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Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03471182
Recruitment Status : Recruiting
First Posted : March 20, 2018
Last Update Posted : March 20, 2018
Information provided by (Responsible Party):
Yale University

Brief Summary:
The proposed research program will investigate the changes in brain chemistry and circuitry that 're-wire' the brain during chronic cocaine use, promote relapse, and complicate treatment efforts. Currently-using and non-treatment-seeking individuals with a cocaine use disorder will undergo a cocaine self-administration paradigm 2-5 days prior to completing positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).

Condition or disease Intervention/treatment Phase
Cocaine Dependence Behavioral: Psychiatric and Cognitive Testing Drug: Cocaine Self-adminstration Radiation: Positron Emission Tomography Other: Magnetic Resonance Imaging Phase 1

Detailed Description:

Cocaine use disorder (CUD) remains a significant public health concern that is resistant to current treatments. Challenges to treating CUD include an imbalance in neurobiological systems that 're-wire' the brain such that appetitive and habitual processes influence decision-making and behavior. This research project aims to provide insight into this reorganized circuitry in CUD by investigating neurofunctional systems related to glutamatergic plasticity and functional brain networks during initial (2-5 days) abstinence. To target this potentially critical period of recovery, currently-using and non-treatment-seeking individuals with CUD will undergo a cocaine self-administration paradigm 2-5 days prior to completing [18F]FPEB positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Healthy comparison (HC) subjects that have participated in [18F]FPEB PET as part of other Yale approved protocols will be recruited to participate in the fMRI portion of this study.

Aim 1: To determine the availability of mGluR5 using [18F]FPEB PET during initial abstinence in individuals with CUD. The investigators hypothesize individuals with CUD, relative to HC, will exhibit concurrently and regionally specific increases (e.g., in the striatum) and decreases (e.g., in the prefrontal cortex) in mGluR5 availability.

Aim 2: To determine patterns of resting-state, response-inhibition, an automaticity related connectivity within and between large-scale functional networks using fMRI during initial abstinence in individuals with CUD. The investigators hypothesize network-based analyses of fMRI will reveal lower frontoparietal and greater limbic network modulation in CUD as compared to HC.

Aim 3: To explore the relationships between mGluR5 availability and functional network activity during initial abstinence in individuals with CUD. The investigators will perform multi-modal analysis of PET and fMRI data to examine links between molecular and functional systems in CUD using emerging 'fusion' approaches. While exploratory in nature, the investigators expect to find links between alterations in mGluR5 systems and functional reorganization in CUD (e.g., greater dorsostriatal mGluR5 may be linked to blunted frontoparietal inhibition).

Aim 4: To explore the relationships between mGluR5 availability, functional network activity (and their linkages) with cocaine self-administration, disease severity and chronicity, and psychometric assessments of impulsivity and compulsivity. While exploratory in nature, the investigators expect more substantial neurofunctional alterations during initial abstinence will be associated with greater cocaine self-administration, disease severity, impulsivity and compulsivity in individuals with CUD.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Investigation of Cocaine Addiction Using mGluR5 PET and fMRI
Actual Study Start Date : February 26, 2018
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: Psychiatric and Cognitive Testing
All participants will complete psychiatric assessment and cognitive testing.
Behavioral: Psychiatric and Cognitive Testing
Interviews, questionnaires, and computer testing.

Active Comparator: Cocaine Self-adminstration
This arm plans to assess the subjective (e.g., euphoric) and behavioral effects (e.g., self-administration) of cocaine in experienced, non-treatment seeking users of the drug in a human laboratory study of self-regulated cocaine administration.
Drug: Cocaine Self-adminstration
The intervention will include a training and safety session that consists of physician/nurse-administered cocaine followed by a self-regulated cocaine administration period under carefully controlled and closely monitored conditions.
Other Name: cocaine hydrochloride

Active Comparator: Positron Emission Tomography
All participants will complete a PET scan to assess mGluR5 receptors using [18-F]FPEB
Radiation: Positron Emission Tomography
PET scans will be performed on a High Resolution Research Tomograph (HRRT), the highest resolution human brain scanner available. Antecubital venous catheters will be used for IV administration of the radiotracer and for venous blood sampling. A radial artery catheter may also be inserted by an experienced physician before the PET scan. At the beginning of each scan, the participants's head will be immobilized and a 6-minute transmission scan, using an orbiting 137Cs point-source, is obtained and used for attenuation correction. PET scans will be acquired using bolus or bolus plus constant infusion administration of [18F]FPEB.
Other Name: PET

Active Comparator: Magnetic Resonance Imaging
All participants will complete one MRI scan to assess brain structure and function.
Other: Magnetic Resonance Imaging
Structural and functional MRI data will be acquired using a Siemens Trio TIM 3.0T system at the Yale Magnetic Resonance Research Center. High-resolution structural MRI data will be acquired to facilitate analysis of PET data and may be used in additional analysis of tissue volume and brain structure. Resting-state and task-based functional MRI data will be acquired using state-of-the-art multiband echo-planar imaging (EPI) gradient-echo sequences. Diffusion-weighted MRI data will also be acquired using multiband imaging sequences to investigate anatomical connectivity.
Other Name: MRI, functional MRI

