carboxylic acids, some of
which are excreted in part as glucuronic acid conjugates. Studies with tritiated I-menthol in rats
indicated about equal excretion in faeces and urine. The main metabolite identified was menthol-
glucuronide. Additional metabolites are mono- or di-hydroxylated menthol derivatives.
2.2.2
Assessor’s overall conclusions on pharmacokinetics
The studies on the pharmacokinetics and bioavailability are few and contradictory.
In animals, peppermint is rapidly absorbed. The major biliary metabolite is menthol glucuronide,
which undergoes enterohepatic circulation. After inhalation, pulmonary absorption depends on various
factors and the rapid elimination indicates that there should be no accumulation during long-term
application.
The urinary metabolites are excreted in part as glucuronic acid conjugates. Studies in rats indicated
equal excretion in feces and urine of essential oil compounds. The main metabolite identified was
menthol-glucuronide
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2.3
Toxicology
2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
and constituents thereof
Toxicity
Peppermint, pulegone, 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 bilirubin were dose dependent, after levels of 0, 200, 400
and 800mg/kg b. w. /day. The NOEL for menthone in this study was lower than 200mg/kg b.w. /day
(Madsen et al, 1986).
A NOEL of 400 mg/kg b. w. /day was reported in a 28 day toxicity study in rats
(Who, 2000).
Genotoxicity
Peppermint oil
Salmonella strains TA1537, TA98, TA1535 and TA100 at concentrations of 800, 160, 32 and 6,4 μg
per plate were used to test peppermint oil. No mutagenic properties were observed
75
. Menthol and
pulegone were also negative.
Peppermint oil was negative on a dose of 150μg/ml in a mouse lymphoma L5178Y TK +/- cell
mutagenesis assay and, on a concentration of 155μg/ml, in an unscheduled DNA synthesis assay, on
rat hepatocytes (Final report on the Safety Assessment of Mentha Piperita, 2001)
The genotoxic activity of dill, peppermint and pine essential oils were studied using chromosome
aberration (CA) and sister chromatide exchange (SCE) tests in human lymphocytes in vitro and
Drosophila melanogaster
somatic mutation and recombination test (SMART) in vivo. The essential
oil of
M. piperita
was shown to weakly induce SCE in a dose independent manner and to be genotoxic
in the wing somatic mutation and recombination tests (SMART). Peppermint oil was the most
cytotoxic and inhibited mitotic activity of human lymphocytes(Lazukta et al
, 2001).
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Menthone
Menthone exhibited mutagenic responses in several Salmonella tester strains, although responses were
rather inconsistent in terms of concentration and requirement of S9. It was also positive in the wing
somatic mutation and recombination tests (SMART)
105
and genotoxic in
D. melanogaster
((Lazukta et al
, 2001).
.
It was weakly positive in the host-mediated assay (mice), but not in
cytogenetic or dominant lethal assays (rats). (Final report on the Safety Assessment of
Mentha piperita
, 2001)
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.
Immunotoxicity
At a very high dose levels (1250mg/kg/day), peppermint did increase mortality and reduce survival
time in the host resistance assay, on the rapid screening protocol, to evaluate humoral and cell-
mediated immune responses (Gaworsky et al, 1994).
Phototoxicity
No effects were produced after the application of 100% peppermint oil on the back of hairless mice,
irradiated with light from a fluorescent black light at an integrated UVA. The same result was obtained
on a second experiment using the same protocol with two miniature swine (Final report on the Safety
Assessment of
Mentha piperita
, 2001)
Teratogenicity
Menthol
No teratogenic effects were noted after oral intubations of Brazilian menthol on pregnant mice, rats,
hamsters and rabbits (Food and Drug Research Labs, 1973).
Carcinogenicity
Menthol
The National Cancer Institute found no evidence of carcinogenicity after dosing Fisher 344 rats with
3750 or 7500 ppm oral dose, or B6C3F
1
mice with 2000 or 4000 ppm
d, l
-menthol, on a two year
study, in 1979. In female mice, was noted a dose related increased deaths.
After 20 weeks of oral dosing with 1% (-) menthol, was reported a significant inhibition of induced
mammary gland carcinogenesis (
p<0,001
) (Russin et al).
3
CLINICAL DATA
-
For all studies cited, 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.
3.1
Clinical Pharmacology
3.1.1
Pharmacokinetics
3.1.1.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
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Oral administration
Peppermint oil is relatively rapidly absorbed after oral administration and eliminated mainly via the
bile.
Menthol
To determine the disposition kinetics and to examine subjective and cardiovascular effects of menthol,
was conducted a crossover placebo-controlled study that compared pure menthol versus placebo,
along with an uncontrolled exposure to menthol in food or beverage. Twelve subjects were studied;
each received a 100 mg l-menthol capsule, a placebo capsule, and 10 mg menthol in mint candy or
mint tea on three different occasions. Plasma and urine levels of menthol and conjugated menthol
(glucuronide), cardiovascular measurements, and subjective effects were measured at frequent
intervals. Menthol was rapidly metabolized, and only menthol glucuronide could be measured in
plasma or urine. The plasma half-life of menthol glucuronide averaged 56.2 minutes (95% confidence
interval [CI], 51.0 to 61.5) and 42.6 minutes (95% CI, 32.5 to 52.7) in menthol capsule and mint
candy/mint tea conditions, respectively (P < .05). The plasma area under the plasma concentration-
time curve ratios for menthol capsule to mint candy/mint tea treatment averaged 9.2 (95% CI, 8.2 to
10.1) (Hadley, Gaarder, 2005).
An aqueous suspension of peppermint oil was injected along the biopsy tract in endoscopic
examinations. Colonic spasm was relieved within 30 seconds in each of 20 patients using this
technique (Leicester, 1982).
After administration of peppermint oil to ileostomy patients, elimination of menthol glucuronide was
less than after administration to healthy subjects, indicating that part of the absorption of menthol took
place in the distal small intestine.
Dermal
Using sensitive and selective gas-chromatographic methods, after skin application of camphor,
menthol and methyl salicylate, the systemic absorption was examined. Concentration time profiles
were erratic and variable and the half-lives relatively shorts (Martin et al, 2004).
Excretion
Pharmacokinetic studies reveal that fractionated urinary recovery of menthol is dependent on the kind
of formulation used for the application of PO. Optimal pH triggered enteric coated formulations start
releasing PO in the small intestine extending release over 10-12 h thus providing PO to the target
organ in irritable bowel syndrome, i.e. the colon. The hypothesis is supported by anecdotal
observations in patients with achlorhydria or ileostoma, respectively (Grigoleitt, 2005).
The excretion in the breast milk is undetermined.
3.1.1.2
Assessor’s overall conclusions on pharmacokinetics
Peppermint oil is relatively rapidly absorbed after oral administration and eliminated mainly via the
bile. Peppermint oil is highly fat soluble and rapidly absorbed at the proximal gut. However, some
studies with ileostomy patients
suggest
that part of the absorption of menthol took place in the distal
small intestine. Nevertheless pharmacokinetic studies reveal that fractionated urinary recovery of
menthol is dependent on the kind of formulation used for the application of PO.
The systemic absorption after dermal application was examined and concentration time profiles were
erratic and variable and the half-lives relatively shorts.
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3.1.2
Pharmacodynamics
3.1.2.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
Antispasmodic action on the smooth muscle
One study documents the relaxation of the muscles around the border from oesophagus to the stomach
through peppermint oil
(Anon, 1990).
