Herb-Drug Interactions: Peppermint

2011

Mentha piperita L. (Lamiaceae)

Synonym(s) and related species

Black mint (Mentha piperita Sole), White mint (Mentha piperita Sole).

Note that Mentha x piperita L. is a hybrid between Mentha spicata L. and Mentha viridis L.

Pharmacopoeias

Concentrated Peppermint Emulsion (British Ph 2009); Gastro-resistant Peppermint Oil Capsules (British Ph 2009); Peppermint (US Ph 32); Peppermint Leaf (British Ph 2009, European Ph 2008); Peppermint Leaf Dry Extract (European Ph 2008); Peppermint Oil (British Ph 2009, European Ph 2008, US Ph 32); Peppermint Spirit (British Ph 2009, US Ph 32); Peppermint Water (The United States Ph 32).

Constituents

Essential oils, including menthol, menthone, menthyl acetate as the main components, and cineole, isomenthone, neomenthol, piperitone, pulegone and limonene. A maximum level of pulegone is permitted, since this is toxic, see pennyroyal. Peppermint also contains flavonoids such as rutin, menthoside, luteolin and phenolic acids, and lactones.

Use and indications

Peppermint leaf and distilled oil have carminative, antispasmodic, diaphoretic and antiseptic properties, and are mainly used to relieve symptoms of indigestion. Peppermint is commonly used as a flavouring ingredient in food, cosmetics and medicines.

Pharmacokinetics

Peppermint tea was found to inhibit the activity of the cytochrome P450 subfamily CYP2E by up to 40% in a study in rats pretreated for 4 weeks with the tea. In an in vitro study, peppermint oil 20 to 500 micrograms/mL was found to moderately inhibit the activity of the cytochrome P450 isoenzymes CYP2C8, CYP2C9, CYP2C19 and CYP2D6.

Both these studies found that there was no significant inhibition of CYP3A4 by peppermint, but see also calcium-channel blockers and ciclosporin. Peppermint oil does not appear to have any clinically relevant effects on the cytochrome P450 isoenzyme CYP1A2, see caffeine. For information on the pharmacokinetics of individual flavonoids present in peppermint, see under flavonoids.

Interactions overview

Food and antacids may compromise the enteric coating of some commercially available peppermint oil capsules. Peppermint oil appears to increase ciclosporin and felodipine levels and topically, in high doses, it may also enhance the skin penetration of some topical medicines. Peppermint tea contains digoxin-like constituents, but the clinical relevance of this is unclear. It may also impair iron absorption, and is unlikely to have a significant effect on the pharmacokinetics of caffeine.

For information on the interactions of individual flavonoids present in peppermint, see under flavonoids.

Peppermint + Antacids

Antacids may compromise the enteric coating of some commercially available peppermint oil capsules. H2-receptor antagonists and proton pump inhibitors may interact similarly.

Evidence, mechanism, importance and management

The manufacturers of some enteric-coated peppermint oil preparations advise that indigestion remedies (antacids) should not be taken at the same time as peppermint oil. This is presumably because a marked rise in pH caused by antacids might cause premature dissolution of the enteric coating and release of the peppermint oil in the stomach, which increases the risk of heartburn with the preparation. Separation of administration by a couple of hours usually avoids this type of interaction with antacids. Some monographs extend this advice to H2-receptor antagonists and proton pump inhibitors and suggest that these drugs should be avoided.

Peppermint + Caffeine

Peppermint oil does not appear to affect the metabolism of caffeine but might slightly delay its absorption.

Clinical evidence

In a crossover study in 11 healthy women, a single 100-mg capsule of menthol (a major constituent of peppermint oil) taken with decaffeinated coffee, to which 200 mg of caffeine had been added, had no effect on caffeine pharmacokinetics except for an increase in time to maximum caffeine concentration of about 30 minutes. The maximum decrease in heart rate seen with caffeine was less in the presence of menthol (about 4 bpm difference), but menthol had no effect on the small changes in blood pressure seen with caffeine.

