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Purpose: Emergency Departments (ED) are important settings for initiating care following a non-fatal opioid overdose (NFOO). While ED-based interventions, including peer-led recovery support and initiation of medications for opioid use disorder (MOUD), are promising methods for reducing subsequent overdoses and mortality, randomized trials of ED-based overdose prevention or treatment- linkage interventions demonstrate that a substantial proportion of patients decline participation. The current secondary analysis is designed to characterize individuals who declined to participate in one such study.

Methods: Data were used from the Peer Intervention to Link Overdose Survivors to Treatment (PILOT) trial (CTN-0107), which was a multi-site study conducted in three US-based EDs that randomized participants to a 6-month peer-led overdose prevention intervention or treatment as usual in the ED. Demographics and clinical characteristics of those enrolled in PILOT (n = 150) were compared to those who declined to participate but completed a screening exit survey (ScrES; n = 46).

Results: Among those who declined study participation, 76% had experienced a prior overdose preceding the current overdose that brought them into the ED (58.7% within the past 72 h), 56.5% were not currently engaged in substance use treatment and among those, 65.4% expressed a desire for treatment. Odds of declining study participation decreased with age by 6% per year (OR = 0.94, 95% CI: 0.9, 0.99); those with any college experience had odds of declining at 3 times greater than those without a high school diploma (OR = 3.4, 95% CI: 1.2, 10.1). Those without health insurance had odds of declining nearly 3 times those with insurance (OR = 2.9, 95% CI: 1.2, 7.0). Frequently cited reasons for declining were a desire to leave the ED or feeling unwell (39.1%), lack of interest in research (30.4%) and a belief the intervention would not be helpful (17.4%).

Conclusions: Results from this analysis characterize ED patients declining to participate in peer-led overdose prevention research with the goals of enhancing future recruitment strategies and enrolling more representative samples to reduce subsequent overdoses. Future work is needed to determine how to better engage priority populations at critical touch points, while ensuring that interventions are flexible, patient-centered, and potentially offer remote access.

Related protocols: CTN-0107

Given the disproportionate impact of substance use on individuals, families, and communities from populations underrepresented in clinical trials, increasing their enrollment in treatment research is critical for ensuring that the findings inform policies and programs that are inclusive of all communities, thereby advancing health equity. However, since underrepresented groups continue to be underenrolled in clinical trials testing the efficacy and effectiveness of psychosocial treatments for substance use disorder, substance use researchers are still grappling with this challenge.

In this commentary, we describe rigorous methodological approaches, such as integrative data analysis (IDA) and related methods (e.g., moderated nonlinear factor analysis and propensity score weighting), that can help address the challenges posed by the underrepresentation of certain populations. By combining individual-level data from multiple studies into a pooled dataset, these methods increase sample size and statistical power while addressing covariate imbalance across treatment groups. We describe how we employed these methods to address the aims of our recently completed secondary data analysis project conducted within the National Drug Abuse Treatment Clinical Trial Network (CTN-0125; Integrative Data Analysis of CTN Studies to Examine the Impact of Psychosocial Treatments for Black People Who Use Cocaine and/or Opioids). Our study used these methods to pool and analyze data from nine completed CTN trials to assess the comparative effectiveness of psychosocial treatments for Black adults who use cocaine and/or opioids, a group underrepresented in registered trials of the NIDA. We illustrate the application of these methodological approaches in CTN-0125 and demonstrate how they complement each other to address unique analytic challenges. We describe how we addressed data harmonization challenges due to variations in data formats and inconsistencies or gaps in the supportive documentation available on the NIDA Data Share website. We conclude with recommendations for the research field on how to further address sample size and data integration challenges.

Related protocols: CTN-0125

Background: Craving is a core clinical feature of cannabis use disorder (CUD) and a predictor of treatment outcomes, yet its temporal course during treatment is not well characterized. This study aimed to identify latent classes of cannabis craving trajectories among adults with CUD and examine associated baseline predictors and cannabis use outcomes.

Methods: This was a secondary analysis of the National Drug Abuse Treatment Clinical Trials Network’s CTN-0053 trial, a 12-week, multisite randomized controlled trial of N-acetylcysteine versus placebo for adults with CUD (N = 302). Cannabis craving was measured using the Marijuana Craving Questionnaire–Short Form at six treatment timepoints (weeks 1–5, 9 and 12) and one 5-week post-treatment follow-up (week 17). Urine cannabinoid tests were conducted twice weekly throughout treatment and follow-up. Latent class growth analysis identified craving trajectories. The present study aimed to identify latent classes of cannabis craving over 12 weeks of treatment and examine baseline predictors of class membership.

