Mechanisms and time course of menthol-induced cutaneous vasodilation.
Level 2 - randomized trial
Randomized controlled physiological microdialysis trial in humans
PubMed 27899298 · doi:10.1016/j.mvr.2016.11.008
What was done
Ten healthy young subjects (age 23 ± 1 years, 5 males, 5 females) participated in two intradermal microdialysis protocols. Study 1 perfused four microdialysis fibers with escalating menthol doses (0.1–500 mM) combined with inhibitors for nitric oxide (NO), endothelium-derived hyperpolarizing factors (EDHFs), or sensory nerves, measuring skin blood flow via laser Doppler flowmetry (%CVC max). Study 2 applied 0.017 mL·cm⁻² of 4% menthol gel over two microdialysis fibers perfused with lactated Ringer's solution, collecting dialysate every 30 minutes for gas chromatography/mass spectrometry alongside laser speckle contrast imaging and sensory ratings.
What was found
In Study 1, menthol caused cutaneous vasodilation at doses ≥100 mM (all p < 0.05). Individual inhibition of NO, EDHFs, or sensory nerves fully suppressed menthol-mediated vasodilation (all p > 0.05). In Study 2, menthol was detected in dialysate at 30 minutes post-application (0.89 ng, p = 0.0002) and cleared by 60 minutes. Cutaneous vasodilation was significantly elevated from 15 to 45 minutes, and subjective sensation was elevated from 5 to 60 minutes (all p < 0.05).
Why it matters
These findings clarify the pharmacological mechanisms and local skin pharmacokinetics of topical menthol, showing that vasodilation relies on multiple distinct pathways and mirrors tissue clearance.
Limits
The sample size was very small (n = 10) and limited to healthy young adults. Long-term effects, systemic absorption, and responses in clinical populations with vascular or sensory impairment were not evaluated.
Cited by
- supports Menthol and eucalyptus compounds bind to cold-sensing TRP receptors on the skin, causing local vasodilation and increased blood flow to generate heat after an initial cold sensation.