One study is an investigation about peppermint oil to reduce colonic spasms during endoscopy in 20
patients. Peppermint oil is injected along the biopsy channel of the colonoscope. Colonic spasm was
relieved within 30 s (Sigmund, McNally, 1969).
The principal pharmacodynamic effect of peppermint oil relevant to the gastrointestinal tract is a dose-
related antispasmodic effect on the smooth musculature, as we can see on the studies presented below,
due to the interference of menthol with the movement of calcium across the cell membrane. The
choleretic and antifoaming effects of peppermint oil may play an additional role in medicinal use.
An aqueous suspension of peppermint oil injected along the biopsy tract in 20 patients prevented the
colonic spasms that otherwise occur in endoscopic examinations (Leicester, 1982). Peppermint oil
relaxes the oesophageal sphincter when administered orally (15 drops of oil suspended in 30 mL of
water), eliminating the pressure differential between the stomach and oesophagus and allowing reflux
to occur (Sigmund, McNally , 1969).
A randomized double-blind, double dummy, controlled trial was conducted in 100 patients to compare
the antispasmodic effects of hyoscine-N-butylbromide IM, and a placebo solution administered
intraluminally by the endoscope, and also the effects of a placebo solution IM with those of a
peppermint oil solution administered intraluminally. The percent change in diameter of the pyloric
ring before and after the administrations was defined as the the opening ratio, and the percent change
in diameter between the maximally and minimally opened pyloric ring states was defined as the
contraction ratio. Time until disappearance of the contraction ring(s) in the gastric antrum and side
effects of the drugs were also determined. The opening ratio was significantly higher in the
peppermint oil administration group than in the hyoscine-N-butylbromide injection group. The
contraction ratio was lower in the peppermint group. The time required for the disappearance of the
antral contraction was shorter in the peppermint oil group (97.1± 11.4) than in the hyoscine-N-
butylbromide group (185.9±10.1 s;
p
<0,0001). No significant side effects were associated with
peppermint oil, whereas such as hyoscine-N-butylbromide injection produced side effects such as dry
mouth, blurred vision and urinary retention (Hiki et Al
, 2003).
In nine studies, 269 healthy subjects or patients underwent exposure to peppermint oil (PO) either by
topical intraluminal (stomach or colon) or oral administration by single doses or 2 weeks treatment (n
= 19). Methods used to detect effects were oro-cecal transit time by hydrogen expiration, total
gastrointestinal transit time by carmine red method, gastric emptying time by radiolabelled test meal
or sonography, direct observation of colonic motility or indirect recording through pressure changes or
relieve of colonic spasms during barium enema examination. The dose range covered in single dose
studies is 0.1-0.24ml of PO/subject. With one exception, which show an unexplained potentiation of
neostigmine stimulated colon activity; all other studies result in effects, indicating a substantial
spasmolytic effect of PO of the smooth muscles of the gastrointestinal tract.
The effectiveness of peppermint oil added to barium sulphate suspension in relieving colonic muscle
spasm during contrast barium enema examination was assessed in a double blind study with 141
patients. No residual spasm was evident in a significant proportion of patients in the treated group
(60%) compared with the control group (35%). There were no adverse effects on the quality of the
examination (Sparks
et al, 1995).
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Another comparative study, with 383 patients on DCBE (double-contrast barium contrast), with
positive results from occult blood tests were performed. 4 groups, peppermint in barium, peppermint
in tube, Buscopan or no treatment. In the group using peppermint oil or buscopan, the rate of patients
with non-spasm examination was higher than that in no-treatment group (
p<0.0005
). Peppermint oil
had the same spasmolytic effect as the systemic administration of Buscopan (n-butylscopolamine
.)
in
the transverse and descending colon.
The pharmacodynamic study on the effect of peppermint oil (90 mg) and caraway oil on
gastrointestinal motility in healthy volunteers was performed, using simultaneous determination of
gastric and gall-bladder emptying and orocecal time, in comparison with placebo, cisapride and n-
butylscopolamine. Peppermint oil shows a relaxing effect on the gallbladder (
P = 0.04
) and slows the
small intestinal transit (
P = 0.004
) (Asao et al, 2003)
160 patients scheduled for outpatient colonoscopy were randomized in a double blind design. The
objective was to determine the efficacy of peppermint oil versus placebo instillation over the ileocecal
valve in the cecum, on the success rate and the duration of time required for terminal ileum intubation.
The time required for TI intubation was shorter in POS group (102 seconds) than the control group
(137 seconds) –
p=0,045
(Goerg et al, 2003)
.
3.1.2.2
Assessor’s overall conclusions on pharmacodynamics
The pharmacodynamic studies demonstrated the spasmolytic effect on the smooth muscle of the
intestinal tract. The different formulations may reach different target organs. An appropriate galenic
formulation minimizes the adverse effects.
Peppermint oil shows activity on the relaxation of the Oddi’s sphincter on the gallbladder,
demonstrating some choleretic properties.
The relaxation of the oesophageal sphincter, plus the reduction in gastric and intestinal foam volume,
observed in vitro, contribute to the carminative effect.
3.2
Clinical Efficacy Studies
3.2.1
Dose response studies
There are no dose-finding studies available.
The recommended dosage of 0.2 ml – 0,4ml for adults, elderly and children over 12 years (2 –3 times
daily) is supported by clinical investigations as noted below, for the treatment of irritable bowel
syndrome.
3.2.2
Clinical studies (case studies and clinical trials)
Oral administration
Irritable bowel syndrome
Non Controlled clinical studies
-
When 50 patients suffering from irritable bowel syndrome were studied in an open multicentre trial,
they received three peppermint oil capsules (of 0.2 mL) per day, each administered orally 30 minutes
before a meal. Evaluation of all signs and symptoms, both pre- and post-treatment (after four weeks of
treatment), confirmed a statistically significant decrease of symptoms.
Controlled clinical studies
- In two double blind, crossover studies of irritable bowel syndrome with 16 and 29 patients
respectively, capsules containing peppermint oil (0.2 mL/capsule) were compared with placebo.
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Patients received orally three times daily 1 or 2 capsules depending on the severity of symptoms. The
overall assessment of each treatment period showed that patients felt significantly better (p<0.01)
while taking peppermint oil capsules compared with placebo, and considered peppermint oil better
than placebo in relieving abdominal symptoms (p<0.005).
- 34 patients with irritable bowel syndrome in whom pain was a prominent symptom were entered in a
double blind clinical trial of peppermint oil (0.2 mL/capsule) versus placebo. Two capsules were taken
orally three times daily. The patients' assessments at the end of two and four weeks of treatment
showed no significant difference between peppermint oil and placebo in terms of overall symptoms.
- Enteric-coated capsules containing peppermint oil (0.2 mL/capsule, taken orally) were compared
with placebo in a double blind, crossover trial involving 18 patients with irritable bowel syndrome.
The patients received three capsules per day for 4 weeks and then changed to the alternative
medication for a further 4 weeks. With peppermint oil, there was a small but statistically significant
increase in frequency of defecation but no significant change in scores for global severity of symptoms
or scores for the specific symptoms of pain, bloating, urgent defecation and the sensation of
incomplete evacuation.
