AAV-only targeting of ventral tegmental area dopamine neurons for optical self-stimulation studies in mice.

In 2022, the US Food and Drug Administration (FDA) announced intentions to reduce the nicotine in cigarettes and other combustible tobacco products to minimally addictive levels to promote cessation and reduce smoking-related harm. A nicotine reduction standard (NRS) will apply to all cigarettes on the market, including menthol cigarettes, which account for 36% of the cigarette market share. Despite reductions in overall smoking prevalence, menthol cigarette smoking increased in young adult smokers from 2008 to 2019, while non-menthol smoking decreased in this age group of individuals who smoke during this same time period. Menthol masks the harshness of inhaled cigarette smoke contributing to nicotine reinforcement, smoking initiation and progression, and greater nicotine dependence. In addition to the primary reinforcing effects of menthol (pleasurable taste and sensory effects), menthol can also become a conditioned reinforcer following repeated pairing with nicotine, thus able to maintain responding even when nicotine is removed. This pairing between nicotine delivery and menthol likely strengthens the learned association between smoking and reward, beyond nicotine alone. As such, even the presence of very low nicotine levels paired with menthol could maintain the potency and reinforcing value of smoking because menthol is naturally pleasant, or because menthol has become a conditioned reinforcer that perpetuates smoking behavior, and thus nicotine exposure. If this were true, it could mean that an NRS may have little impact on reducing young adults’ appeal to smoke if menthol is not also targeted. This has not yet been examined. Clinical trials report reductions in smoking, subjective reinforcement from smoking, biomarkers of harm/exposure, and increases in quit attempts among adults who smoke using very low nicotine cigarettes (VLNCs). Other research found greater reductions in smoking reinforcement when young adult vs older adult smokers used VLNCs. Only a handful of longitudinal studies have examined the influence of menthol preference on VLNC use and subjective appeal. In a secondary analysis of a 20-week clinical trial, the effects of VLNCs were compared to normal nicotine cigarettes (NNCs) among individuals who smoke menthol and non-menthol, with VLNC flavor matched to baseline flavor preference. Use of both menthol or non-menthol VLNCs was associated with reductions in smoking and toxicant exposure a relative to the use of NNCs. However, those using menthol (vs non-menthol) VLNCs had smaller reductions in the number of cigarettes smoked per day and toxicant exposure, as well as decreased odds of abstinence. A pooled analysis among adults who smoke with low SES or mental health conditions who used VLNCs for 18 weeks found non-significant effects of menthol preference on reductions in cigarettes per day and nicotine dependence; though those who smoked menthol did show lower reductions in cotinine. These studies suggest that the benefits of an NRS may be attenuated among individuals who smoke menthol, although Onken et al (2023) did not find differences over time in cigarette smoking among women using menthol or non-menthol VLNCs. No work has compared differences in biomarkers of exposure and subjective appeal across those using both menthol and non-menthol VLNCs, nor has any work focused specifically on young adults who smoke menthol cigarettes.