Translational Neuropsychopharmacology Research of Nicotine Addiction

This study will examine the effects of combining Varenicline (VRN) and N-acetylcysteine (NAC) on neural circuitry function and treating nicotine addiction. Healthy adult nicotine dependent cigarette smokers interested in quitting (n=110) will be randomized to one of four PBO-controlled conditions for 4 weeks: 1) VRN+NAC, 2) VRN+PBO, 3) NAC+PBO or 4) PBO+PBO. Following 1 week of medication, participants will be contingently reinforced for 3 days of smoking abstinence and be scanned using functional magnetic resonance imaging (fMRI) techniques, while nicotine deprived during a resting state and a cue-reactivity (CR) task. Participants will be followed over the next 3 weeks of treatment and clinical variables will be assessed.

Study Overview

• Status: Completed
• Conditions: Nicotine Dependence, Cigarettes
• Intervention / Treatment: Drug: Placebo; Drug: Varenicline (VRN); Drug: N-Acetylcysteine (NAC)

Detailed Description

Cigarette (henceforth nicotine) addiction is a chronic, relapsing brain disorder and remains the leading preventable cause of death and disability in the US, costing nearly $200 billion each year. Although ~20% of adults in the USA currently smoke, the majority want to quit. In spite of the breadth of research focused on improving health outcomes and reducing the societal burden caused by nicotine addiction, the majority of smokers who attempt to quit will relapse. Nicotine withdrawal-related disturbances in executive function, negative affect and reward processes compel a smoker to self-administer nicotine-each in turn representing the loss of control to remain abstinent and risk factors for relapse. Thus, identifying the effects of nicotine addiction on mechanisms of self-regulation, and the value of novel medications for remediating dysregulated behavior are both needed in order to enhance interventions for treating nicotine addiction. The preliminary data, along with the extant literature, suggest that the maintenance of nicotine addiction is subserved by dysregulated neural function in limbic-striatal and corticostriatal neural circuitry. While VRN may be effective in treating limbic-striatal circuitry that is associated with promoting abstinence and reducing acute withdrawal; NAC may be effective in treating corticostriatal circuitry function that is associated with relapse vulnerability. Thus, the current proposal seeks to investigate two medications (VRN & NAC), with potentially complementary effects on the two different brain circuits- limbic-striatal (VRN) and corticostriatal (NAC) circuitry-and that may therapeutically target two different phases in the recovery of nicotine addiction-the promotion of abstinence (VRN) and relapse prevention (NAC). The placebo (PBO)-controlled design in this proposal will allow the team to identify and translate between the neurobiological substrates and the neurocognitive underpinnings of the effects of VRN+NAC on smoking behavior in humans-thus, advancing the understanding of the pathophysiology of nicotine addiction.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29403
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 - 55
2. Right Handed
3. English fluency
4. 20/20 vision with corrective lenses.
5. Smoke ≥ 10 cigarettes/day for a minimum of two years and have an expired carbon monoxide (CO) concentration of ≥ 10 ppm (to confirm inhalation).
6. Interest in quitting smoking or contemplating a quit attempt in the next 6 months
7. If female, agreement to use birth control

Exclusion Criteria:

1. Past head injury or primary neurological disorder associated with MRI abnormalities, including dementia, MCI, brain tumors, epilepsy, Parkinson's disease, or demyelinating diseases
2. Any physical or intellectual disability affecting completion of assessments
3. Any contraindication to MRI
4. Positive urine drug screen for illicit substances (such as marijuana or cocaine).
5. Current or past psychosis
6. Electroconvulsive therapy in last 6 months
7. Use of antidepressant medications or other psychotropic medications in the last month.
8. Positive urine pregnancy test or current breast feeding status

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VRN+ NAC; Titrated VRN up to 1mg BID with NAC at 1200mg BID for 28 days	Drug: Varenicline (VRN); VRN will be provided at the standard recommended dose (0.5 mg daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg twice daily thereafter for the remaining 21 days of active treatment.; Drug: N-Acetylcysteine (NAC); NAC will be dosed at 1200 mg twice daily throughout the 28-day active treatment
Active Comparator: NAC+ PBO; 1200mg BID for 28 days plus VRN placebo for 28 days	Drug: Placebo; Matched placebo; Drug: N-Acetylcysteine (NAC); NAC will be dosed at 1200 mg twice daily throughout the 28-day active treatment
Active Comparator: VRN+ PBO; Titrated VRN up to 1mg BID with NAC placebo for 28 days	Drug: Placebo; Matched placebo; Drug: Varenicline (VRN); VRN will be provided at the standard recommended dose (0.5 mg daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg twice daily thereafter for the remaining 21 days of active treatment.
Placebo Comparator: PBO+PBO; Double placebo taken for 28 days	Drug: Placebo; Matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response	Measure the Effects of Varenicline and N-Acetylcysteine (NAC) on brain activation to smoking images while participants undergo Functional Magnetic Resonance (fMRI) Imaging. Mean percent signal change of fMRI BOLD in the insula and nucleus accumbens will be recorded during smoking images. The lower the BOLD signal response, the better the outcome, meaning reduced reactivity to smoking images.	10 Days
rZ Change Score in Resting State Functional Connectivity From Baseline	Measure the effects of Varenicline and N-Acetylcysteine on resting-state functional connectivity while participants undergo fMRI. Fisher transformed correlation (rZ) scores will be recorded between medial prefrontal cortex and ventral striatum during a resting state scan. The higher the rZ score, the better the outcome, meaning stronger functional connectivity. rZ scores range from -1 to 1. The rZ-score central value is analogous to a central value to of a Z-score of 0, representing the population mean.	Baseline to day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Cigarettes Smoked Per Day	Measure the effects of Varenicline and N-Acetylcysteine on smoking behavior over the course of the study	28 Days

Collaborators and Investigators

• Sponsor: Medical University of South Carolina

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2016
• Primary Completion (Actual): March 9, 2020
• Study Completion (Actual): March 9, 2020

Study Registration Dates

• First Submitted: March 7, 2016
• First Submitted That Met QC Criteria: March 23, 2016
• First Posted (Estimate): March 30, 2016

Study Record Updates

• Last Update Posted (Actual): August 18, 2022
• Last Update Submitted That Met QC Criteria: July 22, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Cholinergic Agents; Antiviral Agents; Protective Agents; Nicotinic Agonists; Cholinergic Agonists; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine; Varenicline
• Other Study ID Numbers: PRO#48152

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No