Menthol: A refreshing look at this

ancient compound
Tejesh Patel, MD,a Yozo Ishiuji, MD,a and Gil Yosipovitch, MDa,b
Winston-Salem, North Carolina
Menthol is a naturally occurring cyclic terpene alcohol of plant origin, which has been used since antiquity
for medicinal purposes. Its use in dermatology is ubiquitous, where it is frequently part of topical
antipruritic, antiseptic, analgesic, and cooling formulations. Despite its widespread use, it was only recently
that the mechanism by which menthol elicits the same cool sensation as low temperature was elucidated
upon, with the discovery of the TRPM8 receptor. Although almost 5 years have passed since the discovery
of this receptor, many dermatologists are still unaware of menthols underlying target. The purpose of this
review is to highlight the recent advances in the mechanism of action of menthol and to provide an
overview of its dermatologic applications. ( J Am Acad Dermatol 2007;57:873-8.)

enthol (C10H20O; molecular weight, 156) is

a naturally occurring cyclic terpene alcohol of plant origin, which gives plants of
the Mentha species their distinctive smell and flavor.
It was first isolated as a crystalline principle in 1771
by the Dutch botanist Gambius. However, Shimoyama
asserted that the peppermint plant, the main source of
menthol, has been cultivated for medicinal purposes
in Japan for more than 2000 years.1
In the present day, menthol consumption is staggering, and exceeds 7000 tons annually, with a raw
product value approaching $300 million.2 Its use is
multifold and includes oral hygiene products, confectionary, pharmaceuticals, cosmetics, pesticides,
and as a flavoring agent, to name but a few.2,3 With
regards to its medicinal purposes, menthol is currently
available in both prescribed and over-the-counter
(OTC) medications for a host of conditions, including gastrointestinal disorders, common cold and
respiratory conditions, and musculoskeletal pain.3
In addition, its use in dermatology is ubiquitous,
where it is frequently part of topical antipruritic, antiseptic, analgesic, and cooling formulations. Despite

From the Departments of Dermatologya and Neurobiology &

Anatomy and Regenerative Medicine,b Wake Forest University
School of Medicine.
Funding sources: None.
Conflicts of interest: None declared.
Reprint requests: Gil Yosipovitch, MD, Department of Dermatology, Wake Forest University Medical Center, Medical Center
Blvd, Winston-Salem, NC 27157. E-mail: gyosipov@wfubmc.edu.
Published online May 11, 2007.
0190-9622/$32.00
2007 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2007.04.008

menthols use since antiquity, the mechanism by

which it is able to impart a cooling sensation when
applied topically to the skin or mucous membrane
remained a mystery until recently. Although almost 5
years have passed since the discovery of a common
receptor for menthol and low temperature, many
dermatologists are still unaware of menthols underlying target. The purpose of this review is to highlight
the recent advances in the mechanism of action of
menthol and to provide an overview of its dermatologic applications.

MECHANISM OF ACTION
Over the past 5 years, understanding of the
mechanism by which menthol elicits the same cool
sensation as low temperature has advanced a great
deal. The ability of menthol to produce such a sensation was attributed to stimulation of thermoreceptors by Goldscheider as early as 1886.4,5 However,
the major breakthrough regarding a common site of
action for both menthol and cold came in 2002
through two independent studies employing different approaches. McKemy et al6 and Peier et al7
cloned and characterized a menthol receptor using a
cDNA expression library and by searching genomic
DNA databases, respectively. Both methods, however, resulted in the identification of the 1104 amino
acid cation channel, TRPM8 (formerly CMR1 or Trpp8). This cloned channel could be activated by both
menthol and thermal stimuli in the cool to cold range
(8-288C), proving that menthol elicits a sensation
of cool by serving as an agonist of a thermally sensitive receptor.6 This finding was reminiscent of the
cloning of the vanilloid receptor (TRPV1), an excitatory ion channel, activated by either temperatures
873

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J AM ACAD DERMATOL
NOVEMBER 2007

Table I. The characteristics of the current thermosensitive TRP channels9

Temperature
range (8C)

Agonists

d
d
d
d

Expression in
keratinocytes

TRPV1

TRPV2

TRPV3

TRPV4

TRPM8

TRPA1

[43

[52

[34-39

25-34

8-28

\17

Capsaicin
Extracellular protons
Lipoxygenase products
Amide derivatives of
arachidonic acid
(eg anandomide
and NADA)
Resiniferatoxin

