Tobacco Use DisorderNCT00830739
A Multi-Modal Investigation of the Smoking Cessation Medication Varenicline: Dopaminergic Modulation of Reward Processing and Cognitive Control
An observational study of Tobacco Use Disorder and Nicotine Dependence, run by National Institute on Drug Abuse (NIDA) at 1 site in United States.
Trial summary
Background: Chronic nicotine exposure through cigarette smoking affects the level of the brain chemical dopamine. Smokers who attempt to quit experience lower levels of dopamine, which increases anxiety and triggers nicotine cravings that make quitting more difficult. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Tobacco Use Disorder, Nicotine Dependence
- How many people
- 61 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Nov 2008to 26 Feb 2013
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- between the ages of 18-55.
- right-handed.
- in good health.
- free of active DSM-IV dependence, or dependence in partial remission, on alcohol or any drug except nicotine. Past active dependence is acceptable provided it is at least five years in the past and total time of active dependence did not exceed 4 years. Those with past dependence may not have any current use (past 6 months) of the substance on which they were dependent.
- able to abstain from alcohol 24hrs before each of the imaging sessions and able to moderate their caffeine intake 12hrs before each session.
- In addition, smokers must:
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- smoke 10 or more cigarettes per day and have smoked for more than 2 years.
- be able to refrain from smoking for up to 12hrs (at 6 different time points) during the study.
- be able to tolerate the nicotine patch.
- In addition, non-smokers must:
- Not have a history of daily cigarette smoking lasting more than a month and no smoking within the past 2 years.
Who cannot join
- are not suitable to undergo an fMRI experiment due to certain implanted devices (cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical clips or other implanted metal parts), body morphology, or claustrophobia.
- have coagulopathies, history of, current superficial, or deep vein thrombosis, musculoskeletal abnormalities restricting an individual s ability to lie flat for extended periods of time.
- have HIV or Syphilis.
- regularly use any prescription, over-the-counter or herbal medication that may alter CNS function, cardiovascular function, or neuronal-vascular coupling.
- have any current, or a history of, neurological illnesses including, but not limited to, seizure disorders, frequent migraines or on prophylaxis, multiple sclerosis, movement disorders, history of significant head trauma, or CNS tumor.
- have any current, or a history of, major psychiatric disorders, substance-induced psychiatric disorders, suicidal ideations and/or suicide attempts, or currently under antidepressant or antipsychotic medication treatment.
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- are cognitively impaired or learning disabled.
- have significant cardiovascular or cerebrovascular conditions.
- have moderate to severe renal impairment.
- are diabetic.
- have any other major medical condition that in the view of the investigators would compromise the safety of an individual during participation.
- pregnant, planning to become pregnant, or breastfeeding.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institute on Drug Abuse, Biomedical Research Center (BRC)
Baltimore, Maryland, 21224
About this study
Background:
- Chronic nicotine exposure through cigarette smoking affects the level of the brain chemical dopamine. Smokers who attempt to quit experience lower levels of dopamine, which increases anxiety and triggers nicotine cravings that make quitting more difficult.
- Varenicline (Chantix) is a smoking cessation medication that is designed to reduce nicotine craving and withdrawal by slightly increasing levels of dopamine in the brain. Research has shown that varenicline is a safe, well-tolerated, and effective treatment for nicotine dependence, but researchers are interested in learning more about how it affects the brain and its function. Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) will help researchers study the brain s response to nicotine and varenicline.
Read more
Objectives:
- To explore how varenicline affects brain function and behavioral performance in current smokers and healthy volunteers.
Eligibility:
- Individuals between 18 and 55 years of age who are either current smokers (10 or more cigarettes per day) or healthy nonsmoking volunteers.
Design:
- The study will involve nine testing and research visits over 5 to 6 weeks. The first visit will provide an initial assessment and training on the tasks that will be completed during the study.
- Six testing visits will involve fMRI and EEG measurements of brain activity. Each visit will contain two 2-hour scanning sessions, and each session will involve thinking tests. During these visits, participants will receive varenicline and placebo tablets, and wear nicotine patches and placebo patches that do not contain nicotine. Participants will not be told which tablet or patch they are given. This is a crossover study so all participants eventually get nicotine and placebo, as well as varenicline and placebo.
