Mentha – Peppermint oil (Menthae piperitae aetheroleum)
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Latin name of the genus: Mentha
Latin name of herbal substance: Menthae piperitae aetheroleum
Botanical name of plant: Mentha x piperita L.
English common name of herbal substance: Peppermint oil
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’
II.ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL
PREPARATION(S) OR COMBINATIONS THEREOF WITH
Mentha x piperita
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
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
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Herbal substance(s)1 2:
Mentha x piperita L., aetheroleum
Herbal preparation(s)1 2: Menthae piperitae aetheroleum
Combinations of herbal substance(s) and/or herbal preparation(s)3
Information on period of medicinal use in the Community regarding the specified indication
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.
2.1.1Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
1According to “Note for guidance on Quality of herbal medicinal products” (CPMP/QWP/2819/00…)
2According to “Note for guidance on Specifications: Test procedures and acceptance criteria for herbal drugs, herbal preparations and herbal medicinal products” (CHMP/QWP/2820/00)
3According to the Guideline on the clinical assessment of fixed combinations of herbal substances/herbal preparations (EMEA/HMPC/166326/2005)
Major chemical constituents
The major constituents are menthol
Antispasmodic action on the smooth muscle
Peppermint oil as a 1 % emulsion exhibited relaxant effects on tracheal smooth muscle of the guinea pig: the I50 was
Peppermint oil emulsified with tween, 1% in aqueous solution, relaxed chemically contracted guinea pig taenia coli (I50: 22.1
μg/mL) and inhibited spontaneous activity in the guinea pig colon (I50: 25.9
μg/mL) and rabbit jejunum (I50: 15.2
μg/mL). Using whole cell clamp configuration in these jejunal muscle cells, the potential
Both menthol and peppermint oil inhibited specific [3H] nitrendipine and [3H] PN
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.
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
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)
To characterize the effects of peppermint and caraway oil individually and in combination on the visceral nociception in a rat model of
Individually both oils had no significantly effect on
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
Peppermint oil showed antimicrobial and antiplasmid activity, demonstrating a synergistic additive interaction with oxytetracycline (Schelz Z, 2006).
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).
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
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
2.1.2Assessor’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
Peppermint appears to have antiseptic properties in vitro and cholagogic action in vivo, but had no significantly effect on
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
2.2.1Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
The absorption rate for Peppermint oil was measured after the application of eserine in a peppermint oil vehicle, to a 2.2cm2 shaved area on the abdomen of mice. The latent period between application and the
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
Oral absorption and metabolism
The major biliary metabolite is menthol glucuronide, which undergoes enterohepatic circulation.
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).
The urinary metabolites result from hydroxylation at the
2.2.2Assessor’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
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
2.3.1Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
Peppermint, pulegone, menthofurane
The oral LD50 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
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).
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 observed75. 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).
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
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
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).
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)
No teratogenic effects were noted after oral intubations of Brazilian menthol on pregnant mice, rats, hamsters and rabbits (Food and Drug Research Labs, 1973).
The National Cancer Institute found no evidence of carcinogenicity after dosing Fisher 344 rats with 3750 or 7500 ppm oral dose, or B6C3F1 mice with 2000 or 4000 ppm d,
After 20 weeks of oral dosing with 1%
–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.
18.104.22.168Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
Peppermint oil is relatively rapidly absorbed after oral administration and eliminated mainly via the bile.
To determine the disposition kinetics and to examine subjective and cardiovascular effects of menthol, was conducted a crossover
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.
Using sensitive and selective
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
The excretion in the breast milk is undetermined.
22.214.171.124Assessor’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
126.96.36.199Overview 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).
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
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).
Another comparative study, with 383 patients on DCBE
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
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)
188.8.131.52Assessor’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.
3.2Clinical Efficacy Studies
3.2.1Dose response studies
There are no
The recommended dosage of 0.2 ml – 0,4ml for adults, elderly and children over 12 years (2
3.2.2 Clinical studies (case studies and clinical trials)
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
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.
