Threshold doses for nicotine discrimination in smokers and non-smokers

Rationale: Tobacco use during initial experimentation often involves modest nicotine exposure, escalating to larger doses and more frequent exposure with the onset of tobacco dependence. Threshold doses for nicotine discrimination therefore may differ between naive and experienced tobacco users. Objectives: We determined the lowest (threshold) dose of nasal spray nicotine that smokers and non-smokers could reliably discriminate from placebo spray. Methods: Male and female smokers (n=18) and non-smokers (n=17) were initially trained to discriminate 20 mug/kg from placebo before proceeding to threshold determination sessions, which involved discrimination of progressively lower doses below 20 mug/kg ("descending order" subgroup) or higher doses above 1 mug/kg ("ascending order" subgroup). Threshold was determined by the lowest dose reliably discriminated from placebo (correct on greater than or equal to 80% of testing trials) and by failure to discriminate the next lowest dose. Results: Threshold doses for nicotine discrimination were low and not different between smokers and non-smokers (median thresholds of 3 ver- sus 2 mug/kg and approximate blood levels of 2.6 versus 1.6 ng/ml, respectively). Thresholds were similar between descending and ascending order subgroups. Several subjective responses differentiated threshold dose from the dose just below threshold, particularly in non-smokers. Conclusions: Threshold doses for nasal spray nicotine discrimination in humans are low, well below the typical nicotine delivery of most cigarette brands, and may not change after long-term smoking exposure.