Pharmacological Smoking Cessation Interventions in People with Cannabis, Opioid, or Stimulant Use Disorders: A Systematic Review

Pharmacological Smoking Cessation Interventions in People with Cannabis, Opioid, or Stimulant Use Disorders: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Pharmacological Smoking Cessation Interventions in People with Cannabis, Opioid, or Stimulant Use Disorders: A Systematic Review Nicole Brar, MD, Imamhulhaq Brula, BS, Dylan H Ballard, MD, Brittany Musselwhite, MD, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9141564/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction . Tobacco use disorder (TUD) is highly prevalent among people with cannabis use disorder (CUD), opioid use disorder (OUD), and stimulant use disorder (StUD), encompassing cocaine use disorder and methamphetamine use disorder. TUD increases the severity of other substance use disorders and leads to increased incidence of health complications, resulting in elevated mortality. We reviewed studies that examined the impact of approved pharmacological smoking cessation strategies, either alone or in combination with behavioral interventions, in people with CUD, OUD, and StUD who smoke tobacco cigarettes. Methods . We registered the systematic review on PROSPERO (CRD42023467758). We searched three databases (PubMed/Medline, Google Scholar, and EMBASE) using specific MeSH terms to identify human clinical trials published in English between January 1 st , 2000, and September 30th, 2024. Results . We selected 27 eligible studies, encompassing 1) CUD (n=7); 2) OUD (n=15); and 3) StUD (n=5). Approved pharmacological smoking cessation interventions, such as nicotine replacement therapy (NRT), varenicline, and bupropion, demonstrated poor efficacy in CUD, OUD, and StUD. We identified just four placebo-controlled trials for varenicline (1 in CUD, 2 in OUD, and 1 in StUD). Varenicline showed the most promise in StUD, short-term benefit in CUD, and, paradoxically, no benefit over placebo in two well-controlled OUD trials. Just four studies performed the recommended biochemical verification using both exhaled carbon monoxide (CO) and urine cotinine. Conclusions . Across the three disorders, pharmacological smoking cessation interventions demonstrated poor efficacy. More importantly, these conclusions were drawn from a sparse number of studies. Outcome measures were inconsistent across studies. Implications . This systematic review reveals a profound evidence gap in smoking cessation treatment for individuals with CUD, OUD, or StUD. Across 27 included studies, we identified only four placebo-controlled varenicline trials combined across all three disorders, in stark contrast to 33 such trials in general populations. The limited available evidence suggests approved pharmacological interventions demonstrate suboptimal and variable efficacy compared to the general population. Varenicline showed the most promise in StUD, short-term benefit in CUD, and no clear benefit in two placebo-controlled OUD trials. Bupropion demonstrated efficacy in StUD but limited evidence in other disorders. Combination pharmacotherapy remains almost completely unstudied in these populations. Most studies followed participants for 12 weeks or less, providing little information about sustained long-term abstinence. Current clinical practice guidelines offer insufficient disorder-specific guidance and do not acknowledge the apparent differential treatment responses across specific disorders. Urgent research priorities include: (1) adequately powered, placebo-controlled trials of single and combination pharmacotherapies with extended follow-up; (2) investigate novel interventions such as cytisine, digital therapeutics, and TMS; (3) and develop disorder-specific treatment approaches. Psychiatry Clinical Pharmacology smoking cessation cannabis opioid stimulant Figures Figure 1 Figure 2 INTRODUCTION Tobacco use disorder (TUD) is the leading cause of preventable disability, disease, and death in the USA 1 . Approximately 18.7% of adults in the United States use a tobacco product, with the majority smoking cigarettes (11.5%) and the rest using e-cigarettes (4.5%), cigars (3.5%), smokeless tobacco (2.1%), and pipes (0.9%) 2 . Despite the availability of smoking cessation interventions, 50–60% of people who quit smoking cigarettes relapse after a year 3 . Even varenicline, perhaps the most effective medication for smoking cessation, has suboptimal long-term efficacy with an abstinence rate of 27.9% at twelve months, compared to six months (38.6%) and three months (43.8%) 4 . Cigarette smoking has a bidirectional association with alcohol use disorder (AUD), cannabis use disorder (CUD), opioid use disorder (OUD), and stimulant use disorder (StUD), encompassing cocaine and methamphetamine 5 – 11 . Smoking prevalence is remarkably high across these populations- AUD (60–80%) 6–8 , CUD (75%) 9 , OUD (74 to 94%) 10 , and StUD (87 to 92%) 11 . Moreover, the presence of these substance use disorders intensifies smoking severity 7 , 11 – 13 , while cigarette smoking compounds the health burden in individuals with comorbid substance use disorders 14 – 17 . The mortality implications are particularly striking. Patients with AUD, OUD, and StUD who smoke experience higher mortality from smoking-related illnesses compared with non-smoking patients with these same disorders 14 . Among those with OUD, concurrent smoking increases cardiovascular mortality risk 2.6-fold 15 , while in methamphetamine use disorder, smoking triples overall mortality risk 16 . Even with CUD, adding cigarette smoking significantly elevates atherosclerosis risk compared with CUD alone 17 . Despite a repertoire of pharmacological and behavioral interventions for smoking cessation, there is a significant gap in optimal smoking cessation strategies in patients with other substance use disorders, as shown by previous systematic reviews 5 , 18 – 20 . Given that a recent meta-analysis summarized the available evidence regarding the efficacy of pharmacological smoking cessation interventions in patients with AUD, we focused on other substance use disorders (CUD, OUD, and StUD) 21 . While previous systematic reviews examined smoking cessation interventions broadly, the most recent was published in 2016 18,20 , and we specifically focused on pharmacological treatments to better characterize their efficacy in CUD, OUD, and StUD. The primary objective of this systematic review is to summarize evidence from studies examining approved pharmacological smoking cessation interventions alone or in combination with behavioral smoking cessation interventions in patients with other substance use disorders (CUD, OUD, and StUD). METHODS We registered the systematic review on PROSPERO (CRD42023467758). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to determine eligibility criteria for studies, conduct the search, and critically evaluate the included studies 22 . We searched three databases (PubMed/Medline, Google Scholar, and EMBASE) using specific MeSH search terms listed in Supplementary Material Table 4 . All studies were published between January 1st, 2000, and September 30th, 2024. All studies were published in English and screened by two authors (NCG and BM) for titles, abstracts, and full texts before deciding whether to include or exclude each study. Disagreements were resolved through discussions with a third reviewer (GR). We included studies that met the following inclusion criteria: 1) Used approved pharmacological interventions alone or in combination with behavioral interventions for smoking cessation; 2) Participants were diagnosed with TUD and a comorbid substance use disorder, which included OUD, CUD, or StUD. We excluded the following studies–1) Case reports and case series; 2) studies that used approved smoking cessation strategies to treat CUD, OUD, or StUD; 3) studies that examined smoking cessation interventions in treatment facilities encompassing people with substance use disorders but did not provide information on specific comorbid substance use disorders; 4) studies that solely examined the efficacy or effectiveness of behavioral interventions for smoking cessation in people with comorbid substance use disorders; and 5) studies examining the utility of electronic nicotine delivery systems (ENDS) in people with these comorbid substance use disorders, given mixed data on their utility/efficacy and lack of approval for smoking cessation 23 , 24 . We reviewed studies across three disorders – CUD, OUD, and StUD. Data extraction was performed independently by two reviewers (NB and BM) using a standardized, piloted data extraction form. Extracted data included: study design, participant characteristics (sample size, demographics, disorder type, concurrent treatment), intervention details (pharmacological agents, doses, duration, behavioral components), comparator/control details, outcome measures and definitions, biochemical verification methods, follow-up timing, results (abstinence rates, cigarettes per day, quit attempts), and adverse events. The quality of RCTs was assessed using the Cochrane Risk of Bias 2.0 and classified as low, some concerns, or high. The NIH Quality Assessment Tool was used to determine the quality of observational cohort studies/secondary analyses of RCTs, and pre-post studies with no control group. Two reviewers (DB and IB) independently assessed the risk of bias in the included studies using these tools. Studies were rated as having low, moderate, or high risk of bias. Disagreements were resolved through discussion or consultation with a third reviewer (GR). RESULTS Figure 1 illustrates the PRISMA diagram outlining the selection process for the studies included in this review. We identified 1,347 English-language studies published between January 1, 2000, and September 30, 2024. We removed duplicates and selected 27 articles that fulfilled our eligibility criteria from 628 unique articles. The 27 articles included in the qualitative synthesis, encompassed 1) comorbid CUD and TUD (n = 7); 2) comorbid OUD and TUD (n = 15); and 3) comorbid StUD and TUD (n = 5) ( Supplementary Table 1 ). These studies enrolled between 5 and 538 participants (median: 100). Studies in OUD were most numerous (n = 15, 54%) and generally had larger sample sizes, while CUD (n = 7, 26%) and StUD (n = 5, 19%) studies were fewer and typically smaller. Follow-up duration across the three disorders ranged from 15 days 25 to 18 months 26 . [ Figure 1 ] Comorbid CUD and TUD Seven studies examined the impact of pharmacological smoking cessation interventions alone or in combination with behavioral interventions in people with CUD and TUD 25 , 27 – 32 ( Supplementary Table 1 ). Three studies used nicotine replacement therapy (NRT) 27 , 28 , 30 , one combined NRT with varenicline 33 , two used solely varenicline 25 , 29 , and one used N-acetylcysteine 32 . The behavioral interventions included cognitive-behavioral therapy (CBT), contingency management (CM), motivational enhancement therapy (MET), and general behavioral counseling 27 – 31 . Of the five studies that utilized behavioral interventions in combination with pharmacology, two combined computer-assisted CBT, CM, and MET 27 , 30 , one combined CBT and CM 28 , one more combined MET and CBT 29 , and one delivered general behavioral counseling 31 . Varenicline was examined in three studies with varying designs and durations ( Supplementary Table 1 ) 25 , 29 , 33 . The only placebo-controlled trial (n = 108) demonstrated significantly higher abstinence in the varenicline group (46%) compared to placebo (24%) at 2 weeks following just 8 days of treatment, notably the shortest treatment duration and follow-up period among all included studies, limiting conclusions about sustained abstinence 25 . Adams 2018 examined varenicline feasibility in a small crossover trial (n = 7) and found comparable reductions in cigarettes per day with both standard clinical care alone and standard clinical care plus varenicline 29 . Rabin et al (n = 440) found that comorbid CUD did not moderate smoking cessation outcomes in individuals receiving varenicline and brief counseling, with similar abstinence rates in those with and without CUD (23.6% vs 26.5%) 31 . Comorbid OUD and TUD Fifteen studies were included in the qualitative synthesis 26 , 34 – 47 ( Supplementary Table 1) . Four studies used pharmacological smoking cessation interventions alone, without behavioral interventions 39 , 41 , 44 , 45 . Of these four studies, two used varenicline 44 , 45 . The other two: 1) compared the effects of naltrexone versus buprenorphine plus naloxone on smoking cessation outcomes 41 , and 2) compared the effects of bupropion and placebo on smoking cessation in patients stabilized on buprenorphine 39 . Eleven of 15 studies utilized behavioral interventions in combination with pharmacological interventions 26 , 34 – 38 , 40 , 42 , 43 , 46 , 47 . One used CM exclusively 46 , one utilized a combination of MET and CBT 36 , one used CM with psychoeducation to enhance coping and relapse prevention skills 38 , and three used MET with education on relapse prevention strategies 26 , 37 , 40 . Three studies utilized the National Cancer Institute’s “5 A’s” of smoking cessation 40 , 42 , 43 , one employed text messaging 35 , and one used brief counseling sessions by a tobacco specialist 47 . One study provided computerized motivational feedback and extended CBT within an innovative system intervention (ISI), which was compared to a standard treatment control (STC) 34 . The E-ISI, based on the Expert System, comprised pharmacological treatments like NRT and varenicline, if needed, in addition to extended CBT 34 . Participants in the E-ISI arm demonstrated greater abstinence (13.4%) compared to 3.7% in the STC arm at 3 months, but not at 6, 12, or 18 months 34 . Four studies used NRT in combination with behavioral interventions, with no significant differences in abstinence between treatment and control groups 34 , 36 , 38 , 40 . Three studies examined the impact of bupropion for smoking cessation, either alone 48 or in combination with motivational interviewing 37 or contingency management 46 . Bupropion’s effects on smoking cessation were suboptimal across these three studies – 1) an open-label trial (combining 7 weeks of bupropion 300 mg, 12 weeks of NRT, and six sessions of motivational interviewing) 37 , 2) a double-blind RCT comparing bupropion to placebo in patients on buprenorphine 39 , and 3) a trial that used contingency management but had bupropion as an option patients on methadone could add on 46 . Although the number of cigarettes smoked decreased from 22 to 10 in the open-label trial 37 and abstinence was greater with people who added bupropion in the trial 46 , the RCT did not find significant differences