Acute effects of inhaled menthol on the rewarding effects of intravenous nicotine in smokers

Objective: This double-blind, placebo controlled study examined whether menthol inhaled from an electronic cigarette (e-cigarette) would change subjective and withdrawal alleviating effects of intravenous nicotine in young adult smokers. Methods: A total of 32 menthol-preferring smokers and 25 non-menthol-preferring smokers participated in the study that consisted of a random sequence of three different inhaled menthol conditions (0.0%, 0.5%, and 3.2%) across three test sessions (a single menthol condition per session). In each test session (performed at least 24 hours apart), a random order of saline, and two different nicotine infusions of 0.25 mg and 0.5 mg/70 kg of bodyweight were administered, one hour apart, concurrent with menthol inhalation. Results: While menthol did not alter the positive subjective effects of nicotine, menthol significantly enhanced aversive effects of nicotine in non-menthol-preferring smokers and reduced smoking urges in menthol-preferring smokers. In addition, menthol-preferring smokers reported blunted positive subjective responses to nicotine and less severe nicotine withdrawal after overnight nicotine deprivation. Finally, compared to non-menthol-preferring smokers, menthol-preferring smokers had a significantly lower baseline nicotine metabolite ratio indicating slower nicotine metabolism within our sample of menthol-preferring smokers. Conclusions: Our findings did not support an enhancement of nicotine's positive subjective effects from inhaled menthol. However, as compared to non-menthol-preferring smokers, menthol-preferring smokers had blunted positive subjective responses to nicotine and reduced overnight withdrawal severity that may be partly due to inhibition of nicotine metabolism from chronic exposure to inhaled menthol. Collectively, these results reveal a more complex and nuanced role of inhaled menthol in smokers than previously recognized.