Results: A four-class solution provided the best fit: low craving (41%), moderate-decreasing craving (38%), moderate-stable craving (11%), and high craving (10%). Participants in higher craving classes exhibited greater baseline anxiety, depression, and obsessive-compulsive symptoms related to cannabis use. The high craving class had the greatest proportion of cannabis positive urine tests (96%) and the lowest urine test completion rate.

Conclusions: Craving follows heterogeneous trajectories during CUD treatment and is associated with co-occurring mental health symptoms and poorer outcomes. Dynamic craving assessment may support personalized treatment and strategies to prevent return to use.

Related protocols: CTN-0053

Introduction: Moral injury is the psychological distress resulting from actions, or the lack thereof, which violate one’s moral or ethical code. There is a notable gap in literature exploring moral injury among substance use disorder (SUD) treatment and community service providers. Despite the lack of literature describing moral injury among the SUD workforce, moral injury was discussed extensively during meetings of the Community Representative Council (CIRCL) of the National Drug Abuse Treatment Clinical Trials Network (CTN), which engages community members within the CTN Nodes to understand perspectives of people with lived/living experience and those providing substance use services.

Methods: In response to this consistently raised topic, this commentary reviews the literature on moral injury related to the SUD workforce, as well as the perspectives of CIRCL members on the unique and persistent challenges faced by SUD treatment and community services providers.

Results: Members of CIRCL in the SUD treatment and community provider workforce consistently described experiencing morally injurious events, including acts of commission and omission, bearing witness, and observing betrayal from those in power. While some experiences are akin to those experienced by providers in other healthcare settings, some were unique to front-line SUD treatment and community services providers. These experiences caused intense experiences of guilt, isolation, and hopelessness, sometimes contributing to turnover.

Conclusions: Addressing moral injury among the SUD provider workforce may require unique mitigation and prevention strategies, potentially involving structural changes at the organizational, social, and policy levels that support the SUD treatment and community service workforce, ultimately improving not just the wellbeing of providers and patients, but the wellbeing of our communities.

Authentic community engagement requires partnership with those who share similar situations, concerns, or challenges. Community engagement in research can promote equitable representation, help inform important research questions and deliverables, and increase the likelihood of developing relevant and appropriate interventions that will be implemented and sustained. Established in 1999, the National Drug Abuse Treatment Clinical Trials Network (CTN) is a cooperative agreement within the National Institute on Drug Abuse (NIDA) and functions as a nationwide consortium of research scientists, treatment providers and other community members collaborating to improve care for substance use in communities across the US. The CTN is committed to community-engaged research. Developed in 2023, the CTN Community Representative Council (CIRCL) formed as a natural progression of this commitment, designed to systematically identify front line challenges warranting research and to recognize emerging community-based innovations – forms of “practice-based evidence” developed in response to real-world needs. CTN Nodes (regional hubs) nominated community members, many of whom are people with lived experience (PWLE) of substance use to serve as Council representatives to enhance the identification, communication, and dissemination of the needs and experiences of individuals served by CTN research across the US. This commentary provides an overview of CIRCL’s conceptualization and creation, operation, and impacts on CTN communities in its first year.

Objectives: To identify and value resources required to implement and sustain the Massachusetts model of office-based addiction treatment (MA Model) in the Primary Care Opioid Use Disorders Treatment trial (NCT03407638) using a nurse care manager (NCM) to support medication for opioid use disorder in primary care settings.

Study design: A site-specific microcosting analysis was conducted via activity-based costing. Guided by a structured costing instrument, we conducted semistructured interviews with relevant personnel and assigned nationally representative costs.

Methods: Data came from 6 health care systems. Costs were categorized as fixed start-up, time dependent, or variable and estimated as annual per-clinic and per-patient costs for implementation and sustainment phases.

Results: Mean implementation cost (ie, year 1 fixed start-up, time-dependent, and variable) was $238,888 per clinic ($3185 per patient); each subsequent year cost $229,676 ($3062 per patient), assuming 75 patients per month and 29% new patient case mix. Mean onetime fixed start-up costs were $9212 per clinic and included supplies and training. Time-dependent costs were $70,446 per clinic and included rent and meetings. Variable costs were $159,229 per clinic and included NCMs’ and prescribers’ clinical duties. On average, NCMs spent 1967.6 hours on MA Model-related work per year (26.2 hours per patient). In sensitivity analyses, costs varied drastically with patient caseload, provider mix, and new patient case mix.

