Nicotine Withdrawal Symptoms and Smoking Relapse

NCT01511614 | Completed Results

• 2 other identifiers: 99991247412-DA-N474
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Smoking is thought to cause changes in the brain that lead to addiction and craving. Smokers who try to quit experience nicotine withdrawal symptoms that include irritability, anxiety, and difficulty concentrating. These symptoms make it difficult for people to stop smoking. Many people say that they continue smoking to help relieve these symptoms, often within the first week after trying to quit. Researchers want to study what is happening in the brain to cause these symptoms, which may help identify new ways to successfully quit smoking. Objectives: \- To study nicotine withdrawal symptoms and brain function in smokers who stop smoking for 36 hours. Eligibility: \- Individuals between 18 and 65 years of age who smoke at least 10 cigarettes per day. Participants must be able to stop smoking for 36 hours on two occasions. Design: Phase 1

• This study will involve three visits to the National Institute on Drug Abuse.
• NOT be able to smoke for 36 hours before the two imaging visits.
• Wear a nicotine skin patch or a placebo (fake) patch during your 36 hour smoking abstinence period and study visits.
• Have your blood drawn to test for levels of stress-related hormones.
• Complete multiple MRI scanning sessions that last about 1.5 to 2 hours each.
• Undergo EEG (brain waves) recording.
• Answer questionnaires about how you think and feel.
• Complete various tasks and procedures inside and outside of the MRI scanner. Phase 2
• This study will involve thirteen visits to the National Institute on Drug Abuse.
• Set a quit date and develop a treatment plan with a study therapist.
• Take Chantix (varenicline) every day for a period of 12 weeks.
• Meet for weekly and biweekly counseling sessions with a therapist.
• Answer questionnaires about how you think and feel. Phase 3
• This study will involve three visits to the National Institute on Drug Abuse.
• Complete an MRI scanning session that will last about 20min each visit
• Meet with a study staff member on each visit who will ask you questions about your smoking behavior and how you think and feel.

Conditions

Nicotine Dependence

Keywords

fMRI; tDCS

Outcome Measures

Primary Outcomes (11)

• BOLD Activation in Right ACC During Parametric Flanker Task tDCS Stimulation

  BOLD percent signal change in right Anterior Cingulate Cortex (rACC) during parametric flanker task. This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo). The 3 task conditions are congruent (i.e. flanker stimuli are identical to target) and medium and high levels of incongruent.

  During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condidtion)

• dACC Glutamate

  Glutamate measured in the dorsal Anterior Cingulate Cortex (dACC) measured as a ratio to Creatine and Phosphocreatine. Cigarette smokers were 12 hour (overnight) abstinent, and had either a nicotine patch or a placebo patch placed 1-2 hours before scanning.

  12 hours nicotine abstinent (plus 1-2 hours after patch)

• Behavioral Accuracy on N-Back Working Memory Task

  Behavioral Performance on N-Back Working Memory Task. Task consisted of 0-back, 1-back and 3-back. In this task, participants respond with a button when the current stimulus is the same as the previous one (1-back), the one 3 stimuli earlier (3-back) or the letter 'D' (0-back) depending upon task condition. Table values are accuracy as a percentage (i.e total times they reponded correctly / total trials). This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).

  During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)

• Behavioral Reaction Speed on N-Back Working Memory Task

  Behavioral Performance on N-Back Working Memory Task. Task consisted of 0-back, 1-back and 3-back. In this task, participants respond with a button when the current stimulus is the same as the previous one (1-back), the one 3 stimuli earlier (3-back) or the letter 'D' (0-back) depending upon task condition. Table values are reaction time speeds. This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).

  During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)

• Behavioral Accuracy on the Parametric Flanker Task

  Behavioral Performance on Parametric Flanker Task. Task consisted of 3 levels of difficulty: congruent trials (where distractors are the same as the target; e.g. HHHHHHH), incongruent2 trials (where the 2 furthest distractors on each side were incongruent with the target; e.g. HHSSSHH) and incongruent3 trials (where all distractors are incongruent with the target; e.g. HHHSHHH). Table values are accuracy as a percentage (i.e total times they reponded correctly / total trials). This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).

