Cannabis Dependence, Continuous, Cannabis Use Disorder
Conditions
Keywords
Marijuana, cannabis, cannabinoid receptor
Brief summary
All participants will be healthy volunteers and all procedures will be completed for research purposes only. Two groups will be recruited, females who use cannabis (marijuana, MJ), and female who do not use cannabis (controls). Female MJ users will be enrolled in a protocol that includes an outpatient drug administration session and a 4-day/3-night inpatient stay on the Johns Hopkins Bayview Clinical Research Unit (CRU). During outpatient visits, MJ users will have an MRI, and complete MJ self-administration and cognitive performance sessions. MJ users will then reside on the CRU,and complete MJ abstinence, and self-report instruments for withdrawal discomfort. A positron emission tomography (PET) scan of brain cannabinoid type 1 receptors will also be completed. Non-users will complete MRI, PET imaging and cognitive testing under an outpatient protocol (no MJ administration).
Detailed description
The primary goals of this project are to examine whether use of cannabis alters brain cannabinoid type 1 receptor (CB1R) availability in females, and if severity of cannabis withdrawal is correlated with CB1 receptor availability. CB1R are widely distributed in the human brain and can be quantified using PET imaging with the radiotracer 11C-OMAR (Carbon-11-OMAR). The effects MJ use on brain CB1R have not been studied in females. The current study will enroll 10 female MJ users in an inpatient protocol that includes administration of smoked MJ, followed by monitored abstinence with daily behavioral assessments, and PET imaging with 11C-OMAR. PET data will collected in 10 matched controls for comparison. The proposed study is an important first step to determine whether localized CB1R changes in female MJ users help explain, and provide a neurobiological target for intervention. Results will increase knowledge of cannabinoid mechanisms of cannabis use and severity of dependence in females, an understudied population.
Interventions
DRUG11C-OMAR
11C-OMAR is a PET radiotracer that binds to cannabinoid type 1 receptors (CB1R). It is an analog of the CB1R antagonist/inverse agonist rimonabant. 11C-OMAR was developed, synthesized and validated for inhuman use at the Johns Hopkins University PET center.
DRUGCannabis
Cannabis will be administered to cannabis users. Doses include 0 and 25 mg THC.
Sponsors
National Institute on Drug Abuse (NIDA)
Johns Hopkins University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
Cannabis THC content (dose) is masked for participant
Intervention model description
Two groups will be recruited. Female cannabis users and nonusers.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Female, healthy adult volunteers who are either MJ users and nonusers (controls) * 18-45 years of age * serum creatinine and hepatic enzymes (AST, ALT) must be within the normal limits * Women of child bearing potential must meet one of the following three criteria: 1\. negative pregnancy test by serum pregnancy test 2 .Following a reliable method of birth control 3. Agreeing to follow a reliable method of birth control during the study and for 1 month following all study procedures Additional inclusion criteria for MJ users * Regular MJ use * present MJ positive urine * meet Diagnostic and Statistical Manual, version 5 (DSM-5) criteria for cannabis use disorder (CUD) Additional inclusion non-users * report no MJ use * present a MJ-negative urine
Exclusion criteria
* \< 5th grade reading level * Current Diagnostic and Statistical Manual, version 5 (DSM-5) psychiatric disorder; * Current DSM-5 alcohol or substance use disorder (excluding MJ or nicotine) * Recent Illicit drug use or positive drug test * Using MJ under the guidance of MD; * History of seizures, closed head trauma; * unstable hypertension; * conditions preventing magnetic resonance imaging (MRI) such as implanted metal, claustrophobia, or anatomical abnormalities (e.g., enlarged ventricles, brain lesions); * Use of medications or herbal supplements which may be counter indicated as determined by study physician * Have had exposure to ionizing radiation that in combination with the study's estimated radiation exposure would result in a cumulative exposure that exceeds recommended exposure limits of 5 rem per year. * Presence or history of drug allergy, or allergic disease diagnosed and treated by a physician. * any serious medical condition in whom participation is contraindicated.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Distribution Volume (VT) | Collected during 90-min PET study | Distribution Volume (VT) is the quantification of 11C-OMAR binding to the CB1R; Per our statistical plan we examined VT for eight volumes of interest in the brain (ventral striatum, amygdala, putamen, cingulate, globus pallidus, insula, frontal cortex, and hippocampus) as well as the composite VT for the brain. The unit of measure is mL/cm\^3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Change From Baseline Marijuana Withdrawal Discomfort Score | Up to 5 days | Marijuana withdrawal discomfort will be self-reported using the marijuana withdrawal checklist, available via PhenXToolkit.org. Items are: depressed mood, irritability, nervousness/anxiety, restlessness, increased aggression, increased anger, violent outbursts, nausea, decreased appetite, stomach pain, shakiness, sweating, sleep difficulty, strange/wild dreams, craving to smoke cannabis, diarrhea/loose stools, dizziness, muscle spasms/aches, hiccups, stuffy nose, feverish feeling, hot flashes, chills, increased appetite, headaches, fatigue/tiredness, yawning, difficulty concentrating, general physical discomfort, and other. Each item is rated as 0=none, 1=mild, 2=moderate, or 3=severe. A sum score is calculated from items that are valid, reliable cannabis withdrawal symptoms (Budney et al, 2003, Journal of Abnormal Psychology,112(3): 393-402). A higher score represents more severe withdrawal. Scores range from 0-36. |
Countries
United States
Participant flow
Pre-assignment details
15 participants (8 females, 7 males) did not start, but were historical controls included for data analysis
Participants by arm
| Arm | Count |
|---|---|
| Female Cannabis Users With CUD Smoked Cannabis plant material (0 and 25 mg THC) will be administered to volunteers who are regular cannabis users. Cannabis users will also complete a PET scan where 20 millicurie of 11C-OMAR
11C-OMAR: 11C-OMAR is a PET radiotracer that binds to cannabinoid type 1 receptors (CB1R). It is an analog of the CB1R antagonist/inverse agonist rimonabant. 11C-OMAR was developed, synthesized and validated for inhuman use at the Johns Hopkins University PET center.
