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.