Experimental evidence

One in vitro study and one animal study found that peppermint oil or tea inhibited the cytochrome P450 isoenzyme CYP1A2.

Mechanism

Experimental evidence suggests that peppermint might inhibit cytochrome P450 isoenzyme CYP1A2, for which caffeine is a probe substrate; the clinical evidence with menthol (a major constituent of peppermint oil) found that caffeine metabolism was not altered. Menthol slightly delayed the absorption of caffeine.

Importance and management

The clinical evidence suggests that peppermint oil might not have clinically relevant effects on the metabolism of substrates of CYP1A2, which would be in keeping with the fact that no such interactions appear to have been reported. Peppermint oil might slightly delay the absorption of caffeine, and presumably other drugs, but the delay of 30 minutes suggests that this is usually unlikely to be clinically relevant.

Peppermint + Calcium-channel blockers

Peppermint oil capsules appear to increase the bioavailability of felodipine, and therefore may increase the incidence of adverse effects such as headache, light-headedness and flushing. In vitro experiments suggest that peppermint oil is a moderate inhibitor of nifedipine metabolism.

Clinical evidence

In a randomised, single-dose study in 12 healthy subjects peppermint oil capsules 600 mg increased the AUC and maximum serum levels of extended-release felodipine 10 mg by about 55% and 40%, respectively, without affecting the half-life. The AUC and maximum serum levels of dehydrofelodipine, the metabolite of felodipine, were increased by 37% and 25%, respectively.

Experimental evidence

Peppermint oil and two of its components, menthol and menthyl acetate, were found to be moderate reversible inhibitors of nifedipine metabolism in in vitro investigations in human liver microsomes.

Mechanism

It is thought that menthol may account for a substantial portion of the interactions reported for peppermint oil. Felodipine undergoes at least two sequential metabolic steps mediated by CYP3A4 and the authors of the clinical study suggest that peppermint may selectively inhibit the secondary step as opposed to the primary step but further study is needed. In contrast, two other in vitro studies found that peppermint did not affect CYP3A4, see Pharmacokinetics.

Importance and management

The clinical study suggests that peppermint oil may modestly increase the bioavailability of felodipine, which might therefore increase the incidence of adverse effects such as headache, light-headedness and flushing. Further study is needed, but, until then, it would be prudent to be aware of this possibility in any patient taking felodipine if they are given oral peppermint oil. It is possible that not all calcium-channel blockers will be affected, since some, unlike felodipine, are highly bioavailable. This interaction is similar to that of grapefruit juice, which affects felodipine and nisoldipine (low oral bioavailability), but only minimally affects amlodipine and diltiazem (high oral bioavailability).

The data would be expected to have relevance only to therapeutic doses of oils, and not to herbal teas, or small amounts in foods, where no clinically relevant interaction is anticipated.

Peppermint + Ciclosporin

The interaction between peppermint oil and ciclosporin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a single-dose study in rats, peppermint oil 100 mg/kg mixed with ciclosporin (Sandimmune formulation) almost tripled the AUC and maximum serum levels of ciclosporin 25 mg/kg.

In vitro studies also found that peppermint oil 50 micrograms/mL inhibits ciclosporin metabolism in rat liver microsomes by up to 85%.

Mechanism

Unclear. The authors rule out P-glycoprotein inhibition as a potential mode of action. They say that inhibition of the cytochrome P450 subfamily CYP3A may have a role, and enhanced gastrointestinal permeability may also be a factor.

Importance and management

Although clinical data are lacking, the experimental study demonstrates that peppermint oil significantly enhances the oral bioavail-ability of ciclosporin in rats. Further study is needed to see if a similar effect occurs in humans. Until then, it may be prudent to be aware of the possibility that peppermint oil might increase ciclosporin levels. If patients taking ciclosporin are given peppermint oil it may be prudent to monitor ciclosporin levels within a few weeks of starting concurrent use, if this is not already planned.

