Comorbidities of substance use: Opportunities realized and future needs

Abstract

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 broadened 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.

1. Introduction

1.1. Introduction and rationale: the evolving landscape of comorbidities

Substance use poses multiple risks of major—sometimes fatal—medical and mental health comorbidities in addition to dependence itself and its associated behavioral problems. These include overdose and overdose fatalities; chronic viral infections (e.g., HIV; hepatitis B, C, and D); sexually transmitted infections (STIs); serious bacterial infections (e.g., infective endocarditis, central nervous system and spinal infections, osteomyelitis, septic arthritis, bacteremia/sepsis, deep tissue abscesses); skin and soft tissue infections; pain; mental illness; suicide; and impaired activities of daily living as a consequence of substance use disorders (SUD). SUD, and the daily subsistence challenges it poses, may also place people with SUD at greater risk during an epidemic, such as the COVID-19 pandemic (Marks, 2025). Fortunately, many of these health consequences can be diagnosed by standard tests and managed with medication and behavioral changes. Some, such as hepatitis B and D, can be prevented by vaccination; HIV can be prevented through both pre-exposure and post-exposure prophylaxis; and chronic hepatitis C (HCV) can even be cured. Yet, each comorbidity entails progression through a care continuum from problem recognition, screening, diagnosis, evaluation, linkage to care, receipt of treatment or prophylaxis, management of symptoms and adverse medication effects, adherence, retention in care, and achievement of sustained treatment effect, as well as reduction of risk behaviors that transmit illness to others and put the individual at risk of future infections. Moreover, treatment as prevention is a strategy that eliminates the ongoing transmission of HIV and viral hepatitis to others.

The National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) presents a platform within which to integrate needed research into the comorbidities associated with substance use. This research can encompass a wide array of studies—spanning descriptive problem assessment, observational assessment of evolving approaches, controlled trials of alternative approaches, and implementation trials of strategies for optimizing healthcare delivery. In addition, CTN trials can contribute to a better understanding of the current comorbidity landscape by including brief, user-friendly assessments of comorbidity-related knowledge, attitudes, and behaviors and by gathering basic data on the diagnosis of comorbid conditions in studies targeting substance use disorders. With this improved understanding of the comorbid landscape, the CTN can develop and implement feasible studies to integrate comorbidity detection, treatment, and prevention into routine SUD practices, as well as to identify the barriers to such implementation.

In the following Commentary, we review findings of major CTN comorbidities research to date. As an example of the utility of CTN Special Interest Groups (SIGs) in supporting research, we describe the work of the Comorbidities SIG that has included the development and implementation of research protocols, publication of secondary analyses, and creation of an annotated registry of standardized mental health assessments. We emphasize the imperative for future research directed at the comorbid conditions associated with substance use to address critical unmet needs. We propose promising opportunities to conduct comorbidity-centered research to develop strategies to integrate prevention, screening, linkage, treatment, adherence, and retention support for comorbid conditions into SUD treatment venues and to integrate SUD treatment into primary care venues, hospitals, and other non-SUD clinical settings.

1.2. The work of the comorbidities SIG: an example of SIG research facilitation

The HIV SIG, the forerunner of the current Comorbidities SIG, had a singular focus on HIV that was aligned with the issues confronting the HIV epidemic in the early 2000s. The HIV SIG supported the historical CTN emphasis on a collaborative process between researchers and community partners by providing a voice for HIV priorities within the CTN. The HIV SIG served as a venue for (1) CTN-wide networking and strategizing among HIV-concerned providers and researchers; (2) conducting a CTN-wide HIV needs assessment survey (Shoptaw et al., 2002); (3) helping launch HIV-focused studies; (4) using the CTN platform for the development of HIV risk reduction studies funded by other NIH mechanisms; and (5) choosing a risk behavior assessment for use in CTN studies, the Risk Behavior Survey (National Institute on Drug Abuse, 1993).

More recently, with the broadening of the SIG mission, the priorities of the Comorbidities SIG now include: (1) providing an ongoing forum for enumerating medical and mental health comorbidities, documenting unmet needs, developing and describing new approaches that could be studied systematically, and identifying strategies for integrating prevention and treatment into both SUD and medical treatment venues; (2) fostering collaboration among CTN researchers and practitioners in the development of new CTN protocols and substudies focused on comorbid conditions; (3) providing brief, feasible standard questions to assess knowledge, attitudes, and behaviors (KAB) related to comorbidities for inclusion in CTN protocols; (4) collaborating with CTN protocol teams on analyses of KAB related to comorbidities, including comparisons across regions and key subgroups (e.g., substances used, demographic factors); and (5) offering consultation on state-of-the-art strategies for integration of testing, linkage, treatment, prevention, adherence, and retention support for medical and mental health comorbidities into SUD and medical treatment venues.

1.3. Comorbidities studies in the CTN

Since 2000, CTN researchers have produced 14 studies focused on medical comorbidities of substance use and five focused on mental health comorbidities (Table 1). Due to space limitations, the aims, methods and findings of each trial are not described in text; instead, we discuss below the salient contributions of these studies to important domains of comorbidities of substance use research and to clinical practice.

Table 1.

Medical Comorbidity-Focused Protocols and Mental Health Comorbidity-Focused Protocols of the CTN.