- In a double blind, crossover study, 40 irritable bowel syndrome patients were treated orally for 2
weeks with peppermint oil in enteric-coated capsules (0.2 mL/capsule), hyoscyamine (0.2 mg) or
placebo. Treatment with peppermint oil tended to have a more pronounced effect on symptoms than
placebo or hyoscyamine, but this was not statistically significant. (Krag,1985, Pittler, Ernst, 1998)
Reviews
On one review, 16 clinical trials in the literature search using 180-200 mg enteric-coated peppermint
oil (PO) in irritable bowel syndrome (IBS) or recurrent abdominal pain in children (1 study) with 651
patients enrolled were identified. There was a prevalence of women.
Some of the studies were performed before the Rome II criteria, but according to the authors of this
review, the inclusion criteria appear to be adequate. The treatment duration was from 2 to 11 weeks
and in one open study was 6 months.
Nine out of 16 studies were randomized double blind cross over trials with (n = 5) or without (n = 4)
run in and/or wash out periods, five had a randomized double blind parallel group design and two
were open labelled studies. Placebo served in 12 and anticholinergics in three studies as comparator.
In 11 of the studies there was a daily patient rating of selected symptoms as abdominal pain,
distension, flatulence, stool frequency, urgency, bloating, stool quality, frequency of attacks, severity
of attacks, or the overall assessment. In two studies, the rating by patients was at intervals of two
weeks. In two studies the interval was not given. In one open trial the physician rating was at the end
of the week. To make this data comparable, the variable “overall success” was used (% of responders).
(Grigoleit, 2005).
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Study no./Ref.
Design
Study drug(s)
Treatment weeks Patients
enrolled
1 Rees (1979)
db,co,wash out
One to two capsules Placebo 1–2 capsules 3/treatment
18
period
t.i.d.b
t.i.d.
2 Evans et al. (1982) db,co,randomized, One to two capsules Placebo
2/treatment
20
wash out?
t.i.d.d
3 Dew et al. (1984) db,co,wash out
One to two capsules Placebo 1–2 capsules 2/treatment
29
period
t.i.d.b
t.i.d.
4 Nash et al. (1986) db,co,no wash out, Two capsules t.i.d.a Placebo 2 capsules
2/treatment
41
randomized
t.i.d.
5 Mu¨ nst et al.
(1987)
db,co,wash out,
One capsule t.i.d.a
Matching mebeverine 3/treatment
16
double dummy,
135 mg 1 tablet t.i.d.
randomized
6 Weiss and Ko¨ lbl db,pg,randomized One capsule t.i.d.a
Placebo,1 capsule
3
60
(1988)
t.i.d.
7 Lawson et al.
(1988)
db,co,no wash out
One capsule t.i.d.b
Placebo,1 capsule
4
25
t.i.d.
8 Lech et al. (1988) db,pg,randomized
One capsule t.i.d.d
Placebo,1 capsule
4
47
t.i.d.
9 Wildgrube (1988)
Matched pairs, db
pg,
Capsules
Matching placebo
2
40
randomized
capsules
10 Carling et al.
db,3 way co, wash One to two capsules Hyoscyamine 0.2 mg 2/treatment
40
(1989)
out
t.i.d.a and matching
and matching
placebo
placebo,1–2 tablets
t.i.d.
11 Schneider and
db,co,wash out,
One capsule t.i.d.a
Placebo 1 capsule
6/treatment
60
Otten (1990)
randomized
t.i.d.
12 Fernandez (1990) Open
One capsule t.i.d.b
4
50
13 Ambross (1990) db,co,randomized
Not specified
Alverine citrate
11/treatment
18
14 Shaw et al.
(1991)
Open, pg,
One capsule t.i.d.a
Stress management
24
35
randomized
program, median 6
psychotherapy
sessions of each
40 min/patient
15 Liu et al. (1997) db,pg,randomized One capsule t.i.d. or Placebo 1 capsule
4
110
q.i.d.a
t.i.d. or q.i.d.
16 Kline and
Barbero
db,pg,randomized One to two capsules Placebo 1–2 capsules
2
42
(1997)
t.i.d.a
t.i.d.
db ¼ double blind, co ¼ cross over, pg ¼ parallel groups. A Colpermins .
B Enteric-coated PO capsule.
C Mentacurs
D Unspecified PO formulation.
(Grigoleit, 2005).
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Table
2.
Summary of ‘‘overall success’’ data for peppermint (PO) oil in IBS
54-56
Study Overall success (%) peppermint
Comparator
Overall success
Comments
no.
oil
comparator (%)
1
50
Placebo
13
P<0:01
2
No numerical data
Placebo
No numerical data
Overall success in favor of PO
(p<0:025)
3
41
Placebo
10
P<0:001
4
39
Placebo
52
n.s.
5
No numerical data
Mebeverine
No numerical data
Except for ‘‘fullness’’ no
difference between treatments
6
74
Placebo
17
P<0:001
7
Placebo
Increase in stool frequency
(p<0:05),formulation problem
8
68
Placebo
26
P<0:02
9
No numerical data
Placebo
No numerical data
All symptoms improved in favour
of peppermint oil (p<0:05)
10
57
Placebo
37
Symptom score before/after PO
Hyoscyamine
38
P<0:01; placebo and hyoscyamine
p<0:05
11 12 57 93
Placebo
39
Difference n.s. p < 0:08 Open study
13
No numerical data
Alverine
No numerical data
No difference between treatments
14
18
Stress
72
Strongly in favour of
management
psychotherapy after 6 months
program
15
79
Placebo
32
Overall success calculated from
mean improvement values of
symptoms, single symptoms all
P<0:05
16
70
Placebo
43
Children/recurrent abdominal
pain, p<0:002
Eight out of 12 placebo controlled studies show statistically significant effects in favour of PO.
Average response rates in terms of "overall success" are 58% (range 39-79%) for PO and 29% (range
10-52%) for placebo. The three studies versus smooth muscle relaxants did not show differences
between treatments hinting for equivalence of treatments.
A total of 71 patients dropped out. The most of them for reasons unrelated with the study. Others (n=6
worsening of symptoms, PO or placebo; n=2 nausea and vomiting by PO; n=3 perianal burning by
PO; n=2 peppermint taste and pyrosis).
Adverse events reported were generally mild and transient, but very specific. PO caused the typical GI
effects like heartburn and anal/perianal burning or discomfort sensations, whereas the anticholinergics
caused dry mouth and blurred vision. Anticholinergics and 5HT3/4-antagonists do not offer superior
improvement rates; placebo responses cover the range as in PO trials, concludes the authors
56
.
The authors conclude that the clinical data in IBS reveals that peppermint oil in an enteric coated form
is safe and efficacious in a sufficient number of studies, as a symptomatic remedy in a short term
treatment
56
.
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Meta-analysis
A statistical meta-analysis of eight studies showed that the treatment of irritable bowel syndrome with
peppermint oil was more effective than treatment with a placebo. It should be noted that some of the
older studies had serious methodologic problems including vague inclusion criteria for patients and
treatment periods that were too short. In five trials the treatment period ranged from two to four weeks
and the doses were 0,2 to 0,4 ml three times daily. In three of five trials, significant benefit over
placebo for global improvement were reported (p<0,001). In the descritive review, one small
controlled trial suggested that stress treatment had better results than peppermint oil on a period of six
months. The other two trials, placebo controlled, had or no significant improvement on pain relief or
no difference from placebo. Overall, there was a significant benefit on four of the six double blind
placebo controlled trials over a two to six weeks treatment period. (Pittler MH, Ernst 1998).
Dyspepsia
- A placebo controlled double-blind study has been studied in 69 woman in the treatment of abdominal
distension and dyspepsia following routine gynaecological surgery, using Peppermint oil (Colpermin –
Tillots Laboratories, St. Albans, Hertfordshire), in enteric coated capsules, 2 capsules, 3 times/day,
during 5 days. No differences were found in abdominal distension, flatulence or abdominal pain
between the two groups. Peppermint oil was not effective, but safe
61
.
- In a double blind, randomized, placebo controlled, multicentre, 4-week trial, 39 patients with
dyspepsia (non ulcerative), with moderate to severe pain were given a combination (Enteroplant ®) of
peppermint (90mg) and caraway oil (50mg). Decrease in pain intensity was significantly greater in the
treatment group (15 days-84, 2% - p=0,002; 29 days – 89, 9% - p=0,015) than in the placebo group
(15 days - 50%; 29 days – 45%) (Barnick C.G., Cardozo, 1990).
Gallbladder – cholelitolytic, cholagogue, choleretic
In these clinical studies it was used a terpene preparation called Rowachol ® (Pinene 17mg,
Camphene 5mg, Cineol 2mg, Menthone 6mg, Menthol 32mg, Borneol 5mg, Olive Oil 33mg – for
each capsule of 100mg).
Uncontrolled study
It was given to19 of 31 patients with common bile duck stones, up to 7 capsules/day initially of
Rowachol ®, and 3 capsules/day later. 8 (42%) patients had total stone disappearance in 3 to 48
months; Bile acid (chenodeoxycholic
in 11, ursodeoxycholic in 4) was given also to 15, from 2 to 60
months, and within 18 months, 11 had complete stone dissolution (Somerville
et al, 1985).
15 patients were treated with Rowachol ®, 3 capsules daily minimum. The treatment was effective in
dissolving stones when administered in one year (Bell, Doran, 1979)
.
.
Controlled study
A human controlled study with two groups, evaluated the biliary lipid secretion and gall bladder bile
composition. Rowachol ® enhanced the cholesterol solubility of gall bladder bile (
p<0,001
) and
human T-tube (
p<0, 05
) bile after the ingestion of 2 capsules three times daily for 48 hours (Bell,
Doran, 1979)
.
.
The Commission E monograph also describes a cholagogic action to peppermint oil.
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Inhalation
Sleep/alertness action
Twenty-one healthy sleepers (11 women and 10 men) completed three consecutive laboratory
sessions, to study the peppermint oil odour effect on polysomnographic sleep, alertness and mood,
when presented before bedtime. Polysomnographic recordings, mood questionnaires like the Stanford
Sleepiness Scale and the Profile of Mood States Questionnaire, and also Liker scales for stimulus
perception, were performed. Peppermint reduced fatigue and improved mood. The subjects who rated
peppermint as very intense had more total sleep than those rating it as moderately intense, showing
more slow-wave sleep then in the control session. It increased NREM sleep in women, but this was
not true in men, where alertness was more evident than in women. So, there are individual factors
influencing the results on the physiological sleep, self-rated mood and alertness (Adam et al, 2006).
Another study examined the influence of essential oils and components (peppermint, jasmine, ylang-
ylang, 1, 8-cineole and menthol) on core attention function. Six experimental groups were compared
with corresponding control groups receiving water (n=20 – 4 groups; n=30 – 2 groups). The results
did not reach statistical significance. The authors indicate complex correlations between subjective
evaluations of substances and objective performance, concluding that the effects are mainly
psychological (Ilmberger et al, 2001).
Respiratory action
According with ESCOP, inhalation of the oil for treating congestion due to common colds is believed
to ease congestion, aiding respiration, by stimulating cold receptors in the respiratory tract.
A secretolytic action in the bronchi and decongestant in the nose were reported (ESCOP monographs,
2003).
Various studies did not demonstrate a change on inspiratory or expiratory nasal airway resistance, but
enhances the sensation of nasal airway latency. It seems that menthol acts upon trigeminal sensory
nerve endings within the nose (Eccles et al, 1988).
Postoperative Nausea
A study was performed with 18 patients in a three condition experimental design, to investigate the
efficacy of peppermint oil on the relief of postoperative nausea in gynaecological surgical patients -
(control group – no treatment; placebo – peppermint essence; experimental – peppermint oil), isolated
from each others due to the volatile nature of the compound. The experimental group had an increased
number of intra-abdominal procedures, received more opioid analgesia postoperatively and required
less traditional antiemetics (Tate S, 1997)
External application
Tension headache
There is not clear clinical and pharmacological data to support this indication, but there are some
studies, which enable an assessment of Peppermint oil for external use in tension headache, as follows
.
Controlled studies
The analgesic effect of peppermint oil (10% in ethanol) was investigated in 32 healthy subjects in a
double blind placebo-controlled, randomized, four-fold crossover study. Neurophysiological,
psychological and experimental algesimetric parameters were investigated. Four different test
preparations were applied to large areas of the forehead and temples using a small sponge.
Preparations containing peppermint with or without
Eucalyptus
were superior in pain reduction and
had a muscle relaxing and mentally relaxing effect.
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Compared to the application of placebo, 10% peppermint oil in ethanol solution significantly reduced
the clinical headache intensity already after 15 minutes (p < 0.01). This significant clinical reduction
of the pain intensity continued over the one-hour observation period (Dresser, 2002).
The effect of a locally applied peppermint oil preparation on tension-type headache was examined in
the design of a randomized, placebo-controlled double-blind crossover study. The preparation was
tested against both the reference substance acetaminophen and to the corresponding placebo. The
liquid test preparation contained 10 g of peppermint oil and ethanol (90%) ad 100 (test preparation
LI 170, Lichtwer Pharma, Berlin); the placebo was a 90% ethanol solution to which traces of
peppermint oil were added for blinding purposes. The reference preparation contained 500 mg
acetaminophen; the placebo tablet was identical to the verum in size and appearance. The study
included the analysis of 164 headache attacks of 41 patients of both sexes ranging between 18 and 65
years of age, suffering from tension-type headache in accordance with the IHS classification.
Compared to the application of placebo, 10% peppermint oil in ethanol solution significantly reduced
the clinical headache intensity already after 15 minutes (
p < 0, 01
). This significant clinical reduction
of the pain intensity continued over the one hour observation period. Acetaminophen, too, proved to
be efficient compared to placebo (
p < 0, 01
). There was no significant difference between the efficacy
of 1,000 mg of acetaminophen and 10% peppermint oil in ethanol solution.
The topical application of peppermint oil produces a prolonged cold sensation at the local of
application, by the stimulation of the cold-sensitive receptors, giving an analgesic effect.
The application to the forehead showed on the EMG activity, a significant reduction of the M
temporalis wave, as a pronounced increase in blood flow through the capillaries of the skin (Fachinfo
Euminz, 1997)
Safety data were available for 150 Patients without AE´s.
Analgesic effect
Case study
Report of a post herpetic neuralgia on a 76 years woman, with relief of the pain during 4-6 hours after
the local application of peppermint oil (containing 10% menthol). During two months of treatment she
continued to feel the same effect (Davies et al, 2002).
