A randomized clinical trial of disulfiram at higher doses for the treatment of cocaine use disorder among methadone-stabilized patients.

A Randomized Clinical Trial of Disulfiram at Higher Doses for the Treatment of Cocaine Use Disorder Among Methadone-Stabilized Patients - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice J Psychiatr Res . Author manuscript; available in PMC: 2026 Jun 1. Published in final edited form as: J Psychiatr Res. 2025 Apr 26;186:387–395. doi: 10.1016/j.jpsychires.2025.04.051 A Randomized Clinical Trial of Disulfiram at Higher Doses for the Treatment of Cocaine Use Disorder Among Methadone-Stabilized Patients 1 Alison H Oliveto a , Janette McGaugh b , Mohit P Chopra c , Jeff Thostenson d , Michael J Mancino a Author information Article notes Copyright and License information a University of Arkansas for Medical Sciences, Department of Psychiatry, 4301 W. Markham St., Little Rock, AR 72205 b Ouachita Behavioral Health and Wellness, 125 Wellness Way, Hot Springs, AR 71913 c University of Massachusetts Medical School, Psychiatry Dept., 55 N Lake Ave S7-823, Worcester, MA 01655 d University of Arkansas for Medical Sciences, Biostatistics Dept., Little Rock, AR 75505 ✉ Corresponding Author : Alison Oliveto, Ph.D., University of Arkansas for Medical Sciences, Department of Psychiatry, Slot 843, 4301 W. Markham St., Little Rock, AR 72205 olivetoalison@uams.edu Issue date 2025 Jun. PMC Copyright notice PMCID: PMC12103833  NIHMSID: NIHMS2079924  PMID: 40306006 The publisher's version of this article is available at J Psychiatr Res Abstract Purpose/Background: Previously, disulfiram less than 250 mg/day increased cocaine use relative to placebo whereas disulfiram at 250 mg/day did not differ from placebo among methadone-stabilized individuals with dual cocaine and opioid dependence, suggesting disulfiram at higher doses needed to be tested. This study determined tolerability and efficacy of disulfiram at higher doses (250–500 mg/day). Methods/Procedures: In a 14-wk, double blind, placebo-controlled clinical trial, 53 participants with cocaine and opioid dependence were enrolled, inducted onto methadone (weeks 1–2), randomized to receive placebo or disulfiram (250, 375 or 500 mg/day) during weeks 3–14, and provided weekly 1-hour individual cognitive behavior therapy throughout. Thrice-weekly urine samples were tested for the presence of cocaine metabolite. Weekly vital signs and monthly mood assessments were obtained. Results/Findings: Disulfiram groups generally did not differ on subject characteristics or retention. Cocaine-positive urine samples showed a significant increase over time in the placebo group (p=0.04), with the placebo slope being significantly greater than horizontal. Cocaine-positive urine samples decreased over time in the disulfiram 250 mg (p=0.014) and 375 mg (p=0.015), but not 500 mg (p=0.11), groups relative to placebo, although slopes of these medication groups did not differ significantly from horizontal (p>0.15). No clinically significant differences across groups with respect to vital signs or mood ratings occurred. Implications/Conclusions: Although preliminary due to the small sample size, disulfiram at 250–375 mg/day may be ineffective in reducing cocaine use and have limited efficacy to prevent increases in cocaine use among methadone-stabilized patients with dual cocaine and opioid dependence. Keywords: Disulfiram, Clinical trial, Cocaine use disorder, Methadone, Opioid use disorder, Randomized, controlled trial INTRODUCTION 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 ; Magura et al., 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., 2004 ; Carroll et al., 1998 ) 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 , b ). 