Yes

d
d

Camphor
Extracts from
oregano
and cloves

d
d
d

Menthol
Icilin
Eucalyptol

d
d
d
d
d
d

No

exceeding 438C or capsaicin (the main pungent

ingredient in hot chilies), both of which evoked a
psychophysical sensation of warmth.8,9
TRPM8 is a member of the transient receptor
potential (TRP) family of excitatory ion channels.
Recent advances in thermosensation have identified
six temperature sensitive TRPs that perceive thermal
input depending on the type or combination of TRPs
stimulated.5 These thermo-TRPs display a wide spectrum of temperature sensitivities, ranging from noxious heat to noxious cold, and include TRPV1-4,
TRPM8, and TRPA1.10 Although studies have shown
that these six TRPs are expressed in small diameter
primary sensory neurons, there is controversy
whether they coexist at this location.7,11-13 In addition, there is evidence that TRPV1, TRPMV3, and
TRPV4 are expressed in keratinocytes, indicating that
keratinocytes are capable of detecting temperature
via receptors similar to those in temperature-sensing
neurons.9,14-16 Epidermal expression of TRPM8 has
yet to be demonstrated, but this receptor is present
in prostate epithelia,17 suggesting that it may, under
certain circumstances, be expressed in nonneuronal
epithelial cells9 (Table I).
Menthol, icilin, and cool temperatures have all
been shown to activate TRPM8.6,7,18 Stimulation of
TRPM8 leads to an increase in intracellular Ca21
through voltage-dependent gating of the channel,
resulting in depolarization and generation of an
action potential.19,20 In addition, Macpherson et al21
recently showed that menthol could also stimulate
heat-activated TRPV3, but at concentrations well
above that needed to activate TRPM8.21 Furthermore,
the authors of the same study went on to demonstrate
that menthol inhibits TRPA1, a thermo-TRP activated
by noxious cold and pungent/burning compounds.21
The original study by Peier et al7 also showed that
repeated exposure to menthol could desensitize
TRPM8. Interestingly, Rohacs et al22 recently

Yes

Yes

No

Icilin
Musturd oil
Wasabi
Garlic
Acrolein
Cinnamaldehyde

No

demonstrated a central role for the lipid second

messenger, phosphatidylinositol 4,5-bisphosphate
(PI(4,5)P2), in both the activation and desensitization
of TRPM8.

MENTHOL AND THE OLFACTORY SYSTEM

Inhalation of menthol elicits a distinctive cooling
sensation which is mediated through the stimulation
of trigeminal nerve, which belongs to the sensory
system of the olfactory epithelium. Menthol also has
a characteristic minty aroma, which has been attributed to stimulation of olfactory nerves.3 The pleasant
aroma associated with menthol may be particularly
beneficial in cosmetic and topical facial formulations, because it increases patient acceptability.
Behrendt et al23 recently suggested that TRPM8,
which is expressed in the trigeminus, could be an
important chemosensory trigeminal nerve receptor.23 Interestingly, Cometto-Muniz and Cain24
showed that anosmics could detect menthol via
pungency, implying that the integrity of the olfactory
system is not essential for menthol detection.24 Of
note, Murphy25 reported that the ability to detect the
intensity and pleasantness associated with menthol
declines with age.

THE PSYCHOPHYSICS OF TOPICAL

MENTHOL
Psychophysical studies have shown that menthol
evokes a cool sensation to the skin or mucous membrane, but only at low concentrations.26-29 Yosipovitch et al29 showed that menthol had no effect on
cold detection or cold pain threshold; however,
recent studies have shown that menthol decreases
cold pain thresholds and enhances pain responses
to suprathreshold noxious cold stimuli.30-32 With
regards to heat stimuli, it has been shown that
menthol has no effect on warmth detection or heat
pain thresholds, although there is again some

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VOLUME 57, NUMBER 5

contradiction.27,30-32 In addition, recent studies have

reported significant mechanical pinprick hyperalgesia with menthol, while others have not.30-32 Discrepancies between these psychophysical studies
may be explained by differences with regards to
menthol concentration, duration of application, and
methods used to assess sensation.

