DESCRIPTION (provided by applicant): Methamphetamine abuse and dependence are persistent public health issues in the United States. To date, no medications have been approved by the FDA for the treatment of methamphetamine use disorders. This clinical study will examine a promising medication for methamphetamine use disorders with strong support from preclinical research. Recently, the neuropeptide oxytocin has been identified as a promising candidate for methamphetamine use disorder pharmacotherapy. Preclinical studies with rodents have found that oxytocin decreases the reinforcing efficacy of methamphetamine by reducing methamphetamine self-administration, stress- and drug-primed reinstatement, and conditioned place preference (Carson et al., 2010a; Qi et al., 2009). Oxytocin has also been shown to decrease hyperactivity induced by methamphetamine and cocaine in rats (Carson et al., 2010a; Qi et al., 2009; Kovacs et al., 1990; Sarnyai, 1998). The proposed clinical study draws on these findings to determine the effects of acute oxytocin administration on the human abuse liability of two methamphetamine doses shown to have dose-dependent abuse-liability effects in previous human behavioral pharmacology research (Hart et al., 2002). In a double-blind, randomized, within-subject, placebo- controlled design, 18 healthy non-treatment seeking stimulant using individuals will be administered either oxytocin (24 IU, intranasal) or placebo prior to receiving methamphetamine (10 or 20 mg, oral) or placebo across 6 sessions. Measures will include abuse-liability related subject-rated effects of methamphetamine (e.g., "drug liking"). We hypothesize that oxytocin will decrease subject-rated abuse liability ratings fo both methamphetamine doses. However, because a reduction in subject-rated effects without a change in drug reinforcement may not predict efficacy in clinical trials (Hart et al., 2004; Hart e al., 2007a, 2007b; Bisaga et al., 2006), a drug vs. money choice procedure (the "multiple-choice procedure"; Griffiths et al., 1993) will determine drug reinforcement effects in each of the initia 6 sessions. That is, each participant will make a series of choices between receiving the drug(s) administered on that session once again vs. receiving various amounts of money. One of the drug vs. money choices across the 6 sessions will be randomly selected to be delivered in a 7th session. If the preference was money, then in the 7th session the participant would receive that amount in addition to unblinded intranasal and oral placebos. We hypothesize that, relative to placebo, oxytocin will decrease the reinforcer efficacy (i.e., monetary value) of both methamphetamine doses. The study will determine if larger resources should be devoted to developing oxytocin as a methamphetamine use disorder medication, including clinical trials in treatment-seeking methamphetamine-dependent individuals. This study may therefore substantially advance the field of pharmacotherapy for methamphetamine use disorders.

PUBLIC HEALTH RELEVANCE: To investigate oxytocin as a potential treatment for methamphetamine dependence, a study in illicit stimulant using individuals will investigate the acute effects of oxytocin administration on the subjective and reinforcing effects of methamphetamine. The study will provide critical information on the ability of oxytocin to attenuate methamphetamine's abuse liability. Because methamphetamine use disorders are a global public health issue, this study should ultimately provide important information for the development of medications to treat methamphetamine misuse among stimulant using individuals.