Protocol	Recruitment dates	Subjects: Sites	Name	Type	Outcome*
Medical comorbidity-focused protocols
0012	07/03–01/05	269 administrators; 1,723 providers; and 38 state administrators	Screening, Evaluation, and Treatment of HIV/AIDS, HCV, and STIs in Substance Use Treatment Programs	Survey of availability of and factors associated with injection-related health services	Wide variability in services by program type, revenue source, and patient characteristics; perceived barriers included lack of funding, regulations constraints, and patient attitudes.
0017	11/05–02/06	632:8	HIV and HCV Intervention for Injection Drug Users in Inpatient Detoxification	RCT of (1) Therapeutic Alliance Intervention (TA) versus (2) TAU for HIV/HCV Testing participation and injection risk behavior	TA > TAU in treatment entry; detox participation was associated with decreased risk behavior (up to 6 months); treatment entry (within 2-months post-detox) was associated with decreased risk behavior.
0018	05/04–10/05	590:14	Safer Sex Skills Groups for Men: Real Men are Safe (REMAS) in Outpatient Substance Use Treatment Programs (SUTP) & Methadone Maintenance (MM) Programs	RCT of (1) 5-session REMAS versus (2) 1-session standard HIV Education (HE)	REMAS > HE in decrease in sexual risk behaviors (at 3-month and 6-month follow-ups).
0019	06/04–10/05	515:12	Safer Sex Skills Groups for Women: Safer Sex Skills Building (SSSB) in SUTP & MM	RCT of (1) 5-session SSSB versus (2) 1-session standard HIV Education (HE) in SUTP	SSSB > HE in decrease in sexual risk behavior (6-month follow-up).
0030		653:	Prescription Opiate Abuse Study	Two-phase RCT of Buprenorphine/Naltrexone (BUP/NX) Paired with: (1) Standard Medical Management (SMM) versus (2) SMM plus individual counseling in prescription opioid analgesic dependent patients	During active BUP/NX treatment, all 3 conditions showed comparable rates of opioid use decrease to minimal levels; but if tapered, likelihood of unsuccessful outcome was high in all conditions. Chronic pain did not influence outcome.
0032	01/09–05/09	1,281:12	HIV Rapid Testing and Counseling in SUTP	RCT of (1) on-site rapid HIV testing and counseling; (2) on-site rapid testing only; and (3) standard referral to off-site HIV testing	On-site HIV testing and counseling increased patient receipt of results; brief counseling did not significantly decrease sexual and injection drug use risk.
Project AWARE	04/10–12/10	5,012:9	Project AWARE: HIV Rapid Testing and Counseling in STI Clinics in the U.S.: An Adaptation of CTN-0032	RCT of (1) on-site rapid HIV rapid testing and counseling versus (2) on-site rapid HIV testing with information only	On-site risk reduction counseling with rapid HIV testing did not significantly decrease STI acquisition.
0049	2012–2014		PROJECT Hope: Inpatient Hospital Visit as Point of Engagement in HIV Care for HIV Viral Load Suppression (VLS) in HIV-Positive PWID	RCT of (1) patient navigation + financial incentives (PN + FI); (2) patient navigation; and (3) TAU	At 12 months, HIV VLS was equal in the three conditions, but at 6 months, VLS and HIV care engagement in PN + FI exceeded that of the other two conditions.
0064	2016–2017	113	Care Facilitation to Advance Movement Along the HCV Care Continuum for Persons With HIV, HCV, and Substance Use	RCT of (1) care facilitation versus (2) standard of care (SOC)	At 12 months, movement along the HCV care cascade in Care Facilitation exceeded that in SOC.
0055	2014–2015	51:2	Comparing Treatments for HIV+ Opioid Users in an Integrated Care Effectiveness Study (CHOICES)	RCT of (1) on-site extended-release naltrexone (XR-NTX) versus (2) TAU in HIV primary care clinics	At 16 weeks, the on-site XR-NTX condition exceeded the TAU condition in percentage retained on medication.
0067	2018–2019	116:6	Comparing Treatments for HIV+ Opioid Users in an Integrated Care Effectiveness Study (CHOICES Scale Up)	RCT of (1) on-site extended-release naltrexone (XR-NTX) versus (2) TAU in HIV primary care clinics	At week 24, viral suppression rates were 52.7% in the XR-NTX condition versus 49.2% in TAU, but formal non-inferiority was not established.
0082	2020–2021	557:13	Implementation Survey of HIV Pre-Exposure Prophylaxis (PrEP) and Opioid Use-Related Services Readiness in STI Clinics, Syringe Services Programs, & Substance Use Treatment Programs in Eight High HIV Incidence Southern Cities	Implementation survey of PrEP and opioid-use related service attitudes in (1) clients (people who use opioids [PWUO] or substance-using MSM [SU-MSM]); (2) providers; and (3) directors	In PWUO, and SU-MSM, the vast majority expressed willingness to use oral and injectable PrEP. In PWUO: Injectable PrEP willingness was negatively associated with less than high school/GED education. In SU-MSM: Injectable PrEP willingness was positively associated with Black race; gay sexual orientation, single relationship status, condomless anal sex, and injection drug use frequency; and negatively associated with non-injection opioid use.
0083	2020	271 young adult MSM	Using Social Media to Deliver HIV Self-Testing Kits and Link to Online PrEP Services	Comparison of (1) social media versus (2) informational sites as venues for uptake of HIV self-testing kits and online PrEP services	Online dating sites far exceeded informational sites in HIV self-testing order rates. There were no associations between ordering and HIV-related stigma, HIV test and treatment perceptions, and mistrust of medical organizations.
0121	In progress	480:6	Integrated Care and Treatment for Severe Infectious Diseases and Substance Use Disorders among Hospitalized PWID	Study of a comprehensive (pharmacologic, behavioral, and harm reduction) intervention for (1) initiation of SUD medication and (2) rapid transfer and retention in integrated outpatient care	In progress
Mental health comorbidity-focused protocols
0015	2004–2005	353:6	Women’s Treatment for Trauma and Substance Use Disorders	RCT of (1) seeking safety (SS) intervention for women with PTSD and SUD versus (2) women’s health education (WHE)	In both SS and WHE, PTSD symptoms significantly decreased, while substance use did not. PTSD improvement was associated with subsequent substance use improvement.
0028		303:11	Osmotic Release Methylphenidate for ADHD in Adolescents with SUD Receiving CBT for SUD	RCT of (1) methylphenidate versus (2) placebo in adolescents receiving CBT for SUD	Both conditions had comparable efficacy for reducing ADHD symptoms and substance use reduction.
0029		255:6	Pilot Study of Osmotic Release Methylphenidate in Initiating and Maintaining Abstinence in Smokers with ADHD	RCT of (1) methylphenidate versus (2) placebo in smokers receiving standard smoking cessation (nicotine patch plus counseling) intervention	Methylphenidate, as compared to placebo, was effective in treating ADHD. Both conditions had comparable prolonged abstinence rates.
0095-A-1	2021–2022	15 clinics	Suicide Prediction and Prevention for People at Risk for OUD	Cluster RCT of integration of a (1) clinical decision support tool for OUD and suicide screening versus (2) clinical decision support Tool for OUD screening only in primary care clinics	Intervention and Comparison clinics had comparable rates of suicide screening.
0140	2011–2021	227,555 Patients at Kaiser Permanente Northern California	Cannabis Use among Pregnant Women with Polysubstance Use and Psychiatric Problems	Electronic health record review of pregnant women at entry into standard prenatal care	Psychiatric disorders and SUDs were associated with elevated odds of cannabis use and CUD during early pregnancy. Associations were stronger for SUDs than psychiatric disorders.

