Effect of Ramelteon on Smoking Abstinence

Ramelteon, an FDA-approved treatment for insomnia, is used to treat sleep problems (e.g.,
specifically sleep onset latency) by enhancing melatonin receptor function. The investigators
propose a randomized double-blind placebo-controlled crossover study.

Fifty chronic smokers will complete a validated procedure for screening new medications. All
subjects will receive 8mg ramelteon and placebo. The order in which ramelteon and placebo is
received will be randomized across participants. This is a 6-week study consisting of two
2-week medication phases separated by a 2-week washout. Each phase includes 1 week of ad
libitum smoking (baseline) and 1 week of medication (ramelteon vs. placebo) plus transdermal
nicotine patches while trying to abstain from smoking (quit assessment). Subjects will
complete the same procedures during each study phase. Following completion of the study,
participants will be offered standard smoking cessation treatment.

For the duration of the study, subjects will be asked to keep sleep diaries and to wear an
armband while sleeping, which provides objective indices of sleep duration and quality
(SensewearPro® armband).

The primary outcome will be the total number of days abstinent (out of 5) during each quit
assessment period. Intermediate outcomes include sleep onset latency (self-report) and sleep
efficiency (SensewearPro®).

This study will provide information about the role of the melatonin system during brief
abstinence and whether enhancing melatonin reduces abstinence-induced sleep problems that
promote smoking relapse. Information obtained in this study may further establish the role of
sleep disturbance in promoting smoking relapse.

Inclusion Criteria:

1. Smokers who are between 18 and 65 years of age who self-report smoking at least 10
cigarettes per day for at least the last 6 months.

2. Interest in quitting smoking in the next 2 to 4 months.

3. Healthy as determined by the Study Physician, based on a medical evaluation including
medical history and physical examination, and psychiatric evaluation.

4. Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the combined consent and HIPAA form.

5. Women of childbearing potential must consent to use a medically accepted method of
birth control while participating in the study (e.g., condoms and spermicide, oral
contraceptive, Depo-provera injection, contraceptive patch, tubal ligation).

Exclusion Criteria:

Smoking Behavior:

1. Current enrollment in a smoking cessation program, or use of other smoking cessation
medications in the last month or plans to do either in the next 2 months.

2. Daily use of chewing tobacco, snuff and/or snus, or electronic cigarettes.

3. Provide a carbon monoxide (CO) breath sample reading less than 10 parts per million
(ppm) at Intake.

Alcohol/Drugs:

1. Self-report current alcohol consumption that exceeds 25 standard drinks/week over the
past 6 months. Subjects will be told to limit or avoid the use of alcohol while in the
study to avoid any adverse reactions to the study medication.

2. Self-reports substance use disorders (abuse or dependence involving alcohol, opiates,
cocaine or other stimulants, or benzodiazepines; not nicotine) in the last 6 months.

3. Providing a breath alcohol concentration (BrAC) reading of greater than or equal to
0.01 during any session.

4. A positive urine drug screen for cocaine, amphetamines, methamphetamines,
benzodiazepines, PCP, methadone, barbiturates, marijuana, ecstasy (MDMA), oxycodone,
tricyclic antidepressants, and opiates (low level cut-off 300 ng/mL) during any
session.

Psychiatric Exclusion (as determined by self-report on phone screen and/or through MINI
during Intake):

1. Current psychiatric disorders (depression, bipolar, schizophrenia, hypomanic/manic
episode) as determined by self-report and/or MINI psychological interview.

2. Past history of psychiatric disorders (including suicide attempt) other than
depression as determined by self-report and/or MINI psychological interview.

3. Suicide risk score on MINI greater than 1.

Medical:

1. Females who are currently pregnant, planning a pregnancy during the study, or
currently breastfeeding/lactating. All female subjects shall undergo a urine pregnancy
test at the Intake and must agree in writing to use an approved method of
contraception. Following enrollment, pregnancy tests will be conducted at the
beginning of each baseline week.