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. MATERIALS AND METHODS Participants Fifty-eight individuals with opioid dependence and seeking cocaine and/or opioid maintenance treatment were recruited from Central Arkansas (see Figure 1 ). Due to lower than anticipated enrollment, recruitment was opened to 77 individuals with cocaine, but not opioid, dependence. However, methodological differences, particularly regarding clinic attendance and disulfiram medication adherence procedures, greatly limited conclusions about disulfiram within the nonopioid dependent group much less across-group comparisons. Thus, only data for participants with opioid dependence are reported here. Each gave written informed consent, as approved by the University of Arkansas for Medical Sciences (UAMS) Institutional Review Board. Participants (aged 18–75 years) had to meet Diagnostic Statistical Manual-IV (DSM-IV) criteria for cocaine dependence based on physician assessment, report use within 30 days of study entry and consumption of ≥7 grams during the preceding 6 months. Participants also had to meet DSM-IV criteria for opioid dependence and have either laboratory confirmation of opioid use during the month prior to study entry or manifested opioid withdrawal. Participants were excluded if they had any of the following: current alcohol physiological dependence; abnormal liver function (with laboratory enzyme levels greater than three times normal); active hepatitis; hypertension; current cardiac condition; occult coronary artery disease; high risk of cardiovascular disease; peripheral neuropathy; seizure disorders; other significant medical condition contraindicating disulfiram or methadone treatment; meeting DSM-IV psychiatric classifications for schizophrenia, bipolar disorder, or other psychotic disorders; exhibiting current suicidality or homicidal intention; current use of a prescribed psychotropic medication that cannot be discontinued; current use of medications such as anticoagulants, isoniazid, metronidazole, clotrimazole, and paraldehyde; failure to submit a benzodiazepine-negative urine toxicology screen; and pregnancy or breastfeeding. Figure 1. Open in a new tab Consort Diagram. Flow diagram of subject progress through the phases of the randomized clinical trial. Research Design and Procedures In this 14-week, randomized, double blind clinical trial, participants were stabilized on methadone during weeks 1–2, during which baseline cocaine use was assessed, and randomized by sex, race and Cocaine Selective Severity Assessment (CSSA) score ( Kampman et al., 1998 ; Mulvaney et al., 1999 ) to receive one of the following during weeks 3–14: disulfiram at 0 mg/day (placebo), 250 mg/day, 375 mg/day, or 500 mg/day. The data manager performed the randomization using a computerized urn randomization program ( Wei and Lachin, 1988 ). Only the research pharmacist and data manager were aware of the medication condition. Participants attended clinic at the UAMS Substance Abuse Treatment Clinic 6 days/week (M-S) to complete study tasks, undergo counseling and receive study medications. On Saturday, participants received take home study medications to take on Sunday. Methadone dispensing procedures occurred in accordance with manufacturer recommendations ( Medical Economics, 1998 ) with participants ingesting methadone in a colored liquid daily (Monday-Saturday) at the dispensing window under observation of the dispensing nurse. Participants initially received 25 mg of methadone. This dose increased by 5 mg/day until participants received 60 mg/day (day 1 of week 2). This dose was adjusted as necessary thereafter, depending upon craving, withdrawal symptoms or side effects. During stabilization onto methadone (weeks 1–2), placebo (microcrystalline cellulose) was suspended in the methadone. Then during weeks 3–14, either crushed disulfiram tablets or placebo (i.e., 300 mg of microcrystalline cellulose) was suspended in the methadone solution. At the beginning of week 15, disulfiram or placebo was no longer suspended in the methadone. At the end of the study, participants either transferred to a local methadone program after a 2-week washout period or underwent methadone taper over a 4- to 6-week period. All participants received weekly, manual-driven, individual cognitive behavior therapy ( Carroll, 1996 ). Subjects were administratively discharged if they missed medications on three successive days, missed more than three consecutive therapy sessions or if breath samples were frequently positive for alcohol. Those discharged from the study were offered methadone taper and referral to a local treatment program. Assessments At