A Pilot Study to Evaluate the Use of Automated Nicotine Metabolite Ratio Reporting within Primary Care as an Implementation Strategy to Increase the Use of Tobacco Treatments.

INTRODUCTION: Concerns about safety and effectiveness of tobacco treatments reduce their use. We explored integrating the nicotine metabolite ratio (NMR), and messaging about its potential for improving safety and effectiveness, as a strategy to increase use of tobacco treatments within primary care. METHODS: Through a prospective cohort design, we explored the effects of integrating NMR testing within primary care on the provision of tobacco treatment; 65 patients completed assessments including NMR before a clinic visit. At the clinic visit, patients' clinicians received an electronic health record alert about the patient's NMR and personalized treatment recommendations to improve effectiveness and safety. Being asked about smoking and advised to quit, and a referral for tobacco treatment or medication prescription, were assessed within 30 days of the appointment and were compared to a usual care cohort (N=85). RESULTS: The NMR and usual care cohorts reported similar rates of being asked about smoking (92.3% vs. 92.9%, p=1.0), being advised to quit (72.3% vs. 74.1%, p=0.85), being referred for tobacco treatment (23.1% vs. 36.5%, p=0.11), and receiving tobacco use medications (20% vs. 27.1%, p=0.34). In the NMR cohort, fast vs. slow metabolizers were more likely to receive medication (26% vs. 0%, p=0.003) and all patients who received varenicline (n=8) were fast metabolizers. CONCLUSIONS: NMR results and treatment recommendations did not increase tobacco treatment rates in primary care, although it may increase treatment rates and use of varenicline for fast metabolizers. Future studies could test ways to use the NMR to increase tobacco treatment rates in clinical settings. IMPLICATIONS: This study generated a novel implementation strategy, namely an electronic health record alert about patients' NMR and personalized treatment recommendations, in an effort to increase tobacco treatment rates in primary care. While the strategy did not increase tobacco treatment rates, it may have boosted the rate of varenicline prescription for patients who metabolize nicotine faster, aligning with evidence-based practice.

Effect of early medication adherence on behavioral treatment utilization and smoking cessation among individuals with current or past major depressive disorder.

SIGNIFICANCE: Little is known about the mechanisms by which medication adherence promotes smoking cessation among adults with MDD. We tested the hypothesis that early adherence promotes abstinence by increasing behavioral treatment (BT) utilization. METHODS: Data for this post-hoc analysis were from a randomized trial of 149 adults with current or past MDD treated with BT and either varenicline (n = 81) or placebo (n = 68). Arms were matched on medication regimen. Early medication adherence was measured by the number of days in which medication was taken at the prescribed dose during the first six of 12 weeks of pharmacological treatment (weeks 2-7). BT consisted of eight 45-minute sessions (weeks 1-12). Bioverified abstinence was assessed at end-of-treatment (week 14). A regression-based approach was used to test whether the effect of early medication adherence on abstinence was mediated by BT utilization. RESULTS: Among 141 participants who initiated the medication regimen, BT utilization mediated the effect of early medication adherence on abstinencea) an interquartile increase in early medication days from 20 to 42 predicted a 4.2 times increase in abstinence (Total Risk Ratio (RR) = 4.24, 95% CI = 2.32-13.37; p <.001); b) increases in BT sessions predicted by such an increase in early medication days were associated with a 2.7 times increase in abstinence (Indirect RR = 2.73, 95% CI = 1.54-7.58; p <.001); and c) early medication adherence effects on abstinence were attenuated, controlling for BT (Direct RR = 1.55, 95% CI = 0.83-4.23, p =.17). CONCLUSIONS: The effect of early medication adherence on abstinence in individuals with current or past MDD is mediated by intensive BT utilization.

Predictors of improved clinician screening, assessment, and treatment for tobacco use for clients in community mental healthcare following training.

Introduction: People with mental illness (MI) are more likely to smoke cigarettes and less likely to receive treatment for tobacco use than the general population. Understanding factors associated with improved staff treatment of tobacco use in community mental health settings has received limited study. Methods: We used data from a completed cluster-randomized clinical trial that tested two interventions designed to increase treatment for tobacco use in mental health clinics. Among 222 clinic staff, we examined demographic and employment characteristics, changes in perceived skills, knowledge, and beliefs using the S-KAP (i.e., perceptions of staff responsibility to treat tobacco use; client quit motivation; client outcomes; and barriers) as predictors of change in clinician reported delivery of tobacco use treatment following training. Results: Clinician reported treatment of client tobacco use significantly increased from baseline to week 52 across both study arms (p<0.001). This increase in reported treatment for tobacco use was associated with increases from baseline to week 52 in clinician reported skills to treat tobacco use, perceptions of responsibility to treat client tobacco use, and perceptions about client motivation to quit smoking (p's<0.05). Conclusions: Training clinicians in community mental healthcare to address client tobacco use may improve outcomes by helping them to develop the needed skills, convincing them that treating tobacco use is part of their role as clinicians, and by helping clinicians to recognize that clients are motivated to quit smoking. These may be targets to improve how clinicians in community health settings address client tobacco use.

