Nicotine Withdrawal Symptoms and Smoking Relapse

* INCLUSION CRITERIA: 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. EXCLUSION CRITERIA: 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 musculoskeletal abnormalities restricting an individual s ability to lie flat for extended periods of time. Justification: MR scanning sessions require participants to lie flat on their backs and remain perfectly still for approximately one hour. Therefore, conditions that would make that difficult (e.g. chronic back pain, significant scoliosis) will be exclusionary. Assessment tool(s): History and physical examination by a qualified IRP clinician, supplemented with a trial of lying in the mock scanner to assess comfort issues. * 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). * Have any current neurological illnesses including, but not limited to, seizure disorders, frequent migraines or on prophylaxis, multiple sclerosis, cerebrovascular accident, movement disorders (except essential tremor, so long as it would not interfere with study tasks such as button pressing), history of significant head trauma, or CNS tumor. Justification: Neurological diseases alter CNS function and, possibly, the neuronal-vascular coupling that forms the basis of the fMRI signal. Assessment tool(s): History and physical examination by a qualified IRP clinician, urine drug screening for anticonvulsants not disclosed by history. History of head trauma with loss of consciousness of more than 30 minutes or with post-concussive sequelae lasting more than two days, regardless of loss of consciousness, will be exclusionary. The MAI who will also retain discretion to exclude based on a history of neurological illness that may compromise data integrity. * Have current major psychotic disorders, mania, substance-induced psychiatric disorders, or any current suicidal ideations or history of suicide attempts. Moderate to severe current symptoms of mood or anxiety disorders will be exclusionary as well. However, mild mood or anxiety disorder symptoms will not be exclusionary, whether medicated or unmedicated. The MAI will reserve the right to exclude on the basis of psychiatric history not explicitly described in this criterion. Justification: Psychiatric disorders involve the central neural system (CNS) and, therefore, can be expected to alter the fMRI measures being used in this study, however, some degree of mood and anxiety symptoms are common in community samples of smokers. Assessment tool(s): Computerized SCID or comparable assessment, and clinical interview confirmation by clinician. * 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. * Have any other major medical condition, such as diabetes mellitus, that in the view of the investigators would compromise the safety of an individual during participation, or the quality of data obtainable. Justification: Many illnesses not explicitly covered here may increase risk or alter important outcome measures. Assessment tool(s): History and physical examination by a qualified IRP clinician and CBC, urinalysis, NIDA chemistry panel (liver function tests, electrolytes, kidney function). The following lab values will result in exclusion from the study: 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. Treatment-seeking smokers will also be excluded if they: * Have moderate to severe renal impairment. Justification. Given that renal secretion is varenicline s major route of clearance, kidney impairment may result in higher systemic levels of the drug than intended. Per Pfizer s chantix insert, varenicline pharmacokinetics were unchanged in subjects with mild renal impairment in comparison to those with normal renal function, whereas individuals with moderate and severe impairment presented with varenicline levels 1.5 and 2.1-fold higher, respectively. Assessment tool(s): Estimated glomerular filtration rate. Renal insufficiency with estimated creatinine clearance \< 60 ml/min calculated by the Cockcroft-Gault equation will be excluded. * Are diabetic. Justification. A recent case report describes multiple episodes of severe hypoglycemia experienced by a 51 year old Type-I diabetic after beginning varenicline treatment. The discontinuation of varenicline resolved any further hypoglycemic episodes. The safety of varenicline has not been investigated in patients with diabetes. Assessment tool(s): Casual plasma glucose testing. Individuals with glucose levels above 200 mg/dl may be further evaluated for diabetes using a fasting glucose test or be excluded. * The following exclusion criteria are new for the tDCS study: * Participated in any brain stimulation session less than two weeks ago, or underwent brain stimulation exposure for treatment purposes in the last 6 months, including tDCS or transcranial magnetic stimulation (TMS). Justification: Prior exposure to brain stimulation may result in carry-over effects that could confound the results of this study. Participants may enroll in the study once the listed time periods have passed. Assessment tool(s): Participant medical history and physical (H\&P).