in smoking abstinence between bupropion and placebo 39 . Seven studies examined the efficacy of varenicline in OUD 26 , 35 , 42 – 45 , 47 . Of these seven, two studies were RCTs that compared the efficacy of varenicline to placebo in people with OUD on methadone 47 , 49 . Of the remaining five studies, three did not have placebo arms 26 , 35 , 45 . One entailed secondary analyses of data acquired in a clinical trial investigating the impact of combining varenicline and NRT for smoking cessation in patients with or without OUD 44 . Another study was a retrospective analysis of varenicline’s efficacy for smoking cessation in patients with OUD, on methadone 42 . Varenicline demonstrated suboptimal efficacy (compared to the general population) across three trials that lacked placebo arms 26 , 35 , 45 . In a study that compared self-administered varenicline (n = 50) versus directly observed therapy with varenicline (n = 50) in participants with OUD and smoking cigarettes, 28/100 participants were abstinent at the end of 12 weeks across both arms 45 . Meanwhile, in a cross-sectional study that provided varenicline to 35 participants with OUD who smoke, the number of cigarettes smoked per day decreased from 20 to 8 in 12 weeks 35 . Although the goal of the study was to examine the acceptability of varenicline and not abstinence, they did observe 3 participants to be abstinent at the end of 12 weeks, as evidenced by expired CO < 5 PPM 35 . In a study that administered varenicline to three groups of participants (psychosis, AUD, and OUD on methadone) for 12 weeks after the quit date, participants with OUD on methadone had the lowest probability of abstinence from smoking compared to the other two groups 26 . Among RCTs comparing varenicline to placebo, one compared varenicline to placebo in 315 participants, divided into three arms: receiving 24 weeks of varenicline, a combination of NRT (patch plus gum), or placebo 43 , 47 . The NRT group was found to have the highest abstinence at 24 weeks (8.3%), while the varenicline group saw 3.7% abstinence, and the placebo group had 2.2% 43 . However, none of the groups showed significant differences in abstinence 43 . The other clinical trial compared varenicline and placebo, with 10.5% in the varenicline arm demonstrating biochemically verified abstinence, and no person in the sham arm demonstrating abstinence at the end of 12 weeks 47 . In a study comparing the effects of naltrexone versus buprenorphine plus naloxone on smoking cessation, those in the naltrexone group smoked fewer cigarettes per day than those in the buprenorphine-naloxone group (11.36 versus 13.33) 41 . Comorbid StUD and TUD Five studies were included in the qualitative synthesis 50 – 54 ( Supplementary Table 1) . Two studies used pharmacological interventions in combination with behavioral interventions (CM, counseling) for smoking cessation in people with stimulant use disorder who smoke 50 , 51 , and three studies used pharmacological interventions alone 52 – 54 . Two studies evaluated the effectiveness of bupropion as an add-on treatment for smoking cessation 50 , 51 . Both studies showed significantly higher abstinence with add-on bupropion to treatment as usual (TAU) at the end of 10 weeks, and at follow-up periods of 3 months and 6 months 50 , 51 . One study examined rivastigmine for smoking cessation, with no apparent benefit to participants 52 . Despite representing only five studies with sample sizes ranging from 13 to 538 participants, the StUD evidence showed the most consistently promising pharmacological results 50 – 54 . The sole placebo-controlled varenicline trial (n = 31) in cocaine use disorder patients maintained on methadone demonstrated substantial benefits: 52.8% reduction in daily cigarettes smoked with varenicline versus only 8.0% with placebo (p < 0.01), significantly more weeks engaged in nonsmoking behavior (44.2% vs 14.8%, p < 0.05), and significant FTND score reductions 53 . Bupropion demonstrated efficacy in two trials by Winhusen and colleagues 50 , 51 . In the larger trial (n = 538), participants receiving treatment-as-usual plus smoking cessation treatment (bupropion, NRT inhaler, counseling, and CM) achieved substantially higher abstinence rates than those receiving treatment-as-usual alone: 25.5% versus 2.2% at 10 weeks, 19.1% versus 3.0% at 3 months, and 13.1% versus 3.7% at 6 months, representing the highest sustained abstinence rates observed across all three disorders in this review 51 . The combination of extended-release bupropion 450 mg/day and injectable extended-release naltrexone (380 mg every three weeks) decreased smoking behaviors in participants with methamphetamine use disorder over the course of 12 weeks 54 . Smoking behaviors were secondary outcomes in this study 54 . Quality of included studies: Risk of Bias Of 14 RCTs across CUD, OUD, and StUD, one was deemed low bias 51 , two were deemed to be of some concern 40 , 53 , and the remaining 11 were considered high bias (Fig. 2). Among the observational cohort studies, secondary analyses of RCTs, and pre-post studies with no control group, two were deemed to be good 44 , 54 and all others fair ( Supplementary Tables 2 and 3 ). Outcome Measures to Measure Smoking Behaviors Studies were not consistent in their outcome measures ( Supplementary Table 1) . The most common outcome measures reported across studies were 1) self-reported abstinence, 2) self-reported quit attempts, or 3) the number of cigarettes smoked every day. Abstinence, if measured, was commonly quantified using point prevalence abstinence (PPA) over the last 7 days, with the timeline follow-back (TLFB) method. This was verified biochemically with either exhaled carbon monoxide (CO) and/or salivary/urine cotinine. The most common method of biochemical verification used in the studies included in this review was expired CO (22 of 27 studies), followed by salivary/urine cotinine (7 of 27 studies) 25 , 28 , 30 , 44 , 46 , 49 , 55 . Two studies utilized urine anatabine/anabasine assays 56 to verify abstinence while on NRT biochemically 30 , 34 . Although 7 out of 27 studies measured salivary or urine cotinine, only 4 studies performed the recommended biochemical verification using both exhaled CO and salivary or urine cotinine 56 consistently for all trial participants 25 , 38 , 44 , 46 . The cutoff values for exhaled CO for biochemical verification varied from 4 to 10 parts per million (PPM). Salivary cotinine cutoff levels ranged from 10 to 15 ng/ml, and the urine cotinine cutoff value was 30 ng/ml across studies. Four of 27 studies included in the qualitative synthesis did not perform any biochemical verification of abstinence 32 , 36 , 54 , 57 . DISCUSSION The goal of our systematic review was to examine the efficacy of pharmacological interventions, alone or in combination with behavioral interventions, for smoking cessation in patients with other substance use disorders (OUD, CUD, and StUD). Optimizing smoking cessation in individuals with comorbid substance use disorders is crucial, given the mortality imposed by smoking in people with comorbid substance use disorders 14 . Seventeen of 27 studies included in this review combined pharmacological and behavioral smoking cessation interventions in people with CUD (n=5), OUD (n=10), and StUD (n=2) 26-31,34-38,40,42,43,46,50,51 . Common behavioral interventions in studies were CM 58 , CBT 59 , and MET 60 . Unfortunately, with variability in study designs, there is a paucity of placebo-controlled trials examining approved efficacious pharmacological smoking cessation interventions in people with CUD, OUD, and StUD. Despite being our most efficacious treatment for smoking cessation 4 , with 33 placebo-controlled trials for varenicline in people without comorbid illnesses 4 , we found just one RCT examining varenicline in CUD for 2 weeks 25 , two in OUD for 12 weeks 47 and 24 weeks 49 , and one in StUD for 12 weeks 53 . Varenicline showed most promise in StUD 53 , short-term benefit in CUD 25 , and, paradoxically, no benefit over placebo in two well-controlled OUD trials 47,49 . Bupropion showed the most promise in StUD 50,51,54 , with limited/mixed evidence in OUD 37,48 . OUD studies had larger sample sizes (300-400) 49,57,61 . Apart from one study in CUD 33 and one in StUD 51 , all others are severely understudied, with small sample sizes. In addition, no trials have examined the long-term efficacy of interventions on smoking cessation; the longest varenicline trial was for 24 weeks in OUD 45 . Despite meta-analytic evidence supporting combination therapy in general populations 60 , combination pharmacotherapy is severely understudied in comorbid populations. Just two studies (one in CUD 31 and one in OUD 44 ) examined the impact of combining varenicline with NRT, with placebo controls. However, the CUD trial examined whether CUD influences smoking cessation 31 , and the OUD trial examined whether OUD impacts smoking cessation 44 . Similarly, only three studies (one in OUD 37 and two in StUD 50,51 ) examined the impact of combining bupropion with NRT. No studies investigated the effects of combining varenicline and bupropion. Clinical TUD treatment guidelines provide limited directions for smoking cessation treatment in people with comorbid substance use disorders 62,63 . The Treating Tobacco Use and Dependence 2008 Update and the American Thoracic Society Clinical Practice Guidelines provide collective guidance to smoking cessation treatments in people with comorbid psychiatric disorders and substance use disorders 62,63 . The Treating Tobacco Use and Dependence 2008 Update recommends that pharmacological and behavioral smoking cessation treatments are effective in people with comorbid substance use disorders 62 . It does not offer any special recommendations for smoking cessation treatments in people with comorbid substance use disorders 62 . The American Thoracic Society Clinical Practice Guidelines also provide collective guidance on smoking cessation treatments in people with comorbid psychiatric disorders and substance use disorders 63 . They recommend starting varenicline over the nicotine patch for smoking cessation in people with comorbid substance use disorders 63 . Both guidelines recommend higher NRT doses, combination NRT, combining behavioral and pharmacological interventions, extended treatment with varenicline for up to 6 months, and combining first-line medications, including varenicline and NRT, for people with severe TUD 62,63 . However, the limited number of studies makes it difficult to draw valid conclusions. Our systematic review also highlights the need for more consensus-based definitions of abstinence that can be applied consistently across trials. In 2020, the Society for Research on Nicotine and Tobacco (SRNT) Treatment Research Network updated the 2003 SRNT Biochemical Verification Report recommendations 56 . They recommended bio-verification with urine or salivary cotinine, in addition to expired CO, to measure abstinence from smoking in RCTs 56 . We found that only 4 of the 27 trials included in this review performed the recommended biochemical verification of abstinence 25,38,44,46 . Clinical Implications Evidence Quality : The current evidence is insufficient to make strong recommendations, with remarkably few placebo-controlled trials across all three disorders despite the high prevalence of comorbid smoking. Disorder-Specific Considerations : In StUD, both varenicline and bupropion showed promise and should be considered as first-line options. In CUD, varenicline may provide short-term benefit, though long-term efficacy remains unclear. In OUD, standard pharmacotherapy shows limited efficacy, with two placebo-controlled varenicline trials showing no benefit. Combination Therapy : Despite theoretical benefits and evidence in general populations, combination pharmacotherapy (varenicline + NRT or varenicline + bupropion) lacks adequate evidence in CUD, OUD, and StUD. Behavioral Interventions : CM emerges as a particularly effective behavioral component across all three disorders and should be incorporated when feasible. Extended Treatment : Given higher relapse rates, treatment duration beyond the standard 12 weeks may be warranted, though evidence supporting this approach is limited. Biochemical Verification : Routine use of both exhaled CO and cotinine testing is recommended. Integrated Treatment : Smoking cessation interventions should be integrated with substance use disorder treatment rather than delayed, as evidence suggests concurrent treatment is feasible and may benefit both conditions. Future Directions Our systematic review highlights 1) the urgent need for adequately powered, placebo-controlled trials of varenicline in CUD and StUD with ≥24-week follow-up, 2) replication of OUD varenicline findings to resolve the discrepancy between negative placebo-controlled trials and positive uncontrolled studies, and 3) combination pharmacotherapy trials examining varenicline + bupropion, varenicline + NRT at adequate doses and duration, and optimizing bupropion + NRT regimens. Trials need to have consistent biochemical verification (CO + cotinine), standardized abstinence definitions, and long-term follow-up (≥52 weeks). Our review also demonstrates significant knowledge gaps regarding the efficacy of two interventions that have shown effectiveness in the general population: cytisine (or cytisinicline) and digital therapeutics. Cytisine was more effective than NRT or placebo, but not varenicline, in the general population 64 . While one trial showed cytisine’s smoking cessation efficacy among people with AUD, no trials have examined its smoking cessation efficacy in people with CUD, OUD, or StUD 65 . More trials of cytisine are necessary to offer clinicians and tobacco treatment specialists one more pharmacological alternative for smoking cessation in people with comorbid substance use disorders. Another notable facet is the lack of studies combining pharmacological strategies with digital therapeutics for smoking cessation across CUD, OUD, and StUD 66 . Digital therapeutics encompass mobile/smartphone apps that can 1) generate daily text messages, 2) deliver behavioral interventions such as CM and CBT, or 3) provide adaptive, just-in-time interventions that provide real-time support based on a range of data indicating vulnerable situations involving craving or a risk of relapse 66,67 . The FDA recently granted breakthrough designation approval to an app (DCH-001) that supports tobacco cessation in pregnant women using CM. Given evidence of their smoking cessation efficacy in the general population 68 , these interventions can be beneficial in populations with high dropout rates in clinical trials, such as OUD and StUD. Transcranial magnetic stimulation (TMS) is also another FDA-approved