Exploration of Baseline Alterations on the Dopamine D2/D3 Receptor System and the Effects of Vitamin D in Opioid Use Disorder: an [11C]-PHNO Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Non-displaceable Tracer Binding Potentials (BPND)
研究概览
简要总结
The research team is investigating Opioid Use Disorder (OUD), a disorder characterized by dysregulated dopaminergic tone, to evaluate the mechanisms of adjunctive treatment with calcitriol. The investigators will recruit 12 subjects with OUD and 12 healthy subjects to participate in a double-blind, randomized study design where subjects will complete up to 2 Positron Emission Tomography (PET) scans using [11C]-PHNO. The investigators will compare subjects in differences between their own study days and in differences between healthy control subjects and subjects with OUD.
详细描述
Previous research has indicated that Dopamine (DA) may play a role in withdrawal and dependence in Opioid Use Disorder (OUD). The present study will investigate dopamine receptor availability in 12 subjects with OUD compared with 12 HC subjects using [11C](+)-PHNO and the impact of calcitriol on these receptors.
Research has indicated that a common feature in substance use disorders (SUD) is a hypo-dopaminergic state. Further, preclinical and observational research has pointed to a possible benefit of calcitriol in individuals who have OUD and our research group has previously shown the potential benefits of calcitriol on addressing this hypo-dopaminergic state. If successful, the results of this research study may improve the standard treatment for OUD through calcitriol supplementation.
Specifically, the present study seeks to address the following aims:
Specific Aim 1: As part of a between-subject study design, to determine whether acute calcitriol (vs. placebo) administration is associated with greater dopamine (DA) release in the caudate, putamen, ventral striatum (VST), and substantia nigra / ventral tegmental area (SN/VTA) of subjects with OUD compared to healthy control subjects (HCs).
Specific Aim 2: As part of a within-subject, two-day study design, to determine whether acute calcitriol (vs. placebo) administration is associated with greater dopamine (DA) release in the caudate, putamen, ventral striatum (VST), and substantia nigra / ventral tegmental area (SN/VTA) of subjects with OUD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age 18-50 years
- •Voluntary, written, informed consent
- •Physically healthy by medical history, physical, neurological, ECG, and laboratory examinations
- •Meets the criteria for OUD, as determined by the Structured Clinical Interview for DSM-5 (SCID)
- •Stable and receiving buprenorphine treatment for OUD
- •For females, non-lactating, with a negative serum or urine pregnancy (hCG) test
- •Lab results without clinically relevant findings (e.g., renal function, electrolytes, and vitamin D levels)
- •English speaking
- •Exclusion criteria:
- •Medical contraindication to calcitriol administration (e.g., history of hypersensitivity to calcitriol or any component of the formulation, hypercalcemia or vitamin D toxicity)
- •History of substance dependence (e.g., alcohol, sedative hypnotics), except for nicotine and opiates.
- •A primary major DSM-5 psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depression, etc.) as determined by the SCID, except for Opioid Use Disorder and related conditions.
- •A history of significant medical (e.g., cardiovascular, diabetic/metabolic) or neurological (e.g., cerebrovascular accidents, seizure, traumatic brain injury) illness
- •Positive answers on the cardiac history questionnaire that may place the subject at higher risk, as determined by the study physician's review of both the questionnaire responses and screening ECG. If there is concern for the subject's safety due to these assessments, research staff will consult a Yale PET Center affiliated cardiologist prior to including the subject for the study.
- •Current use of psychotropic and/or potentially psychoactive prescription medications
- •Receiving medications for OUD other than buprenorphine (e.g., methadone treatment)
- •For females, laboratory (β-HCG) or physical evidence of pregnancy/lactation
- •MRI-incompatible implants and other contraindications for MRI (i.e., aneurysm clip, metal fragments, internal electrical devices such as a cochlear implant, spinal cord stimulator or pacemaker)
- •History of claustrophobia or feeling of inability to lie still on his/her back for the PET or MRI scans
- •History of any bleeding disorder or current anticoagulant therapy
- •Donation or loss of 550 mL of blood or more (including plasmapheresis) or receipt of a transfusion of any blood product within 8 weeks prior to the first test day.
