Peppermint Pharmacology and Pharmacokinetics

Peppermint oil has been extensively researched for its effect on the
digestive system. An article in Phytomedicine details the
pharmacodynamics the fact on the gastrointestinal tract as an antispasmodic effect on smooth muscle. The authors describe the metabolism and elimination of menthol and peppermint oil.

“The principal pharmacodynamic effect of peppermint oil relevant to the
gastrointestinal tract is a dose-related antispasmodic effect on the
smooth musculaturedue 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.”

“Peppermint oil is relatively rapidly absorbed after oral administration
and eliminated mainly via the bile. The major biliary metabolite is
menthol glucuronide, which undergoes enterohepatic circulation. The
urinary metabolites result from hydroxylation at the C-7 methyl group
at C-8 and C-9 of the isopropyl moiety, forming a series of mono- and
dihydroxymenthols and carboxylic acids, some of which are excreted in
part as glucuronic acid conjugates. Studies with tritiated I-menthol in
rats indicated about equal excretion in feces and urine. The main
metabolite indentified was menthol-glucuronide. Additional metabolites
are mono- or di-hydroxylated menthol derivatives.”

[c] 2005 Published by Elsevier GmbH.

Keywords: Peppermint oil; Spasmolysis; Calcium antagonist; Antifoaming activity; Choleresis; Pharmacokinetics


Peppermint oil has a long history of safe use both in medicinal
preparations and as a flavoring agent in foods and confectionery.
Peppermint oil is indicated for both external and internal use. In an
ESCOP monograph in 1997 (ESCOP, 1997) the medicinal use is summarized
and FDA granted the oil a so-called “generally recognized as safe”
(GRAS) status (Food and drugs, 1998).

The major constituents
of the oil include the terpenes (-)-menthol (30-55%), (-)-menthone
(14-32%), (+)-isomenthone (1.5-10%), (-)-menthyl acetate (2.8-10%),
(+)-menthofuran (1.0-9.0%) and 1.8-cineol (3.5-14%).

purpose of this review is to summarize preclinical research data with
peppermint oil or its constituents, relevant to the gastrointestinal

Dynamics and mode of action

antipasmodic activity of 2.5 and 10.0 ml/l of alcoholic extracts of
Melissa officinalis, Rosmarinus officinalis, Mentha piperita,
Matricaria chamomilla, Foeniculum vulgare, Carum carvi and Citrus
aurantium prepared from 1 part of the plant and 3.5 parts of ethanol
(31% w/w) was tested employing the guinea pig ileum and using
acethylcholine and histamine as spasmogens (Forster et al., 1980). Most
of the extracts shifted the dose response curves of acetylcholine and
histamine to the right in a dose-dependent manner. Extracts from Carum
carvi, Mentha piperita, Citrus aurantium and Matricaria chamonilla
showed a significant rise of the D[E.sub.50] of acetylcholine-induced
contractions and a significant decrease of the maximal possible
contractility. In histamine-induced contractions, all plant extracts
except Extractum Melissae exhibited a significant increase of the
D[E.sub.50], and all extracts used decreased the maximal possible
contractility produced by histamine. The alcoholic extract of Mentha
piperita was most effective when tested with acetylcholine and the
extract of Citrus aurantium was most active when tested with histamine.
Melissa officinalis did not show significant antispasmodic activity.
When the antispasmodic activities of the most effective plant extracts
were compared with the activity of atropine, it was evident that their
effects were less than that of the usual therapeutic dosage of atropine
in man. The most pronounced effects with 10 ml/l Extractum Citrus
aurantii and 10 ml/l Extractum Menthae piperitae correspond to the
effect of 0.07 resp. 0.13 mg atropine.

The antispasmodic
effects of peppermint oil have been directly demonstrated in vitro in a
series of experiments with smooth muscle fibres isolated from the
guinea pig, including the trachea and ileum (Reiter and Brandt, 1985;
Taddei et al., 1988) and the sphincter of Oddi (Giachetti et al.,
1988). Peppermint oil was shown to be effective in reducing muscle tone
in all three systems either at rest or following electrical stimulation
or morphine treatment. The effects of peppermint oil were shown to be
due largely to its menthol constituent.

