Addiction · Feb 20, 2026

Personalizing smoking cessation pharmacotherapy using neuroaffective reactivity profiles: A randomized controlled trial

By Versace F, Green CE, Cui Y et al.

BACKGROUND AND AIMS: By assessing neuroaffective response to motivationally relevant cues before a quit attempt, we have shown that smokers who attribute greater incentive salience to cigarette-related cues than non-cigarette-related rewards (Sign-trackers, ST) benefit more from varenicline compared with smokers with the opposite neuroaffective reactivity profile (Goal-trackers, GT). This proof-of-concept trial aimed to extend this work by testing whether the efficacy of varenicline relative to nicotine replacement treatment differs across the two neuroaffective reactivity profiles. DESIGN: A 2-group, double-blind, randomized controlled clinical trial with stratification on ST versus GT classification (based on baseline-assessed neuroaffective reactivity profiles) for adults seeking to quit smoking using varenicline or nicotine replacement therapy (NRT). SETTING: Hospital-based outpatient clinic specializing in smoking cessation treatment, located in Houston, Texas, USA. PARTICIPANTS: 158 community volunteers (78 randomized to varenicline and 80 to NRT): 18-75 years of age, smoking 5 or more cigarettes/day and without severe comorbid psychiatric disorders, uncontrolled medical illnesses or contraindications for pharmacotherapy. INTERVENTIONS AND COMPARATORS: Twelve weeks of varenicline or NRT combined with brief cessation counseling. MEASUREMENTS: Primary outcome: continuous smoking abstinence over the last 4 weeks of treatment. SECONDARY OUTCOMES: continuous abstinence at 3- and 6-month follow-ups. FINDINGS: Using a Bayesian approach, we estimated the probability that an interaction between treatment and neuroaffective profile exists. We pre-specified a probability above 80% as evidence for an interaction. Logistic regression indicated a 92.7% probability that an interaction between treatment and neuroaffective profile exists, exceeding the pre-specified threshold. Individuals with the ST profile responded better to varenicline than to NRT. At the end of treatment, the ST group showed a 35% Absolute Risk Difference (ARD) favoring varenicline over NRT (absolute cessation rates: 47% and 11%, respectively). In contrast, among individuals with the GT profile, the benefit of varenicline was smaller, with an ARD of 13% (absolute cessation rates of 29% for varenicline and 17% for NRT). The varenicline advantage for the ST group persisted at 3- and 6-month follow-ups. CONCLUSIONS: Smokers seeking to quit who attribute greater incentive salience to cigarette-related cues than non-cigarette-related rewards benefit more from varenicline than from nicotine replacement therapy. These findings support using neuroaffective biomarkers to inform personalized smoking cessation interventions.

doi.org/10.1111/add.70354Open accessPubMed 41720599Interventions