Glucocorticoid Antagonist Treatment for Tobacco Use Disorder

This will be a double-blind, placebo-controlled study that tests the effects of a 7-day
treatment with 600 mg mifepristone, or placebo, on cognitive function, tobacco withdrawal
severity and smoking behavior. Once the intake and physical examination is completed and
eligibility is determined, subjects will participate in a baseline session to become familiar
with the study procedures and to assess baseline measures of withdrawal, smoking urges, pain
sensitivity, and cognitive performance. Subjects will be asked to refrain from consuming
alcoholic beverages and drugs during their study participation. This will be verified by
urine drug screening and breathalyzer before the session and during outpatient visits. If
results indicate non-compliance with these study procedures, subjects will be discharged from
the study.

Participants will be assessed for compliance with medication treatment, withdrawal severity,
recent smoking behavior, and cognitive function during treatment visits on Days 1 and 4. On
Day 7, following overnight abstinence from smoking, participants will attend a test session
that models relapse to smoking. During this session, subjects will have the option to smoke,
or to delay smoking in exchange for monetary compensation (45). To examine if mifepristone's
proposed therapeutic effects last beyond the treatment duration (as observed in previous
studies), there will be 1-week and 1-month follow-up assessments on smoking behavior, urges
to smoke, endocrine biomarkers, and cognitive function.

Participants in each group will complete the laboratory-based, delayed smoking procedure in a
designated, negative pressure room in Bldg. 36 of the West Haven VA just after assessing pain
sensitivity with the cPT. This sequence allows the cPT to assess pain sensitivity, a
potential biomarker of relapse behavior, and to also be used as a mild stressor prior to
participation in the smoking relapse model. Participants will be instructed to abstain from
smoking after 10 pm the night before Test Sessions. Abstinence will be confirmed the morning
of the session by measuring a breath CO level of < 8 ppm.

Inclusion Criteria:

- Male smokers aged 18 to 55 years;

- History of smoking at least 5 cigarettes daily for the past 12 months;

- In good health as verified by medical history, screening examination, and -screening
laboratory tests

Exclusion Criteria:

- History of mifepristone allergy;

- Requirement of any form of regular psychotropic medication (antidepressants,
antipsychotics, or anxiolytics) and recent psychiatric history (in the past 6 months);

- Medical illnesses including diabetes, cardiovascular, renal, endocrine, or hepatic
disorders;

- Prolonged QTc interval >450 msec;

- History of adrenal insufficiency or a morning plasma cortisol level less than 5 mcg/dl
at screening;

- Hypokalemia at screening (defined as potassium level < 3.5 mEq/L);

- Current use of clinically significant CYP 3A4 substrates including, simvastatin,
lovastatin, cyclosporine, ergotamines, fentanyl, pimozide, quinidine, sirolimus,
tacrolimus, triazolam, midazolam.

- use of rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's Wort.

- Current use of strong 3A4 inhibitors including ketoconazole, itraconazole, nefazodone,
ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenivir, boceprevir,
clarithromycin, conivaptan, lopinavir, mibefradil, posaconazole, saquinavir,
telaprevir, telithromycin, voriconazole.

- Treatment with systemic corticosteroids

- Current use of clinically significant CYP 3A inducers (e.g., rifampin, rifabutin);

- Abuse of alcohol or any other illicit or prescription drugs;

- Inability to tolerate cold exposure due to conditions such as peripheral -vascular
disease or Raynaud's phenomenon;

- Inability to fulfill all scheduled visits and examination procedures throughout the
study period.