Peppermint

Peppermint is a common spice that is a cross between two plants, watermint (Mentha aquatica) and spearmint (Mentha spicata) and is sometimes also referred to by the name of Mentha piperita or balsamea; the mentha genera refers to all mint plants in general, and they all belong to the Lamiaceae family.^[1] The herb is a traditional medicine for mostly gastrointestinal disorders,^[2] and has a GRAS status.

Peppermint is a hybrid plant, and it appears to have some medicial usage for gastrointestinal complications as well as being a general flavoring agent and spice

The essential oil fragment of peppermint oil (commonly called the 'peppermint oil') contains:

• (-)-Menthol (2-isopropyl-5-methyl-cyclohexanol), seen as the main active ingredient^[3] at 33-55% of the oil^[4][2] with some reports noting up to 75%^[5]
• (-)-Menthone (14-33%)^[4]
• (-)-Isomenthone (1.5-10%)^[2]
• Neomenthol (trace to 4.6%^[6])
• (+)-Menthofuran (1-9%)^[2][6]
• 1,8-Cineole (3.5-14%)^[4][2]
• Menthyl acetate (2.8-10%)^[4][2]
• (-)-Mintlactone^[7]
• (+)-Isomintlactone^[7]
• (+)-pulegone (0.8-24.9%, highest in very young leaves and progessively declines^[6])
• Limonene (1.3-26.8%, highest in very young leaves and progessively declines^[6])
• Linalool (0.2-0.8%^[6])
• Piperitone (0.7-1.2%^[6])
• Sabinene (0.3-1.6%^[6])
• Myrcene (trace to 0.7%^[6])
• α-pinene (0.8-2%^[6])
• β-pinene (1.0-2.9%^[6])
• α-terpineol (trace to 0.4%^[6])

For the most part, the composition of peppermint oil is menthol. Very young leaves (not commonly used in supplementation) are a good source of limonene and pulegone, but these decline over the process of the leafs aging process and the oil accumulates around a third to half of its weight as menthol

Adding the scent and taste of peppermint to bitter tasting capsules (in this study, Famotidine) is able to mask the bitterness when orally ingested, and words in an additive manner with physical methods (coating a capsule to prevent the bitter molecules from touching sensors on the tongue).^[8]

May be useful in masking bitter tones

'Colpermin' is a pharmaceutical brand name for peppermint oil, in which one capsule contains 0.1mL of peppermint oil concentrated to 187mg of bioactives^[9][10] and around 60mg menthol per 0.1mL.^[11] Colpermin is a gel capsule with an enteric coating, and is unlikely to influence the esophageus or stomach as it disintegrates in the pH of the intestines

Mintec is also a delayed release formulation of peppermint oil with a somewhat comparable menthol content (110+/-5mg per 0.2mL or 55mg per 0.1mL^[11]) although mintec has a slightly faster release rate than does Colpermin.^[11]

Colpermin and Mintec are two brand names that both are enteric coated capsules with a delay release, designed specifically for the treatment of intestinal complications (since enteric capsules are degraded in the intestines and not stomach) and bypassing anything in the stomach or esophagus

Menthol-β-D-glucuronide is a prodrug variant of menthol. It is a glucuronide conjugate, and it is stable in the stomach and small intestine while degraded in the cecum and colon; this is thought to avoid any muscle relaxing properties in the esophagous or stomach while retaining the therapeutic effects on IBS and the colon.^[12]

Menthol-β-D-glucuronide is a variant of menthol that aims for the same purpose as enteric coated capsules, but it itself is not an enteric coating

Menthol appears to be metabolized predominately to menthol glucuronide in humans, with urinary menthol glucuronide reaching 65–68% of all absorbed menthol.^[13] Other minor metabolites include hydroxyl menthol glucuronide, dihydroxyl menthol glucuronide, and menthol sulfoconjugate and some metabolites such as aldehyde-hydroxyl menthol glucuronide or dialdehyde menthol glucuronide were barely detectable.^[13]

The half-life of menthol appears to be an average of 1.34 hours or slightly longer,^[11][13] but with a large range of 0.42–5.84 hours.^[13]

Menthol has a fairly wide variation in serum concentration and the time required to reach peak levels, and seems to be mostly metabolized by phase II conjugation (glucuronidation)

Topical application of aminophylline in a base of peppermint oil appears to have greater absorption relative to aminophylline alone (28% increased peak absorption), which was significantly greater than rosemary and ylang oils yet lesser than jojoba and ethanol.^[14]

Peppermint also appears to be recommended for headaches via topical application^[15] and a solution containing 10% peppermint oil and 90% ethanol has been shown to be bioactive in humans;^[16][17] while the aroma of peppermint was not ruled out in these studies, it is plausible that it can be topically absorbed.