Evans et al. (1975)
studied the effect of menthol on the colonic motility in dogs.
Biological activity was estimated on colonic motility using mongrel
dogs with an exteriorized terminal ileum which allowed direct access to
the colon and which had been kept in continuity with both the ileum and
the remainder of the large intestine. Each dog was given an enema on
the day prior to experimentation and colonic motility was examined by
recording intra-luminal pressure with three water-filled polyethylene
tubes inserted through the ileal stoma into the proximal, medial and
distal regions and linked to a multi-channel pen-recorder. A recording
of the normal pattern of colonic motility was first obtained following
the introduction of 30 ml normal saline into the colon. A similar
volume of menthol, at a concentration of 1.0 mg/ml, was then introduced
into the colon and the effect on intra-luminal pressure recorded. It
produced an immediate decrease in colonic motility, which lasted from
20-25 min, before the normal pattern of motility was restored.
Decreased motility was observed as a reduction in intra-luminal

Hills and Aaronson (1991) studied the mechanism of
action of peppermint oil on gastrointestinal smooth muscle in isolated
organs. Peppermint oil relaxed carbachol-contracted guinea pig taenia
coli (I[C.sub.50] 22.1 [micro]g/ml) and inhibited spontaneous activity
in the guinea pig colon (I[C.sub.50] 25.9 [micro]g/ml) and rabbit
jejunum (I[C.sub.50] 15.2 [micro]g/ml). Peppermint oil markedly
attenuated contractile responses in the guinea pig taenia coli to
acetylcholine, histamine, 5-hydroxytryptamine, and substance P.
Peppermint oil reduced contractions evoked by potassium depolarization
and calcium contractions evoked in depolarizing Krebs solutions in
taenia coli. Potential-dependent calcium currents recorded using the
whole cell clamp configuration in rabbit jejunum smooth muscle cells
were inhibited by peppermint oil in a concentration-dependent manner.
Peppermint oil both reduced peak current amplitude and increased the
rate of current decay. The effect of peppermint oil resembled that of
dihydropyridine calcium antagonists. The authors concluded that
peppermint oil relaxes gastrointestinal smooth muscle by reducing
calcium influx.

Taylor et al. (1985) studied in guinea pig
isolated ileum and human isolated taenia coli the relaxant activity of
peppermint oil and its constituents. Carbachol was used as antagonist.
Doses required to bring about 50% relaxation (I[D.sub.50]) were then
compared. Menthol (3.0 X [10.sup.-5] w/w) was the most active
constituent, being more active than peppermint oil (4.4 X [10.sup.-5]
w/w) while menthone, menthyl acetate and cineole were considerable less
active than peppermint oil. Using strips (30 X 3 mm) of human isolated
taenia coli suspended in normal Krebs’ solution bubbled with 5%
C[O.sub.2] in [O.sub.2] at 37[degrees]C, peppermint oil and menthol
inhibited basal tone and contractions to carbachol
([10.sup.-7]-[10.sup.-4]M) and to potassium chloride (5-150 mM) in a
non-competitive manner. In calcium-free, depolarizing Krebs’ solution
(mM: NaCl 82.7; KCL 40.0; NaHC[O.sub.3] 25.0; Na[H.sub.2]P[O.sub.4]
1.4; glucose 11.5) parallel shifts in dose response curves to calcium
(0.1-20 mM) indicated that peppermint oil and menthol posses specific
calcium antagonist activity. To further investigate this effect the
influx of [.sup.25][Ca.sup.2+] ([micro] mol/kg wet weight) into
carbachol ([10.sup.-6] M) or potassium (80 mM) stimulated rings of
guinea pig ileum (7-15 mg) suspended in buffered HEFES solution
containing [.sup.45][Ca.sup.2+] ([10.sup.-5] = Ci/ml) was studied.
Following carbachol or potassium stimulation the extracellular
concentration of [CA.sup.2+] increased significantly (p < 0.001).
However, in the presence of menthol (0.64 = M) no such influx was
observed. The calcium antagonist, verapanil ([10.sup.-5] M) likewise
inhibited [.sup.45][Ca.sup.2+] uptake in response to carbachol and
potassium stimulation. In addition, peppermint oil and menthol
inhibited carbachol-induced contractions of the guinea pig isolated
ileum suspended in calcium-free Tyrode’s solution in the readmission of
calcium ions, further indicating that peppermint oil and menthol are
able to inhibit carbachol-induced influx of extracellular calcium ions.

