Oral irritant properties of menthol: sensitizing and desensitizing effects of repeated application and cross-desensitization to nicotine

Physiol Behav. 2001 May;73(1-2):25-36. doi: 10.1016/s0031-9384(01)00431-0.


The irritant properties of menthol and its interactions with nicotine were investigated psychophysically in human subjects. In the first experiment, 0.3% L-menthol was applied successively to one side of the tongue 10 times at a 1-min interval (30-s interstimulus interval, ISI), and subjects rated the intensity of the perceived irritation. The intensity of irritation progressively decreased across trials, consistent with desensitization. To test for cross-desensitization of nicotine-evoked irritation by menthol, nicotine (0.6%) was applied to both sides of the tongue simultaneously, 5 min after the conclusion of menthol application. Using both a two-alternative forced choice (2-AFC) paradigm, and also by obtaining independent ratings of the irritant intensity on each side of the tongue, it was found that nicotine-evoked irritation was significantly weaker on the menthol-pretreated side. To control for a possible confounding effect of cooling, nicotine was applied bilaterally only after the cooling sensation of menthol had subsided. Nicotine-induced irritation was still significantly weaker on the menthol-pretreated side, consistent with cross-desensitization of nicotine-evoked irritation by menthol. In a final experiment, menthol was repeatedly applied to one side of the tongue at a shorter (20 s) interval (5-s ISI), and elicited a rapid increase in irritant sensation over the initial trials, consistent with sensitization, followed in subsequent trials by a progressive reduction in irritation (desensitization). After a 5-min rest period, self-desensitization was confirmed. Repeated application of menthol at the same short ISI was then resumed, and resulted in a significant mean increase in irritant intensity consistent with stimulus-induced recovery (SIR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Desensitization, Psychologic*
  • Drug Interactions
  • Humans
  • Irritants / pharmacology*
  • Menthol / pharmacology*
  • Middle Aged
  • Nicotine / pharmacology*
  • Nociceptors / drug effects*
  • Psychophysics
  • Sensory Thresholds / drug effects
  • Thermoreceptors / drug effects*
  • Tongue / innervation*
  • Trigeminal Nerve / drug effects


  • Irritants
  • Menthol
  • Nicotine