Depression Severity Moderates Reward Learning Among Smokers with Current or Past Major Depressive Disorder in a Smoking Cessation Randomized Clinical Trial.

INTRODUCTION: Behavioral and pharmacological smoking cessation treatments are hypothesized to increase patients' reward learning to reduce craving. Identifying changes in reward learning processes that support effective tobacco dependence interventions among smokers who experience depression may guide patients towards efficient treatment strategies. The objective was to investigate the extent to which adult daily cigarette smokers with current or past major depressive disorder (MDD) learned to seek reward during 12 weeks of treatment combining behavioral activation and varenicline. We hypothesized that a decline in reward learning would be attenuated (least to most) in the following order: 1) Behavioral activation integrated with ST (BASC) + varenicline, 2) BASC + placebo, 3) Standard behavioral cessation treatment (ST) + varenicline, 4) ST + placebo. METHODS: We ran a Phase 4, placebo-controlled, randomized clinical trial with 300 participants receiving 12 weeks of one of four conditions across two urban medical centers. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI). Reward learning was ascertained at Weeks 1, 7, and 14 using the Probabilistic Reward Task (PRT), a laboratory task that uses an asymmetric reinforcement schedule to assess (a) learning to seek reward (response bias), (b) differentiate between stimuli, and (c) time to react to cues. RESULTS: There was a significant interaction of BDI group x PRT response bias. Response bias declined from Week 7 to 14 among participants with high baseline depression symptoms. The other two BDI groups showed no change in response bias. CONCLUSIONS: Controlling for baseline depression, participants showed a decrease in response bias from Week 1 to 14, and from Weeks 7 to 14. Treatment condition and abstinence status were unassociated with change in reward learning. IMPLICATIONS: Smokers who report greater depression severity show a decline in reward learning despite their participation in smoking cessation treatments, suggesting that depressed populations pose unique challenges with standard smoking cessation approaches.

Seeing Through the Blind: Belief about Treatment Randomization and Smoking Cessation Outcome among People with Current or Past Major Depressive Disorder who Smoke in a Placebo-Controlled Trial of Varenicline.

INTRODUCTION: Blinding participants to randomization is a cornerstone of science. However, participant beliefs about their allocation can influence outcomes. We examined blind integrity, the association between trial arm belief and cessation, and potential mechanisms linking treatment arm and treatment arm belief among people with major depressive disorder (MDD) who smoke receiving varenicline in a placebo-controlled trial. METHODS: 175 participants were asked at the end of treatment (EOT) if they thought they received placebo, varenicline, or were not sure. We assessed the relationship between treatment arm belief and actual treatment allocation, examined the association between treatment arm belief and EOT cessation, and evaluated changes in craving, withdrawal, side effects, depression symptoms, and smoking reward as mediators through which treatment arm was believed. RESULTS: Treatment arm belief was significantly associated with actual arm assignment (χ2(2)=13.0, p=0.002). Participants in the varenicline arm were >3 times as likely to believe they were taking varenicline, vs. "not sure" (RR=3.05 [1.41-6.60], p=0.005). Participants in the placebo arm were just as likely to believe they were taking placebo vs. "not sure" (χ2[2]=0.75, p=0.69). Controlling for treatment arm, belief that one received varenicline was significantly associated with an increase in cessation rate (OR=5.91 [2.06-16.92], p=0.001). Change in the rewarding experience of smoking may mediate participant ability to discern getting varenicline B=0.077 [0.002-0.192], p <0.05). CONCLUSIONS: Participants receiving varenicline can discern that they received varenicline and this belief is associated with higher cessation rates. Research is needed to continue to examine how participants correctly identify their allocation to varenicline.

Cluster Randomized Pragmatic Clinical Trial Testing Behavioral Economic Implementation Strategies to Improve Tobacco Treatment for Patients With Cancer Who Smoke.