3.2.3
Clinical studies in special populations (such as elderly and children)
Clinical studies in children
In a randomized, double-blind controlled trial of two weeks, 42 children (8 to 17 years old) with
irritable bowel sd were given ph dependent enteric coated peppermint oil capsules, versus placebo.
The patients weighing more than 45kg received 2 capsules, 3 times a day. The smaller children, who
weighed 30Kg to 45 kg, received 1 capsule 3 times a day. After two weeks, 75% of those receiving
peppermint oil, reduced severity of pain associated with the IBS, but not the other symptoms, like
heartburn, gas, urgency of stools, belching, stool pattern or stool consistency. No adverse events were
reported (Kline Robert et al, 2001).
3.2.4
Assessor’s overall conclusions on clinical efficacy
Oral administration
IBS
The Rome II diagnostic criteria of Irritable Bowel Syndrome always presumes the absence of a
structural or biochemical explanation for the symptoms and is made only by a physician.
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Irritable Bowel Syndrome can be diagnosed based on at least 12 weeks (which need not be
consecutive) in the preceding 12 months, of abdominal discomfort or pain that has two out of three of
these features
:
1. Relieved with defecation; and/or
2. Onset associated with a change in frequency of stool; and/or
3. Onset associated with a change in form (appearance) of stool.
Other symptoms that are not essential but support the diagnosis of IBS:
•
Abnormal stool frequency (greater than 3 bowel movements/day or less than 3 bowel
movements/week);
•
Abnormal stool form (lumpy/hard or loose/watery stool);
•
Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation);
•
Passage of mucus;
•
Bloating or feeling of abdominal distension
It affects more women than men and is more common in patients 30 to 50 years of age (Hadley et al,
2005)
According to the document “Points to Consider on the Evaluation of Medicinal Products for the
Treatment of Irritable Bowel Syndrome” (CPMP/2003), considering the chronic character of this
disease, it may be acceptable to conduct a number of studies with different designs to provide all the
required efficacy data (dose response studies, efficacy with first use – 4 weeks duration,
withdrawal/rebound effect, efficacy with repeated use). The trials must be long, considered as
necessary 6 months of active treatment. Other studies should be justified. On short term studies of 4
weeks, would be required a 50% of the time on the response on the specified improvement in
symptoms.
IBS is a complex disorder that affects many patients. Its treatment is also complex, because a variety
of processes appear to be involved. So, it is difficult to find treatment suitable for all sort of IBS
patients, but effective towards specific aspects. IBS is a chronic condition, with unpredictable periods
of exacerbation and remission. Thus, clinical trials of only few weeks are of limited relevance to
conclude about the effectiveness of the treatment.
Some studies in the literature show methodological problems, as use of no validated scales, the
randomization procedure is not clear, there is lack of adequate washout period, limited treatment
period (2-4 weeks), have small sample sizes and unclear diagnostic criteria. Despite this, some
interventions with peppermint oil have been shown to be clinically effective in the treatment of
symptoms of IBS, in several randomized well designed controlled trials. A variety of outcome
measures have been used, making it difficult to compare the results of the trials.
The meta-analysis by Pittler and Ernst reported that the role of peppermint oil in the symptomatic
treatment has not been established and more studies are needed to clarify the issue.
Nevertheless, the clinical studies demonstrated a reduction in spasms during barium enemas and
endoscopies, as smooth muscle relaxing properties, pointing peppermint oil as an antispasmodic agent
on the GI tract, reducing abdominal pain. The enteric-coated capsules are generally recommended to
reach the target organ and avoid undesirable effects like heartburn and oesophageal reflux.
The carminative properties attributed to peppermint were documented by the literature, helping to
relief the flatulence.
Dyspepsia
(non-ulcer)
Small number of controlled trials with a combination of peppermint and caraway oil shows some
benefits on dyspepsia symptoms. It is not clear what constituent is the most effective.
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Antispasmodic
During endoscopy and colonoscopy, the topical intraluminal administration of peppermint oil, was
used as antispasmodic agent in several studies, with superior efficacy than placebo and also than
hyoscine-N-butylbromide, with less adverse reactions.
Cholagogic, cholelitolytic, and choleretic
Some studies appointed cholagogic, cholelitolytic, and choleretic properties, but some more trials are
necessary, with a better design.
Tension headache
According to the IHS classification (
ICHD-II) -
International Headache Society 2003, tension type
headache is classified as:
2. Tension-type headache (TTH)
2.1 Infrequent episodic tension-type headache
2.1.1 Infrequent episodic tension-type headache associated with pericranial tenderness
2.1.2 Infrequent episodic tension-type headache not associated with pericranial tenderness
2.2 Frequent episodic tension-type headache
2.2.1 Frequent episodic tension-type headache associated with pericranial tenderness
2.2.2 Frequent episodic tension-type headache not associated with pericranial tenderness
2.3 Chronic tension-type headache
2.3.1 Chronic tension-type headache associated with pericranial tenderness
2.3.2 Chronic tension-type headache not associated with pericranial tenderness
2.4 Probable tension-type headache
2.4.1 Probable infrequent episodic tension-type headache
2.4.2 Probable frequent episodic tension-type headache
2.4.3 Probable chronic tension-type headache
This kind of primary headache is very common, ranging from 30 to 78% in several studies. It was first
considered as psychogenic, but recent studies suggest a neurobiological basis, especially for the more
severed cases. The last edition of
The International Classification of Headache Disorders
subdivided
episodic tension-type headache further, into an
infrequent
subtype with headache episodes less than
once per month and a
frequent
subtype. Another difference in this edition is related with the disorder
of the precranial muscles, using now for the subdivision the tenderness on manual palpation and not
the surface EMG or pressure algometry (The International Classification of Headache Disorders,
2004).
This indication is mentioned in the ESCOP monograph. The Commission E monograph only
includes the indication, muscle and neuralgic complaints“
The peppermint oil, by laboratory tests, seems to exert some actions on mechanisms associated with
the pathophysiology of tension headache, producing an analgesic affect, after administering a 10%
solution on the forehead and the temples of the patients.
The comparative clinical study with 1,000 mg acetaminophen, demonstrated no significant difference
between both products on the relief of the pain. The numbers of patients in the studies were small; the
inclusion criteria are not well defined with a large range of ages. The characteristics of the pain
described – 4,99 days per month for 14,12 years – fulfil the point A of the diagnostic criteria of the
Frequent episodic tension-type headache
(ICHD-II) and Episodic tension-type headache (IHS code).
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More research is needed to conclude about the effectivity on this indication. In Finland the indication
“herbal medicinal product for temporary headache” is authorized since 2003.
Also for the relief of headache, for adults and children over 6 years, a local application (100% oil) of
the forehead with the aid of an applicator several times at intervals of 15 minutes, is proposed
(Germany – MA, 1978)
3.3
Clinical Safety / Pharmacovigilance
3.3.1
Patient exposure
Peppermint essential oil widely used in flavouring, cosmetic formulations and skin-conditioning agent.
In general is considered as safe ingredient for use in dietary supplements and common as a folk
medicine.
The FDA calculated the estimated human exposure from cosmetic use, based on the concentration of
use information supplied by industry. Using a body splash product containing 0.2% Peppermint Oil
and assuming 100% absorption over a body surface of 17,000 cm2 and a daily application of 1
mg/cm2 (»17 ml of the product), the FDA estimated an exposure of 34 mg/day. For a 60-kg person,
this amounted to an estimated daily dose of 0.6 mg/kg/day (FDA 1997) (Final report on the Safety
Assessment of
Mentha Piperita
, 2001).
