such as clozapine (McEvoy et al., 1999). It has been speculated that this behavioral response may represent an attempt at self-medication, and some evidence for a disease-related abnormality in central nAchR sensory gating in schizophrenia has begun to emerge (Breese et al., 2000; Dalack et al., 1998).
Much less information is available concerning the effects of nicotine on other systems. Examples of potentially important observations include impairment of the immune response (Sopori et al., 1998), adverse effects on bone formation (Fung et al., 1999), and testicular hypogonadism (Kavitharaj and Vijayammal, 1999; Reddy et al., 1998), all observed with nicotine in model systems. The relevance of these observations, if any, to the doses of nicotine achieved in humans during NRT is unknown and should be evaluated.
Finally, cigarette smoking may result in drug interactions. While polycyclic hydrocarbons in cigarette smoke induce CYP isozymes of potential relevance to carcinogenesis, nicotine itself can induce CYP2E1, CYP2A1/ 2A2, and CYP2B1/2B2 in animal studies. Cutaneous vasoconstriction due to nicotine can delay the absorption of transdermal and subcutaneously administered medication, including insulin and heparin, and the stimulant effects of nicotine can diminish the analgesic effects of some opioids and the sedative effects of benzodiazapines (Zevin and Benowitz, 1999). Cigarette smoking reduces the hypotensive response to β-blockers (Fox et al., 1984), but the contribution of nicotine to this effect is unknown. Smoking reduces portal blood flow velocity and volume in humans and may modulate the disposition of drugs subject to hepatic metabolism (Rapaccini et al., 1996).
NRT has proven an effective strategy in the cessation of cigarette smoking that is remarkably well tolerated at least in the short to medium term. Although the experience is much more limited, NRT also holds promise as a strategy for reducing the number of cigarettes smoked by those who cannot or will not quit.
Both of these observations prompt considerations for future research. Thus, for those who quit smoking but continue to take NRT indefinitely, are there reasons to be concerned? First, nicotine can be addictive and although the daily exposure may be lower on NRT than when the individual was smoking, continued use implies psychological dependence, if not physical addiction. It is arguable whether this should be a concern, given the marked reduction of risk compared to smoking. However, it would seem reasonable to include surveillance of the dependence potential and various methods to determine abuse liability of various nicotine