intervention that could have potential utility in populations with suboptimal response rates to pharmacological smoking cessation interventions 69 . Emerging data suggest TMS could have utility in decreasing craving for cannabis, opioids, and stimulants 70 . This makes it a valuable intervention for smoking cessation in people with CUD, OUD, and StUD 70 . Limitations and Conclusions Several limitations warrant highlighting in our interpretation of the results. Substantial heterogeneity across studies in designs, populations, interventions, doses, durations, and outcome measures limits the strength of conclusions that can be drawn. Many included studies lacked rigorous placebo controls (only four placebo-controlled varenicline trials across all disorders), had small sample sizes (8 studies with n<50), and employed variable biochemical verification methods (only 4 of 27 used recommended dual verification). Most studies followed participants for 12 weeks or less, with very few extending to 24 weeks and almost none to 52 weeks, limiting assessment of long-term sustained abstinence. We could not adequately assess dose-response relationships, optimal treatment duration, or optimal combinations due to limited number of studies examining these parameters. This systematic review reveals a profound evidence gap in smoking cessation treatment for individuals with comorbid CUD, OUD, or StUD. Despite high prevalence of tobacco use and substantial mortality burden in these populations, remarkably few rigorous studies have examined pharmacological smoking cessation interventions. Across 27 included studies, we identified only four placebo-controlled varenicline trials combined across all three disorders, in stark contrast to 33 such trials in general populations. The limited available evidence suggests approved pharmacological interventions demonstrate suboptimal and variable efficacy compared to general populations. Varenicline shows most promise in StUD, short-term benefit in CUD, and no clear benefit in two placebo-controlled OUD trials. Bupropion demonstrated efficacy in StUD but limited evidence in other disorders. Combination pharmacotherapy, despite theoretical benefits, remains almost completely unstudied in these populations, with no trials examining varenicline plus bupropion. Most studies followed participants for 12 weeks or less, providing little information about sustained long-term abstinence. Current clinical practice guidelines provide insufficient disorder-specific guidance, offering only general recommendations for "substance use disorders" without acknowledging the apparent differential treatment responses across specific disorder types. CM emerges from our review as a particularly effective behavioral component that warrants emphasis in future guidelines. Urgent research priorities include: (1) adequately powered, placebo-controlled trials of single and combination pharmacotherapies with extended follow-up; (2) standardized outcome measures including dual biochemical verification; (3) investigation of novel interventions such as cytisine, digital therapeutics, and TMS; (4) mechanistic studies to understand differential treatment responses; and (5) development of disorder-specific treatment approaches. Until stronger evidence emerges, clinicians could maximize evidence-based behavioral interventions, particularly CM; consider varenicline or bupropion for StUD; use extended treatment duration; ensure adequate medication doses; maintain realistic expectations about treatment outcomes; and emphasize to patients the critical importance of smoking cessation in reducing overall mortality in these vulnerable populations. The high mortality attributable to smoking in comorbid substance use disorder populations makes this research gap a public health priority requiring immediate attention. Declarations Data availability statement – Not applicable References Smoking and Tobacco Use : Data and Statistics. https://www.cdc.gov/tobacco/data_statistics/index.htm#:~:text=Tobacco%20use%20is%20the%20leading,product%2C%20including%20e%2Dcigarettes. Cornelius ME, Loretan CG, Jamal A, et al. Tobacco Product Use Among Adults - United States, 2021. MMWR Morb Mortal Wkly Rep . May 5 2023;72(18):475-483. doi:10.15585/mmwr.mm7218a1 García-Rodríguez O, Secades-Villa R, Flórez-Salamanca L, Okuda M, Liu S-M, Blanco C. Probability and predictors of relapse to smoking: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug and Alcohol Dependence . 10/2013 2013;132(3):479-485. doi:10.1016/j.drugalcdep.2013.03.008 Shang X, E F, Guo K, et al. Effectiveness and Safety of Varenicline for Smoking Cessation: An Overview and Meta-analysis. J Addict Med . Sep-Oct 01 2023;17(5):536-543. doi:10.1097/ADM.0000000000001171 Guydish J, Passalacqua E, Tajima B, Chan M, Chun J, Bostrom A. Smoking Prevalence in Addiction Treatment: A Review. Nicotine & Tobacco Research . 2011-06-01 2011;13(6):401-411. doi:10.1093/ntr/ntr048 Daeppen JB, Smith TL, Danko GP, et al. Clinical correlates of cigarette smoking and nicotine dependence in alcohol-dependent men and women. The Collaborative Study Group on the Genetics of Alcoholism. Alcohol Alcohol . Mar-Apr 2000;35(2):171-5. doi:10.1093/alcalc/35.2.171 van Amsterdam J, van den Brink W. The effect of alcohol use on smoking cessation: A systematic review. Alcohol (Fayetteville, NY) . 2023-06 2023;109:13-22. doi:10.1016/j.alcohol.2022.12.003 van Amsterdam J, van den Brink W. Smoking As an Outcome Moderator In the Treatment of Alcohol Use Disorders. Alcohol Alcohol . Nov 11 2022;57(6):664-673. doi:10.1093/alcalc/agac027 Schauer GL, Berg CJ, Kegler MC, Donovan DM, Windle M. Differences in Tobacco Product Use Among Past Month Adult Marijuana Users and Nonusers: Findings From the 2003-2012 National Survey on Drug Use and Health. Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco . 2016-03 2016;18(3):281-288. doi:10.1093/ntr/ntv093 Zirakzadeh A, Shuman C, Stauter E, Hays J, Ebbert J. Cigarette Smoking in Methadone Maintained Patients: An Up-to-Date Review. Current Drug Abuse Reviews . 2013-06-01 2013;6(1):77-84. doi:10.2174/1874473711306010009 Weinberger AH, Sofuoglu M. The impact of cigarette smoking on stimulant addiction. Am J Drug Alcohol Abuse . 2009;35(1):12-7. doi:10.1080/00952990802326280 Nighbor TD, Coleman SRM, Bunn JY, et al. Using the Cigarette Purchase Task to examine the relative reinforcing value of cigarettes among mothers with versus without opioid dependence. Experimental and Clinical Psychopharmacology . 12/2020 2020;28(6):706-713. doi:10.1037/pha0000353 Weinberger AH, Sofuoglu M. The impact of cigarette smoking on stimulant addiction. The American Journal of Drug and Alcohol Abuse . 2009 2009;35(1):12-17. doi:10.1080/00952990802326280 Callaghan RC, Gatley JM, Sykes J, Taylor L. The prominence of smoking-related mortality among individuals with alcohol- or drug-use disorders. Drug Alcohol Rev . Jan 2018;37(1):97-105. doi:10.1111/dar.12475 Hser YI, Mooney LJ, Saxon AJ, et al. High Mortality Among Patients With Opioid Use Disorder in a Large Healthcare System. J Addict Med . Jul/Aug 2017;11(4):315-319. doi:10.1097/ADM.0000000000000312 Yi G, Javanbakht M, Rosen AD, Gorbach P, Clark J, Shoptaw S. Speed and smoking kill: A time-varying survival analysis linking methamphetamine use, cigarette smoking, and mortality in sexual minority men. Int J Drug Policy . Jun 11 2025;143:104874. doi:10.1016/j.drugpo.2025.104874 Auer R, Sidney S, Goff D, et al. Lifetime marijuana use and subclinical atherosclerosis: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Addiction . May 2018;113(5):845-856. doi:10.1111/add.14110 Thurgood SL, McNeill A, Clark-Carter D, Brose LS. A Systematic Review of Smoking Cessation Interventions for Adults in Substance Abuse Treatment or Recovery. Nicotine Tob Res . May 2016;18(5):993-1001. doi:10.1093/ntr/ntv127 Prochaska JJ, Delucchi K, Hall SM. A meta-analysis of smoking cessation interventions with individuals in substance abuse treatment or recovery. J Consult Clin Psychol . Dec 2004;72(6):1144-56. doi:10.1037/0022-006X.72.6.1144 Apollonio D, Philipps R, Bero L. Interventions for tobacco use cessation in people in treatment for or recovery from substance use disorders. Cochrane Database Syst Rev . Nov 23 2016;11(11):CD010274. doi:10.1002/14651858.CD010274.pub2 Guo K, Li J, Li J, et al. The effects of pharmacological interventions on smoking cessation in people with alcohol dependence: A systematic review and meta-analysis of nine randomized controlled trials. Int J Clin Pract . Nov 2021;75(11):e14594. doi:10.1111/ijcp.14594 Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol . Oct 2009;62(10):1006-12. doi:10.1016/j.jclinepi.2009.06.005 Auer R, Schoeni A, Jacot-Sadowski I. Electronic Nicotine-Delivery Systems for Smoking Cessation. Reply. N Engl J Med . May 16 2024;390(19):1831-1832. doi:10.1056/NEJMc2403709 Rigotti NA. Electronic Nicotine-Delivery Systems for Smoking Cessation. Reply. N Engl J Med . May 16 2024;390(19):1832. doi:10.1056/NEJMc2403709 Herrmann ES, Cooper ZD, Bedi G, et al. Varenicline and nabilone in tobacco and cannabis co-users: effects on tobacco abstinence, withdrawal and a laboratory model of cannabis relapse. Addict Biol . Jul 2019;24(4):765-776. doi:10.1111/adb.12664 Raich A, Pinet C, Ballbè M, et al. Multimodal treatment for smoking cessation with varenicline in alcoholic, methadone-maintained, and psychotic patients: A one-year follow-up. Tobacco Induced Diseases . 2018 2018;16:58. doi:10.18332/tid/99541 Lee DC, Walker DD, Hughes JR, et al. Sequential and simultaneous treatment approaches to cannabis use disorder and tobacco use. J Subst Abuse Treat . Mar 2019;98:39-46. doi:10.1016/j.jsat.2018.12.005 Beckham JC, Adkisson KA, Hertzberg J, et al. Mobile contingency management as an adjunctive treatment for co-morbid cannabis use disorder and cigarette smoking. Addict Behav . Apr 2018;79:86-92. doi:10.1016/j.addbeh.2017.12.007 Adams TR, Arnsten JH, Ning Y, Nahvi S. Feasibility and Preliminary Effectiveness of Varenicline for Treating Co-Occurring Cannabis and Tobacco Use. J Psychoactive Drugs . Jan-Mar 2018;50(1):12-18. doi:10.1080/02791072.2017.1370746 Lee DC, Budney AJ, Brunette MF, Hughes JR, Etter JF, Stanger C. Outcomes from a computer-assisted intervention simultaneously targeting cannabis and tobacco use. Drug Alcohol Depend . Oct 1 2015;155:134-40. doi:10.1016/j.drugalcdep.2015.08.001 Rabin RA, Ashare RL, Schnoll RA, et al. Does cannabis use moderate smoking cessation outcomes in treatment-seeking tobacco smokers? Analysis from a large multi-center trial. Am J Addict . Jun 2016;25(4):291-6. doi:10.1111/ajad.12382 McClure EA, Baker NL, Sonne SC, et al. Tobacco use during cannabis cessation: Use patterns and impact on abstinence in a National Drug Abuse Treatment Clinical Trials Network study. Drug Alcohol Depend . Nov 1 2018;192:59-66. doi:10.1016/j.drugalcdep.2018.07.018 Rabin RA, Ashare RL, Schnoll RA, et al. Does cannabis use moderate smoking cessation outcomes in treatment-seeking tobacco smokers? Analysis from a large multi-center trial. The American Journal on Addictions . 2016-06 2016;25(4):291-296. doi:10.1111/ajad.12382 Hall SM, Humfleet GL, Gasper JJ, Delucchi KL, Hersh DF, Guydish JR. Cigarette Smoking Cessation Intervention for Buprenorphine Treatment Patients. Nicotine Tob Res . Apr 2 2018;20(5):628-635. doi:10.1093/ntr/ntx113 Felicione NJ, Ozga JE, Dino G, Berry JH, Sullivan CR, Blank MD. Timing of smoking cessation treatment integrated into outpatient treatment with medications for opioid use disorder: Feasibility trial. J Subst Abuse Treat . Jan 2022;132:108579. doi:10.1016/j.jsat.2021.108579 Cooperman NA, Lu SE, Richter KP, Bernstein SL, Williams JM. Pilot Study of a Tailored Smoking Cessation Intervention for Individuals in Treatment for Opioid Dependence. Nicotine Tob Res . Aug 14 2018;20(9):1152-1156. doi:10.1093/ntr/ntx189 Richter KP, McCool RM, Catley D, Hall M, Ahluwalia JS. Dual pharmacotherapy and motivational interviewing for tobacco dependence among drug treatment patients. J Addict Dis . 2005;24(4):79-90. doi:10.1300/j069v24n04_06 Shoptaw S, Rotheram-Fuller E, Yang XW, et al. Smoking cessation in methadone maintenance. Addiction . Oct 2002;97(10):1317-1328. doi:DOI 10.1046/j.1360-0443.2002.00221.x Mooney ME, Poling J, Gonzalez G, Gonsai K, Kosten T, Sofuoglu M. Preliminary study of buprenorphine and bupropion for opioid-dependent smokers. Am J Addict . Jul-Aug 2008;17(4):287-92. doi:10.1080/10550490802138814 Stein MD, Weinstock MC, Herman DS, Anderson BJ, Anthony JL, Niaura R. A smoking cessation intervention for the methadone-maintained. Addiction . Apr 2006;101(4):599-607. doi:10.1111/j.1360-0443.2006.01406.x Montgomery L, Winhusen T, Scodes J, et al. Reductions in tobacco use in naltrexone, relative to buprenorphine-maintained individuals with opioid use disorder: Secondary analysis from the National Drug Abuse Treatment Clinical Trials Network. J Subst Abuse Treat . Nov 2021;130:108489. doi:10.1016/j.jsat.2021.108489 Lee SW, Yu PC, Yen TT, et al. Impact of the Ottawa model on opiate screening and smoking cessation in methadone-treated patients with opioid use disorder: A retrospective cohort analysis. Tob Induc Dis . 2024;22doi:10.18332/tid/191247 Stein MD, Caviness CM, Kurth ME, Audet D, Olson J, Anderson BJ. Varenicline for smoking cessation among methadone-maintained smokers: a randomized clinical trial. Drug Alcohol Depend . Dec 1 2013;133(2):486-93. doi:10.1016/j.drugalcdep.2013.07.005 Martin RA, Rohsenow DJ, Tidey JW. Smokers with opioid use disorder may have worse drug use outcomes after varenicline than nicotine replacement. Journal of Substance Abuse Treatment . 2019-09 2019;104:22-27. doi:10.1016/j.jsat.2019.06.005 Nahvi S, Adams TR, Ning Y, Zhang C, Arnsten JH. Effect of varenicline directly observed therapy versus varenicline self-administered therapy on varenicline adherence and smoking cessation in methadone-maintained smokers: a randomized controlled trial. Addiction (Abingdon, England) . 2021-04 2021;116(4):902-913. doi:10.1111/add.15240 Dunn KE, Sigmon SC, Reimann EF, Badger GJ, Heil SH, Higgins ST. A contingency-management intervention to promote initial smoking cessation among opioid-maintained patients. Exp Clin Psychopharmacol . Feb 2010;18(1):37-50. doi:10.1037/a0018649 Nahvi S, Ning Y, Segal KS, Richter KP, Arnsten JH. Varenicline efficacy and safety among methadone maintained smokers: a randomized placebo-controlled trial: Varenicline RCT among methadone patients. Addiction . 09/2014 2014;109(9):1554-1563. doi:10.1111/add.12631 Mooney ME, Poling J, Gonzalez G, Gonsai K, Kosten T, Sofuoglu M. Preliminary study of buprenorphine and bupropion for opioid-dependent smokers. The American Journal on Addictions . 