The data would have relevance only to therapeutic doses of oils, and not to herbal teas, or small amounts in foods, which would not be expected to interact to a clinically relevant extent.

Peppermint + Digitalis glycosides

Many herbal medicines contain cardiac glycosides, which could in theory have additive effects with digoxin or digitoxin, or interfere with their assays. However, there appear to be few such interactions reported.

Evidence, mechanism, importance and management

In an in vitro study, 46 commercially packaged herb teas and 78 teas prepared from herbs were assayed for digoxin-like factors by their cross-reactivity with digoxin antibody, and these values were used to give approximate equivalent daily doses of digoxin. Peppermint was found to contain greater than 30 micrograms of digoxin equivalents per cup and was suggested that this would provide a therapeutic daily dose of digoxin if 5 cups of peppermint tea a day were drunk.However, note that some common teas sampled in this study (e.g. English Breakfast, Earl Grey) contained over 20 micrograms of digoxin equivalents per cup. Given that these teas are commonly consumed in the UK and an interaction with digoxin has not been reported, the interpretation of the findings of this study is unclear.

Theoretical interactions with herbal medicines are not always translated into practice. On the basis of this one study, no special precautions would be expected to be necessary in patients taking digoxin who drink peppermint tea.

Peppermint + Food

Food may compromise the enteric coating of some commercially available peppermint oil capsules.

Evidence, mechanism, importance and management

The manufacturers of some enteric-coated peppermint oil preparations advise that they should not be taken immediately after food.This is presumably because presence of food in the stomach will delay gastric emptying and might cause premature dissolution of the enteric coating and release of the peppermint oil before it reaches the intestine. This may result in adverse effects, such as indigestion.

Peppermint + Herbal medicines

No interactions found.

Peppermint + Iron compounds

Peppermint tea appears to reduce iron absorption similarly to conventional tea.

Clinical evidence

In a study in 9 healthy subjects a 275-mL serving of peppermint tea reduced the absorption of iron from a 50-g bread roll by about 85%. The tea was prepared by adding 300 mL of boiling water to 3 g of the herb tea, then infusing for 10 minutes before straining and serving. In this study, the inhibitory effect of peppermint tea on iron absorption was equivalent to that of black tea (Assam tea, Camellia sinensis L.), which is known to inhibit iron absorption, see Tea + Iron compounds.

Experimental evidence

Peppermint leaf tea 2.2g/kg daily was found to inhibit iron absorption in rats. Serum iron and ferritin levels were reduced by about 20%. Conversely, a tea prepared from Mentha spicata did not inhibit iron absorption to a significant extent and so the authors suggested that menthol, a major constituent of peppermint, but not Mentha spicata, is involved.

Mechanism

The polyphenols in peppermint tea may bind to iron in the gastrointestinal tract and reduce its absorption.

Importance and management

The clinical impact of this interaction between peppermint tea and iron is not fully known, but be aware that some herbal teas such as peppermint reduce iron absorption similarly to conventional tea. See Tea + Iron compounds. Note that tea and coffee are not generally considered to be suitable drinks for babies and children, because of their effects on iron absorption.

Peppermint + Miscellaneous

The information regarding the use of topical peppermint oil preparations is based on experimental evidence only.

Evidence, mechanism, importance and management

Preliminary in vitro experiments using human skin samples have found that low-dose peppermint oil (0.1% and 1%) on the skin surface can significantly reduce the amount of topical benzoic acid penetrating the dermal barrier. Conversely, at higher concentrations (5%), peppermint oil decreased the integrity of the dermal barrier. In another study, peppermint oil enhanced the fluorouracil permeation across rat skin.

These experimental studies suggest that topical peppermint oil might increase the absorption of other topical drugs; however, there is currently insufficient evidence to make any clinical recommendations.