Primary Outcome Measures :
  1. Glutamate receptor (mGluR5) availability [ Time Frame: Within 2-5 days of self-administration in cocaine participants; within 5 days of fMRI as possible for healthy comparison participants ]
    Glutamate receptor (mGluR5) availability as measured during [18F]FPEB PET

Secondary Outcome Measures :
  1. Brain activity patterns [ Time Frame: Within 2-5 days of self-administration in cocaine participants; within 5 days of PET as possible for healthy comparison participants ]
    Brain activity patterns as measured during task-based and resting-state fMRI

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • All participants:

    • Age 21 - 55 years
    • Provide voluntary, written, informed consent
    • Physically healthy by medical history, physical, neurological, ECG, and laboratory examinations
    • For females: non-lactating, no longer of child-bearing potential or agreeing to practice effective contraception during the study (e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device [IUD] or intrauterine system [IUS]; barrier methods: condom or occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository; male partner sterilization; true abstinence when this is in line with the preferred and usual lifestyle of the subject), and a negative serum pregnancy test
  • Participants with a cocaine use disorder:

    • DSM-5 criteria for moderate or severe cocaine-use disorder
    • Recent street cocaine use in excess of quantities used in the current study
    • Intravenous and/or smoked (crack/freebase) cocaine use
    • Positive urine toxicology screen for cocaine
  • Healthy comparison participants:

    • Successful completion of an [18F]FPEB scan as part of another Yale approved protocol as a healthy control/comparison subject

Exclusion Criteria:

  • All participants:

    • Any condition that, in the opinion of investigators, would prevent compliance with the study protocol
    • A history of significant medical or neurological illness (e.g., coronary artery disease, significant anemia, seizures)
    • Current use of psychotropic and/or potentially psychoactive medications
    • Physical or laboratory evidence of pregnancy
    • Meet any additional PET/MR imaging-related exclusion criteria, including:
    • Presence of MRI incompatible implants and other contraindications for MRI (e.g., pacemaker, artificial joints, non-removable body piercings, etc.)
    • Participation in other research studies involving ionizing radiation within one year of the PET scans that would cause the participant to exceed the yearly dose limits
    • History of a bleeding disorder or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto).
    • Claustrophobia
    • Severe motor problems that prevent the subject from lying still for PET/MR imaging
    • Complaints of chronic pain (e.g., as the result of rheumatoid arthritis)
    • Current, past or anticipated exposure to radiation in the work place
  • Participants with a cocaine use disorder:

    • Other drug use disorder (except for tobacco-use disorder)
    • Less than 1 year of cocaine use disorder
    • A DSM-5 major psychiatric diagnosis (schizophrenia, bipolar disorder, etc.) unrelated to cocaine
  • Healthy comparison participants:

    • Any DSM-5 major psychiatric diagnosis (schizophrenia, bipolar disorder, etc.), except tobacco-use disorder
    • Positive drug screen

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 identifier (NCT number): NCT03471182

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Contact: Jessica Costeines, MA 203-974-7559

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United States, Connecticut
Connecticut Mental Health Center Recruiting
New Haven, Connecticut, United States, 06519
Contact: Jessica Costeines    203-974-7559   
Principal Investigator: Patrick Worhunsky, PhD         
Sponsors and Collaborators
Yale University
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Principal Investigator: Patrick Worhunsky, PhD Assistant Professor

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Responsible Party: Yale University Identifier: NCT03471182     History of Changes
Other Study ID Numbers: 2000021196
First Posted: March 20, 2018    Key Record Dates
Last Update Posted: March 20, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Consistent with NIH Grants Policy on Sharing of Unique Research Resources, including the "Sharing of Biomedical Research Resources: Principles and Guidelines for Recipients of NIH Grants and Contracts" (December, 1999), all research resources generated will be freely distributed, as available, to appropriate, qualified academic investigators for non-commercial research purposes. All data will be de-identified before sharing, using procedures in compliance with HIPPA and Yale Human Investigation Committee standards. No available data sets or supporting information will contain subject names, addresses or other specific personal identification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame: In accordance with institutional standards and guidelines, after termination of this study and completion of all analysis and publications, all data and screening information will be anonymized and kept in a secure fashion for the purpose of further analyses indefinitely unless prevailing University or Federal guidelines at the time require a change.
Access Criteria: In accordance with institutional standards and guidelines, researchers must submit a requisition form that describes their specific hypotheses and details specific data or supporting information being requested. Requests will be reviewed by senior study personnel.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Yale University:
Cocaine Dependence
Cocaine Addiction

Additional relevant MeSH terms:
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Cocaine-Related Disorders
Behavior, Addictive
Compulsive Behavior
Impulsive Behavior
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Anesthetics, Local
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents