The pH of Smokeless Tobacco Determines Nicotine Buccal Absorption: Results of a Randomized Crossover Trial.

Nicotine absorption rate influences tobacco products' addictiveness. For smokeless tobacco, nicotine buccal absorption is associated with its free-base form; the pH of smokeless tobacco defines the proportion of free-base (i.e., unprotonated) vs. protonated nicotine. This was the first study to compare nicotine pharmacokinetics (PK) and pharmacodynamics (PD) after the use of commercial smokeless tobacco products that were experimentally manipulated to differ only in pH and percent free-base nicotine. Moist snuff users (N = 40) completed four crossover visits and used a single 2 g portion of Copenhagen Original Long Cut amended to 4 pH levels: 5.0, 7.7, 8.2, and 8.6 (free-base nicotine 0.1, 32, 60, and 79%) for 30 minutes. Nicotine PK and PD were assessed for 4 hours post-use. Nicotine PK substantially depends on its free-base proportion, with more than 4-fold increases in mean plasma nicotine maximum concentration and area under the curve over 240 minutes (3.9 to 16.7 ng/mL; 385 to 1810 ng min/mL, respectively, both P < 0.001) from pH 5.0 to 8.6. The autonomic cardiovascular effects of smokeless tobacco use reflected percent free-base nicotine, with small (albeit significant) systematic increases in heart rate and blood pressure associated with free-base nicotine. Smokeless tobacco product pH and percent free-base nicotine play a major role in the rate and extent of nicotine absorption, determining product PD effects and abuse potential. Research and regulation of smokeless tobacco products should consider both total nicotine content and product pH. Further research may address the impact of modifying pH on the addictiveness of smokeless tobacco and associated use behaviors.