European Journal of Clinical Pharmacology

, Volume 59, Issue 5–6, pp 417–422

Influence of menthol on caffeine disposition and pharmacodynamics in healthy female volunteers

  • Ayse Gelal
  • Hulya Guven
  • Dilara Balkan
  • Levent Artok
  • Neal L. Benowitz
Pharmacogenetics and Disposition



The present study was undertaken to determine whether a single oral dose of menthol affects the metabolism of caffeine, a cytochrome P450 1A2 (CYP1A2) substrate, and pharmacological responses to caffeine in people.


Eleven healthy female subjects participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of caffeine (200 mg) in coffee taken together with a single oral dose of menthol (100 mg) or placebo capsules. Serum caffeine concentrations and cardiovascular and subjective parameters were measured throughout the study.


Co-administration of menthol resulted in an increase of caffeine tmax values from 43.6±20.6 min (mean±SD) to 76.4±28.0 min (P<0.05). The Cmax values of caffeine were lower in the menthol phase than in the placebo phase, but this effect was not statistically significant (P=0.06). (AUC)0–24, (AUC)0–∞, terminal half-life and oral clearance were not affected by menthol. Only nine subjects' cardiovascular data were included in the analysis because of technical problems during the measurements. After caffeine, heart rate decreased in both treatment phases. The maximum decrease in heart rate was less in the menthol phase (−8.9±3.9 beats/min) than in the placebo phase (−13.1±2.1 beats/min) (P=0.024). There were no statistically significant differences in systolic and diastolic blood pressures between the two treatments.


We conclude that a single oral dose of pure menthol (100 mg) delays caffeine absorption and blunts the heart-rate slowing effect of caffeine, but does not affect caffeine metabolism. The possibility that menthol slows the absorption of other drugs should be considered.


Menthol Caffeine Monoterpenes 


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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Ayse Gelal
    • 1
  • Hulya Guven
    • 2
  • Dilara Balkan
    • 3
  • Levent Artok
    • 4
  • Neal L. Benowitz
    • 5
  1. 1.Associated Professor in PharmacologyDokuz Eylul University Medical Faculty, Department of PharmacologyIzmirTurkey
  2. 2.Professor in PharmacologyDokuz Eylul University Medical Faculty, Department of PharmacologyIzmirTurkey
  3. 3.Assistant in PharmacologyDokuz Eylul University Medical Faculty, Department of PharmacologyIzmirTurkey
  4. 4.Professor in Chemistry, Izmir Institute of TechnologyFaculty of Science, Department of ChemistryIzmir Turkey
  5. 5.Professor of Medicine, Psychiatry and Biopharmaceutical SciencesUniversity of California San FranciscoUSA

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