The mesolimbic dopamine system is thought to be a critical substrate for drugs of addiction including nicotine. Since dopamine may play a critical role in mediating the reinforcing effects of nicotine, we hypothesized that administering levodopa in its therapeutic form (carbidopa/levodopa) might be effective for smoking cessation by replacing the effects of dopamine that smokers may seek during smoking. A pilot open-label study using carbidopa/levodopa for smokers wanting to stop smoking was carried out at the Mayo Clinic Nicotine Research Center, Rochester, MN. The dosing schedule was one tablet TID for 1 week, 1 1/2 tablets TID for 1 week, then two tablets TID for 6 weeks. Each tablet contained 25 mg of carbidopa and 100 mg of levodopa. The subjects were 40 adult smokers smoking > or = 20 cigarettes per day for 3 or more years. Self-reported abstinence from smoking was confirmed by expired air CO level of < or = 8 ppm. Nicotine withdrawal symptoms were assessed at baseline and daily during the medication phase. Smoking abstinence rates and withdrawal symptom relief were compared to the placebo (n = 153) arm of a previously reported bupropion smoking cessation trial. The biochemically confirmed, 7-day point-prevalence smoking abstinence rate at the end of carbidopa/levodopa treatment was 20.0% versus 19.0% for the placebo group (p > 0.10), and 12.5% of the carbidopa/levodopa group were abstinent versus 15.7% for the placebo group (p > 0.10) at 6 months. Subjects from both studies had significant increases in withdrawal scores from baseline, but there were no significant differences between the two groups at any time period. We found no differences in smoking abstinence rates or nicotine withdrawal symptom relief in smokers receiving carbidopa/levodopa compared to placebo. Despite the theoretical reasons why carbidopa/levodopa might be effective as a pharmacological adjunct in treating smokers, it was not observed in this group of smokers at this dose.