The highest recommended daily dose in EU is 1,2 ml peppermint oil i.e. 1080 mg peppermint oil,
which contains maximum 140mg pulegone +menthofurane (Ph Eur). For a 60Kg person this would
correspond to a daily intake of 2.3 mg/kg
Menthol
In 1976, FAO/WHO Joint Expert Committee on Foods Additives established an ADI of 0, 2 mg/kg
body weight/day for menthol. On 2000, an ADI of 0-4mg/kg of body weight/day was allocated (WHO
2000.
Pulegone and menthofurane
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):
Menthofurane is the proximate hepatotoxin of pulegone. Tolerated daily intake (TDI) of menthofurane
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. Menthofurane is
listed in the register of chemically defined flavouring substances laid down in Commission Decision
(1999/217/EC, 2002/113/EC).
USA: Pulegone and menthofurane 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)-(+)-menthofurane.
3.3.2
Adverse events
A total of 213 patients and healthy volunteers have been included in 8 studies where efficacy and
safety in the use of peppermint oil were investigated. Oral administration in capsules or direct
injection into the colon varied from a single dose to two and four weeks of treatment at daily doses of
3-6 x 0.2 mL of the oil. Peppermint oil, at concentrations of 20-50 μg/ml, evoked ion permeability of
heart cell membranes.
PO caused the typical GI effects like heartburn and anal / perianal burning or discomfort sensations in
a literature search; 16 clinical trials investigating 180–200 mg enteric-coated peppermint oil (PO) in
irritable bowel syndrome (IBS) or recurrent abdominal pain in children (1 study) with 651 patients
enrolled were identified (Grigoleit
, 2005).
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Adverse effects were reported in six trials, in the vero treatment, like heartburn, perianal burning
blurred vision, nausea and vomiting. The frequency ranged from 11% to 36% (
Pittler, Ernst, 1998).
Menthol
A case of asthma due to menthol is reported in a 40-year-old woman with no history of asthma or any
other allergy. The aetiology was suggested by the history of exposure. The diagnosis was confirmed
by the clinic history as by skin tests (Santos, 2001)
A form of stomatites and glossites with extremely prominent circumvallated papillae in patients who
consumed excessive amounts of mint-flavoured sweets was described (Santos, 2001)
Pulegone
A literature review of cases of human intoxication with pennyroyal oil (pulegone content 62-97%)
indicate that ingestion of 10 ml (corresponding to ca 5.4-9 g pulegone, ca 90-150 mg/kg bw for a
60 kg person; calculated with a relative density of 0.9 as for peppermint oil) resulted in moderate to
severe toxicity and ingestion of greater than 15 ml (corresponding to ca 8-13 g pulegone,
ca 130-215 mg/kg bw for a 60 kg person) resulted in death. The clinical pathology was characterised
by massive centrilobular necrosis of the liver, pulmonary edema and internal haemorrhage
(SCF, 2002). A non-urgent information request was sent out to the member states concerning use and
association of licensed herbal medicinal products containing pennyroyal oil, peppermint oil and mint
oil with reports of liver damage.
The highest recommended daily dose in EU is 1.2 ml peppermint oil i.e. 1080 mg peppermint oil,
which contains maximum 140 mg pulegone + menthofurane (Ph Eur). For a 60 kg person this would
correspond to a daily intake of 2.3 mg/kg bw. Clearly, this recommended daily dose of peppermint oil
in herbal medicinal products results in an intake of pulegone/menthofurane that exceeds the TDI
(0.1 mg/kg) set for food by CEFS.
No certain cases of liver damage caused by peppermint oil or mint oil were reported
(EMEA/HMPC/138386/2005).
Inhalation
Some reports about auricular fibrillation after the inhalation and ingestion of excessive amounts of
mentholated products were published in medical journals (The Lancet, 1962)
Inhalation of large doses of menthol was reported to cause dizziness, confusion, muscle weakness,
nausea or double vision (Natural Standard Research Collaboration
,
2005)..
3.3.3
Serious adverse events and deaths
Anaphylactic shock is reported (Germany).
3.3.4
Laboratory findings
Not relevant
3.3.5
Safety in special populations and situations
3.3.5.1
Intrinsic (including elderly and children) /extrinsic factors
Contact sensitivity
Report of 12 cases of contact sensitivity to the flavouring agents, menthol and peppermint oil, in
patients presenting with intra-oral symptoms in association with burning mouth syndrome, recurrent
oral ulceration or a lichenoid reaction. The patients were referred from the Glasgow Dental Hospital
over a 4-year period for assessment of the possible contribution of contact sensitivity to their
complaints. 5 patients with burning mouth syndrome demonstrated contact sensitivity to menthol
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and/or peppermint, with 1 patient sensitive to both agents, 3 positive to menthol only and 1 to
peppermint only. 4 cases with recurrent intra-oral ulceration were sensitive to both menthol and
peppermint. 3 patients with an oral lichenoid reaction were positive to menthol on patch testing, with
2 also sensitive to peppermint. 9 of the 12 cases demonstrated additional positive patch test results.
After a mean follow-up of 32.7 months (range 9-48 months), of the 9 patients that could be contacted,
6 patients described clearance or improvement of their symptoms as a consequence of avoidance of
menthol/peppermint (Goel, Lao, 2005).
Positive reactions were observed in 7 of 450 dermatitic patients tested with a patch of 2% Peppermint
oil in yellow soft paraffin. Other study revealed reaction on in 6 of 86 dermatitic patients (Ernst,
2000).
Clinical dermal testing demonstrated that 8% Peppermint oil was not a sensitizer and 2% gave a small
number of positive reactions in dermatitic patients (Final report on the Safety Assessment of
Mentha
piperita
, 2001).
There are some reports referring allergic contact dermatitis after topical application on the skin of
peppermint oil. These reactions are the most of the time transient and of mild to moderate sensivity
(Ernst, 2000).
Use in children
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
(Dost., Leiber, 1966).
The occurrence of jaundice in babies exposed to menthol is mentioned in one report at the Medline,
advising patients with G6PD deficiency to use menthol cautiously (Natural Standard Research
Collaboration, 2005).
According to the proposal of SPC for herbal medicinal products containing the essential oils
Eucalyptus oil, Peppermint oil, Mint oil and Camphor, Cineol, Menthol, the product should not be
used in children under the age of 2 years and in children with a history of seizures (febrile or not).
3.3.5.2
Drug interactions
Peppermint oil used on the skin with 5-fluouracil may increase the absorption rate of 5-fluouracil.
Use of food or antacids administered at the same time could cause early release of capsule content, if
this is the pharmaceutical form used. Other medicinal products used for the normalization of the
digestive function, should be avoided.
3.3.5.3
Use in pregnancy and lactation
Safety during pregnancy and lactation has not been established. As a precautionary measure, because
of lack of data, use during pregnancy and lactation is not recommended.
3.3.5.4
In animal studies, at 40 and 100 mg/kg body weight/day dose levels, histopathological changes in the
cerebellum white matter were seen.
Overdose may cause severe gastro-intestinal symptoms, diarrhoea, epileptic convulsions, loss of
consciousness, apnoea, nausea and disturbances in cardiac rhythms, ataxia and other CNS problems,
probably due to the presence of menthol.
