The increased susceptibility to developing nicotine dependence encountered by youth who are slow metabolizers compared to normal metabolizers has been hypothesized to reflect prolonged exposure to nicotine because of its longer half-life during initial smoking experiences (Chenoweth et al., 2013; Malaiyandi et al., 2005; Rubinstein et al., 2013). Although accumulating evidence supports this role, it is important to note that a few studies show the opposite effect where slow metabolism is associated with decreased risk of smoking behaviors in youth (Audrain-McGovern et al., 2007; Moolchan et al., 2009; Rubinstein et al., 2008). For example, Audrain-McGovern (2007) examined 222 adolescent ever-smokers of European ancestry and found that normal CYP2A6 metabolizers developed symptoms of dependence at a faster rate than slower CYP2A6 metabolizers. Other studies suggest that the increased risk of slower metabolizers for developing nicotine dependence in adolescence disappears by young adulthood (Chenoweth et al., 2016). Cannon et al. (2016) followed 296 participants across ages 16–24 and found that using a CYP2A6 diplotype predictive metric, intermediate metabolism compared to slow and normal was a risk factor for smoking frequency and nicotine
