Intoxication Alcohol, Intoxication THC, Intoxication Combined Alcohol THC
Conditions
Keywords
fNIRS, THC, Intoxication
Brief summary
This study will assess effects of tetrahydrocannabinol (THC) and THC + alcohol in marijuana users on prefrontal brain activity, using functional near-infrared spectroscopy (fNIRS) during resting state and during memory task performance. Participants will complete fNIRS testing 120 minutes following THC or identical placebo (Phase 2A), or THC/ethanol, THC/placebo ethanol, placebo THC/ethanol, and placebo THC/placebo ethanol (Phase 2B), and oxygenated hemoglobin (HbO) concentration will be measured.
Detailed description
This study will assess the effects of THC intoxication using dronabinol (synthetic THC) on the oxyhemoglobin (HbO) signal during resting state and task-based activation in the prefrontal cortex (PFC) and resting state connectivity, as well as on neurocognitive task performance and correlations between these measurements and clinical signs of intoxication. Participants will be 150 adults who use marijuana at least monthly (aged 18-55) will be recruited to participate in this study. Participants will be given up to 80 mg of dronabinol, an FDA-approved synthetic form of THC that is used to treat loss of appetite that causes weight loss in people with AIDS. THC is the principle psychoactive drug in marijuana. The study will be conducted in regular cannabis users who present at their first study visit with a positive urine screen for THC metabolites. Phase 2A. Investigate the effect of THC on fNIRS brain signature and its association with self-reported intoxication, laboratory measures of impairment, and the gold-standard behavioral field test of driving impairment used by law enforcement, the primary classifier. Phase 2B. Examine potential interaction following co-administration of THC with oral ethanol exposure in healthy volunteers. Phase II is a randomized, double-blind, placebo-controlled, 2 by 2 crossover study of effect of dronabinol, ethanol, and combined dronabinol and ethanol on brain activation and connectivity as measured by fNIRS.
Interventions
DRUGDronabinol
Dronabinol at physician determined doses of 10-80mg designed to produce intoxication.
DRUGEthanol
Oral Ethanol, dosed to obtain a breath alcohol concentration (BrAC) of approximately 0.05 BrAC (equal to 1-2 standard drinks).
Identical in appearance to active dronabinol (overencapsulation of both active and placebo dronabinol)
DRUGPlacebo ethanol
Placebo ethanol will consist of diet soda used in the active ethanol condition with 0.25ml ethanol floated on top to provide the odor of ethanol and blind the study drug.
Sponsors
National Institute on Drug Abuse (NIDA)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Subjects will be randomly assigned to one of the possible orders according to a randomization schedule generated by the study staff using a random number generator and computer program. The Massachusetts General Hospital (MGH) research pharmacy will generate a blinded randomization code for order of dosing and will dispense blinded drug in the dose ordered and identical placebo for use on separate study days. Ethanol or placebo drink will be prepared by a member of the research unit staff not otherwise associated with study visits.
Intervention model description
In Phase 2A, a double-blind placebo-controlled, random order cross-over study of single dose dronabinol, participants received dronabinol or identical placebo on two separate study visits in randomized order. In Phase 2B, a randomized, double-blind, 4-treatment, 4-period, crossover study with THC or placebo administration and ethanol or placebo administration, participants were randomly assigned to 1 of 24 sequences of each of the following treatments: placebo dronabinol and placebo ethanol, placebo dronabinol and ethanol, dronabinol and placebo ethanol, and dronabinol and ethanol.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
General 1. Men and women aged 18-55 years, inclusive; (for Phase 2B: men and women aged 21-55 years, inclusive) 2. Competent and willing to provide written informed consent; 3. Able to communicate in English language. 4. Regular, at least monthly, marijuana use, confirmed by positive urine screen for THC Additional Inclusion Criteria For Phase 2B: 5. Past consumption of at least two alcoholic beverages in one occasion. 6. Past co-consumption of alcohol and THC at least once in lifetime with no serious adverse effects. 7. Weigh more than 100 lbs.