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In the event of over usage, the stomach should be emptied by gastric lavage. Observation should be
carried out with symptomatic treatment if necessary.
Inhalation of larges doses of menthol may lead to dizziness, confusion, muscle weakness, nausea and
double vision (Natural Standard Research Collaboration, 2005).
3.3.5.5
Drug abuse
One case of fulminant pulmonary oedema following IV injection of 5 ml of peppermint oil was
described, on a patient with history of drug abuse (Matthias B. et al. 2005)
3.3.5.6
Withdrawal and rebound
Not relevant
3.3.5.7
Effects on ability to drive or operate machinery or impairment of mental ability
Not relevant
3.3.5.8
Contraindications
Hypersensitivity to peppermint and menthol.
Oral application
People with chronic heartburn, severe liver damage, and inflammation of the gallbladder, obstruction
of bile ducts and other occlusive disorders of the GI tract should avoid it (Matthias B. et al. 2005)
People with gallstones should consult a physician before using peppermint oil (Sigmund DJ, McNally,
1969)
External application
Open skin areas of small children, especially on the nose, face and chest, are not recommended.
Children under 2 years of age.
3.3.6
Assessor’s overall conclusions on clinical safety
The adverse events reported were generally mild and transient, in the doses recommended for the
therapeutic indications, in non-allergic adults.
When used orally, it may cause heartburn, perianal burning, blurred vision, nausea and vomiting.
Heartburn is related with the release of the oil in the upper GI tract, which relaxes the lower
oesophageal sphincter, facilitating the reflux. The same occurs in the cases of hiatal hernia. This
particular undesirable effect is minimized by an appropriate pharmaceutical formulation.
People with gallbladder disease, severe liver damage, gallstones and chronic heartburn should avoid
the intake of peppermint oil.
Menthol and peppermint oil caused burning mouth syndrome, recurrent oral ulceration or a lichenoid
reaction, by contact sensitivity in the intra-oral mucosa, in sensitive patients.
When applied on the skin, it may cause allergic reactions, as skin rashes, contact dermatitis and eye
irritation.
Use in infants or children is not recommended, when inhaled, taken by mouth or if applied on open
skin areas, on the face or chest, due to the potential toxicity of the product.
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Because there is a lack of information about the safety during pregnancy and breastfeeding, the use is
not recommended
.
. In animals (rats), peppermint oil increases levels of cyclosporine in the blood, but this is not clear in
humans.
On laboratory studies, peppermint oil is a moderately potent
reversible inhibitor of in vitro CYP3A4
activity. The levels of drugs and supplements, which are processed by this enzyme, may be increased.
4.
ASSESSOR’S OVERALL CONCLUSIONS
Peppermint oil has been use for generations as a digestive and carminative. More recently, as an
authorized medicinal product for oral use, has been prescribed under the approved indication for the
symptomatic relief of the irritable bowel syndrome. It has been also used topically, as a medicinal
product, for the symptomatic treatment of neuralgic pain, in mild to moderate tension headache and
for the relief of symptoms in cough and colds.
There are a lack of clinical studies to conclude about the efficacy of peppermint oil on the treatment of
dyspepsia and on the treatment of cough and colds.
According to the preclinical and clinical data assessed and presented on this report, peppermint oil
demonstrated an antispasmodic action of the smooth muscle of the GI tract, relieving minor spasms,
flatulence and abdominal pain.
In general, the safety clinical studies showed transient and mild adverse effects. To minimise the
adverse effects, like heartburn, the enteric-coated tablets are recommended. Some interactions were
reported in vitro and in vivo studies, but more research should be done.
The peppermint oil, by laboratory tests, seems to exert some actions on mechanisms associated with
the pathophysiology of tension headache, producing an analgesic affect, after administering a 10%
solution on the forehead and the temples of the patients. The clinical studies are small but the results
demonstrated the efficacy of peppermint oil on the episodic tension-type headache, according to the
IHS classification. More research is needed to confirm these studies.
Nevertheless, this kind of indication needs the diagnosis of a medical doctor and must not be
considered as a traditional medicinal product.
The indications proposed considered as proven, for well-established use are:
•
Oral use
1. Herbal medicinal product for the symptomatic relief of minor spasms of the gastrointestinal tract,
flatulence and abdominal pain, especially in patients with irritable bowel syndrome.
•
Cutaneous use
2. Herbal medicinal product for the symptomatic relief of mild tension type headache.
ANNEXES
PROPOSED COMMUNITY HERBAL MONOGRAPHS FOR
MENTHA X PIPERITA L., AETHEROLEUM
©
EMEA 2008
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III.
ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL
PREPARATION(S) OR COMBINATIONS THEREOF WITH
TRADITIONAL USE
Mentha x piperita
L., aetheroleum
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)
Mentha x piperitae
L., aetheroleum
Herbal preparation(s)
Menthae piperita aetheroleum
Pharmaceutical forms
Liquid dosage forms
Dr Helena Pinto Ferreira
Rapporteur
Dr Ana Paula Martins
©
EMEA 2008
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1
INTRODUCTION
Peppermint is an herbaceous plant highly aromatic, yielding a valuable essential oil widely used in
flavouring, medicine and toiletries. Native to Europe, peppermint was much used to ancient times,
having a long history of medicinal use, dating to ancient Egypt, Greece and Rome. Peppermint oil has
been used historically for several health conditions, such as common cold conditions, cramps,
headache, indigestion, joint pain and nausea, given orally or topically.
1.1
Description of the traditional herbal substance(s), herbal preparation(s) or
combinations thereof
Mentha x piperitae
L., aetheroleum
Herbal preparation(s)
1 2
:
Menthae piperita aetheroleum
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
See point 2.3.1
2.2
Type of tradition, where relevant
European phytotherapy.
Ayurvedic medicine.
2.3
Bibliographic/expert evidence on the medicinal use
It is not certain if peppermint oil was produced in the Middle Ages (Gildemeister and Hoffman, 1900).
One of the oldest specimens of peppermint is included in the herbarium of the English botanist John
Ray (1628-1705).
There are reports of pharmacological and clinical studies published in medical, pharmacological and
toxicological Journals since 1941. Oswald, N.C., in the British Medical Journal, concludes that the
most desirable property of menthol is their pleasant smell because the main virtue of steam inhalation
“is the expectorant effect of hot, moist hair”.
According to Commission E, the uses proposed are:
Internal: Spastic discomfort of the upper gastrointestinal tract and bile ducts, irritable colon,
catarrhs of the respiratory tract, inflammation of the oral mucosa.
External: Myalgia and neuralgia.
4
According to “Note for guidance on Quality of herbal medicinal products” (CPMP/QWP/2819/00…)
5
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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From ESCOP:
Internal use: Symptomatic treatment of digestive disorders such as flatulence; irritable bowel
syndrome; symptomatic treatment of coughs and colds.
External use: Relief of coughs and colds; symptomatic relief of rheumatic complaints; tension-type
headache; pruritus, urticaria and pain in irritable skin conditions
.
There is a reference on Martindale The Extra Pharmacopoeia, 27
th
Edition, June 1977, that refers
peppermint oil as “an aromatic carminative, relieving gastric and intestinal flatulence and colic and is
employed with purgatives to prevent griping”.