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.
–In a double blind, crossover study, 40 irritable bowel syndrome patients were treated orally for 2 weeks with peppermint oil in
On one review, 16 clinical trials in the literature search using
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).
1 Rees (1979)
2 Evans et al. (1982)
3 Dew et al. (1984)
4 Nash et al. (1986)
5 Mu¨ nst et al.
6 Weiss and Ko¨ lbl
7 Lawson et al.
8 Lech et al. (1988)
9 Wildgrube (1988)
10 Carling et al.
11 Schneider and Otten (1990)
12 Fernandez (1990)
13 Ambross (1990)
14 Shaw et al.
15 Liu et al. (1997)
16 Kline and Barbero (1997)
db,co,wash out period db,co,randomized, wash out? db,co,wash out period
db,co,no wash out, randomized
db,co,wash out, double dummy, randomized db,pg,randomized
db,co,no wash out
Matched pairs, db pg,
db,3 way co, wash out
db,co,wash out, randomized Open db,co,randomized
Open, pg, randomized
One to two capsules t.i.d.b
One to two capsules t.i.d.d
One to two capsules t.i.d.b
Two capsules t.i.d.a
One capsule t.i.d.a
One capsule t.i.d.a
One capsule t.i.d.b
One capsule t.i.d.d
One to two capsules t.i.d.a and matching
One capsule t.i.d.a
One capsule t.i.d.b
Not specified One capsule t.i.d.a
One capsule t.i.d. or q.i.d.a
One to two capsules t.i.d.a
db ¼ double blind, co ¼ cross over, pg ¼ parallel groups. A Colpermins .
DUnspecified PO formulation.
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
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
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 treatment56.
–A placebo controlled
during 5 days. No differences were found in abdominal distension, flatulence or abdominal pain between the two groups. Peppermint oil was not effective, but safe61.
–In a double blind, randomized, placebo controlled, multicentre,
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).
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)..
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
The Commission E monograph also describes a cholagogic action to peppermint oil.
Another study examined the influence of essential oils and components (peppermint, jasmine, ylang- ylang, 1,
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).
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
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.
The analgesic effect of peppermint oil (10% in ethanol) was investigated in 32 healthy subjects in a double blind
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
The effect of a locally applied peppermint oil preparation on
The topical application of peppermint oil produces a prolonged cold sensation at the local of application, by the stimulation of the
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.
Report of a post herpetic neuralgia on a 76 years woman, with relief of the pain during
3.2.3 Clinical studies in special populations (such as elderly and children)
Clinical studies in children
In a randomized,
3.2.4 Assessor’s overall conclusions on clinical efficacy
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.
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
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
The carminative properties attributed to peppermint were documented by the literature, helping to relief the flatulence.
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.
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
Cholagogic, cholelitolytic, and choleretic
Some studies appointed cholagogic, cholelitolytic, and choleretic properties, but some more trials are necessary, with a better design.
According to the IHS classification
Tension-type headache (TTH)
2.1 Infrequent episodic
2.4.1Probable infrequent episodic
2.4.2Probable frequent episodic
2.4.3 Probable chronic
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
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
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)
3.3Clinical Safety / Pharmacovigilance
Peppermint essential oil widely used in flavouring, cosmetic formulations and
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
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
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
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
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
PO caused the typical GI effects like heartburn and anal / perianal burning or discomfort sensations in a literature search; 16 clinical trials investigating
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).
A case of asthma due to menthol is reported in a
A form of stomatites and glossites with extremely prominent circumvallated papillae in patients who consumed excessive amounts of
A literature review of cases of human intoxication with pennyroyal oil (pulegone content
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).
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)..
3.3.3Serious adverse events and deaths
Anaphylactic shock is reported (Germany).
