Use of Electronic Cigarettes Leads to Significant Beta2-Nicotinic Acetylcholine Receptor Occupancy: Evidence From a PET Imaging Study

Abstract

Background: Electronic cigarettes (ECs) can influence nicotine addiction by delivering aerosolized nicotine. We investigated if nicotine from ECs is delivered to the brain β2*-nicotinic acetylcholine receptors (β2*-nAChR) and how this relates to the behavioral effects and nicotine delivery from cigarettes.

Methods: Seven nicotine users participated in positron emission tomography (PET) studies with (-)-[18F]Flubatine before and after nicotine challenge with 0, 8, and 36 mg/ml nicotine in a 3.3 Volt, 1.5 Ohm EC or a standard tobacco cigarette. Craving was evaluated before and after product use.

Results: Average β2*-nAChR occupancy was higher after 36 mg/ml EC challenge compared to 8 mg/ml EC at trend level. Average β2*-nAChR occupancy after tobacco cigarette smoking was 68 ± 18% and was not different compared with 8 mg/ml (64 ± 17%,) or 36 mg/ml (84 ± 3%) nicotine in EC users. Area under the curve (AUC) of blood nicotine level was higher in the cigarette smoking group compared with the 8mg/ml group (p = 0.03), but similar compared with the 36 mg/ml EC (p = 0.29). Drug craving was reduced after use of the tobacco cigarette, 8 mg/ml EC, and 36 mg/ml EC.

Conclusions: In this novel investigation of EC effects at β2*-nAChRs, we show that average β2*-nAChR occupancy was higher after 36 mg/ml EC challenge compared with 8 mg/ml EC. Receptor occupancy and arterial blood nicotine levels after cigarette smoking were similar to 36 mg/ml EC use under controlled conditions. These findings suggest that the ECs studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers.

Implications: This is the first study to directly determine the neurologic effects of electronic cigarettes on human brain beta-2 nicotinic acetylcholine receptors using PET neuroimaging with (-)-[18F]Flubatine, a novel radiotracer. Our findings suggest that the e-cigarettes studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers.

Figure 1.

Time activity curve of [¹⁸F]Flubatine in a representative EC user. 55–85 min post-nicotine challenge was sufficient to reach a new steady state and allow calculation of receptor occupancy.

Figure 2.

Lassen Plots for calculation of nicotinic receptor occupancy. The slope of the line corresponds to the receptor occupancy fraction. Top left: EC user #1 after 36 mg/ml EC; Top right: EC user #1 after 8 mg/ml EC; Bottom: smoker after tobacco cigarette.

Figure 3.

Parametric images at baseline and after use of different nicotine delivery systems in two representative subjects. The top row shows a tobacco cigarette smoker, and the bottom row shows an electronic cigarette user. (Top row left to right: Baseline, tobacco cigarette (89% occupancy); Bottom row left to right: Baseline, 36 mg/ml (84% occupancy), 8 mg/ml (41% occupancy), 0 mg/ml (no significant occupancy).

Figure 4.

Arterial blood nicotine concentrations after 5 min (10 puff) use of different nicotine delivery systems. Top left: 36 mg/ml EC; Top right: 8 mg/ml EC; Bottom: tobacco cigarette.