intake, portions of the Structured Clinical Interview for the Diagnostic Statistical Manual-IV (SCID) ( First et al., 1995 ), Addiction Severity Index (ASI) ( McLellan et al., 1980 ), and demographics form were completed. The CSSA, a clinician-administered instrument measuring early cocaine abstinence symptomatology by rating 18 signs and symptoms associated with early cocaine abstinence based on a scale of 0 (no symptoms) to 7 (maximum score) ( Kampman et al., 1998 ; Mulvaney et al., 1999 ), was completed during week 1. Supervised urine samples were obtained thrice weekly and tested for the presence of cocaine metabolite (benzoylecgonine) and other drugs using a Hitachi 717 Automated Analyzers (Boehringer Mannheim Corp., Indianapolis, IN), with a cut-off concentration of 300 ng/ml. Hamilton Depression (HAM-D) and Anxiety (HAM-A) Scales were completed monthly. Participants were monitored at every visit for adverse symptoms. Vital signs (systolic and diastolic blood pressure, and heart rate) were obtained weekly. Training of Raters Raters had previous experience in clinical rating and interviewing and at least a bachelor’s level education or its equivalent in experience. Under supervision, raters received one month of training on the ASI, SCID and DSM-IV. Training included observation of interviews and ratings, co-rating, and interviewing with another experienced staff member present. In order to conduct interviews for this study, raters were required to complete three consecutive conjoint interviews on which DSM-IV diagnoses were in complete agreement with those of more experienced raters. After training, reliability was periodically spot-checked. Data Analyses Cox Proportional Hazards Regression was performed to test for differences in retention (weeks retained) with medication group and opioid dependence status as factors. Differences in baseline subject characteristics across medication groups were determined using Analysis of Variance (ANOVA) or its non-parametric analogue, Wilcoxon or Kruskal-Wallis test, for continuous variables and Pearson Chi Square tests for categorical variables with medication group or opioid dependence status as factors. Differences in drug use during week 2 (baseline use) for those who actually received disulfiram were analyzed using ANOVA for either parametric or non-parametric data, depending on the distribution of the outcome variable, with medication group as the factor. The primary outcome of interest was reduction in cocaine use over time, as assessed by thrice-weekly urine toxicology screens. Secondary outcomes included vital signs, depression and anxiety symptom severity, and adverse event profiles. To determine whether cocaine use or ratings differentially changed over time across medication groups, data were analyzed using a random coefficient regression model, also known as hierarchical linear model (HLM) with medication group and study assessment time point as factors ( Bryk and Raudenbush, 1987 ; Gibbons et al., 1993 ). These analyses were performed in SAS PROC GLIMMIX, an HLM modeling program within SAS in order to determine whether outcomes improve differentially across conditions ( Bryk and Raudenbush, 1987 ; Gibbons et al., 1993 ). This a priori approach of modeling repeated measures was chosen in order to allow for easier comparison with results of our prior study with disulfiram ( Oliveto et al., 2011b ) and because it is specifically designed for unbalanced repeated measures designs with missing data, allowing for intra-subject serial correlation and unequal variance and covariance structures over time. Solution of these problems, common to clinical trial data, is accomplished by equally incorporating available trend data for each individual, regardless of the total number of data points, with information on the behavior of the group from which the subject is drawn. HLM models generate the overall slope of each group trend data and HLM point estimates are calculated for graphic representations of the slopes. Because individuals were stabilized onto methadone during weeks 1–2 and disulfiram administration started at the beginning of week 3, data from week 2, day 5 through week 14, day 5 were used in the