Role of Metabolites in Nicotine Dependence (4) - 13

Previous studies have shown that cotinine, a metabolite of nicotine, antagonizes some of the
effects of nicotine. One study showed that nicotine eliminates some of the beneficial
effects of the nicotine patch in reducing withdrawal symptoms. The purpose of this study was
to replicate and extend these findings and examine the effects of various doses of cotinine
base compared placebo on withdrawal symptom as well as drug preference among abstinent
smokers while using the nicotine patch. We hypothesized that cotinine will reduce the
beneficial effects of the nicotine patch in reducing withdrawal symptoms and that placebo
will be preferred over cotinine during the forced drug choice period.

Inclusion Criteria:

Male/Female subjects, aged 21-45 years inclusive, with a smoking history of at least 20
cigarettes daily (greater than or equal to 50) for at lease 1 year. 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 recreation aor prescription drug (more tha 3 drinks per day or 21 drinks per week).
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 1 year since last episode of major
depressive episode.