Cocaine use disorder continues to be a major United States public health problem. After years of decreasing prevalence, cocaine use has been increasing since 2012 or so (Gangu et al., 2022; John and Wu, 2017; Mustaquim et al., 2021; Schneider et al., 2018). Cocaine-involved overdose deaths have also increased since 2014 (National Institute on Drug Abuse, 2024). Problems associated with cocaine use include profound medical (Gangu et al., 2022; Maraj et al., 2010; Nolan et al., 2019), psychiatric (Haasen et al., 2005; Morton, 1999; Mustaquim et al., 2021) and social issues (Higgins et al., 1991; Perez et al., 2004; Sorenson et al., 1991). Cocaine use has also been a major problem among methadone maintenance programs, where rates of cocaine use may range from 30 % to more than 50 % (Black et al., 1987; Condelli et al., 1991; Meandzija et al., 1994; Roux et al., 2016). Cocaine use during methadone maintenance has been associated with several medical (Bux et al., 1995; MacGowan et al., 1997; Meandzija et al., 1994; Wolf et al., 2004), psychiatric (Bovasso and Cacciola, 2003; Compton et al., 1995; El-Bassel et al., 2004; Grella et al., 1995; Hartell et al., 1995; King et al., 2001; Kosten et al., 1988; Ledgerwood and Downey, 2002; Magura et al., 1998, 2002) and legal (Grella et al., 1995; Hunt et al., 1986) problems, as well as greater attrition (Fendrich et al., 2021; Magura et al., 1998; Salamina et al., 2010) and poorer treatment outcomes (Senbanjo et al., 2009; Tzilos et al., 2009; Williamson et al., 2006). Despite these compelling factors, no medication thus far has been developed to treat cocaine use disorder (Bentzley et al., 2021; Kampman, 2019; Vocci and Montoya, 2009). Moreover, only a few psychosocial interventions, such as cognitive behavioral therapy (CBT) (Carroll, 1998) and contingency management (Bentzley et al., 2021; Petry et al., 2005), have shown moderate efficacy in treating this disorder (Vocci and Montoya, 2009), producing not necessarily robust and/or sustained outcomes (Rawson et al., 2006), Thus, developing and testing novel strategies for treating cocaine use disorder is vital.

The nonselective enzyme inhibitor disulfiram, which is used therapeutically to prevent return to substance use in abstinent individuals with an alcohol use disorder (e.g., (Brewer, 1984), has shown some initial promise (Traccis et al., 2024) in treating cocaine use disorder in both nonopioid-dependent (Baldaçara et al., 2013; Carroll et al., 1998, 2004) and opioid agonist stabilized individuals with opioid use disorder who also use cocaine (George et al., 2000; Kosten et al., 2013; Petrakis et al., 2000; Schottenfeld et al., 2014). Originally considered a potential treatment agent due to the high prevalence of alcohol use in people with cocaine use disorder (Carroll et al., 1993; Higgins et al., 1993), disulfiram has been shown to directly impact cocaine's effects, including increasing cocaine plasma levels and cocaine-induced behavioral effects in some individuals (Hameedi et al., 1995; McCance-Katz et al., 1998a, 1998b). Our prior 14-week, randomized, clinical trial examined the clinical efficacy of disulfiram in methadone-stabilized participants with cocaine use disorder at doses lower than the 250 mg/day typically studied previously (e.g., George et al., 2000; Petrakis et al., 2000) in order to determine whether these doses would still be efficacious while producing fewer side effects (Oliveto et al., 2011b). Results showed disulfiram at 62.5 or 125 mg/day exacerbated cocaine use over time relative to placebo or disulfiram at 250 mg/day. Disulfiram at 250 mg/day decreased self-reported cocaine use, but not cocaine-positive urine samples, over time relative to placebo and produced few adverse events that were not dose related (Oliveto et al., 2011b). These findings suggest administering disulfiram at higher doses might be feasible and necessary to be effective. Thus, the purpose of this study was to determine the relative clinical efficacy and safety of disulfiram at 250, 375 and 500 mg/day, which approach the upper limit of the recommended daily dose range for disulfiram, in participants with dual cocaine and opioid dependence stabilized on methadone using the same study design as our prior trial (Oliveto et al., 2011b); that is, a 14-week, randomized, placebo-controlled trial.