30-60% of patients receiving methadone for opioid use disorder (OUD) actively use cocaine. Cocaine use disorder (CUD) has no FDA-approved pharmacological treatment; existing psychosocial treatments are inadequate. Oxytocin, a social neuropeptide, has preclinical promise as an adjunctive treatment for both OUD and CUD. Twenty-two individuals receiving methadone for OUD with co-occurring CUD were randomized to receive oxytocin or placebo intranasally 40 IU twice daily for two weeks. A priori aims were feasibility and safety. Exploratory effectiveness aims included laboratory-based measures of drug craving, drug-related implicit cognition, and drug use. High retention rates (93.5%), the absence of study-related adverse events, and the fact that oxytocin was well tolerated in this population support the feasibility of larger trials. Two weeks of oxytocin (but not placebo) significantly reduced cocaine craving at day 15 compared to baseline (mean change±SD: OT=−0.23±0.19, p=0.004; PL=−0.16±0.29, p=0.114). For heroin craving, the placebo group reported a trend-level increase over time while the oxytocin group remained unchanged - with medium to large effect sizes between the groups (Cohen's d=0.71-0.90). Oxytocin led to a significant switch from implicit self-association with drugs to implicitly associating drugs with others (mean change±SD: 0.25±0.35, p=0.037) and a trend-level reduction in self-reported cocaine use over time (Z=−1.78, p=0.075). Furthermore, oxytocin significantly increased the accuracy of self-reported cocaine use when correlated with quantitative urine levels of cocaine metabolite. This proof-of-concept study provides promising early evidence that oxytocin may be an effective adjunct to the treatment of co-occurring CUD and OUD. Further investigation with larger trials is warranted.

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