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Dopamine D2/D3 Receptor Upregulation by Varenicline in Methamphetamine Users

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ClinicalTrials.gov Identifier: NCT03059563
Recruitment Status : Enrolling by invitation
First Posted : February 23, 2017
Last Update Posted : October 16, 2018
Sponsor:
Information provided by (Responsible Party):
Edythe London, University of California, Los Angeles

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Dopamine D2/3 Receptor Availability Cognitive Function Methamphetamine Abuse Drug: Varenicline Other: Placebo Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Dopamine D2/D3 Receptor Upregulation by Varenicline in Methamphetamine Users
Actual Study Start Date : January 11, 2018
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2019


Arm Intervention/treatment
Experimental: 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.
Drug: Varenicline
Varenicline is an FDA-approved medication to facilitate smoking cessation. it is also a promising candidate to enhance dopamine signaling by upregulating dopamine D2/D3 (type 2) receptors in the striatum and improve cognitive function.
Other Name: Chantix

Placebo Comparator: 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.
Other: Placebo
A placebo containing no active ingredients will be used as a control to assess the effects of varenicline on dopamine D2/D3 receptor availability and cognitive function.




Primary Outcome Measures :
  1. Dopamine D2-type receptor availability [ Time Frame: 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.


Secondary Outcome Measures :
  1. Sustained attention [ Time Frame: 21 days ]
    The Continuous Performance Task will be used to assess sustained attention at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  2. Working memory [ Time Frame: 21 days ]
    The Sternberg Spatial task will be used to assess working memory at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  3. Declarative memory [ Time Frame: 21 days ]
    The Rey Auditory Verbal Learning Test will be used to assess declarative memory at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  4. Inhibitory control - stop signal task [ Time Frame: 21 days ]
    The Stop-signal task will be used to assess inhibitory control at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  5. Inhibitory control - reversal learning [ Time Frame: 21 days ]
    A reversal learning task will be used to assess inhibitory control at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  6. Reward-based decision-making [ Time Frame: 21 days ]
    A monetary delay-discounting task and the Balloon Analogue Risk task will be used to assess reward-based decision-making at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  7. Resting state functional connectivity [ Time Frame: 21 days ]
    Striatum resting state functional connectivity will be measured with a functional magnetic resonance imaging scan at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  8. Task-based brain activity (functional magnetic resonance imaging) - balloon analog risk [ Time Frame: 21 days ]
    Performance on a cognitive task (the Balloon Analog Risk Task) will be assessed during a functional magnetic resonance imaging scan at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  9. Task-based brain activity (functional magnetic resonance imaging - stop signal [ Time Frame: 21 days ]
    Performance on a cognitive task the (Stop Signal Task), will be assessed during a functional magnetic resonance imaging scan at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  10. Decision making under risk and ambiguity [ Time Frame: 21 days ]
    A task involving decision making under during differing types of risk and ambiguity will be used to determine decision making under risk and ambiguity at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.

  11. Loss Aversion [ Time Frame: 21 days ]
    A computer task and written questionnaire assessing loss preferences will be used to assess loss aversion at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment.


Other Outcome Measures:
  1. Personality - impulsivity [ Time Frame: 21 days ]
    Self-report of impulsivity will be measured at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment using the Barratt Impulsiveness Scale.

  2. Personality - novelty seeking [ Time Frame: 21 days ]
    Self-report of novelty seeking will be measured at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment using the Temperament and Character Inventory.

  3. Personality - reward dependence [ Time Frame: 21 days ]
    Self-report of reward dependence will be measured at baseline prior to varenicline/placebo and after 3 weeks of varenicline/placebo treatment using the Temperament and Character Inventory.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03059563


Locations
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United States, California
University of California Los Angeles
Los Angeles, California, United States, 90024
Sponsors and Collaborators
University of California, Los Angeles
Investigators
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Principal Investigator: Edythe D London, Ph.D. University of California, Los Angeles

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Responsible Party: Edythe London, Professor of Psychiatry and Biobehavioral Sciences and Molecular and Medical Pharmacology, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT03059563     History of Changes
Other Study ID Numbers: 17-000445
First Posted: February 23, 2017    Key Record Dates
Last Update Posted: October 16, 2018
Last Verified: October 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Edythe London, University of California, Los Angeles:
Varenicline
Positron Emission Tomography
Functional Magnetic Resonance Imaging
Methamphetamine Abuse

Additional relevant MeSH terms:
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Varenicline
Dopamine
Methamphetamine
Nicotinic Agonists
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Dopamine Agents
Protective Agents
Central Nervous System Stimulants
Adrenergic Agents
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Dopamine Uptake Inhibitors