PURPOSE: Few cancer centers systematically engage patients with evidence-based tobacco treatment despite its positive effect on quality of life and survival. Implementation strategies directed at patients, clinicians, or both may increase tobacco use treatment (TUT) within oncology. METHODS: We conducted a four-arm cluster-randomized pragmatic trial across 11 clinical sites comparing the effect of strategies informed by behavioral economics on TUT engagement during oncology encounters with cancer patients. We delivered electronic health record (EHR)-based nudges promoting TUT across four nudge conditions: patient only, clinician only, patient and clinician, or usual care. Nudges were designed to counteract cognitive biases that reduce TUT engagement. The primary outcome was TUT penetration, defined as the proportion of patients with documented TUT referral or a medication prescription in the EHR. Generalized estimating equations were used to estimate the parameters of a linear model. RESULTS: From June 2021 to July 2022, we randomly assigned 246 clinicians in 95 clusters, and collected TUT penetration data from their encounters with 2,146 eligible patients who smoke receiving oncologic care. Intent-to-treat (ITT) analysis showed that the clinician nudge led to a significant increase in TUT penetration versus usual care (35.6% v 13.5%; OR = 3.64; 95% CI, 2.52 to 5.24; P < .0001). Completer-only analysis (N = 1,795) showed similar impact (37.7% clinician nudge v 13.5% usual care; OR = 3.77; 95% CI, 2.73 to 5.19; P < .0001). Clinician type affected TUT penetration, with physicians less likely to provide TUT than advanced practice providers (ITT OR = 0.67; 95% CI, 0.51 to 0.88; P = .004). CONCLUSION: EHR nudges, informed by behavioral economics and aimed at oncology clinicians, appear to substantially increase TUT penetration. Adding patient nudges to the implementation strategy did not affect TUT penetration rates.

Change in cardiovascular health among adults with current or past major depressive disorder enrolled in intensive smoking cessation treatment.

BACKGROUND: Elevated depressive symptoms and cigarette smoking are independently associated with poorer cardiovascular health (CVH), but it is unknown whether their treatment can synergistically improve CVH. We sought to characterize CVH of adults with comorbid depression and smoking and examine changes in CVH associated with changes in smoking and depression. METHODS: Participants (N = 300, 55 % women) were adult smokers (≥ 1 cigarette/day) with lifetime major depressive disorder enrolled in a 12-week intervention trial targeting depression and smoking. Multiple linear regression examined prospective associations between changes in depression (Beck Depression Inventory-II), smoking (past 24-hour cigarettes or smoking abstinence), and modified CVH score (per American Heart Association, excluding smoking: diet, physical activity, body mass index, blood glucose, cholesterol, blood pressure). RESULTS: Baseline mean CVH score was 5.87/12 points (SD = 2.13). No participants met "ideal" on all CVH components (blood glucose: 48 %, cholesterol: 46 %, physical activity: 38 %, body mass index: 24 %, blood pressure: 22 %, diet: 3 %). CVH scores did not change from baseline to end-of-treatment (M = 0.18 points, SD = 1.36, p = .177), nor did change in depression × smoking predict change in CVH (p = .978). However, greater reductions in depression were significantly associated with greater improvements in CVH (ß = -0.04, SE = 0.01, p = .015). LIMITATIONS: This study was limited by a short follow-up period, missing blood glucose and cholesterol data, and treatment-seeking smokers. CONCLUSIONS: Adults with comorbid depression and smoking had poor CVH. Although integrated treatment for depression and smoking improved both conditions, only reductions in depression were associated with improvements in CVH. These findings have implications for integrating psychosocial treatment into CVH promotion efforts. REGISTRATION: NCT02378714 (clinicaltrials.gov).

Efficacy and safety of combination behavioral activation for smoking cessation and varenicline for treating tobacco dependence among individuals with current or past major depressive disorder: A 2 × 2 factorial, randomized, placebo-controlled trial.