^*All comparisons that dascribe treatment effects or associations between variables are statistically significant.

The methods and sources used to identify studies in each category differed. Studies in the Medical Comorbidity-Focused Protocols and Mental Health Comorbidity-Focused Protocols category were identified from the CTN Dissemination Library (ctnlibrary.org), a “digital repository” of CTN research and supplementary materials “approved for dissemination,” created and maintained by the Addictions, Drug and Alcohol Institute of the University of Washington School of Medicine in the CTN Pacific Northwest Node. Studies in the section “Examples of Studies Using Multiple CTN Protocols for HIV Risk or Other Comorbidity Secondary Analyses” consisted of studies produced by CTN Comorbidities SIG collaborators that were identified as examples and thus not as an exhaustive list of all such CTN Comorbidity Secondary Analyses.

In addition to the text, two tables present the basic features of each of two categories of CTN Comorbidities studies. In Table 1, “Medical Comorbidity-Focused Protocols and Mental Health Comorbidity-Focused Protocols of the CTN,” the following features are presented: study dates; (N) subjects/sites; study title; study type; and study outcomes. In Table 2, “Examples of Studies Using Multiple CTN Protocols for HIV Risk or Other Comorbidity Secondary Analyses,” the following features are presented: study authors; (N) subjects/protocols; study title; study type; and study outcomes.

Table 2.

Examples of studies using multiple CTN protocols for HIV risk or other comorbidity secondary analyses.

Study	Recruitment subjects/# protocols	Name	Type	Outcomea
Brooks et al., 2010	1,429/5	Gender Differences in Rates and Correlates of HIV Risk Behaviors among Drug-Dependent Individuals	Cross-sectional comparative analyses	Women exceeded men in rates of sex with multiple partners, unprotected sex with regular partners, and overall high risk sexual behaviors. Men exceeded women in injection drug use behavior.
Brown et al., 2018	1,305/8	Impact of Behavioral Drug Abuse Treatment on Sexual Risk Behaviors: An Integrative Data Analysis of Eight Trials Conducted Within the National Drug Abuse Treatment Clinical Trials Network	Longitudinal comparative analyses	In both intervention and control conditions, sexual risk behaviors decreased until 8 weeks (control) or 9 weeks (intervention), when the behaviors subsequently increased.
Horigian et al., 2022	2,541/8	Suicidality as a Predictor of Overdose in Patients with Substance Use Disorders	Multiple logistic regression	Concise Health Risk Tracking Self-Report (CHRTSR) sociality scores were associated with overdose events. Patients with lifetime heroin use were more likely to overdose.
Schmidt et al., 2023	2,541/8	High Suicidality Predicts Overdose Events among People with Substance Use Disorder: A Latent Class Analysis	Latent class analysis of Concise Health Risk Tracking Self-Report data	Three suicidality classes were identified (at Minimal, Moderate, and High Severity levels). The High Suicidality class contained the highest proportions of males, Black individuals, individuals with psychiatric histories, and individuals with baseline depression compared to the other two classes.
Schmidt et al., 2024	793/3	Sleep Disturbance and Substance Use among Individuals with Substance Use Disorder	Cross-lagged panel analysis of the association between stimulant use and sleep disturbance over 8 weeks	Psychiatric history and baseline depression were associated with higher odds of baseline disturbed sleep. Increased stimulant use was associated with higher odds of subsequent sleep disturbance after baseline.

^aAll comparisons that describe treatment effects or associations between variables are statistically significant.

Due to the heterogeneity of these studies, which include individual or cluster randomized trials, individual or agency surveys, and cross-protocol secondary analyses of determinants of target outcomes, and which employed diverse analytic strategies, there were no uniform indices of effect (e.g. effect sizes) that applied to, and that could be reported for, all studies. However, all results reported here, whether treatment effects or associations between variables, were statistically significant.