2008 2008;17(4):287-292. doi:10.1080/10550490802138814 Stein MD, Caviness CM, Kurth ME, Audet D, Olson J, Anderson BJ. Varenicline for smoking cessation among methadone-maintained smokers: A randomized clinical trial. Drug and Alcohol Dependence . 12/2013 2013;133(2):486-493. doi:10.1016/j.drugalcdep.2013.07.005 Winhusen TM, Kropp F, Theobald J, Lewis DF. Achieving smoking abstinence is associated with decreased cocaine use in cocaine-dependent patients receiving smoking-cessation treatment. Drug and Alcohol Dependence . 2014-01-01 2014;134:391-395. doi:10.1016/j.drugalcdep.2013.09.019 Winhusen TM, Brigham GS, Kropp F, et al. A randomized trial of concurrent smoking-cessation and substance use disorder treatment in stimulant-dependent smokers. The Journal of Clinical Psychiatry . 2014-04 2014;75(4):336-343. doi:10.4088/JCP.13m08449 De la Garza R, Yoon JH. Evaluation of the effects of rivastigmine on cigarette smoking by methamphetamine-dependent volunteers. Progress in Neuro-Psychopharmacology & Biological Psychiatry . 2011-12-01 2011;35(8):1827-1830. doi:10.1016/j.pnpbp.2011.07.006 Poling J, Rounsaville B, Gonsai K, Severino K, Sofuoglu M. The safety and efficacy of varenicline in cocaine using smokers maintained on methadone: a pilot study. Am J Addict . Sep-Oct 2010;19(5):401-8. doi:10.1111/j.1521-0391.2010.00066.x Schmitz JM, Stotts AL, Yoon JH, et al. Naltrexone plus bupropion reduces cigarette smoking in individuals with methamphetamine use disorder: A secondary analysis from the CTN ADAPT-2 trial. J Subst Use Addict Treat . Aug 2023;151:208987. doi:10.1016/j.josat.2023.208987 Shoptaw S, Rotheram-Fuller E, Yang X, et al. Smoking cessation in methadone maintenance. Addiction (Abingdon, England) . 2002-10 2002;97(10):1317-1328; discussion 1325. doi:10.1046/j.1360-0443.2002.00221.x Piper ME, Bullen C, Krishnan-Sarin S, et al. Defining and Measuring Abstinence in Clinical Trials of Smoking Cessation Interventions: An Updated Review. Nicotine Tob Res . Jun 12 2020;22(7):1098-1106. doi:10.1093/ntr/ntz110 Montgomery L, Winhusen T, Scodes J, et al. Reductions in tobacco use in naltrexone, relative to buprenorphine-maintained individuals with opioid use disorder: Secondary analysis from the National Drug Abuse Treatment Clinical Trials Network. Journal of Substance Abuse Treatment . 2021-11 2021;130:108489. doi:10.1016/j.jsat.2021.108489 Secades-Villa R, Aonso-Diego G, Garcia-Perez A, Gonzalez-Roz A. Effectiveness of contingency management for smoking cessation in substance users: A systematic review and meta-analysis. J Consult Clin Psychol . Oct 2020;88(10):951-964. doi:10.1037/ccp0000611 Zamboni L, Centoni F, Fusina F, et al. The Effectiveness of Cognitive Behavioral Therapy Techniques for the Treatment of Substance Use Disorders: A Narrative Review of Evidence. J Nerv Ment Dis . Nov 1 2021;209(11):835-845. doi:10.1097/NMD.0000000000001381 Li Y, Gao L, Chao Y, et al. Effects of interventions on smoking cessation: A systematic review and network meta-analysis. Addict Biol . Mar 2024;29(3):e13376. doi:10.1111/adb.13376 Stein MD, Anderson BJ, Niaura R. Smoking cessation patterns in methadone-maintained smokers. Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco . 2007-03 2007;9(3):421-428. doi:10.1080/14622200701188885 Phs Guideline Update Panel L, Staff. Treating tobacco use and dependence: 2008 update U.S. Public Health Service Clinical Practice Guideline executive summary. Respir Care . Sep 2008;53(9):1217-22. Leone FT, Zhang Y, Evers-Casey S, et al. Initiating Pharmacologic Treatment in Tobacco-Dependent Adults. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med . Jul 15 2020;202(2):e5-e31. doi:10.1164/rccm.202005-1982ST Puljevic C, Stjepanovic D, Meciar I, et al. Systematic review and meta-analyses of cytisine to support tobacco cessation. Addiction . Oct 2024;119(10):1713-1725. doi:10.1111/add.16592 Tindle HA, Freiberg MS, Cheng DM, et al. Effectiveness of Varenicline and Cytisine for Alcohol Use Reduction Among People With HIV and Substance Use: A Randomized Clinical Trial. JAMA Netw Open . Aug 1 2022;5(8):e2225129. doi:10.1001/jamanetworkopen.2022.25129 Naughton F, Nadkarni A. The Contribution of Digital Treatment to Efforts to Reduce Global Tobacco Use. N Engl J Med . Oct 16 2025;393(15):1449-1452. doi:10.1056/NEJMp2500683 Hebert ET, Kendzor DE, Vidrine DJ, et al. Just-in-Time Adaptive Intervention for Smoking Cessation in Low-Income Adults: A Randomized Clinical Trial. JAMA Netw Open . Aug 1 2025;8(8):e2526691. doi:10.1001/jamanetworkopen.2025.26691 Li S, Li Y, Xu C, et al. Efficacy of digital interventions for smoking cessation by type and method: a systematic review and network meta-analysis. Nat Hum Behav . Oct 2025;9(10):2054-2065. doi:10.1038/s41562-025-02295-2 Zangen A, Moshe H, Martinez D, et al. Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial. World Psychiatry . Oct 2021;20(3):397-404. doi:10.1002/wps.20905 Mehta DD, Praecht A, Ward HB, et al. A systematic review and meta-analysis of neuromodulation therapies for substance use disorders. Neuropsychopharmacology . Mar 2024;49(4):649-680. doi:10.1038/s41386-023-01776-0 Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryTable2.docx Table 2. Risk of Bias in Observational Cohort Studies/secondary analyses of RCTs SupplementaryTable2.docx Table 2. Risk of Bias in Observational Cohort Studies/secondary analyses of RCTs SupplementaryTable4.docx Table 4. Search Terms SupplementaryTable1.docx Table 1. Characteristics of Studies Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9141564","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":607160300,"identity":"680192da-f0b6-4711-a048-d5af1203b233","order_by":0,"name":"Nicole Brar, MD","email":"","orcid":"","institution":"University of Kentucky College of Medicine, Lexington, KY","correspondingAuthor":false,"prefix":"","firstName":"Nicole","middleName":"","lastName":"Brar","suffix":"MD"},{"id":607160301,"identity":"aae10e05-9da6-4aea-bf1b-7844f7b0f792","order_by":1,"name":"Imamhulhaq Brula, BS","email":"","orcid":"","institution":"University of Kentucky College of Medicine, Lexington, KY","correspondingAuthor":false,"prefix":"","firstName":"BS","middleName":"Imamhulhaq","lastName":"Brula","suffix":""},{"id":607160302,"identity":"e7676d4c-2477-45a2-9456-72156812129d","order_by":2,"name":"Dylan H Ballard, MD","email":"","orcid":"","institution":"Primary Plus FQHC, Maysville, KY","correspondingAuthor":false,"prefix":"","firstName":"Dylan","middleName":"H","lastName":"Ballard","suffix":"MD"},{"id":607160303,"identity":"13d240df-6aec-4f9b-a2da-bd0d4ad9835d","order_by":3,"name":"Brittany Musselwhite, MD","email":"","orcid":"","institution":"Trinity Health Livonia Hospital, Livonia, MI","correspondingAuthor":false,"prefix":"","firstName":"Brittany","middleName":"","lastName":"Musselwhite","suffix":"MD"},{"id":607160304,"identity":"da9956de-e3df-40b7-9a4c-5971b5aba542","order_by":4,"name":"Gopalkumar Rakesh, MD","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYLCCBwdgLCDDgL2BGcRkbMCnJQFFC88BkrVIJODXIu/ee/BDwpnD0fyzD7B9+HHGxt5c8o2xMQ+DjeyGA9i1GJ45lyyRcONw7oxzCcwze26kJe6cnWOczMOQZoxTy4wcoEs+HM5tOMPAzMDz4XCCwe0c48M8DIcT8Wgx/gHSMh+ohfHPh//2BjfPgLT8x6lFXiLHDOywDUAtzDw3DjBuuMEDctgBnFoMeM6lWSScSc/deIaxmVnmTHLihjNpxYZzDJKNZ+Kypb338I0Px6xz551hPsz45pidvcHxw5sl3lTYyfbhsuUAD4yJFBFMPAbYlYNtaeDBIsr4A7eOUTAKRsEoGHkAALTzaqfHffrAAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7134-2804","institution":"University of Kentucky College of Medicine, Lexington, KY","correspondingAuthor":true,"prefix":"","firstName":"Gopalkumar","middleName":"","lastName":"Rakesh","suffix":"MD"}],"badges":[],"createdAt":"2026-03-16 20:09:50","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9141564/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9141564/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104888039,"identity":"93d5b1cd-0de4-43e9-9d69-0a73ea4dec97","added_by":"auto","created_at":"2026-03-18 10:13:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":135846,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for \u0026nbsp;figure legend.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9141564/v1/a71a1724d4f12177709f03cb.png"},{"id":104887942,"identity":"87c04021-f95f-4ab4-8178-2f3b03943482","added_by":"auto","created_at":"2026-03-18 10:12:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":300144,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for \u0026nbsp;figure legend.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9141564/v1/8fdf3483411f4a83a2bd9a7a.png"},{"id":104888076,"identity":"d411668c-9b2f-4dd3-ad59-5c115c1baa7c","added_by":"auto","created_at":"2026-03-18 10:13:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1008409,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9141564/v1/07e88ccd-c192-4417-9262-0729dd6e000c.pdf"},{"id":104887860,"identity":"524bbe64-0dca-44fc-9a89-a0661156cfa6","added_by":"auto","created_at":"2026-03-18 10:12:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20969,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2. Risk of Bias in Observational Cohort Studies/secondary analyses of RCTs\u003c/p\u003e","description":"","filename":"SupplementaryTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9141564/v1/2eb1930c991a092578c521ce.docx"},{"id":104887947,"identity":"2542b315-7bd1-469e-8a99-bfe14d7aaaf0","added_by":"auto","created_at":"2026-03-18 10:13:00","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20969,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2. Risk of Bias in Observational Cohort Studies/secondary analyses of RCTs\u003c/p\u003e","description":"","filename":"SupplementaryTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9141564/v1/36f7e277183bf0c110c1e234.docx"},{"id":104887956,"identity":"1b136184-f6b7-46d4-9d20-0571d523fbd6","added_by":"auto","created_at":"2026-03-18 10:13:03","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19670,"visible":true,"origin":"","legend":"\u003cp\u003eTable 4. Search Terms\u003c/p\u003e","description":"","filename":"SupplementaryTable4.docx","url":"https://assets-eu.researchsquare.com/files/rs-9141564/v1/738268b6b72b7b1cb2ff3748.docx"},{"id":104887910,"identity":"975133a9-8bb9-40cc-a9a8-3d4f3b24019e","added_by":"auto","created_at":"2026-03-18 10:12:56","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":50324,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1. Characteristics of Studies\u003c/p\u003e","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9141564/v1/c7e506346aab8e73af31ab36.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003ePharmacological Smoking Cessation Interventions in People with Cannabis, Opioid, or Stimulant Use Disorders: A Systematic Review\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eTobacco use disorder (TUD) is the leading cause of preventable disability, disease, and death in the USA\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Approximately 18.7% of adults in the United States use a tobacco product, with the majority smoking cigarettes (11.5%) and the rest using e-cigarettes (4.5%), cigars (3.5%), smokeless tobacco (2.1%), and pipes (0.9%)\u003csup\u003e2\u003c/sup\u003e. Despite the availability of smoking cessation interventions, 50\u0026ndash;60% of people who quit smoking cigarettes relapse after a year\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Even varenicline, perhaps the most effective medication for smoking cessation, has suboptimal long-term efficacy with an abstinence rate of 27.9% at twelve months, compared to six months (38.6%) and three months (43.8%)\u003csup\u003e4\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCigarette smoking has a bidirectional association with alcohol use disorder (AUD), cannabis use disorder (CUD), opioid use disorder (OUD), and stimulant use disorder (StUD), encompassing cocaine and methamphetamine\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Smoking prevalence is remarkably high across these populations- AUD (60\u0026ndash;80%)\u003csup\u003e6\u0026ndash;8\u003c/sup\u003e, CUD (75%)\u003csup\u003e9\u003c/sup\u003e, OUD (74 to 94%)\u003csup\u003e10\u003c/sup\u003e, and StUD (87 to 92%)\u003csup\u003e11\u003c/sup\u003e. Moreover, the presence of these substance use disorders intensifies smoking severity\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, while cigarette smoking compounds the health burden in individuals with comorbid substance use disorders\u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe mortality implications are particularly striking. Patients with AUD, OUD, and StUD who smoke experience higher mortality from smoking-related illnesses compared with non-smoking patients with these same disorders\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Among those with OUD, concurrent smoking increases cardiovascular mortality risk 2.6-fold\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e, while in methamphetamine use disorder, smoking triples overall mortality risk\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Even with CUD, adding cigarette smoking significantly elevates atherosclerosis risk compared with CUD alone\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite a repertoire of pharmacological and behavioral interventions for smoking cessation, there is a significant gap in optimal smoking cessation strategies in patients with other substance use disorders, as shown by previous systematic reviews\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Given that a recent meta-analysis summarized the available evidence regarding the efficacy of pharmacological smoking cessation interventions in patients with AUD, we focused on other substance use disorders (CUD, OUD, and StUD)\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. While previous systematic reviews examined smoking cessation interventions broadly, the most recent was published in 2016\u003csup\u003e18,20\u003c/sup\u003e, and we specifically focused on pharmacological treatments to better characterize their efficacy in CUD, OUD, and StUD. The primary objective of this systematic review is to summarize evidence from studies examining approved pharmacological smoking cessation interventions alone or in combination with behavioral smoking cessation interventions in patients with other substance use disorders (CUD, OUD, and StUD).\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eWe registered the systematic review on PROSPERO (CRD42023467758). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to determine eligibility criteria for studies, conduct the search, and critically evaluate the included studies\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. We searched three databases (PubMed/Medline, Google Scholar, and EMBASE) using specific MeSH search terms listed in \u003cb\u003eSupplementary Material Table\u0026nbsp;4\u003c/b\u003e. All studies were published between January 1st, 2000, and September 30th, 2024. All studies were published in English and screened by two authors (NCG and BM) for titles, abstracts, and full texts before deciding whether to include or exclude each study. Disagreements were resolved through discussions with a third reviewer (GR).