ANTIPRURITIC ACTIONS OF TOPICAL

MENTHOL
Although menthol has been used to relive pruritus
for many years, there is surprisingly little literature
assessing its efficacy. Bromm et al33 showed cooling
the skin by 28C to 48C resulted in a reduction in the
intensity of histamine-induced itch. More importantly, application of 1% menthol yielded a similar
reduction of pruritus.33 In contrast, Yosipovitch et al29
showed that 10% menthol had no effect on histamineinduced itch duration or magnitude. Of note, Riser
et al34 have described a menthol-containing itch relief product, formulated in a sprayable, moisturizing
microemulsion, which is safe, tolerable, and fastacting. The optimal concentration of menthol for the
relief of pruritus has not been established; however,
we frequently use concentrations of 1% in our own
practice to relieve this distressing symptom.
The mechanism by which menthol alleviates
pruritus is unknown. Bromm et al33 suggested the
activation of A-delta fibres by menthol centrally inhibits itch. An imbalance of the endogenous opioidergic system has received recent attention in terms
of the pathophysiology of pruritus.35 Different opioid receptors have contrasting effects upon pruritus.
Both -opioid receptor agonists and k-opioid receptor antagonists can induce itch, while -receptor
antagonists and k-receptor agonists can reduce it.
Menthol has been shown to selectively activate
k-opioid receptors,36 and thus we postulate that this
mechanism may also possibly explain the antipruritic
properties of this compound. Furthermore, there is a
subset of patients who suffer from chronic pruritic
conditions, such as atopic dermatitis, uremic pruritus, and psoriasis, who report a reduction in itch
associated with cold showers.37-40 It is thus possible
that the cooling sensation menthol imparts to the
skin serves as a possible mechanism to reduce itch
perception in these patients.

ACTIONS OF TOPICAL MENTHOL ON PAIN

In the present day, menthol can be found in a
variety of topical pain relief medications because of
its counter-irritant and local anesthetic properties.
In concentrations of 1% or less, menthol depresses
cutaneous sensory receptors, while at concentrations

between 1.25% and 16%, it stimulates sensory receptors and thus acts as a counter-irritant.41
Menthol at high concentrations (30% and above)
can induce cold pain. Wasner et al42 showed that
topical application of menthol induces cold pain by
activation and sensitization of cold-sensitive C nociceptors and activation of cold-specific A-delta fibers.
In a recent study, Hatem et al30 proposed that the
hyperalgesic effects of menthol may not only result
from C nociceptor sensitization, but also depend on
the balance between the activation of A-delta and C
nociceptor fibers.30 This study also highlighted individual variability in response to menthol. Menthol
evoked no cold allodynia or hyperalgesia in onethird of the study population. The authors of this
study postulated that a subpopulation exists in which
the menthol-sensitive receptor is either underexpressed on C nocicpetor fibres or overexpressed in
A-delta fibers.30 Green and Schoen43 provided further
evidence that TRPM8 plays a role in cold nociception
and showed that dynamic contact may modify perception of nonpainful cold.43
Similar to capsaicin, menthol may also cause
analgesia by desensitizing nociceptive C fibres. Cliff
and Green26 demonstrated that 0.3% menthol produced irritation that declined in intensity over repeated exposure. The authors went on to show that
this decline was caused by desensitization rather
than adaptation. In addition to self-desensitization,
Green and McAuliffe28 showed that menthol can
transiently desensitize capsaicin-sensitive fibers, but
persistent nociceptive stimuli in the form of capsaicin
overrides this effect.
The exact underlying mechanism by which menthol produces analgesia is unresolved. Macpherson
et al21 postulated that menthols analgesic properties can be explained via its activation of TRPM8
and/or inhibition of TRPA1. The latter of these two
TRPs is activated by a variety of noxious stimuli,
including cold temperatures, pungent natural compounds, and environmental irritants.44 In addition,
Galeotti et al36 demonstrated that oral menthol
produced a dose-dependent increase in murine
pain thresholds, and that this analgesic effect was
mediated through a selective activation of k-opioid
receptors. Furthermore, menthol has been shown to
increase cutaneous blood flow at the site of application.32 Such a vasodilatation would result in an
increase in skin temperature, and it is therefore
possible that menthol mediates at least part of its
analgesic effect in a similar fashion to superficial
heat therapy.5 Despite the use of heat to relieve
musculoskeletal pain since ancient times, the mechanisms responsible for this therapeutic effect remain
controversial.45

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NOVEMBER 2007

LOCAL ANAESTHETIC ACTIVITY OF

TOPICAL MENTHOL
Galeotti et al46 demonstrated that menthol has a
strong dose-dependent local anesthetic action assessed in vivo in the rabbit conjunctival reflex test
and in vitro in a rat phrenic nerve hemidiaphragm
preparation. Interestingly, both of the enantiomers
of menthol were equiactive in terms of local anesthetic activity. In a more recent study, Haeseler et al47
concluded that menthol blocks voltage-gated neuronal and skeletal muscle sodium channels in a
concentration-dependent manner in resting and
inactivated states. Furthermore, the authors suggested that this effect provided a molecular basis
for the antinociceptive and local anesthetic properties of this compound.

