ReviewMenthol: A refreshing look at this ancient compound
Section snippets
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
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
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, 27, 28, 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, 31, 32 With regards to heat stimuli, it has been shown that menthol has no effect on warmth detection or
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 2°C to 4°C 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 histamine-induced itch duration or magnitude. Of note, Riser et al34 have described a
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
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
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, 49, 50 In addition, both have recently been shown to display synergy with
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
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 post-marketing 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
Conclusion
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
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Conflicts of interest: None declared.