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Introduction: Increases in morbidity and mortality associated with stimulant use disorders (StUDs) combined with limited pharmacological research and development highlight the need to explore repurposing existing medications with mechanisms of action relevant to the management of StUDs. This paper presents findings regarding a common set of symptoms common across StUDs, impulsivity and compulsivity, that offer compelling rationale to identify future interventions for evaluation in CTN trials and elsewhere.

Methods: A virtual Task Force meeting held in 2024 by the National Drug Abuse Treatment Clinical Trials Network (CTN) assembled national experts to consider pharmacological and non-pharmacological candidates for repurposing in StUD treatment. Discussion centered on evidence regarding their mechanisms of action, preclinical and clinical evidence in StUD management, and how these interventions could be further researched or applied in clinical practice.

Results: Discussions referenced medications including: suvorexant, GLP-1 agonists, guanfacine, clavulanic acid, cariprazine, cannabidiol and psychedelics. Non-medication therapeutic strategies to consider for managing StUDs include novel neuromodulation techniques (low-intensity focused ultrasound (LIFU), photobiomodulation (tPBM)), which are believed to precisely and deeply penetrate brain tissues, targeting areas responsible for StUDs-related behaviors.

Task Force findings with high enthusiasm for possible consideration as candidate medication options for future research based on novel strategies for StUDs include suvorexant and GLP-1R agonists. Findings with less enthusiasm, but with evidence-based rationale include cariprazine, clavulanic acide, and guanfacine. Findings noted strong rationale for the promise of new neuromodulation therapies; constraints of their time-consuming nature over through multiple sessions across several weeks are challenges.

Discussion: Task Force findings provide guidance for a possible pipeline of candidate therapeutic options for future research on novel strategies for treatment of StUDs. A cross-cutting theme emerged in recognition of heterogeneous behavioral phenotypes presenting challenges to recovery, suggesting that beyond understanding the mechanism of action and efficacy of each therapeutic strategy, it is important to pursue personalized medicine approaches to improve outcomes for StUDs.

Background and aims: Sleep disruptions increase the risk of substance misuse. Substance use-especially stimulants-can increase acute and chronic sleep dysfunction. This study aimed to estimate the associations between sleep disturbance and stimulant use over time among participants with stimulant use disorder (StUD).

Design: In this secondary analysis, a Random Intercept Cross-Lagged Panel Model (RI-CLPM) was used to assess sleep disturbance and stimulant use over 8 weeks among participants with StUD.

Setting: United States of America.

Participants: The analysis included 793 participants with StUD enrolled across 3 randomized controlled trials in the National Institute on Drug Abuse’s Clinical Trials Network (CTN): CTN-0037, CTN-0048 and CTN-0068.

Measurements: Self-reported sleep disturbance was harmonized as a binary indicator across trial measures at each week. Stimulant use days per week were captured by Timeline Follow Back. Baseline covariates included age, sex, race/ethnicity, employment status, presence of depressive symptoms, any psychiatric history, treatment arm and trial.

Findings: Sleep disturbance was associated with a higher average number of stimulant use days the following week [β = 0.15, 95% confidence interval (CI) = 0.09, 0.22, P < 0.001], and greater stimulant use was linked to increased odds of subsequent sleep disturbance (odds ratio = 1.20, 95% CI = 1.14, 1.26, P < 0.001).

Conclusions: Higher-than-usual stimulant use appears to be associated with increased likelihood of sleep disturbance the following week, and vice versa.

Related protocols: CTN-0037, CTN-0048, CTN-0068

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

Background: Patient-perceived Quality-of-Life (QOL) and treatment effectiveness (TEA) have previously been shown to be positively associated with better substance use treatment outcomes.

Objectives: This study examined potentially causal relationships amongst QOL, TEA, and cocaine abstinence.

Methods: Secondary data analyses (CTN-0148) were conducted on the NIDA Clinical Trial Network study, Cocaine Use Reduction with Buprenorphine (CTN-0048). N = 301 participants with DSM-IV cocaine dependence and opioid use history were administered injectable naltrexone and randomized to one of three buprenorphine/naloxone doses, 4 mg/1 mg, 16 mg/4 mg or placebo. Mediation models estimated direct and indirect effects amongst QOL, TEA, and cocaine abstinence.

