Neural Substrates in Nicotine Withdrawal
Condition: Tobacco Use Disorder
MeSH terms: Tobacco Use Disorder
Intervention: Tolcapone; Placebo
Intervention description: 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.; 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.
Intervention MeSH terms: Tolcapone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 218.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Genetics; Nicotine; Cognition; fMRI

Summary:

      This study will test the hypothesis that a medication called tolcapone (Brand Name: Tasmar)
      will help reduce cognitive problems that smokers experience when they quit. This study will
      also determine whether the benefits of this medication differ depending on a smokers' genetic
      background.
    

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.