- Two other visits involve different thinking tasks. These visits will not require fMRI or EEG scans.
Read the detailed description
Objective. Chronic nicotine exposure is thought to lead to alterations in the dopamine (DA) system that leaves smokers in a hypo-dopaminergic state during periods of abstinence. Varenicline (Chantix), a new efficacious smoking cessation medication, is thought to lead to a modest but sustained increase of DA release thereby reducing nicotine craving and withdrawal. While numerous studies have shown that varenicline is a safe, well-tolerated, and effective pharmacological treatment for nicotine dependence, studies exploring the neurophysiological impact of this drug in the human brain have not been conducted. This protocol will utilize an array of reward processing and cognitive control tasks to explore the effects of subtle DA manipulations (induced by smoking cessation, transdermal nicotine, and varenicline) on brain function and behavioral performance. Brain function will be assessed using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG).
Study Population. There will be two study populations: 1) healthy nicotine-dependent adults who smoke 10 or more cigarettes per day; and 2) healthy non-smoking, non-drug dependent controls. Participants must be generally healthy, right-handed, male or non-pregnant/non-lactating females between the ages of 18-55.
Design. After being medically cleared and giving informed consent, each participant will complete several imaging visits (6 visits, on separate days) before and after taking varenicline. Two of these visits will take place before varenicline administration (baseline), two visits after a two-week varenicline dosing period (post-varenicline), and another two after a two-week placebo-pill period (post-placebo-pill). Each set of two scans will involve the randomized, double blind administration of a nicotine transdermal or placebo patch. fMRI and EEG data will be collected after patch application and will involve several tasks designed to probe brain regions in a corticolimbic circuit that may mediate aspects of reward-processing, learning, attention, goal-directed behaviors, and drug abuse.
Outcome Measures. This study involves assessing neurophysiological and behavior differences between cohorts (smokers vs. non-smokers) and conditions (nicotine vs. placebo-patch; baseline vs. varenicline vs. placebo-pill). The primary outcome measures used to ascertain these differences will be: 1) percentage change in fMRI BOLD signal during performance of cognitive control and reward processing tasks; 2) change in ERP component (e.g., error-related negativity) amplitudes; 3) behavioral measures during task performance including reaction times and error rates; 4) scores on mood, personality, and smoking questionnaires; and 5) variations in genes related to nicotinic receptors and DA functioning.
- Conditions
- Tobacco Use Disorder, Nicotine Dependence
- Keywords
- Smoking Cessation, Dopamine, Cognitive Control, Reward Processing, Varenicline
- Medical subject headings
- Tobacco Use Disorder, Smoking Cessation
What is being measured
The primary outcome is the main question the study is designed to answer.
To improve understanding of the neural and cognitive consequences of nicotine dependence, nicotine abstinence, and varenicline treatment.
Secondary outcomes (1)
To better understand individual differences that may relate to the effects of nicotine in the brain to improve future smoking cessation treatments.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jan 2009 (estimated)
- Study start25 Nov 2008
- Study completion26 Feb 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Tobacco Use DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Time perspective
- Other
- Enrolment
- 61 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute on Drug Abuse (NIDA)
- Sponsor type
- US National Institutes of Health
- Investigators
- Elliot Stein, Ph.D., Principal investigator, National Institute on Drug Abuse (NIDA)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00830739
- Sponsor's protocol ID
- 999909044
- Other IDs
- 09-DA-N044
- Status last verified
- 26 Feb 2013
- First submitted
- 27 Jan 2009
- Last updated
- 5 Jul 2018
- Results posted
- No
Publications
Aceto MD, Martin BR. Central actions of nicotine. Med Res Rev. 1982 Jan-Mar;2(1):43-62. doi: 10.1002/med.2610020104. No abstract available.
PubMed 6125634Ahmed SH, Kenny PJ, Koob GF, Markou A. Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci. 2002 Jul;5(7):625-6. doi: 10.1038/nn872.
PubMed 12055635Alain C, McNeely HE, He Y, Christensen BK, West R. Neurophysiological evidence of error-monitoring deficits in patients with schizophrenia. Cereb Cortex. 2002 Aug;12(8):840-6. doi: 10.1093/cercor/12.8.840.