Conclusions: Fixed start-up and time-dependent costs were minimal. Variable costs were 66.7% of implementation costs and 69.3% of costs annually afterward. The primary cost driver was NCM time conducting MA Model-related work. The additional value of the model will depend on associated downstream outcomes. These results may be helpful to health care systems considering implementing the MA Model.

Related protocols: CTN-0074

This is the primary outcomes article for CTN-0080-A-2. Introduction: Racial and ethnic inequities persist in medication treatment initiation and adherence for pregnant and postpartum people with opioid use disorder (OUD). Our objective was to understand the experiences of “positive outliers,” specifically pregnant and postpartum people of color with OUD who utilized medication treatment and engaged in a randomized clinical trial for buprenorphine despite historical, cultural, and structural barriers.

Methods: We conducted two sets of semi-structured qualitative interviews. First, trained peers with lived expertise as mothers in recovery interviewed individuals who identified with a non-white race and/or ethnicity and enrolled in the Medication Treatment for OUD in Expectant Mothers (MOMs) trial (NCT03918850). Second, we interviewed principal investigators, clinicians, and research coordinators from the 13 MOMs trial sites. We used an inductive thematic approach informed by the Social Ecological Model of Racism and Anti-Racism. Transcripts were double-coded and reviewed until consensus was reached. Preliminary findings from participant and staff interviews were merged and triangulated with peers to inform theme development.

Results: We completed 17 interviews with MOMs trial participants from 7 sites. Participants identified as Hispanic (29%), Black non-Hispanic (24%), multi-racial Hispanic (18%), multi-racial non-Hispanic (18%), and American Indian, Native Hawaiian, or Pacific Islander (12%). Thirty-two interviews with trial staff were also completed. Three themes emerged: (1) Although some participants expected racist treatment and research exploitation, all participants interviewed reported non-discriminatory, non-judgmental care within the MOMs trial; (2) Compassionate care, frequent, personalized, and integrated encounters, and emotional support helped counteract prior stigmatizing and discriminatory health care interactions, enabling participants of color to feel particularly supported, trusted, and empowered during the MOMs trial; and (3) Despite pervasive cultural stigma around addiction and concerns about taking an investigational drug while pregnant, participants expressed that pregnancy status, care team trust, and transparent communication with MOMs trial staff encouraged medication utilization and adherence.

Conclusion: Facilitators of successful engagement in the MOMs trial and retention in medication treatment among pregnant and postpartum people of color with OUD included non-judgmental care, sustained trust, and frequent contact. Key perinatal OUD clinical interventions and trial improvements include personalized communication and scheduling flexibility to promote engagement of marginalized populations.

Related protocols: CTN-0080-A-2

Background: Stigma toward people with substance use disorders (SUD) remains a major barrier to care. There have been multiple calls to action to address SUD stigma in healthcare settings and other reviews have clarified the need for more rigorous effectiveness research. In addition to attention to effectiveness research, there is a need to attend to the implementation strategies used to deliver SUD stigma reduction interventions. Delineating discrete implementation strategies that have been used to address stigma will support future research efforts to arrive at the most optimal interventions to address SUD stigma.

Methods: We searched three databases and extracted data to identify interventions tested to reduce SUD stigma. We used the adapted Expert Recommendations for Implementing Change (ERIC) taxonomy to characterize the discrete implementation strategies used to support the adoption, implementation, sustainment, and scale-up (or spread) of each intervention.

Results: This scoping review synthesized 108 peer-reviewed studies reporting on interventions which to address SUD stigma among healthcare professionals. Most interventions were implemented in training environments, including higher education and continuing education settings, and focused on providing basic education on SUD broadly or opioid use disorder. Within interventions, educational and training implementation strategies were most prominent with 74% of studies using educational meetings and 39% distributing training materials. Far fewer studies used implementation strategies that used experiential approaches such interactive assistance, simulation, case-based learning, or contact with people with lived experience. Most studies (73%) reported reductions in stigmatizing attitudes, most often immediately post-intervention, though the need for higher study quality was notable.

Conclusions: Existing stigma-reduction interventions are overwhelmingly education-focused and primarily implemented in academic settings, with limited use of strategies that promote reflective learning, contact-based engagement, or organizational change. Future work should employ more rigorous designs that systematically test implementation strategies to create packaged SUD stigma reduction interventions optimized for effectiveness and implementation.

