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In this session, Kathleen T. Brady, MD, PhD, of the Medical University of South Carolina, will discuss the NIDA Clinical Trials Network (CTN) study CTN-0108, “Transcranial Magnetic Stimulation for the Treatment of Methamphetamine/Cocaine Use Disorder,” a pilot study that aims to determine the feasibility, effectiveness, and safety for 20 sessions of repetitive transcranial magnetic stimulation (rTMS) versus sham in adults with a diagnosed methamphetamine or cocaine use disorder. Dr. Brady, co-Principal Investigator for CTN-0108, presented the rationale for the study, including the literature supporting the use of rTMS in stimulant use disorder, as well as the study methodology and preliminary results.

Related protocols: CTN-0108

Background and objectives: Patients using fentanyl have worse treatment outcomes; however, little is known about other drugs that complicate treatment.

Methods: A national survey (n = 396) was conducted for CTN-0135 using a random sample of clinicians waivered to prescribe buprenorphine in the United States. This study reports the results of a single survey item on clinicians’ perceptions of other drugs, besides IMF, complicating treatment.

Results: Clinicians reported methamphetamine (86.4%), synthetic cannabinoids (42.7%), and xylazine (41.4%) were complicating treatment; reports varied by geographic region.

Conclusions and scientific significance: Rapid clinician surveys can provide real-time data on changing patterns of drug use’s impact treatment outcomes.

Related protocols: CTN-0135

This is the primary outcomes article for Aim 1 of CTN-0129.

Substance use, specifically opioid and methamphetamine use, is of increasing concern among American Indian (AI) populations in the Great Plains. This community-driven participatory study investigated the impacts of substance use and community-defined needs in treating addiction. It determined the priorities for future research on behavioral health and substance misuse in the Great Plains region. Behavioral health and social services professionals and community stakeholders were identified from eight Great Plains communities and invited to attend eight focus groups (N=47). Conversations were audio-recorded, transcribed, and coded by the research team.

The qualitative data analysis identified four themes: (1) Challenges with Treatment and Recovery, (2) Impact of Substance Use, (3) Reasons for Substance Use, (4) Solutions and Research Priorities.

The findings highlight barriers to substance use disorder (SUD) treatment ranging from policy issues to lack of funding. The most significant finding centered on integrating cultural strengths into treatment and recovery programs, including Ceremony Assisted Treatment (CAT). Data reports for each participating organization were provided to disseminate outcomes in their respective communities. Other key findings suggest that addressing the root causes of substance use disorder, along with early intervention and comprehensive counseling services, are essential for long-term success.

Related protocols: CTN-0129

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

Background: Cocaine and methamphetamine use disorders (CcUD/MtUD) have serious public health, medical, and psychiatric consequences. Yet, there are no U.S. Food and Drug Administration (FDA) approved treatments available. The STIMULUS study is a multi-site trial, sponsored by NIDA’s National Drug Abuse Treatment Clinical Trials Network (CTN), that aims to investigate the feasibility and preliminary efficacy of repetitive transcranial magnetic stimulation (rTMS) as a potential treatment for moderate to severe CcUD/MtUD.

Methods: The study is a double-blind, sham-controlled trial seeking to recruit 160 participants with a current moderate to severe CcUD or MtUD diagnosis, randomized to receive active rTMS (10-Hz stimulation at 120% motor threshold over the left dorsolateral prefrontal cortex) or sham. Feasibility is assessed by a target of at least 20 treatment sessions administered within an 8-week period. Additionally, the study aims to evaluate the efficacy of rTMS in reducing stimulant use and craving, the impact of rTMS on mood, anxiety, sleep, and other measures, and the utility of electroencephalography as a treatment response biomarker.

Discussion: Studies exploring rTMS for stimulant use disorders remain limited by small sample sizes, as well as great heterogeneity in defined study population, treatment parameters, retention in treatment, and number of sessions. In this paper, we highlight key study design decisions, such as safety, sham procedure, and schedule flexibility.

Conclusions:
We hope that the data collected will lay the groundwork for a robust randomized controlled trial of rTMS as a therapeutic intervention for individuals with CcUD/MtUD.

