Ketamine-enhanced psychotherapy for smoking cessation: A pilot study of feasibility, safety, and clinical outcomes

BACKGROUND: Tobacco use remains a leading preventable cause of morbidity and mortality. Although several pharmacotherapies and behavioral treatments for tobacco use disorder (TUD) exist, their overall efficacy is modest, underscoring the need for innovative treatment approaches. Ketamine, a rapid-acting glutamate receptor antagonist with neuroplasticity-enhancing properties, has shown promise in the treatment of other substance use disorders. Combining ketamine with motivational enhancement therapy (MET) may complement behavioral treatment in TUD by facilitating cognitive and psychological flexibility while strengthening individuals' ability to quit smoking. OBJECTIVE: The primary aim of this open-label pilot study was to evaluate the feasibility and preliminary clinical outcomes of ketamine treatments delivered in conjunction with MET for smoking cessation in individuals with TUD. METHODS: Seven cigarette smokers (ages 29-64) with a history of unsuccessful quit attempts underwent three weekly intramuscular ketamine sessions (0.71 mg/kg) combined with MET. Feasibility, the primary outcome, was assessed by study completion rates. Secondary outcomes included changes in smoking patterns, craving, nicotine dependence, withdrawal, and motivation to quit. RESULTS: All participants completed the interventional sessions. Ketamine sessions were well-tolerated, and no adverse events other than the expected transient psychoactive effects were observed. Cigarette consumption decreased, accompanied by reductions in nicotine craving. Withdrawal symptoms, nicotine dependence severity, and motivation to quit remained stable. CONCLUSIONS: Ketamine-enhanced psychotherapy for TUD was feasible and was associated with reductions in smoking and craving. These preliminary findings support further trials investigating ketamine's potential to enhance behavioral interventions for addiction.