Usage of peppermint oil as a base may enhance the absorption of other molecules slightly (less than ethanol as a reference) and it itself may be topically absorbed

Menthol appears to inhibit calcium channels with an IC₅₀ in the range of 7.7-28.1µg/mL (intestinal cells), 17.2-26.6µg/mL (retinal cells), and 10.1-68.5µg/mL (cardiac cells) and is about two-fold more potent than peppermint oil itself (IC₅₀ on retinal cells being 20.3-41.7µg/mL).^[3] It seems to influence intestinal cells more than cardiac and neuronal cells, and it is competitive with the pharmaceutical calcium channel blocker nitrendipine (when either menthol or peppermint oil is at 78µg/mL).^[3]

Menthol appears to be a calcium channel antagonist at the same binding site as nitrendipine

Menthol has been confirmed to inhibit coumarin 7-hydroxylation (CYP2D6 mediated) with an IC₅₀ of 70.49μM (the (-)-menthol isomer) or 37.77μM (the (+)-menthol isomer)^[18] which is thought to underlie the increased ratio of nicotine to cotinine seen with coingestion of peppermint tea with nicotine,^[19] as nicotine is converted to cotinine by two enzymes (one of which is CYP2D6^[20]).

Peppermint also appears to inhibit CYP3A4 in a reversible manner, which was thought to be due to the menthol content; peppermint oil had a K_i of 35.9+/-3.3µg/mL and menthol a K_i of 87.0+/-7.0nM/mL.^[21] This was confirmed to increase the AUC of felodipine by 140%, which underperformed relative to grapefruit juice as a reference (173%).^[21]

Peppermint oil, due to the menthol component, appears to inhibit both the CYP2D6 enzyme and the CYP3A4 enzyme. This suggests a possibility for drug-drug interactions

Peppermint oil is commonly used in aromatherapy as a stimulating/arousing scent, which may be related to the 1,8-cineole content (thought to be the stimulating component in rosemary^[22]) which is present at 3.5-14% of the essential oil.^[2]

In an (unblinded) study using either peppermint or ylang-ylang (Cananga odorata) aromatherapy versus control, usage of a steam distiller to spread the aroma five minutes prior to cognitive testing found that peppermint failed to be associated with improved memory or recall and no significant alterations in cognition (speed, accuracy, and quality of memories or mood)^[23] although elsewhere during a sustained visual attention task (40m) task peppermint aroma (rated as pleasant to smell) has been noted to improve performance relative to no aroma.^[24] One trial has investigated the influence of peppermint aroma (20µL) on vigilence, and noted that it was improved relative to control early on in testing but not later on (whereas linalyl acetate, a component of lavender, was effective later).^[25]

There does appear to be some interactions with peppermint and attention, although it is not clear exactly how this interaction works. Beyond that, it is not sure if the influence on attention is due to the menthol component itself or due to the perception of a pleasurable scent (a relatively large confound in aromatherapy research)

A pilot study on aromatherapy assigning persons to either an aroma mixture (5:4:2:1 ratio of peppermint, basil, jojoba, and helichrysum) or placebo (rose water) noted that the intervention group had a significantly greater reduction in symptoms of mental fatigue and exhaustion (as assessed by a 0-10 rating scale), although the magnitude was small (0.2 point reduction).^[26]

No convincing evidence for an anti-fatigue effect of peppermint, as the only human study is confounded with other herbs and has a very small effect size

Beyond the traditional recommendations for peppermint oil against digestive disorders and its use as a carminative, it has also been recommended for reducing nausea (mostly secondary to its relaxing effect on stomach tissue).^[27] Peppermint (as well as various other aromatics) have been noted to be useful during labor, with half of women (n=8,058) rating aromatherapy as helpful and it being associated with less pain medication usage.^[28] Specifically for nausea, there were more women reporting peppermint oil as helpful (44-54%) than not helpful (11-17%).^[28]

