¹Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, and Departments of Medicine, Psychiatry, and Biopharmaceutical Sciences, University of California, San Francisco, Calif.

Correspondence: Neal L. Benowitz, MD, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, Box 1220, San Francisco, CA 94143-1220. E-mail: nbenowitz@medsfgh.ucsf.edu

^*Supported by US Public Health Service grants CA78603 and DA12393 from the National Institute on Drug Abuse, National Institutes of Health. Carried out in part at the General Clinical Research Center at San Francisco General Hospital Medical Center with support of the Division of Research Resources, National Institutes of Health (RR-00083).

Received 18 November 2005; Accepted 7 September 2006.

Abstract

Objectives: The progressive reduction of the nicotine content of cigarettes has been suggested as a way to wean smokers from nicotine and tobacco. As a first step in evaluating this strategy, we studied smokers smoking cigarettes containing tobacco with differing nicotine content.

Methods: Twelve healthy smokers participated in a semiblinded, within-subject, crossover study. Subjects were asked to smoke 1 of their usual brand of cigarette and then on 5 subsequent occasions to smoke a research cigarette, each with differing nicotine content. The research cigarettes contained 0.6 to 10.1 mg nicotine per cigarette. Plasma nicotine and blood carboxyhemoglobin levels, as well as subjective and cardiovascular responses, were measured after smoking. Systemic nicotine intake per cigarette was estimated by use of plasma nicotine concentrations over time and clearance data from the general population.

Results: Systemic nicotine intake (0.26-1.47 mg per cigarette) varied with nicotine content of the cigarette (r = 0.82, P < .001). Compensation when smoking single low–nicotine content cigarettes ranged from -1% (95% confidence interval, -23% to 21%) to 34% (95% confidence interval, -39% to 107%) for 1-mg to 8-mg research cigarettes. Carbon monoxide intake and estimated tar exposure were similar across cigarettes. Low–nicotine content cigarettes were rated as being of lower quality and less satisfying than the 12-mg research cigarette or the usual brand (P < .05 for both comparisons). Cigarette smoking increased heart rate and decreased skin temperature, but the nicotine dose-response curve flattened at higher doses, with a maximal response being observed in cigarettes at a nicotine content level of about 8 mg.

Conclusions: Our study suggests that reduced–nicotine content cigarettes are reasonable candidates for trying to reduce the level of nicotine addiction in smokers. The flat nicotine dose–cardiovascular response curve is consistent with other studies demonstrating tolerance to the cardiovascular effects of nicotine.