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Objectives: The accelerated development of additive pharmacotherapy treatment (ADAPT-2) for methamphetamine use disorder (MUD) trial demonstrated the efficacy of extended-release injectable naltrexone (NTX) and oral bupropion (BUP). In this secondary analysis, we determined whether craving and impulsivity levels could predict subsequent use of methamphetamine.

Methods: Participants (N = 357) of the ADAPT-2 trial with at least one transition point [transition from positive-to-negative urine drug screen (UDS) or vice versa] during stage 1 (baseline through week-6) were included in this secondary analysis. Craving was assessed using the Visual Analog Scale (VAS). Impulsivity was assessed using the 2-item impulsivity factor of the Concise Health Risk Tracking (CHRT) Scale.

Results: A significant treatment by craving by time interaction was noted (P = 0.018), where higher craving levels were consistently associated with a lower likelihood positive-to-negative UDS transition at the next visit in both NTX-BUP and placebo groups. However, no such effect was present by week 6 of treatment in the placebo group. CHRT Impulsivity also had a significant effect on the probability of a positive-to-negative UDS transition (P = 0.019) in addition to the 3-way interaction of VAS, week, and treatment group. Individuals with lower craving levels but higher impulsivity exhibited a lower probability of transitioning to negative UDS at the next visit. Higher craving, but not impulsivity, was associated with a higher likelihood of negative-to-positive UDS transition at the next visit in both treatment groups.

Conclusions: Further investigations are necessary to optimize NTX-BUP treatment, focusing on the impact of craving and impulsivity on outcomes.

Related protocols: CTN-0068

Objective: This study evaluated whether depressive symptom severity improved early with extended-release naltrexone and bupropion combination (naltrexone bupropion) compared to a placebo in individuals with moderate/severe methamphetamine use disorder and predicted subsequent use of methamphetamine.

Methods: This secondary analysis from the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2, CTN-0068) trial, which was conducted from May 23, 2017-July 25, 2019, included 326 individuals with a 9-item Patient Health Questionnaire (PHQ-9) score =5 at baseline. Repeated-measures mixed model analyses evaluated early (baseline-to-week-4) changes in depressive symptom severity with naltrexone-bupropion versus placebo and provided slope estimates for PHQ-9 change. Additional depression outcomes included response (=50% reduction in PHQ-9 from baseline) and remission (PHQ-9 =4). Methamphetamine treatment response was ascribed if 3 out of 4 urine drug screens were negative during weeks 5 and 6. Logistic regression analyses evaluated whether changes in depression predicted methamphetamine treatment response. Covariates included age, sex, race, ethnicity, and baseline PHQ-9.

Results: There was a greater reduction in PHQ-9 scores at week 4 with naltrexone-bupropion versus placebo (estimate = -2.52; standard error = 0.81). At week 4, depression response (odds ratio [OR] = 2.54; 95% confidence limit [CL], 1.42-4.55) and remission (OR = 3.04; 95% CL, 1.57-5.87) were more likely with naltrexone-bupropion versus placebo. Greater baseline-to-week 4 reduction in PHQ-9 was associated with a higher likelihood of methamphetamine treatment response (OR = 3.74, 95% CL, 1.28-10.93) and explained 24.8% (95% CI, 6.7%-60.3%) of the effect of naltrexone-bupropion on methamphetamine treatment response.

Conclusion: Use of naltrexone bupropion was associated with early reduction in depressive symptom severity compared to a placebo, which was associated with a higher likelihood of reduction in subsequent methamphetamine use.

Related protocols: CTN-0068

There has been a significant increase in methamphetamine use and methamphetamine use disorder (Meth UD) in the United States, with evolving racial and ethnic differences. This secondary analysis of data from CTN-0069 (ADAPT-2) explored racial and ethnic differences in baseline sociodemographic and clinical characteristics as well as treatment effects on a measure of substance use recovery, depression symptoms, and methamphetamine craving among participants in a pharmacotherapy trial for Meth UD.

The ADAPT-2 trial (ClinicalTrials.gov number, NCT03078075; N=403; 69% male) was a multisite, 12-week randomized, double-blind, trial that employed a two-stage sequential parallel design to evaluate the efficacy of combination naltrexone (NTX) and oral bupropion (BUP) vs. placebo for Meth UD. Treatment effect was calculated as the weighted mean change in outcomes in the NTX-BUP minus placebo group across the two stages of treatment.

Of the 403 participants in the ADAPT-2 trial, the majority (65%) reported non-Hispanic White, while 14%, 11% and 10% reported Hispanic, non-Hispanic Black, and non-Hispanic other racial and ethnic categories respectively. At baseline non-Hispanic Black participants reported less severe indicators of methamphetamine use than non-Hispanic White. Treatment effects for recovery, depression symptoms and methamphetamine cravings did not significantly differ by race and ethnicity.

Conclusions: Although we found racial and ethnic differences at baseline, our findings did not show racial and ethnic differences in treatment effects of NTX-BUP on recovery, depression symptoms and methamphetamine cravings. However, our findings also highlight the need to expand representation of racial and ethnic minority groups in future trials.