Peppermint (as a spirit; peppermint in an aromatic ethyl alcohol base used as aromatherapy) is able to reduce post-operative nausea relative to control and placebo in women who underwent C-sections when aromatherapy is administered when women started to feel nauseous.^[27] The efficacy in this trial was relatively large, causing 55% of the subjects to experience no nausea within 5 minutes of inhalation and reducing the 55% of women who reported that they were 'about to vomit' down to 5-9% within 2-5 minutes.^[27]

A small placebo controlled pilot study in women who underwent major gynaecological surgery with peppermint essence (no menthol content) as placebo, the aroma of peppermint oil was associated with some slight reductions in nausea.^[29] A later double blind study in persons with postoperative nausea using the inhalation of peppermint oil noted that the benefits observed (reductions on a 100mm VAS scale from 60.6 down to 28) was not significantly different than placebo.^[30] This study did use a controlled breathing technique which could have explained the observed reductions in nausea, but it remains a possiblity that the peppermint that was lightly infused into the nurses masks (to blind the treatment to participants) could have influenced all groups.^[30]

Peppermint as aromatherapy is traditionally recommended for nausea, and while most preliminary research came back very positive the two double blind trials are opposite of each other (the more statistically robust one potentially having complications with the methods, and the one showing promise being much less robust). More evidence is needed

Peppermint appears to be traditionally recommended as a remedy for headaches when topically applied to the head.^[15]

10% peppermint oil preparation (90% ethanol) was effective in reducing tension headaches within 15 minutes when applied to the head at the onset of headaches and again at both 15 and 30 minutes afterwards; its potency was comparable to 1,000mg of the reference drug acetominophen with both treatments exceeding placebo.^[16] This same method of application has been used elsewhere in tension headaches (with or without 5% eucalyptus oil) with peppermint oil being confirmed to reduce temporal muscle activity by 28.8% (assesed by EMG) and improved mood state (irritability) relative to placebo.^[17]

It is thought that peppermint may also be beneficial for migraines since one of the measurements (Contingent negative variation or CNV) is known to be significantly increased in migraines without aura^[31] and it has been noted to be reduced by 35.3% with topical application of peppermint oil.^[17]

In tension headaches, peppermint as a topical application appears to be able to reduce muscular tension and improve symptoms associated with headaches. It is thought that this may be useful for migraines, and is effective within 15 minutes of topical application

Peppermint oil has been noted to inhibit the short circuit current (SCC) associated with glucose uptake at a concentration of 1-5mg/mL by around 58-59% (no concentration dependence noted, but 0.1-0.5mg/mL was ineffective) without any influence on basal SCC.^[32] This was though to be related to sodium channel inhibiting properties (since sodium dependent processes such as glycine or glucose absorption were also inhibited), and peppermint oil was able to inhibit glucose uptake in vitro by 45-65%.^[32]

It is plausible that peppermint can inhibit glucose uptake, but this has not yet been tested for biological relevance

Peppermint has been noted to influence up to 10.7% of muscle activity via aromatherapy, although the degree of change (stimulation of sedation) was not reliably predicted.^[33]

Aromatherapy of peppermint appears to influence muscle contractility, although how it influences it is not certain

The muscle relaxing properties of peppermint oil appear to apply to the throat and esophagus, insofar that peppermint oil is one of the first therapies to recommend in persons with esophageal spasms (after nitrates and calcium channel blockers).^[34]

In persons with diffuse esophageal spasm (a relatively rare esophageal disorder associated that may cause chest pain and dysphagia^[35][36]), supplementation of peppermint oil at 5 drops (in a 10mL solution) is able to abolish esophageal spasms in all patients tested in a pilot study.^[37]

Peppermint oil has shown antispasmolytic activity in a few medical instances, such as barium meal examination^[38] and during esophagogastroduodenoscopy where 20mL of a solution containing 1.6% peppermint oil performed equally to the other two therapies (20mg hyoscine butyl bromie and 1mg glucagon injections).^[39]

The muscle relaxing properties of peppermint oil appear to occur in the esophagous, and conditions associated with abnormal contractility or spasms are effectively treated with very low doses of peppermint oil