Objectives: To estimate all-cause and cause-specific mortality burden in patients who received medication treatment for opioid use disorder (OUD).

Methods: We (the CTN Health Systems Node) conducted a cohort study of 27,230 patients who received medications for opioid use disorder (MOUD), buprenorphine or naltrexone, matched 1:1 to individuals without MOUD from 4 US health systems in California, Colorado, and Michigan between 2012 and 2021. We calculated standardized mortality ratios (SMRs) with bootstrapped 95% CI to assess mortality burden.

Results: Patients who received treatment for OUD were 4 times more likely to die from any cause (SMR 4.37, 95% CI 3.80-4.64) and 37 times more likely to die from drug overdose (SMR 37.58, 95% CI 29.33-55.09; 41.6% of all deaths) compared to demographically similar individuals. Deaths from non-overdose causes showed modest but significant burden (SMR 2.68, 95% CI 2.31-2.86; 58.4% of deaths). The top contributors to non-overdose deaths were circulatory system diseases (SMR 3.06, 95% CI 1.73-3.63; 13.9% of deaths), other external causes (SMR 4.50, 95% CI 3.64-5.62; 11.3% of deaths), and cancers (SMR 1.59, 95% CI 1.30-1.86; 9.4% of deaths), which all showed elevated mortality.

Conclusions: Continued efforts are needed to prevent high burden of mortality from both overdose and non-overdose causes among patients with MOUD treatment.

Background: Rural communities face disproportionate rates of opioid use disorder (OUD) and overdose mortality but continue to be underrepresented in clinical research and underserved in access to medications for opioid use disorder (MOUD). Structural barriers including shortages of qualified providers, transportation challenges, and stigma limit uptake of evidence-based treatment. To address these gaps, the National Drug Abuse Treatment Clinical Trials Network (CTN) launched two pragmatic trials focused exclusively on rural populations: CTN-0102, a telemedicine (TM) feasibility study connecting rural primary care patients to external MOUD providers, and CTN-0102XR (RXR), a pilot randomized trial evaluating extended-release buprenorphine (Brixadi®) compared to sublingual buprenorphine-naloxone.

Objective: The article aims to describe the implementation of these two rural pragmatic trials, identify challenges encountered in study implementation, and present lessons learned. We applied frameworks from implementation science, including the Consolidated Framework for Implementation Research (CFIR) and the Expert Recommendations for Implementing Change (ERIC), to demonstrate how pragmatic trial implementation mirrors implementation of evidence-based programs and practices, and can benefit from established implementation frameworks and strategies.

Results: Across 13 rural clinics in 10 states, both trials demonstrated the feasibility of integrating MOUD into primary care settings through pragmatic study designs closely aligned with routine clinical workflows. Principal challenges included limited clinic research capacity, staff stigma toward OUD treatment, communication barriers between local clinics and external TM vendors, and variable digital access. Solutions included engaging local champions, co-developing workflows tailored to each clinic’s operations, simplifying technology requirements, and emphasizing bi-directional communication among clinic, research, and vendor teams. Continuous technical assistance and protocol flexibility and adaptation were crucial for sustaining engagement and aligning study procedures with clinical realities. Findings demonstrated that rural clinics can feasibly implement TM-based MOUD coordination and extended-release buprenorphine with adequate support and contextual adaptation.

Conclusions: Lessons from CTN-0102 and CTN-0102XR underscore that pragmatic trials in rural settings benefit from early contextual assessment, engagement of community stakeholders, adaptable protocols, and strong implementation support. Applying implementation science frameworks facilitates solutions to real-world barriers and enhances study sustainability. Future CTN efforts should continue to prioritize rural site inclusion, capacity building, and equitable access to evidence-based OUD treatment.

Related protocols: CTN-0102, CTN-0102-XR

Despite comprising one-fifth of the population, individuals living in rural areas are underrepresented in clinical trials on substance use disorders (SUD). The inclusion of rural residents is critical to reducing disparities in health outcomes and improving adoption of evidence-based interventions for SUDs. The current commentary provides five guiding principles to assist researchers in including rural populations in trials. These principles emphasize including rural communities in the study design phase and throughout the research process, understanding the local rural context, consideration of operationalization of rural in research, suggested adaptions for research, and embracing opportunities for bi-directional and sustainable partnerships. When approached thoughtfully, research funding can catalyze rural capacity, foster durable partnerships, and enrich scientific inference to assist in establishing the evidence-base for SUD research.

