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Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

Primary Purpose

Cocaine Dependence

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Psychiatric and Cognitive Testing

Cocaine Self-adminstration

Positron Emission Tomography

Magnetic Resonance Imaging

About this trial

This is an interventional other trial for Cocaine Dependence focused on measuring Cocaine Dependence, Cocaine Addiction

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Connecticut Mental Health Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Arm Label

Psychiatric and Cognitive Testing

Cocaine Self-adminstration

Positron Emission Tomography

Magnetic Resonance Imaging

Arm Description

All participants will complete psychiatric assessment and cognitive testing.

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.

All participants will complete a PET scan to assess mGluR5 receptors using [18-F]FPEB

All participants will complete one MRI scan to assess brain structure and function.

Outcomes

Primary Outcome Measures

Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5)

Receptor availability assessed as the volume of distribution (VT) of [18F]FPEB radiotracer, measured using positron emission tomography (PET). Higher [18F]FPEB VT values indicate a greater availability of mGluR5 receptors.

Functional Brain Network Engagement Associated With Response Inhibition

Independent component analysis (ICA) of functional MRI data separates brain activity associated with distinct functional networks. Comparing the activity in these networks to the fMRI task events using a regression analysis produces a beta-weight where a larger beta indicates the network was more activated or 'engaged' in processing the task demands. In this study, participants completed a Go/NoGo task to assess brain processing associated with infrequent-stimulus response inhibition (i.e., correct NoGo's) compared to frequent-stimulus responses (i.e., correct Go's).

Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF)

Independent component analysis (ICA) of functional MRI data separates brain activity associated with distinct functional networks. The fractional amplitude of low-frequency fluctuations (fALFF) during resting-state reflects a measure of the general health status of a network, comprised of both the strength of network activity and within-network connectivity absent of any specific cognitive demands.

Secondary Outcome Measures

Full Information

NCT ID

NCT03471182

First Posted

February 26, 2018

Last Updated

October 5, 2023

Sponsor

Yale University

Collaborators

National Institute on Drug Abuse (NIDA)

1. Study Identification

Unique Protocol Identification Number

NCT03471182

Brief Title

Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

Official Title

Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Completed

Study Start Date

February 26, 2018 (Actual)

Primary Completion Date

August 18, 2022 (Actual)

Study Completion Date

August 18, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Yale University

Collaborators

National Institute on Drug Abuse (NIDA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cocaine Dependence

Keywords

Cocaine Dependence, Cocaine Addiction

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

32 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Psychiatric and Cognitive Testing

Arm Type

Active Comparator

Arm Description

All participants will complete psychiatric assessment and cognitive testing.

Arm Title

Cocaine Self-adminstration

Arm Type

Active Comparator

Arm Description

Arm Title

Positron Emission Tomography

Arm Type

Active Comparator

Arm Description

All participants will complete a PET scan to assess mGluR5 receptors using [18-F]FPEB

Arm Title

Magnetic Resonance Imaging

Arm Type

Active Comparator

Arm Description

All participants will complete one MRI scan to assess brain structure and function.

Intervention Type

Behavioral

Intervention Name(s)

Psychiatric and Cognitive Testing

Intervention Description

Interviews, questionnaires, and computer testing.

Intervention Type

Drug

Intervention Name(s)

Cocaine Self-adminstration

Other Intervention Name(s)

cocaine hydrochloride

Intervention Description

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.

Intervention Type

Radiation

Intervention Name(s)

Positron Emission Tomography

Other Intervention Name(s)

PET

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Magnetic Resonance Imaging

Other Intervention Name(s)

MRI, functional MRI

Intervention Description

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.

Primary Outcome Measure Information:

Title

Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5)

Description

Time Frame

Following 2-5 days of cocaine abstinence

Title

Functional Brain Network Engagement Associated With Response Inhibition

Description

Time Frame

Following 2-5 days of cocaine abstinence.

Title

Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF)

Description

Time Frame

Following 2-5 days of cocaine abstinence.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: All participants: Age 21 - 60 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Patrick Worhunsky, PhD

Organizational Affiliation

Assistant Professor

Official's Role

Principal Investigator

Facility Information:

Facility Name

Connecticut Mental Health Center

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06519

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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.

IPD Sharing 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.

IPD Sharing 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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Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

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