Gastroesophageal reflux disease (GERD; also known as heartburn and occurring when acidic stomach contents reflux into the esophagus^[40]) is known to interact with a few herbal remedies of which include peppermint^[41] which is thought to be related to the ability of peppermint to relax cells of the gastrointestinal path (IC₅₀ between 15.2-25.9µg/mL).^[42] This muscle relaxing property of peppermint oil is associated with menthol's calcium channel inhibiting properties^[4][2] and it is thought that it may benefit symptoms of GERD by accelerating the passing of food in the stomach as demonstrated in otherwise healthy men given a 200mL test solution where T_lag and the β contant were reduced (T_1/2 not); it was concluded that the early phase of gastric emptying was increased.^[43] Furthermore, peppermint oil has failed to alter gastric pH inherently although it also failed to increase the efficacy of lafutidine (H₂ receptor antagonist) in reducing gastric pH.^[44]

Conversely, it has been hypothesized that the muscle relaxing effects of peppermint may influence the lower esophageal sphincter (LES) and exacerbate acid reflux.^[15] This has not been noted in persons with diffuse esophageal spasms given peppermint oil^[37] although some cases of using peppermint oil have reported heartburn to a level greater than placebo.^[45]

The muscle relaxing properties of peppermint can increase the speed of food passing through the stomach, and that is thought to reduce symptoms of GERD. However, supplementation may also reduce lower esopageal pressure and exacerbate symptoms of GERD. Overall there are mixed effects as to whether heartburn is treated or exacerbated with peppermint oil supplemention, and it may be advisable for those with GERD to use enteric coated capsules to avoid this issue

Peppermint oil has been confirmed to, as a intragastric spray during gastrointestinal endoscopy, cause relaxation of peristalsis in the stomach and could fully inhibit it in 35.6-37.5% of patients,^[46][47] with higher rates of complete suppression in those with heliobacter pylori infection (59.1%)^[47] and the overall amount of participants reporting either absolute or moderate inhibition reaching 77.8%.^[46]

A phase II trial using 20mL of a solution with 0.4-1.6% menthol which found dose-dependent relaxation up to 0.8% (reaching 47.4%),^[48] and these studies did not use oral ingestion of peppermint oil but rather used intragastric spraying techniques (spraying the solution directly on the antrum of the stomach with a spraying catheter.^{[46][47][48][13]}

Directly spraying low doses of menthol onto the stomach wall is able to potently suppress peristalsis of the stomach due to the muscle relaxing properties of menthol. This likely applies to oral supplementation as well

Peppermint is commonly thought to aid in dyspepsia, and is a component of an anti-dyspepsia combination formula known as STW-5 (alongside Lemon Balm, Licorice, caraway, bitter candy tuft, and matricaria flower) that appears effective^[49][50][51] although a combination of just peppermint oil (36mg thrice daily) with caraway oil (20mg thrice daily) also seems effective in relieving symptoms of dyspepsia such as pressure, sensation of fullness, and pain intensity^[52][53][54] secondary to relaxing effects on the stomach wall (acute doses of 90mg and 50mg, respectively).^[55][56] Benefits are seen in functional dyspepsia^[53][54] and non-ulcerous dyspepsia^[52] with infection of heliobacter pylori not influencing efficacy.^[57]

Peppermint oil appears to be somewhat effective in reducing symptoms of dyspepsia, although most of the research uses peppermint alongside caraway oil (at a 1.8:1 ratio). It seems to benefit dyspepsia in general, and the presence or absence of ulcerations of heliobacter pylori does not influence efficacy

In the intestines, peppermint has been noted to increase the DE₅₀ and reduce maximum contractility of intestinal cells by acetylcholine and histamine,^[42][58] which was the most potent herb tested in this study against acetylcholine (Carum carvi, Matricaria chamonilla, and Melissa officinalis which was inactive) but underperformed relative to Citrus aurantium on histamine.^[58] 10mL pepperment oil (per liter solution) was as effective as 130µg atropine.^[58] These effects have been replicated elsewhere in other digestive tract tissue (including the trachea and sphincter of Oddi)^[59][60] and has also shown efficacy against carbachol-contracted ileal cells and serotonin induced contractions,^[42] and the observed relaxing effects are mostly due to the menthol content.^[2]

