Smoking Cessation in Primary Care: A Narrative Review of Evidence-Based Treatment,Emerging Technology,and Harm Reduction Approaches

Abstract

Conventional cigarette smoking remains a leading preventable cause of morbidity and mortality despite declining prevalence, yet evidence-based treatments remain underused. This narrative review examines guideline-supported therapies and emerging approaches, including digital tools, neuromodulation, and harm-reduction strategies. Standard care typically combines FDA-approved pharmacotherapy with behavioral counseling. Digital interventions can extend access and support adherence, particularly when integrated with pharmacotherapy and follow-up. Repetitive transcranial magnetic stimulation (rTMS) can be considered as an adjunctive option for patients who do not respond to pharmacotherapy and is FDA-approved. For patients unable to quit, structured harm-reduction strategies may help reduce risk while supporting progression toward eventual abstinence. These approaches should be used alongside, not in place of, guideline-recommended pharmacotherapy and behavioral counseling, which remain the gold standard for care. This review outlines a pragmatic, primary care–oriented model that integrates stepped-care with harm-reduction strategies.

Keywords

smoking cessation primary health care nicotine dependence harm reduction behavioral therapy tobacco use disorder telemedicine tobacco cessation devices

Introduction

Smoking remains a major preventable cause of morbidity and mortality, contributing to cardiovascular, oncologic, and pulmonary and other chronic diseases. In the United States, adult cigarette smoking prevalence declined from approximately 45% in 1965 to 11% in 2021–2022, although an estimated 28.8 million adults continue to use combustible tobacco products.^1,2 Globally, approximately 1.3 billion individuals use tobacco products, with smoking prevalence estimated at 17% overall.^3-5

Primary care plays a central role in managing chronic conditions, including tobacco dependence. Primary care clinicians (PCCs) can deliver evidence-based treatment by identifying smokers, initiating counseling and medication, and ensuring timely follow-up.⁶ However, these treatments remain underused, and many smokers attempt to quit without medication or structured support. Among U.S. adults who smoke, approximately two-thirds (66%) report wanting to quit in 2022, with most smokers making anywhere from six to 30 quit attempts to stop smoking.^7,8 Among smokers attempting cessation, a clinician supervises fewer than 10% of smoking cessation attempts, and 4 out of 10 (36.3%) report using any form of evidence-based treatment. These categories are not mutually exclusive: 36.3% report using FDA-approved medication, 7.3% report using cognitive behavioral therapy, and only 5.3% report using both FDA-approved medications and behavioral counseling.^7,8 Successful smoking cessation and sustained abstinence remain difficult to achieve, in part due to these gaps in evidence-based treatment.

These treatment gaps can be clinically addressed by following the US Preventive Services Task Force (USPSTF) recommendations.⁹ Even brief advice (3 minutes) from the healthcare team and treatment offers can increase quit attempts and success in smoking cessation.⁹ Using the 5 A’s intervention framework, these recommendations emphasize universal screening (ask), advice to quit (advise), determining willingness to quit (assess), offering behavioral interventions, and, where appropriate, pharmacotherapy (assist), and follow-up (arrange).⁹ Unfortunately, competing visit demands, time constraints, inconsistent access to counseling resources, and fragmented medical coverage reduce the ability to help smokers quit.¹⁰

New alternative nicotine products and delivery devices are becoming readily available. Electronic cigarettes (e-cigarettes) and other non-combustible nicotine delivery devices (such as nicotine pouches) are among the more popular nicotine alternatives to traditional tobacco cigarettes. Some smokers turn to e-cigarettes in an attempt to quit smoking. However, these products are not recommended as first-line cessation therapies in current clinical guidelines in the United States, nor are they FDA-approved as smoking cessation aids. These changes make smoking cessation treatment more complex. They challenge the conventional abstinence-only approach, raise concerns about the risk of e-cigarette vapor exposure, and may increase the risk of “dual use” of both combustible and non-combustible cigarettes.¹¹

In parallel, treatment delivery models are evolving. Digital treatment platforms have expanded access to behavioral therapy and can support adherence when integrated with pharmacotherapy (see Table 1). When integrated into health-system workflows (e.g., documentation and referral pathways within the electronic health record [EHR]), these tools can help make tobacco treatment part of routine care.^9,12

Table 1.

Evidence-Based and Adjunctive Smoking Cessation Interventions for Primary Care

Intervention	Clinical role	Evidence strength	Typical primary care use
Behavioral counseling (brief advice, CBT, MI)	Core foundation of treatment	High	Brief counseling during visits; referral to quitlines, telehealth, or TTS programs
Varenicline	First-line pharmacotherapy	High	Initiate with counseling and follow-up; consider extended duration for relapse prevention
Combination NRT (patch + short-acting NRT)	First-line pharmacotherapy	High	Patch plus gum, lozenge, or spray for breakthrough cravings
Bupropion SR	First-line pharmacotherapy	High	Initiate with counseling and follow-up; consider when trying to manage post-cessation weight gain concerns.
Quitlines and telehealth counseling	Behavioral support extension	Moderate-High	Universal referral option; supports rural and underserved populations
Smartphone app–based behavioral programs	Digital adjunctive support	Moderate; heterogeneous	Between-visit support for motivated patients
Clinician- or coach-assisted digital CBT programs	Structured adjunctive support	Moderate; emerging RCT evidence	Patients need accountability and ongoing engagement
Text-message support programs	Scalable behavioral reinforcement	Moderate	Low-barrier between-visit outreach and adherence support
EHR prompts and opt-out referral systems	System-level implementation strategy	Moderate	Standardize tobacco screening and referral workflows
rTMS	Specialty adjunctive intervention	Moderate	Selected patients not responding to optimized pharmacotherapy and counseling
Harm-reduction approaches (extended NRT, structured reduction to quit)	Secondary strategy for refractory patients	Moderate/Mixed	Patients unwilling or unable to achieve abstinence after adequate first-line therapy
E-cigarettes/noncombustible nicotine products	Harm-reduction consideration	Mixed	Consider only after failure/intolerance of evidence-based first-line therapies
VR, EEG-based wearables, noninvasive VNS	Investigational adjunctive approaches	Low/Preliminary	Not recommended for routine primary care use

Abbreviations: CBT, cognitive behavioral therapy; EHR, electronic health record; MI, motivational interviewing; NRT, nicotine replacement therapy; rTMS, repetitive transcranial magnetic stimulation; RCT, randomized controlled trial; TTS, tobacco treatment specialist; VNS, vagal nerve stimulation.

This narrative review synthesizes current smoking cessation evidence relevant to primary care using guideline statements, systematic reviews, meta-analyses, and selected randomized controlled trials identified through targeted searches of PubMed and guideline repositories from approximately 2015–2026, with emphasis on clinically applicable interventions and emerging approaches. Unlike prior reviews focused primarily on pharmacotherapy or guideline summaries, this review integrates chronic-care and stepped-care principles with emerging technologies, harm-reduction strategies, and practical workflow implementation considerations relevant to contemporary primary care practice. ^8,9,13

Evidence-Based Foundations of Smoking Cessation

US clinical practice guidance for tobacco smoking cessation in adults,^9,13,14 urges healthcare professionals to engage all adult patients about tobacco use and explore cessation. These guidelines support combined behavioral counseling and FDA-approved pharmacotherapy as the most effective approach for smoking cessation. Pharmacotherapy improves cessation outcomes compared with placebo or minimal support, and counseling plus medication increases quit rates more than either modality alone (see Tables 1 and 2).