\u003c/p\u003e \u003cp\u003eWe included studies that met the following inclusion criteria: 1) Used approved pharmacological interventions alone or in combination with behavioral interventions for smoking cessation; 2) Participants were diagnosed with TUD and a comorbid substance use disorder, which included OUD, CUD, or StUD. We excluded the following studies\u0026ndash;1) Case reports and case series; 2) studies that used approved smoking cessation strategies to treat CUD, OUD, or StUD; 3) studies that examined smoking cessation interventions in treatment facilities encompassing people with substance use disorders but did not provide information on specific comorbid substance use disorders; 4) studies that solely examined the efficacy or effectiveness of behavioral interventions for smoking cessation in people with comorbid substance use disorders; and 5) studies examining the utility of electronic nicotine delivery systems (ENDS) in people with these comorbid substance use disorders, given mixed data on their utility/efficacy and lack of approval for smoking cessation\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe reviewed studies across three disorders \u0026ndash; CUD, OUD, and StUD. Data extraction was performed independently by two reviewers (NB and BM) using a standardized, piloted data extraction form. Extracted data included: study design, participant characteristics (sample size, demographics, disorder type, concurrent treatment), intervention details (pharmacological agents, doses, duration, behavioral components), comparator/control details, outcome measures and definitions, biochemical verification methods, follow-up timing, results (abstinence rates, cigarettes per day, quit attempts), and adverse events.\u003c/p\u003e \u003cp\u003eThe quality of RCTs was assessed using the Cochrane Risk of Bias 2.0 and classified as low, some concerns, or high. The NIH Quality Assessment Tool was used to determine the quality of observational cohort studies/secondary analyses of RCTs, and pre-post studies with no control group. Two reviewers (DB and IB) independently assessed the risk of bias in the included studies using these tools. Studies were rated as having low, moderate, or high risk of bias. Disagreements were resolved through discussion or consultation with a third reviewer (GR).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e \u003cb\u003eFigure 1\u003c/b\u003e illustrates the PRISMA diagram outlining the selection process for the studies included in this review. We identified 1,347 English-language studies published between January 1, 2000, and September 30, 2024. We removed duplicates and selected 27 articles that fulfilled our eligibility criteria from 628 unique articles. The 27 articles included in the qualitative synthesis, encompassed 1) comorbid CUD and TUD (n\u0026thinsp;=\u0026thinsp;7); 2) comorbid OUD and TUD (n\u0026thinsp;=\u0026thinsp;15); and 3) comorbid StUD and TUD (n\u0026thinsp;=\u0026thinsp;5) (\u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e). These studies enrolled between 5 and 538 participants (median: 100). Studies in OUD were most numerous (n\u0026thinsp;=\u0026thinsp;15, 54%) and generally had larger sample sizes, while CUD (n\u0026thinsp;=\u0026thinsp;7, 26%) and StUD (n\u0026thinsp;=\u0026thinsp;5, 19%) studies were fewer and typically smaller. Follow-up duration across the three disorders ranged from 15 days\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e to 18 months\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e[\u003cb\u003eFigure 1\u003c/b\u003e]\u003c/p\u003e\n\u003ch3\u003eComorbid CUD and TUD\u003c/h3\u003e\n\u003cp\u003eSeven studies examined the impact of pharmacological smoking cessation interventions alone or in combination with behavioral interventions in people with CUD and TUD\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan additionalcitationids=\"CR28 CR29 CR30 CR31\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e (\u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e). Three studies used nicotine replacement therapy (NRT)\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, one combined NRT with varenicline\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, two used solely varenicline\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, and one used N-acetylcysteine\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. The behavioral interventions included cognitive-behavioral therapy (CBT), contingency management (CM), motivational enhancement therapy (MET), and general behavioral counseling\u003csup\u003e\u003cspan additionalcitationids=\"CR28 CR29 CR30\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Of the five studies that utilized behavioral interventions in combination with pharmacology, two combined computer-assisted CBT, CM, and MET\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, one combined CBT and CM\u003csup\u003e28\u003c/sup\u003e, one more combined MET and CBT\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, and one delivered general behavioral counseling\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVarenicline was examined in three studies with varying designs and durations (\u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e) \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. The only placebo-controlled trial (n\u0026thinsp;=\u0026thinsp;108) demonstrated significantly higher abstinence in the varenicline group (46%) compared to placebo (24%) at 2 weeks following just 8 days of treatment, notably the shortest treatment duration and follow-up period among all included studies, limiting conclusions about sustained abstinence\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Adams 2018 examined varenicline feasibility in a small crossover trial (n\u0026thinsp;=\u0026thinsp;7) and found comparable reductions in cigarettes per day with both standard clinical care alone and standard clinical care plus varenicline\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Rabin et al (n\u0026thinsp;=\u0026thinsp;440) found that comorbid CUD did not moderate smoking cessation outcomes in individuals receiving varenicline and brief counseling, with similar abstinence rates in those with and without CUD (23.6% vs 26.5%)\u003csup\u003e31\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eComorbid OUD and TUD\u003c/h3\u003e\n\u003cp\u003eFifteen studies were included in the qualitative synthesis\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan additionalcitationids=\"CR35 CR36 CR37 CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e (\u003cb\u003eSupplementary Table\u0026nbsp;1)\u003c/b\u003e. Four studies used pharmacological smoking cessation interventions alone, without behavioral interventions\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Of these four studies, two used varenicline\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. The other two: 1) compared the effects of naltrexone versus buprenorphine plus naloxone on smoking cessation outcomes\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, and 2) compared the effects of bupropion and placebo on smoking cessation in patients stabilized on buprenorphine\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEleven of 15 studies utilized behavioral interventions in combination with pharmacological interventions\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan additionalcitationids=\"CR35 CR36 CR37\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. One used CM exclusively\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e, one utilized a combination of MET and CBT\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, one used CM with psychoeducation to enhance coping and relapse prevention skills\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, and three used MET with education on relapse prevention strategies\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Three studies utilized the National Cancer Institute\u0026rsquo;s \u0026ldquo;5 A\u0026rsquo;s\u0026rdquo; of smoking cessation\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e, one employed text messaging\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, and one used brief counseling sessions by a tobacco specialist\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. One study provided computerized motivational feedback and extended CBT within an innovative system intervention (ISI), which was compared to a standard treatment control (STC)\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. The E-ISI, based on the Expert System, comprised pharmacological treatments like NRT and varenicline, if needed, in addition to extended CBT\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Participants in the E-ISI arm demonstrated greater abstinence (13.4%) compared to 3.7% in the STC arm at 3 months, but not at 6, 12, or 18 months\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFour studies used NRT in combination with behavioral interventions, with no significant differences in abstinence between treatment and control groups\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Three studies examined the impact of bupropion for smoking cessation, either alone\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e or in combination with motivational interviewing\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e or contingency management\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. Bupropion\u0026rsquo;s effects on smoking cessation were suboptimal across these three studies \u0026ndash; 1) an open-label trial (combining 7 weeks of bupropion 300 mg, 12 weeks of NRT, and six sessions of motivational interviewing)\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, 2) a double-blind RCT comparing bupropion to placebo in patients on buprenorphine\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, and 3) a trial that used contingency management but had bupropion as an option patients on methadone could add on\u003csup\u003e46\u003c/sup\u003e. Although the number of cigarettes smoked decreased from 22 to 10 in the open-label trial\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e and abstinence was greater with people who added bupropion in the trial\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e, the RCT did not find significant differences in smoking abstinence between bupropion and placebo\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeven studies examined the efficacy of varenicline in OUD\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan additionalcitationids=\"CR43 CR44\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Of these seven, two studies were RCTs that compared the efficacy of varenicline to placebo in people with OUD on methadone\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. Of the remaining five studies, three did not have placebo arms\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. One entailed secondary analyses of data acquired in a clinical trial investigating the impact of combining varenicline and NRT for smoking cessation in patients with or without OUD\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Another study was a retrospective analysis of varenicline\u0026rsquo;s efficacy for smoking cessation in patients with OUD, on methadone\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVarenicline demonstrated suboptimal efficacy (compared to the general population) across three trials that lacked placebo arms\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. In a study that compared self-administered varenicline (n\u0026thinsp;=\u0026thinsp;50) versus directly observed therapy with varenicline (n\u0026thinsp;=\u0026thinsp;50) in participants with OUD and smoking cigarettes, 28/100 participants were abstinent at the end of 12 weeks across both arms\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Meanwhile, in a cross-sectional study that provided varenicline to 35 participants with OUD who smoke, the number of cigarettes smoked per day decreased from 20 to 8 in 12 weeks\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Although the goal of the study was to examine the acceptability of varenicline and not abstinence, they did observe 3 participants to be abstinent at the end of 12 weeks, as evidenced by expired CO\u0026thinsp;\u0026lt;\u0026thinsp;5 PPM\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. In a study that administered varenicline to three groups of participants (psychosis, AUD, and OUD on methadone) for 12 weeks after the quit date, participants with OUD on methadone had the lowest probability of abstinence from smoking compared to the other two groups\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAmong RCTs comparing varenicline to placebo, one compared varenicline to placebo in 315 participants, divided into three arms: receiving 24 weeks of varenicline, a combination of NRT (patch plus gum), or placebo\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. The NRT group was found to have the highest abstinence at 24 weeks (8.3%), while the varenicline group saw 3.7% abstinence, and the placebo group had 2.2%\u003csup\u003e43\u003c/sup\u003e. However, none of the groups showed significant differences in abstinence\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. The other clinical trial compared varenicline and placebo, with 10.5% in the varenicline arm demonstrating biochemically verified abstinence, and no person in the sham arm demonstrating abstinence at the end of 12 weeks\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn a study comparing the effects of naltrexone versus buprenorphine plus naloxone on smoking cessation, those in the naltrexone group smoked fewer cigarettes per day than those in the buprenorphine-naloxone group (11.36 versus 13.33)\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eComorbid StUD and TUD\u003c/h3\u003e\n\u003cp\u003eFive studies were included in the qualitative synthesis\u003csup\u003e\u003cspan additionalcitationids=\"CR51 CR52 CR53\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e (\u003cb\u003eSupplementary Table\u0026nbsp;1)\u003c/b\u003e. Two studies used pharmacological interventions in combination with behavioral interventions (CM, counseling) for smoking cessation in people with stimulant use disorder who smoke\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e, and three studies used pharmacological interventions alone\u003csup\u003e\u003cspan additionalcitationids=\"CR53\" citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. Two studies evaluated the effectiveness of bupropion as an add-on treatment