2. For those with a history of jaundice/liver disease: liver function tests more than 20%
outside of the normal range; Gamma-glutamyl Transpepsidase (GGT) values more than 20%
outside of the normal range. If Albumin/Globulin ratios are 20% outside of normal
range the abnormal value will be evaluated for clinical significance by the Study
Physician and eligibility will determined on a case-by-case basis.

3. Heart/Cardiovascular disease (e.g., angina, coronary heart disease, stroke, etc.) in
the past 6 months.

4. Endocrine or metabolic disorders (e.g., Type-I diabetes).

5. Blood disorders (e.g., anemia or hemophilia).

6. Uncontrolled hypertension (BP systolic greater than 159 and/or diastolic greater than
99)*.

7. Clinically significant dyssomnia (except insomnia; e.g. sleep apnea syndrome,
narcolepsy).

- Participants presenting with SBP greater than 159 mmHg and/or DBP greater than 99
mmHg at the Intake visit will be instructed to sit quietly for 10 minutes. Then
the participant will have a second blood pressure reading taken after a 10 minute
period. If, after the second reading the SBP greater than 159 mmHg and the DBP
greater than 99 mmHg, the individual will be instructed to sit comfortably for 10
minutes and then have a third blood pressure reading. If, after the third reading
the SBP greater than 159 mmHg and the DBP greater than 99 mmHg, the individual
will be ineligible to participate.

Medication:

1. Current use or recent discontinuation (within the past month) of any of the following
medications:

1. Anti-anxiety or panic disorder medications (e.g., clonazepam, alprazolam).

2. Anti-psychotic medications (e.g., thorazine, Seroquel).

3. Mood-stabilizers (e.g., Lithium, Lamictal/lamotrigine, valproic acid,
Neurontin/gabapentin, Topamax/topiramate, Tegretol/carbamazepine).

4. Prescription stimulants (e.g., Provigil, Ritalin, Adderall).

5. Medications contraindicated with ramelteon (e.g., fluvoxamine, buprenorphine or
other medications metabolized by certain cytochrome P450 enzymes)

2. Current use or recent discontinuation (within the past 2 weeks) of any of the
following medications (subjects must agree to refrain from using any other sleep aids
while enrolled in the study):

1. Sleep medications (e.g., zolpidem/Ambien, eszopiclone/Lunesta)

2. Over-the-counter sleep aids (e.g., melatonin, diphenhydramine/Benadryl)

3. Daily use of opiate-containing medications for chronic pain (Duragesic/fentanyl
patches, Percocet, Oxycontin). Smokers who report taking opiate-containing medications
on an "as-needed" basis will be instructed to refrain from use until their study
participation is over and that they will be tested to ensure they have complied with
this requirement.

4. Known allergy to study medication (e.g., angioedema).

Subjects will be instructed to refrain from using any study prohibited drugs/medications
(both recreational and prescription) throughout their participation in the study. After
final eligibility is confirmed, subjects who report taking contraindicated medication(s)
over the course of the study period may only remain eligible if the Study Physician and/or
Principal Investigator determines that the contraindicated medication(s) do/did not impact
the study design, data quality, and/or subject safety/welfare. Subjects are permitted to
take necessary prescription medications not included within the exclusion list during the
study.

General Exclusion:

1. Current, anticipated, or pending enrollment in another research program over the next
2-3 months that could potentially affect subject safety and/or the study data/design
as determined by the Principal Investigator and/or Study Physician.

2. Not planning to live in the area for the next two months.

3. Currently working night shift or rotating shift or other habitual alteration of the
sleep/wake cycle.

4. Allergy to latex or adhesive tape.

5. Inability to provide informed consent or complete any of the study tasks as determined
by the Principal Investigator.

6. Not able to effectively communicate in English (reading, writing, speaking).

7. Missing 2 or more doses during the medication period determined by self-report.