Table 2.

Pharmacotherapies for Smoking Cessation

Medication	FDA approved	Mechanism	Clinical role	Common adverse effects	Key considerations
Nicotine Replacement Therapy (patch, gum, lozenge, nasal spray)	Yes	Nicotine receptor agonist	First-line	Skin irritation, insomnia (patch); oral irritation (gum/lozenge)	Combination (patch + short-acting) improves efficacy
Bupropion SR	Yes	NE/DA reuptake inhibitor; nAChR antagonist	Alternative/adjunct	Insomnia, dry mouth	Contraindicated in seizure risk and eating disorders
Varenicline	Yes	Partial nAChR agonist	First-line (most effective single agent)	Nausea, vivid dreams	Monitor neuropsychiatric symptoms
Cytisine	No (US)	Partial nAChR agonist	Second-line (outside US)	Nausea, sleep disturbance	Increasing global use; emerging evidence
Nortriptyline	No	Tricyclic antidepressant	Second-line/off-label	Sedation, anticholinergic effects	Cardiac risk; overdose concern
Clonidine	No	α2-adrenergic agonist	Second-line/off-label	Hypotension, sedation	Taper to avoid rebound hypertension

Data adapted from clinical guidelines and systematic reviews.^9,11,13,15.

Note. All pharmacotherapies are most effective when combined with behavioral support.

Abbreviations: nAChR, nicotinic acetylcholine receptor; NE, norepinephrine; DA, dopamine.

The guidelines also inform us that when treating pregnant women who smoke, behavioral counseling is preferred as limited evidence and safety data constrain pharmacotherapy options.^9,13 In addition, the guidelines also remind us that although some randomized controlled trials (RCTs) suggest that nicotine e-cigarettes may support smoking cessation when paired with behavioral interventions,^9,13,16,17 they are not recommended as first-line therapy compared with FDA-approved pharmacotherapies.^16,17

Behavioral Interventions

Behavioral interventions address the learned and contextual components of nicotine use, helping patients manage triggers, interrupt habitual patterns, and sustain changes that pharmacotherapy alone might not achieve. Behavioral counseling is a core component of evidence-based tobacco treatment.^9,12 Brief advice using structured approaches such as the 5A’s (ask, advise, assess, assist, and arrange follow-up) is effective and feasible in primary care. Counseling can take the form of self-help manuals (e.g., Clearing the Air),¹⁸ in-person counseling,^9,13 remote counseling^9,13 (e.g., quitlines), or digital connections (e.g., text messaging,¹⁹ chatbots,^20,21 web-based apps^12,22). Across formats, counseling should incorporate motivational interviewing principles (e.g., empathic, nonjudgmental engagement; eliciting change talk; and supporting patient autonomy).^18,23 Although evidence supports the use of motivational interviewing (MI) as an effective counseling approach in tobacco treatment, effect sizes across studies are generally modest and heterogeneous. A meta-analysis of RCTs found MI increased 6-month cessation rates by approximately 30% compared with brief advice or usual care, with larger effects observed when clinicians received dedicated training, when counseling included ≥2 sessions, and when sessions lasted >20 minutes.²³ Contemporary guidance also emphasizes that MI may be most effective when used proactively to enhance treatment engagement (e.g., entry, attendance, and adherence) and to connect patients to evidence-based cessation treatment, rather than as a standalone intervention.^18,24,25 Motivational counseling supports engagement and is particularly useful for patients who are ambivalent or not ready to quit.^18,25

More intensive counseling, particularly cognitive behavioral therapy (CBT) delivered with motivational interviewing techniques, can further improve cessation outcomes.¹⁸ CBT helps patients identify high-risk situations, modify thoughts and routines linked to smoking, and practice coping skills. Motivational interviewing supports engagement by eliciting the patient’s own reasons for change.^18,24,25 These interventions can be delivered in person or via telehealth, and they may be complemented by between-visit supports (e.g., text messaging or app-based check-ins) to reinforce skills and maintain momentum. When available, referral to a tobacco treatment specialist (TTS) can provide multi-session, multicomponent intensive behavioral counseling that complements pharmacotherapy prescribed by clinicians by addressing the learned and psychological components of tobacco dependence. Tobacco treatment specialists (TTSs) are healthcare professionals with specialized training in tobacco dependence treatment and behavioral counseling, often through programs aligned with Council for Tobacco Treatment Training Programs (CTTTP) standards. They are a key component of team-based cessation care alongside physicians, nurses, and other healthcare providers (HCPs). In clinical reviews, TTS-delivered intensive counseling has been associated with higher cessation rates than minimal contact alone (approximately 11.4% vs 7.7%; RR 1.48, 95% CI 1.34-1.64).¹³

Behavioral support can be delivered across a range of intensities and formats. Self-help materials (e.g., Clearing the Air) can reinforce brief clinician advice and provide a low-barrier starting point for patients who are not ready for formal counseling.^9,13,18,26 For patients who benefit from higher-intensity support, structured counseling with a TTS may include a personalized quit plan, skill-building with CBT and motivational interviewing strategies, and scheduled follow-up visits delivered in person or via telehealth.^13,18 Remote options such as state quitlines and follow-up appointments provide access to live counseling and can be paired with medication initiation in primary care (“ask, advise, refer” model).^9,13 Technology-enabled support, including interactive text messaging programs, chatbot-guided CBT content, and web-based resources (e.g., smokefree.gov, cdc.gov/quit), can extend support between visits, improve adherence, and increase reach when integrated into routine care workflows.^9,12,19-22

Pharmacotherapy

First-line pharmacotherapies approved by the FDA and recommended by tobacco treatment guidelines^14,27,28 include nicotine replacement therapy (NRT), bupropion, and varenicline.^14,15,28 NRT includes long-acting nicotine patches as well as short-acting options for ad lib use in the form of nicotine gum, nicotine lozenges, and nicotine nasal spray. Evidence from systematic reviews and meta-analyses indicates that combining a long-acting nicotine patch with a short-acting NRT increases quit rates compared with NRT monotherapy.^13-15 Bupropion, a selective norepinephrine dopamine reuptake inhibitor, is also effective and may be useful as an alternative or adjunct for selected patients with concerns about post-cessation weight gain.^13-15 Varenicline, a selective partial agonist at the α4β2 nicotinic acetylcholine receptor, is the most effective single-agent pharmacotherapy for smoking cessation when combined with counseling and follow-up to support adherence and manage adverse effects.^13-15 Common causes of early discontinuation include adverse effects, incorrect use (especially short-acting NRT), and under-treatment of cravings. Combined varenicline plus NRT has shown improved abstinence in some randomized trials compared with monotherapy, but the overall evidence remains mixed; in a recent meta-analysis, the long-term benefit was no longer statistically significant after exclusion of high-risk-of-bias trials.^17,22,29 Temporary disruptions in varenicline availability after the 2021 Chantix recall also affected prescribing and access in some settings.³⁰ Nonetheless, combining pharmacologic and behavioral approaches is effective because these interventions target distinct but complementary components of nicotine dependence, including reducing nicotine reward, stabilizing baseline dopamine levels, and alleviating withdrawal symptoms, which together improve the likelihood of sustained abstinence.