for smoking cessation\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. Both studies showed significantly higher abstinence with add-on bupropion to treatment as usual (TAU) at the end of 10 weeks, and at follow-up periods of 3 months and 6 months\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. One study examined rivastigmine for smoking cessation, with no apparent benefit to participants\u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite representing only five studies with sample sizes ranging from 13 to 538 participants, the StUD evidence showed the most consistently promising pharmacological results\u003csup\u003e\u003cspan additionalcitationids=\"CR51 CR52 CR53\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. The sole placebo-controlled varenicline trial (n\u0026thinsp;=\u0026thinsp;31) in cocaine use disorder patients maintained on methadone demonstrated substantial benefits: 52.8% reduction in daily cigarettes smoked with varenicline versus only 8.0% with placebo (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), significantly more weeks engaged in nonsmoking behavior (44.2% vs 14.8%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and significant FTND score reductions\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBupropion demonstrated efficacy in two trials by Winhusen and colleagues\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. In the larger trial (n\u0026thinsp;=\u0026thinsp;538), participants receiving treatment-as-usual plus smoking cessation treatment (bupropion, NRT inhaler, counseling, and CM) achieved substantially higher abstinence rates than those receiving treatment-as-usual alone: 25.5% versus 2.2% at 10 weeks, 19.1% versus 3.0% at 3 months, and 13.1% versus 3.7% at 6 months, representing the highest sustained abstinence rates observed across all three disorders in this review\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe combination of extended-release bupropion 450 mg/day and injectable extended-release naltrexone (380 mg every three weeks) decreased smoking behaviors in participants with methamphetamine use disorder over the course of 12 weeks\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. Smoking behaviors were secondary outcomes in this study\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eQuality of included studies: Risk of Bias\u003c/h3\u003e\n\u003cp\u003eOf 14 RCTs across CUD, OUD, and StUD, one was deemed low bias\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e, two were deemed to be of some concern\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e, and the remaining 11 were considered high bias (Fig.\u0026nbsp;2). Among the observational cohort studies, secondary analyses of RCTs, and pre-post studies with no control group, two were deemed to be good\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e and all others fair (\u003cb\u003eSupplementary Tables\u0026nbsp;2 and 3\u003c/b\u003e).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measures to Measure Smoking Behaviors\u003c/h2\u003e \u003cp\u003eStudies were not consistent in their outcome measures (\u003cb\u003eSupplementary Table\u0026nbsp;1)\u003c/b\u003e. The most common outcome measures reported across studies were 1) self-reported abstinence, 2) self-reported quit attempts, or 3) the number of cigarettes smoked every day. Abstinence, if measured, was commonly quantified using point prevalence abstinence (PPA) over the last 7 days, with the timeline follow-back (TLFB) method. This was verified biochemically with either exhaled carbon monoxide (CO) and/or salivary/urine cotinine.\u003c/p\u003e \u003cp\u003eThe most common method of biochemical verification used in the studies included in this review was expired CO (22 of 27 studies), followed by salivary/urine cotinine (7 of 27 studies) \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. Two studies utilized urine anatabine/anabasine assays\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e to verify abstinence while on NRT biochemically\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Although 7 out of 27 studies measured salivary or urine cotinine, only 4 studies performed the recommended biochemical verification using both exhaled CO and salivary or urine cotinine\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e consistently for all trial participants\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. The cutoff values for exhaled CO for biochemical verification varied from 4 to 10 parts per million (PPM). Salivary cotinine cutoff levels ranged from 10 to 15 ng/ml, and the urine cotinine cutoff value was 30 ng/ml across studies. Four of 27 studies included in the qualitative synthesis did not perform any biochemical verification of abstinence\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e,\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe goal of our systematic review was to examine the efficacy of\u0026nbsp;pharmacological interventions, alone or in combination with behavioral interventions, for smoking cessation in patients with other substance use disorders (OUD, CUD, and StUD). Optimizing smoking cessation in individuals with comorbid substance use disorders is crucial, given the mortality imposed by smoking in people with comorbid substance use disorders\u003csup\u003e14\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeventeen of 27 studies included in this review combined pharmacological and behavioral smoking cessation interventions in people with CUD (n=5), OUD (n=10), and StUD (n=2)\u003csup\u003e26-31,34-38,40,42,43,46,50,51\u003c/sup\u003e. \u0026nbsp;Common behavioral interventions in studies were CM\u003csup\u003e58\u003c/sup\u003e, CBT\u003csup\u003e59\u003c/sup\u003e, and MET\u003csup\u003e60\u003c/sup\u003e.\u0026nbsp;Unfortunately, with variability in study designs, there is a paucity of placebo-controlled trials examining approved efficacious pharmacological smoking cessation interventions in people with CUD, OUD, and StUD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDespite being our most efficacious treatment for smoking cessation\u003csup\u003e4\u003c/sup\u003e, with 33 placebo-controlled trials for varenicline in people without comorbid illnesses\u003csup\u003e4\u003c/sup\u003e, we found just one RCT examining varenicline in CUD for 2 weeks\u003csup\u003e25\u003c/sup\u003e, two in OUD for 12 weeks\u003csup\u003e47\u003c/sup\u003e and 24 weeks\u003csup\u003e49\u003c/sup\u003e, and one in StUD for 12 weeks\u003csup\u003e53\u003c/sup\u003e. Varenicline showed most promise in StUD\u003csup\u003e53\u003c/sup\u003e, short-term benefit in CUD\u003csup\u003e25\u003c/sup\u003e, and, paradoxically, no benefit over placebo in two well-controlled OUD trials\u003csup\u003e47,49\u003c/sup\u003e.\u0026nbsp;Bupropion showed the most promise in StUD\u003csup\u003e50,51,54\u003c/sup\u003e, with limited/mixed evidence in OUD\u003csup\u003e37,48\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOUD studies had larger sample sizes (300-400)\u003csup\u003e49,57,61\u003c/sup\u003e. Apart from one study in CUD\u003csup\u003e33\u003c/sup\u003e and one in StUD\u003csup\u003e51\u003c/sup\u003e, all others are severely understudied, with small sample sizes. In addition, no trials have examined the long-term efficacy of interventions on smoking cessation; the longest varenicline trial was for 24 weeks in OUD\u003csup\u003e45\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Despite meta-analytic evidence supporting combination therapy in general populations\u003csup\u003e60\u003c/sup\u003e, combination pharmacotherapy is severely understudied in comorbid populations. Just two studies (one in CUD\u003csup\u003e31\u003c/sup\u003e and one in OUD\u003csup\u003e44\u003c/sup\u003e) examined the impact of combining varenicline with NRT, with placebo controls. However, the CUD trial examined whether CUD influences smoking cessation\u003csup\u003e31\u003c/sup\u003e, and the OUD trial examined whether OUD impacts smoking cessation\u003csup\u003e44\u003c/sup\u003e. Similarly, only three studies (one in OUD\u003csup\u003e37\u003c/sup\u003e and two in StUD\u003csup\u003e50,51\u003c/sup\u003e) examined the impact of combining bupropion with NRT. No studies investigated the effects of combining varenicline and bupropion.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;Clinical TUD treatment guidelines provide limited directions for smoking cessation treatment in people with comorbid substance use disorders\u003csup\u003e62,63\u003c/sup\u003e. The Treating Tobacco Use and Dependence 2008 Update and the American Thoracic Society Clinical Practice Guidelines provide collective guidance to smoking cessation treatments in people with comorbid psychiatric disorders and substance use disorders\u003csup\u003e62,63\u003c/sup\u003e. The Treating Tobacco Use and Dependence 2008 Update recommends that pharmacological and behavioral smoking cessation treatments are effective in people with comorbid substance use disorders\u003csup\u003e62\u003c/sup\u003e. It does not offer any special recommendations for smoking cessation treatments in people with comorbid substance use disorders\u003csup\u003e62\u003c/sup\u003e. The American Thoracic Society Clinical Practice Guidelines also provide collective guidance on smoking cessation treatments in people with comorbid psychiatric disorders and substance use disorders\u003csup\u003e63\u003c/sup\u003e. They recommend starting varenicline over the nicotine patch for smoking cessation in people with comorbid substance use disorders\u003csup\u003e63\u003c/sup\u003e. Both guidelines recommend higher NRT doses, combination NRT, combining behavioral and pharmacological interventions, extended treatment with varenicline for up to 6 months, and combining first-line medications, including varenicline and NRT, for people with severe TUD\u003csup\u003e62,63\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;However, the limited number of studies makes it difficult to draw valid conclusions. Our systematic review also highlights the need for more consensus-based definitions of abstinence that can be applied consistently across trials. In 2020, the Society for Research on Nicotine and Tobacco (SRNT) Treatment Research Network updated the 2003 SRNT Biochemical Verification Report recommendations\u003csup\u003e56\u003c/sup\u003e. They recommended bio-verification with urine or salivary cotinine, in addition to expired CO, to measure abstinence from smoking in RCTs\u003csup\u003e56\u003c/sup\u003e. We found that only 4 of the 27 trials included in this review performed the recommended biochemical verification of abstinence\u003csup\u003e25,38,44,46\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical Implications\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEvidence Quality\u003c/em\u003e: The current evidence is insufficient to make strong recommendations, with remarkably few placebo-controlled trials across all three disorders despite the high prevalence of comorbid smoking.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDisorder-Specific Considerations\u003c/em\u003e: In StUD, both varenicline and bupropion showed promise and should be considered as first-line options. In CUD, varenicline may provide short-term benefit, though long-term efficacy remains unclear. In OUD, standard pharmacotherapy shows limited efficacy, with two placebo-controlled varenicline trials showing no benefit.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCombination Therapy\u003c/em\u003e: Despite theoretical benefits and evidence in general populations, combination pharmacotherapy (varenicline + NRT or varenicline + bupropion) lacks adequate evidence in CUD, OUD, and StUD.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBehavioral Interventions\u003c/em\u003e: CM emerges as a particularly effective behavioral component across all three disorders and should be incorporated when feasible.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eExtended Treatment\u003c/em\u003e: Given higher relapse rates, treatment duration beyond the standard 12 weeks may be warranted, though evidence supporting this approach is limited.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBiochemical Verification\u003c/em\u003e: Routine use of both exhaled CO and cotinine testing is recommended.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIntegrated Treatment\u003c/em\u003e: Smoking cessation interventions should be integrated with substance use disorder treatment rather than delayed, as evidence suggests concurrent treatment is feasible and may benefit both conditions.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFuture Directions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Our systematic review highlights 1) the urgent need for adequately powered, placebo-controlled trials of varenicline in CUD and StUD with \u0026ge;24-week follow-up, 2) replication of OUD varenicline findings to resolve the discrepancy between negative placebo-controlled trials and positive uncontrolled studies, and 3) combination pharmacotherapy trials examining varenicline + bupropion, \u0026nbsp; varenicline + NRT at adequate doses and duration, and optimizing bupropion + NRT regimens. Trials need to have consistent biochemical verification (CO + cotinine), standardized abstinence definitions, and long-term follow-up (\u0026ge;52 weeks).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Our review also demonstrates significant knowledge gaps regarding the efficacy of two interventions that have shown effectiveness in the general population: cytisine (or cytisinicline) and digital therapeutics. Cytisine was more effective than NRT or placebo, but not varenicline, in the general population\u003csup\u003e64\u003c/sup\u003e. While one trial showed cytisine\u0026rsquo;s smoking cessation efficacy among people with AUD, no trials have examined its smoking cessation efficacy in people with CUD, OUD, or StUD\u003csup\u003e65\u003c/sup\u003e. More trials of cytisine are necessary to offer clinicians and tobacco treatment specialists one more pharmacological alternative for smoking cessation in people with comorbid substance use disorders.