Dissociation of nicotine tolerance from tobacco dependence in humans

Chronic functional tolerance to nicotine generally is believed to be associ ated with processes responsible for tobacco dependence. The dose-related ef fects of nicotine (0-20 mug/kg by nasal spray) on subjective, cardiovascula r, and performance responses were compared among four groups varying in cur rent or past dependence: dependent smokers (21 cigarettes per day for 20 ye ars; n = 45), nondependent smokers (three cigarettes per day for 14 years; n = 12), former dependent smokers (mean of 7 years quit after smoking 25 ci garettes 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 we re corrected for plasma nicotine concentration to rule out dispositional to lerance. Chronic tolerance was observed for most subjective responses, but little or none for cardiovascular and performance effects. Tolerance was su bstantial and virtually identical between dependent and nondependent smoker s, whereas tolerance of former smokers was intermediate between nonsmokers and dependent smokers. Identical chronic tolerance between dependent and no ndependent smokers indicates that tolerance is not a linear function of smo king exposure and does not require presence of dependence. Thus, the wide v ariability in daily smoking rate among smokers cannot be attributed to diff erences in tolerance and must involve other processes of adaptation to nico tine. The modest reversal of tolerance in long-time former smokers suggests that such tolerance reversal is either limited or extremely slow after ext ended abstinence, despite loss of dependence. These results suggest there i s no close link between nicotine tolerance and dependence and question the utility of tolerance as one of the criteria for defining dependence.