Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers

J Clin Psychopharmacol. 2017 Aug;37(4):419-428. doi: 10.1097/JCP.0000000000000721.


Background/purpose: Ethanol coadministered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (Cmax) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on (1) inhibition of postabsorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, spheroidal oral drug absorption systems of dl-MPH and d-MPH.

Methods: In a randomized, 4-way crossover study, 14 healthy subjects received pulsatile dl-MPH (40 mg) or d-MPH (20 mg), with or without ethanol (0.6 g/kg), dosed 4 hours later. These 4 hours allowed the delayed-release second MPH pulse to reach a more distal region of the gut to preclude gastric biopharmaceutical influences. Plasma was analyzed using a highly sensitive chiral method. Subjective/physiological effects were recorded.

Findings/results: Ethanol increased the second pulse of d-MPH Cmax for dl-MPH by 35% (P < 0.01) and the partial area under the plasma concentration curve from 4 to 8 hours by 25% (P < 0.05). The respective values for enantiopure d-MPH were 27% (P = 0.001) and 20% (P < 0.01). The carboxylesterase 1-mediated transesterification metabolite ethylphenidate served as a biomarker for coexposure. Ethanol significantly potentiated stimulant responses to either formulation.

Implications/conclusions: These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations. Understanding the pharmacology underlying the frequent coabuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid attention-deficit/hyperactivity disorder-alcohol use disorder.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Biological Availability
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / blood
  • Cross-Over Studies
  • Dexmethylphenidate Hydrochloride / administration & dosage*
  • Dexmethylphenidate Hydrochloride / blood*
  • Drug Interactions / physiology
  • Ethanol / administration & dosage*
  • Ethanol / blood*
  • Female
  • Healthy Volunteers
  • Humans
  • Male
  • Methylphenidate / administration & dosage*
  • Methylphenidate / blood*
  • Young Adult


  • Central Nervous System Stimulants
  • Dexmethylphenidate Hydrochloride
  • Methylphenidate
  • Ethanol