Dissociation of nicotine tolerance from tobacco dependence in humans.

Chronic functional tolerance to nicotine generally is believed to be associated with processes responsible for tobacco dependence. The dose-related effects of nicotine (0-20 microg/kg by nasal spray) on subjective, cardiovascular, and performance responses were compared among four groups varying in current or past dependence: dependent smokers (21 cigarettes per day for 20 years; n = 45), nondependent smokers (three cigarettes per day for 14 years; n = 12), former dependent smokers (mean of 7 years quit after smoking 25 cigarettes per day for 19 years; n = 17), and life-long nonsmokers (n = 19). Chronic tolerance was determined by a shift to the right, or flattening, of the dose-response curve relative to the curve for nonsmokers. Responses were corrected for plasma nicotine concentration to rule out dispositional tolerance. Chronic tolerance was observed for most subjective responses, but little or none for cardiovascular and performance effects. Tolerance was substantial and virtually identical between dependent and nondependent smokers, whereas tolerance of former smokers was intermediate between nonsmokers and dependent smokers. Identical chronic tolerance between dependent and nondependent smokers indicates that tolerance is not a linear function of smoking exposure and does not require presence of dependence. Thus, the wide variability in daily smoking rate among smokers cannot be attributed to differences in tolerance and must involve other processes of adaptation to nicotine. The modest reversal of tolerance in long-time former smokers suggests that such tolerance reversal is either limited or extremely slow after extended abstinence, despite loss of dependence. These results suggest there is no close link between nicotine tolerance and dependence and question the utility of tolerance as one of the criteria for defining dependence.