The proposed research will characterize the acute and chronic effects of phentermine, a dopamine releaser, and fenfluramine, a serotonin releaser, alone and in combination, on responses to smoking, smoking withdrawal symptoms, and post-cessation weight gain in 120 women. Phentermine and fenfluramine, when administered in combination, have been shown to promote weight loss in obese patients and clinical reports indicate that they may also reduce craving for alcohol and cocaine. Thus, this drug combination may also be efficacious in reducing the weight gain and craving experienced by cigarette smokers attempting to quit, symptoms which are major contributors to smoking relapse in may individuals. The proposed study will evaluate the effects of phentermine and fenfluramine on subjective, physiologic and cognitive effects of smoking, as well as on symptoms of smoking withdrawal in women concerned about weight gain during smoking cessation. Subjects will be randomly assigned to receive either phentermine, fenfluramine, phentermine = fenfluramine, or placebo during one laboratory session followed by a six week clinical trial. During the laboratory session, subjects will receive a single acute dose of the treatment drug under double-blind conditions, and will smoke a nicotine-containing and de- nicotinized cigarette. Subjective, physiologic and cognitive effects of smoking each type of cigarette will be measured. In the double-blind clinical phase, subjects will receive six weeks of treatment with whichever drug they received during the laboratory sessions. Smoking abstinence, withdrawal symptoms, weight gain, and physiologic measures will be assessed at weekly intervals during six weeks of treatment, and at one, three, and six months thereafter. Subjects will receive brief counseling and support for smoking cessation, diet and exercise during each of the laboratory visits during the clinical trial. At the follow- up visits, smoking status, withdrawal symptoms, and weight will be monitored. The results of this study will contribute to the understanding of the neurochemical mechanisms underlying cigarette smoking and smoking cessation, and may provide a new and efficacious treatment for smoking cessation.
