Intervention: Tolcapone
Trial phase: Phase 2
ATC code: N04BX01
SMILES: Cc1ccc(C(=O)c2cc(O)c(O)c([N+](=O)[O-])c2)cc1
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 218
Group description: 11-day phase, tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily); oral dosing; medication is encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)

Tolcapone: Participants will be asked to take study medication each day for both 11-day study medication periods.

The study medication assignments for each participant in this project is randomized and counterbalanced. This means that approximately 50% of participants will take tolcapone during the first medication period, followed by the placebo in the second medication period. Alternatively, approximately 50% of participants will take the placebo during the first medication period, followed by tolcapone during the second medication period.
Eligibility criteria:
Inclusion Criteria:

Smokers who are between 18 and 65 years of age who self-report smoking at least 10 cigarettes (menthol and non-menthol) per day for at least the last 6 months.
Healthy as determined by the Study Physician, based on a medical evaluation including medical history and physical examination, psychiatric evaluation, and liver function tests (LFTs and GGT enzyme levels).
Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and HIPAA form.
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) and have 3 months of regular menstrual cycles.
Capable of providing a Carbon Monoxide (CO) breath test reading greater than 10 parts per million (ppm) at the medical screening visit.

Exclusion Criteria:

Smoking behavior

Current enrollment or plans to enroll in another research or smoking cessation program in the next 3 months.
Provide a CO reading less than or equal to 10ppm at the medical screening visit.
Plans to use nicotine substitutes (gum, patch, lozenge, e-cigarette) while enrolled in the study.

Alcohol/Drug Exclusion:

History (past 2 years) or current diagnosis of substance abuse and/or currently receiving treatment for substance abuse (alcohol, THC, cocaine, PCP, amphetamines, methamphetamines, MDMA/ecstasy, opiates, methadone, benzodiazepines, tricyclic antidepressants, and barbiturates).
Current alcohol consumption that exceeds 21 standard drinks/week over the last 6 months.
Positive urine drug screen (for substances listed previously) at the medical screening visit or either testing day.
Breath Alcohol Concentration (BrAC) assessment greater than or equal to 0.01 at medical screening visit or either testing day.

Medication Exclusion Criteria:

Current use or recent discontinuation (within last 28 days) of any medication including the following:

Any form of psychotropic medications including: Antipsychotics; Mood-stabilizers (e.g., lithium, valproic acid, carbamazepine/tegretol); Anti-depressants (tricyclics, SSRI's, MAOI's, non-selective MAOIs, Wellbutrin, St. John's Wort); Anti-anxiety/Anti-panic agents; Anti-obsessive agents; Prescription stimulants (e.g., Provigil, Ritalin); Diet Pills/Anorectics; Systemic Steroids; Daily medication for chronic pain (e.g., opiates) or muscle spasms; Daily use of over the counter stimulants in pill form (e.g., ephedrine)
Anti-coagulants (e.g., Warfarin)
Any heart medications (e.g., dobutamine, isoproterenol)
Daily medication for asthma
Parkinson's disease medications (e.g., levodopa, methyldopa, apomorphine)
Sympathomimetic (e.g., albuterol, pseudoephedrine)
Other smoking cessation medications (Wellbutrin/Zyban, Chantix/varenicline)

Medical Exclusion Criteria:

Women who are pregnant, planning a pregnancy within the next 3 months, or lactating.
History or current diagnosis of any Axis 1 disorder as identified by the MINI (Mini International Neuropsychiatric Interview) or self-report. For major depression, only a current diagnosis will be exclusionary.
History or current diagnosis of Attention-Deficit Hyperactivity Disorder (ADHD).
Serious or unstable disease (e.g., cancer within the past 6 months [except squamous cell carcinoma], HIV, Parkinson's disease).
History of epilepsy or a seizure disorder.
History or current diagnosis (last 6-months) of abnormal rhythms and/or tachycardia (>100 beats/minute); history or current diagnosis of COPD, cardiovascular disease (stroke, angina, coronary heart disease); heart attack in the last 6 months; uncontrolled hypertension (SBP>150 or DBP>90).
History or current kidney and/or liver failure (including transplant), disease, or impairment (e.g., cirrhosis); history or current diagnosis of hepatitis (excluding hepatitis A); liver function tests more than 20% outside of the normal range; Gamma-glutamyl Transpepsidase (GGT) values greater than 20% outside the normal range.
Allergy to the study medication, tolcapone (Tasmar).
History of severe, uncontrolled muscle movements (e.g., uncontrolled jerking, twitching) or a certain severe muscle problem (rhabdomyolysis).
Low or borderline intellectual functioning - determined by receiving a score of less than 90 on the Shipley Institute of Living Scale (SILS) which correlates with the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Estimated IQ Test (administered at the medical screening visit).
Experience of dizziness or lightheadedness upon standing on a daily basis.
Lifetime history of stroke.

fMRI Exclusion Criteria:

Self-reported history of claustrophobia.
Left-handedness.
Color blindness.
Any impairment preventing subjects from using response pad necessary for cognitive testing.
Circumstances or conditions that may interfere with magnetic resonance imaging (MRI).
Having a cochlear implant or wearing bilateral hearing aids.
Self-reported history of head trauma (including being knocked unconscious for 3 minutes or greater and diagnosis of a concussion) or CNS tumor.
Self-reported use of pacemakers, certain metallic implants, or presence of metal in the eye as contraindicated for MRI.
History of gunshot wound.
Weight greater than 300lbs. at medical screening or either testing day.
Completion of cognitive testing in study #810493 or #811325 within the last 6 months.

Genetic Profile Exclusion Criteria:

In order to balance the distribution of males and females, some participants who meet genotype and other eligibility criteria may not be enrolled in the study.

General Exclusion Criteria:

Any medical condition or concomitant medication that could compromise subject safety or treatment, as determined by the Principal Investigator and/or Study Physician.
Inability to provide informed consent or complete any of the study tasks as determined by the Principal Investigator and/or Study Physician.