Three additional medications, not yet approved by the FDA for smoking cessation, are used off-label or outside the United States. These are often referred to as second-line treatment therapies. They include cytisine, nortriptyline, and clonidine.^13,14 Cytisine, a partial agonist at nicotinic acetylcholine receptors, has been widely used in Eastern Europe and has shown quit rates comparable to those of varenicline in RCTs.^31,32 Nortriptyline, a tricyclic antidepressant, and clonidine, an α2-adrenergic agonist, have both been shown to improve quit rates compared with placebo. However, they are generally less effective and less well tolerated than first-line options.^33,34 These agents may be used in selected patients who do not tolerate or respond to first-line medications.^13,14 Table 2 summarizes the profiles of first- and second-line medications for smoking cessation, including their mechanisms of action, side effects, and treatment efficacy.

Additional investigational or repurposed approaches have been explored for smoking cessation, though evidence remains limited. These include cannabidiol (CBD) and other neurobiologically targeted therapies. While preliminary studies suggest potential effects on craving and withdrawal, current evidence is insufficient to support routine clinical use, and these approaches should be considered experimental pending further RCTs.

Nicotine withdrawal symptoms typically emerge within the first several days after cessation, with peak intensity occurring in the first one to two weeks. This early period represents a critical window for relapse risk. Tailoring treatment and thinking of smoking cessation as a long-term process, sometimes extending medication use beyond 8 to 12 weeks, can be especially helpful for those who are severely addicted or who tend to relapse early.^9,35,36 Some patients may benefit from a gradual reduction approach before complete cessation rather than abrupt discontinuation, which can be facilitated by medication.³⁷ In cases of unsuccessful initial quit attempts, treatment modification, such as intensifying behavioral support or adjusting pharmacotherapy, should be considered consistent with chronic disease management principles.

Health-System Approaches in Primary Care

A key concept in tobacco dependence treatment is the “teachable moment,” defined as a life event or situation that increases receptivity to behavioral change.³⁸ Teachable moments often occur, such as after an adverse health event attributable to smoking, but clinicians have opportunities for teachable moments to be created during every clinic visit. Effective counseling requires repeated education about both the short- and long-term effects of smoking, delivered in a safe and nonjudgmental manner. This process can also strengthen trust between patients and clinicians. These moments, in which health concerns become primary motivators for making a quit attempt, provide opportunities for HCPs to offer guidance and support for smoking cessation. Addressing motivation and barriers during these times with a personalized approach, indicating the benefits that exist from smoking cessation, and repeated advice to stop can significantly increase the likelihood of the patient quitting successfully. ^26,38-40

For primary care practices, ensuring tobacco treatment as a routine part of care delivery can take advantage of otherwise unrecognized potential ‘teachable moments’ to foster behavior change and cessation. Operationally, this can be facilitated by the use of automated tobacco-use documentation, prompts in the electronic health record, and opt-out referrals to treatment services.⁴¹ A proactive and integrated system-based approach to follow-up can strengthen tobacco cessation efforts by ensuring more consistent patient engagement. Embedding screening and cessation support into routine care workflows lessens both clinician and patient burden, enabling sustained population -level impact without requiring intensive reassessment of tobacco use at every clinical encounter. Opt-out approaches facilitate greater enrollment for treatment as compared to opt-in approaches.⁴² Programs that combine medication, counseling, and regular follow-up are more effective than single interventions.^38,43 A stepped-care model (see Figure 1) incorporates behavioral support, first-line pharmacotherapy, early and frequent follow-up, and adds additional treatments when needed. Within this model, patients achieving abstinence continue maintenance therapy and relapse prevention strategies, whereas patients who continue smoking despite initial treatment undergo reassessment, escalation of behavioral or pharmacologic support, and consideration of specialty referral or adjunctive therapies. These system-level approaches shift tobacco treatment from episodic intervention to routine care.^38,43

Figure 1.

Stepped-care for smoking cessation

Emerging and Innovative Treatment Approaches

Digital Support

Digital therapeutics and other technology-enabled interventions are increasingly used as adjuncts to standard cessation care. These approaches extend standard care by addressing aspects of nicotine dependence not fully covered by pharmacotherapy and counseling. Programs that combine structured behavioral support, proactive messaging, and human coaching improve engagement and may increase quit rates. In a large RCT, an acceptance and commitment therapy-based cessation app demonstrated a greater probability of smoking abstinence at 12 months compared with a standard-of-care comparator app aligned with evidence-based cessation treatment.⁴⁴ In a separate pilot RCT, a comprehensive mobile cessation program combining a breath sensor, app-based behavioral support, human coaching, and optional NRT demonstrated more patient engagement and higher biochemically validated abstinence than a comparator app.⁴⁵ Digital tools are most effective when integrated into clinical workflows and paired with pharmacotherapy, rather than used as standalone interventions.⁴⁶

Smartphone app-based interventions have shown benefit for improving smoking abstinence, particularly in the short term. For PCCs, the key distinction is whether a tool offers low-intensity self-guided content versus a structured, multi-component program that integrates behavioral treatment with proactive follow-up and medication support.^12,22 Selecting tools that align with guideline-based care, provide clear behavioral skill-building, and support adherence is more important than recommending any single approach.

Text-message programs are among the most scalable technology-enabled approaches. Meta-analyses of eHealth interventions suggest that SMS- or app-based text messaging can increase abstinence compared with minimal support, with the strongest signals often observed for interactive or personalized messaging.⁴⁷ In practice, text-message programs can be deployed at scale as a between-visit intervention, triggered by EHR documentation of tobacco use or opt-out referral workflows, and paired with pharmacotherapy initiation and brief follow-up. In primary care, clinicians should preferentially recommend evidence-based digital tools that incorporate behavioral support and can be integrated with pharmacotherapy and follow-up, rather than standalone or unstructured applications.

Digital tools and telehealth can help more patients access support, especially those who have difficulty with in-person visits. However, variability in access to digital technologies, internet connectivity, and digital literacy may limit the reach of these interventions. Health systems can help reduce this issue by individualizing support. For digital options, alternative treatments could include combining them with human support, such as quitline coaches, offering choices for people who prefer non-digital resources, and ensuring medications are easy to prescribe and covered by insurance.

Device-Based Therapies

Neuromodulation strategies attempt to reduce craving and relapse by influencing brain regions involved in reward processing, cue reactivity, and inhibitory control. These interventions aim to alter neural activity using electrical or magnetic stimulation to influence brain networks involved in behavior and emotional regulation. In nicotine dependence, they are intended to act on dysregulated systems underlying reward processing, executive control, and stress responses. Chronic nicotine exposure alters reward signaling, weakens prefrontal inhibitory control, and increases sensitivity to cues and stress, contributing to craving, withdrawal, and relapse. Neuromodulation is intended to rebalance these systems by improving inhibitory control, reducing cue-driven craving, and stabilizing stress-related responses, thereby supporting smoking cessation. At present, these approaches are best reserved for patients who do not respond to first-line pharmacologic and behavioral therapies.