  During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)

• Behavioral Reaction Speed on the Parametric Flanker Task

  Behavioral Reaction speed on Parametric Flanker Task. Task consisted of 3 levels of difficulty: congruent trials (where distractors are the same as the target; e.g. HHHHHHH), incongruent2 trials (where the 2 furthest distractors on each side were incongruent with the target; e.g. HHSSSHH) and incongruent3 trials (where all distractors are incongruent with the target; e.g. HHHSHHH). Table values are reaction time speeds. This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).

  During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)

• Behavioral Accuracy on the Matching Task

  Behavioral Performance on the Matching Task. Task consisted of 2 conditions: match faces, where 2 faces appeared at the top of the screen and one at the bottom (target). Participants needed to press a button corresponding to the top row face that matched the target; the control condition was identical, except instead of faces the images consisted of simple shapes (e.g. ovals). Table values are accuracy as a percentage (i.e total times they reponded correctly / total trials). This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).

  During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)

• Behavioral Reaction Speed on the Matching Task

  Behavioral Reaction speed on the Matching Task. Task consisted of 2 conditions: match faces, where 2 faces appeared at the top of the screen and one at the bottom (target). Participants needed to press a button corresponding to the top row face that matched the target; the control condition was identical, except instead of faces the images consisted of simple shapes (e.g. ovals).Table values are reaction time speeds. This table is during 2mA Anodal tDCS at the left Dorsolateral prefrontal cortex (dlPFC), 2mA Cathodal tDCS at left dlPFC, or sham stimulation (i.e. placebo).

  During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condition)

• Nicotine Withdrawal From WSWS

  Nicotine withdrawal as measured from the total score on the Wisconsin Smoking Withdrawal Scale (WSWS). The WSWS is a 28-item questionnaire ranging from 0 (strongly disagree) to 4 (strongly agree). The total score ranges from 0 to 112, with higher scores indicating more withdrawal symptoms. Cigarette smokers were 12 hour (overnight) abstinent and had either a nicotine patch or a placebo patch placed 1-2 hours before scanning.

  12 hours nicotine abstinent (plus 1-2 hours after patch)

• Nicotine Craving From TCQ-SF

  Nicotine craving as measured from the total score on the Tobacco Craving Questionnaire-Short Form (TCQ-SF). The TCQ-SF is a 12-item questionnaire designed to measure craving for cigarettes. Each question is answered on a 7-point scale from 1 (Strongly Disagree) to 7 (Strongly Agree). Total scores range from 12 to 84, with higher scores indicating more craving. Cigarette smokers were 12 hour (overnight) abstinent and had either a nicotine patch or a placebo patch placed 1-2 hours before scanning.

  12 hours nicotine abstinent (plus 1-2 hours after patch)

• Affect From PANAS

  Positive and Negative mood from the Positive and Negative Affect Schedule (PANAS). The PANAS consists of 20 words related to emotions that participants indicate to what extent they felt this way in the last week. Words are rated from 1 (very slightly or not at all) to 5 (extremely). The PANAS is broken into a Positive and Negative subscale, each consisting of 10 questions and thus ranging from 10 to 50. Higher numbers are indicative of higher levels of positive affect and higher levels of negative affect respectively. Cigarette smokers were 12 hour (overnight) abstinent, and had either a nicotine patch or a placebo patch placed 1-2 hours before scanning.