Related protocols: CTN-0108

Background: Methamphetamine (MA) use has been linked to engaging in sexual risk behaviors (SRBs) that are associated with HIV/STIs, particularly among men who have sex with men (MSM) and men who have sex with men and women (MSMW; hereafter MSM/W). The objectives of this analysis were to determine whether reduced MA is associated with decreases in SRBs in a sample of MSM/W.

Method: Data came from the ADAPT-2 trial, a randomized, double-blind, two-stage sequential parallel design trial evaluating extended-release injectable naltrexone (NTX) and oral bupropion (BUP) vs. placebo for MA use disorder. In the first 6 weeks of the trial (stage 1), participants were randomized to receive NTX-BUP or placebo. In the second 6 weeks, participants in the placebo group who did not have a treatment response were rerandomized (stage 2). For this secondary analysis, the independent variable was the number of MA-negative urine drug screens (UDS). The dependent variables included three different types of SRBs. Regression models of the independent and dependent variables were adjusted for age, race/ethnicity status, marital status, treatment assignment, and baseline SRBs.

Results: Of the 151 participants, median age was 40 years and majority were non-Hispanic white (52%) and completed more than high school education (82%). Each additional MA-negative UDS was associated with a 7% (adjusted rate ratio (aRR) =0.93; 95% CI, 0.87, 0.99) reduction in total number of sex partners in stage 2 only. Each additional MA-negative UDS was associated with a 13% (aRR =0.87 95%; confidence interval (CI), (0.76, 0.98)) and 9% (aRR =0.91; 95% CI, 0.84, 0.99) reduction in number of condomless sexual encounters in stage 1 and stage 2, respectively. Lastly, each additional MA-negative UDS was associated with a 16% (aRR =0.84; 95% (CI), 0.75, 0.94)) and 27% (aRR =0.73; 95% CI, 0.64, 0.84) reduction in number of sexual encounters when high on MA.

Conclusions: Our analysis showed that reductions in MA use was associated with reductions in several sexual risk behaviors associated with HIV/STI. These findings provide further support for exploring reductions in sexual risk behaviors as a clinical endpoint in future treatment interventions for MA use.

Related protocols: CTN-0068

This paper reports on a cost-effectiveness study of protocol CTN-0007, designed to determine if prize-based contingency management (CM), which has been shown to improve treatment outcomes over usual care (UC) alone, is worth the additional cost to treatment agencies. Six methadone maintenance community-based treatment programs (CTPs) in the CTN participated, with a study sample of 388 participants, 190 in the UC condition and 198 in the CM condition (which combined usual care with contingency management).

The authors found that prize-based contingency management provided better patient outcomes than usual care, but required additional costs. Compared to usual care, the incremental cost of using prize-based contingency management to lengthen the longest duration of abstinence (LDA) by one week was $141. The incremental cost to obtain an additional stimulant-negative urine sample was $70. Whether this extra expenditure is worthwhile depends upon the value placed on these outcomes. Using only the benefit of averted crime, an acceptability curve developed by the authors demonstrates a cost-effectiveness benefit of 90%. However, this estimate is quite conservative because averted crime is only one of the many potential benefits of a reduction in substance abuse. By comparing this study to a companion study, the authors also found that adding prize-based contingency management to usual care may be more cost-effective in methadone maintenance clinics than in counseling-based drug-free clinics. Further empirical analyses are needed to help policy makers decide whether CM is worth the extra expense; this paper helps to build an empirical basis for these important decisions.

Related protocols: CTN-0007-A-2

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

This study was a secondary analysis of two CTN trials comparing buprenorphine (BUP-NX) and extended-release naltrexone (XR-NTX), CTN-0051, X:BOT and CTN-0067, CHOICES. The purpose was to estimate how ongoing stimulant use affects return to illicit opioid use after initiation onto medication for opioid use disorder (MOUD).

A total of 528 participants who initiated MOUD as part of trial participation were included; participants were recruited from 13 opioid treatment programs and HIV clinics across 10 states in the U.S. from 2014-2019. Nearly half (49%) were between 30 and 49 years of age, 69% were male and 66% were non-Hispanic White.