Exclusion criteria
General (Phase 2A, 2B 3) 1. Any unstable, serious medical illness, or cardiovascular disease or events. 2. New or unstable psychiatric symptoms, schizophrenia, or bipolar I disorder, 3. Diabetes, cirrhosis, renal failure, Hepatitis C, HIV, 4. History of syncope without an identified situational stressor, migraines \>1x/month, head injury with prolonged unconsciousness (\> 24 hours); 5. Allergy to sesame oil (contained in Marinol pills) or Marinol capsules 6. Daily use of benzodiazepines or barbiturates, antihistamines, atropine, scopolamine, or other strong anticholinergic agents; 7. Current pregnancy or lactation, or trying to become pregnant (confirmed by urine pregnancy test) 8. In the opinion of the investigator, not able to safely participate in this study. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | The first Nback scan session was run before dosing (t ≈ -35min). Drug was administered (t = 0min). The second Nback scan session was run at the time of expected peak pharmacokinetic effect (t ≈ 100min). Each scan session was six minutes in duration. | Subjects completed the N-back task before and after receiving a combination of active dronabinol or placebo dronabinol and active ethanol or placebo ethanol. During the task, the fNIRS device was used to capture change in concentration of oxygenated hemoglobin to assess prefrontal brain activity. Outcomes reflect average change from baseline in HbO concentration over pre-dose scan and average change from baseline in HbO concentration over post-dose scan (expected peak intoxication). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | The first resting-state scan session was run before dosing (t ≈ -45min). Drug was administered (t = 0min). The second resting-state scan session was run at the time of expected peak high (t ≈ 90min). Each scan session was six minutes in duration. | Subjects completed resting-state fNIRS scans before and after receiving a combination of active dronabinol or placebo dronabinol and active ethanol or placebo ethanol. During the task, the fNIRS device was used to capture concentration of oxygenated hemoglobin to assess prefrontal brain activity. Outcomes reflect average change from baseline in HbO concentration over pre-dose scan and average change from baseline in HbO concentration over post-dose scan (expected peak intoxication). |
Countries
United States
Participant flow
Recruitment details
Participants were recruited by study staff at the MGH Center for Addiction Medicine through advertising by email, web and bulletin board announcements posted within the local site network community.
Pre-assignment details
A screening visit took place before randomization. After randomization, phase 2A completed two visits and phase 2B completed four visits. Washout achieved with at least one week between visits. Participant dropout affected by the COVID-19 pandemic. Due to character limit, sequences coded as follows: A: Placebo Dronabinol B: Dronabinol C: Placebo Dronabinol & Placebo Ethanol D: Dronabinol & Placebo Ethanol E: Placebo Dronabinol & Ethanol F: Dronabinol & Ethanol
Participants by arm
| Arm | Count |
|---|---|
| Phase 2A - Total Sample In a double-blind placebo-controlled, random order cross-over study of single dose dronabinol, participants received dronabinol or identical placebo on two separate study visits in randomized order. | 138 |
| Phase 2B - Total Sample In a randomized, double-blind, 4-treatment, 4-period, crossover study with THC or placebo administration and ethanol or placebo administration, participants were randomly assigned to 1 of 4 sequences and received each of the following treatments: placebo dronabinol + placebo ethanol, placebo dronabinol + ethanol, dronabinol + placebo ethanol, & dronabinol + ethanol. | 52 |
| Total | 190 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 | FG018 | FG019 | FG020 | FG021 | FG022 | FG023 | FG024 | FG025 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 3 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 8 | 1 | 0 | 0 | 1 | 3 | 1 | 2 | 0 | 0 | 1 | 0 | 3 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 2 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase 2A - Total Sample | Phase 2B - Total Sample | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 138 Participants | 52 Participants | 190 Participants |
| Age, Continuous | 24.9 years STANDARD_DEVIATION 6.49 | 25.6 years STANDARD_DEVIATION 5.16 | 25.1 years STANDARD_DEVIATION 6.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 10 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 107 Participants | 41 Participants | 148 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 2 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 6 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 12 Participants | 4 Participants | 16 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) White | 93 Participants | 36 Participants | 129 Participants |
| Region of Enrollment United States | 138 participants | 52 participants | 190 participants |
| Sex: Female, Male Female | 67 Participants | 27 Participants | 94 Participants |
| Sex: Female, Male Male | 71 Participants | 25 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 128 | 0 / 126 | 0 / 39 | 0 / 39 | 0 / 32 | 0 / 38 |
| other Total, other adverse events | 13 / 128 | 6 / 126 | 7 / 39 | 12 / 39 | 3 / 32 | 4 / 38 |
| serious Total, serious adverse events | 0 / 128 | 0 / 126 | 0 / 39 | 0 / 39 | 0 / 32 | 0 / 38 |
Outcome results
Primary
Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task.
Subjects completed the N-back task before and after receiving a combination of active dronabinol or placebo dronabinol and active ethanol or placebo ethanol. During the task, the fNIRS device was used to capture change in concentration of oxygenated hemoglobin to assess prefrontal brain activity. Outcomes reflect average change from baseline in HbO concentration over pre-dose scan and average change from baseline in HbO concentration over post-dose scan (expected peak intoxication).