Repetitive Transcranial Magnetic Stimulation (rTMS)

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that operationalizes this network-based approach by using magnetic fields to target cortical regions involved in craving, reward processing, and impulse control, particularly the dorsolateral prefrontal cortex. Both surface and deep TMS modalities have been studied, with deep TMS receiving FDA clearance for smoking cessation in 2020 (following prior approval for depression in 2008). In a pivotal multicenter randomized controlled trial, continuous quit rates were approximately 25% vs. 6% at 4 weeks and 28% vs. 12% at 18 weeks, while sustained abstinence approached one-third at 6 months.^48,49 Treatment is generally well tolerated, with the most common adverse effects including transient scalp discomfort, headache, lightheadedness, and facial muscle twitching.⁴⁸ Given cost, access, and the need for specialized equipment, rTMS is best positioned as an adjunctive option for patients who have not achieved cessation with optimized pharmacotherapy and behavioral counseling.^{13,14,27,48,49}

In addition to TMS, which has been approved by the FDA, three additional investigational approaches are being explored for smoking cessation. These include Vagal Nerve Stimulation (VNS), EEG-based wearables and virtual reality, which are not currently recommended as routine primary care smoking cessation interventions and remain areas of ongoing investigation.

Vagal Nerve Stimulation (VNS)

Vagal nerve stimulation (VNS) is an emerging neuromodulatory approach with potential relevance to nicotine dependence through its effects on autonomic regulation and neurocircuitry implicated in addiction. Chronic tobacco use has been associated with alterations in vagal tone and heart rate variability, both of which are linked to stress reactivity, craving, and relapse risk. VNS is hypothesized to modulate these pathways by influencing central neurotransmission, and by promoting neuroregulatory and anti-inflammatory effects. VNS may influence stress, autonomic regulation, and neural pathways involved in craving and relapse. Although implantable VNS devices are FDA-approved for conditions such as epilepsy and treatment-resistant depression, newer noninvasive, portable devices are expanding the feasibility for broader clinical applications.^50,51 Although VNS has demonstrated biologic plausibility and potential relevance across several substance use disorders, smoking cessation-specific clinical evidence remains sparse. To date, evidence consists primarily of mechanistic studies and extrapolation from other addiction populations. However, interest in this approach is growing, and an NIH-funded exploratory clinical trial (R21CA302802) is currently evaluating non-invasive vagal nerve stimulation as an adjunct to nicotine replacement therapy for smoking cessation.⁵² Larger controlled studies will be needed before routine clinical adoption.

EEG-Based Wearables and Neuroadaptive Behavioral Interventions

Electroencephalogram (EEG)-based wearable devices represent a novel intersection of digital therapeutics and neurofeedback, capable of delivering adaptive behavioral interventions in real time based on detected brain activity patterns. These devices, often configured as headband-style sensors, can guide users through brief cognitive behavioral therapy (CBT) or mindfulness-based exercises aimed at reducing stress and enhancing self-regulation, key drivers of smoking behavior and relapse. In early pilot studies, regular use over several weeks has been associated with statistically significant reductions in perceived stress, along with improvements in resilience, cognitive function, and quality of life.^53-55 Importantly, most of the current EEG-based wearable studies have evaluated stress reduction, mindfulness training, or symptom management in non-smoking populations rather than tobacco dependence specifically. While these findings highlight the potential role of neuroadaptive feedback in addressing the behavioral and affective components of nicotine dependence, current evidence remains limited to small, early-phase trials. As such, these technologies remain investigational and best used as adjunctive tools within a comprehensive cessation strategy.

Virtual Reality–Based Interventions

Virtual reality (VR)–based interventions offer an immersive platform for delivering behavioral therapy through simulated, controlled environments that replicate real-world smoking cues and high-risk situations. Grounded in principles of cue exposure therapy, VR allows for repeated, graded exposure to triggers while enabling patients to practice coping strategies in a safe and structured setting. Systematic reviews of VR interventions targeting health behaviors, including smoking, suggest potential benefits for both smoking cessation and reduction, with several studies demonstrating improved outcomes compared with minimal or standard behavioral support.^56,57 In addition to cue exposure, VR platforms may incorporate relaxation training, cognitive restructuring, and skills rehearsal, enhancing engagement and experiential learning. Despite these promising signals, most available studies remain small, heterogeneous, and frequently evaluate broader health-behavior outcomes rather than smoking cessation alone.^58-60 Consequently, heterogeneity in intervention design and the lack of large-scale RCTs limit definitive conclusions, and VR is best used as an adjunctive behavioral tool pending further evidence.

Integrative Perspective on Device-Based Therapies

Among device-based interventions, rTMS currently has the strongest clinical evidence and is the only modality with FDA clearance for smoking cessation. In contrast, VR-based interventions, EEG-guided wearables, and noninvasive VNS remain investigational and are supported primarily by pilot studies or small heterogeneous trials.^{13,14,27,48-51,53-56} At present, these approaches are not ready for routine primary care implementation, although they may help inform future adjunctive treatment strategies for patients with persistent nicotine dependence. Major limitations include limited availability, implementation variability, cost, and the lack of long-term outcome data.

Pharmacologic, behavioral, and device-based interventions address different components of nicotine dependence, supporting a multimodal approach that reflects the biologic and behavioral complexity of addiction.

Harm Reduction Strategies and Noncombustible Nicotine Products

For patients who do not achieve abstinence despite optimized treatment, alternative strategies such as harm reduction can be considered.^18,61,62 The increasing availability of e-cigarettes and other noncombustible nicotine products has complicated smoking cessation counseling in primary care.^13,18,62 While harm-reduction strategies may reduce toxicant exposure, current clinical guidelines continue to prioritize complete cessation with FDA-approved therapies as first-line treatment. Most of the health risk from tobacco use comes from combustion, which generates high levels of toxicants and carcinogens. Nevertheless, from a harm-reduction perspective, moving a patient from combustible cigarettes to noncombustible products may reduce exposure to those toxicants, even if nicotine use persists. Harm reduction does not eliminate risk, and counseling should address both potential reductions in exposure and ongoing uncertainties about long-term risks and the possibility of sustained nicotine dependence. In this context, smoking cessation (abstinence from combustible tobacco), nicotine abstinence, and harm reduction represent distinct but overlapping clinical goals. In practice, harm reduction is typically considered after adequate trials of evidence-based first-line therapies and is generally reserved for patients who are unable or unwilling to achieve abstinence after adequate trials of first-line therapies.

Current U.S. clinical guidelines do not recommend e-cigarettes as first-line smoking cessation therapies, and no e-cigarette product is FDA-approved for smoking cessation.

Although recent Cochrane reviews report high-certainty evidence that nicotine e-cigarettes can increase smoking cessation rates compared with some comparators,¹⁵ the overall clinical evidence base remains more complex than efficacy outcomes alone. Concerns regarding product heterogeneity, long-term safety, dual use, regulatory status, and variability in real-world implementation continue to influence guideline recommendations and clinical adoption.^9,14,18 Systematic reviews focused on new nicotine products emphasize the need for robust study designs, clear definitions of quit motivation, adequate familiarization, and better compliance verification beyond self-report. Despite growing evidence, many clinical practice guidelines continue to prioritize approved pharmacotherapies and counseling as first-line treatment, reflecting safety concerns, product variability, and limited long-term outcome data.