  12 hours nicotine abstinent (plus 1-2 hours after patch)

Study Arms (5)

active tDCS

ACTIVE COMPARATOR

(1) anodal left-dlPFC + cathodal right-vmPFC stimulation, with anode over the left dlPFC and cathode over the right-vmPFC; (2) cathodal left-dlPFC + anodal right-vmPFC stimulation, in which polarity is reversed between the two electrodes

Device: Transcranial Direct Current Stimulation

sham tDCS

SHAM COMPARATOR

To simulate the experience of tDCS stimulation, current is ramped on and turned off at the beginning and end of the tDCS session. An additional sham option is to have the current ramp up and down only at the beginning of the sham session, and not at the end. This second sham is supported in the literature as an effective blinding technique, which subjects cannot distinguish from active stimulation (Gandiga et al 2006, Brunoni et al 2012) . One of these sham options will be used for data that will be analyzed together, to be determined based on equipment capabilities and preliminary analysis of blinding efficacy in our cross over design. We will assess the efficacy of sham condition by providing participants and the investigator with a questionnaire on the MRI/tDCS session, wherein they will report whether they thought the tDCS session was active or sham. The MRI operator (or other non protocol personnel) will control active/sham conditions.

Device: sham

Main Study - Treatment

OTHER

Healthy male and female adults who smokers are actively seeking treatment for smoking cessation were asked to complete three study phases: pre-treatment study visits, treatment visits and post-treatment follow-up visits. Pre-treatment (phase 1): 2 MRI sessions: dose-matched nicotine patch or placebo patch during a 36hr smoking abstinence period completed prior to each. Within \~ 2wks of their second scan visit, participants will have 1-3 pre-treatment preparation visits with a therapist. Treatment (Phase 2): 15-18 visits over \~16-19 weeks. First dose of varenicline (0.5 - 1mg/day), 1 week prior to their quit date followed by 12wks of daily varenicline (2mg/day) as well as weekly and biweekly 30min counseling sessions. Follow-up Phase 3: visits at 1, 6, and 12 months after their last treatment visit to assess quit status and smoking abstinence since last visit, complete a series of state measures and complete a 15-20 min scan session.

Drug: Nicotine patch; Drug: Placebo patch; Drug: Varenicline Pill; Drug: Placebo pill

Main Study - Non-Treatment

OTHER

Healthy male and female adults who have a history of 1 or more years of consistently smoking cigarettes with a urine cotinine level corresponding to smoker status for the specific test being used, typically corresponding to a urine cotinine above about 200 ng/ml, but who are not currently seeking treatment for smoking cessation. Non-treatment seeking smokers will not set a quit date or make a quit attempt, will not complete a treatment program as part of this study and will not be followed up after they complete the two pre-treatment visits.

Drug: Nicotine patch; Drug: Placebo patch

Main Study - Motivational Interviewing

OTHER

Current smokers who meet criteria for participation but who are not currently ready to enter treatment for smoking cessation. These subjects will receive motivational interviewing to prepare them for a tobacco cigarette quit attempt.

Behavioral: Motivational Interviewing

Interventions

Transcranial Direct Current Stimulation DEVICE

Transcranial Direct Current Stimulation (tDCS), a type of Non-invasive Brain Stimulation (NIBS), has the potential to modify neuronal circuits by application of a subthreshold conductive current through the scalp. Two potential targets for tDCS as a smoking cessation aid are the dorsolateral pre-frontal cortex (dlPFC), a node of the ECN, and the ventromedial prefrontal cortex (vmPFC), a node of the DMN. tDCS can potentially strengthen the control of the ECN through excitatory stimulation of the dlPFC, and weaken the influence of the DMN (Lerman et al 2014) by inhibitory stimulation of the vmPFC. The tDCS model we will use is the neuroConn DC-Stimulator MR (neuroCare Group GmbH, Munchen, Germany).