BACKGROUND AND AIMS: Treatment of depression-related psychological factors related to smoking behavior may improve rates of cessation among adults with major depressive disorder (MDD). This study measured the efficacy and safety of 12 weeks of behavioral activation for smoking cessation (BASC), varenicline and their combination. DESIGN, SETTING, PARTICIPANTS: This study used a randomized, placebo-controlled, 2 × 2 factorial design comparing BASC versus standard behavioral treatment (ST) and varenicline versus placebo, taking place in research clinics at two urban universities in the United States. Participants comprised 300 hundred adult smokers with current or past MDD. INTERVENTIONS: BASC integrated behavioral activation therapy and ST to increase engagement in rewarding activities by reducing avoidance, withdrawal and inactivity associated with depression. ST was based on the 2008 PHS Clinical Practice Guideline. Both treatments consisted of eight 45-min sessions delivered between weeks 1 and 12. Varenicline and placebo were administered for 12 weeks between weeks 2 and 14. MEASUREMENTS: Primary outcomes were bioverified intent-to-treat (ITT) 7-day point-prevalence abstinence at 27 weeks and adverse events (AEs). FINDINGS: No significant interaction was detected between behavioral treatment and pharmacotherapy at 27 weeks (χ2 (1) = 0.19, P = 0.67). BASC and ST did not differ (χ2 (1) = 0.43, P = 0.51). Significant differences in ITT abstinence rates (χ2 (1) = 4.84, P = 0.03) emerged among pharmacotherapy arms (16.2% for varenicline, 7.5% for placebo), with results favoring varenicline over placebo (rate ratio = 2.16, 95% confidence interval = 1.08, 4.30). All significant differences in AE rates after start of medication were higher for placebo than varenicline. CONCLUSION: A randomized trial in smokers with major depressive disorder found that varenicline improved smoking abstinence versus placebo at 27 weeks without elevating rates of adverse events. Behavioral activation for smoking cessation did not outperform standard behavioral treatment, with or without adjunctive varenicline therapy.

A randomized clinical trial testing two implementation strategies to promote the treatment of tobacco dependence in community mental healthcare.

INTRODUCTION: People with serious mental illness (SMI) are more likely to smoke and less likely to receive tobacco treatment. Implementation strategies may address clinician and organizational barriers to treating tobacco in mental healthcare. METHODS: A cluster-randomized trial (Clinic N=13, Client N=610, Staff N=222) tested two models to promote tobacco treatment in community mental healthcare: standard didactic training vs. Addressing Tobacco Through Organizational Change (ATTOC), an organizational model that provides clinician and leadership training and addresses system barriers to tobacco treatment. Primary outcomes were changes in tobacco treatment from clients, staff, and medical records. Secondary outcomes were changes in smoking, mental health, and quality of life (QOL), and staff skills and barriers to treat tobacco. RESULTS: Clients at ATTOC sites reported a significant increase in receiving tobacco treatment from clinician at weeks 12 and 24 (ps<0.05) and tobacco treatments and policies from clinics at weeks 12, 24, 36, and 52 (ps<0.05), vs. standard sites. ATTOC staff reported a significant increase in skills to treat tobacco at week 36 (p=0.05), vs. standard sites. For both models, tobacco use medications, from clients (week 52) and medical records (week 36), increased (ps<0.05), while perceived barriers decreased at weeks 24 and 52 (ps<0.05); 4.3% of clients quit smoking which was not associated with model. QOL and mental health improved over 24 weeks for both models (ps<0.05). CONCLUSIONS: Standard training and ATTOC improve use of evidence-based tobacco treatments in community mental healthcare without worsening mental health, but ATTOC may more effectively address this practice gap.

Smoking Cessation, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

Although the harmful effects of smoking after a cancer diagnosis have been clearly demonstrated, many patients continue to smoke cigarettes during treatment and beyond. The NCCN Guidelines for Smoking Cessation emphasize the importance of smoking cessation in all patients with cancer and seek to establish evidence-based recommendations tailored to the unique needs and concerns of patients with cancer. The recommendations contained herein describe interventions for cessation of all combustible tobacco products (eg, cigarettes, cigars, hookah), including smokeless tobacco products. However, recommendations are based on studies of cigarette smoking. The NCCN Smoking Cessation Panel recommends that treatment plans for all patients with cancer who smoke include the following 3 tenets that should be done concurrently: (1) evidence-based motivational strategies and behavior therapy (counseling), which can be brief; (2) evidence-based pharmacotherapy; and (3) close follow-up with retreatment as needed.

Treatment adherence in a smoking cessation clinical trial for individuals with current or past major depressive disorder: Predictors and association with cessation.

