These findings in young adults should be considered in the context of the literature about adult smoking. Previous studies of adults demonstrate that once dependent, slower metabolizers smoke fewer cigarettes to reach target blood nicotine levels (Benowitz, 2008) (step 3 in Figure 3). Although we did not observe an effect of slow metabolism on risk of smoking more than 20 cigarettes per day among daily smokers (Table 2, Figure 2), only 26% of these young adults were heavy smokers, and heaviness of smoking continues to increase throughout adulthood (NSDUH, 2015). In the entire COGEND sample ages 25–45, a previous analysis demonstrated that among nicotine dependent smokers, slower metabolism is associated with decreased cigarette consumption (Bloom et al., 2012). It is possible that slow metabolism is primarily protective at high levels of cigarette consumption, which is most evident in older populations of adults. Overall, these findings underscore that variation in CYP2A6 has a variety of effects on smoking behaviors across stages of development: slow metabolism leads to increased risk for developing nicotine dependence in young adult daily smokers through time to first cigarette, but once dependent, slow metabolism is protective against heaviness of smoking.