PubMed 12122032Lesage E, Aronson SE, Sutherland MT, Ross TJ, Salmeron BJ, Stein EA. Neural Signatures of Cognitive Flexibility and Reward Sensitivity Following Nicotinic Receptor Stimulation in Dependent Smokers: A Randomized Trial. JAMA Psychiatry. 2017 Jun 1;74(6):632-640. doi: 10.1001/jamapsychiatry.2017.0400.
PubMed 28403383Sutherland MT, Carroll AJ, Salmeron BJ, Ross TJ, Hong LE, Stein EA. Down-regulation of amygdala and insula functional circuits by varenicline and nicotine in abstinent cigarette smokers. Biol Psychiatry. 2013 Oct 1;74(7):538-46. doi: 10.1016/j.biopsych.2013.01.035. Epub 2013 Mar 15.
PubMed 23506999
Study at a glance
From the registry record, last updated by the sponsor on 5 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multi-Modal Investigation of the Smoking Cessation Medication Varenicline: Dopaminergic Modulation of Reward Processing and Cognitive Control
- ClinicalTrials.gov ID
- NCT00830739
- Acronym / sponsor ID
- 999909044
- Conditions
- Tobacco Use Disorder, Nicotine Dependence
- Keywords
- Smoking Cessation, Dopamine, Cognitive Control, Reward Processing, Varenicline
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 61 participants (actual)
- Lead sponsor
- National Institute on Drug Abuse (NIDA)US National Institutes of Health
- Study start
- 25 Nov 2008
- Study completion
- 26 Feb 2013
- First posted
- 28 Jan 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- Chronic nicotine exposure through cigarette smoking affects the level of the brain chemical dopamine. Smokers who attempt to quit experience lower levels of dopamine, which increases anxiety and triggers nicotine cravings that make quitting more difficult.
- Varenicline (Chantix) is a smoking cessation medication that is designed to reduce nicotine craving and withdrawal by slightly increasing levels of dopamine in the brain. Research has shown that varenicline is a safe, well-tolerated, and effective treatment for nicotine dependence, but researchers are interested in learning more about how it affects the brain and its function. Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) will help researchers study the brain s response to nicotine and varenicline.
Objectives:
- To explore how varenicline affects brain function and behavioral performance in current smokers and healthy volunteers.
Eligibility:
- Individuals between 18 and 55 years of age who are either current smokers (10 or more cigarettes per day) or healthy nonsmoking volunteers.
Design:
- The study will involve nine testing and research visits over 5 to 6 weeks. The first visit will provide an initial assessment and training on the tasks that will be completed during the study.
- Six testing visits will involve fMRI and EEG measurements of brain activity. Each visit will contain two 2-hour scanning sessions, and each session will involve thinking tests. During these visits, participants will receive varenicline and placebo tablets, and wear nicotine patches and placebo patches that do not contain nicotine. Participants will not be told which tablet or patch they are given. This is a crossover study so all participants eventually get nicotine and placebo, as well as varenicline and placebo.
- Two other visits involve different thinking tasks. These visits will not require fMRI or EEG scans.
Detailed description
Objective. Chronic nicotine exposure is thought to lead to alterations in the dopamine (DA) system that leaves smokers in a hypo-dopaminergic state during periods of abstinence. Varenicline (Chantix), a new efficacious smoking cessation medication, is thought to lead to a modest but sustained increase of DA release thereby reducing nicotine craving and withdrawal. While numerous studies have shown that varenicline is a safe, well-tolerated, and effective pharmacological treatment for nicotine dependence, studies exploring the neurophysiological impact of this drug in the human brain have not been conducted. This protocol will utilize an array of reward processing and cognitive control tasks to explore the effects of subtle DA manipulations (induced by smoking cessation, transdermal nicotine, and varenicline) on brain function and behavioral performance. Brain function will be assessed using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG).
Study Population. There will be two study populations: 1) healthy nicotine-dependent adults who smoke 10 or more cigarettes per day; and 2) healthy non-smoking, non-drug dependent controls. Participants must be generally healthy, right-handed, male or non-pregnant/non-lactating females between the ages of 18-55.
