Nicotine flux, a potentially powerful tool for regulating nicotine delivery from electronic cigarettes: significance of nicotine flux to the rate of nicotine delivery and subjective effects - Project summary. Electronic nicotine delivery systems (ENDS) heat and vaporize a nicotine-containing liquid to produce an aerosol that can deliver nicotine to the blood and the brain. ENDS are considered tobacco products in the US and are under the regulatory authority of the Food and Drug Administration. ENDS use has increased rapidly in the last decade, especially among youth: over 20% of US high school students are current ENDS users, and there is evidence of nicotine dependence in this population. Federal legislation has been proposed that would restrict ENDS liquid nicotine concentration to make ENDS “significantly less addictive and appealing to youth.” However, these and other efforts to curb addiction by limiting nicotine liquid concentration are unlikely to succeed because nicotine emissions from ENDS depend on multiple variables. For example, where nicotine concentration is limited, users can turn to a higher power ENDS device to attain more nicotine. To achieve the intended public health aims, regulations targeting addiction must focus on nicotine delivery, not nicotine concentration. While nicotine delivery cannot be regulated directly, the rate at which an ENDS emits nicotine, the “nicotine flux” can be regulated and, importantly, predicted from first-principles based on knowledge of a few device design and operating variables. However, to date there is no empirical evidence demonstrating the relationship between flux and delivery, nor between flux and the physiological and subjective effects that support nicotine dependence. Closing this gap is essential for providing an effective, first-principles framework for regulating ENDS. In Aim1, we will examine the relationship between nicotine flux, nicotine form, and the rate and dose of nicotine delivery. In the clinical lab at Yale University, participants will puff on ENDS devices under conditions that differ by flux and form, while arterial blood is sampled in high time resolution. The outcome will indicate the degree to which nicotine flux and form determine the speed and dose of ENDS nicotine delivery, and thus, abuse liability. In Aim2, we will assess the relationship between nicotine flux, form, and subjective effects. At the American University of Beirut, participants will use ENDS devices with varying nicotine fluxes and forms. Dependency measures, such as urge to smoke, craving, and abstinence, will be assessed. The outcome will indicate the degree to which nicotine flux/form influence subjective effects related to dependency, puffing intensity, and exposure to toxicants. In summary, this project will provide the empirical evidence needed for public health agencies to use nicotine flux as an encompassing and convenient construct to regulate nicotine delivery from ENDS.