Related protocols: CTN-0068

Cocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration-approved pharmacotherapy. Depressive disorders are common psychiatric comorbidity amongst individuals with CUD.

A retrospective cohort study was conducted among 161,544 patients diagnosed with CUD and depression to evaluate the effectiveness of 13 antidepressants on CUD remission. For any antidepressant found to be associated with CUD remission that had an additional indication, we conducted an additional analysis to evaluate the effectiveness of the candidate drug in patients with CUD with that indication. We then analyzed publicly genomic and functional databases to identify potential explanatory mechanisms of action of the candidate drug in the treatment of CUD.

Among these antidepressants, bupropion was associated with higher rates of CUD remission compared to propensity-score matched patients prescribed other antidepressants: hazard ratio (HR) and 95% confidence interval (CI) 1.57 (95% CI: 1.27-1.94). Bupropion is also approved for smoking cessation. We identified CUD patients with co-occurring nicotine dependence and observed that patients prescribed bupropion displayed a higher rate of CUD remission compared to matched individuals prescribed other drugs for nicotine dependence: 1.38 (95% CI: 1.11-1.71). Genetic and functional analyses revealed that bupropion interacts with four protein-encoding genes (COMT, DRD2, SLC6A3, and SLC6A4) which are also associated with CUD and targets CUD-associated pathways including serotonergic synapses, cocaine addiction, and dopaminergic synapses.

Conclusions: Our findings suggest that bupropion might be considered a treatment for improving CUD remission in patients with CUD and co-occurring depression or nicotine dependence.

Related protocols: CTN-0114

Methamphetamine (MA) use is marked by high rates of comorbid tobacco smoking, which is associated with more severe drug use and worse clinical outcomes compared to single use of either drug. Research has shown the combination of naltrexone plus oral bupropion (NTX-BUP) improves smoking cessation outcomes in non-MA-using populations. In the National Drug Abuse Treatment Clinical Trials Network (CTN) Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) study, NTX-BUP successfully reduced MA use. Our aim in this secondary data analysis was to examine changes in cigarette smoking among the subgroup of participants reporting comorbid tobacco use in the ADAPT-2 trial.

The multi-site ADAPT-2 study used a randomized, double blind, sequential parallel comparison design to evaluate treatment with extended-release injectable NTX (380 mg every 3 weeks) combined with once-daily oral extended-release BUP (450 mg/day) vs matching injectable and oral placebo in outpatients with moderate or severe MA use disorder. The study assessed smoking outcomes, based on self-reported timeline followback (TLFB) data, twice/week for 13 weeks.

Of the 403 participants in the ADAPT-2 trial, 290 reported being current cigarette smokers (71.9 %). The study found significant differences (p’s < 0.0001) for each smoking outcome indicating greater change in the proportion of nonsmoking days, number of cigarettes smoked per week, and consecutive nonsmoking days, all favoring the group receiving NTX-BUP versus placebo.

Conclusions: NTX-BUP was associated with significant reductions in self-reported cigarette smoking in the context of concurrent treatment for MA use disorder. These off-target medication effects warrant prospective investigation using biochemically confirmed measures of smoking abstinence. The development of NTX-BUP as a co-addiction treatment strategy has a potential for high public health impact.

Related protocols: CTN-0068

This is the primary outcomes article for CTN-0068.

The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone–bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone–bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.

A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone–bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone–bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone–bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone–bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone–bupropion during the trial.

Conclusions: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo.

Related protocols: CTN-0068

This article describes how smartphones were used to monitor and encourage medication adherence in a pilot study evaluating the potential efficacy of a combination pharmacotherapy for methamphetamine use disorder. It examines the feasibility, utility, and acceptability of using smartphones to capture dosing videos from the perspectives of participants and staff.

The study, CTN-0054 (“Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT) for Methamphetamine Use Disorder”), was an 8-week, open-label evaluation of extended-release bupropion (BRP, Wellbutrin XL, 450mg/day). Participants attended visits twice weekly for observed BRP dosing, assessments, and medical management. BRP was dispensed once weekly for dosing on nonclinic days. Medication adherence was assessed objectively (by observation at the clinic and smartphone videos for dosing at home) and subjectively (self-reports of dosing). Surveys assessing the smartphone component were completed by participants and study staff.

Participants (N=49) reported taking 93.6% of the dispensed BRP doses while 86.6% of dispensed doses were confirmed via dosing video and in-person observations. Most participants who completed the survey agreed that the smartphone was easy to use (92.6%) and that taking the dosing videos helped them remember to take the study medication (80.5%). Staff agreed that the smartphone helped collect accurate dosing data for most (77.5%) participants.

Conclusions: The use of smartphones for video-based oral medication dosing in this study provided a feasible and acceptable mechanism to encourage, monitor, and confirm medication adherence. Video-confirmed dosing adherence provides an objective numerical indicator of the lowest medication adherence rate participants achieve, allowing investigators to more confidently interpret results.

Related protocols: CTN-0054

This is the primary outcomes article for CTN-0054.

