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Nicotinic Receptor Availability in Slow and Fast Nicotine Metabolizers

18 Years
65 Years
Not Enrolling
Nicotine Addiction

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Trial Information

Nicotinic Receptor Availability in Slow and Fast Nicotine Metabolizers

The nicotine metabolite ratio (NMR), a stable marker of nicotine clearance rate, is a robust
predictor of smoking relapse. Individuals who are fast nicotine metabolizers have higher
rates of relapse, compared to slow metabolizers, on nicotine replacement or placebo
treatment. Nicotine exerts its reinforcing properties, in part, by binding to α4β2*
nicotinic acetylcholine receptors (nAChRs) in the brain. The α4β2* nAChRs are abundant and
have high affinity for nicotine relative to other nAChR subtypes. The goal of this project
is to identify abstinence-induced changes in neuronal nicotinic receptor availability that
may underlie risk for smoking relapse.

The investigators propose to utilize positron emission tomography (PET) imaging to examine
the association of variation in nicotine metabolism with return to availability of α4β2*
nAChRs during early abstinence. The investigators will measure α4β2* receptor availability
using the PET radio-ligand 2-[18F]FA, administered with bolus injection, on two separate
occasions: during smoking as usual and after 24 hours of abstinence. The proposed study will
help us understand the neurochemical mechanisms that underlie the higher risk of relapse
among faster nicotine metabolizers, thereby pointing to potential targets for tailored
therapy for these smokers at increased risk.

In addition, the investigators will invite six subjects who have completed the two PET scans
described above to complete a third PET scan. During this third PET scan, the investigators
plan to measure α4β2* receptor availability using the PET radio-ligand 2-[18F]FA,
administered as bolus plus constant infusion after 24 hours of abstinence. The purpose will
be to compare α4β2* nAChR binding potential data from the bolus 2-[18F]FA infusion protocol
used in the main study to the bolus plus constant infusion protocol used in this third PET

The protocol of this third PET scan will help the investigators demonstrate the feasibility
at the University of Pennsylvania of administering the radiotracer as a bolus plus constant
infusion, and the feasibility of scanning for two hours (versus one hour in the current
protocol) paradigm. This data is important pilot data for future NIH grant submissions using
this radiotracer.

Inclusion Criteria:

1. Ages 18 to 65 years old.

2. Smoke 10 cigarettes per day for the previous 6 months.

3. Weigh less than 300lbs (due to limitations of the PET and MRI scanners).

Exclusion Criteria:

1. Smoking behavior:

1. Current enrollment or plans to enroll in a smoking cessation program, or use
other smoking cessation medications in the next 2 months.

2. Provide a CO reading of less than 10 ppm at medical screening.

2. Alcohol/Drugs:

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

2. Positive drug screen at any of the sessions (see page 8 for list of drugs and/or
contra-indicated medications).

3. Current alcohol consumption that exceeds 25 standard drinks/week.

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

3. Medical:

1. Women who are pregnant, planning a pregnancy, or lactating; all female subjects
shall undergo a serum pregnancy test at the medical screening session and urine
pregnancy tests at the two PET scans and MRI scan.

2. Women of child-bearing age must agree in writing to use an approved method of
contraception or agree to abstain from sexual intercourse

3. History or current diagnosis of the following psychiatric diagnoses identified
by the MINI (Mini International Neuropsychiatric Interview) such as psychosis,
bipolar disorder, schizophrenia, major current depression, or any Axis 1

4. Self-report of serious or unstable disease within the past 6 months (e.g.,
cancer [except melanoma], HIV/AIDS, stroke, angina, coronary disease, heart

5. History of epilepsy or a seizure disorder.

6. Any medical or neurological condition that might interfere with the distribution
of the radiotracer as determined by the study M.D.

4. Medication:

a. Current use or recent discontinuation (within last 14-days) of the following

- Any form of smoking cessation medication (Zyban, Wellbutrin, Wellbutrin SR,
Chantix, NRT);

- Recent (within last 14 days) or planned use of psychotropic medications
(anti-psychotics, anti-depressants, anti-anxiety, anti-panic medications, mood
stabilizers, opioids, and stimulants).

- Participants shall be instructed to refrain from using any study prohibited
drugs (note - participants are allowed to take prescription medicines not in the
exclusion list) throughout their participation in the study.

5. Imaging-Related Exclusion Criteria:

1. Self-reported history of head trauma or brain (or CNS) tumor.

2. Self-reported history of claustrophobia (contraindicated for PET and MRI).

3. Having a cochlear implant or wearing bilateral hearing aids.

4. Self-reported use of pacemakers, certain metallic implants, or presence of metal
in the eye as contraindicated for MRI.

5. History of gunshot wound.

6. Circumstances or conditions that may interfere with magnetic resonance imaging

7. Inability to complete the baseline study procedures within four hours and/or
correctly, as determined by the PI.

Type of Study:


Study Design:

Observational Model: Cohort, Time Perspective: Prospective

Outcome Measure:

Change in α4β2* nAChR binding potential

Outcome Description:

This study uses a mixed design. A within-subject positron emission tomography (PET) study comparing α4β2* nAChR availability, using 2-[18F]FA PET imaging, at two timepoints (1) during smoking as usual; and (2) after 24 hours of overnight abstinence. The order of the PET scans will be counterbalanced across subjects to prevent order effects that could bias the study results. Nicotine metabolite ratio (NMR) serves as the between-subject factor. The minimum amount of time between scans will be separated by one week. The maximum amount of time allowable between scans will be 4 weeks.

Outcome Time Frame:

Week 1 and up to Week 5

Safety Issue:


Principal Investigator

Caryn Lerman, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pennsylvania


United States: Food and Drug Administration

Study ID:




Start Date:

October 2010

Completion Date:

December 2012

Related Keywords:

  • Nicotine Addiction
  • PET Scan
  • Tobacco Use Disorder
  • Behavior, Addictive



Center for Interdisciplinary Research on Nicotine Addiction, University of PennsylvaniaPhiladelphia, Pennsylvania  19104