1.3.1. Studies of medical comorbidities

Since 2001, the SIG has been integrally involved in the development and implementation of nine of the above-described medical comorbidity-focused studies. SIG members have also been initiators and collaborators in numerous secondary analysis manuscripts, based either in single protocol or cross-protocol databases. As part of its mission to support CTN comorbidities research, the SIG has initiated two projects to make existing CTN assessments more accessible to researchers contemplating new protocols and secondary analyses of CTN data. Using the existing list of all commonly used standardized CTN assessments posted on the CTN Data and Statistics Center (DSC) website (https://ctntpr.com/group/291), the Comorbidities SIG Mental Health Subcommittee created an annotated registry that describes the salient characteristics of various mental health assessments used across CTN studies, including the original reference, mode of administration, population, and other characteristics (Table 3). Planned future enhancements include adding operational details to each assessment, such as average administration time, availability of translated versions, and staffing requirements, including whether administration requires a licensed professional or if specific scores necessitate referral to a clinician. These additions aim to aid CTN investigators in planning and implementing future studies more effectively. Another Comorbidities SIG subcommittee examined various medical domains in the DSC list that could be analyzed in secondary analyses, including medical test results and symptoms, quality of life measures, and adverse event reports. Using this information, Schmidt et al. (2023) successfully used adverse event reporting to assess propensity for overdose in a cross-study analysis of suicidality. Our examination revealed that CTN studies have almost exclusively used self-reported test results for the diagnosis of medical comorbidities rather than observational or biological data, which sharply limits utility. This constitutes an important gap in CTN data that warrants enhancement to conduct future research in medical comorbidities.

Table 3.

Example of annotated registry for mental health assessments from the comorbidities SIG Mental Health Subcommittee.

Mental health domain	Assessment	Origin	Administration mode	Timeframe	Populations	Notable features Recommendations
Depression	DSM-5 for major depressive disorder	CTN-0097 developed but did not use	Clinician-rated	Past 7 days. Should represent a change in functioning from baseline. Not well-suited to assess changes over time.	Adults
	Patient Health Questionnaire-9 (PHQ-9) (alternate short-form versions: PHQ-2, PHQ-4, PHQ-8)	Kroenke et al., 2001	Self-administered	Past 14 days	Adults in primary care settings, but has received empirical support for valid use with many subgroups	Multiple versions; can use shorter versions (PHQ-2, PHQ-4) or without the suicidal ideation item (PHQ-8) as appropriate; free.
	Inventory for Depression Symptomatology-Self-Report (IDS-SR)	Rush et al., 1986	Self-administered	Past 7 days	Adults	Assesses three domains: mood, sleep, and appetite
Attention-deficit/hyperactivity disorder	Adult ADHD Self-Report Scale for DSM-5 (ASRS-5)	DSM-5 Based (updated version of ASRS1.1)	Self-administered	Lifetime	Adults	Widely considered the “gold standard” assessment
(ADHD)	DSM-5 for ADHD	CTN-0097 developed but did not use	Clinician-administered	Lifetime	All ages

1.3.1.1. Formative implementation-focused studies.

Some comorbidities studies provided formative lay-of-the-land surveys of services and resources available or needed in substance use or medical settings in the community for emerging comorbid medical conditions. This is best exemplified by CTN-0012: Characteristics of Screening, Evaluation, and Treatment of HIV/AIDS, Hepatitis C Viral Infections, and Sexually Transmitted Infections in Substance Abuse Treatment Programs (Lawrence Brown, Jr., Lead Investigator). At a relatively early point in the HIV and HCV epidemics, this study provided novel information about the availability and factors associated with provision of infection-related health services in substance use treatment settings. Data were obtained from health departments and substance use agencies in 48 states and 269 substance use treatment programs regarding state policies, state priority level, provider reimbursement, and treatment program characteristics. Results revealed that HIV/AIDS services were more common than HCV or STI services and that nonmedical services were more common than medical services. Reimbursement was the most significant predictor of infection-related health services, suggesting that increased funding of these services in substance use treatment settings, facilitated by supportive state policies, could be an effective response to the excess morbidity and mortality of substance use-related infections (Brown Jr et al., 2007).

More recently, CTN-0082: Implementation Survey of PrEP and Opioid Use Related Services in STI Clinics and Community Based Organizations (Susan Tross and Mary Hatch, Co-Lead Investigators) served a similar purpose with respect to providing novel information about the availability of and factors associated with HIV pre-exposure prophylaxis (PrEP)and opioid use disorder (OUD)-related services in community sites that were active service hubs for people who use drugs in eight high HIV incidence southern U.S. cities. At a time when PrEP is widely recognized as highly effective in preventing HIV acquisition but uptake is extremely limited among people who use or inject drugs, the information obtained from this study is crucial for improved implementation of PrEP. This study assessed PrEP awareness, experience, willingness, barriers, facilitators, and suggested strategies for implementation of PrEP, and similar implementation factors for OUD services. Participants included high-risk substance-using men who have sex with men (SU-MSM) and people who use opioids (PWUO), the frontline providers serving these individuals, and the directors in three types of community-based organizations: sexually transmitted infection (STI) clinics (n = 6), syringe services programs (SSPs) (n = 5), and outpatient substance use treatment programs (n = 2). This study has produced multiple publications on the prevalence and predictors of PrEP willingness and use among SU-MSM and PWUO, attitudes toward medication for OUD among PWUO and frontline providers, and attitudes toward naloxone for prevention of overdose fatality among PWUO. Primary outcome analyses demonstrated that the vast majority of both patient groups expressed willingness to take oral (PWUO 69%, SU-MSM 78%) or long-acting injectable PrEP (PWUO 62%, SU-MSM 66%). This is particularly important as the study was performed when long-acting injectable PrEP was first becoming widely available (Hatch et al., 2024; Tross et al., 2025). Findings from these two studies identified marked gaps in services and contributed to the data that support implementation of service enhancements.