Other harm-reduction strategies include extended use of approved NRT for patients who cannot discontinue conventional cigarette smoking immediately, structured reduction-to-quit approaches, and contingency-based support in selected settings. Some patients also use oral nicotine products (e.g., nicotine pouches). Nicotine pouches are tobacco-free oral nicotine products that deliver nicotine without combustion or aerosol generation. Although they likely expose users to substantially fewer toxicants than combustible cigarettes, evidence supporting their use as smoking cessation therapies remains limited.^63,64 Most available studies focus on toxicant exposure profiles, pharmacokinetics, product appeal, and patterns of use rather than long-term smoking abstinence outcomes.^63-66 Importantly, much of the available evidence regarding noncombustible nicotine products focuses on reductions in toxicant exposure rather than durable smoking cessation outcomes, and these endpoints should not be considered equivalent. Still, evidence supporting their use as cessation tools is sparse and often focuses on toxicant exposure rather than durable clinical outcomes.⁶⁶ When discussing these products, clinicians should distinguish between complete abstinence from combustibles (i.e., conventional cigarettes) and a reduction in combustibles. This clarity helps avoid miscommunication in which “cutting down” is perceived as equivalent to meaningful risk reduction without changes in toxicant exposure or compensatory smoking.

Harm reduction also intersects with vaping cessation and dual-use management. Some patients, including young adults, seek to stop vaping nicotine; randomized trials of automated text-message programs have demonstrated efficacy for vaping cessation among young adult e-cigarette users. For dual users of conventional cigarettes and e-cigarettes, counseling must address both products and avoid unintended substitution of one harmful behavior for another. In primary care, the most defensible approach is to prioritize elimination of combustible exposure while supporting patients in reducing and ultimately discontinuing all nicotine when feasible. Although noncombustible nicotine products may reduce exposure to combustion-related toxicants, the long-term cardiopulmonary and vascular effects of sustained e-cigarette use remain uncertain. In addition, persistent dual use of combustible and noncombustible products may attenuate potential risk reduction and prolong nicotine dependence. In practice, follow-up should assess combustible and noncombustible product use, frequency of dual use, progression toward eliminating combustible exposure, nicotine dependence severity, adverse effects, quit readiness, and progress toward further nicotine reduction or eventual abstinence.

In primary care, harm reduction can be considered for selected patients, particularly those with repeated unsuccessful quit attempts or intolerance to first-line therapies. For patients who are unwilling or unable to quit combustible cigarettes despite optimized evidence-based therapy, clinicians may discuss switching to noncombustible products after failure or intolerance of evidence-based first-line therapies. A structured plan including clear goals, monitoring, and ongoing efforts toward eventual abstinence should be provided. Patients should be advised to avoid long-term dual use, and clinicians and practices should have a plan in place for monitoring, follow-up, and reassessment.

Special Populations

Important disparities persist in tobacco use prevalence, cessation success, and access to evidence-based treatment. Smoking rates remain disproportionately high among individuals with lower socioeconomic status, rural populations, sexual and gender minority groups, and persons with serious mental illness or substance use disorders. Structural barriers, including limited access to counseling, insurance coverage variability, prior authorization requirements, limited reimbursement for counseling, out-of-pocket costs for medications, transportation challenges, digital inequities, and targeted tobacco marketing, contribute to these disparities and limit treatment uptake and continuity. Primary care systems implementing smoking cessation interventions should prioritize equitable access, culturally responsive counseling, and flexible treatment delivery models.^67-69

Smoking prevalence remains substantially elevated among individuals with depression, schizophrenia spectrum disorders, and substance use disorders. These populations often experience higher nicotine dependence severity, greater relapse risk, and lower access to treatment. Nevertheless, evidence supports the effectiveness and safety of evidence-based pharmacotherapy and behavioral interventions in these populations when accompanied by close monitoring and integrated behavioral support.^70-73

In pregnant individuals, behavioral counseling remains the preferred first-line intervention because evidence supporting pharmacotherapy remains limited and safety data are less robust. Intensive counseling, motivational interviewing, pregnancy-specific quitline support, and repeated follow-up visits may improve cessation outcomes during pregnancy.^74,75 These disparities underscore the importance of equitable implementation strategies, culturally responsive counseling, and flexible treatment delivery models within primary care systems.

Implications for Primary Care Practice

PCCs and practices play a central role in identifying, initiating treatment for, and managing tobacco dependence over time. Integrating device-based therapies, digital tools, and harm-reduction strategies into routine practice can expand the reach of evidence-based interventions, especially for patients who do not respond to behavioral counseling and first-line pharmacotherapy. In practice, this means consistently delivering guideline-concordant care, including same-visit pharmacotherapy initiation and proactive behavioral support, with early follow-up to adjust treatment as needed, including extended duration pharmacotherapy or referral to more intensive services rather than repeated unsupported quit attempts.

Device-based and technology-enabled adjuncts are promising but should be reserved for patients with persistent dependence after adequate trials of established therapies, and clear goals, monitoring, and ongoing reassessment should guide their use. Harm reduction may be appropriate for those unable or unwilling to achieve abstinence, but should be approached as a secondary strategy, accompanied by structured plans to avoid long-term dual use and to support eventual cessation of all tobacco and nicotine products. Clinicians should educate patients on the distinctions between reducing combustible tobacco use and achieving meaningful risk reduction, as well as the limitations and uncertainties associated with noncombustible products.

Embedding these interventions into routine primary care workflows through opt-out referral systems, digital support integration, and stepwise care escalation can help overcome barriers to treatment delivery and sustain engagement. Continued evaluation of new technologies and harm-reduction approaches in real-world primary care settings is needed to guide best practices as the landscape of nicotine products and cessation tools evolves. Established pharmacotherapy and behavioral counseling remain the standard of care. Digital and device-based approaches should generally be considered adjunctive or investigational depending on the evidence base (Table 3). Figure 1 provides a stepwise, chronic-care algorithm that is practical for primary care implementation.^9,14

Table 3.

Evidence Status of Smoking Cessation Interventions

Intervention	Evidence strength	Guideline supported	Clinical status
Behavioral counseling + pharmacotherapy	High	Yes	Standard of care
Combination NRT	High	Yes	Standard of care
Varenicline	High	Yes	Standard of care
Bupropion SR	High	Yes	Standard of care
Digital CBT/text support	Moderate	Adjunctive	Emerging adjunct
rTMS	Moderate	Limited specialty role	Adjunctive/select use
E-cigarettes for cessation	Mixed	No	Harm-reduction option
VNS	Low/Preliminary	No	Investigational
EEG wearables	Low/Preliminary	No	Investigational
VR interventions	Low/Preliminary	No	Investigational

Device-based therapies and digital tools can improve access to cessation interventions, particularly in settings with limited access to TTSs or where referrals are not feasible. Digital support and opt-out referral systems can streamline workflows, allowing care teams to deliver guideline-concordant interventions more efficiently and reduce missed opportunities. Multimodal approaches, including harm reduction, offer flexibility for patients with complex needs, supporting individualized care and potentially improving outcomes among those not responsive to standard therapies. Integrating these interventions within routine visits for acute, chronic, or preventive care leverages established patient relationships and continuity of care.