The effect of peppermint oil and menthol on isolated human
coli was investigated by Taylor et al. (1984). A total of 50 strips of
taenia, approximately 30 X 3 mm, were dissected from 20 resections for
carcinoma. Peppermint oil and menthol produced both inhibition of
spontaneous activity and decrease in basal tone in all tissues in a
dose-dependent manner. Under isotonic conditions (tension 2g),
I[D.sub.50] values (concentration of antagonist producing 50% reduction
in response to carbachol, [10.sup.-6] M) were calculated for menthol
(0.29 [+ or -] 0.11 mM; n = 5) and for peppermint oil (0.41 [+ or -]
0.06 mM; n = 5: estimated MW 160). Under isometric conditions,
dose-response curves to carbachol ([10.sup.-7]-[10.sup.-4]M and to
potassium (5-150 mM) demonstrated non-competitive inhibition by both
peppermint oil and menthol, this effect being rapidly reversible on
wash-out. In calcium-free, depolarizing Kreb’s solution (mM; NaCl 82.7;
KCL 40.0; NaHC[O.sub.3] 25.0; Na[H.sub.2]P[O.sub.4] 1.4; glucose 11.5),
dose-response curves to calcium (0.1-20 mM) showed a specific calcium
antagonist effect of menthol, which was dose-related and rapidly

Beesley et al. (1996) studied the influence of
peppermint oil on absorptive and secretory processes in rat small
intestine using both intestinal sheets mounted in Ussing chambers and
brush border membrane vesicles. Peppermint oil in the intestinal lumen
inhibited enterocyte glucose uptake via a direct action on the brush
border membrane. Intestinal secretion was inhibited by peppermint oil,
which is consistent with a reduced availability of calcium.

The action of menthol and/or peppermint oil as a calcium channel
antagonist has been demonstrated in vitro by Hawthorn et al. (1988).
These investigators used 45[Ca.sup.2+] uptake and radioligand-binding
assays to measure the effects of menthol and peppermint oil in a range
of mammalian tissues. Both showed [Ca.sup.2+] channel-blocking activity
in guinea-pig ileum, rat and guinea-pig cardiac muscle, rat brain
synaptosomes and also in chick retinal neurones. The results of binding
studies supported a [Ca.sup.2+] channel-specific effect in both cases.

Palade et al. (1989) classified menthol as activator of the
[Ca.sup.2+]-induced [Ca.sup.2+] release in sarcoplasmatic reticulum,
which more than doubled the control rate of ruthenium red-insensitive
unidirectional 45Ca efflux. Rampe and Triggle (1990) reviewed new
ligands for L-type [Ca.sup.2+] channels of different chemical
structure, among them menthol. The identity of the binding site has not
yet been established; however, such ligands were proposed for new
directions of [Ca.sup.2+] channel drug structures. Zygmunt et al.
(1993) performed structure activity studies on the calcium antagonistic
properties of terpenes and suggested that these substances represent a
new chemical class of calcium antagonists, which interact with
dihydropyridine binding sites.

Using isolated ganglia from
Helix pomatia and cultured dorsal root ganglion cells from chick and
rat embryos, Swandulla et al. (1986, 1987), Schafer et al. (1988) found
that menthol blocks currents through the low-voltage-activated Ca
channel, and facilitates inactivation gating of the classical high
voltage-activated Ca channel. Schafer et al. (1995) reported similar
findings in afferent discharges from electroreceptor organs of catfish.

These results indicate that the spasmolytic effect of
peppermint oil on the intestinal smooth musculature appears to involve
calcium antagonism. Menthol, which is the major constituent of
peppermint oil exerts its effect most probably via a calcium channel
antagonistic effect. This leads to antispasmodic activity observed in
pharmacodynamic studies with peppermint oil or menthol. The activity
appears to be dose dependent. The mechanism by which this is brought
about is associated with the ability of menthol to decrease the influx
of extracellular calcium ions through potential dependent channels.

Antifoaming activity

Harries et al. (1978) studied in an apparatus specially designed to
assess foams in digestive fluids in vitro the antifoaming effect of
various carminatives. The effects of caraway, cinnamon, dill, orange
and peppermint oils on gastric and intestinal foams were examined.
Reductions in foam volume were observed in every case, although the
effects were not as great as those produced by a combination of
dimethicone and silica. m-Cresol, p-hydroxybenzaldehyde, isobutanol,
menthol and phenoxyethanol also reduced foam volume. It is suggested
that carminative action is a combination of effects, one of which is a
reduction of gastrointestinal foam.

