INTRODUCTION: Psychomotor restlessness and agitation (PMA)-unintentional motor activity (e.g., fidgeting, pacing) stemming from mental tension-is a transdiagnostic psychopathological trait linked to several psychiatric conditions comorbid with tobacco dependence. Prior work suggests that PMA is cross-sectionally associated with retrospective reports of more severe tobacco withdrawal during prior quit attempts. Whether PMA is associated with tobacco withdrawal symptoms during experimentally-manipulated smoking abstinence is currently unknown. This study investigated PMA as a predictor of tobacco withdrawal symptom severity using a controlled laboratory design in a non-clinical sample of adults who smoke cigarettes daily. METHOD: Participants (N = 778
37.5% Female
M [SD] age = 47 years [11.2]) attended a baseline session that assessed PMA severity. Participants then attended two counterbalanced sessions (one preceded by 16-hr tobacco abstinence vs. non-abstinence) where they completed self-report questionnaires on urges to smoke, nicotine withdrawal symptoms, positive and negative affect states, and a task assessing smoking lapse behavior. RESULTS: Higher PMA at baseline was positively associated with abstinence-induced increases in urges to smoke, nicotine withdrawal symptoms, several negative affect states, cognition (in covariate-adjusted analyses), and smoking reinstatement behavior (in unadjusted, but not adjusted analyses). Trait PMA was not associated with abstinence-induced changes in positive affect states. CONCLUSIONS: Higher trait PMA may heighten vulnerability to experiencing more severe smoking urges, nicotine withdrawal, negative affect, confusion, and (to some extent) motivation to reinstate smoking during acute smoking abstinence. These findings may inform precision medicine approaches and the development of tailored interventions for populations with PMA during smoking cessation. IMPLICATIONS: This study shows how psychomotor restlessness and agitation-a transdiagnostic psychopathological trait-is associated with cognitive, affective, and behavioral features of tobacco withdrawal in a non-clinical sample of adults who smoke cigarettes daily. The implications of our findings may inform precision medicine approaches and the development of tailored interventions that address PMA during smoking cessation.