Peppermint oil (mostly menthol) appears to be able to relax muscle cells in the intestines as well as other muscle tissue in the gastrointestinal tract, and this relaxation appears to be relatively potent when compared against other herbs and quite general against various contracting stressors

When looking at the colon, one study (pepperment enemas) has noted a transient decrease in colonic motility associated with a 1mg/mL concentration of menthol causing reductions in colonic pressure.^[61]

One study in persons given colpermin capsules (0.2mL peppermint oil per capsule) four hours prior to a colonoscopy, the colonic spasms and pain associated with colonoscopy were significantly reduced and the treatment was deemed as more tolerable by both patient and practitioner.^[62]

Possibly general anti-diarrhetic and known relaxing effects in the colon, and in humans the relaxing effect of peppermint oil on the colon seems to occur within four hours of absorption

Peppermint oil has been noted to be somewhat beneficial as a first-line treatment (due to low cost and side-effects) in some patients with IBS^[63] based on results from a meta-analysis where a cumulative 392 patients given peppermint oil or placebo noted a relative risk of 0.43 (95% CI of 0.32-0.59), suggesting a halving of overall symptoms of IBS.^[64] These studies^[65][66][67] (one not located online) using a dosage in the range of 187-225mg two to four times daily (the ultimate dosage range being 450-750mg) and the reduced symptomology was mostly associated with abdominal pain and diarrhea. This was confirmed in a later study, where although abdominal pain and diarrhea were benefitted with peppermint oil other symptoms were unaffected.^[68]

Other studies not included in the aforementioned meta-analysis note that peppermint oil thrice daily over six weeks that is able to induce a reduction in symptoms (20%) yet is no longer effective two weeks after supplement cessation,^[68] and that Colpermin tablets given to outpatients with IBS was able to reduce abdominal pain and improve quality of life over 14 weeks.^[69] Colpermin tablets (3-6 capsules of 0.1mL; containing 187mg peppermint oil per capsule) appears to also be effective in children in the age range of 8-17.^[9]

Peppermint oil appears to be quite effective and reliable for reducing abdominal pain specifically in persons with irritable bowel syndrome, although this effect is only a band-aid effect and not curative

Peppermint oil appears to be traditionally recommended for the dissolution of gallstones^[70] and rat studies with oral ingestion of 100-1,000mg/kg peppermint oil have noted 30-140% increases in bile secretion^[2] which were later found to be dose and time dependent.^[71]

In a study using urosdeoxycholic acid (UDCA) at 11.1mg/kg in persons with gallstones and comparing it to an UDCA and menthol combination therapy (both at 4.75mg/kg) failed to note any differences in overall response rates but enhanced the frequency of complete dissolutions (up to 53% from 38%).^[70]

May possess chloretic activities and caused a reduction in gallstones

In southwestern Turkey, ingestion of peppermint or spearmint tea is said to cause a reduction in libido.^[72]

The addition of peppermint to rat drinking water at 20g/L (equal to making 250mL of tea from 5g of tea leaves) was able to reduce circulating testosterone by 23% although a more significant reduction was noted with spearmint (51%).^[73]

In women with hirsutism (21 overall, 12 diagnosed with PCOS), ingestion of spearmint tea at 5g tea leaves twice daily is associated with a significant reduction in free testosterone (29%) without altering total testosterone levels^[72] which has been confirmed in other trials.^[74] It is unsure if this applies to peppermint, as while peppermint is up to 50% menthol by weight spearmint is 29-74% carvone.^[75]

In rats, peppermint and spearmint both have antiandrogenic effects. Spearmint, but not peppermint, has been confirmed in human females to possess antiandrogenic effects

Supplementation of spearmint tea to women with hirsutism is able to increase circulating levels of estradiol (36%) with two 250mL cups of tea made from 5g tea leaves daily.^[72]

Peppermint has not been tested in regards to estrogen, but the related herb of spearmint has shown pro-estrogenic effects

Supplementation of spearmint tea to women with hirsutism is able to increase circulating levels of FSH (17.5%) with 10g of tea leaves in two divided doses of tea^[72] and in male rats given 20g/L peppermint in their drinking water an increase of FSH has been noted to the degree of 7.1%.^[73]

