Impact of delivery rate on the acute response to intravenous nicotine: A human laboratory study with implications for regulatory science

Abstract

Faster delivery rate enhances the abuse potential of drugs of abuse, yet systematic studies on the impact of delivery rate on the acute effects of nicotine in humans are lacking. Using an intravenous (IV) nicotine infusion procedure that allows precise control of rate of delivery, we examined the impact of nicotine delivery rate on the positive subjective drug effects, smoking urges, withdrawal, heart rate, blood pressure and attention function in smokers. Twenty-four male and female (ages 21-35) dependent smokers attended five experimental sessions, following overnight abstinence from smoking. Using a crossover design, participants attended five sessions, where they were assigned to a random sequence of saline infusion or 1 mg nicotine delivered over 1, 2.5, 5 or 10 min at rates of 1, 0.4, 0.2 or 0.1 mg/min, respectively.The positive subjective effects of nicotine were most robust under the two faster delivery rate conditions, 1-and 0.4-mg nicotine/min. In contrast, all nicotine delivery rates were equally more effective than saline in alleviating urges to smoke. Likewise, nicotine-induced heart rate increases did not vary with the rate of nicotine delivery.Lastly, the cognitive enhancing effects of nicotine were observed only under the two slowest delivery rate conditions-0.1-and 0.2-mg nicotine/min. Collectively, these findings support the critical role of delivery rate in optimizing nicotine's abuse potential versus potential therapeutic effects and have timely implications for developing novel therapeutics for nicotine dependence, as well as for tobacco regulatory science.

Nicotine and Microvascular Responses in Skeletal Muscle from Acute Exposure to Cigarettes and Vaping

“…While there is an abundance of data reporting that nicotine is capable of constricting blood vessels via several mechanisms (see review [ 33 ]), it is important to note that much of this evidence comes from studies that have used other (than inhalational) methods for nicotine delivery, such as intravenous, transdermal, or oral routes (i.e., gum, medication, etc.) [ 34 , 35 , 36 , 37 ]. Indeed, intravital and ex vivo vascular studies that topically applied or intravenously delivered nicotine do observe vasoconstriction [ 38 , 39 ].…”

Nicotine flux and pharmacokinetics-based considerations for early assessment of nicotine delivery systems

“…The systemic nicotine delivery rate was proposed to play a critical role in decreasing abuse liability potential vs. optimizing therapeutic effects (i.e., alleviation of craving and withdrawal symptoms) ( De Aquino et al, 2022 , Jensen et al, 2020 ). In humans, a nicotine delivery rate of 16.8 and 6.67 µg/s (IV infusion of 1 mg in 1 and 2.5 min, respectively) produced robust positive subjective effects (i.e., greater pleasure and stimulation) and alleviated smoking urges ( De Aquino et al, 2022 , Jensen et al, 2020 ).…”

“…The systemic nicotine delivery rate was proposed to play a critical role in decreasing abuse liability potential vs. optimizing therapeutic effects (i.e., alleviation of craving and withdrawal symptoms) ( De Aquino et al, 2022 , Jensen et al, 2020 ). In humans, a nicotine delivery rate of 16.8 and 6.67 µg/s (IV infusion of 1 mg in 1 and 2.5 min, respectively) produced robust positive subjective effects (i.e., greater pleasure and stimulation) and alleviated smoking urges ( De Aquino et al, 2022 , Jensen et al, 2020 ). While a nicotine delivery rate of 3.36 µg/s (IV infusion of 1 mg in 5 min) only alleviated smoking urges, a nicotine delivery rate of 1.68 µg/s (IV infusion of 1 mg in 10 min) is reported to be least effective in alleviating smoking urges ( Jensen et al, 2020 ).…”