The frequent persistence of attention-deficit hyperactivity disorder (ADHD) into adulthood is now well recognized. Appropriate drug therapy for this older ADHD population requires a special consideration of lifestyle and life span comorbidity. Treatment may be complicated by alcohol use disorder (AUD) and/or substance use disorder (SUD). Both AUD and SUD are over-represented in adult ADHD, especially in women. dl-Methylphenidate (MPH) is the drug of choice for ADHD. MPH related emergency department visits number in the thousands per year from 1995-2002, and ethanol (ETOH)-in-combination with drugs in general has risen 63% for ages18-19 and 100% for ages 45-54 during this period. The present proposal will characterize mechanisms underlying a newly discovered drug interaction between MPH and ETOH, as well as characterize the systems underlying MPH sex dimorphism. This is important because: (a) We have found that ETOH inhibits the esterase mediated metabolism of dl-MPH, especially in men compared to women. This results in significantly elevated plasma MPH concentrations (d-MPH>l-MPH);(b) ETOH also serves as a substrate for the esterase(s) in the transesterification of dl-MPH to yield the novel active metabolite ethylphenidate (plasma l-EPH>d-EPH);(c) We have found that women have significantly lower oral bioavailability than men when dosed with MPH in extended-release (ER) formulations, but not when dosed with immediate-release (IR)-MPH.
Our SPECIFIC AIMS are to: (1) determine if /-MPH is responsible for the elevation of plasma d-MPH after ETOH;(2) determine the sites of presystemic metabolism of MPH with and without ETOH;and (3) characterize MPH-ETOH interactions with C57 mouse models. Application of our findings to clinical pharmacology will contribute to the optimization of ADHD therapy as it relates to gender and interaction with ETOH, e.g., use of IR- vs. ER-MPH and dl-MPH vs. d-MPH formulations. Comorbid ADHD/AUD patients may become first-line candidates for amphetamine or non-stimulant therapy such as atomoxetine. Finally, these basic investigations will contribute to an understanding of MPH-ETOH toxicology essential for avoidance of adverse drug events/fatalities, and for the rational emergency management of concomitant overdose. For instance, ETOH induced elevation of plasma MPH may predispose a patient to cardiovascular accidents in the absence of informed treatment interventions.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Roach, Deidra
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical University of South Carolina
Schools of Pharmacy
United States
Zip Code
Zhu, Hao-Jie; Patrick, Kennerly S; Straughn, Arthur B et al. (2017) Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers. J Clin Psychopharmacol 37:419-428
Patrick, Kennerly S; Straughn, Arthur B (2016) Absorption Differences between Immediate-Release Dexmethylphenidate and dl-Methylphenidate. Drug Metab Dispos 44:418-21
Patrick, Kennerly S; Straughn, Arthur B; Reeves 3rd, Owen T et al. (2015) Comparative Ethanol-Induced Potentiation of Stimulatory Responses to Dexmethylphenidate Versus Methylphenidate. J Clin Psychopharmacol 35:464-7
Patrick, Kennerly S; Corbin, Timothy R; Murphy, Cristina E (2014) Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker. J Pharm Sci 103:3834-3842
Griffin 3rd, William C; McGovern, Robin W; Bell, Guinevere H et al. (2013) Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice. Psychopharmacology (Berl) 225:613-25
Patrick, Kennerly S; Straughn, Arthur B; Reeves 3rd, Owen T et al. (2013) Differential influences of ethanol on early exposure to racemic methylphenidate compared with dexmethylphenidate in humans. Drug Metab Dispos 41:197-205
Bell, Guinevere H; Griffin 3rd, William C; Patrick, Kennerly S (2011) Oral and transdermal DL-methylphenidate-ethanol interactions in C57BL/6J mice: potentiation of locomotor activity with oral delivery. Pharmacol Biochem Behav 100:264-70
Zhu, Hao-Jie; Patrick, Kennerly S; Markowitz, John S (2011) Enantiospecific determination of DL-methylphenidate and DL-ethylphenidate in plasma by liquid chromatography-tandem mass spectrometry: application to human ethanol interactions. J Chromatogr B Analyt Technol Biomed Life Sci 879:783-8
McGovern, Robin W; Middaugh, Lawrence D; Patrick, Kennerly S et al. (2011) The discriminative stimulus properties of methylphenidate in C57BL/6J mice. Behav Pharmacol 22:14-22
Bell, Guinevere H; Novak, Andrew J; Griffin 3rd, William C et al. (2011) Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations. J Pharm Sci 100:2966-78

Showing the most recent 10 out of 17 publications