IV Pulsed-Nicotine as a Model of Smoking: The Effects of Dose and Delivery Rate

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Abstract Although both the dose and the rate of delivery impact the abuse potential of drugs of abuse, tobacco control strategies focus primarily on the total amount of nicotine delivered by tobacco products with a high abuse potential – such as cigarettes and electronic cigarettes (EC). Further, systematic human studies examining the relationship between the individual and interactive effects of the dose and delivery rate of nicotine on its abuse potential are lacking. Likewise, it is also unknown if the dose and delivery rate of nicotine impact its potentially beneficial effects (i.e., alleviation of smoking urges and withdrawal) and its abuse potential in a distinct manner. This knowledge gap is partly due to the inability to experimentally control the rate of nicotine delivery with inhaled tobacco products. In a pilot study using intravenous (IV) nicotine infusion – which provides precise control over delivery rate – we found that 1 mg/70kg nicotine, the average amount of nicotine delivered by smoking a cigarette, infused IV over 1 minute, produced greater positive subjective effects – indicating greater abuse potential – compared to the same amount of nicotine delivered over 5 or 10 minutes. In contrast, both the 1-minute and 5-minute delivery rates were equally effective in reducing smoking urges. These findings support a greater impact of the rate of delivery on nicotine’s abuse potential, than its effects on suppressing urges to smoke – supporting the role of delivery rate to inform regulatory science and reducing harm from tobacco use. Still, unlike the puff-sized nicotine delivery provided by tobacco cigarettes or EC, our pilot study was limited by a continuous infusion of nicotine. Hence, to improve the ecological validity of our design, we further refined our IV nicotine infusion procedure, by developing a pulsed-nicotine infusion as a model for nicotine delivery by inhaled tobacco products like EC. Using this procedure, we seek to systematically examine the impact of nicotine dose and delivery rate on the risk of abuse potential – assessed by measures of positive subjective effects and reinforcement – vs. potentially beneficial effects – assessed by measures of smoking urges and withdrawal symptoms. We propose a double-blind, placebo-controlled study employing a mixed design: nicotine dose as the between-subject and delivery rate as the within-subject factors. Seventy smokers will be randomized to a dose of either 0.2 mg/70 kg or 1 mg/70 kg of nicotine. Across 5 test sessions, within each dose group, participants will be assigned to random sequences of 5 treatment conditions, including placebo (saline) and 4 different delivery rates of nicotine. In each session, participants will receive a total of 10 nicotine or saline-pulsed infusions, every 30 seconds. Concurrently with the pulsed infusions, participants will inhale tobacco-flavored EC, which will allow a closer matching of the sensory aspects of inhaled tobacco use. For the placebo test session, participants will receive 10 pulsed-saline infusions. In sum, this study represents an important step in demonstrating the potential utility of the rate of nicotine delivery as a benchmark for reducing the risks from ECs and other nicotine delivery products.