Choleretic activity

A choleretic action has traditionally been ascribed to peppermint oil,
in keeping with the occasional use of menthol in the treatment of
gallstones (Leuschner et al., 1988). Increases in bile production of
1.3-2.4-fold were recorded (Mans and Pentz, 1987) after oral doses of
0.1-1.0 g/kg bw in male rats. Trabace et al. (1993) found dose- and
time-dependent choleretic effects of peppermint oil and menthol in
anesthetized rats and used these as standards for testing other
essential oils. The mechanism of action underlying the observed
choleretic activity of menthol or other constituents of peppermint oil
is not clearly understood, but may result from the marked biliary
output of metabolized menthol (Mans and Pentz, 1987).


Mans and Pentz (1987) studied the pharmacokinetic behaviour of menthol
administered orally at a range of doses (0.1-1.0 g/kg b.w.) in male
rats. Plasma levels and biliary and renal excretion of unchanged versus
conjugated menthol were measured. The levels of unchanged compound were
low in plasma, bile and urine, with a preponderance of the glucuronide
(60%) present in the urine and of the sulphate (60-90%) present in the
bile. Renal recovery of total menthol within 24 h was dose dependent,
ranging from 5.4% (0.1 g/kg) to 2.1% (1 g/kg). The recovery in bile
over 8 h was substantially higher, ranging from 16% to 6% at the
corresponding dose levels. Dose-related increases in volume of both
urine and bile were recorded.


Madyastha and Srivatsan (1988) investigated the metabolism of l-menthol
in rats both in vivo and in vitro. Metabolites isolated and
characterized from the urine of rats after oral administration (800
mg/kg) of l-menthol were the following: p-menthane-3,8-diol,
p-menthane-3,9-diol, 3,8-oxy-p-menthane-7-carboxylic acid, and
3,8-dihydroxy-p-menthane-7-carboxylic acid. Repeated administration of
800 mg/kg l-menthol to rats for 3 days resulted in the increase of both
liver mitochondrial cytochrome P-450 content and NADPH-cytochrome C
reductase activity by nearly 80%. Rat liver microsomes readily
converted l-menthol to p-menthane-3,8-diol in the presence of NADPH and
O2. A metabolic pathway of l-menthol in rats was proposed. Yamaguchi et
al. (1994) administered [3-3H]-l-menthol by oral gavage to intact and
bile duct-cannulated male Fischer 344 rats at a dose level of 500
mg/kg. Excreta were collected for up to 48 h and metabolites in urine
and bile analysed by TLC, solid phase extraction, GLC, and GC/MS. In
intact rats, some 71% of the dose was recovered in 48 h with
approximately equal amounts in urine and feces. In total, 74% of the
dose was recovered from bile duct-cannulated rats, with 67% in the bile
and 7% in the urine. The major biliary metabolite was menthol
glucuronide, which undergoes enterohepatic circulation. The urinary
metabolites resulted from hydroxylation at the C-7 methyl group at C-8
and C-9 of the isopropyl moiety, resulting in a series of mono- and
dihydroxymenthols and carboxylic acids, some of which are excreted in
part as glucuronic acid conjugates. The results enabled the
construction of a metabolic map for menthol in the rat.

twofold difference in the formation rate of glucuronides of (+)- and
(-)-menthol by rat liver slices and by rat liver microsomes was found
by Caldwell (1995). The plasma elimination half-life of (-)-menthol is
2.4h compared with 4.0 h for (+)-menthol, with the plasma AUC of
(-)-menthol being threefold less than for the (+)-isomer. These
pharmacokinetic differences arise from the enormous difference between
the isomers in terms of the biliary excretion of their glucuronides:
69% of a dose of the more rapidly cleared (-)-menthol is excreted in
the bile in 24 h compared with only 32% for (+)-menthol.


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Caldwell, J., 1995.
Stereochemical determinants of the nature and consequences of drug
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H.-G. Grigoleit*, P. Grigoleit

Johann-Sebastian-Boch-Str. 27, 65193 Weisbaden, Germany

Received 13 September 2004; accepted 26 October 2004

*Corresponding author. Tel.: +49 611 520509; fax: +49 611 5990443.

E-mail address: (H.-G. Grigoleit).

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