Effect of Galantamine on Short-term Abstinence

Galantamine, an FDA-approved treatment for Alzheimer's disease, is used to treat cognitive
impairment by enhancing acetylcholine through inhibition of the enzyme, acetylcholinesterase.
We propose randomized double-blind placebo-controlled study of short-term (23 days) treatment
with galantamine.

Eighty chronic smokers will complete a validated procedure for screening new medications. An
equal number of subjects will be assigned to one of two groups: galantamine-ER or placebo.
Participants in both groups will take one capsule each day and follow the same procedures.
This is not a cross-over trial.

For participants in the galantamine group, following an initial 1-week drug run-up phase (8mg
daily of galantamine-ER), the medication dose will be increased to 16mg daily of
galantamine-ER for the remainder of the study (up to Day 23).

On Day 15, smokers will begin a mandatory 24-hour abstinence period, which will be followed
by a programmed smoking lapse on Day 16. Smokers will then be instructed to abstain for the
following 7 days (observed abstinence). Following completion of the study, participants will
be offered standard smoking cessation treatment.

On Days 0 (Baseline), 14, and 16, subjects will perform the following computer tasks: a
working memory task (Visual/Spatial N-Back), sustained attention tasks (Penn Continuous
Performance Task [PCPT-nl] and XO Reaction Time Task), a recall memory task (Word
Recognition), an interference control task (Stroop test), and a response inhibition task
(Stop Signal Task).

The primary outcome is to identify changes in behavioral performance and subjective symptoms
following two weeks treatment of galantamine and after 24 hours of abstinence, compared to
baseline.

This study will provide information about the role of the cholinergic system during brief
abstinence and whether enhancing acetylcholine reduces abstinence-induced cognitive symptoms
that promote smoking relapse. Information obtained in this study may further establish
cognitive performance measures as endophenotypes for nicotine dependence.

Inclusion Criteria:

1. Smokers who are between 18 and 60 years of age who self-report smoking at least 10
cigarettes (menthol and non-menthol) per day for at least the last 6 months.

2. Interest in quitting smoking in the next 2 to 6 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:

1. Smoking behavior

1. Use of chewing tobacco, snuff, and/or snus.

2. 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.

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

2. Alcohol/Drugs

1. Lifetime history of substance abuse (other than nicotine) and/or currently
receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine,
stimulants, PCP, benzodiazepines, or study-prohibited medications/recreational
drugs) as determined by self-report during the phone screen and/or through the
MINI during the Intake visit.

2. Current alcohol consumption that exceeds 25 standard drinks/week over the past 6
months.

3. Providing a breath alcohol concentration (BrAC) reading of greater than or equal
to 0.01 at the Intake, Baseline, or Testing Days.

4. A positive urine drug screen for cocaine, amphetamines, methamphetamines,
benzodiazepines, PCP, methadone, barbiturates, and opiates at the Intake visit,
Baseline visit, or the Testing days.

3. Medical

1. Women who are pregnant, planning a pregnancy in the next 3 months, or lactating;
all female subjects shall undergo a urine pregnancy test at the Intake visit and
must agree in writing to use an approved method of contraception. Following
enrollment, pregnancy tests will be conducted at the Baseline visit and Testing
days for all female subjects of child-bearing potential.

2. Diagnosis of Alzheimer's Disease or dementia.

3. Current treatment of cancer or diagnosed with cancer (except basal cell
carcinoma) in the past 6 months.

4. Liver/kidney failure, peptic ulcer disease, benign prostate hypertrophy.

5. Asthma or chronic obstructive pulmonary disease (COPD).

6. History (last 6 months) of abnormal heart rhythms, tachycardia and/or
cardiovascular disease (stroke, angina, heart attack). These conditions will be
evaluated on a case by case basis by the Study Physician/Health Care Provider.

7. Serious or unstable disease within the past 6 months, as determined by the Study
Physician/Health Care Provider.

8. Clinically significant abnormalities within physical examination and vital signs
at Medical Screen. Abnormalities will be assessed by the Study Physician/Health
Care Provider and eligibility will be determined on a case-by-case basis.

9. Any impairment (physical and/or neurological) including visual or other
impairment preventing cognitive task performance.

10. Uncontrolled high blood pressure (Systolic BP greater than 160 and/or Diastolic
BP greater than 100).

11. Hearing impairment, significant hearing loss (more than 20% in either ear),
cochlear implants, or bi-lateral hearing aids.

12. History of brain injury.

13. History of epilepsy or a seizure disorder.

14. Color Blindness.

15. 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 Intake visit).

4. Psychiatric Exclusions (determined by self-report on phone screen and/or through the
MINI during the Intake visit)

1. Current diagnosis of major depression. Persons with a history of major
depression, in remission for 6 months or longer, are eligible, provided they are
not excluded based on medications (below).

2. Suicide risk score on MINI greater than 0.

3. History or current diagnosis of schizophrenia, psychosis, and/or bipolar
disorder.

4. Current or past hypomanic/manic episode.

5. Current or history of a diagnosis of Attention-Deficit/Hyperactivity Disorder
(ADHD).

5. Medication

1. Current use, recent discontinuation (within the last month) of any form of
smoking cessation medications (i.e., Zyban, Wellbutrin, Wellbutrin SR, Chantix,
nicotine replacement therapy).

2. Current use or recent discontinuation (within the last 60 days) of any of the
following:

- Anti-anxiety or panic disorder medications.

- Anti-psychotic medications.

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

- Anti-depressants (e.g., Wellbutrin, MAOIs, SSRIs, tricyclic
antidepressants).

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

- Systemic Steroids (e.g., Prednisone).

- Alzheimer's disease medications (e.g., Acetylcholinesterase inhibitors
(ACIs), Aricept/donepezil, Exelon/rivastigmine, Tacrine, or memantine).

- Parkinson's disease medications(e.g., Cogentin/benztropine).

- Irritable bowel syndrome medication (e.g., Dicylomine/Bentyl).

- Heart medications (e.g., quinidine or Procardia/nifedipine).

- Peptic ulcer disease medication (e.g, Zantac/ranitidine).

- Muscle relaxants (e.g., Soma/carisoprodol, Anectine/succinylcholine).

- Anti-fungal medication (e.g., Nizoral/ketoconazole).

- Anti-seizure medications (e.g., Ativan, Banzel, Carbatrol, Dilantin,
Lamictal, Gabitril, Lyrica, Neurontin, Tegretol, Topamax).

- COPD medication (e.g., Atrovent/Ipratropium Bromide).

- Urinary retention medications (e.g., Duvoid/bethanechol,
Proscar/finasteride, Avodart/dutasteride, Dibenzyline/phenoxybenzamine,
Regitine/phentolamine).

- Eye medication (e.g., Atropine).

3. Daily use of any of the following:

- Opiate-containing medications for chronic pain (Duragesic/fentanyl patches,
Percocet, Oxycontin).

- Medication for asthma (albuterol, Serevent, Combivent, Advair, Flovent,
Azmacort, Symbicort).

4. Known drug allergy to the study medication.

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.

6. General exclusions

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

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

5. Completion of neurocognitive assessments and/or use of study medication(s) at the
CIRNA in the past 6-months that could influence performance on study tasks as
determined by the Principal Investigator.

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

7. Missing 2 or more consecutive sessions, or 3 or more sessions during the
medication period.

8. Missing 2 or more consecutive doses during the medication period.

9. Missing 3 or more doses throughout the medication period.