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 w ith the onset of tobacco dependence. Threshold doses for nicotine discrimin ation therefore may differ between naive and experienced tobacco users. Obj ectives: 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 initi ally trained to discriminate 20 mug/kg from placebo before proceeding to th reshold determination sessions, which involved discrimination of progressiv ely lower doses below 20 mug/kg ("descending order" subgroup) or higher dos es above 1 mug/kg ("ascending order" subgroup). Threshold was determined by the lowest dose reliably discriminated from placebo (correct on greater th an or equal to 80% of testing trials) and by failure to discriminate the ne xt lowest dose. Results: Threshold doses for nicotine discrimination were l ow 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, r espectively). Thresholds were similar between descending and ascending orde r subgroups. Several subjective responses differentiated threshold dose fro m 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.