analyses (week 0 was used as baseline for monthly assessments). Week 2 and the week 2, day 5 (Friday) assessment time points were used as baseline for weekly and thrice-weekly assessments, respectively, because participants underwent methadone induction during week 1 and reached the initial methadone maintenance dose (60 mg/day) by the beginning of week 2. Only data for those who participated past week 2 and completed assessments after exposure to disulfiram were included in these analyses. For each model, contrasts were performed for placebo versus each dose. Slopes vs. horizontal point estimates and standard errors were calculated within the HLM model as linear combinations of the estimated model coefficients. A t-value was then calculated and a p-value found based on the t-value degrees of freedom to determine significance of slope relative to horizontal. Although not an a priori analysis, we also conducted a responder-type analysis, such that, participants were defined as being a responder if the percentage of urine screens positive for cocaine was lower during week 14 relative to week 2 and a non-responder if the converse was true. A Fisher Exact Test was used to analyze group differences in the proportion of responders versus non-responders for those who completed all 14 weeks as well as for all participants who began week 3, with non-completers being defined as non-responders. For all analyses, p < 0.05 was used to infer statistical significance. SAS software (SAS System for Windows Version 9.2, SAS Institute Inc., Cary, NC, USA) was employed. RESULTS Demographics and Baseline Measures Of the 53 enrolled into the study proper, 4 participants did not receive the allocated intervention ( Figure 1 ). Table 1 shows demographic data for 49 participants who participated long enough to receive disulfiram study medication. Medication groups did not differ on demographic characteristics, psychiatric diagnoses, self-reported recent drug use or severity of cocaine use ( Table 1 ). On average, participants were aged 37.0 (+/− 12.6) years, scored 28.2 (+/− 17.4) on the CSSA, and reported using cocaine, opioids and alcohol on 11.5 (+/−7.6), 20.3 (+/− 11.3) and 4.1 (+/− 6.8) days of the past 30, respectively. Table 1. Subject characteristics. Disulfiram Dose (mg) Measure Placebo 275 375 500 n: 13 13 13 10 Test statistic (df), ** p value Age (years; mean ± SD) 38.4±14.0 37.0±14.2 35.1±11.5 37.5±11.8 F (3,45)=0.15, >0.92 Race (AA/non-AA) 0/13 0/13 1/13 1/10 Fisher p=0.57 Gender (% female) 46.2 53.8 46.2 40.0 χ 2 (3)= 0.45, >0.92 Education Level (% >HS) 69.2 84.6 69.2 30.0 Fisher p=0.06 CSSA Score (mean±SD) 33.7±19.3 27.9±14.3 26.0±20.6 24.3±14.9 F (3,45)=0.65, >0.96 ASI (days/past 30 days; mean+SD): Cocaine use 11.8±8.7 12.1±7.2 10.6±8.5 11.3±6.3 F (3,45)=0.09, >0.96 Opiate use 22.0±11.1 17.2±12.4 23.4±9.5 18.0±12.7 F (3,45)=0.87, >0.46 Alcohol use 2.8±5.8 2.8±5.1 4.9±7.5 6.3±8.9 F (3,45)=0.73, >0.53 SCID diagnoses (%): Cocaine Dependence (current) 100.0 100.0 92.3 100.0 Fisher p=1.00 Cocaine Dependence (Lifetime) 100.0 100.0 92.3 100.0 Fisher p=1.00 Alcohol Dependence (current) 7.7 7.7 15.4 20.2 Fisher p>0.79 Alcohol Dependence (Lifetime) 23.1 23.1 46.2 30.0 Fisher p>0.80 Opiate Dependence (current) 100.0 100.0 100.0 100.0 - Opiate Dependence (Lifetime) 100.0 92.3 100.0 100.0 Fisher p=1.00 Open in a new tab Retention, Missing Urine Data and Therapy Attendance Retention rates did not differ among medication groups (Log-Rank=5.3840, p=0.1457), with average retention ranging from 9.07+/−4.37(mean+/−SD) to 11.85+/−4.13 weeks in the 375 mg disulfiram and placebo groups, respectively ( Figure 2 ). Twenty-four of the 49 (49.0%) participants receiving at least one dose of disulfiram did not complete the protocol for reasons specified in Figure 1 . Figure 2. Open in a new tab Number of participants retained each week for the four treatment groups across the 14-week study: in the placebo (open circles), disulfiram at 250 mg/day (closed triangles), disulfiram at 375 mg/day (closed squares), and disulfiram at 500 mg/day (closed circles). The mean percentage of missing urine samples out of the total possible (i.e., 39 urine samples) ranged from 21.0+/−31.9% to 42.6+/−33.6% in