Cannabis Use DisorderEarly Phase 1NCT05664763
Understanding Effects of Cannabis Use and Abstinence on Neural Glutamate Homeostasis
A Early Phase 1 study testing [18F]FPEB with PET and Cannabis abstinence in people with Cannabis Use Disorder, run by Yale University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Cannabis Use Disorder
- What is being tested?
- [18F]FPEB with PET and Cannabis abstinence
- Type of treatment
- Injection or infusion, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Mar 2023to 3 Jul 2024
- Phase
- Early Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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:
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- 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.
Who cannot join
- 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
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- 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 locations and contacts
1 site in 1 country.
About this study
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.
Read the 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
- Being tested
- [18F]FPEB with PET, Cannabis abstinence
- Keywords
- Cannabis, neuroimaging, marijuana, glutamate, tetrahydrocannabinol (THC)
- Medical subject headings
- Marijuana Abuse
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
[18F]FPEB with PETDrug
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 abstinenceBehavioural
Motivational enhancement and contingency management (CM) to promote and maintain cannabis abstinence after the baseline scan.
| Study group | Role | What they receive |
|---|---|---|
| Cannabis use disorder | Experimental | 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. Receives: Drug: [18F]FPEB with PET; Behavioral: Cannabis abstinence |
| Healthy control | Experimental | Healthy control participants undergo neuroimaging, cognitive testing, and EEG at baseline. Receives: Drug: [18F]FPEB with PET |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Metabotropic Glutamate Receptor 5 (mGluR5) Availability
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.
Measured: Baseline and Day 28
Secondary outcomes (2)
Change in Neurocognitive Function Using CogState Cognitive Battery
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.
Measured: Baseline and Day 28
Change in Verbal Memory Measured Using Electroencephalography (EEG)
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.
Measured: Baseline and Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Dec 2022
- Study start1 Mar 2023
- Primary completion3 Jul 2024
- Study completion3 Jul 2024
Why it stopped: Insufficient funding
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Cannabis Use DisorderStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Responsible party
- Principal investigator, Stephen Baldassarri, Yale University
- Investigators
- Stephen R Baldassarri, M.D., Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05664763
- Sponsor's protocol ID
- 2000033244
- Other IDs
- K23DA045957
- Status last verified
- Aug 2025
- First submitted
- 14 Dec 2022
- Last updated
- 19 Aug 2025
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Understanding Effects of Cannabis Use and Abstinence on Neural Glutamate Homeostasis
- ClinicalTrials.gov ID
- NCT05664763
- Acronym / sponsor ID
- 2000033244
- Conditions
- Cannabis Use Disorder
- Keywords
- Cannabis, neuroimaging, marijuana, glutamate, tetrahydrocannabinol (THC)
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Insufficient funding
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Study start
- 1 Mar 2023 (actual)
- Primary completion
- 3 Jul 2024 (actual)
- Study completion
- 3 Jul 2024 (actual)
- First posted
- 27 Dec 2022 (actual)
- Results
- Posted 19 Aug 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cannabis use disorder | Experimental | Drug: [18F]FPEB with PET, Behavioral: Cannabis abstinenceCUD 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. |
| Healthy control | Experimental | Drug: [18F]FPEB with PETHealthy control participants undergo neuroimaging, cognitive testing, and EEG at baseline. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (12 listed)
- 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).
- Cannabis use disorder as determined by DSM-5 structured interviews
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| [18F]FPEB with PETradioactive 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 | Drug | Cannabis use disorder, Healthy control |
| Cannabis abstinenceMotivational enhancement and contingency management (CM) to promote and maintain cannabis abstinence after the baseline scan. | Behavioural | Cannabis use disorder |
Primary outcome
Change in Metabotropic Glutamate Receptor 5 (mGluR5) Availability
Time frame: Baseline and Day 28
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.
2 secondary outcomes
Change in Neurocognitive Function Using CogState Cognitive Battery
Time frame: Baseline and Day 28
Change in Verbal Memory Measured Using Electroencephalography (EEG)
Time frame: Baseline and Day 28
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Aug 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Stephen R Baldassarri, M.D. principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing [18F]FPEB with PET and Cannabis abstinence in people with Cannabis Use Disorder, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 19 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Aug 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Metabotropic Glutamate Receptor 5 (mGluR5) Availability (time frame: Baseline and Day 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Aug 2025.