Does menthol affect nicotine's impact on brain reinforcement mechanisms in dependent and nondependent users of electronic nicotine delivery systems?

The use of Electronic Nicotine DeliverySystems (ENDS) is increasing significantly in Canada. Evidence suggests that the presence of flavouring is associated with both the initiation of ENDS use and their continued use. Although several jurisdictions have initiated bans on certain flavourings of ENDS, menthol, a common flavour additive in ENDS, is often exempt from such bans. Nicotine, the primary active ingredient in ENDS, is widely assumed to be responsible for their addictive potential; however, there is growing evidence that nicotine addiction can be impacted by menthol. For example, in animal studies menthol has been demonstrated to modulate the actions of nicotine receptors in the brain areas that are known to be involved in addiction. Our group recently reported that menthol-containing flavoured nicotine inhalers significantly altered neural responses in brain regions known to be involved in nicotine addiction. However, this study did not include unflavoured inhaler conditions. In the proposed research, we aim to determine the separate and combined effects of nicotine and menthol on subjective and neural responses, in two sex-balanced samples of ENDS users, occasional non- dependent users (ONUs) and daily dependent users (DDUs). It is expected that menthol will increase the magnitude of nicotine related effects on neural responses in each sample, but that for DDUs this will primarily involve areas linked to the expression of withdrawal and for ONUs these effects will be related to brain regions involved in reward. We plan to conduct a four-session experiment that will include male and female ENDS users. Participants will receive nicotine inhalers during two conditions, and nicotine-free inhalers during the others. For each type of inhaler, half the sessions will involve the co-administration of menthol and half will not. Across conditions, brain responses will be measured using magnetic resonance imaging before and after inhaler administration.