The primary outcome was first self-reported day of non-prescribed opioid use following MOUD initiation, and the exposure of interest was daily stimulant use (methamphetamine, amphetamines or cocaine). Both were defined using time-line follow-back. Among participants reporting at least 1 day of illicit opioid use, we also examined relapse to ongoing use, defined as (1) 7 days of continuous opioid use or (2) 4 consecutive weeks with self-reported opioid use, one or more positive urine drug screens (UDS) for opioids or one or more missing UDS.

Forty-seven per cent of participants reported stimulant use following MOUD initiation, 58% returned to illicit opioid use and 66% of those relapsed to ongoing use. Stimulant use was strongly associated with increased risk of misusing opioids after MOUD initiation when measured daily [adjusted hazard ratio (aHR)=9.23, 95% confidence interval (CI)=6.80–12.50, P<0.001] and over a 7-day period (aHR=1.27 for each additional day, CI=1.18–1.37, P<0.001). Using stimulants weekly or more often was associated with increased likelihood of relapse to ongoing opioid use compared with less than weekly or no stimulant use (adjusted odds ratio=2.30, CI=1.05–5.39, P=0.044).

Conclusions: People initiated on medication for opioid use disorder who subsequently use stimulants appear to be more likely to return to and continue using non-prescribed opioids compared with those without stimulant use. The association appears to be stronger among patients who initiate buprenorphine compared with those who initiate extended-release naltrexone.

Related protocols: CTN-0051, CTN-0067

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

Methamphetamine use disorder (MethUD) disproportionately affects men who have sex exclusively with men or with men and women (collectively MSM/W), compared to men who have sex with women (MSW). This study is the first MethUD medication trial to compare treatment effect for these groups, hypothesizing that extended-release injectable naltrexone 380 mg every 3 weeks plus oral extended-release bupropion 450 mg daily would be less effective for MSM/W than MSW.

Data come from men (N=246) in a multi-site, double-blind, randomized, placebo-controlled trial with sequential parallel comparison design (CTN-0068, ADAPT-2). In Stage 1 (6-weeks), participants were randomized to active treatment or placebo. In Stage 2 (6-weeks), Stage 1 placebo non-responders were rerandomized. Treatment response was =3 methamphetamine-negative urine samples, out of four obtained at the end of Stages 1 and 2. Treatment effect was the active-versus-placebo between-group difference in the weighted average Stages 1 and 2 responses.

MSM/W (n=151) were more likely than MSW (n=95) to be Hispanic, college-educated, and living with HIV. Adjusting for demographics, among MSM/W, response rates were 13.95 % (active treatment) and 2.78 % (placebo) in Stage 1; 23.26 % (active treatment) and 4.26 % (placebo) in Stage 2. Among MSW, response rates were 7.69 % (active treatment) and 5.80 % (placebo) in Stage 1; 3.57 % (active treatment) and 0 % (placebo) in Stage 2. Treatment effect was significantly larger for MSM/W than MSW.

Conclusions: Findings suggest efficacy of extended-release naltrexone plus bupropion for MSM/W, a population heavily burdened by MethUD. While a secondary outcome, this intriguing finding merits testing in prospective trials.

Related protocols: CTN-0068

The co-occurrence of suicidality and substance use disorders has been well established, but rating scales to examine suicidal behavior and risk are sparse among participants with substance use disorders. In this study, part of the CTN ADAPT-2 protocol (CTN-0068), researchers examined the psychometric properties of the 16-item Concise Health Risk Tracking Scale – Self Report (CHRT-SR16) to measure suicidality among adults with moderate-to-severe methamphetamine use disorder.

Participants (n = 403) with moderate-to-severe methamphetamine use disorder completed the CHRT-SR16 as part of a randomized, double-blind, placebo-controlled pharmacotherapy trial. The CHRT-SR16 factor structure was assessed using confirmatory factor analysis (CFA). Internal consistency was estimated with coefficients alpha (a) and omega ( ), test-retest reliability with intraclass correlation coefficient (ICC) and standard error of measurement, and convergent validity using Spearman’s rank order correlation coefficient test between CHRT-SR16 factors and the Patient Health Questionnaire (PHQ-9). The analyses utilized baseline and week 1 data (for test-retest reliability only).