PCC and practices will need to navigate likely challenges in adopting these approaches. Resource constraints, including limited time, staffing, and reimbursement, can make it difficult to deliver and follow up on smoking cessation interventions, particularly when clinicians must also address competing demands across acute, chronic, and preventive health needs. Access to device-based therapies and digital tools may be hindered by cost or patient digital literacy, potentially widening disparities if not implemented equitably. The availability of TTS or behavioral health support also varies widely, and cumbersome or delayed referral processes can reduce the effectiveness of stepped-care models. Economic pressures, such as productivity targets and reimbursement models, may deprioritize preventive interventions, such as smoking cessation, when urgent acute or chronic issues require immediate attention. Managing harm reduction also requires careful counseling and monitoring to avoid unintended consequences, such as long-term dual use or misunderstanding of risk reduction, which can be particularly challenging in brief primary care encounters. Yet, despite these considerations, expanding access to comprehensive tobacco treatment and cessation support through these approaches has the potential to reduce smoking prevalence and associated morbidity and mortality.

This narrative review highlights several strengths, such as digital tools, messaging programs, device-based therapies, and harm-reduction strategies, to support smoking cessation in primary care. However, there are important limitations. The evidence supporting some of these emerging approaches, including neuromodulation, digital therapeutics, and noncombustible nicotine products, is still evolving and often based on early-phase or short-term studies. Additionally, implementation in primary care is challenged by issues of accessibility, cost, and varying levels of patient engagement. The rapid evolution of nicotine products and digital tools may outpace current evidence and guideline recommendations, underscoring the need for ongoing evaluation in real-world settings. Despite these limitations, embedding proactive follow-up, opt-out referral systems, and prioritizing early pharmacotherapy initiation within routine workflows offers a practical way to increase the reach and sustainment of smoking cessation interventions. Continued research and adaptation will be essential to maximize the benefits of these strategies while addressing their inherent challenges.

Conclusions

Smoking cessation remains one of the most impactful interventions in primary care. Approaches that treat nicotine dependence as a chronic, relapsing condition—emphasizing early treatment, proactive follow-up, and timely adjustment—are better aligned with real-world patient needs than episodic care alone.

Pharmacotherapy and behavioral counseling remain the foundation of treatment. However, digital tools, messaging programs, and selected device-based interventions can extend reach and support adherence when used as part of a coordinated care strategy. Harm-reduction approaches may have a role for select patients, particularly those who have not achieved abstinence with standard therapies but should remain secondary to evidence-based treatments.

A pragmatic stepped-care model that integrates these approaches provides a flexible framework for primary care. Future work should prioritize long-term outcomes and identify implementation strategies that improve reach, equity, and sustainability in routine clinical practice.

Footnotes

Acknowledgments

The study team would like to acknowledge the use of Artificial Intelligence (AI) Tools. Undermind was used to assist with the literature search. Grammarly was used for grammar and language editing. ChatGPT (OpenAI) was used to assist with minor editorial revisions for clarity and flow. These tools were used solely for supportive purposes. The authors independently reviewed all sources, verified accuracy, and take full responsibility for the interpretation, writing, and final content of the manuscript.

ORCID iDs

Ivana T. Croghan

Muhamad Y. Elrashidi

Aditya K. Ghosh

Jon O. Ebbert

Author Contributions

All the authors participated in the manuscript concept and design, interpretation of literature findings, drafting and revising the paper, and have seen and approved the final version of the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institutes of Health (NIH), National Cancer Institute (NCI) under Award Number 1R21CA302802 (co-PIs: RT Hurt, IT Croghan).

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RTH is a consultant for Nestlé Nutrition for research activities unrelated to the content of this paper. JOE has a royalty-bearing relationship with Applied Aerosol Technologies. All other authors declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work.

Data Availability Statement

All data supporting the study findings are contained within this manuscript.*

Appendix

References

Cornelius

Loretan

Wang

Jamal

Homa

. Tobacco Product Use Among Adults - United States, 2020. MMWR Morb Mortal Wkly Rep. 2022;71(11):397-405. doi:10.15585/mmwr.mm7111a1.

Cancer Prevention and Early Detection: Facts and Figures 2025-2026. Accessed 13 March 2026.https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer-prevention-and-early-detection-facts-and-figures/2025-cped-files/cped-cff-2025-2026.pdf.Report

World Health Organization . Tobacco. Updated 25 June 2025. https://www.who.int/news-room/fact-sheets/detail/tobacco. Accessed 13 Mar 2026.

Tobacco Collaborators

GBD

. Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet. 2021;397(10292):2337-2360. doi:10.1016/S0140-6736(21)01169-7.

Cornelius

Loretan

Jamal

, et al. Tobacco Product Use Among Adults - United States, 2021. MMWR Morb Mortal Wkly Rep. 2023;72(18):475-483. doi:10.15585/mmwr.mm7218a1.

Reynolds

Dennis

Hasan

, et al. A systematic review of chronic disease management interventions in primary care. BMC Fam Pract. 2018;19(1):11. doi:10.1186/s12875-017-0692-3.

Cai

Chen

Bai

. Global, Regional, and National Burden of Smoking-Related Diseases and Associations With Health Workforce Distribution, 1990-2021: Analysis From the Global Burden of Disease Study 2021. Int J Public Health. 2025;70:1608217. doi:10.3389/ijph.2025.1608217.

VanFrank

Malarcher

Cornelius

Schecter

Jamal

Tynan

. Adult Smoking Cessation - United States, 2022. MMWR Morb Mortal Wkly Rep. 2024;73(29):633-641. doi:10.15585/mmwr.mm7329a1.

Krist

Davidson

Mangione

, et al. Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Persons: US Preventive Services Task Force Recommendation Statement. Jama. 2021;325(3):265-279. doi:10.1001/jama.2020.25019.

10.

Lindson

Pritchard

Hong

Fanshawe

Pipe

Papadakis

. Strategies to improve smoking cessation rates in primary care. Cochrane Database Syst Rev. 2021;9(9):CD011556. doi:10.1002/14651858.CD011556.pub2.

11.

Coleman

SRM

Piper

Byron

Bold

. Dual Use of Combustible Cigarettes and E-cigarettes: a Narrative Review of Current Evidence. Curr Addict Rep. 2022;9(4):353-362. doi:10.1007/s40429-022-00448-1.

12.

Fang

Zhang

Wang

, et al. Effectiveness of eHealth Smoking Cessation Interventions: Systematic Review and Meta-Analysis. J Med Internet Res. 2023;25:e45111. doi:10.2196/45111.

13.

Rigotti

Kruse

Livingstone-Banks

Hartmann-Boyce

. Treatment of Tobacco Smoking: A Review. Jama. 2022;327(6):566-577. doi:10.1001/jama.2022.0395.

14.

Leone

Zhang

Evers-Casey

, et al. Initiating Pharmacologic Treatment in Tobacco-Dependent Adults. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005-1982ST.

15.

Livingstone-Banks

Lindson

Hartmann-Boyce

Aveyard

. Effects of interventions to combat tobacco addiction: Cochrane update of 2019 and 2020 reviews. Addiction. 2022;117(6):1573-1588. doi:10.1111/add.15769.

16.

Lindson

Butler

McRobbie

, et al. Electronic cigarettes for smoking cessation. Cochrane Database Syst Rev. 2025;1(1):Cd010216. doi:10.1002/14651858.CD010216.pub9.

17.