This 2-stage open-label pilot study evaluated the safety and potential efficacy of naltrexone + bupropion as a pharmacotherapy for methamphetamine (MA) use disorder. The study was conducted in 2 stages of recruitment across 3 sites; 20 participants were enrolled in stage 1 and 29 participants were enrolled in stage 2. Eight weeks of open-label pharmacotherapy with a combination of extended-release injectable naltrexone (XR-NTX; Vivitrol) plus extended-release oral bupropion (BRP, Wellbutrin XL) were provided with a smartphone-assisted medication adherence platform. Participants met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for severe MA use disorder, self-reported 20 days or more of MA use in the 30 days prior to consent, and submitted 3 MA-positive urine drug screens (UDS) out of 4 collected during screening. Participants attended clinic twice weekly for observed BRP dosing, UDS testing, assessments, and medical management; XR-NTX was administered at weeks 1 and 5. A BRP taper and follow-up visit occurred in week 9.

Analyses evaluated effects of XR-NTX + BRP to determine the number of “responders” according to a statistically predefined response criterion (6 of 8 MA-negative UDS during the last 4 weeks of medication). The 2-stage design required that stage 1 yield 3 or more responders to continue to stage 2; 11 of the 49 participants met responder criteria across both stages (5 in stage 1, 6 in stage 2).

Conclusions: The primary objective of this single-arm, open-label pilot study was to evaluate the safety and preliminary efficacy of XR-NTX + BRP as a potential treatment for MA use disorder. Under the statistical analysis plan, study “success” required 9 or more responders. With 11 responders, the study demonstrated sufficient potential of naltrexone plus bupropion as a combination pharmacotherapy for MA use disorder to warrant further study. Findings also support the general safety and tolerability of this medication combination in MA users, and had high rates of retention and medication adherence.

Related protocols: CTN-0054

Smoking is highly prevalent in substance dependence, but smoking-cessation treatment (SCT) is more challenging in this population. To increase the success of smoking cessation services, it is important to understand potential therapeutic targets, like nicotine craving, that have meaningful but highly variable relationships with smoking outcomes. This secondary analysis of data from National Drug Abuse Treatment Clinical Trials Network protocol CTN-0046 (Smoking Cessation and Stimulant Treatment) characterized the presence, magnitude, and specificity of nicotine craving as a mediator of the relationship between SCT and smoking abstinence in the context of stimulant-dependence treatment. The original trial was a randomized, 10-week study conducted at 12 outpatient substance use disorder (SUD) treatment programs. Adults with cocaine and/or methamphetamine dependence (n=538) were randomized to SUD treatment as usual (TAU) or TAU+SCT. Participants reported nicotine craving, nicotine withdrawal symptoms, and substance use in the week following a uniform quit attempt of the TAU+SCT group, and self-reported smoking 7-day point prevalence abstinence (verified by carbon monoxide) at end-of-treatment.

Bootstrapped regression models indicated that, as expected, nicotine craving in the week following a quit attempt was a significant mediator between SCT and smoking abstinence, accounting for 14% of the total effect. Nicotine withdrawal symptoms and substance use were not significant mediators. This pattern held for separate examinations of cocaine and methamphetamine dependence.

Conclusions: Nicotine craving accounts for a small but meaningful portion of the relationship between smoking-cessation treatment and smoking-abstinence during SUD treatment. Nicotine craving, particularly during the week following a quit attempt, may be a useful therapeutic target for increasing the effectiveness of smoking-cessation treatment in substance dependence. This timing is useful for clinicians and researchers attempting to predict outcomes within SUD treatment, as the increased variability and intensity of craving after a quit attempt may produce a clearer relationship between craving and nicotine outcomes.

Related protocols: CTN-0046

Cigarette smoking is prevalent in cocaine/methamphetamine-dependent patients and associated with significant morbidity and mortality, yet the provision of smoking cessation treatment in conjunction with substance use disorder (SUD) treatment is not standard practice. This is due, in part, to clinician concern that combining smoking cessation treatment with SUD treatment could lead to poorer SUD outcomes. The National Drug Abuse Treatment Clinical Trials Network is conducting a 10-week, two-group, randomized trial to evaluate the impact of providing smoking cessation treatment (SCT) with SUD treatment as usual (TAU), compared to TAU alone, in smokers who are in outpatient treatment for cocaine or methamphetamine dependence (protocol CTN-0046, S-CAST). Approximately 528 participants recruited from 12 community treatment programs will be randomized into the trial. This paper describes key design decisions make during protocol development. The trial is designed to evaluate the relationship between cigarette smoking and stimulant use, which prior research suggests is linked, and should contribute to our understanding of how best to address the co-occurring problems of nicotine dependence and cocaine/methamphetamine-dependence.

Unique aspects of the trial include the primary question of interest, which concerns the impact of providing SCT on SUD outcomes rather than on smoking outcomes, and the intensity of the SCT chosen, which includes bupropion, nicotine replacement, and two psychosocial interventions. S-CAST is designed to answer questions of interest to clinicians as well as more basic researchers and should contribute significantly to our understanding of how best to address the co-occurring problems of nicotine and cocaine/methamphetamine dependence.

Related protocols: CTN-0046