Exploring the role of nicotine and smoking in sleep behaviours: A multivariable Mendelian Randomisation study

Research has shown bidirectional relationships between smoking and adverse sleep behaviours, including late chronotype and insomnia, but the underlying mechanisms are not understood. One potential driver is nicotine, but its role in sleep is unclear. For this study, we estimated the direct effect of nicotine on six sleep behaviours measured in UK Biobank (chronotype, ease of getting up in the morning, insomnia symptoms, napping, daytime sleepiness and sleep duration). We conducted a Mendelian randomisation (MR) study to explore whether nicotine metabolism has a causal effect on these sleep behaviours. We explored whether the effects could be explained by regular nicotine exposure using genetic proxies of the nicotine metabolite ratio (NMR) and cigarettes per day (CPD) in a multivariable MR design. We found a higher NMR (indicating lower levels of circulating nicotine per cigarette smoked) decreased the likelihood of being an evening person when accounting for CPD in current (β = -0.04, 95%CI -0.06 to -0.02, p < 0.001) and ever smokers (β = -0.03 95%CI -0.04 to -0.01, p = 0.003). A higher NMR also increased the ease of getting up (β = 0.02, 95%CI 0.01 to 0.04, p = 0.015) and likelihood of napping (β = 0.02, 95%CI CI 0.002 to 0.03, p = 0.029) in current smokers. Increased nicotine exposure may directly affect sleep and could underlie relationships between smoking and sleep behaviours identified previously. Sleep could also be impacted in individuals using nicotine delivery systems or using nicotine replacement therapies. Further research is warranted to strengthen this conclusion.