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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.

A quarter century ago, research-to-practice gaps in addiction care gained national attention and prompted formation of the National Drug Abuse Treatment Clinical Trials Network (CTN) and formalization of the Addiction Technology Transfer Centers (ATTCs). Soon after, the RE-AIM explanatory framework was developed to enable examination of the public health impact of healthcare innovations—with its domain of adoption corresponding most directly to the CTN’s mission of transferring research results of its trials to the addiction workforce. A node-level CTN-ATTC collaboration, the Western States CTN Node Training and Dissemination Workgroup, seeks to contribute to this national mission. Our workgroup—currently comprising leadership of the Western States CTN Node, Northwest ATTC, Pacific Southwest ATTC, and CTN Dissemination Library—promotes workforce adoption of scientific advancements in addiction care via two long-running universal technical assistance activities: a semi-annual webinar series, and a monthly column in the ATTC Messenger newsletter.

In this commentary, we provide historical context for the salience of bridging research-to-practice gaps, and then describe the origin of this workgroup, detail its pair of long-running universal technical assistance activities intended to increase adoption of healthcare advancements among addiction workforce members, and offer metrics concerning the audiences attracted over a recent five-year period. In celebration of the CTN’s 25th anniversary, we also reflect on the value of this multi-institutional partnership for the Western States CTN Node and propose a dissemination agenda to prompt future efforts whereby the CTN mission may be more fully and effectively achieved.

Despite rising rates of substance use disorders (SUD) in women and the narrowing of the SUD gender prevalence ratio in the U.S., large knowledge gaps in gender-specific treatment remain. The NIDA Clinical Trials Network (CTN) Gender Special Interest Group (GSIG) has provided opportunities to bring the gender lens to national multi-site clinical trials, ancillary studies, secondary data analyses, recommendations for data collection and demographic data, among other contributions to CTN and the SUD treatment field. This commentary provides background on gender differences and the knowledge gap, a history of the CTN GSIG, and its accomplishments via gender specific trials and key secondary analyses. The commentary will close with future directions and recommendations for research including improving the inclusion of intersectional identities in recruitment reach and analyses, reproductive health, pregnant and parenting people, and methodological considerations for clinical trials to enhance capacity to collect and understand data related to gender.

While approximately one in five Americans with substance use disorder (SUD) receives treatment in addiction treatment programs, a majority have seen a primary care medical provider in the past year. Recognizing the critical role of primary care in addressing prevention and treatment of unhealthy substance use, for over a decade the National Drug Abuse Treatment Clinical Trials Network (CTN) has supported research to build the tools and evidence needed to support the integration of SUD care, while remaining realistic about the barriers to doing so. Authored by primary care and addiction medicine physician researchers, this commentary provides an overview of CTN primary care-focused research, from developing and implementing substance use screening tools to advancing evidence-based SUD treatment delivery in primary care settings. We identify three priority areas for research and practice innovations: 1) identifying effective treatment interventions to address polysubstance use; 2) improved screening and treatment for cannabis use; and 3) building the evidence base for substance use interventions among non-treatment seeking patients who have unhealthy drug use identified through screening. Addressing these areas can help primary care fulfill its potential as a key component of the substance use services continuum of care.

Buprenorphine and other medication treatments for opioid use disorder (OUD) in general medical settings are effective in preventing drug overdoses related to opioid use, although treatment retention is often challenging. Real-world data indicate high medication discontinuation rates at 6 months or greater following treatment initiation, partially indicative of a common failure to optimize medication dosing to minimize side effects, maximize therapeutic effects, and sustain treatment engagement and adherence. These barriers hinder the achievement of optimal clinical outcomes in managing conditions like OUD, which is often a chronic relapsing condition and frequently associated with mood disorders. Measurement-based care (MBC) may be defined as an evidence-based healthcare approach in which systematic outcome monitoring of disease severity and symptomatology over time yields actionable feedback to providers to guide their clinical decision-making on how to customize medication dosing promptly to improve patients’ treatment outcomes.

This opinion piece describes a proposed research agenda evaluating measurement-based care for opioid use disorder among patients with co-occurring depressive disorders that emphasizes pragmatic, multisite effectiveness-implementation trials to operationalize MBC in real-world, community-based, and primary care settings. The National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) is positioned as a potential platform for advancing this agenda, leveraging its experience in bridging research and practice.

In addition to the studies underway, CTN participants are planning multi-site clinical trials with emerging results that address HIV/AIDS. The CTN has a HIV/AIDS Special Interest Group (SIG) that meets regularly to discuss study ideas and policy approaches. The SIG provides a supportive place to discuss HIV research related to the CTN, share information with each other about opportunities and developments, promote AIDS ideas and research in the CTN, and link CTN research with the AIDS Research Office of NIDA. The SIG periodically reviews and prioritizes study ideas before they work their way up the organizational hierarchy, and, in the latest CTN Call for Concepts, had developed approximately ten suggestions for HIV-related research studies.

Several studies using the CTN ?platform? have also been fielded with external resources. The term ?platform study? describes extramurally funded research that builds on the CTN infrastructure. Studies can add a dimension to a CTN trial, test an intervention by using the infrastructure of the CTN, focus on CTN programs to understand an issue, include CTN programs in data collection, or provide training or career development in the CTN. Extramurally funded platform studies are addressing such issues as models of care for HIV and hepatitis, integrating medical treatment with addiction treatment, and improving adherence to HIV medications.

This booklet contains an overview of the National Drug Abuse Treatment Clinical Trials Network, along with a description of each participating Node.