Over the past two decades, the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) has made major contributions to progress in substance use treatment research. However, contributions to research addressing the considerable medical and mental health comorbidities of substance use, which can impede treatment efficacy and compromise health, have been emphasized less. In this Commentary, we review the contributions of CTN studies focused on medical comorbidities, initially centered on the HIV epidemic in people who use drugs, and subsequently broadening to address hepatitis C and life-threatening bacterial infections; as well as mental health comorbidities, especially post-traumatic stress disorder, attention-deficit/hyperactivity disorder, and suicidality. These studies demonstrate that comorbidities assessments and treatment can be feasibly implemented in substance use treatment programs and, conversely, that substance use assessments and treatments can be feasibly implemented in clinical care sites. We highlight the NIDA CTN Data Share as an invaluable resource for secondary analyses of comorbidities using data from CTN substance use treatment protocols and provide examples of its use. We describe the work of the CTN Comorbidities of Substance Use Special Interest Group (SIG), formerly known as the HIV SIG, as an example of the role that SIGs can play in facilitating CTN research in areas of emerging significance. We emphasize the importance of implementing a “whole person” approach—one that integrates both substance use and comorbidities outcomes. We identify promising opportunities for conducting this research by studying strategies for integrating prevention, screening, linkage, treatment, adherence, and retention support for comorbidities into substance use disorder (SUD) treatment venues; as well as strategies for integrating SUD treatment into primary care venues, hospitals, and other non-SUD clinical settings.

Adolescent substance use (SU) presents a distinct public health challenge, as this developmental stage carries heightened vulnerability for progression to problematic use. Early SU—before age 18—is a major risk factor for later Substance Use Disorders (SUD), with long-term neurobiological and psychosocial consequences. National surveillance data show a continued decline in alcohol and cigarette use, yet persistent concerns around cannabis (including synthetic variants) and sharp increases in vaping. The frequent occurrence of polysubstance use further complicates prevention and intervention efforts.

The intersection of SU and mental health conditions, such as anxiety and depression, compounds these challenges. The 2024 National Survey on Drug Use and Health data reveal that nearly one-third (27.9%) of adolescents aged 12–17 with both SUD and a Major Depressive Episode receive no treatment for either condition. Despite promising evidence-based interventions, their implementation remains limited, revealing a critical translational gap between research efficacy and real-world effectiveness.

To close this gap, the National Drug Abuse Treatment Clinical Trials Network (CTN) is leveraging its multi-site research infrastructure to conduct pragmatic clinical trials that emphasize the inclusion of adolescents from all backgrounds. The CTN’s agenda identifies six priorities to advance scalable, impactful solutions:

• Implementation Science and Real-World Effectiveness – embedding interventions into existing systems of care.
• Precision Medicine and Personalized Interventions – integrating biological, psychological, and social data to tailor treatments.
• Family and Environmental Contexts – expanding family-based and peer-supported models.
• Digital Innovations and Technology Integration – evaluating technology-assisted and AI-driven interventions.
• Longitudinal Outcomes and Lifespan Perspective – assessing developmental, academic, and quality-of-life outcomes over time.
• Community-Led and Co-Designed Research – engaging community partners and individuals with lived experience as co-researchers.

Through this coordinated agenda, the CTN aims to build an equitable, evidence-informed framework that bridges discovery and practice, drives innovation, and informs policies that foster resilient, healthy futures for adolescents nationwide.

The integration of data across randomized controlled trials (RCTs) testing interventions and treatments for substance use disorder (SUD) offers a rich opportunity for improving the evidence base and analytic methods used in SUD research. With over 50 completed trials of the National Institute on Drug Abuse (NIDA) National Drug Abuse Treatment Clinical Trials Network (CTN) available for secondary analysis and harmonization, the possibilities are extensive, but the effort to harmonize and document datasets demands complex analytic formulation and methodology. This commentary discusses strengths and challenges of data harmonization, sharing clinical and data science considerations based on four exemplar studies that harmonized data across multiple CTN trials. We offer recommendations for others planning data harmonization for secondary analysis, discuss guiding principles for research data management, outline suggestions to bridge gaps in the context of the CTN, and finally frame considerations for using state-of-the-art tools such as generative AI and integration of data from clinical trials and electronic health records to enhance the promise of data harmonization.

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.