Dopamine D2/D3 Receptor Upregulation by Varenicline in Methamphetamine Users
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 62
- 试验地点
- 1
- 主要终点
- Dopamine D2-type receptor availability
研究概览
简要总结
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.
详细描述
- Participants will be recruited from the Tarzana Treatment Center, the Domiciliary Residential Rehabilitation Program, or Chabad Treatment Center, where they will be residing in a residential substance use disorder program. Potential participants recently admitted with stimulant use disorder will be given a flyer describing the study, and interested parties will meet with a research associate to discuss details of the protocol and sign the informed consent form. Prior to enrollment, they will be screened for initial eligibility criteria and exclusion criteria. Participants who provide written consent will complete questionnaires about their mood, medical, psychiatric and drug use history, personality and life experiences. They will also give a urine sample to determine what drugs they have recently used, a breath sample to determine the carbon monoxide levels in their system, and a blood sample to assess complete blood count, metabolic panel, screening for infectious diseases, and tests of kidney function. This blood sample will also be used to determine follicular and luteal phase in female participants.
- Consenting participants will meet with the study physician for additional screening. The study physician will take a medical history, take a personal and family health profile, perform a physical examination, and collect and review laboratory tests to determine eligibility.
- Participants will be seen at least weekly for follow-up throughout the study via a set of self-report questionnaires, including the Mini International Neuropsychiatric Interview (MINI), Patient Health Questionnaire-9, 4-Item Positive Symptom Rating Scale, Mood Disorder Questionnaire, International Physical Activity Questionnaire, and side effect questionnaires. Urine samples and exhaled breath will also be collected at these follow-up visits.
- After completing screening procedures, eligible participants will complete the following baseline assessments:
A) Visit 1:
i. Structural magnetic resonance imaging (MRI): High-resolution structural MRI scans of the brain Magnetization-Prepared Rapid Acquisition Gradient Echo will be obtained before positron emission tomography (PET) scans to confirm the absence of structural brain lesions and to aid in localization of volumes of interest.
ii. Functional MRI (fMRI): The purpose of this session is to collect information on brain function and activity while participants are engaged in cognitive tasks and at rest, while accounting for physiological variability. During the scan, non-invasive physiological measurements, including respiration, pulse and rate of eye blinks will be collected to determine signals in fMRI data related to physiology. Resting state scans will be acquired to examine the functional connectivity of brains regions in the absence of cognitive demands. Participants will be asked to stare at a black screen. Participants will be asked to smoke 15-30 minutes prior to the fMRI scan.
Participants may be asked to complete two or three of the following cognitive tasks in the scanning environment:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
- •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.
研究组 & 干预措施
Varenicline
A standard dose titration regimen that is used for smoking-cessation will be followed. The pharmacist will prepare capsules of varenicline for each week of study participation. Under observation by a study clinician, participants will receive one capsule containing 0.5 mg VAR each day (0900 h) for 3 days, then one capsule containing 0.5 mg VAR twice daily (0900 h, 2100 h) for 4 days, and finally a capsule containing 1 mg VAR twice daily (0900 h, 2100 h) for the next 2 weeks.
干预措施: Varenicline (Drug)
Placebo
The same procedure used for varenicline treatment will be followed. The pharmacist will prepare capsules of placebo for each week of study participation. Under observation by a study clinician, participants will receive one capsule containing placebo each day (0900 h) for 3 days, then one capsule containing placebo twice daily (0900 h, 2100 h) for 4 days, and finally a capsule containing placebo twice daily (0900 h, 2100 h) for the next 2 weeks.
干预措施: Placebo (Other)
结局指标
主要结局
Dopamine D2-type receptor availability
时间窗: 21 days
Dopamine D2-type receptor binding potential in the striatum measured with positron emission tomography scanning measured at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.
次要结局
- Sustained attention(21 days)
- Inhibitory control - stop signal task(21 days)
- Resting state functional connectivity(21 days)
- Working memory(21 days)
- Inhibitory control - reversal learning(21 days)
- Task-based brain activity (functional magnetic resonance imaging - stop signal(21 days)
- Declarative memory(21 days)
- Reward-based decision-making(21 days)
- Loss Aversion(21 days)
- Task-based brain activity (functional magnetic resonance imaging) - balloon analog risk(21 days)
- Decision making under risk and ambiguity(21 days)
研究者
Edythe London
Professor of Psychiatry and Biobehavioral Sciences and Molecular and Medical Pharmacology
University of California, Los Angeles