1.3.1.2. Studies embedding HIV testing and risk reduction services in substance use treatment programs or STI clinics.

Some CTN Comorbidities studies embedded HIV testing and risk reduction services in substance use treatment programs or STI clinics, at a time when people who use drugs were not being reached by testing and behavioral prevention initiatives. CTN-0017: HIV and HCV Intervention in Drug Treatment Settings (Robert Booth, Lead Investigator) tested three interventions to increase HIV testing and reduce drug and sexual risk behaviors in detoxification programs. Participants were randomized to: (1) a two-session HIV/HCV counseling and education model added to treatment as usual (TAU), (2) a single-session therapeutic alliance intervention conducted by outpatient counselors to facilitate treatment entry plus treatment as usual, or (3) treatment as usual. While significant reductions in drug and sexual risk behaviors occurred in all three groups over a 6-month follow-up period, participation in HIV testing appointments was significantly higher for participants in the counseling and education arm (Booth et al., 2011).

CTN-0032: HIV Rapid Testing and Counseling Study (Lisa Metsch, Lead Investigator) was launched in 2009 to examine SUD treatment programs as effective settings for HIV testing at a time when most programs did not offer on-site testing despite the 2006 Centers for Disease Control (CDC) recommendation for universal HIV testing in all healthcare settings. This study investigated both the effectiveness and cost-effectiveness of on-site rapid testing and the efficacy of risk-reduction counseling in 12 outpatient SUD treatment programs. Participants were randomized to receive a referral for off-site HIV testing; a brief, participant-tailored risk-reduction counseling session with the offer of an on-site rapid HIV test; or streamlined on-site rapid HIV testing only. Offering on-site HIV rapid testing significantly increased patient receipt of test results, but there was no substantial effect of brief counseling on reducing sexual and injection drug use risks (Metsch et al., 2012). On-site HIV rapid testing increased quality of life at a cost-effectiveness ratio less than $100,000 per quality-adjusted life-year. Based on these findings, policymakers and treatment leaders were urged to seek funding to implement on-site rapid HIV testing in substance use treatment programs (Schackman et al., 2013). These results spurred the development of a NIDA/Substance Abuse and Mental Health Services Administration (SAMHSA) initiative geared to supporting the implementation of on-site rapid HIV testing (Technology Transfer Centers, 2018).

Building on CTN-0032 findings, Project AWARE: Effect of Risk Reduction Counseling with Rapid Testing on STI Acquisition (Lisa Metsch and Grant Colfax, Co-Lead Investigators) evaluated the effectiveness of counseling and HIV testing in STI clinics. Over 5,000 patients attending nine STI clinics were randomized to receive a rapid HIV test with either patient-centered, evidence-based HIV risk-reduction counseling or with written educational information only. Risk-reduction counseling in conjunction with a rapid HIV test did not significantly affect STI acquisition. As a result, the CDC ultimately defunded its mandatory counseling initiative and instead supported expanded rapid testing with reduced counseling.

Two parallel protocols, CTN-0018 and CTN-0019, embedded gender-specific safer sex skills training in methadone maintenance or psychosocial outpatient treatment programs. CTN-0018: Reducing HIV/STD Risk Behaviors: A Research Study for Men in Drug Abuse Treatment (Donald A. Calsyn, Lead Investigator) compared a five-session HIV prevention intervention for men called Real Men Are Safe (REMAS) to a single session of standardized HIV education (HIV-Ed) in seven methadone maintenance and seven psychosocial outpatient programs. At the time, recognition of the concept that sex and drugs were mutually reinforcing and should be addressed jointly as an integral part of treatment was uncommon. REMAS participants reported significantly fewer unprotected vaginal and anal sexual encounters during the 90 days prior to the 3and 6-month follow-up visits compared to HIV-Ed participants, with an effect size of 0.34 among intervention completers compared to standard of care. CTN-0018 was also a platform for identifying racial disparities in outcome, leading to subsequent cultural adaptations of treatments for Black and Hispanic men (Calsyn et al., 2009; Calsyn et al., 2012). Of note, this study was the first and only intervention tested in the CTN that focused only on the unique cultural needs of men— and one of only three CTN studies that tested a gender-specific intervention.

Similarly, CTN-0019: Reducing HIV/STD Risk Behaviors: A Research Study for Women in Drug Abuse Treatment (Susan Tross, Lead Investigator) compared two sexual risk reduction interventions for women who used drugs and were participating in methadone or psychosocial outpatient treatment programs: Safer Sex Skills Building, consisting of five 90-minute group sessions designed to build cognitive and behavioral skills for safer sex decision-making compared to standard HIV/STI education. At the 3-month follow-up, women in both conditions had reduced their unprotected sexual encounters, but women in skills arm had significantly fewer such encounters at 6 months, while sexual encounters in education group returned to baseline levels (Tross et al., 2008). The effect size was 0.60 among intervention completers compared to standard of care. CTN-0019 was subsequently culturally adapted for Black women (Burlew et al., 2023).

1.3.1.3. Using internet sites as a platform for access to HIV self-testing kits.

CTN-0083: Using Social Media to Deliver HIV Self-Testing Kits and Link to Online PrEP Services (Lisa Marsch and Jeffrey Klausner, Co-Lead Investigators) compared the relative effectiveness of using the internet—either social media sites or informational sites—to promote HIV self-testing through simplified access to test kits and PrEP uptake among young (18–30 years old), minority MSM with SUD. Among 254 participants, 177 (69.7%) ordered a home HIV self-test kit; the majority were ordered by participants enrolled from dating apps (Stafylis et al., 2022).