In the US, methadone treatment can only be provided to patients with opioid use disorder (OUD) through federal and state-regulated opioid treatment programs (OTPs). There is a shortage of OTPs, and racial and geographic inequities exist in access to methadone treatment. The National Institute on Drug Abuse Clinical Trials Network convened the Methadone Access Research Task Force to develop a research agenda to expand and create more equitable access to methadone treatment for OUD. This research agenda included mechanisms that are available within and outside the current regulations. The task force identified 6 areas where research is needed: (1) access to methadone in general medical and other outpatient settings; (2) the impact of methadone treatment setting on patient outcomes; (3) impact of treatment structure on outcomes in patients receiving methadone; (4) comparative effectiveness of different medications to treat OUD; (5) optimal educational and support structure for provision of methadone by medical providers; and (6) benefits and harms of expanded methadone access. In addition to outlining these research priorities, the task force identified important cross-cutting issues, including the impact of patient characteristics, treatment, and treatment system characteristics such as methadone formulation and dose, concurrent behavioral treatment, frequency of dispensing, urine or oral fluid testing, and methods of measuring clinical outcomes. Together, the research priorities and cross-cutting issues represent a compelling research agenda to expand access to methadone in the US.

Over the past two decades, the National Drug Abuse Treatment Clinical Trials Network (CTN), a program of the National Institute on Drug Abuse (NIDA), has expanded from the initial six Nodes to 16 Nodes, as a nationwide consortium of research scientists and treatment providers working together to improve care for substance use in the nation’s communities. Encompassing both specialty care programs and general medical settings, the Network has become a unique resource for expertise on clinically focused research, bridging the gap between research and treatment delivery.

Over 22 years, the CTN has completed 101 studies, resulting in 650 publications. In response to the opioid epidemic, a CTN task force generated a comprehensive list of research priorities in the areas of prevention, treatment, knowledge dissemination, and workforce training, to form the basis of the Network’s opioid portfolio. The Network’s opioid portfolio currently includes five main categories of studies: (1) large multi-site studies; (2) studies aimed at closing the treatment gap; (3) expansion of ongoing studies to improve service delivery and implementation; (4) studies to explore the use of substance use data in electronic health record systems; (5) training and dissemination projects to expand the research/health care provider workforce.

With funding from the Helping to End Addiction Long-Term Initiative^SM (HEAL), the CTN established five new Nodes, which, along with the pre-existing Nodes, are distributed in every region of the nation and engage researchers and clinicians in areas that have been among the hardest hit by the opioid epidemic. Through this expanded network and its commitment to developing personalized, evidence-based treatments, the CTN is poised to address and provide solutions for the ongoing epidemic of opioid use and addiction.

Economic evaluations provide evidence that informs stakeholders on how to efficiently allocate real and financial healthcare resources. The purpose of this study was to review and discuss the integration of economic evaluations into the National Drug Abuse Treatment Clinical Trials Network (CTN) since its inception, as well as expectations for the future of this relationship.

A systematic review was performed on published and planned CTN economic evaluations in the CTN dissemination library and PubMed. The well-established Drummond checklist was used to evaluate the comprehensiveness and methodological rigor of published articles. One hundred thirty-eight ancillary, follow-up, or original protocols were reviewed, and 78 potentially relevant published articles were identified. A total number of 14 protocols included an economic evaluation. Of these, 6 protocols were completed, 2 were reported as active, and 6 were reported as in-development at the time of this review. Of the 78 published articles, 9 met the inclusion criteria. As gauged by the Drummond checklist, the quality of CTN published economic evaluations were found to improve over time, and recent published articles were identified as guides to cutting-edge economic research. As the CTN continues to grow and mature, it is imperative that high-quality economic evaluations are incorporated alongside trials in order to maximize the public health impact of the CTN.

The application of digital technologies to better assess, understand, and treat substance use disorders (SUDs) is a particularly promising and vibrant area of scientific research. The National Drug Abuse Treatment Clinical Trials Network (CTN), launched in 1999 by the U.S. National Institute on Drug Abuse, has supported a growing line of research that leverages digital technologies to glean new insights into SUDs and provide science-based therapeutic tools to a diverse array of persons with SUDs.

This article provides an overview of the breadth and impact of research conducted in the realm of digital health within the CTN. This work has included the CTN’s efforts to systematically embed digital screeners for SUDs into general medical settings to impact care models across the nation. This work has also included a pivotal multi-site clinical trial conducted on the CTN platform, whose data led to the very first “prescription digital therapeutic” authorized by the U.S. Food and Drug Administration (FDA) for the treatment of SUDs. Further CTN research includes the study of telehealth to increase capacity for science-based SUD treatment in rural and under-resourced communities. In addition, the CTN has supported an assessment of the feasibility of detecting cocaine-taking behavior via smartwatch sensing. And, the CTN has supported the conduct of clinical trials entirely online (including the recruitment of national and hard-to-reach/under-served participant samples online, with remote intervention delivery and data collection). Further, the CTN is supporting innovative work focused on the use of digital health technologies and data analytics to identify digital biomarkers and understand the clinical trajectories of individuals receiving medications for opioid use disorder (OUD).

This paper concludes by outlining the many potential future opportunities to leverage the unique national CTN research network to scale-up the science on digital health to examine optimal strategies to increase the reach of science-based SUD service delivery models both within and outside of healthcare.

Related protocols: CTN-0044, CTN-0059, CTN-0073-Ot, CTN-0076, CTN-0083, CTN-0084-A-2, CTN-0090, CTN-0095, CTN-0101, CTN-0102