Pluym

Burkhardt

Scherer

. The potential of new nicotine and tobacco products as tools for people who smoke to quit combustible cigarettes - a systematic review of common practices and guidance towards a robust study protocol to measure cessation efficacy. Harm Reduct J. 2024;21(1):130. doi:10.1186/s12954-024-01047-1.

18.

National Comprehensive Cancer Network . NCCN Clinical Practice Guidelines in Oncology: Smoking Cessation. In: National Comprehensive Cancer Network. Updated 2026/04/15. https://www.nccn.org/professionals/physician_gls/pdf/smoking.pdf. Accessed 15 Apr 2026.

19.

Blomqvist

Gunnarsson

Bendtsen

. Effects of a text messaging smoking cessation intervention amongst online help-seekers and primary health care visitors: findings from a randomised controlled trial. BMC Med. 2023;21(1):382. doi:10.1186/s12916-023-03073-5.

20.

Whittaker

Dobson

Garner

. Chatbots for Smoking Cessation: Scoping Review. J Med Internet Res. 2022;24(9):e35556. doi:10.2196/35556.

21.

Bricker

Sullivan

Mull

Santiago-Torres

Lavista Ferres

. Conversational Chatbot for Cigarette Smoking Cessation: Results From the 11-Step User-Centered Design Development Process and Randomized Controlled Trial. JMIR Mhealth Uhealth. 2024;12:e57318. doi:10.2196/57318.

22.

Guo

Chen

Dabbs

. The Effectiveness of Smartphone App-Based Interventions for Assisting Smoking Cessation: Systematic Review and Meta-analysis. J Med Internet Res. 2023;25:e43242. doi:10.2196/43242.

23.

Lindson

Thompson

Ferrey

Lambert

Aveyard

. Motivational interviewing for smoking cessation. Cochrane Database Syst Rev. 2019;7(7):Cd006936. doi:10.1002/14651858.CD006936.pub4.

24.

Department of Veterans Affairs . VA/DoD Clinical Practice Guideline for Tobacco Use Treatment; 2026. https://www.healthquality.va.gov/

25.

Fiore

Baker

. Clinical practice. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231. doi:10.1056/NEJMcp1101512.

26.

Butler

Pill

Stott

. Qualitative study of patients' perceptions of doctors' advice to quit smoking: implications for opportunistic health promotion. BMJ. 1998;316(7148):1878-1881. doi:10.1136/bmj.316.7148.1878.

27.

Prochaska

Benowitz

. Current advances in research in treatment and recovery: Nicotine addiction. Sci Adv. 2019;5(10):eaay9763. doi:10.1126/sciadv.aay9763.

28.

Graham

Amato

Cha

Jacobs

Bottcher

Papandonatos

. Effectiveness of a Vaping Cessation Text Message Program Among Young Adult e-Cigarette Users: A Randomized Clinical Trial. JAMA Intern Med. 2021;181(7):923-930. doi:10.1001/jamainternmed.2021.1793.

29.

Zhou

Huang

Song

, et al. Efficacy of combined varenicline and nicotine replacement therapy compared with varenicline or nicotine replacement therapy alone for smoking cessation: A systematic review and meta-analysis. Addiction. 2026;121(3):499-509. doi:10.1111/add.70235.

30.

Lang

Patel

Fitzpatrick

Lee

McFarland

Good

. Association of the Chantix Recall With US Prescribing of Varenicline and Other Medications for Nicotine Dependence. JAMA Netw Open. 2023;6(2):e2254655. doi:10.1001/jamanetworkopen.2022.54655.

31.

Walker

Howe

Glover

, et al. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014;371(25):2353-2362. doi:10.1056/NEJMoa1407764.

32.

Courtney

McRobbie

Tutka

, et al. Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial. Jama. 2021;326(1):56-64. doi:10.1001/jama.2021.7621.

33.

Hughes

Stead

Hartmann-Boyce

Cahill

Lancaster

. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2014(1):CD000031. doi:10.1002/14651858.CD000031.pub4.

34.

Gourlay

Benowitz

. Is Clonidine an Effective Smoking Cessation Therapy? Drugs. 1995;50(2):197-207. doi:10.2165/00003495-199550020-00001.

35.

Hughes

. Effects of abstinence from tobacco: Valid symptoms and time course. Nicotine & Tobacco Research. 2007;9(3):315-327.

36.

Fiore

Jaen

Baker

, et al. Treating Tobacco Use and Dependence: 2008 Update, Clinical Practice Guideline. In: Executive Summary. U.S. Department of Health and Human Services. Public Health Service. https://www.rcjournal.com/contents/09.08/09.08.1217.pdf. Accessed 1 April 2011, 2011.

37.

Sun

Zeng

. Effect of Smoking Reduction Therapy on Smoking Cessation for Smokers without an Intention to Quit: An Updated Systematic Review and Meta-Analysis of Randomized Controlled. Int J Environ Res Public Health. 2015;12(9):10235-10253. doi:10.3390/ijerph120910235.

38.

McBride

Emmons

Lipkus

. Understanding the potential of teachable moments: the case of smoking cessation. Health Education Research. 2003;18(2):156-170.

39.

Bailey

Stevens

Fortmann

, et al. Long-Term Outcomes From Repeated Smoking Cessation Assistance in Routine Primary Care. Am J Health Promot. 2018;32(7):1582-1590. doi:10.1177/0890117118761886.

40.

Breitling

Rothenbacher

Stegmaier

Raum

Brenner

. Older smokers' motivation and attempts to quit smoking: epidemiological insight into the question of lifestyle versus addiction. Dtsch Arztebl Int. 2009;106(27):451-455. doi:10.3238/arztebl.2009.0451.

41.

Jose

Ohde

Hays

Burke

Warner

. Design and Pilot Implementation of an Electronic Health Record-Based System to Automatically Refer Cancer Patients to Tobacco Use Treatment. Int J Environ Res Public Health. 2020;17(11). doi:10.3390/ijerph17114054.

42.

Richter

Catley

Gajewski

, et al. The Effects of Opt-out vs Opt-in Tobacco Treatment on Engagement, Cessation, and Costs: A Randomized Clinical Trial. JAMA Intern Med. 2023;183(4):331-339. doi:10.1001/jamainternmed.2022.7170.

43.

Vidrine

Shete

, et al. The Ask-Advise-Connect approach for smokers in a safety net healthcare system: a group-randomized trial. Am J Prev Med. 2013;45(6):737-741. doi:10.1016/j.amepre.2013.07.011.

44.

Bricker

Watson

Mull

Sullivan

Heffner

. Efficacy of Smartphone Applications for Smoking Cessation: A Randomized Clinical Trial. JAMA Intern Med. 2020;180(11):1472-1480. doi:10.1001/jamainternmed.2020.4055.

45.

Marler

Fujii

Utley

Balbierz

Galanko

Utley

. Outcomes of a Comprehensive Mobile Smoking Cessation Program With Nicotine Replacement Therapy in Adult Smokers: Pilot Randomized Controlled Trial. JMIR Mhealth Uhealth. 2022;10(11):e41658. doi:10.2196/41658.

46.

Webb

Peerbux

Ang

, et al. Long-Term Effectiveness of a Clinician-Assisted Digital Cognitive Behavioral Therapy Intervention for Smoking Cessation: Secondary Outcomes From a Randomized Controlled Trial. Nicotine Tob Res. 2022;24(11):1763-1772. doi:10.1093/ntr/ntac113.