active tDCS

sham DEVICE

Sham Comparator

sham tDCS

Nicotine patch DRUG

Dose-match Nicotine for non-deprived scan

Main Study - Non-Treatment; Main Study - Treatment

Placebo patch DRUG

Nicotine deprived

Main Study - Non-Treatment; Main Study - Treatment

Varenicline Pill DRUG

Treatment

Main Study - Treatment

Placebo pill DRUG

Active comparator to varenicline

Main Study - Treatment

Motivational Interviewing BEHAVIORAL

Motivational Interviewing for smoking cessation preparation

Main Study - Motivational Interviewing

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All Subjects must:
• Be between the ages of 18-65.
• Be right-handed. Assessment tool(s): Edinburgh Handedness Inventory.
• Be in good health. Justification: Many illnesses may alter fMRI signals as well as cognitive processes and neural functioning. Assessment tool(s): Participants will provide a brief health history during phone screening, and undergo a medical history and physical examination with a qualified IRP clinician.
• Be free of current moderate to severe DSM-V Substance Use Disorder on any drug, except nicotine in smokers. Those with past moderate to severe use disorder on substances may be included, provided they are in sustained remission (and not on maintenance therapy for opioid use disorder) and are not intoxicated on the day of the imaging session. Justification: Moderate to severe use disorder on other substances may result in unique CNS deficits that could confound results and introduce excessive variance, while mild substance use disorder and substance use disorder in remission are common in community samples of smokers. Assessment tool(s): Computerized SCID or comparable assessment and DSM-5 substance use disorder assessment.
• Be able to abstain from alcohol and other recreational drugs for 24 hours before each imaging session, and able to moderate caffeine intake 12 hours before each imaging session. Justification: Recent substance use, including alcohol, and caffeine modulate neural functioning in a way that would complicate data interpretation. Assessment tool(s): Self-report, breathalyzer, and urine toxicology screen with follow up neuromotor assessment to ensure absence of acute impairment with positive urine test.
• Smokers must meet the additional criteria:
• Have a urine cotinine level corresponding to smoker status for the specific test being used, typically corresponding to a urine cotinine above about 200 ng/ml, and have been smoking for at least 1 year. Justification: The present protocol is interested in neurobiological mechanisms that underlie nicotine withdrawal, and is thus contingent on the presence of nicotine dependence. Assessment tool(s): Selfreport, commercial urine cotinine test corresponding to smoker status for the specific test being used, typically corresponding to a urine cotinine above about 200 ng/ml.
• Be able to abstain from smoking for 12 hours prior to MRI-tDCS study sessions. Justification: The present protocol will investigate the effect of acute nicotine withdrawal on cognitive processes and response to tDCS. Assessment: Self-report and expired CO levels
• In addition, non-smokers must meet:
• Not have a history of daily cigarette smoking or have used any nicotine products continuously lasting more than a month, and no smoking or continuous use of any nicotine products within the past year. Assessment Tools: Self-report, urine cotinine test, and expired CO levels.

You may not qualify if:

