Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics

Clin Pharmacol Ther. 2007 Mar;81(3):346-53. doi: 10.1038/sj.clpt.6100082.


This study explores the hypotheses that: (1) ethanol will interact with dl-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dl-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P<0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C(max) (+/-SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). l-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where l-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P<0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C(max) and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Area Under Curve
  • Biotransformation
  • Blood Pressure / drug effects
  • Body Temperature / drug effects
  • Central Nervous System Depressants / pharmacokinetics*
  • Central Nervous System Depressants / pharmacology*
  • Central Nervous System Stimulants / pharmacokinetics*
  • Central Nervous System Stimulants / pharmacology*
  • Cross-Over Studies
  • Drug Interactions
  • Ethanol / pharmacokinetics*
  • Ethanol / pharmacology*
  • Female
  • Heart Rate / drug effects
  • Humans
  • Male
  • Methylphenidate / analogs & derivatives
  • Methylphenidate / metabolism
  • Methylphenidate / pharmacokinetics*
  • Methylphenidate / pharmacology*
  • Pharmacogenetics
  • Respiratory Mechanics / drug effects
  • Sex Characteristics
  • Stereoisomerism


  • Central Nervous System Depressants
  • Central Nervous System Stimulants
  • Methylphenidate
  • Ethanol
  • ethylphenidate