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Another notable facet is the lack of studies combining pharmacological strategies with digital therapeutics for smoking cessation across CUD, OUD, and StUD\u003csup\u003e66\u003c/sup\u003e. Digital therapeutics encompass mobile/smartphone apps that can 1) generate daily text messages, 2) deliver behavioral interventions such as CM and CBT, or 3) provide adaptive, just-in-time interventions that provide real-time support based on a range of data indicating vulnerable situations involving craving or a risk of relapse\u003csup\u003e66,67\u003c/sup\u003e. \u0026nbsp;The FDA recently granted breakthrough designation approval to an app (DCH-001) that supports tobacco cessation in pregnant women using CM. Given evidence of their smoking cessation efficacy in the general population\u003csup\u003e68\u003c/sup\u003e, these interventions can be beneficial in populations with high dropout rates in clinical trials, such as OUD and StUD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Transcranial magnetic stimulation (TMS) is also another FDA-approved intervention that could have potential utility in populations with suboptimal response rates to pharmacological smoking cessation interventions\u003csup\u003e69\u003c/sup\u003e. Emerging data suggest TMS could have utility in decreasing craving for cannabis, opioids, and stimulants\u003csup\u003e70\u003c/sup\u003e. This makes it a valuable intervention for smoking cessation in people with CUD, OUD, and StUD\u003csup\u003e70\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e"},{"header":"Limitations and Conclusions","content":"\u003cp\u003eSeveral limitations warrant highlighting in our interpretation of the results. Substantial heterogeneity across studies in designs, populations, interventions, doses, durations, and outcome measures limits the strength of conclusions that can be drawn. Many included studies lacked rigorous placebo controls (only four placebo-controlled varenicline trials across all disorders), had small sample sizes (8 studies with n\u0026lt;50), and employed variable biochemical verification methods (only 4 of 27 used recommended dual verification). Most studies followed participants for 12 weeks or less, with very few extending to 24 weeks and almost none to 52 weeks, limiting assessment of long-term sustained abstinence. We could not adequately assess dose-response relationships, optimal treatment duration, or optimal combinations due to limited number of studies examining these parameters.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; This systematic review reveals a profound evidence gap in smoking cessation treatment for individuals with comorbid CUD, OUD, or StUD. Despite high prevalence of tobacco use and substantial mortality burden in these populations, remarkably few rigorous studies have examined pharmacological smoking cessation interventions. Across 27 included studies, we identified only four placebo-controlled varenicline trials combined across all three disorders, in stark contrast to 33 such trials in general populations.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;The limited available evidence suggests approved pharmacological interventions demonstrate suboptimal and variable efficacy compared to general populations. Varenicline shows most promise in StUD, short-term benefit in CUD, and no clear benefit in two placebo-controlled OUD trials. Bupropion demonstrated efficacy in StUD but limited evidence in other disorders. Combination pharmacotherapy, despite theoretical benefits, remains almost completely unstudied in these populations, with no trials examining varenicline plus bupropion.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Most studies followed participants for 12 weeks or less, providing little information about sustained long-term abstinence. Current clinical practice guidelines provide insufficient disorder-specific guidance, offering only general recommendations for \"substance use disorders\" without acknowledging the apparent differential treatment responses across specific disorder types. CM emerges from our review as a particularly effective behavioral component that warrants emphasis in future guidelines.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Urgent research priorities include: (1) adequately powered, placebo-controlled trials of single and combination pharmacotherapies with extended follow-up; (2) standardized outcome measures including dual biochemical verification; (3) investigation of novel interventions such as cytisine, digital therapeutics, and TMS; (4) mechanistic studies to understand differential treatment responses; and (5) development of disorder-specific treatment approaches.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Until stronger evidence emerges, clinicians could maximize evidence-based behavioral interventions, particularly CM; consider varenicline or bupropion for StUD; use extended treatment duration; ensure adequate medication doses; maintain realistic expectations about treatment outcomes; and emphasize to patients the critical importance of smoking cessation in reducing overall mortality in these vulnerable populations. The high mortality attributable to smoking in comorbid substance use disorder populations makes this research gap a public health priority requiring immediate attention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eData availability statement – Not applicable\u003c/u\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSmoking and Tobacco Use : Data and Statistics. https://www.cdc.gov/tobacco/data_statistics/index.htm#:~:text=Tobacco%20use%20is%20the%20leading,product%2C%20including%20e%2Dcigarettes.\u003c/li\u003e\n \u003cli\u003eCornelius ME, Loretan CG, Jamal A, et al. Tobacco Product Use Among Adults - United States, 2021. \u003cem\u003eMMWR Morb Mortal Wkly Rep\u003c/em\u003e. May 5 2023;72(18):475-483. doi:10.15585/mmwr.mm7218a1\u003c/li\u003e\n \u003cli\u003eGarc\u0026iacute;a-Rodr\u0026iacute;guez O, Secades-Villa R, Fl\u0026oacute;rez-Salamanca L, Okuda M, Liu S-M, Blanco C. Probability and predictors of relapse to smoking: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). \u003cem\u003eDrug and Alcohol Dependence\u003c/em\u003e. 10/2013 2013;132(3):479-485. doi:10.1016/j.drugalcdep.2013.03.008\u003c/li\u003e\n \u003cli\u003eShang X, E F, Guo K, et al. Effectiveness and Safety of Varenicline for Smoking Cessation: An Overview and Meta-analysis. \u003cem\u003eJ Addict Med\u003c/em\u003e. Sep-Oct 01 2023;17(5):536-543. doi:10.1097/ADM.0000000000001171\u003c/li\u003e\n \u003cli\u003eGuydish J, Passalacqua E, Tajima B, Chan M, Chun J, Bostrom A. Smoking Prevalence in Addiction Treatment: A Review. \u003cem\u003eNicotine \u0026amp; Tobacco Research\u003c/em\u003e. 2011-06-01 2011;13(6):401-411. doi:10.1093/ntr/ntr048\u003c/li\u003e\n \u003cli\u003eDaeppen JB, Smith TL, Danko GP, et al. Clinical correlates of cigarette smoking and nicotine dependence in alcohol-dependent men and women. The Collaborative Study Group on the Genetics of Alcoholism. \u003cem\u003eAlcohol Alcohol\u003c/em\u003e. Mar-Apr 2000;35(2):171-5. doi:10.1093/alcalc/35.2.171\u003c/li\u003e\n \u003cli\u003evan Amsterdam J, van den Brink W. The effect of alcohol use on smoking cessation: A systematic review. \u003cem\u003eAlcohol (Fayetteville, NY)\u003c/em\u003e. 2023-06 2023;109:13-22. doi:10.1016/j.alcohol.2022.12.003\u003c/li\u003e\n \u003cli\u003evan Amsterdam J, van den Brink W. Smoking As an Outcome Moderator In the Treatment of Alcohol Use Disorders. \u003cem\u003eAlcohol Alcohol\u003c/em\u003e. Nov 11 2022;57(6):664-673. doi:10.1093/alcalc/agac027\u003c/li\u003e\n \u003cli\u003eSchauer GL, Berg CJ, Kegler MC, Donovan DM, Windle M. Differences in Tobacco Product Use Among Past Month Adult Marijuana Users and Nonusers: Findings From the 2003-2012 National Survey on Drug Use and Health. \u003cem\u003eNicotine \u0026amp; Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco\u003c/em\u003e. 2016-03 2016;18(3):281-288. doi:10.1093/ntr/ntv093\u003c/li\u003e\n \u003cli\u003eZirakzadeh A, Shuman C, Stauter E, Hays J, Ebbert J. Cigarette Smoking in Methadone Maintained Patients: An Up-to-Date Review. \u003cem\u003eCurrent Drug Abuse Reviews\u003c/em\u003e. 2013-06-01 2013;6(1):77-84. doi:10.2174/1874473711306010009\u003c/li\u003e\n \u003cli\u003eWeinberger AH, Sofuoglu M. The impact of cigarette smoking on stimulant addiction. \u003cem\u003eAm J Drug Alcohol Abuse\u003c/em\u003e. 2009;35(1):12-7. doi:10.1080/00952990802326280\u003c/li\u003e\n \u003cli\u003eNighbor TD, Coleman SRM, Bunn JY, et al. Using the Cigarette Purchase Task to examine the relative reinforcing value of cigarettes among mothers with versus without opioid dependence. \u003cem\u003eExperimental and Clinical Psychopharmacology\u003c/em\u003e. 12/2020 2020;28(6):706-713. doi:10.1037/pha0000353\u003c/li\u003e\n \u003cli\u003eWeinberger AH, Sofuoglu M. The impact of cigarette smoking on stimulant addiction. \u003cem\u003eThe American Journal of Drug and Alcohol Abuse\u003c/em\u003e. 2009 2009;35(1):12-17. doi:10.1080/00952990802326280\u003c/li\u003e\n \u003cli\u003eCallaghan RC, Gatley JM, Sykes J, Taylor L. The prominence of smoking-related mortality among individuals with alcohol- or drug-use disorders. \u003cem\u003eDrug Alcohol Rev\u003c/em\u003e. Jan 2018;37(1):97-105. doi:10.1111/dar.12475\u003c/li\u003e\n \u003cli\u003eHser YI, Mooney LJ, Saxon AJ, et al. High Mortality Among Patients With Opioid Use Disorder in a Large Healthcare System. \u003cem\u003eJ Addict Med\u003c/em\u003e. Jul/Aug 2017;11(4):315-319. doi:10.1097/ADM.0000000000000312\u003c/li\u003e\n \u003cli\u003eYi G, Javanbakht M, Rosen AD, Gorbach P, Clark J, Shoptaw S. Speed and smoking kill: A time-varying survival analysis linking methamphetamine use, cigarette smoking, and mortality in sexual minority men. \u003cem\u003eInt J Drug Policy\u003c/em\u003e. Jun 11 2025;143:104874. doi:10.1016/j.drugpo.2025.104874\u003c/li\u003e\n \u003cli\u003eAuer R, Sidney S, Goff D, et al. Lifetime marijuana use and subclinical atherosclerosis: the Coronary Artery Risk Development in Young Adults (CARDIA) study. \u003cem\u003eAddiction\u003c/em\u003e. May 2018;113(5):845-856. doi:10.1111/add.14110\u003c/li\u003e\n \u003cli\u003eThurgood SL, McNeill A, Clark-Carter D, Brose LS. A Systematic Review of Smoking Cessation Interventions for Adults in Substance Abuse Treatment or Recovery. \u003cem\u003eNicotine Tob Res\u003c/em\u003e. May 2016;18(5):993-1001. doi:10.1093/ntr/ntv127\u003c/li\u003e\n \u003cli\u003eProchaska JJ, Delucchi K, Hall SM. A meta-analysis of smoking cessation interventions with individuals in substance abuse treatment or recovery. \u003cem\u003eJ Consult Clin Psychol\u003c/em\u003e. Dec 2004;72(6):1144-56. doi:10.1037/0022-006X.72.6.1144\u003c/li\u003e\n \u003cli\u003eApollonio D, Philipps R, Bero L. Interventions for tobacco use cessation in people in treatment for or recovery from substance use disorders. \u003cem\u003eCochrane Database Syst Rev\u003c/em\u003e. Nov 23 2016;11(11):CD010274. doi:10.1002/14651858.CD010274.pub2\u003c/li\u003e\n \u003cli\u003eGuo K, Li J, Li J, et al. The effects of pharmacological interventions on smoking cessation in people with alcohol dependence: A systematic review and meta-analysis of nine randomized controlled trials. \u003cem\u003eInt J Clin Pract\u003c/em\u003e. Nov 2021;75(11):e14594. doi:10.1111/ijcp.14594\u003c/li\u003e\n \u003cli\u003eMoher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. \u003cem\u003eJ Clin Epidemiol\u003c/em\u003e. Oct 2009;62(10):1006-12. doi:10.1016/j.jclinepi.2009.06.005\u003c/li\u003e\n \u003cli\u003eAuer R, Schoeni A, Jacot-Sadowski I. Electronic Nicotine-Delivery Systems for Smoking Cessation. Reply. \u003cem\u003eN Engl J Med\u003c/em\u003e. May 16 2024;390(19):1831-1832. doi:10.1056/NEJMc2403709\u003c/li\u003e\n \u003cli\u003eRigotti NA. Electronic Nicotine-Delivery Systems for Smoking Cessation. Reply. \u003cem\u003eN Engl J Med\u003c/em\u003e. May 16 2024;390(19):1832. doi:10.1056/NEJMc2403709\u003c/li\u003e\n \u003cli\u003eHerrmann ES, Cooper ZD, Bedi G, et al. Varenicline and nabilone in tobacco and cannabis co-users: effects on tobacco abstinence, withdrawal and a laboratory model of cannabis relapse. \u003cem\u003eAddict Biol\u003c/em\u003e. Jul 2019;24(4):765-776. doi:10.1111/adb.12664\u003c/li\u003e\n \u003cli\u003eRaich A, Pinet C, Ballb\u0026egrave; M, et al. Multimodal treatment for smoking cessation with varenicline in alcoholic, methadone-maintained, and psychotic patients: A one-year follow-up. \u003cem\u003eTobacco Induced Diseases\u003c/em\u003e. 2018 2018;16:58. doi:10.18332/tid/99541\u003c/li\u003e\n \u003cli\u003eLee DC, Walker DD, Hughes JR, et al. Sequential and simultaneous treatment approaches to cannabis use disorder and tobacco use. \u003cem\u003eJ Subst Abuse Treat\u003c/em\u003e. Mar 2019;98:39-46. doi:10.1016/j.jsat.2018.12.005\u003c/li\u003e\n \u003cli\u003eBeckham JC, Adkisson KA, Hertzberg J, et al. Mobile contingency management as an adjunctive treatment for co-morbid cannabis use disorder and cigarette smoking. \u003cem\u003eAddict Behav\u003c/em\u003e. Apr 2018;79:86-92. doi:10.1016/j.addbeh.2017.12.007\u003c/li\u003e\n \u003cli\u003eAdams TR, Arnsten JH, Ning Y, Nahvi S. Feasibility and Preliminary Effectiveness of Varenicline for Treating Co-Occurring Cannabis and Tobacco Use. \u003cem\u003eJ Psychoactive Drugs\u003c/em\u003e. Jan-Mar 2018;50(1):12-18. doi:10.1080/02791072.2017.1370746\u003c/li\u003e\n \u003cli\u003eLee DC, Budney AJ, Brunette MF, Hughes JR, Etter JF, Stanger C. Outcomes from a computer-assisted intervention simultaneously targeting cannabis and tobacco use. \u003cem\u003eDrug Alcohol Depend\u003c/em\u003e. Oct 1 2015;155:134-40. doi:10.1016/j.drugalcdep.2015.08.001\u003c/li\u003e\n \u003cli\u003eRabin RA, Ashare RL, Schnoll RA, et al. Does cannabis use moderate smoking cessation outcomes in treatment-seeking tobacco smokers? Analysis from a large multi-center trial. \u003cem\u003eAm J Addict\u003c/em\u003e. Jun 2016;25(4):291-6. doi:10.1111/ajad.12382\u003c/li\u003e\n \u003cli\u003eMcClure EA, Baker NL, Sonne SC, et al. Tobacco use during cannabis cessation: Use patterns and impact on abstinence in a National Drug Abuse Treatment Clinical Trials Network study. \u003cem\u003eDrug Alcohol Depend\u003c/em\u003e. Nov 1 2018;192:59-66. doi:10.1016/j.drugalcdep.2018.07.018\u003c/li\u003e\n \u003cli\u003eRabin RA, Ashare RL, Schnoll RA, et al. Does cannabis use moderate smoking cessation outcomes in treatment-seeking tobacco smokers? Analysis from a large multi-center trial. \u003cem\u003eThe American Journal on Addictions\u003c/em\u003e. 2016-06 2016;25(4):291-296. doi:10.1111/ajad.12382\u003c/li\u003e\n \u003cli\u003eHall SM, Humfleet GL, Gasper JJ, Delucchi KL, Hersh DF, Guydish JR. Cigarette Smoking Cessation Intervention for Buprenorphine Treatment Patients. \u003cem\u003eNicotine Tob Res\u003c/em\u003e. Apr 2 2018;20(5):628-635. doi:10.1093/ntr/ntx113\u003c/li\u003e\n \u003cli\u003eFelicione NJ, Ozga JE, Dino G, Berry JH, Sullivan CR, Blank MD. Timing of smoking cessation treatment integrated into outpatient treatment with medications for opioid use disorder: Feasibility trial. \u003cem\u003eJ Subst Abuse Treat\u003c/em\u003e. Jan 2022;132:108579. doi:10.1016/j.jsat.2021.108579\u003c/li\u003e\n \u003cli\u003eCooperman NA, Lu SE, Richter KP, Bernstein SL, Williams JM. Pilot Study of a Tailored