the placebo and 375 mg disulfiram groups, respectively, and did not differ across groups (F(3, 45)=1.58, p>0.20). The percentage of scheduled individual therapy sessions attended ranged from 88.7+/−11.6% in the 375 mg disulfiram group to 92.3+/−7.3% in the placebo group and did not differ across medication groups (F(3, 45)=0.58, p>0.77). Disulfiram Effects on Cocaine Use Cocaine use during the trial is shown in Figure 3 . During week 2, the percentage of urine screens testing positive for cocaine did not differ across groups, with the percentage of urines positive for cocaine ranging from 28.21+/− 11.23 to 47.22+/− 13.27 in the placebo and 500 mg disulfiram groups, respectively (p>0.43; Figure 3 ). Similarly, the last urine screen obtained during week 2 (used in the urine drug use outcomes analysis) also did not differ across groups (Fisher Exact Test > 0.35). From the last urine obtained during week 2 to week 14 inclusive, cocaine-positive urine screens increased over time in the placebo group, whereas cocaine-positive urine screens decreased over time in the 250 (t=−2.45, p<0.015; slope=−0.038) and 375 (t=−2.44, p=0.015; slope=−0.033), but not the 500 (t= −1.57, p>0.11; slope=0.003) mg disulfiram groups relative to placebo (slope=0.064; Figure 3 ). However, although the placebo trend over time was significantly greater than horizontal (t=2.02; p<0.05), trends for the 250 (t=−1.42; p>0.15), 375 (t=−1.37; p>0.17), or 500 (t=0.14; P>0.89) groups did not differ from horizontal. Figure 3. Open in a new tab Weekly mean percentage (+/− S.E.M.) of urine toxicology screens positive for cocaine (top panel) and their respective HLM point estimates ((+/− S.E.M., bottom panel) for the four treatment groups across the 14-week trial: placebo (open circles), disulfiram at 250 mg/day (closed triangles), disulfiram at 375 mg/day (closed squares), and disulfiram at 500 mg/day (closed circles). Among those who completed the trial, the percentage of responders was 0% (0/10), 14.3% (1/7), 25% (1/4), and 50% (2/4), respectively in the placebo, 250, 375 and 500 disulfiram groups (p = 0.088). Among all participants who started week 3, the percentage of placebo, 250, 375, and 500 mg group responders was 0% (0/13), 7.7% (1/13), 7.7% (1/13), and 20% (2/10), respectively (p > 0.42). Disulfiram Effects on HAM-A and HAM-D Scores, Vital Signs, and Adverse Events Regardless of medication group, HAM-A scores decreased over time (t=−3.58, p<0.001; Figure 4 ). No medication group by time interactions occurred (p>0.08). HAM-D scores significantly decreased over time relative to horizontal in the placebo (t=−3.00, p<0.004) and disulfiram 500 (t=−2.21, p<0.03), but not 250 (t=−1.09, p>0.27) or 375 (t=0.17, p>0.86) mg, groups. A medication group by time interaction occurred, such that placebo group scores decreased more rapidly over time than disulfiram 375 mg group scores (t=2.10, p<0.04; Figure 4 ). Figure 4. Open in a new tab Monthly mean score on the HAM-A (top left panel) and HAM-D (top right panel) rating scales and their respective HLM point estimates (bottom panels) for the four treatment groups across the 14-week trial: placebo (open circles), disulfiram at 250 mg/day (closed triangles), disulfiram at 375 mg/day (closed squares), and disulfiram at 500 mg/day (closed circles). Neither systolic or diastolic blood pressure showed a medication group by week interaction (F(3, 45)=2.52; p=0.0575 and F(3, 45)=2.17; p=0.0906, respectively; data not shown). Similarly no medication group by week effect occurred with heart rate (F(3, 45)=1.22; p=0.3009; data not shown). One hundred fifty-four instances of adverse events (AEs; defined as any untoward events or increase in severity or frequency of prior existing symptoms) occurred, of which 72 were deemed at least possibly related to the study before breaking the blind ( Table 2 ). Four individuals left the study citing they did not want to take methadone (N=2) or disulfiram (N=2). Investigators discharged four participants from the study due to the following AEs thought to be at least possibly related to the study medication: repeated episodes of nausea/vomiting due to continued alcohol use (N=1), syncope (N=1), auditory hallucinations (N=1), and cocaine-induced paranoia (N=1). One serious AE unrelated to study participation (spinal abscess; N=1), but no deaths, occurred during study participation. Medication groups did not differ in terms of proportion of participants experiencing at least one study-related AE (χ 2 =2.26, p>0.52). Table 2. Summary of adverse events (AEs) deemed at least possibly related to study participation. Serious adverse events at least possibly related to study medications are indicated by an asterisk (*). Disulfiram Dose (mg/day) Study-Related Adverse Event NR 0 250 375 500 Prior to Disulfiram/Placebo Administration: Nausea/vomiting (methadone) 2 2 2 Sedation/lethargy (methadone) 1 1 1 After Starting Disulfiram/Placebo Administration: Cocaine-induced paranoia, sweating, headache, insomnia, anxiety 1* Cocaine-induced racing heart, elevated blood pressure 1 Confusion 1 2 Constipation (methadone) 3 1 2 Elevated blood pressure and/or heart rate 3 3 Garlic-like breath or metallic taste 1 1 3 Methamphetamine-induced hallucinations/delusions 1* Headache 1 2 Itching 1 Lethargy or no energy 1 Lightheaded or dizzy 1 1 Muscle tremors 1 Nausea, vomiting, indigestion, abdominal cramping 2 5 6 6* Nightmares or vivid dreams 1 Paranoid thoughts, feelings and ideas of reference 1 Shortness of breath 1 Sleepiness, sedation or fatigue 2 1 Slurred speech 2 Sweating or hot spells 2 1 Syncope (due to overheating/dehydration) 1* Tingling in digits and edema 1 Total # of AEs: 3 9 25 15 20 Open in a new tab DISCUSSION To our knowledge, this is the first clinical trial to examine the efficacy and tolerability of disulfiram at fixed doses greater than 250 mg/day in participants with dual cocaine and opioid dependence. The increased cocaine use observed over time in the placebo group is consistent with prior reports of increased cocaine use in methadone-stabilized patients ( Black et al., 1987 ; Condelli et al., 1991 ; Meandzija et al., 1994 ), but not in our prior trial ( Oliveto et al., 2011a ). The reason for this inconsistency is unclear. In contrast, cocaine use did not increase over time in the 250 and 375 mg disulfiram groups relative to placebo, suggesting 250–375 mg/day may be within the most efficacious dose range for preventing the greater severity of cocaine use in these populations. Nevertheless, this efficacy appears very limited, given actual reductions in cocaine use over time were not observed. These results extend the findings of our prior study, which showed disulfiram at doses lower than 250 mg/day exacerbated cocaine use ( Oliveto et al., 2011b ), as well as other studies in which disulfiram at 250 mg/day showed reductions in self-reported and/or biologically verified cocaine use ( Carroll et al., 2004 ; Carroll et al., 1998 ; George et al., 2000 ; Kosten et al., 2013 ; Petrakis et al., 2000 ; Pettinati et al., 2008 ) relative to placebo. Nevertheless, cocaine use findings with the 250 mg dose of disulfiram have historically been mixed, in that, although disulfiram-induced reductions relative to placebo may have typically been reported in terms of self-reported use, some studies reported disulfiram-induced reductions in cocaine-positive urine results ( Carroll et al., 2004 ; Grassi et al., 2007 ; Kosten et al., 2013 ) while others reported no differences ( Carroll et al., 2012 ; Oliveto et al., 2011a ; Schottenfeld et al., 2014 ) or did not mention urine results ( Petrakis et al., 2000 ). According to a recent Cochrane review of prior disulfiram clinical trials, disulfiram appeared to increase the number of individuals who achieve abstinence at the end of the treatment period relative to placebo; however, disulfiram had minimal effects on frequency or amount of cocaine use, continuous cocaine abstinence, or dropout ( Traccis et al., 2024 ). At the same time, the doses of disulfiram tested across these trials varied greatly, ranging from 62.5 to 400 mg/day with a median dose of 250.5 mg/day and most frequent dose 250 mg/day and dose did not appear to have been considered in the analyses ( Traccis et al., 2024 ). Overall, the efficacy of disulfiram to reduce cocaine use per se appears to be limited, with evidence suggesting cocaine use increases at doses lower than 250 