Another important consideration is that the fraction of slow metabolizers in the population of smokers has been observed to decrease with age, suggesting that slow metabolizers are more likely to quit smoking (Benowitz, 2008) (step 4 in Figure 3). In the COGEND dataset, among current nicotine dependent smokers ages 25–30 years, we found that 36% (60/166) were slow metabolizers. However, among current nicotine dependent smokers over 30 years old, only 28% (250/883) were slow metabolizers (Chi-square, p=0.04), supporting that proportionally more slow metabolizers have quit by this time. Furthermore, other studies directly support that slow nicotine metabolism, measured by CYP2A6 genotypes or the nicotine metabolite ratio, is associated with increased cessation rates in both youth (Chenoweth et al., 2013) and adults enrolled in clinical trials (Chen et al., 2014; Ray et al., 2009). Taken together, these findings suggest that across development, slow metabolizers may quit smoking more easily. Therefore, the observation that slow metabolism is associated with increased risk of nicotine dependence may be most pronounced in samples of youth when symptoms of dependence are first developing and before cessation attempts occur.