• All participants will be excluded if they:
• 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. Justification: MR scanning is one of the primary measurement tools used in the protocol. Assessment tool(s): Prospective participants will fill out an MRI screening questionnaire and undergo an interview with an MR technologist. Questions concerning suitability for scanning will be referred to the MR Medical Safety Officer. Prospective participants will be questioned about symptoms of claustrophobia and placed in the mock scanner during their first visit to assess for possible difficulty tolerating the confinement of the scanner and for ability to fit into the scanner.
• Have HIV or Syphilis. Justification: HIV and Syphilis both can have central nervous system (CNS) sequelae, thus introducing unnecessary variability into the data. Assessment tool(s): Oral HIV followed by blood test if oral test is + and STS+ without adequate prior treatment
• Regularly or intermittently use any prescription (e.g., benzodiazepines, barbiturates), over-the-counter (e.g., cold medicine) medications that are likely to alter BOLD signal (neuronal-vascular coupling). Justification: The use of these substances may alter the fMRI signal and/or neural functions of interest in the current study. Assessment tool(s): History and comprehensive urine drug screening to detect benzodiazepines, antipsychotics, anticonvulsants, and barbiturates. Note: If a participant is intermittently taking a medication likely to affect BOLD signal, the participant may be excluded or if scanned, will be scanned in the same medication state for data continuity purposes (i.e. either all scan days are scheduled after 5 half-lives since last medication use; or all scan days are scheduled on medication).
• Are cognitively impaired or learning disabled. Justification: Cognitive impairment and learning disabilities may be associated with altered brain functioning in regions recruited during laboratory task performance. Cognitive impairment may affect one s ability to give informed consent. Assessment tool(s): History of placement in special-education classes as a consequence of serious learning problems and not solely as a consequence of behavioral problems, assessed during the History and Physical screening assessment.
• Have significant cardiovascular conditions that would make use of nicotine patch unsafe. Justification: Nicotine patch may cause significant arrhythmias in susceptible individuals. Assessment tool(s): History and physical exam, including 12-lead EKG.
• i. Hemoglobin \< 10 g/dl
• ii. White Blood Cell Count \< 2400/microl
• iii. Liver Function Tests \> 3X upper limit of normal
• iv. Serum glucose \> 200 mg/dl
• v. Urine protein \> 2+
• vi. Serum creatinine \> 2 mg/dl
• The MAI will retain discretion to exclude based on less extreme lab results. After the screening process has been completed, the MAI will take into account all data collected in order to decide if there is an existing medical illness that would compromise participation in this research.
• Are pregnant, planning to become pregnant, or breastfeeding. Females are instructed in the consent to use effective forms of birth control during the study period. Justification: study procedures and drugs used in the current protocol may complicate pregnancy or be transferred to nursing children. Assessment tool(s): Urine and/or serum pregnancy tests, and clinical interview. Urine pregnancy tests will be conducted at the beginning of each imaging visit.
• Are non-English speaking. Justification: To include non-English speakers, we would have to translate the consent and other study documents and hire and train bilingual staff, which would require resources that we do not have and could not justify given the small sample size for each experiment. Additionally, the data integrity of some of the cognitive tasks and standardized questionnaires used in this study would be compromised as they have only been validated in English. Most importantly, ongoing communication regarding safety procedures is necessary when participants are undergoing MRI procedures. The inability to effectively communicate MRI safety procedures in a language other than English could compromise the safety of non-English speaking participants. Assessment tool(s): self-report.

Sponsors & Collaborators

• National Institute on Drug Abuse (NIDA): lead

Study Sites (1)

National Institute on Drug Abuse

Baltimore, Maryland, 21224, United States

Location

Related Publications (2)

• Abulseoud OA, Ross TJ, Nam HW, Caparelli EC, Tennekoon M, Schleyer B, Castillo J, Fedota J, Gu H, Yang Y, Stein E. Short-term nicotine deprivation alters dorsal anterior cingulate glutamate concentration and concomitant cingulate-cortical functional connectivity. Neuropsychopharmacology. 2020 Oct;45(11):1920-1930. doi: 10.1038/s41386-020-0741-9. Epub 2020 Jun 19.

  PMID: 32559759 RESULT

• Aronson Fischell S, Ross TJ, Deng ZD, Salmeron BJ, Stein EA. Transcranial Direct Current Stimulation Applied to the Dorsolateral and Ventromedial Prefrontal Cortices in Smokers Modifies Cognitive Circuits Implicated in the Nicotine Withdrawal Syndrome. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Apr;5(4):448-460. doi: 10.1016/j.bpsc.2019.12.020. Epub 2020 Jan 13.

  PMID: 32151567 RESULT

MeSH Terms

Conditions

Tobacco Use Disorder

Interventions

Transcranial Direct Current Stimulation; Tobacco Use Cessation Devices; Varenicline; Motivational Interviewing

Condition Hierarchy (Ancestors)

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics; Convulsive Therapy; Psychiatric Somatic Therapies; Behavioral Disciplines and Activities; Electroshock; Psychological Techniques; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quinoxalines; Directive Counseling; Counseling; Mental Health Services; Health Services; Health Care Facilities Workforce and Services

Results Point of Contact

• Title: Dr. Amy Janes
• Organization: NIH/NIDA

amy.janes@nih.gov

667.312.5164

Study Officials

• Amy Janes, Ph.D.

  National Institute on Drug Abuse (NIDA)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2012
• First Posted: January 18, 2012
• Study Start: May 20, 2013
• Primary Completion: March 30, 2020
• Study Completion: March 30, 2020
• Last Updated: May 31, 2024
• Results First Posted: May 31, 2024

Record last verified: 2023-07-25

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)