Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

NCT03471182 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 20000211961K01DA042998-01A1
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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).

Conditions

Cocaine Dependence

Keywords

Cocaine Dependence; Cocaine Addiction

Outcome Measures

Primary Outcomes (3)

• 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.

  Following 2-5 days of cocaine abstinence

• 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).

  Following 2-5 days of cocaine abstinence.

• 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.

  Following 2-5 days of cocaine abstinence.

Study Arms (4)

Psychiatric and Cognitive Testing

ACTIVE COMPARATOR

All participants will complete psychiatric assessment and cognitive testing.

Behavioral: Psychiatric and Cognitive Testing

Cocaine Self-adminstration

ACTIVE COMPARATOR

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

Positron Emission Tomography

ACTIVE COMPARATOR

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

Radiation: Positron Emission Tomography

Magnetic Resonance Imaging

ACTIVE COMPARATOR

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

Other: Magnetic Resonance Imaging

Interventions

Psychiatric and Cognitive Testing BEHAVIORAL

Interviews, questionnaires, and computer testing.

Psychiatric and Cognitive Testing

Cocaine Self-adminstration 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.

Also known as: cocaine hydrochloride

Cocaine Self-adminstration

Positron Emission Tomography 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.

Also known as: PET

Positron Emission Tomography

Magnetic Resonance Imaging 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.

Also known as: MRI, functional MRI

Magnetic Resonance Imaging

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Yale University: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Connecticut Mental Health Center

New Haven, Connecticut, 06519, United States

Location

Related Publications (1)

• 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.

  PMID: 38551365 DERIVED

MeSH Terms

Conditions

Cocaine-Related Disorders

Interventions

Psychiatry; Neuropsychological Tests; Cocaine; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Behavioral Sciences; Behavioral Disciplines and Activities; Psychological Tests; Tropanes; Azabicyclo Compounds; Aza Compounds; Organic Chemicals; Alkaloids; Heterocyclic Compounds; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Limitations and Caveats

This study was greatly impacted by a COVID-related suspension in research activities and subsequent restrictions on facility operations. This resulted in lower participation and study adjustments including the discontinuation of cocaine self-administration procedures, the use of historical HC-PET data, and the collection of an HC-MRI sample (no HC completed both PET and fMRI). These alterations limit the statistical power of primary outcomes and the ability to perform planned secondary analyses.

Results Point of Contact

• Title: Patrick Worhunsky
• Organization: Yale University School of Medicine

patrick.worhunsky@yale.edu

203-737-2668

Study Officials

• Patrick Worhunsky, PhD

  Assistant Professor

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Psychiatry

Study Record Dates

• First Submitted: February 26, 2018
• First Posted: March 20, 2018
• Study Start: February 26, 2018
• Primary Completion: August 18, 2022
• Study Completion: August 18, 2022
• Last Updated: February 29, 2024
• Results First Posted: October 6, 2023

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

US (1)