Understanding Effects of Cannabis Use and Abstinence on Neural Glutamate Homeostasis

NCT ID: NCT05664763

Last Updated: 2025-08-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-01
• Study Completion Date: 2024-07-03

Brief Summary

This study will be the first in vivo human multimodal neuroimaging study exploring the relationship between mGluR5 availability (PET), neural oscillations (EEG), and cognitive function in people with CUD. The goal is to test the overall hypothesis that mGluR5 availability is higher in people with CUD compared with HC. In Aim 1, the investigators will determine differences in mGluR5 availability between people with CUD and HC in the fronto-limbic brain circuit. Aim 2 examines the associations between mGluR5 availability, CUD severity, neural oscillations, and cognitive function in CUD subjects. Aim 3 will determine how prolonged abstinence from chronic cannabis use affects mGluR5 availability, neural oscillations, and cognitive function in CUD subjects.

Detailed Description

Cannabis use and availability continue to rise significantly in the US. It is critical to expand our knowledge of the negative and positive effects of cannabis to "catch up" to the current reality of widespread and growing use. Cannabis and tetrahydrocannabinol (THC), its primary psychoactive chemical, have widespread effects on neural glutamate homeostasis, and specifically metabotropic glutamate receptor 5 (mGluR5). mGluR5 regulates transmission of glutamate and plays a critical role in neural plasticity (i.e., long-term potentiation; LTP), memory, learning, mood, and addiction. Specifically, it is thought that mGluR5 activation by glutamate initiates production of endocannabinoids (i.e., 2-AG) that bind retrograde to presynaptic cannabinoid receptor 1. This pathway inhibits further glutamate release and modulates synaptic plasticity diffusely in the brain. However, cannabis use disrupts this normal mechanism of glutamate homeostasis. While the relationship between cannabis use and glutamate regulation has been explored in preclinical models, it has not been well-characterized in humans, and particularly in people with cannabis use disorder (CUD).

The goal is to test the overall hypothesis that mGluR5 availability is higher in people with CUD compared with HC. This study will advance our understanding of cannabis effects on the neural glutamate system in humans and may lead to the development of novel therapeutics and biomarkers to treat people with CUD. Aim 1 will determine differences in mGluR5 availability between people with CUD and HC in the fronto-limbic brain circuit. Aim 2 examines the associations between mGluR5 availability, CUD severity, neural oscillations, and cognitive function in CUD subjects. Aim 3 will determine how prolonged abstinence from chronic cannabis use affects mGluR5 availability, neural oscillations, and cognitive function in CUD subjects.

Conditions

Cannabis Use Disorder

Study Design

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

Study Groups

Cannabis use disorder

CUD participants participants undergo neuroimaging, cognitive testing, and EEG at baseline and following cannabis abstinence at 4 weeks follow-up. Participants will receive motivational enhancement and contingency management during the 4-week abstinence period.

Group Type: EXPERIMENTAL

[18F]FPEB with PET

Intervention Type: DRUG

radioactive tracer \[18F\]FPEB administered by bolus infusion over up to 2 hours with PET performed in the last 30 minutes of infusion with Positron emission tomography (PET) neuroimaging

Cannabis abstinence

Intervention Type: BEHAVIORAL

Motivational enhancement and contingency management (CM) to promote and maintain cannabis abstinence after the baseline scan.

Healthy control

Healthy control participants undergo neuroimaging, cognitive testing, and EEG at baseline.

Group Type: EXPERIMENTAL

[18F]FPEB with PET

Intervention Type: DRUG

radioactive tracer \[18F\]FPEB administered by bolus infusion over up to 2 hours with PET performed in the last 30 minutes of infusion with Positron emission tomography (PET) neuroimaging

Interventions

[18F]FPEB with PET

radioactive tracer \[18F\]FPEB administered by bolus infusion over up to 2 hours with PET performed in the last 30 minutes of infusion with Positron emission tomography (PET) neuroimaging

Intervention Type: DRUG

Cannabis abstinence

Motivational enhancement and contingency management (CM) to promote and maintain cannabis abstinence after the baseline scan.

Intervention Type: BEHAVIORAL

Eligibility Criteria

Inclusion Criteria

HC and CUD Group:

• Voluntary, written, informed consent
• Physically healthy by medical history, physical, neurological, ECG and laboratory exams
• No personal or first-degree relative history of psychiatric disorders (outside of cannabis use for CUD group)
• Full scale and verbal IQs > 80 (Wechsler Adult Intelligence Scale, Fourth Edition; WAIS-IV).

CUD group:

• Cannabis use disorder as determined by DSM-5 structured interviews
• Urine toxicology evidence of cannabinoid use

HC group:

• lifetime cannabis exposure less than 20 times
• no cannabis use in the past 2 years by self-report
• a negative urine drug screen.

Exclusion Criteria

• Other substance use disorder within 1 year, except for nicotine
• Another primary DSM-5 Axis I major psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depression, etc.) per SCID-5
• Urine toxicology results positive for other drugs such as opiates / opiate metabolites (e.g., methadone, buprenorphine, etc.)
• A history of significant medical (cardiac, infectious, metabolic) or neurological illness (e.g., cerebrovascular disease, traumatic brain injury)
• A history of seizures/epilepsy
• Current use of psychotropic and/or potentially psychoactive prescription medications
• Medical contraindications to MRI imaging (e.g., ferromagnetic implants/foreign bodies, claustrophobia, etc.)
• Pregnancy or breastfeeding (women).
• Subjects will be excluded for major medical or neurological illness or laboratories consistent with these illnesses or suggesting contraindication to PET or MR imaging

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 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

Stephen Baldassarri

Assistant Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Stephen R Baldassarri, M.D.

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

The Anlyan Center

New Haven, Connecticut, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

K23DA045957

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2000033244

Identifier Type: -

Identifier Source: org_study_id