Background: Menthol upregulates nicotinic acetylcholine receptors and is associated with tobacco dependence. The effects of menthol when smoking cigarettes with varying low nicotine content up to 98 % (e.g., non-addicting) less than commercial cigarettes is not well understood. The U.S. Food and Drug Administration is considering two tobacco product standards in cigarettes including banning menthol and reducing nicotine content. These new standards have the potential to significantly reduce smoking initiation and maintenance by limiting the mechanistic effects of nicotine and menthol on the brain. Methods: We conducted two parallel randomized clinical trials of gradually reduced nicotine in cigarettes from 11.6 mg down to 0.2 mg nicotine/cigarette (very low nicotine content; VLNC) vs. usual nicotine content (11.6 mg; UNC) over an 18-week period in people who smoke cigarettes with low socioeconomic status (SES) and mental health conditions. Results: Compared to UNC, VLNC was associated with significant reductions in cotinine, cigarettes per day, expired carbon monoxide levels, nicotine dependence and symptomology. These associations did not differ between menthol and non-menthol cigarettes, except people who smoke menthol cigarettes had less of a cotinine reduction in the SES trial. The pooled odds ratio of being adherent with using only VLNC study cigarettes in the gradual nicotine reduction arm for people who smoke non-menthol vs. menthol cigarettes was 2.6 (95 % CI:1.0, 6.4; p-value: 0.04). Conclusions: When nicotine is lowered to non-addicting levels, the results indicate an independent effect of menthol on the need to sustain nicotine intake in addicted people who smoke cigarettes.

Original languageEnglish (US)
Pages (from-to)131-138
Number of pages8
JournalBrain Research Bulletin
StatePublished - Oct 15 2022

All Science Journal Classification (ASJC) codes

  • General Neuroscience


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