Preliminary data suggest that
cotinine, the major metabolite of
nicotine, may be behaviorally active. Studies involving the administration of
cotinine at doses that produce high blood concentrations (in excess of those produced by cigarette smoking) may be of interest. This inpatient, 10-day human study examined the safety and the effects from several high doses of oral
cotinine fumarate (40, 80, or 160 mg) or placebo in abstinent cigarette smokers. All subjects smoked cigarettes ad lib during the first 2 days of the study, then were required to be abstinent beginning on the third day. All subjects were given placebo on this day to wash out
nicotine before the administration of
cotinine. Subjects were subsequently randomly assigned in a double-blind manner to
cotinine or placebo for the next 3 days to determine the safety profile of
cotinine. All subjects were given placebo on the final 3 days to examine
cotinine withdrawal symptoms. The results showed no significant physiologic, subjective, or performance effects across the various doses of
cotinine and placebo. Furthermore, no
cotinine withdrawal effects were observed. This study demonstrates that short-term administration of
cotinine to humans at levels as high as 10 times that attained from cigarette smoking is safe with no observable acute or withdrawal effects from
cotinine in this setting.