Role of Metabolites in Nicotine Dependence (3) - 6

Previous studies have shown that cotinine, a metabolite of nicotine, antagonizes the
beneficial effects of the nicotine patch in redugin withdrawal symptoms. Studies have also
shown that cotinine enhances serotonin levels. This study examined the effects of several
doses of a 5HT3 antagonist, ondanstron, in combination with the nicotine patch. This
medication has been observed to reduce nicotine withdrawal symptoms in rats. These effects
were compared to the nicotine patch alone. The results of this study produced some modest
effects showing that the 8mg dose of ondansetron suppressed tobacco withdrawal symptoms to a
greater extent than the nicotine patch alone.

Inclusion Criteria:

Male/Female subjects ages 21-45 years inclusive, with a smoking history of at least 15
cigarettes daily (greater than or equal to 50) for at least 1 yr. Subject is in good
health as verified by medical history, screening examination, and screening laboratory
tests as outlined above. Subject has provided written informed consent to participate in
the study and is motivated to stop smoking. Subject has experienced at least 4 withdrawal
symptoms upon abstinence.

Exclusion Criteria:

History of myocardial infarction, angina pectoris, sustained or episodic cardiac
arrhythmias, symptomatic peripheral vascular disease, current peptic ulcer disease or any
other medical condition which the physician investigator deems inappropriate for subject
participation. Insulin-dependent diabetes. Pregnant or lactating, or not using adequate
birth control methods. Requirement of any form of regular psychotropic medication
(antidepressants, antipsychotics, or anxiolytics) and recent psychiatric history (less
than 1yr). Chronic use of systemic steroids or antihistamines. Abuse of alcohol or any
other recreational or prescription drug (more than 3 drinks per day or 21 drinks per wk).
use of any other nicotine products, including smokeless tobacco, cigars and nicotine
replacement products. Inability to fulfill all scheduled visits and examination procedures
throughout the study period. History of schizophrenia or manic depressive disorder. Recent
history of other psychiatric illness (less than 1yr since last episode of major depressive
episode).