Results: The QOL Environment domain exerted a significant indirect effect (B=0.01, SE=0.01, 95% CI=[0.00, 0.02]) on cocaine abstinence and a direct effect on TEA (B=0.57, SE=0.22, 95% CI=[0.16, 1.01]). Other QOL domains and individual QOL items exerted no statistically significant direct effects on cocaine abstinence. Overall QOL exerted a significant direct effect on TEA (95% CI=[0.32, 2.45]) along with a significant indirect effect on cocaine abstinence (95% CI=[0.01, 0.05]). TEA had a significant positive direct effect on cocaine abstinence (95% CI=[0.01, 0.02]).

Conclusion: Overall QOL and environmental QOL are related to treatment response through their relationship with patients’ perception of treatment effectiveness. TEA is directly related to cocaine abstinence at the end of treatment. QOL and TEA measures may serve as indicators of a need for additional support within care plans. These findings highlight the impact of a patient’s sense of well-being and their perceived treatment effectiveness on biochemically validated cocaine abstinence.

Related protocols: CTN-0148

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 remains the most abused stimulant, causing considerable morbidity and mortality. Despite decades of research, there is no FDA-approved medication to treat cocaine use disorder (CUD). In individuals with cocaine and opioid dependence/abuse, extended-release injectable naltrexone (XR-NTX) and sublingual buprenorphine (BUP; 16 mg with naloxone; Suboxone) reduced cocaine use compared to placebo and XR-NTX in the “Cocaine Use Reduction with Buprenorphine” (CURB; CTN-0048) study.

Objectives: The CURB-2 (CTN-0109) study aims to examine whether administering XR-NTX in combination with extended-release injectable buprenorphine (XR-BUP), thus creating a “kappa antagonist,” is an effective pharmacotherapy compared to placebo for the treatment of CUD.

Study design: CURB-2 is a fully powered, phase IIb, randomized, placebo-controlled trial. Approximately 426 participants will be randomized across 12 study sites in the United States. There will be a 1-week medication induction phase, an 8-week active medication phase, and a 4-week follow-up phase. XR-NTX (Day 1, Week 3, Week 6) will be administered before XR-BUP (Day 4, Week 4). With naltrexone blocking the mu-opioid receptors, the reinforcing effects of buprenorphine will be blocked while leaving the kappa antagonist effects.

Discussion: If this kappa antagonist approach demonstrates efficacy in reducing urine-verified cocaine use compared to placebo, XR-NTX and XR-BUP combination therapy would be an important tool in addressing cocaine use disorder.

Related protocols: CTN-0109

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

Illicit stimulant use among individuals initiating medication for opioid use disorder (MOUD) has significantly increased over the past decade. Co-use of these substances is associated with increased risk of mortality as well as worse treatment outcomes. This study examines the potential predictive role of stimulant urinalysis result at baseline on treatment retention and opioid and stimulant use outcomes amongst individuals initiating MOUD treatment.

This is a cross-sectional secondary analysis of data from a multi-site randomized clinical trial (CTN-0027). A total of 1269 individuals were randomized to receive 24 weeks of buprenorphine (n=740) or methadone (n=529) treatment across nine sites. Multiple linear and logistic regressions were conducted to determine the impact of baseline stimulant urinalysis results on treatment retention, and stimulant and opioid use outcomes.

Individuals initiating MOUD with a stimulant negative urinalysis result at baseline submitted more negative stimulant and opioid urinalyses during treatment, were more likely to complete treatment, and had better outcomes at six-month follow-up, measured as negative urinalysis for stimulant, and opioid.

Conclusions: Baseline stimulant use is associated with worse MOUD treatment outcomes, underscoring the need for novel integrated interventions designed to address opioid and stimulant co-use.

Related protocols: CTN-0027

Background and aims: Amphetamine-type stimulants are the second-most used illicit drugs globally, yet there are no US Food and Drug Administration (FDA)-approved treatments for amphetamine-type stimulant use disorders (ATSUD). The aim of this study was to utilize a drug discovery framework that integrates artificial intelligence (AI)-based drug prediction, clinical corroboration and mechanism of action analysis to identify FDA-approved drugs that can be repurposed for treating ATSUD.