1.3.1.4. Trials embedding substance use treatment services in HIV clinics.

A pair of studies, including a pilot and the following scaled-up trial, demonstrated that HIV clinics could be effective sites for delivering substance use treatment. CTN-0055: Comparing Treatments for HIV-Positive Opioid Users in an Integrated Care Effectiveness Study (CHOICES) (Todd Korthuis, Lead Investigator) was a non-blinded, randomized pilot trial comparing treatment initiation, retention, and safety using the opioid antagonist extended-release naltrexone (XR-NTX) compared to treatment with buprenorphine or methadone in HIV clinics. Fifty-one people living with HIV seeking treatment for opioid (n = 16) or alcohol use disorder (n = 27) or both (n = 8) were randomized. Treatment initiation was lower, but retention was greater for the XR-NTX group. XR-NTX was well-tolerated, with no precipitated withdrawals, supporting its use for treatment of opioid and alcohol use disorders in HIV clinics (Korthuis et al., 2017).

A follow-up study, CTN-0067: Comparing Treatments for HIV-Positive Opioid Users in an Integrated Care Effectiveness Study (CHOICES Scale-Up) (Todd Korthuis, Lead Investigator), compared HIV clinic-based initiation of extended-release naltrexone (XR-NTX) versus treatment buprenorphine or methadone in people living with HIV and HIV RNA > 200 copies/mL who also have untreated OUD. One hundred fourteen participants were randomized (n = 55 XR-NTX, n = 59 TAU). Fewer participants in XR-NTX arm initiated medication (Korthuis et al., 2022). At week 24, viral suppression rates did not exceed the pre-specified non-inferiority margin of 0.75. The XR-NTX condition had modestly lower mean days of opioid use. Results suggested that while uptake of XR-NTX was limited, among those who did engage, virologic suppression was comparable to standard OUD treatment, and opioid use reduction was favorable, suggesting that embedding XR-NTX treatment within HIV care may help close gaps in the HIV care cascade.

1.3.1.5. Trials embedding substance use treatment in hospitalized people who use drugs.

Three studies by one team of collaborators leveraged the potential of hospitalization as an opportunity for initiating substance use treatment among patients admitted for serious infections. CTN-0049 Project HOPE (Hospital Visit as an Opportunity for Prevention and Engagement for HIV-Infected Drug Users) (Lisa Metsch, Carlos Del Rio, and Daniel Feaster, Co-Lead Investigators) was conducted in 11 hospitals from 2012 to 2014 and enrolled people living with HIV who had a detectable or unknown viral load in the past 6 months, baseline CD4 cell count lower than 350 cells/μL, and a history of opioid, stimulant or heavy alcohol use within the past year. The study compared treatment as usual to two 6-month-long interventions: patient navigation plus financial incentives (PN + FI) versus patient navigation only (PN), with the goal of achieving HIV viral suppression (≤ 200 copies/mL) at the 12-month assessment (i.e., six months after the interventions). While there were no differences between the groups at 12 months, short-term efficacy for the PN + FI approach showed higher engagement in substance use treatment at the completion of the intervention as well as significant increases in HIV care engagement and viral load suppression (Metsch et al., 2016).

CTN-0064: Linkage to Hepatitis C Virus (HCV) Care among HIV/HCV Co-Infected Substance Users (Lisa Metsch, Carlos Del Rio, and Daniel Feaster, Co-Lead Investigators) compared a care facilitation intervention to the standard of care in individuals co-infected with HIV and HCV who are vulnerable to faster disease progression of both viral illnesses (Hernandez & Sherman, 2011). Approximately 12% of participants in both groups achieved a sustained virologic response (i.e., HCV cure) by the 12-month follow-up. Care facilitation resulted in a modest but statistically significant impact in progression along the HCV care continuum (Metsch et al., 2021).

Recently, CTN-0121: Integrated Care and Treatment for Severe Infectious Diseases and Substance Use Disorders (SUD) among Hospitalized Patients (Lisa Metsch, David Serota, Daniel Feaster, and Carlos del Rio, Co-Lead Investigators) has focused on increases in severe bacterial and fungal infections– such as bacteremia, infective endocarditis, bone and joint infections, and central nervous system infections– which have been described as “inextricably linked” (primarily through injection drug use) to the opioid epidemic (NASEM, 2020, p. 20). This study employs a comprehensive (i.e., pharmacologic, behavioral, harm reduction) intervention for people who inject drugs hospitalized with serious infections. Targeted outcomes include in-hospital initiation of SUD medication and retention of patients following rapid transfer to less costly, integrated outpatient care post-discharge.

1.3.1.6. A study examining the role of chronic pain and opioid use treatment.

Recognizing the significant role of opiate analgesic use in the opioid epidemic, CTN-0030: Prescription Opiate Abuse Treatment Study (POATS) (Roger Weiss and Walter Ling, Lead Investigators) was a two-phase randomized controlled trial (RCT) of buprenorphine/naltrexone (BUP/NTX) for treatment of prescription opioid dependence. Two BUP/NTX conditions were compared: BUP/NTX plus standard medical management, and BUP/NTX plus standard medical management plus enhanced medical management consisting of individualized counseling. In both conditions equally, there was decreased opioid use during BUP/NTX treatment. Yet, when BUP/NTX was tapered, unsuccessful outcomes increased comparably in both conditions. Notably, chronic pain had no influence on outcome (Weiss et al., 2011).

1.3.2. Studies of mental health comorbidities

Since 2000, building on the powerful connection between substance use and mental health conditions, the CTN has implemented five mental health comorbidities-focused studies (Table 1) that targeted the common conditions of post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), and suicidality. CTN-0015: Women’s Treatment for Trauma and Substance Use Disorders (Denise Hien, Lead Investigator) was the first randomized controlled trial of an intervention for comorbid SUD and PTSD in women, an area of high prevalence and grave morbidity. Three hundred forty-six women from six community treatment programs were randomized to either 12 sessions of Seeking Safety, a cognitive behavioral intervention, or women’s health education, an attention control psychoeducational group. While PTSD symptoms significantly decreased in both groups, substance use did not (Hien et al., 2009). However, trajectory analysis revealed that in those for whom PTSD symptoms decreased, reductions in substance use followed (Hien et al., 2010, 2020), demonstrating the powerful role that treating comorbid PTSD can have on reducing problem substance use.

