Pilot Study of Tolcapone in Smokers

Despite decades of research to develop pharmacotherapies for nicotine dependence (ND), with
current FDA approved medications (bupropion, varenicline and NRTs) the majority (>60%) of
smokers relapse in the first year following treatment (Lerman, Patterson et al. 2005;
Tonstad, Tonnesen et al. 2006). Testing novel medications that may reduce abstinence symptoms
that prompt smoking relapse is a plausible route to identifying new treatments for nicotine
dependence. The goals of this within-subject pilot study are: (1) assess the feasibility and
safety of administering the Catechol-O-Methyl-Transferase (COMT) inhibitor, tolcapone, to
smokers, and (2) explore whether tolcapone may reduce abstinence-induced cognitive and
affective symptoms that promote relapse. A secondary exploratory goal is to assess whether
these effects may be more pronounced in smokers who carry a high risk COMT genotype for
smoking relapse: COMT val/val. Sixteen smokers (8 met/met genotype and 8 val/val genotype)
who meet study eligibility criteria will complete two 10-day medication periods: one while
taking tolcapone and one while taking placebo (order counterbalanced). The testing session
will occur on day 7 of each medication phase and include three computerized tasks.
Participants will be asked to refrain from smoking for at least 14 hours (overnight) prior to
the testing day in each medication phase. There will be a 3-day medication taper on days 8-10
of each medication period, followed by a washout period of at least 7 days between medication
periods. The main outcomes to be evaluated are participant enrollment and retention, side
effects, and performance on computerized tasks. Positive results from this pilot study would
provide a basis for a larger scale investigation to assess the efficacy of tolcapone as a
medication that ameliorates abstinence induced neurocognitive symptoms in smokers.

Inclusion Criteria:

1. Healthy as determined by a responsible physician, based on a medical evaluation
including history, physical and psychiatric examination, laboratory tests, liver
function monitoring.

2. Smokers who are between 18 and 55 years of age and have an IQ greater than 90.

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

4. Based upon self-report, subjects must smoke >10 cigarettes/day and be interested in
quitting smoking in the next 6 months (i.e., treatment-seekers).

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

Exclusion Criteria:

Smoking Behavior

1. Use of chewing tobacco or snuff

2. Current enrollment or plans to enroll in another smoking cessation program in the next
month

3. Plan to use other nicotine substitutes or smoking cessation treatments in the next
month

4. Provide a baseline carbon monoxide (CO) reading < 10ppm

Alcohol/Drug Exclusion Criteria

1. History of substance abuse and/or currently receiving treatment for substance abuse
(e.g., alcohol, opioids, cocaine, marijuana, MDMA/ecstasy, or stimulants)

2. Current alcohol consumption that exceeds >14 standard drinks/week for men and >7
standard drinks/week for women over the last 6 months

Medication Exclusion Criteria

1. Current use or recent discontinuation (within last 4-weeks) of any medication
including the following:

- Any form of psychotropic medications including:

- antipsychotics,

- atypical antipsychotics,

- mood-stabilizers,

- anti-depressants (tricyclics, SSRI's, MAOI's, nonselective MAOIs,
Wellbutrin/Zyban),

- anti-panic agents,

- anti-obsessive agents,

- anti-anxiety agents, and

- stimulants (e.g., Provigil, Ritalin)

- Varenicline

- Medication for chronic pain

- Anti-coagulants (e.g., Warfarin)

- Any heart medications

- Daily medication for asthma

- Apomorphine, dobutamine, isoproterenol, levodopa, methyldopa, or sympathomimetic
(e.g., albuterol, pseudoephedrine)

2. Current use of any smoking cessation medication.

Medical Exclusion Criteria

1. Women who are pregnant, planning a pregnancy, or lactating.

2. History or current diagnosis of psychosis, major depression or bipolar disorder,
schizophrenia, or any Axis 1 disorder as identified by the MINI.

3. Serious or unstable disease within the past 6 months (e.g., cancer [except squamous
cell carcinoma], heart disease, HIV, liver disease, Parkinson's disease).

4. History of epilepsy or a seizure disorder.

5. History or current diagnosis (last 6-months) of abnormal rhythms and/or tachycardia
(>100 beats/minute); history or current diagnosis of chronic obstructive pulmonary
disease (COPD), cardiovascular disease (stroke, angina, coronary heart disease), heart
attack in the last 6 months, uncontrolled hypertension (SBP>150 or DBP>90)

6. History of Kidney and/or liver failure (including transplant) or problems (e.g.,
cirrhosis); current liver disease or impairment.

7. History or current diagnosis of hepatitis.

8. Liver function tests more than 20% outside of the normal range.

9. Allergies to the study medication, tolcapone (Tasmar).

10. History of severe, uncontrolled muscle movements (e.g., uncontrolled jerking,
twitching) or a certain severe muscle problem (rhabdomyolysis).

11. Experience of dizziness or lightheadedness upon standing on a regular basis (i.e.,
daily).

Genetic Profile

1. Individuals with the heterozygous genotype (val/met) on the catechol-methyl
transferase (COMT) gene. (Note: this is a small pilot study comparing effects of
Tolcapone on cognitive performance between val/val (n=8) individuals.) Future research
done at our center will plan to include those carrying the val/met genotype.

2. Individuals with the homozygous genotype, met/met, on the COMT gene. As of December
2008, the study has accrued 8 met/met participants. To balance the genotype groups,
the study will recruit an equal number of participants with the val/val genotype on
the COMT gene and not include any further participants with the homozygous, met/met
genotype. Future research done at our center will plan to include those carrying the
met/met genotype.

3. Non-European ancestry as determined by self report at initial telephone screening; we
expect there to be ethnic differences in allele frequencies for COMT; therefore, as of
December 2008, to reduce ethnic admixture that could bias the genetic analysis of this
small sample, the study will be restricted to individuals of European ancestry. All
participants of non-European ancestry will be referred to other studies at our center.

General Exclusion

1. Any medical condition or concomitant medication that could compromise participant
safety or treatment, as determined by the Principal Investigator and/or Study
Physician.

2. Inability to provide informed consent or complete any of the study tasks as determined
by the Principal Investigator and/or Study Physician.