- •Use of any prescription medications and/or over-the-counter medications, vitamins and/or herbal supplements which could have a negative clinical interaction with calcitriol or which could confound scientific results of the study, within 2 weeks prior to each test day (e.g., thiazide diuretics, Mg based antiacids, digoxin, etc,).
- •Serum levels of 25(OH)D3 below 12 ng/ml.
- •Morbid obesity i.e., BMI over 35 (more prone to lower vitamin D levels)
- •Subjects with history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over FDA limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year.
- •Subjects with current, past or anticipated exposure to radiation in the workplace
- •History of kidney stones within the past 5 years
- •Any degree of renal failure
- •History of parathyroid disorder (hyper or hypoparathyroidism)
- •History of osteoporosis or any pathologic fractures
- •Vitamin D supplementation in any form in the past 3 months
- •Known hypersensitivity to [11C]-PHNO or calcitriol
- •Malabsorption syndromes (i.e., Celiac sprue)
- •Serum corrected calcium > 10.5 mg/dl or phosphate > 4.2 mg/dL
排除标准
- 未提供
研究组 & 干预措施
Calcitriol
Subjects with OUD will receive a baseline MRI. On the night before and day of testing, subjects with OUD will receive two doses of calcitriol (3.0mcg total), followed by PHNO injection and PET Scan for the calcitriol condition. All subjects will complete the study with both active calcitriol and a placebo control and the order these interventions are received will be randomized.
干预措施: [11C]-PHNO (Drug)
Calcitriol
Subjects with OUD will receive a baseline MRI. On the night before and day of testing, subjects with OUD will receive two doses of calcitriol (3.0mcg total), followed by PHNO injection and PET Scan for the calcitriol condition. All subjects will complete the study with both active calcitriol and a placebo control and the order these interventions are received will be randomized.
干预措施: Calcitriol (Dietary Supplement)
Calcitriol
Subjects with OUD will receive a baseline MRI. On the night before and day of testing, subjects with OUD will receive two doses of calcitriol (3.0mcg total), followed by PHNO injection and PET Scan for the calcitriol condition. All subjects will complete the study with both active calcitriol and a placebo control and the order these interventions are received will be randomized.
干预措施: PET Scan (Procedure)
Placebo
Subjects with OUD will receive a baseline MRI. On the night before and day of testing, subjects with OUD will receive two doses of an inactive placebo, followed by PHNO injection and PET Scan for the placebo condition. All subjects will complete the study with both active calcitriol and a placebo control and the order these interventions are received will be randomized.
干预措施: [11C]-PHNO (Drug)
Placebo
Subjects with OUD will receive a baseline MRI. On the night before and day of testing, subjects with OUD will receive two doses of an inactive placebo, followed by PHNO injection and PET Scan for the placebo condition. All subjects will complete the study with both active calcitriol and a placebo control and the order these interventions are received will be randomized.
干预措施: Placebo Control (Other)
Placebo
Subjects with OUD will receive a baseline MRI. On the night before and day of testing, subjects with OUD will receive two doses of an inactive placebo, followed by PHNO injection and PET Scan for the placebo condition. All subjects will complete the study with both active calcitriol and a placebo control and the order these interventions are received will be randomized.
干预措施: PET Scan (Procedure)
结局指标
主要结局
Non-displaceable Tracer Binding Potentials (BPND)
时间窗: Two 120-minute scans, at least 6 days apart between study conditions.
BPND is a metric that assesses the level of dopamine activity in a priori regions of interest. For Specific Aim 2, the investigators plan to assess the differences in BPND in dopamine D2/D3 receptors within subjects who have OUD. The investigators will compare BPND on the placebo-controlled experimental day and BPND on the active calcitriol experimental day.
次要结局
- Continuous Performance Task - Identical Pairs (CPT-IP)(Two 10-minute tasks, at least 6 days apart between study conditions.)
- Probabilistic Reversal Learning Task (PRLT)(Two 10-minute tasks, at least 6 days apart between study conditions.)
- Spontaneous Blink Rate (SBR)(Two 5-minute tasks, at least 6 days apart between study conditions.)