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Variation in the rate at which drugs reach the brain influences many different drug effects and is also thought to influence liability to addiction. For example, rapid intravenous delivery of cocaine and nicotine is more effective in producing hedonic effects, tolerance, psychomotor sensitization, and in inducing gene expression. Smoking is thought to result in an especially rapid rate of rise of nicotine in the brain, but whether this is true has never been adequately addressed. Thus, in this study, we sought to determine the true rate of rise of smoked nicotine in human brain and compare this with previous intravenous nicotine delivery. Positron emission tomography scans of lung and brain regions and arterial and venous blood curves were obtained in human subjects after single puffs from cigarettes formulated with [11C]nicotine. The rise of nicotine concentration following a single puff was rapid, reaching more than 50% of maximum brain levels within 15 s of bolus arrival in the brain in most subjects. This rate of rise was considerably faster than that seen in previous studies using intravenous administration. Uptake in human brain from a single inhalation was sufficiently rapid that it is plausible that fast rate-of-rise contributes to nicotine dependence in smokers. [ABSTRACT FROM AUTHOR]