Understanding Effects of Cannabis Use and Abstinence on Neural Glutamate Homeostasis

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.

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.

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.

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

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

Participants will undergo a Positron Emission Tomography (PET) scan to visualized mGluR5 availability in the regions of interest (ROIs): orbitofrontal cortex (OFC), anterior cingulate, ventromedial prefrontal cortex (vmPFC), dorsolateral prefrontal cortex (dlPFC), hippocampus, and amygdala. Only done at baseline for HC group.

A battery of neuropsychological tests from the well-validated CogState Cognitive Battery are sensitive to detecting cognitive deficits in mood disorders, executive control and working memory. The entire battery takes approximately 30 minutes. Change in CUD group at baseline and day 28 compared to HC at baseline.

Theta band power and coherence will be assessed. EEG data are collected in three separate conditions. In the passive listening condition, subjects will passively listen to a list of 15 words (presented one at a time) six times in a row. In the memory encoding condition, subjects will be administered a list of 15 words played one at a time, five times, and will be told to try and remember the list and to repeat as many words as possible after each list. Twenty minutes after the end of the encoding phase, subjects will be asked to repeat as many words as they can from the original list of words. In the computerized recognition condition, subjects will hear words from the (1) original memorized list, (2) the distractor list, and (3) novel words not heard that day. Subjects will respond with a three-choice button box to indicate from which list each word originated. Change in CUD group at baseline and day 28 compared to HC at baseline.

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