Design and setting: An AI-based knowledge graph model was first utilized to prioritize FDA-approved drugs in their potential efficacy for treating ATSUD. Among the top 10 ranked candidate drugs, ketamine represented a novel candidate with few studies examining its effects on ATSUD. We therefore conducted a retrospective cohort study to assess the association between ketamine and ATSUD remission using US electronic health record (EHR) data. Finally, we analyzed the potential mechanisms of action of ketamine in the context of ATSUD.

Participants and measurements: ATSUD patients who received anesthesia (n = 3663) or were diagnosed with depression (n = 4328) between January 2019 and June 2022. The outcome measure was the diagnosis of ATSUD remission within one year of the drug prescription.

Findings: Ketamine for anesthesia in ATSUD patients was associated with greater ATSUD remission compared with other anesthetics: hazard ratio (HR) = 1.58, 95% confidence interval (CI) = 1.15-2.17. Similar results were found for ATSUD patients with depression when comparing ketamine with antidepressants and bupropion/mirtazapine with HRs of 1.51 (95% CI = 1.14-2.01) and 1.68 (95% CI = 1.18-2.38), respectively. Functional analyses demonstrated that ketamine targets several ATSUD-associated pathways including neuroactive ligand-receptor interaction and amphetamine addiction.

Conclusions: There appears to be an association between clinician-prescribed ketamine and higher remission rates in patients with amphetamine-type stimulant use disorders.

Related protocols: CTN-0114

This is the Primary Outcomes Article for CTN-0125.

Cocaine- and opioid-related overdose deaths have increased among Black people, which makes identifying effective treatments for Black people a high priority. We investigated the comparative effectiveness of behavioral treatments among Black adults who use cocaine and/or opioids.

Methods: Identified multisite randomized clinical trials (RCTs) of behavioral interventions that targeted substance use, had participants who self-identified as Black, and included cocaine use outcome measures from the National Drug Abuse Treatment Clinical Trials Network (CTN) datashare. We estimated cocaine use and opioid use severity scale scores while considering study-level measurement non-invariance. Then, we estimated the inverse probability of treatment-weighted (IPTW) linear mixed models to assess comparative effectiveness of treatments that address social-contextual factors and those focused solely on substance use (e.g., contingency management (CM)) relative to treatment-as-usual/controls on cocaine use and opioid use severity scores during- and post-treatment.

Results: Nine RCTs met inclusion criteria, with a combined sample of 1,381 Black adults who used cocaine and/or opioids. The IPTW linear mixed models indicated that cocaine use severity decreased from baseline to end-of-treatment across three treatment groups, with a greater decrease for social-contextual treatments and CM relative to treatment-as-usual/controls. However, this greater reduction was maintained at 12-month follow-ups for social-contextual treatments, while CM worsened relative to TAU/controls. We found decreases in latent opioid use severity with no or minor differences between treatment groups.

Conclusions: The findings suggest that addressing social-contextual factors is an essential treatment component for long-term reduction of cocaine use among Black adults.

Related protocols: CTN-0125

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.

Stimulants are the drivers of the fourth wave of the United States drug overdose epidemic. Kappa opioid receptor antagonists promote feelings of wellbeing and represent a medication addressing the “dark side.” In a pilot study, extended-release naltrexone (XR-NTX) plus oral buprenorphine (BUP), 4mg and 16mg, produced modest, though statistically significant, reductions in cocaine use among those adherent to oral BUP compared to placebo. This presentation describes CTN-0110, a study designed to test monotherapy for buprenorphine as the medication is used for treatment of refractory depression in people with no opioid use disorder (OUD).

Related protocols: CTN-0110

More than half of individuals admitted for specialty substance use disorder treatment in California identify stimulants as their primary or secondary drug, yet many people who use stimulants do not seek treatment. Numerous studies have shown that contingency management (CM) is the most effective treatment for stimulant use disorder. California’s innovative Recovery Incentives Program is a groundbreaking initiative that benefits California and serves as a potential blueprint for other states. In this webinar, Drs. Freese and Urada will delve into the program’s achievements and challenges by providing an overview of the Program, and preliminary quantitative and qualitative evaluation findings. Presenters will talk about the connection to technology and the potential for telehealth implementation in the future. Time will be provided for Q&A and discussion with the audience.