3.3.5Safety in special populations and situations
184.108.40.206 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
and/or peppermint, with 1 patient sensitive to both agents, 3 positive to menthol only and 1 to peppermint only. 4 cases with recurrent
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).
Peppermint oil used on the skin with
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.
220.127.116.11Use 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.
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
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).
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)
18.104.22.168Withdrawal and rebound
22.214.171.124Effects on ability to drive or operate machinery or impairment of mental ability
Hypersensitivity to peppermint and menthol.
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)
Open skin areas of small children, especially on the nose, face and chest, are not recommended. Children under 2 years of age.
3.3.6Assessor’s overall conclusions on clinical safety
The adverse events reported were generally mild and transient, in the doses recommended for the therapeutic indications, in
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
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.
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
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
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
• 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.
PROPOSED COMMUNITY HERBAL MONOGRAPHS FOR
MENTHA X PIPERITA L., AETHEROLEUM
III.ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS THEREOF WITH TRADITIONAL USE
Mentha x piperita
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
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.
Description of the traditional herbal substance(s), herbal preparation(s) or combinations thereof
Herbal substance(s)4 5:
Mentha x piperitae L., aetheroleum
Herbal preparation(s)1 2:
Menthae piperita aetheroleum
2TRADITIONAL 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.
Information on period of medicinal use in the Community regarding the specified indication
See point 2.3.1
2.2Type of tradition, where relevant
2.3Bibliographic/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
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.
4According to “Note for guidance on Quality of herbal medicinal products” (CPMP/QWP/2819/00…)
5According to “Note for guidance on Specifications: Test procedures and acceptance criteria for herbal drugs, herbal preparations and herbal medicinal products” (CHMP/QWP/2820/00)
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;
There is a reference on Martindale The Extra Pharmacopoeia, 27th 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 (3rd 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
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 2nd edition
4.Myalgia and neuralgia – Commission E Monographs
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))
7.Symptomatic treatment of coughs and colds – ESCOP monograph 2nd 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
2.3.2Evidence regarding the specified strength
Peppermint oil should be used with caution. Doses of menthol over 1 g/Kg b.w. may be deadly.
The data from
Germany, on the authorized products is mentioned:
Indication 2, 5% – 100% essential oil – cutaneous liquid
From Martindale The Extra Pharmacopoeia, 27th 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:
In nasal ointments
Indication 3 – In dilute liquid or semisolid preparations equivalent to 1,1 – 1,0% m/m menthol or 1.25 – 16% m/m menthol.
2.3.3Evidence regarding the specified posology
3 or 4 drops of the oil added to hot water, up to three times daily (Germany – authorized medicinal products, ESCOP, Commission E monographs)
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)
For oral use:
6 – 12 drops daily, that means: 2 – 3 times daily
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)
2.3.4Evidence regarding the route of administration
See point 2.3
2.3.5Evidence 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.
2.4Assessor’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.
2.5Bibliographic review of safety data of the traditional herbal medicinal substances
See point 3.3.2
2.5.3Serious events and deaths
2.5.4Intrinsic (including elderly and children)/extrinsic factors
See point 126.96.36.199
Drug-drug interactions and other interactions
Peppermint oil used on the skin with
2.5.6Use in pregnancy and lactation
Inhalation of larges doses of menthol may lead to dizziness, confusion, muscle weakness, nausea and double vision 107.
For oral mucosal use see point 188.8.131.52.
2.5.9Withdrawal and rebound
2.5.10Effects on ability to drive or operate machinery
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).
Non-clinical safety data
2.6.1Overview 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).
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
The indications proposed, which demonstrated traditional use and plausibility, according to the pharmacological properties, are the following:
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.
IV) For the relief of symptoms in coughs and colds.
V)For the relief of symptoms in coughs and colds
PROPOSED COMMUNITY HERBAL MONOGRAPHS ON
MENTHA X PIPERITA L., AETHEROLEUM
6 Not required as per Article 16c(1)(a)(ii) of Directive 2001/83/EC as amended