Supplementation of spearmint tea to women with hirsutism is able to increase circulating levels of LH (26.8%) with two servings of spearmint tea (5g tea leaves each time)^[72] which has been noted in rats given 20g/L of peppermint in their drinking water, causing a 21% increase in luteinizing hormone.^[73]

Supplementation of spearmint tea to women with hirsutism does not significantly alter concentrations of sulfated DHEA.^[72]

A phenomena known as 'nipple crack' (a soreness of the nipples that may ultimately cause breaking of the skin, known to reduce the frequency of breastfeeding^[76][77]) may occur in breastfeeding mothers, and it appears that topical application of peppermint (either water or oil) is used in some mid-eastern countries for the treatment of sore nipples from breastfeeding.^[78]

When looking at trials, applying peppermint water (via cotton) to the areola followed breastfeeding (and washing the area prior to the next session) over the course of two weeks is able to reduce the frequency of nipple cracks from 23% in control to 7% while reducing the frequency of severe symptoms from 15% down to none.^[78] Benefits have also been seen with peppermint oil in a placebo-controlled trial, where topical application for six weeks exceeded both placebo and lanolin oil (reference) in the risk of developing nipple cracks.^[79]

Peppermint oil or water appears to be effective in reducing nipple cracks when applied topically

Cigarettes tend to sometimes contain menthol as a flavoring agent and to increase the 'cooling' sensation of inhalation (they are equally dangerous as cigarettes without menthol^[80][81]) and mentholated cigarettes seem to be able to inhibit metabolism of nicotine into its metabolite cotinine^[82] which is known to correlate with urinary menthol metabolites.^[83]

The process of nicotine conversion into cotinine is first catalyzed by the CYP2D6 enzyme (to form nicotine iminium ions) and then by aldehyde oxidase to form cotinine,^[20] and a peppermint drink (3 cups of 150mL peppermint tea) has been found to increase the nicotine to continine ratio in humans (from 0.995 to 1.327; a 33% increase).^[19]

Menthol has been confirmed to inhibit coumarin 7-hydroxylation (CYP2D6 mediated) with an IC₅₀ of 70.49μM (the (-)-menthol isomer) or 37.77μM (the (+)-menthol isomer).^[18]

The addition of menthol (from peppermint) to cigarettes is common to enhance the 'cooling' sensation of inhaling a cigarette, and menthol appears to reduce the conversion of nicotine into continine via inhibiting the CYP2D6 enzyme

Ingestion of peppermint tea has been noted to inhibit the absorption of non-heme iron from a standardized meal by 84%, which was less than black tea (source of theaflavins at 79-94%) yet more than chocolate (cocoa extract) at 71%.^[84] The addition of milk did not alter absorption inhibition by peppermint tea.^[84]

May inhibit iron absorption when used as a tea

The LD₅₀ of peppermint oil in rats is 4,400mg/kg, which is approximately 300mL/kg as an estimated human equivalent.^[85]

Toxicity has been established with peppermint oil, although it requires a significantly high oral dose. The recommended doses of peppermint oil seem to be free from toxicity

It appears that two particular components of peppermint oil, (+)-menthofuran and (-)-pulegone, may be somewhat toxic due to inducing brain lesions at high doses^[86] and their usage in aromatherapy not recommended.^[29] Although the former is usually low at all times, pulegone may be in concentration as high as 24.9% in leaves that are less than a week old^[6] being reduced to less than 1% after 45 days; the recommended pulegone content for peppermint oil is less than 2%.^[29]

It may be advisable to use older leaves which bioaccumulate menthol for supplemental and aromatherapy purposes

Contact dermatitis has been reported with peppermint oil and the leaves of peppermint.^[87]

One case study appears to have associated the usage of peppermint oil with interstitial nephritis and acute renal failure (mentioned in this review^[15]).

A few case studies suggest contact dermatitis with peppermint (common among plants and plausible) and one case study has noted kidney damage (no biological plausibility, requires investigation)

One case study has noted that ingestion of peppermint oil in a hospitalized patient with diarrhea (20 loose stools daily) resulted in a large burning sensation in the anus associated with peppermint oil, but that the patient was able to tolerate peppermint oil once defecation frequency was normalized with diet.^[88]

At least one case study has noted anal burning with peppermint oil when given to somebody with severe diarrhea, the patient seemed to tolerate peppermint oil when not suffering from said diarrhea