Threshold for the pleasurable effects of nicotine are lower than its reinforcing effects during self-administration.

Abstract

A recent study demonstrated that during a single sampling period, 0.1 mg of intravenous (IV) nicotine (vs. placebo) was found to be the threshold for subjective and physiological drug effects. The present study is a secondary analysis evaluating whether the threshold for subjective and physiological effects is similar when the subject has repeated opportunities to choose blinded doses of nicotine versus placebo. We also examined whether cigarette craving, withdrawal, and rate of nicotine metabolism affected nicotine reinforcement, defined by a greater number of nicotine choices than placebo. Young adult (n = 34; 68% male), daily smokers had five laboratory sessions after overnight abstinence. After sampling an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg/70 kg) versus saline (placebo), participants completed a nicotine self-administration (NSA) procedure that included 10 opportunities to self-administer IV dose of nicotine or placebo. The threshold for subjective positive effects of nicotine during the NSA was equal to or lower than the sampling period, 0.05-0.1 mg versus 0.1 mg. The threshold for nicotine-induced heart rate increase was higher during the NSA than during the sampling period (0.2 mg vs. 0.1 mg). Higher baseline craving and nicotine metabolite ratio (NMR) were associated with nicotine reinforcement at 0.2 mg and 0.1 mg doses, respectively ( p < .05). The results suggest that subjective effects during NSA are reported at doses lower than the sampling period. Taken together, tobacco products thought to be subthreshold for reinforcement should be carefully evaluated for their subjective effects, including their discriminative stimulus effects. Public Health SignificanceIn young adult nondependent smokers, the threshold for positive subjective effects of nicotine was 2-4 times lower than its reinforcing threshold (0.05-0.1 mg vs. 0.2 mg) during a nicotine self-administration procedure. Additionally, higher abstinence-induced craving and faster nicotine metabolism were associated with greater reinforcement from nicotine. A four times lower threshold for the subjective pleasurable effects than the reinforcing effects of nicotine suggests that tobacco products that are deemed to be subthreshold for reinforcement should be carefully evaluated for their subjective effects, including their discriminative stimulus effects.