This study will investigate the effects of intranasal administration of oxytocin, a social neuropeptide, on reducing stimulant use, enhancing therapeutic engagement, and susceptibility to stress-induced relapse in Veterans with stimulant use disorders and enrolled in opioid replacement therapy (ORT) program for co-occurring opioid use disorder (OUD).

High rates of substance use disorders (SUDs) in Veterans compared to the general population are heavily influenced by psychosocial factors - such as difficulty reintegrating into civilian life due to avoidance of vital support systems - leading to disproportionately elevated unmet addiction treatment needs. Although the gold standard for treatment for most SUDs involves pharmacological interventions, there are currently no effective pharmacological interventions approved by the Federal Drug Administration for stimulant users, who have the most difficulty adhering to treatment programs and the most susceptibility to stress-induced relapse of any SUD. Administering oxytocin, a mammalian neuropeptide, intranasally to healthy controls facilitates the stress-buffering properties of social support. Oxytocin may also have an independent role in mitigating the symptoms of SUDs. For example, in animal models of addiction, oxytocin administration directly reduces tolerance, withdrawal effects, self-administration, and stress-induced reinstatement of drug seeking for a range of addictive substances. A more integrated understanding of oxytocin's distinct effects on the behavior and psychology of 1) addiction, 2) sociality, and 3) stress reactivity could be the key to defining oxytocin's role in SUD treatment. This study proposes to translate promising preclinical and early proof-of-concept clinical results related to the anti-addiction, pro-social, and stress-tempering properties of oxytocin administration in Veterans with moderate-severe stimulant use disorders enrolled in a opioid replacement therapy (ORT) program for co-occurring opioid use disorder (OUD) at the San Francisco VA Medical Center (SFVAMC). The investigators' primary outcome is Aim 1) reduction in stimulant use, as measured by stimulant positive urine drug screen. Secondarily, the investigators will focus on Aim 2) improving psychosocial treatment engagement (social support) and Aim 3) mitigating social stress-related relapse, targeting two important barriers to stimulant use disorder recovery likely to respond to oxytocin administration.