Impact of CYP2A6 Activity on Nicotine Reinforcement and Cue-Reactivity in Daily Smokers

Abstract

Introduction Variation in CYP2A6, the primary enzyme responsible for nicotine metabolism, is associated with nicotine dependence, cigarette consumption, and abstinence outcomes in smokers. The impact of CYP2A6 activity on nicotine reinforcement and tobacco cue-reactivity, mechanisms that may contribute to these previous associations, has not been fully evaluated. Methods CYP2A6 activity was indexed using three genetic approaches in 104 daily smokers completing forced-choice and cue-induced craving tasks assessing nicotine reinforcement and tobacco cue-reactivity, respectively. First, smokers were stratified by the presence or absence of reduced/loss of function CYP2A6 gene variants (normal vs. reduced metabolizers). As nicotine metabolite ratio (NMR) is a reliable biomarker of CYP2A6 activity, our second and third approaches used additional genetic variants identified in genome-wide association studies of NMR to create a weighted genetic risk score (wGRS) to stratify smokers (fast vs. slow metabolizers) and calculate a wGRS-derived NMR. Results Controlling for race and sex, normal metabolizers (vs. reduced) selected a greater proportion of puffs from nicotine-containing cigarettes (vs. denicotinized) on the forced-choice task (p=0.031). In confirmatory analyses, wGRS-based stratification (fast vs. slow metabolizers) produced similar findings. Additionally, wGRS-derived NMR, which correlated with actual NMR assessed in a subset of participants (n=55), was positively associated with the proportion of puffs from nicotine-containing cigarettes controlling for race and sex (p=0.015). None of the CYP2A6 indices were associated with tobacco cue-reactivity in minimally deprived smokers. Conclusions Findings suggest increased nicotine reinforcement is exhibited by smokers with high CYP2A6 activity, which may contribute to heavier smoking and poorer cessation outcomes previously reported in faster metabolizers. Implications CYP2A6 activity is a key determinant of smoking behaviour and outcomes. Therefore, these findings support the targeting of CYP2A6 activity, either therapeutically or as a clinically relevant biomarker in a precision medicine approach, for tobacco use disorder treatment.

Threshold for the pleasurable effects of nicotine are lower than its reinforcing effects during self-administration.

“…In previous human studies, NMR has been associated with smoking heaviness, greater reinforcement from cigarettes, and IV nicotine (Benowitz et al, 2003; Butler et al, 2021; Sofuoglu et al, 2012). Previous studies used various cutoff points to separate slower from faster nicotine metabolizers, but there is no agreed-upon cutoff to separate these groups (Siegel et al, 2020).…”

“…In previous human studies, NMR has been associated with smoking heaviness, greater reinforcement from cigarettes, and IV nicotine (Benowitz et al, 2003;Butler et al, 2021;.…”

“…Based on previous work, we hypothesized that greater baseline cigarette craving and withdrawal severity would be associated with a greater percentage of nicotine choice over placebo (i.e., greater nicotine reinforcement) during NSA. Similarly, higher NMR has previously been associated with greater cigarette consumption (Benowitz et al, 2003; Butler et al, 2021) and positive subjective effects from nicotine (Sofuoglu et al, 2012). However, similar to craving and withdrawal, the impact of NMR on the reinforcement threshold is unknown.…”

“…In previous human studies, NMR has been associated with smoking heaviness, greater reinforcement from cigarettes, and IV nicotine (Benowitz et al, 2003;Butler et al, 2021;. Previous studies used various cutoff points to separate slower from This document is copyrighted by the American Psychological Association or one of its allied publishers.…”

Inhibition of Nicotine Metabolism by Cannabidiol (CBD) and 7-Hydroxycannabidiol (7-OH-CBD)

“…75 In addition, a predictive nicotine metabolism model based on CYP2A6 haplotypes showed a similar association between nicotine oxidation to cotinine and cpd in African American smokers, 76 and recent clinical studies recommend the targeting of CYP2A6 activity for tobacco use disorder treatment. 77 Therefore, with the vast majority of the population having active CYP2A6, pharmacological reduction of CYP2A6 activity is expected to mimic the effects of naturally occurring CYP2A6 variants in the human population, reducing both smoking behavior and dependence. In a previous randomized, double-blind placebo-controlled study, the ad-hoc use of CBD by inhaler in cigarette smokers resulted in a significant ∼40% reduction of the number of cigarettes smoked during treatment.…”