Dopamine D2/D3 Receptor Upregulation by Varenicline in Methamphetamine Users
While deficits in dopamine D2-type receptor availability have been linked to substance use disorders, higher availability associates with better behavioral treatment outcomes for stimulant dependence and resilience to addiction. Varenicline has been shown to upregulate D2-type receptors in drug-naive rats, and could be a useful therapeutic approach for the treatment of addictive disorders in humans.The purpose of the study is to assess the relationship between varenicline, dopamine signaling (specifically, D2-type receptor availability), functional connectivity within corticostriatal circuitry, genetic markers associated with smoking and methamphetamine abuse, and measures of cognitive performance. The investigators hypothesize that varenicline but not placebo will upregulate (increase) striatal dopamine D2-type receptor availability and improve cognition, and that the change in availability will correlate with the change in cognition. The investigators also hypothesize that varenicline but not placebo treatment will repair dysregulated connectivity between the striatum and prefrontal cortex observed in methamphetamine users, and will correlate with the change in cognition. The study design consists of two positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans to measure dopamine D2-type receptor availability and functional connectivity between the prefrontal cortex and striatum, two cognitive testing sessions including a battery of tests assessing working memory, declarative memory, sustained attention, inhibitory control, and reward-based decision making. Following eligibility screening, thirty six methamphetamine users will be enrolled and tested/scanned once prior to initiation of varenicline or placebo treatment and then again after completion of treatment.
- English fluency in order to provide informed consent and complete questionnaires
- Age of 18-60 years [Children younger than 18 years will be excluded because of the potential risk of radiation exposure. Recruitment will be restricted to individuals within the first 5 decades of life to avoid effects of aging on DRD2/3 (dopamine type-2 receptor) BPND (binding potential).
- Meeting DSM (Diagnostic and Statistical Manual of Mental Disorders) 5 criteria for stimulant-use disorder
- Being within 2 weeks of admission to treatment and < 2 months abstinent from stimulant use
- Vital signs as follows: resting pulse between 50 and 95 beats per minute (bpm), blood pressures between 90-150 mm Hg (millimeter of mercury) systolic and 45-95 mm Hg diastolic
- Hematology and chemistry laboratory test results within normal (+/- 10%) limits and normal kidney function (estimated glomerular filtration rate ≥ 90 ml/min/1.73m2)
- Baseline ECG (electrocardiogram) demonstrating normal conduction (including QTc [QT interval]) without clinically significant arrhythmias
- Absence of clinically significant contraindications for participation, in the judgment of the admitting physician and the principal investigator, assessed by a medical history and physical examination.
- History or evidence of seizure disorder or brain injury with loss of consciousness >30 min
- Previous adverse reaction to varenicline (VAR)
- Neurological disorder that would compromise informed consent or complicate data interpretation (e.g., organic brain disease or dementia)
- Past-year psychotic disorder assessed by the Mini-International Neuropsychiatric Interview (MINI)
- History of a suicide attempt and/or current suicidal ideation or plan, as assessed by the MINI
- Evidence of clinically significant heart disease or hypertension, as determined by physical exam, or ECG showing cardiac ischemia or other clinically significant abnormality, or use of warfarin
- Evidence of untreated or unstable medical illness, including endocrine, autoimmune, renal, hepatic, or active infectious disease which might compromise safety during participation, as determined by history and physical examination and laboratory tests
- Diabetes or use of insulin
- Pregnancy or nursing [Note: Female participants must be either postmenopausal or using a reliable form of contraception (e.g., abstinence, oral contraceptive pills, intrauterine device, sterilization, condoms or spermicide). Women must have negative urine tests for pregnancy at study entry and on positron emission tomography (PET) scan days]
- Asthma or use of theophylline, α- or β-adrenergic agonists, or other sympathomimetics; 12) use of any medications (e.g., neuroleptics) that directly affect dopaminergic neurotransmission in brain; 13) claustrophobia [Participants will be questioned about their potential discomfort if in an enclosed space, such as a PET or magnetic resonance imaging (MRI) scanner]
- Exceed radiation exposure limits [Participation in any other research involving exposure to ionizing radiation in the past year will be exclusionary if the total cumulative exposure from the past and current research would exceed the limits set by the Food and Drug Administration in 21 Code of Federal Regulations 361.1. The total cumulative dose to the whole body, active blood-forming organs, lens of the eye, and gonads must remain < 5 rems, and the cumulative dose to all other organs must remain < 15 rems. Volunteers who were exposed to ionizing radiation in the year before potential entry to this study will be excluded if they cannot provide proper documentation of the amount of past research radiation exposure.]
- A metal device (e.g., pacemaker, infusion pump, aneurysm clip, prosthesis or plate) in the body [Presence of such a device could either interfere with scan acquisition or pose a potential risk during MRI. A participant who has an implanted device can enroll if s/he provides documentation that the device is MRI-compatible.];
- Any condition that, as deemed by the investigators and study physician, would compromise safe participation.