Design. After being medically cleared and giving informed consent, each participant will complete several imaging visits (6 visits, on separate days) before and after taking varenicline. Two of these visits will take place before varenicline administration (baseline), two visits after a two-week varenicline dosing period (post-varenicline), and another two after a two-week placebo-pill period (post-placebo-pill). Each set of two scans will involve the randomized, double blind administration of a nicotine transdermal or placebo patch. fMRI and EEG data will be collected after patch application and will involve several tasks designed to probe brain regions in a corticolimbic circuit that may mediate aspects of reward-processing, learning, attention, goal-directed behaviors, and drug abuse.
Outcome Measures. This study involves assessing neurophysiological and behavior differences between cohorts (smokers vs. non-smokers) and conditions (nicotine vs. placebo-patch; baseline vs. varenicline vs. placebo-pill). The primary outcome measures used to ascertain these differences will be: 1) percentage change in fMRI BOLD signal during performance of cognitive control and reward processing tasks; 2) change in ERP component (e.g., error-related negativity) amplitudes; 3) behavioral measures during task performance including reaction times and error rates; 4) scores on mood, personality, and smoking questionnaires; and 5) variations in genes related to nicotinic receptors and DA functioning.
Study design
- Time perspective
- Other
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (11 listed)
- smoke 10 or more cigarettes per day and have smoked for more than 2 years.
- be able to refrain from smoking for up to 12hrs (at 6 different time points) during the study.
- be able to tolerate the nicotine patch.
- Not have a history of daily cigarette smoking lasting more than a month and no smoking within the past 2 years.
Key exclusion criteria (12 listed)
- are not suitable to undergo an fMRI experiment due to certain implanted devices (cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical clips or other implanted metal parts), body morphology, or claustrophobia.
- have coagulopathies, history of, current superficial, or deep vein thrombosis, musculoskeletal abnormalities restricting an individual s ability to lie flat for extended periods of time.
- have HIV or Syphilis.
- regularly use any prescription, over-the-counter or herbal medication that may alter CNS function, cardiovascular function, or neuronal-vascular coupling.
- have any current, or a history of, neurological illnesses including, but not limited to, seizure disorders, frequent migraines or on prophylaxis, multiple sclerosis, movement disorders, history of significant head trauma, or CNS tumor.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
To improve understanding of the neural and cognitive consequences of nicotine dependence, nicotine abstinence, and varenicline treatment.
1 secondary outcome
To better understand individual differences that may relate to the effects of nicotine in the brain to improve future smoking cessation treatments.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Jul 2018.
- Background: PubMed 6125634Aceto MD, Martin BR. Central actions of nicotine. Med Res Rev. 1982 Jan-Mar;2(1):43-62. doi: 10.1002/med.2610020104. No abstract available.
- Background: PubMed 12055635Ahmed SH, Kenny PJ, Koob GF, Markou A. Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci. 2002 Jul;5(7):625-6. doi: 10.1038/nn872.
- Background: PubMed 12122032Alain C, McNeely HE, He Y, Christensen BK, West R. Neurophysiological evidence of error-monitoring deficits in patients with schizophrenia. Cereb Cortex. 2002 Aug;12(8):840-6. doi: 10.1093/cercor/12.8.840.
- Derived from this study: PubMed 28403383Lesage E, Aronson SE, Sutherland MT, Ross TJ, Salmeron BJ, Stein EA. Neural Signatures of Cognitive Flexibility and Reward Sensitivity Following Nicotinic Receptor Stimulation in Dependent Smokers: A Randomized Trial. JAMA Psychiatry. 2017 Jun 1;74(6):632-640. doi: 10.1001/jamapsychiatry.2017.0400.
- Derived from this study: PubMed 23506999Sutherland MT, Carroll AJ, Salmeron BJ, Ross TJ, Hong LE, Stein EA. Down-regulation of amygdala and insula functional circuits by varenicline and nicotine in abstinent cigarette smokers. Biol Psychiatry. 2013 Oct 1;74(7):538-46. doi: 10.1016/j.biopsych.2013.01.035. Epub 2013 Mar 15.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Elliot Stein, Ph.D. principal investigator
National Institute on Drug Abuse (NIDA)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Tobacco Use Disorder and Nicotine Dependence, run by National Institute on Drug Abuse (NIDA) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To improve understanding of the neural and cognitive consequences of nicotine dependence, nicotine abstinence, and varenicline treatment.. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00830739, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jul 2018.