mg/day ( Oliveto et al., 2011b ) and possibly decreases and/or does not increase cocaine use relative to placebo at 250–325 mg/day. These findings highlight the importance of examining potential treatment agents across a wide range of doses to determine optimal as well as contraindicated doses. The seeming complexity of disulfiram’s dose-related impact on cocaine use may be due nonspecific disulfiram-induced inhibition of a myriad of enzymes, including aldehyde dehydrogenases ( Faiman, 1979 ; Gibbons et al., 1993 ; Haley, 1979 ; Wright and Moore, 1990 ), dopamine beta-hydroxylase (DBH) and other esterases ( Faiman, 1979 ; Haley, 1979 ; Honjo and Netter, 1969 ), including those involved in cocaine metabolism ( Faiman, 1979 ; Stewart et al., 1979 ). The potency of disulfiram to inhibit these enzymes differs, with disulfiram being a more potent inhibitor of aldehyde dehydrogenase and esterases than of DBH ( Karamanakos et al., 2001 ). DBH converts dopamine to norepinephrine. Thus, inhibition of DBH would result in decreased norepinephrine and increased dopamine levels. Similar to the selective DBH inhibitor nepicastat, disulfiram has been shown to decrease norepinephrine levels at a dose that blocks cocaine-primed reinstatement of drug seeking in rodents ( Schroeder et al., 2010 ). Given disulfiram is thought to be at least partially responsible for altering the self-reported effects of cocaine through its regulation of the dopamine-norepinephrine ratio in the brain ( Stanley et al., 1997 ), we previously suggested ( Oliveto et al., 2011b ) low-dose-disulfiram-induced exacerbation of cocaine use may be due to low-dose-induced prolongation of cocaine effects through inhibition of cocaine metabolism without significantly altering DBH-activity-related quality of the cocaine-induced subjective aversive or craving effects. Thus, the disulfiram-induced prolongation of cocaine’s actions without altering the quality of self-reported effects may sustain and enhance priming effect for more cocaine use ( Oliveto et al., 2011b ). Although speculative, given disulfiram at doses of 250–375 mg/day appears somewhat efficacious in the whole sample, disulfiram may be effective at inhibiting DBH at these doses. The severity of anxiety and depressive symptoms was mild on average at baseline and did not increase over time in any medication group. Although the severity of anxiety symptoms diminished over time in the placebo relative to disulfiram 375 mg group, this difference is likely not clinically significant due to low baseline scores. Interestingly, the overall frequency of study-related adverse events was not dose dependent, which is similar to what we observed in our prior study examining lower doses of disulfiram ( Oliveto et al., 2011b ). Nevertheless, given the inability of the 500 mg disulfiram dose to significantly impact cocaine use as well as apparent dose-related increases in the frequency of gastrointestinal disturbances, disulfiram at 500 mg/day may not have utility for people who use cocaine. Indeed, a study examining the safety of cocaine, alcohol and disulfiram combinations among individuals with a history of cocaine use terminated further examination of disulfiram at 500 mg/day due to medically serious changes in vital signs after combining disulfiram at this dose with alcohol ( Roache et al., 2011 ). In addition, there was some indication of disulfiram-induced increases in blood pressure in the absence of cocaine by day 6 of disulfiram treatment ( Roache et al., 2011 ), although this effect was not observed in the present study with participants being maintained on methadone. Disulfiram has been speculated to have potential utility particularly in structured, well-monitored treatment regimens such as methadone maintenance, especially as suspending the disulfiram in methadone vehicle assures compliance ( Soyka, 2015 ). As with prior reports of disulfiram in methadone-maintained patients with alcohol ( Bickel et al., 1987 ; Ling et al., 1983 ) and/or cocaine dependence ( Kosten et al., 2013 ; Oliveto et al., 2011a ; Petrakis et al., 2000 ; Traccis et al., 2024 ), disulfiram was generally well tolerated in the present study. Indeed, we also examined the impact