Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

NCT ID: NCT03471182

Last Updated: 2024-02-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-26
• Study Completion Date: 2022-08-18

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.

Conditions

Cocaine Dependence

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Psychiatric and Cognitive Testing

All participants will complete psychiatric assessment and cognitive testing.

Group Type: ACTIVE_COMPARATOR

Psychiatric and Cognitive Testing

Intervention Type: BEHAVIORAL

Interviews, questionnaires, and computer testing.

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.

Group Type: ACTIVE_COMPARATOR

Cocaine Self-adminstration

Intervention Type: DRUG

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.

Positron Emission Tomography

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

Group Type: ACTIVE_COMPARATOR

Positron Emission Tomography

Intervention Type: RADIATION

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.

Magnetic Resonance Imaging

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

Group Type: ACTIVE_COMPARATOR

Magnetic Resonance Imaging

Intervention Type: OTHER

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.

Interventions

Psychiatric and Cognitive Testing

Interviews, questionnaires, and computer testing.

Intervention Type: BEHAVIORAL

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.

Intervention Type: DRUG

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.

Intervention Type: RADIATION

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.

Intervention Type: OTHER

Other Intervention Names

cocaine hydrochloride; PET; MRI, functional MRI

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
• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Drug Abuse (NIDA)

NIH

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: lead

Responsible Party

Patrick Worhunsky

Assistant Professor of Psychiatry

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Patrick Worhunsky, PhD

Role: PRINCIPAL_INVESTIGATOR

Assistant Professor

Locations

Connecticut Mental Health Center

New Haven, Connecticut, United States

Countries

United States

References

Kohler RJ, Zhornitsky S, Potenza MN, Yip SW, Worhunsky P, Angarita GA. Cocaine self-administration behavior is associated with subcortical and cortical morphometry measures in individuals with cocaine use disorder. Am J Drug Alcohol Abuse. 2024 May 3;50(3):345-356. doi: 10.1080/00952990.2024.2318585. Epub 2024 Mar 29.

Reference Type: DERIVED

PMID: 38551365 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

1K01DA042998-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2000021196

Identifier Type: -

Identifier Source: org_study_id