INTRODUCTION: Individuals with major depressive disorder (MDD) exhibit high rates of tobacco use and lower responsiveness to tobacco cessation treatments. Treatment adherence is a strong predictor of treatment outcomes in the general population but has not been evaluated in this under-served community of smokers with MDD. METHODS: We used data from a randomized clinical trial on smoking cessation treatment among 300 smokers with MDD to examine the rate of adherence (medication and counseling), the association of adherence with cessation outcomes, and factors associated with adherence, including demographic and smoking characteristics, psychiatric characteristics, smoking cessation processes (e.g., withdrawal, reinforcers), and treatment-related side effects (e.g., nausea). RESULTS: Overall, 43.7% of participants were adherent with medication and 63.0% were adherent with counseling. Medication adherence was significantly associated with cessation, with 32.1% of adherent vs. 13.0% of non-adherent participants quitting smoking at EOT. Counseling adherence was also significantly associated with cessation, with 32.3% of adherent vs. 2.7% of non-adherent participants quitting smoking. Multivariate regression models showed that medication adherence was associated with higher engagement in complementary reinforcers and higher baseline smoking reward, while counseling adherence was associated with identifying as female, lower alcohol use and nicotine dependence, higher baseline smoking reward, and higher engagement in substitute and complementary reinforcers within the first weeks of medication use. CONCLUSIONS: As with the general population of smokers, non-adherence to treatment in smokers experiencing depression is widespread and a significant barrier to cessation. Interventions that target reinforcers may improve rates of treatment adherence.

Molecular Imaging of Pulmonary Inflammation in Users of Electronic and Combustible Cigarettes: A Pilot Study.

Electronic cigarette (EC) use has increased dramatically, particularly among adolescents and young adults, and, like cigarette use, can cause pulmonary inflammation and increase the risk of lung disease. Methods: This preliminary study used PET with 18F-6-(1/2)(2-fluoro-propyl)-4-methylpyridin-2-amine (18F-NOS) to quantify inducible nitric oxide synthase expression to characterize oxidative stress and inflammation in the lungs in vivo in 3 age- and sex-matched groups: 5 EC users, 5 cigarette smokers, and 5 controls who had never smoked or vaped. Results: EC users showed greater 18F-NOS nondisplaceable binding potential (BPND) than cigarette smokers (P = 0.03) and controls (P = 0.01), whereas BPND in cigarette smokers did not differ from that in controls (P > 0.1). 18F-NOS lung tissue delivery and inducible nitric oxide synthase distribution volume did not significantly differ among groups. Although there were no group differences in peripheral inflammatory biomarker concentrations, 18F-NOS BPND correlated with the proinflammatory cytokine tumor necrosis factor-α concentrations (rs = 0.87, P = 0.05) in EC users. Additionally, when EC users and cigarette smokers were pooled together, number of vaping episodes or cigarettes per day correlated with interleukin-6 levels (rs = 0.86, P = 0.006). Conclusion: This is the first PET imaging study to compare lung inflammation between EC and cigarette users in vivo. We found preliminary evidence that EC users have greater pulmonary inflammation than cigarette smokers and controls, with a positive association between pulmonary and peripheral measures of inflammation.

The Impact of the COVID-19 Pandemic on Stress, Isolation, Smoking Behaviors, and Motivation to Quit in People with HIV Who Smoke.

People with HIV (PWH) smoke at higher rates compared with the general population and have lower cessation rates. The primary aim of this study was to examine the impact of the COVID-19 pandemic on smoking in PWH. A survey was administered to participants in two smoking cessation trials in the United States. Mean cigarettes per day was 13.9 (SD 8.6), and participants reported they had smoked on average for 30.93 years (SD 10.4). More than half (55.7%) of participants (N = 140) reported not changing their smoking during the pandemic, while 15% reported decreasing, and 25% reported increasing their smoking. In bivariate analyses, worrying about food due to lack of money (χ2 = 9.13, df 2, p = 0.01) and greater Covid-related worry (rs = 0.19, p = 0.02) were significantly associated with increased smoking. Qualitative research may be needed to more clearly elucidate factors related to smoking behaviors among PWH.

Varenicline for Tobacco-Dependent Adults Who Are Not Ready to Discontinue Use: A Systematic Review and Meta-Analysis.