of disulfiram on QTc interval changes at screening, week 2 (after methadone induction) and week 4 (while on disulfiram) of the trial among a subgroup of these (N=23) and nonopioid dependent participants (N=18) ( Atkinson et al., 2013 ). While participants with opioid dependence showed a trend toward higher QTc interval regardless of time point or disulfiram, disulfiram had no differential impact on QTc interval, but recent cocaine use was associated with significant increases in QTc interval ( Atkinson et al., 2013 ). Thus, disulfiram, at least to a dose of 250 mg/day, may be as safe in cocaine dependent as alcohol dependent populations when prescribed appropriately ( Malcolm et al., 2008 ). The major limitation of this pilot trial is the sample size finally achieved for analysis, which likely resulted in the study being underpowered. Although we employed random regression HLM statistical models that made use of all available data to compare potential changes in use over time, dropout rates were relatively high and limited the estimation of the effects of 12 weeks of treatment. In addition, administering modest initial doses of methadone and targeting cocaine use early in their methadone treatment may have confounded our findings. Meanwhile, although the apparently lower retention rates in the higher dose disulfiram groups in our present trial relative to our prior trial ( Oliveto et al., 2011a ) may suggest lower acceptability or tolerability of disulfiram at higher doses, site differences, including degree of rurality, perceived stigma of opioid maintenance treatment, and transportation resources available to participants, make any definitive conclusions about dose-related acceptability difficult. Overall, the present findings preliminarily suggest disulfiram may be optimally, if minimally, efficacious at 250–375 mg/day and contraindicated at 500 mg/day for treating cocaine dependence during early methadone maintenance. More research is necessary to replicate these findings, investigate combination strategies with disulfiram to enhance treatment response, and identify those subpopulations of cocaine dependent patients most likely to benefit from disulfiram therapy. Highlights. Cocaine use can increase during methadone maintenance with worse treatment outcomes Disulfiram (250–375 mg/day) may prevent increases in, but not reduce, cocaine use Disulfiram (500 mg/day) may be contraindicated for reducing cocaine use during opioid maintenance ACKNOWLEDGEMENTS The authors thank Warren Bickel, PhD, [post-humus] for his scientific input, D. Keith Williams, PhD, for his biostatistical expertise, J. Benjamin Guise, MD, and Christopher Cargile, MD, for providing medical coverage, and Nichole Sanders, PhD, for her assistance with the preparation of the manuscript. Sources of Support: This work was supported by grants R01DA13441 (AO) and T32DA022981 (AB) from the National Institute on Drug Abuse, and RR020146 (EG-R) and RR029884 (CL) from the National Center for Research Resources. The authors have no financial disclosures. Footnotes Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alison H. Oliveto reports financial support was provided by National Institute on Drug Abuse. Alison H. Oliveto reports a relationship with National Institute on Drug Abuse that includes: funding grants. Alison H. Oliveto reports a relationship with Substance Abuse and Mental Health Services Administration that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. AUTHOR DISCLOSURE INFORMATION The authors declare no disclosures or conflicts of interest with this work. 1 This work was conducted at the University of Arkansas for Medical Sciences, Department of Psychiatry, Little Rock, AR under IND 76,241. A preliminary report of this work was presented at the Annual Meeting of the College on Problems of Drug Dependence on June 14, 2012 in Palm Springs, CA. A subsample of data examining the impact of disulfiram, opioid dependence status and recent cocaine use on QTc interval has been published ( Atkinson et al., 2013 ). Trial Registration: Clinicaltrials.gov identifier NCT00395850 . Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 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