For CTN-0028: Osmotic-Release Methylphenidate for ADHD in Adolescents with SUD (Paula Riggs and T. John Winhusen, Lead Investigators), lively discourse over the use of stimulant treatment in adolescents with SUD led to the development of this randomized, placebo-controlled study of osmotic-release methylphenidate for ADHD in adolescents with SUD who were also receiving cognitive behavioral therapy. Three hundred three patients from community treatment sites were randomized. While both conditions showed comparable efficacy for reducing ADHD symptoms and substance use, the methylphenidate group experienced somewhat stronger declines on some secondary ADHD and substance use outcomes. Methylphenidate was relatively well tolerated (Riggs et al., 2011).

CTN-0029: Pilot Study of Osmotic-Release Methylphenidate in Initiating and Maintaining Abstinence in Smokers with ADHD (Eugene Somoza and T. John Winhusen, Lead Investigators) was a pilot randomized, placebo-controlled trial of osmotic-release methylphenidate for initiating and maintaining abstinence in smokers with ADHD who were also receiving standard smoking cessation treatment with nicotine patches and individual counseling. Two hundred fifty-five patients from six sites were randomized. Methylphenidate, as compared to placebo, was effective in treating ADHD, and both groups had comparable prolonged abstinence rates (Winhusen et al., 2010).

With people with OUD at heightened risk for mental health problems and associated suicidality, CTN-0095-A-1: Suicide Prediction and Prevention for People at Risk for OUD (Rebecca Rossom and Gavin Bart, Lead Investigators) targeted primary care clinics as promising venues for care. A cluster randomized trial in 15 primary care clinics compared integration of a clinical decision support tool for OUD and suicide screening versus a support tool for OUD screening only. Intervention and control clinics had comparable rates of suicide screening (Rossom et al., 2025).

Concern about widespread increasing cannabis use during pregnancy led to CTN-0140: Cannabis Use among Pregnant Women with Polysubstance Use and Psychiatric Problems (Kelly Young-Wolff, Lead Investigator), that examined risk for prenatal cannabis use in women with non-cannabis SUD and psychiatric disorders. Leveraging the vast electronic health record database of 227,555 pregnant women treated in the Kaiser Permanente Northern California health system, this study examined possible associations between a range of SUD and psychiatric disorders with occasional cannabis use and cannabis use disorder. While a range of psychiatric disorders and SUDs were associated with elevated odds of both occasional cannabis use and cannabis use disorder during early pregnancy, associations were stronger for substance use disorders than for psychiatric disorders (Young-Wolff et al., 2024).

1.3.3. Comorbidity-focused secondary analyses using CTN data share

Data from completed CTN trials are made publicly available on the NIDA Data Share website (https://datashare.nida.nih.gov/), which facilitates: (1) using existing data for new research; (2) pooling of data files for cross-study analyses that may address common challenges, such as achieving sufficient sample sizes for subgroup analyses of specific comorbidities; and (3) sorting studies based on inclusion of substance use, physical health, mental health, and other assessments. It is an extremely useful resource for identifying and accessing data that can be used in cross-study analyses of comorbidity outcomes that are otherwise not feasible in smaller single-protocol samples, facilitating data synthesis and enabling large-scale impactful research. Examples of cross-study comorbidity analyses are described below (Table 2).

1.3.3.1. Gender differences in rates and correlates of HIV risk behaviors among drug-dependent individuals.

Using data from five studies (N = 1429 substance users, 45% women), this analysis found that women had more sex with multiple partners, unprotected sex with regular partners, and overall more high-risk sexual behaviors compared to men, although men had higher injection drug use rates. Among women, sexual risk behaviors were positively associated with alcohol use and psychiatric problem severity. Among men, sexual risk behaviors were negatively associated with impairment in social function. Among both, sexual risk behaviors were associated with sexual abuse history, drug use severity, and legal system involvement (Brooks et al., 2010).

1.3.3.2. Effect of substance use treatment on sexual risk behaviors.

This analysis examined the impact of behavioral substance use treatments on sexual risk behaviors in 1,305 sexually active participants across eight randomized controlled trials. The majority (64.1%) were racial/ethnic minorities and almost half (48.7%) were female, with a mean age of 34.9 years (SD = 9.6 years). Longitudinal logistic regression estimated the probability of risky sexual behavior (defined as inconsistent condom use and/or > 1 sexual partner in the past 30 days) post-intervention, with an indicator variable for post-intervention, study condition (control, intervention), and their interaction as predictors. Approximately 84.2% reported risky sexual behaviors at baseline. Trial participation was associated with decreased risky sexual behaviors in both the intervention and control conditions, demonstrating a secondary benefit of substance use treatment on reducing risky sexual behaviors, with 17.3% and 18.5% less likely to report risky sexual behavior post-intervention, respectively (Brown et al., 2018).