47.

Whittaker

McRobbie

Bullen

Rodgers

Dobson

. Mobile phone text messaging and app-based interventions for smoking cessation. Cochrane Database Syst Rev. 2019;10(10):Cd006611. doi:10.1002/14651858.CD006611.pub5.

48.

Dinur-Klein

Dannon

Hadar

, et al. Smoking cessation induced by deep repetitive transcranial magnetic stimulation of the prefrontal and insular cortices: a prospective, randomized controlled trial. Biol Psychiatry. 2014;76(9):742-749. doi:10.1016/j.biopsych.2014.05.020.

49.

Zangen

Moshe

Martinez

, et al. Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial. World Psychiatry. 2021;20(3):397-404. doi:10.1002/wps.20905.

50.

Farmer

Strzelczyk

Finisguerra

, et al. International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020). Front Hum Neurosci. 2020;14:568051. doi:10.3389/fnhum.2020.568051.

51.

Yuan

Silberstein

. Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part I. Headache. 2016;56(1):71-78. doi:10.1111/head.12647.

52.

gov

. A Study Of Vagal Nerve Stimulation In Conjunction With NRT For Smoking Cessation. Identifier NCT07487818. https://clinicaltrials.gov/study/NCT07487818. Updated 2026. Accessed 23 June 2026.

53.

Ghosh

Nanda

Hurt

, et al. Mindfulness Using a Wearable Brain Sensing Device for Health Care Professionals During a Pandemic: A Pilot Program. J Prim Care Community Health. 2023;14:21501319231162308. doi:10.1177/21501319231162308.

54.

Hurt

Ganesh

Schroeder

, et al. Using a Wearable Brain Activity Sensing Device in the Treatment of Long COVID Symptoms in an Open-Label Clinical Trial. J Prim Care Community Health. 2025;16:21501319251325639. doi:10.1177/21501319251325639.

55.

Millstine

Bhagra

Jenkins

, et al. Use of a Wearable EEG Headband as a Meditation Device for Women With Newly Diagnosed Breast Cancer: A Randomized Controlled Trial. Integr Cancer Ther. 2019;18:1534735419878770. doi:10.1177/1534735419878770.

56.

Tatnell

Atorkey

Tzelepis

. The Effectiveness of Virtual Reality Interventions on Smoking, Nutrition, Alcohol, Physical Activity and/or Obesity Risk Factors: A Systematic Review. Int J Environ Res Public Health. 2022;19(17):10821. doi:10.3390/ijerph191710821.

57.

Croghan

Hurt

Aakre

, et al. Virtual Reality for Health Care Professionals During a Pandemic: A Pilot Program. J Prim Care Community Health. 2022;13:21501319221086716. doi:10.1177/21501319221086716.

58.

Tamburin

Dal Lago

Armani

, et al. Smoking-related cue reactivity in a virtual reality setting: association between craving and EEG measures. Psychopharmacology (Berl). 2021;238(5):1363-1371. doi:10.1007/s00213-020-05733-3.

59.

Kroczek

Schröder

Rosenbaum

, et al. Virtual reality cue exposure as an add-on to smoking cessation group therapy: a randomized controlled trial. Addiction Science & Clinical Practice. 2025;20(1):34. doi:10.1186/s13722-025-00561-2.

60.

Schröder

Kroczek

LOH

Ehlis

A-C

Batra

Mühlberger

. Cigarette craving in virtual reality cue exposure in abstainers and relapsed smokers. Scientific Reports. 2024;14(1):7538. doi:10.1038/s41598-024-58168-7.

61.

Lindson-Hawley

Hartmann-Boyce

Fanshawe

Begh

Farley

Lancaster

. Interventions to reduce harm from continued tobacco use. Cochrane Database of Systematic Reviews. 2016;10(10):CD005231. doi:10.1002/14651858.CD005231.pub3.

62.

American Society of Addiction M . Integrating Tobacco Use Disorder Interventions in Addiction Treatment: A Guide for Addiction Treatment Clinicians and Programs. https://www.asam.org

63.

Azzopardi

Liu

Murphy

. Chemical characterization of tobacco-free “modern” oral nicotine pouches and their position on the toxicant and risk continuums. Drug and Chemical Toxicology. 2021;45(5):2246-2254. doi:10.1080/01480545.2021.1925691.

64.

Lunell

Fagerström

Hughes

Pendrill

. Pharmacokinetic Comparison of a Novel Non-tobacco-Based Nicotine Pouch (ZYN) With Conventional, Tobacco-Based Swedish Snus and American Moist Snuff. Nicotine & Tobacco Research. 2020;22(10):1757-1763. doi:10.1093/ntr/ntaa068.

65.

Mallock-Ohnesorg

Rabenstein

Stoll

, et al. Small pouches, but high nicotine doses—nicotine delivery and acute effects after use of tobacco-free nicotine pouches. Original Research. Frontiers in Pharmacology. 2024:15-2024doi. doi:10.3389/fphar.2024.1392027.

66.

O'Connor

Schneller

Felicione

Talhout

Goniewicz

Ashley

. Evolution of tobacco products: recent history and future directions. Tob Control. 2022;31(2):175-182. doi:10.1136/tobaccocontrol-2021-056544.

67.

Doogan

Roberts

Wewers

, et al. A growing geographic disparity: Rural and urban cigarette smoking trends in the United States. Prev Med. 2017;104:79-85. doi:10.1016/j.ypmed.2017.03.011.

68.

Johnson

Holder-Hayes

Tessman

King

Alexander

Zhao

. Tobacco Product Use Among Sexual Minority Adults: Findings From the 2012-2013 National Adult Tobacco Survey. Am J Prev Med. 2016;50(4):e91-e100. doi:10.1016/j.amepre.2015.07.041.

69.

Cokkinides

Halpern

Barbeau

Ward

Thun

. Racial and ethnic disparities in smoking-cessation interventions: analysis of the 2005 National Health Interview Survey. American Journal of Preventive Medicine. 2008;34(5):404-412. doi:10.1016/j.amepre.2008.02.003.

70.

Cook

Wayne

Kafali

Liu

Shu

Flores

. Trends in smoking among adults with mental illness and association between mental health treatment and smoking cessation. JAMA. 2014;311(2):172-182. doi:10.1001/jama.2013.284985.

71.

Dickerson

Schroeder

Katsafanas

, et al. Cigarette Smoking by Patients With Serious Mental Illness, 1999-2016: An Increasing Disparity. Psychiatr Serv. 2018;69(2):147-153. doi:10.1176/appi.ps.201700118.

72.

Prochaska

. Smoking and mental illness--breaking the link. The New England journal of medicine. 2011;365(3):196-198. doi:10.1056/NEJMp1105248.

73.

Anthenelli

Benowitz

West

, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507-2520. doi:10.1016/s0140-6736(16)30272-0.

74.

Chamberlain

O'Mara-Eves

Porter

, et al. Psychosocial interventions for supporting women to stop smoking in pregnancy. Cochrane Database Syst Rev. 2017;2(2):CD001055. doi:10.1002/14651858.CD001055.pub5.

75.

Coleman

Chamberlain

Davey

Cooper

Leonardi-Bee

. Pharmacological interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev. 2015(12):CD010078. doi:10.1002/14651858.CD010078.pub2.