Combination bupropion–zonisamide facilitates rapid reduction in smoke exposure and prevents weight gain during switching to electronic nicotine delivery systems: A randomized clinical trial

INTRODUCTION: A pilot study suggested that the combination of bupropion (BUP) and zonisamide (ZON) could facilitate smoking reduction during switching to an electronic nicotine delivery system (ENDS). This randomized controlled trial tested the hypothesis that BUP/ZON would produce greater smoking reduction than BUP alone or placebo (PLAC). METHODS: Adults who smoked cigarettes, but were not seeking cessation treatment, were asked to switch to ENDS provided during study Weeks 1-12. Participants were randomized to receive BUP/ZON, BUP, or PLAC (N = 60 per group) during Weeks 2-8. Assessments included exhaled carbon monoxide (eCO), self-reported cigarette and ENDS use, dependence level, withdrawal symptoms, reward ratings, body weight, and adverse events. Outcomes were analyzed using modified intent-to-treat (mITT), complete-case, and per-protocol treatment-adherent samples (≥80% medication adherence). RESULTS: The mITT analysis showed no treatment differences in end-of-treatment eCO but higher smoking abstinence rates in both active treatment groups than PLAC (26.7% BUP/ZON, 25.0% BUP, 10.0% PLAC). In the per-protocol sample, eCO was significantly lower with BUP/ZON than with BUP or PLAC. Early reductions in eCO during the first treatment week-more common with BUP/ZON-strongly predicted later outcomes. Exploratory complete-case analyses showed lower tobacco dependence and craving in BUP/ZON than control groups. Weight gain occurred in BUP and PLAC, whereas weight loss was observed in BUP/ZON. CONCLUSIONS: Bupropion plus zonisamide shows promise for smoking reduction and cessation, particularly when medication adherence is maintained. Prevention of post-cessation weight gain may offer additional clinical and public health benefits. Larger trials with longer treatment duration are warranted.