ANTIBACTERIAL AND ANTIFUNGAL

PROPERTIES OF MENTHOL
Menthol not only has an effect on sensory parameters, but also has antibacterial and antifungal activity.48 Such properties are exploited in diverse
products, including dental root canal sealers, antiseptics, food preservatives, and feed supplements.49
Both peppermint oil and menthol have been shown
to be active against a variety of microorganisms,
including both gram-positive and -negative bacteria,
as well as fungi.48-50 In addition, both have recently
been shown to display synergy with oxytetracycline.50 The toxic effects on membrane structure
and function have generally been used to explain the
antimicrobial activity of peppermint oil and menthol,
although the exact mechanism of action is not fully
understood.49 Trombetta et al49 recently speculated
that the antimicrobial effect of menthol may result, at
least partially, from a perturbation of the lipid fraction of microorganism plasma membrane, resulting
in alterations of membrane permeability and in leakage of intracellular materials. Furthermore, Schelz
et al50 demonstrated that peppermint oil and menthol displayed antiplasmid activity.

but detectable human plasma levels of menthol

following application of dermal patches.
More importantly, menthol has been shown to act
as a penetration enhancer, demonstrating that it not
only permeates the epidermis, but also acts to increase the accessibility of other drug molecules.56,57
This effect may be explained by menthols ability to
disrupt the lipid bilayer of the stratum corneum as
well as forming pools within it.58,59 In addition, polar
groupecontaining terpenes, such as menthol, have
been suggested to provide particular enhancement
for hydrophilic permeants.54 The ability of menthol
to act as a penetration enhancer, along with its other
beneficial properties, makes it an ideal vehicle to be
used in topical combination therapies. Although the
US Food and Drug Administration (FDA) discourages the use of such combination therapies, the
prospect of combining menthol with topical steroids
in the treatment of atopic dermatitis and other
pruritic conditions, for example, is particularly appealing. Menthol is already used in combination with
camphor and pramoxine for the treatment of itch.

SAFETY AND TOXICITY

Menthol is considered a safe and effective topical
OTC product according to the FDA. Concentrations
of menthol up to 16% have been approved by the
FDA for OTC external use, and their safety profile
has been well established. Based on the large postmarketing data, the FDA panel concluded that menthol in these concentrations have an excellent safety
profile. Customer complaints of 1 per 310,000 were
reported by one major manufacturer, while a second
manufacturer reported 1 per 950,000. No complaints
of a serious nature have been filed with the FDA.41
Menthol in concentrations of 40% (but not 30%)
resulted in skin erythema and spontaneous burning.30,31 In addition, menthol has been associated
with allergic contact dermatitis60,61 and systemic
allergic reactions.62

CONCLUSION
MENTHOL AS A VEHICLE
In topical and transdermal formulations, the selection of an appropriate vehicle is highly important,
because it can influence both drug release and
percutaneous absorption.51 Menthol has long been
used as a vehicle because it is derived from natural
sources, has a pleasant aroma (increasing patient
acceptability), and is effective at low concentrations
(in the range 0.5-5%).52 Topical and transdermal
menthol formulations have been shown to facilitate
drug permeation in both animal and human
models.51,53,54 Of note, Martin et al55 reported low

Menthol has been used since antiquity for medicinal purposes, but it is only the relatively recent
discovery of TRPM8 that has identified its underlying
receptor. This thermosensitive cation channel finally
provides the answer to how menthol can elicit the
same cool sensation as low temperatures. Menthol
is widely used in dermatologic practice, where it is
frequently part of topical antipruritic, analgesic,
antiseptic, and cooling formulations. It has an excellent safety as well as toxicity profile, and is currently
used as a vehicle in a host of topical and transdermal
formulations. The future potential dermatologic uses

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Patel, Ishiuji, and Yosipovitch 877

VOLUME 57, NUMBER 5

of this ancient compound is exciting, particularly in

the setting of topical combination therapies.
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