On the Indian Materia Medica by Dr K. M. Nadkarni’s (3
rd
revised edition – 1976, reprinted 1999),
peppermint is referred as a powerful anodyne, anaesthetic, antiseptic and germicide used in herpes
zoster, pruritus; for congestive headaches, rheumatism and neuralgia; indicated also for toothache
caused by caries, and as an antiseptic for inhalation.
2.3.1
Evidence regarding the indication/traditional use
External use
1.
For the relief of coughs and colds – WHO monographs; Germany 1978
(marketing authorization)
2.
For symptomatic relief of muscle pain and of neuralgic pain, for example in mild to moderate
tension headache – Germany – 1978, 1983 (marketing authorization)
3.
Pruritus, urticaria and pain in irritable skin conditions – ESCOP monograph 2
nd
edition
4.
Myalgia and neuralgia - Commission E Monographs
For inhalation
5.
For the relief of symptoms in coughs and colds – Germany – 1978, 1983 (marketing
authorization)
Traditionally used in cases of nasal congestion and common cold – France, Traditional Use 2005
6.
Herbal medicinal products to treat symptoms of cold - Finland (marketing authorization,
March 2003))
Oral use
7.
Symptomatic treatment of coughs and colds – ESCOP monograph 2
nd
edition
Treat symptoms of cold – Finland (marketing authorization, March 2003)
Catarrhs of the respiratory tract, inflammation of the oral mucosa – Commission E Monographs
Traditionally used locally (oromucosal spray solutions, lozenges) as an analgesic in conditions
of the oral cavity and/or pharynx. - France, Traditional Use, 2005
8.
Herbal medicinal product to balance mild, temporary and functional disorders in digestive tract
- Finland (marketing authorization, March 2003)
On Ayurvedic medicine (Pudine, paparaminta):
External use: For muscle and joint stiffness
For cold, flu –
kapha
2.3.2
Evidence regarding the specified strength
Peppermint oil should be used with caution. Doses of menthol over 1 g/Kg b.w. may be deadly.
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EMEA 2008
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The data from
Germany
, on the authorized products is mentioned:
Indication 2, 5% - 100% essential oil - cutaneous liquid
From
Martindale The Extra Pharmacopoeia
, 27
th
Edition, June 1977:
Peppermint water (U.S.N.F) – a saturated solution of peppermint oil in water.
Peppermint spirit (B.P.C.) – Spiritus Menthae Piperitae; Peppermint oil 10 ml, alcohol (90%) to
100 ml. Dose: 0, 3 to 2 ml.
From
Commission E Monographs
:
External use: Semi-solid and oily preparations 5-20%
In aqueous-ethanol preparations 5-10%
In nasal ointments 1-5% essential oil.
From
ESCOP
External use:
Indication 3 – In dilute liquid or semisolid preparations equivalent to 1,1 – 1,0% m/m menthol or
1.25 – 16% m/m menthol.
- Children 4-10 years
Semi-solid preparations 2 -10% ; hydroethanolic preparations 2-4%
- Children 10-16 years
Semi-solid preparations 5 - 15% ; hydroethanolic preparations 3 – 6%
2.3.3
Evidence regarding the specified posology
For inhalation:
3 or 4 drops of the oil added to hot water, up to three times daily (Germany - authorized medicinal
products, ESCOP, Commission E monographs)
2-3 drops spread on a stick and inhale – not more than three times/da
y-
Finland (marketing
authorization, March 2003) - not recommended for children under 12 years old.
4 x daily 4 spray nasal (2 in each nostril ) or 4 buccal spray for adults and children over 6 years –
France (TMP)
3-4 drops in hot water - Commission E Monographs
For oral use:
6 – 12 drops daily, that means: 2 – 3 times daily 3-4 drops - Germany (authorized medicinal products):
2-3 drops (0,08-0,12 ml) 3-4 times per day (0,2 – 0-5 ml) – Finland (marketing authorization, March
2003) - not recommended for children under 12 years old.
External use:
100% peppermint oil – some drops locally applied with the aid of an applicator several times at
intervals of 15 minutes - Germany (authorized medicinal products)
Peppermint oil in ethanol solution in an applicator - Germany (authorized medicinal products)
2.3.4
Evidence regarding the route of administration
See point 2.3
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2.3.5
Evidence regarding the duration of use
Finland – not recommended to use this product continuously over three months time.
Because of safety concerns the duration must be limited. If the symptoms persist during the treatment
a medical doctor must be consulted.
2.4
Assessor’s overall conclusion on the traditional medicinal use
Peppermint oil had been used for a long time as a medicine, orally, topically and for inhalation. There
are sufficient data to demonstrate its traditional use for several indications, with more than 15 years in
the EU countries, as more than 30 years on others.
2.5
Bibliographic review of safety data of the traditional herbal medicinal substances
2.5.1
Patient exposure
2.5.2
Adverse events
See point 3.3.2
2.5.3
Serious events and deaths
See 3.3.3
2.5.4 Intrinsic (including elderly and children)/extrinsic factors
See point 3.3.5.1
2.5.5
Drug-drug interactions and other interactions
Peppermint oil used on the skin with 5-fluouracil may increase the absorption rate of 5-fluouracil.
2.5.6
Use in pregnancy and lactation
2.5.7
Inhalation of larges doses of menthol may lead to dizziness, confusion, muscle weakness, nausea and
double vision
107
.
For oral mucosal use see point 3.3.5.4.
2.5.8
Drug abuse
2.5.9
Withdrawal and rebound
Not relevant
2.5.10
Effects on ability to drive or operate machinery
Not relevant
2.5.11 Contra indications (hypersensitivity and allergic potential to be both covered)
It is contraindicated in cases of hypersensitivity to peppermint oil.
Use in children under 2 years old, because menthol can induce reflex apnoea and laryngospasm.
In children with history of seizures (febrile or not).
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2.6
Non-clinical safety data
2.6.1
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)
Assessor’s overall conclusions on safe use
It is contraindicated in cases of hypersensitivity to peppermint oil and in children under the age of two
years old because menthol can induce reflex apnoea and laryngospasm.
In children with history of seizures (febrile or not).
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
4
LITERATURE REFERENCES
5
ASSESSOR’S OVERALL CONCLUSIONS
Peppermint oil has been used historically for several health conditions, orally, topically and for
inhalation, existing in countries of the EU as medicinal products with marketing authorization. The
oral use for digestive complaints was subject to several pharmacological and clinical studies, giving
sufficient data to be considered with a well-established use for the indication “Symptomatic relief of
minor spasm of the gastrointestinal tract, flatulence and abdominal pain, experienced by patients with
irritable bowel syndrome”.
The indications proposed, which demonstrated traditional use and plausibility, according to the
pharmacological properties, are the following:
External use:
I)
For the relief of symptoms in coughs and colds;
II)
For symptomatic relief of localized muscle pain,
III)
For the symptomatic relief of localised pruritic conditions in intact skin.
Inhalation:
IV)
For the relief of symptoms in coughs and colds.
Oramucosal use
V)
For the relief of symptoms in coughs and colds
ANNEXES
PROPOSED COMMUNITY HERBAL MONOGRAPHS ON
MENTHA X PIPERITA L., AETHEROLEUM
LITERATURE REFERENCES
6
Not required as per Article 16c(1)(a)(ii) of Directive 2001/83/EC as amended
©
EMEA 2008
32/32
Source: European Medicines Agency
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