Nicotine is considered to be the main addictive ingredient in tobacco. Therefore, the nicotine content of tobacco products serves as a logical target in the development of effective tobacco-control policies. In an influential article, Benowitz and Henningfield proposed that the gradual reduction of the nicotine content of cigarettes to an amount below an addictive threshold could prevent the development of nicotine addiction among young smokers. More recently, a similar addictive threshold was proposed for electronic cigarettes (EC) based on their rate of nicotine delivery. Accordingly, if an EC delivers nicotine at rates above a certain, yet undetermined threshold, they can be addictive and potentially harmful, especially in nicotine nave users. In contrast, if the nicotine delivery rate of an EC is below a critical threshold, it may have low addiction liability but provide sufficient nicotine delivery to help smokers quit smoking by alleviating urges to smoke and reducing tobacco withdrawal symptoms. This proposed critical rate of delivery that underlies the addictive effects of nicotine, however, has yet to be empirically validated by controlled human studies. This knowledge gap is partly due to the difficulty in accurately controlling the rate of nicotine delivery with currently available nicotine delivery products like tobacco cigarettes or EC. To close this knowledge gap, we propose to use intravenous (IV) nicotine administration because the rate of nicotine exposure by the IV and inhaled routes are comparable. IV nicotine administration also allows for accurate dosing over a wide range of delivery rates. We propose a placebo-controlled study that will enroll male and female tobacco smokers (n=18) who will participate in four experimental sessions. During the experimental session, subjects will be given an IV infusion of either saline or 1 mg nicotine at rapid, moderate or slow infusion rates (nicotine at 0.24, 0.05 and 0.02, g per kg body weight per sec). The infusion conditions for each experimental session will be determined in random order.
Aim 1 is to establish a dose-effect curve for nicotine reinforcement as a function of nicotine delivery rate.
Aim 2 is to establish a dose-effect curve for nicotine's positive and negative subjective effects as a function of nicotine delivery rate.
Aim 3 is to establish a dose-effect curve for nicotine's effect to alleviate symptoms of nicotine withdrawal in abstinent smokers as a function of nicotine delivery rate.
Aim 4 is to establish a dose-effect curve for nicotine's acute cardiovascular health effects. Data from this project will help to establish benchmark values for nicotine's threshold effects that will guide policies on the nicotine yield of tobacco products.
This project will determine how the rate of nicotine delivery affects the abuse potential of nicotine. This project will help establish policies designed to prevent or reduce the health risks associated with tobacco products.
| Polimanti, Renato; Jensen, Kevin P; Gelernter, Joel (2017) Phenome-wide association study for CYP2A6 alleles: rs113288603 is associated with hearing loss symptoms in elderly smokers. Sci Rep 7:1034 |
