Understanding Effects of Cannabis Use and Abstinence on Neural Glutamate Homeostasis

Yale University

Status and phase: Terminated; Early Phase 1

Conditions: Cannabis Use Disorder

Treatments: Drug: [18F]FPEB with PET; Behavioral: Cannabis abstinence

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05664763

K23DA045957 (U.S. NIH Grant/Contract)

2000033244

Details and patient eligibility

About

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.

Full 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.

Enrollment: 6 patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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6 participants in 2 patient groups

Cannabis use disorder

Experimental group

Description:

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.

Treatment:

Behavioral: Cannabis abstinence

Drug: [18F]FPEB with PET

Healthy control

Experimental group

Description:

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

Treatment:

Drug: [18F]FPEB with PET