Varenicline attenuates some of the subjective and physiological effects of intravenous nicotine in humans

Rationale: Varenicline, a partial nicotinic acetylcholine receptor (nAChR) agonist, is approved for smoking cessation. A few preclinical studies examined the pharmacological effects of varenicline, alone or in combination with nicotine. How varenicline affects the pharmacological effects of pure nicotine has not been examined in humans. The goal of this study was to characterize varenicline's actions on nicotine's dose-dependent effects in abstinent smokers. Methods: Six male and six female smokers participated in a double-blind, placebo-controlled, crossover study. Smokers had two 4-day treatment periods, assigned in random sequence, to varenicline (1 mg/day) or placebo treatment. On day∈4 of each treatment phase, smokers had an experimental session, where they received three escalating doses of intravenous (IV) nicotine (0.1, 0.4, and 0.7 mg/70 kg), in 30-min intervals. Varenicline's effects were assessed through subjective, physiological, and cognitive performance outcomes to nicotine administered via IV route. Results: In response to IV nicotine, varenicline treatment attenuated the rating of drug strength, high, head rush, and stimulated. Varenicline also attenuated nicotine-induced increases in heart rate. Varenicline had mixed effects on cognitive performance. Smokers under varenicline treatment, compared with placebo, reported enhanced positive mood measured with the Positive and Negative Affect Schedule. Conclusions: These findings provide new insights into the mechanisms of action of varenicline in smoking cessation.