1.3.3.3. Suicidality as a predictor of overdose.

Using data from eight clinical trials from 2012 to 2021, two secondary analyses examined suicidality as a possible predictor of overdose events among 2,541 participants. The first study revealed that suicidality scores assessed by the Concise Health Risk Tracking Self-Report (CHRT-SR) were associated with overdose events during the trial, and the likelihood of overdose increased as continuous CHRT-SR scores increased (OR 1.02) (Horigian et al., 2022). The second study used latent class analysis and yielded three classes: Minimal Suicidality (Class 1), with low probabilities of endorsing each CHRT-SR construct; Moderate Suicidality (Class 2), with high probabilities of endorsing pessimism, helplessness, and lack of social support, but minimal report of despair or suicidal thoughts; and High Suicidality (Class 3), with high probabilities of endorsing all constructs. Compared to the other classes, the High Suicidality class had the highest proportions of males, Black/African Americans, and people with a psychiatric history and baseline depression. In regression analyses, those in the High Suicidality class were more likely to overdose compared to individuals in the Minimal Suicidality class (Schmidt et al., 2023).

1.3.3.4. Sleep disturbance and substance use among individuals with stimulant use disorder.

A cross-lagged panel model assessed the association between stimulant use and sleep disturbance over eight weeks using data from three clinical trials for reduction in any stimulant use, cocaine use, or methamphetamine use, respectively. Among the 793 participants, psychiatric history and baseline depression were both associated with higher odds of experiencing baseline sleep disturbance. Increased stimulant use was associated with higher odds of experiencing subsequent sleep disturbance at timepoints other than baseline. Current sleep disturbance was positively associated with subsequent sleep disturbance on a weekly basis, and current stimulant use was consistently and positively associated with subsequent use (Schmidt et al., 2024).

2. Discussion

The individual and public health costs of the medical conditions associated with SUDs are enormous. Unaddressed, these looming comorbidities may even undermine the potential success of SUD treatment. The breadth and experience of CTN investigators could readily facilitate cutting-edge research to integrate care for the comorbid complications of SUD into clinical research, but this requires a commitment to the importance of this work. As the incidence of hepatitis B and C, HIV, STIs, and serious bacterial infections in people with SUD continues to rise (Kolla et al., 2020), evaluation of strategies for integrating testing, linkage to care, treatment, adherence, retention, and prevention through trials focused on acute and chronic comorbid conditions would significantly enhance our approach to the overall health of people with SUDs and would provide this population with critical health benefits.

2.1. Moving forward: strategies for enhancing future comorbidities research

Leveraging the wide array of potential research sites, such as substance use treatment programs, primary care clinics, hospitals, and syringe services programs, among others, we envision several major future approaches to comorbidities research. Such approaches have been shown to be feasible within the CTN. These include: (1) clinical trials of evidence-based comorbidity interventions in people whio use drugs in service settings where they have not previously been implemented. For example, CTN-0032 compared an established HIV testing and counseling intervention to receipt of standard of care HIV information in psychosocial outpatient treatment programs and methadone clinics. (2) Implementation trials that evaluate strategies for delivery of interventions for comorbid conditions in service settings where they have not previously been implemented, such as CTN-0083, which compared the feasibility of distributing HIV self-testing kits through different types of social media sites, and CTN-0121, which compared a comprehensive in-hospital and post-discharge intervention (OUD, behavioral, and harm reduction) delivered by medical providers to standard of care in people who inject drugs with severe infections. (3) Trials that compare different methods for training and supporting primary care and addiction care providers to diagnose and deliver comorbidity treatment are a special type of implementation research. For example, one of the authors (JF) has demonstrated that an online training and support program, the West Virginia Hepatitis Academic Mentoring Partnership, that uses a HIPAA-compliant REDCap-based consultation model and incorporates bilateral communication between expert faculty and rural providers has resulted in a 98% cure rate, consistent with the 95–99% rate expected of specialists (Baus et al., 2022; Feinberg et al., 2021). We envision the CTN as a ready platform for using this training model on a larger scale and applying it to the treatment of other target comorbidities as well as to the provision of SUD care in underserved communities. (4) Formative implementation studies that use mixed methods to obtain information essential for tailoring delivery strategies for new populations or new settings, such as CTN-0082, which elicited information about willingness, facilitators of, and barriers to PrEP and OUD treatment implementation from diverse stakeholders in three types of community programs. (5) Lastly, we would like to strongly emphasize the enormous yield—in terms of knowledge of comorbidities and their correlates—to be gained from inclusion of standard, basic data on comorbidities in every CTN protocol.

3. Conclusion

The pressing impact of comorbid conditions faced by people who use drugs offers exciting opportunities for NIDA’s CTN research platform to pioneer discovery in these intersecting fields of medicine. The early work of the HIV SIG galvanized research and articulated essential strategies to integrate screening, diagnosis, and care for HIV into addiction research protocols. Comorbidities SIG investigators have emphasized the foundational need for common measures of comorbidities that facilitate comparison of outcomes across studies. The CTN platform offers two valuable mechanisms for augmenting comorbidities research: the development of multisite trials that are explicitly dedicated to assessment and treatment of comorbid conditions, and use of the NIDA Data Share database for secondary analyses of comorbidities that can account for the types of substances used, sociodemographic factors, and other variables that are potentially important factors in understanding comorbidities. Overall, 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 to advance research and practice to improve the health of people with SUD.

The expertise of Comorbidities SIG investigators encompasses a broad range of medical and behavioral disciplines. Defining composite outcome variables that combine stringent measurement of treatment for both SUD and one or more comorbid medical or mental health conditions demands multidisciplinary discussion to capture significant, compelling “whole person” outcomes. Early on, the HIV SIG was at the forefront of such discussion and the selection of standard measures in studies conducted at the intersection of addiction medicine and infectious diseases. By broadening focus on the wide range of comorbid conditions faced by people who use drugs, the CTN Comorbidities SIG provides a venue for foundational discussions by experts from various fields to support the development of the next wave of intersectional studies. This work not only promises improved “whole person” health outcomes, but will also pioneer new areas of clinical science.