Cannabis: Cannabis will be administered to cannabis users. Doses include 0 and 25 mg THC. | 10 |
| Nonuser Female Healthy Controls (Contemporary and Historical) No cannabis administration. Non-user controls will complete a PET scan where 20 millicuries of 11C-OMAR.
11C-OMAR: 11C-OMAR is a PET radiotracer that binds to cannabinoid type 1 receptors (CB1R). It is an analog of the CB1R antagonist/inverse agonist rimonabant. 11C-OMAR was developed, synthesized and validated for inhuman use at the Johns Hopkins University PET center.
Contemporary and historical female non-user healthy controls were collapsed into one group due to low enrollment of contemporary healthy controls. | 10 |
| Male Non-user Historical Controls Historical male non-user healthy controls used for comparison | 7 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | failure to place arterial line | 2 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 6 | 4 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Female Cannabis Users With CUD | Nonuser Female Healthy Controls (Contemporary and Historical) | Male Non-user Historical Controls | Total |
|---|---|---|---|---|
| Age, Continuous | 23.2 years STANDARD_DEVIATION 2.7 | 25.5 years STANDARD_DEVIATION 5 | 29.6 years STANDARD_DEVIATION 6.9 | 25.7 years STANDARD_DEVIATION 5.3 |
| Age of first cannabis use | 15.3 years STANDARD_DEVIATION 3 | — | — | 15.3 years STANDARD_DEVIATION 3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 1 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 9 Participants | 1 Participants | 14 Participants |
| Sex: Female, Male Female | 10 Participants | 10 Participants | 0 Participants | 20 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 7 Participants | 7 Participants |
| Years of cannabis use | 7.9 years STANDARD_DEVIATION 4.3 | — | — | 7.9 years STANDARD_DEVIATION 4.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 7 | 0 / 8 | 0 / 7 |
| other Total, other adverse events | 0 / 21 | 0 / 7 | 0 / 8 | 0 / 7 |
| serious Total, serious adverse events | 0 / 21 | 0 / 7 | 0 / 8 | 0 / 7 |
Outcome results
Primary
Distribution Volume (VT)
Distribution Volume (VT) is the quantification of 11C-OMAR binding to the CB1R; Per our statistical plan we examined VT for eight volumes of interest in the brain (ventral striatum, amygdala, putamen, cingulate, globus pallidus, insula, frontal cortex, and hippocampus) as well as the composite VT for the brain. The unit of measure is mL/cm\^3.