Rationale: Not all individuals with tobacco dependence are ready to give up smoking. Research reveals behavioral differences between adults ready to discontinue tobacco use and those who are not. Thus, the interventions applied to these populations might differ. However, the evidence of using varenicline in individuals who are not ready to discontinue tobacco use is uncertain. Objectives: To determine if, in tobacco-dependent adults who report not being ready to discontinue tobacco use, clinicians should begin treatment with varenicline or wait until subjects are ready to discontinue tobacco use. Methods: We conducted a systematic review to assess the effectiveness and safety of treatment with varenicline in tobacco-dependent adults who are not ready to discontinue tobacco use. We systematically searched the Cumulative Index to Nursing and Allied Health Literature, Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials comparing varenicline versus placebo for individuals who were not ready to discontinue tobacco use. Outcomes of interest include point prevalence abstinence during treatment or at six months or longer, smoking reduction, motivation to quit, adverse events, and withdrawal symptoms. Two authors independently extracted data and assessed eligibility and risk of bias using a standardized data collection form. We followed the Grading of Recommendations, Assessment, Development and Evaluations approach to assess the certainty of evidence. Results: Five trials met our inclusion criteria. All 2,616 participants were adults who were not ready to discontinue tobacco use at study entry. For 7-day point prevalence abstinence at six months or longer, high-certainty evidence suggested that varenicline increased abstinence compared with placebo (relative risk, 2.00 [95% confidence interval (CI), 1.70-2.35]; absolute risk reduction, 173 more per 1,000 [95% CI, 121 more to 234 more]). We identified moderate-certainty evidence suggesting that varenicline increased serious adverse events (relative risk, 1.75 [95% CI, 0.98-3.13]; absolute risk reduction, 12 more per 1,000 [95% CI, 0 fewer to 35 more]). For withdrawal, low-certainty evidence suggested that varenicline treatment was associated with a lower symptom score (mean difference, 1.54 points lower; 95% CI, 2.15-0.93 points lower; low certainty) assessed using the Brief Questionnaire of Smoking Urges. Conclusions: In tobacco-dependent adults who are not ready to discontinue tobacco use, initiating varenicline treatment results in a large increase in abstinence and likely results in a slight increase in serious adverse events.

Characterizing the semantic and form-based similarity spaces of the mental lexicon by means of the multi-arrangement method.

Collecting human similarity judgments is instrumental to measuring and modeling neurocognitive representations (e.g., through representational similarity analysis) and has been made more efficient by the multi-arrangement task. While this task has been tested for collecting semantic similarity judgments, it is unclear whether it also lends itself to phonological and orthographic similarity judgments of words. We have extended the task to include these lexical modalities and compared the results between modalities and against computational models. We find that similarity judgments can be collected for all three modalities, although word forms were considered more difficult to sort and resulted in less consistent inter- and intra-rater agreement than semantics. For all three modalities we can construct stable group-level representational similarity matrices. However, these do not capture significant idiosyncratic similarity information unique to each participant. We discuss the potential underlying causes for differences between modalities and their effect on the application of the multi-arrangement task.

Extended Duration Treatment of Tobacco Dependence: A Systematic Review and Meta-Analysis.

Rationale: The American Thoracic Society (ATS) developed a clinical practice guideline on initiating pharmacologic treatment in tobacco-dependent adults. Controller pharmacotherapies treat tobacco dependence effectively when taken as prescribed, but relapse after pharmacologic discontinuation is common. Objectives: To evaluate the effectiveness and safety of initiating controller for an extended (>12 wk) versus a standard duration (6-12 wk) in tobacco-dependent adults. Methods: We systematically searched PubMed, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials from database inception to December 2021 to identify randomized controlled trials comparing extended versus standard duration of controllers for tobacco-dependent adults. We conducted meta-analyses using the Mantel-Haenszel method with random effects model. Outcomes of interest include point-prevalent abstinence at 1-year follow-up or longer, relapse, adverse events, quality of life, and withdrawal symptoms. Subgroup analyses were conducted according to types of treatment and duration of extended therapy when feasible. We assessed the certainty of the estimate following the grading of recommendations, assessment, development and evaluation methodology. Results: We included 13 randomized controlled trials including 8,695 participants that directly compared extended- (>12 wk) versus standard-duration controller therapy with varenicline, bupropion, or nicotine replacement therapy. Compared with standard-duration controller therapy, extended-duration controller therapy probably increased abstinence at 1-year follow-up, measured as 7-day point-prevalence abstinence (relative risk, 1.18; 95% confidence interval [CI], 1.05-1.33; moderate certainty). Extended-duration controller therapy probably reduced relapse compared with standard-duration controller therapy, assessed at 12-18 months after initiation of therapy (hazard ratio, 0.43; 95% CI, 0.29-0.64; moderate certainty). Moderate certainty evidence also suggested that extended-duration controller therapy probably did not increase risk of serious adverse events (relative risk, 1.37; 95% CI, 0.79-2.36). Conclusions: This systematic review supported the recommendation for extended-duration therapy with controllers. Further studies on optimal extended duration are warranted.