CFA revealed a seven-factor model of Pessimism, Helplessness, Social Support, Despair, Impulsivity, Irritability, and Suicidal Thoughts as the best-fitting model. The CHRT-SR16 also exhibited strong internal consistency (a = 0.89; = 0.89), test-retest reliability (ICC = 0.78) and convergent validity with the PHQ-9 total score ( = 0.62).

Conclusions: The results of this study offer evidence for strong reliability and convergent validity of the CHRT-SR16, among the first validated instruments to measure Suicidal Thoughts and behavior in a population that is disproportionately experiencing overdose and death due to methamphetamine use. The CHRT-SR16 builds upon prior work with the CHRT-SR and allows for the novel assessment of impulsivity and irritability as possible risk factors for suicidal behavior.

Related protocols: CTN-0068

Traditional treatments for substance use disorders (SUDs) rely heavily on face-to-face interactions, which pose substantial limitations for patients. A clinical trial of a digital therapeutic (DT) delivering behavioral therapy demonstrated safety and efficacy in a population including patients with opioid use disorder (OUD) not treatment with buprenorphine, which is not a guideline-recommended approach. This study re-analyzed the data excluding patients with OUD to more closely approximate real-world patient populations.

The study was a secondary analysis of data from CTN-0044 (“Web-Delivery of Evidence-Based, Psychosocial Treatment for Substance Use Disorders;” n=399 after patients with OUD were excluded). Patients received 12 weeks of outpatient treatment-as-usual (TAU; n=193) or TAU with reduced counseling plus a digital therapeutic (DT; n=206) providing computerized cognitive behavioral therapy and contingency management (the reSET, a commercial version of the Therapeutic Education System (TES)). Primary outcomes were abstinence in weeks 9-12 and retention in treatment.

The 399 patients in the analysis (206 in the DT group and 193 in the TAU group) reported substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (e.g. methamphetamine). Demographic and baseline characteristics including age, sex, race, education, and reported primary substance use disorder were balanced between treatment groups. Abstinence was significantly higher in the DT group compared to the TAU group (40.3 vs. 17.6%), as was retention in therapy (76.2 vs. 63.2%).

Conclusions: These results demonstrate that use of a digital therapeutic safely increased abstinence (reduced substance use) and retention in treatment among patients with substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (including methamphetamines).

Related protocols: CTN-0044

Methamphetamine use is increasing among persons with opioid use disorder (OUD). The study aims were to describe methamphetamine/amphetamine (MA/A) use among patients treated for OUS with buprenorphine/naloxone (BUP-NX) or extended-release naltrexone (XR-NTX), and to explore associations between treatment arm and MA/A use.

The study used data from the CTN X:BOX trial (CTN-0059), a multi-site, open-label, randomized controlled trial of XR-NTX vs. BUP-NX for 24 weeks. The outcome variable was MA/A use defined by either positive urine drug toxicology or self-report. The main predictor was treatment assignment (BUP-NX vs. XR-NTX). Longitudinal mixed-effects logistic regression models were fit to model the odds of MA/A use during the study. Additional predictors included study visit and baseline MA/A use.

Among the sample of 570 participants with OUD, baseline use of MA/A was observed in 105 (18.4%). There was no significant treatment effect over the study period, though BUP-NX subjects, on average, had about half the odds of MA/A use compared to XR-NTX subjects. In the same model, baseline MA/A use and study visit were both significantly associated with MA/A use over time.

Conclusions: In this sample of treated OUD patients, nearly a fifth (18.4%) of participants had MA/A use at baseline and the frequency of use did not decline over time: in fact, the odds of use slightly increased for each later visit. These secondary analyses found no significant difference in MA/A use between BUP-NX and XR-NTX treatment arms, however, the observation of less MA/A in the buprenorphine arm merits further investigation.

Related protocols: CTN-0051