Inhibition of CYP2A6-mediated nicotine metabolism: A potential strategy for smoking cessation therapy

Despite the availability of US Food and Drug Administration-approved pharmacotherapies, smoking continues to be a significant public health problem, with long-term cessation rates often falling below 20%. The cytochrome P450 2A6 (CYP2A6) enzyme plays a critical role in nicotine metabolism, and individuals with genetically reduced CYP2A6 activity exhibit slower nicotine clearance, lower cigarette consumption, and greater cessation success. This observation has led researchers to explore pharmacological inhibition of CYP2A6 as a strategy to aid in smoking cessation. In this review, we discuss 4 CYP2A6 inhibitors, methoxsalen, tranylcypromine, 5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine, and cannabidiol, describing their potency, translational potential, and safety considerations. Methoxsalen, a mechanism-based inactivator, inhibits nicotine metabolism in both animals and humans, but there are concerns about its phototoxicity and off-target effects. Tranylcypromine, although a competitive inhibitor of CYP2A6, may also increase nicotine consumption via monoaminergic effects, thereby limiting its practical use in cessation therapies. 5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine is a novel synthetic inhibitor with unprecedented potency and specificity in vitro, but lacks clinical validation to support this claim. Cannabidiol is a promising dual-action candidate because it inhibits CYP2A6 in vitro and reduces nicotine intake in rodents, as well as reduces cigarette use and cue reactivity in early human trials. Although these findings emphasize the therapeutic potential of targeting CYP2A6 in smoking cessation efforts, additional validation is required for clinical translation. These include the need for robust human pharmacokinetic studies, long-term safety evaluations, and assessment across genetically diverse populations. With additional research, CYP2A6 inhibition could become a practical and personalized way to improve smoking cessation outcomes. SIGNIFICANCE STATEMENT: This study highlights the clinical significance of inhibiting CYP2A6-mediated nicotine metabolism as a novel smoking cessation strategy by reviewing in vitro, preclinical, and clinical data of agents that mimic the slow CYP2A6 metabolizer phenotype and improve smoking cessation outcomes.