Time frame: Collected during 90-min PET study
Population: Nonuser female healthy controls group includes 2 contemporary female controls and 8 historical female controls.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cannabis Users | Distribution Volume (VT) | Putamen VT | 1.52 mL/cm^3 | Standard Error 0.21 |
| Cannabis Users | Distribution Volume (VT) | Amygdala VT | 1.27 mL/cm^3 | Standard Error 0.19 |
| Cannabis Users | Distribution Volume (VT) | Cingulate VT | 1.31 mL/cm^3 | Standard Error 0.2 |
| Cannabis Users | Distribution Volume (VT) | Frontal lobe VT | 1.29 mL/cm^3 | Standard Error 0.19 |
| Cannabis Users | Distribution Volume (VT) | Globus Pall VT | 1.77 mL/cm^3 | Standard Error 0.29 |
| Cannabis Users | Distribution Volume (VT) | Hippocampus VT | 1.28 mL/cm^3 | Standard Error 0.2 |
| Cannabis Users | Distribution Volume (VT) | Insula VT | 1.37 mL/cm^3 | Standard Error 0.21 |
| Cannabis Users | Distribution Volume (VT) | Ventral straitum VT | 1.36 mL/cm^3 | Standard Error 0.22 |
| Cannabis Users | Distribution Volume (VT) | Composite VT | 1.27 mL/cm^3 | Standard Error 0.19 |
| Nonuser Female Healthy Controls | Distribution Volume (VT) | Hippocampus VT | 1.54 mL/cm^3 | Standard Error 0.29 |
| Nonuser Female Healthy Controls | Distribution Volume (VT) | Putamen VT | 1.69 mL/cm^3 | Standard Error 0.29 |
| Nonuser Female Healthy Controls | Distribution Volume (VT) | Amygdala VT | 1.54 mL/cm^3 | Standard Error 0.29 |
| Nonuser Female Healthy Controls | Distribution Volume (VT) | Ventral straitum VT | 1.52 mL/cm^3 | Standard Error 0.26 |
| Nonuser Female Healthy Controls | Distribution Volume (VT) | Globus Pall VT | 1.87 mL/cm^3 | Standard Error 0.35 |
| Nonuser Female Healthy Controls | Distribution Volume (VT) | Cingulate VT | 1.56 mL/cm^3 | Standard Error 0.27 |
| Nonuser Female Healthy Controls | Distribution Volume (VT) | Insula VT | 1.62 mL/cm^3 | Standard Error 0.28 |
| Nonuser Female Healthy Controls | Distribution Volume (VT) | Composite VT | 1.45 mL/cm^3 | Standard Error 0.24 |
| Nonuser Female Healthy Controls | Distribution Volume (VT) | Frontal lobe VT | 1.51 mL/cm^3 | Standard Error 0.26 |
| Historical Non-user Male Healthy Controls | Distribution Volume (VT) | Insula VT | 1.24 mL/cm^3 | Standard Error 0.18 |
| Historical Non-user Male Healthy Controls | Distribution Volume (VT) | Globus Pall VT | 1.38 mL/cm^3 | Standard Error 0.24 |
| Historical Non-user Male Healthy Controls | Distribution Volume (VT) | Ventral straitum VT | 1.21 mL/cm^3 | Standard Error 0.18 |
| Historical Non-user Male Healthy Controls | Distribution Volume (VT) | Hippocampus VT | 1.19 mL/cm^3 | Standard Error 0.19 |
| Historical Non-user Male Healthy Controls | Distribution Volume (VT) | Composite VT | 1.15 mL/cm^3 | Standard Error 0.16 |
| Historical Non-user Male Healthy Controls | Distribution Volume (VT) | Frontal lobe VT | 1.18 mL/cm^3 | Standard Error 0.16 |
| Historical Non-user Male Healthy Controls | Distribution Volume (VT) | Amygdala VT | 1.14 mL/cm^3 | Standard Error 0.18 |
| Historical Non-user Male Healthy Controls | Distribution Volume (VT) | Putamen VT | 1.31 mL/cm^3 | Standard Error 0.19 |
| Historical Non-user Male Healthy Controls | Distribution Volume (VT) | Cingulate VT | 1.19 mL/cm^3 | Standard Error 0.16 |
Comparison: VT in the 8 volumes of interest were analyzed using linear regression model group coded encoded as a dummy variable \[1=females cannabis users; 2= female healthy controls\], age as a covariate, and VT for VOIs (ventral striatum, amygdala, putamen, cingulate, globus pallidus, insula, frontal cortex, and hippocampus) as dependent variables, followed by post hoc Tukey's HSD between between groups.p-value: 0.02t-test, 2 sided
p-value: 0.03t-test, 2 sided
p-value: 0.03t-test, 2 sided
p-value: 0.04t-test, 2 sided
Secondary
Peak Change From Baseline Marijuana Withdrawal Discomfort Score
Marijuana withdrawal discomfort will be self-reported using the marijuana withdrawal checklist, available via PhenXToolkit.org. Items are: depressed mood, irritability, nervousness/anxiety, restlessness, increased aggression, increased anger, violent outbursts, nausea, decreased appetite, stomach pain, shakiness, sweating, sleep difficulty, strange/wild dreams, craving to smoke cannabis, diarrhea/loose stools, dizziness, muscle spasms/aches, hiccups, stuffy nose, feverish feeling, hot flashes, chills, increased appetite, headaches, fatigue/tiredness, yawning, difficulty concentrating, general physical discomfort, and other. Each item is rated as 0=none, 1=mild, 2=moderate, or 3=severe. A sum score is calculated from items that are valid, reliable cannabis withdrawal symptoms (Budney et al, 2003, Journal of Abnormal Psychology,112(3): 393-402). A higher score represents more severe withdrawal. Scores range from 0-36.
Time frame: Up to 5 days
Population: Females with CUD who completed cannabis administration sessions 1 and 2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cannabis Users | Peak Change From Baseline Marijuana Withdrawal Discomfort Score | Marijuana Withdrawal Discomfort Score: Score Pre Cannabis Administration session 2 | 2.30 score on a scale | Standard Deviation 2.26 |
| Cannabis Users | Peak Change From Baseline Marijuana Withdrawal Discomfort Score | Marijuana Withdrawal Discomfort Score: Peak score during 3 day Inpatient abstinence period | 4.80 score on a scale | Standard Deviation 3.85 |
p-value: 0.03t-test, 2 sided