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.