Smoking Cessation Intervention for Individuals in Treatment for Opioid Dependence. \u003cem\u003eNicotine Tob Res\u003c/em\u003e. Aug 14 2018;20(9):1152-1156. doi:10.1093/ntr/ntx189\u003c/li\u003e\n \u003cli\u003eRichter KP, McCool RM, Catley D, Hall M, Ahluwalia JS. Dual pharmacotherapy and motivational interviewing for tobacco dependence among drug treatment patients. \u003cem\u003eJ Addict Dis\u003c/em\u003e. 2005;24(4):79-90. doi:10.1300/j069v24n04_06\u003c/li\u003e\n \u003cli\u003eShoptaw S, Rotheram-Fuller E, Yang XW, et al. Smoking cessation in methadone maintenance. \u003cem\u003eAddiction\u003c/em\u003e. Oct 2002;97(10):1317-1328. doi:DOI 10.1046/j.1360-0443.2002.00221.x\u003c/li\u003e\n \u003cli\u003eMooney ME, Poling J, Gonzalez G, Gonsai K, Kosten T, Sofuoglu M. Preliminary study of buprenorphine and bupropion for opioid-dependent smokers. \u003cem\u003eAm J Addict\u003c/em\u003e. Jul-Aug 2008;17(4):287-92. doi:10.1080/10550490802138814\u003c/li\u003e\n \u003cli\u003eStein MD, Weinstock MC, Herman DS, Anderson BJ, Anthony JL, Niaura R. A smoking cessation intervention for the methadone-maintained. \u003cem\u003eAddiction\u003c/em\u003e. Apr 2006;101(4):599-607. doi:10.1111/j.1360-0443.2006.01406.x\u003c/li\u003e\n \u003cli\u003eMontgomery L, Winhusen T, Scodes J, et al. Reductions in tobacco use in naltrexone, relative to buprenorphine-maintained individuals with opioid use disorder: Secondary analysis from the National Drug Abuse Treatment Clinical Trials Network. \u003cem\u003eJ Subst Abuse Treat\u003c/em\u003e. Nov 2021;130:108489. doi:10.1016/j.jsat.2021.108489\u003c/li\u003e\n \u003cli\u003eLee SW, Yu PC, Yen TT, et al. Impact of the Ottawa model on opiate screening and smoking cessation in methadone-treated patients with opioid use disorder: A retrospective cohort analysis. \u003cem\u003eTob Induc Dis\u003c/em\u003e. 2024;22doi:10.18332/tid/191247\u003c/li\u003e\n \u003cli\u003eStein MD, Caviness CM, Kurth ME, Audet D, Olson J, Anderson BJ. Varenicline for smoking cessation among methadone-maintained smokers: a randomized clinical trial. \u003cem\u003eDrug Alcohol Depend\u003c/em\u003e. Dec 1 2013;133(2):486-93. doi:10.1016/j.drugalcdep.2013.07.005\u003c/li\u003e\n \u003cli\u003eMartin RA, Rohsenow DJ, Tidey JW. Smokers with opioid use disorder may have worse drug use outcomes after varenicline than nicotine replacement. \u003cem\u003eJournal of Substance Abuse Treatment\u003c/em\u003e. 2019-09 2019;104:22-27. doi:10.1016/j.jsat.2019.06.005\u003c/li\u003e\n \u003cli\u003eNahvi S, Adams TR, Ning Y, Zhang C, Arnsten JH. Effect of varenicline directly observed therapy versus varenicline self-administered therapy on varenicline adherence and smoking cessation in methadone-maintained smokers: a randomized controlled trial. \u003cem\u003eAddiction (Abingdon, England)\u003c/em\u003e. 2021-04 2021;116(4):902-913. doi:10.1111/add.15240\u003c/li\u003e\n \u003cli\u003eDunn KE, Sigmon SC, Reimann EF, Badger GJ, Heil SH, Higgins ST. A contingency-management intervention to promote initial smoking cessation among opioid-maintained patients. \u003cem\u003eExp Clin Psychopharmacol\u003c/em\u003e. Feb 2010;18(1):37-50. doi:10.1037/a0018649\u003c/li\u003e\n \u003cli\u003eNahvi S, Ning Y, Segal KS, Richter KP, Arnsten JH. Varenicline efficacy and safety among methadone maintained smokers: a randomized placebo-controlled trial: Varenicline RCT among methadone patients. \u003cem\u003eAddiction\u003c/em\u003e. 09/2014 2014;109(9):1554-1563. doi:10.1111/add.12631\u003c/li\u003e\n \u003cli\u003eMooney ME, Poling J, Gonzalez G, Gonsai K, Kosten T, Sofuoglu M. Preliminary study of buprenorphine and bupropion for opioid-dependent smokers. \u003cem\u003eThe American Journal on Addictions\u003c/em\u003e. 2008 2008;17(4):287-292. doi:10.1080/10550490802138814\u003c/li\u003e\n \u003cli\u003eStein MD, Caviness CM, Kurth ME, Audet D, Olson J, Anderson BJ. Varenicline for smoking cessation among methadone-maintained smokers: A randomized clinical trial. \u003cem\u003eDrug and Alcohol Dependence\u003c/em\u003e. 12/2013 2013;133(2):486-493. doi:10.1016/j.drugalcdep.2013.07.005\u003c/li\u003e\n \u003cli\u003eWinhusen TM, Kropp F, Theobald J, Lewis DF. Achieving smoking abstinence is associated with decreased cocaine use in cocaine-dependent patients receiving smoking-cessation treatment. \u003cem\u003eDrug and Alcohol Dependence\u003c/em\u003e. 2014-01-01 2014;134:391-395. doi:10.1016/j.drugalcdep.2013.09.019\u003c/li\u003e\n \u003cli\u003eWinhusen TM, Brigham GS, Kropp F, et al. A randomized trial of concurrent smoking-cessation and substance use disorder treatment in stimulant-dependent smokers. \u003cem\u003eThe Journal of Clinical Psychiatry\u003c/em\u003e. 2014-04 2014;75(4):336-343. doi:10.4088/JCP.13m08449\u003c/li\u003e\n \u003cli\u003eDe la Garza R, Yoon JH. Evaluation of the effects of rivastigmine on cigarette smoking by methamphetamine-dependent volunteers. \u003cem\u003eProgress in Neuro-Psychopharmacology \u0026amp; Biological Psychiatry\u003c/em\u003e. 2011-12-01 2011;35(8):1827-1830. doi:10.1016/j.pnpbp.2011.07.006\u003c/li\u003e\n \u003cli\u003ePoling J, Rounsaville B, Gonsai K, Severino K, Sofuoglu M. The safety and efficacy of varenicline in cocaine using smokers maintained on methadone: a pilot study. \u003cem\u003eAm J Addict\u003c/em\u003e. Sep-Oct 2010;19(5):401-8. doi:10.1111/j.1521-0391.2010.00066.x\u003c/li\u003e\n \u003cli\u003eSchmitz JM, Stotts AL, Yoon JH, et al. Naltrexone plus bupropion reduces cigarette smoking in individuals with methamphetamine use disorder: A secondary analysis from the CTN ADAPT-2 trial. \u003cem\u003eJ Subst Use Addict Treat\u003c/em\u003e. Aug 2023;151:208987. doi:10.1016/j.josat.2023.208987\u003c/li\u003e\n \u003cli\u003eShoptaw S, Rotheram-Fuller E, Yang X, et al. Smoking cessation in methadone maintenance. \u003cem\u003eAddiction (Abingdon, England)\u003c/em\u003e. 2002-10 2002;97(10):1317-1328; discussion 1325. doi:10.1046/j.1360-0443.2002.00221.x\u003c/li\u003e\n \u003cli\u003ePiper ME, Bullen C, Krishnan-Sarin S, et al. Defining and Measuring Abstinence in Clinical Trials of Smoking Cessation Interventions: An Updated Review. \u003cem\u003eNicotine Tob Res\u003c/em\u003e. Jun 12 2020;22(7):1098-1106. doi:10.1093/ntr/ntz110\u003c/li\u003e\n \u003cli\u003eMontgomery L, Winhusen T, Scodes J, et al. Reductions in tobacco use in naltrexone, relative to buprenorphine-maintained individuals with opioid use disorder: Secondary analysis from the National Drug Abuse Treatment Clinical Trials Network. \u003cem\u003eJournal of Substance Abuse Treatment\u003c/em\u003e. 2021-11 2021;130:108489. doi:10.1016/j.jsat.2021.108489\u003c/li\u003e\n \u003cli\u003eSecades-Villa R, Aonso-Diego G, Garcia-Perez A, Gonzalez-Roz A. Effectiveness of contingency management for smoking cessation in substance users: A systematic review and meta-analysis. \u003cem\u003eJ Consult Clin Psychol\u003c/em\u003e. Oct 2020;88(10):951-964. doi:10.1037/ccp0000611\u003c/li\u003e\n \u003cli\u003eZamboni L, Centoni F, Fusina F, et al. The Effectiveness of Cognitive Behavioral Therapy Techniques for the Treatment of Substance Use Disorders: A Narrative Review of Evidence. \u003cem\u003eJ Nerv Ment Dis\u003c/em\u003e. Nov 1 2021;209(11):835-845. doi:10.1097/NMD.0000000000001381\u003c/li\u003e\n \u003cli\u003eLi Y, Gao L, Chao Y, et al. Effects of interventions on smoking cessation: A systematic review and network meta-analysis. \u003cem\u003eAddict Biol\u003c/em\u003e. Mar 2024;29(3):e13376. doi:10.1111/adb.13376\u003c/li\u003e\n \u003cli\u003eStein MD, Anderson BJ, Niaura R. Smoking cessation patterns in methadone-maintained smokers. \u003cem\u003eNicotine \u0026amp; Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco\u003c/em\u003e. 2007-03 2007;9(3):421-428. doi:10.1080/14622200701188885\u003c/li\u003e\n \u003cli\u003ePhs Guideline Update Panel L, Staff. Treating tobacco use and dependence: 2008 update U.S. Public Health Service Clinical Practice Guideline executive summary. \u003cem\u003eRespir Care\u003c/em\u003e. Sep 2008;53(9):1217-22.\u003c/li\u003e\n \u003cli\u003eLeone FT, Zhang Y, Evers-Casey S, et al. Initiating Pharmacologic Treatment in Tobacco-Dependent Adults. An Official American Thoracic Society Clinical Practice Guideline. \u003cem\u003eAm J Respir Crit Care Med\u003c/em\u003e. Jul 15 2020;202(2):e5-e31. doi:10.1164/rccm.202005-1982ST\u003c/li\u003e\n \u003cli\u003ePuljevic C, Stjepanovic D, Meciar I, et al. Systematic review and meta-analyses of cytisine to support tobacco cessation. \u003cem\u003eAddiction\u003c/em\u003e. Oct 2024;119(10):1713-1725. doi:10.1111/add.16592\u003c/li\u003e\n \u003cli\u003eTindle HA, Freiberg MS, Cheng DM, et al. Effectiveness of Varenicline and Cytisine for Alcohol Use Reduction Among People With HIV and Substance Use: A Randomized Clinical Trial. \u003cem\u003eJAMA Netw Open\u003c/em\u003e. Aug 1 2022;5(8):e2225129. doi:10.1001/jamanetworkopen.2022.25129\u003c/li\u003e\n \u003cli\u003eNaughton F, Nadkarni A. The Contribution of Digital Treatment to Efforts to Reduce Global Tobacco Use. \u003cem\u003eN Engl J Med\u003c/em\u003e. Oct 16 2025;393(15):1449-1452. doi:10.1056/NEJMp2500683\u003c/li\u003e\n \u003cli\u003eHebert ET, Kendzor DE, Vidrine DJ, et al. Just-in-Time Adaptive Intervention for Smoking Cessation in Low-Income Adults: A Randomized Clinical Trial. \u003cem\u003eJAMA Netw Open\u003c/em\u003e. Aug 1 2025;8(8):e2526691. doi:10.1001/jamanetworkopen.2025.26691\u003c/li\u003e\n \u003cli\u003eLi S, Li Y, Xu C, et al. Efficacy of digital interventions for smoking cessation by type and method: a systematic review and network meta-analysis. \u003cem\u003eNat Hum Behav\u003c/em\u003e. Oct 2025;9(10):2054-2065. doi:10.1038/s41562-025-02295-2\u003c/li\u003e\n \u003cli\u003eZangen A, Moshe H, Martinez D, et al. Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial. \u003cem\u003eWorld Psychiatry\u003c/em\u003e. Oct 2021;20(3):397-404. doi:10.1002/wps.20905\u003c/li\u003e\n \u003cli\u003eMehta DD, Praecht A, Ward HB, et al. A systematic review and meta-analysis of neuromodulation therapies for substance use disorders. \u003cem\u003eNeuropsychopharmacology\u003c/em\u003e. Mar 2024;49(4):649-680. doi:10.1038/s41386-023-01776-0\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Kentucky","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"smoking cessation, cannabis, opioid, stimulant","lastPublishedDoi":"10.21203/rs.3.rs-9141564/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9141564/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cu\u003eIntroduction\u003c/u\u003e. Tobacco use disorder (TUD) is highly prevalent among people with cannabis use disorder (CUD), opioid use disorder (OUD), and stimulant use disorder (StUD), encompassing cocaine use disorder and methamphetamine use disorder. TUD increases the severity of other substance use disorders and leads to increased incidence of health complications, resulting in elevated mortality. We reviewed studies that examined the impact of approved pharmacological smoking cessation strategies, either alone or in combination with behavioral interventions, in people with CUD, OUD, and StUD who smoke tobacco cigarettes.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eMethods\u003c/u\u003e. We registered the systematic review on PROSPERO (CRD42023467758). We searched three databases (PubMed/Medline, Google Scholar, and EMBASE) using specific MeSH terms to identify human clinical trials published in English between January 1\u003csup\u003est\u003c/sup\u003e, 2000, and September 30th, 2024.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eResults\u003c/u\u003e. We selected 27 eligible studies, encompassing 1) CUD (n=7); 2) OUD (n=15); and 3) StUD (n=5). Approved pharmacological smoking cessation interventions, such as nicotine replacement therapy (NRT), varenicline, and bupropion, demonstrated poor efficacy in CUD, OUD, and StUD. We identified just four placebo-controlled trials for varenicline (1 in CUD, 2 in OUD, and 1 in StUD). Varenicline showed the most promise in StUD, short-term benefit in CUD, and, paradoxically, no benefit over placebo in two well-controlled OUD trials. Just four studies performed the recommended biochemical verification using both exhaled carbon monoxide (CO) and urine cotinine.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConclusions\u003c/u\u003e. Across the three disorders, pharmacological smoking cessation interventions demonstrated poor efficacy. More importantly, these conclusions were drawn from a sparse number of studies. Outcome measures were inconsistent across studies.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eImplications\u003c/u\u003e. This systematic review reveals a profound evidence gap in smoking cessation treatment for individuals with CUD, OUD, or StUD. Across 27 included studies, we identified only four placebo-controlled varenicline trials combined across all three disorders, in stark contrast to 33 such trials in general populations. The limited available evidence suggests approved pharmacological interventions demonstrate suboptimal and variable efficacy compared to the general population. Varenicline showed the most promise in StUD, short-term benefit in CUD, and no clear benefit in two placebo-controlled OUD trials. Bupropion demonstrated efficacy in StUD but limited evidence in other disorders. Combination pharmacotherapy remains almost completely unstudied in these populations. Most studies followed participants for 12 weeks or less, providing little information about sustained long-term abstinence. Current clinical practice guidelines offer insufficient disorder-specific guidance and do not acknowledge the apparent differential treatment responses across specific disorders. Urgent research priorities include: (1) adequately powered, placebo-controlled trials of single and combination pharmacotherapies with extended follow-up; (2) investigate novel interventions such as cytisine, digital therapeutics, and TMS; (3) and develop disorder-specific treatment approaches.\u003c/p\u003e","manuscriptTitle":"Pharmacological Smoking Cessation Interventions in People with Cannabis, Opioid, or Stimulant Use Disorders: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-18 10:11:25","doi":"10.21203/rs.3.rs-9141564/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"95768da4-a883-4689-a061-253e19f611c1","owner":[],"postedDate":"March 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":64697637,"name":"Psychiatry"},{"id":64697638,"name":"Clinical Pharmacology"}],"tags":[],"updatedAt":"2026-03-18T10:11:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-18 10:11:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9141564","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9141564","identity":"rs-9141564","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}