Time frame: The first Nback scan session was run before dosing (t ≈ -35min). Drug was administered (t = 0min). The second Nback scan session was run at the time of expected peak pharmacokinetic effect (t ≈ 100min). Each scan session was six minutes in duration.
Population: Note: The Participant Flow lists Phase 2A by randomization sequence (recommended for crossover studies).~Phase 2A: Includes participants that completed scans after receiving dronabinol (119 subjects) and after placebo (115 subjects) Phase 2B: Incudes participants that completed scans after receiving dronabinol + ethanol (30 subjects), dronabinol + placebo ethanol (31 subjects), placebo dronabinol + ethanol (28 subjects) and placebo dronabinol + placebo ethanol (34 subjects)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2A: Dronabinol Only | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Peak | 0.00000000013 Δ mol/L | Standard Deviation 1.019e-7 |
| Phase 2A: Dronabinol Only | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Predose | 0.00000000042 Δ mol/L | Standard Deviation 1.1109e-7 |
| Phase 2A: Placebo Dronabinol Only | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Peak | 0.00000000029 Δ mol/L | Standard Deviation 1.2394e-7 |
| Phase 2A: Placebo Dronabinol Only | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Predose | -0.00000000126 Δ mol/L | Standard Deviation 1.2928e-7 |
| Phase 2B: Dronabinol and Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Peak | -0.00000000041 Δ mol/L | Standard Deviation 1.0552e-7 |
| Phase 2B: Dronabinol and Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Predose | -0.00000000271 Δ mol/L | Standard Deviation 1.5932e-7 |
| Phase 2B: Dronabinol and Placebo Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Peak | -0.00000000020 Δ mol/L | Standard Deviation 1.2457e-7 |
| Phase 2B: Dronabinol and Placebo Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Predose | -0.00000000114 Δ mol/L | Standard Deviation 1.5048e-7 |
| Phase 2B: Placebo Dronabinol and Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Peak | -0.00000000018 Δ mol/L | Standard Deviation 9.089e-8 |
| Phase 2B: Placebo Dronabinol and Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Predose | -0.00000000151 Δ mol/L | Standard Deviation 9.318e-8 |
| Phase 2B: Placebo Dronabinol and Placebo Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Predose | -0.00000000219 Δ mol/L | Standard Deviation 1.2507e-7 |
| Phase 2B: Placebo Dronabinol and Placebo Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans of Patients Completing the N-back Task. | Peak | 0.00000000070 Δ mol/L | Standard Deviation 1.1546e-7 |
Comparison: The mean difference in average HbO levels (converted to z-scores) between the pre and post-dose scans for conditions where a participant was dosed with dronabinol (i.e., a main effect for dronabinol dose), estimated via a linear model with with a subject-varying intercept and covariates for (a) overall differences between pre and post-dose scans and (b) visit order.p-value: 0.9495% CI: [-0.259, 0.184]Regression, Linear
Comparison: The mean difference in average HbO levels (converted to z-scores) between the pre and post-dose scans for conditions where a participant was dosed with ethanol (i.e., a main effect for ethanol dose), estimated via a linear model with with a subject-varying intercept and covariates for (a) overall differences between pre and post-dose scans and (b) visit order.p-value: 0.9495% CI: [-0.421, 0.386]Regression, Linear
Comparison: The mean difference in average HbO levels (converted to z-scores) between the pre and post-dose scans for conditions where a participant was dosed with both dronabinol and ethanol (i.e., the interaction between dronabinol and ethanol doses), estimated via a linear model with with a subject-varying intercept and covariates for (a) overall differences between pre and post-dose scans and (b) visit order.p-value: 0.9495% CI: [-0.535, 0.568]Regression, Linear
Other Pre-specified
Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State.
Subjects completed resting-state fNIRS scans before and after receiving a combination of active dronabinol or placebo dronabinol and active ethanol or placebo ethanol. During the task, the fNIRS device was used to capture concentration of oxygenated hemoglobin to assess prefrontal brain activity. Outcomes reflect average change from baseline in HbO concentration over pre-dose scan and average change from baseline in HbO concentration over post-dose scan (expected peak intoxication).
Time frame: The first resting-state scan session was run before dosing (t ≈ -45min). Drug was administered (t = 0min). The second resting-state scan session was run at the time of expected peak high (t ≈ 90min). Each scan session was six minutes in duration.
Population: Note: The Participant Flow lists Phase 2A by randomization sequence (recommended for crossover studies).~Phase 2A: Includes participants that completed scans after receiving dronabinol (119 subjects) and after placebo (115 subjects) Phase 2B: Incudes participants that completed scans after receiving dronabinol + ethanol (30 subjects), dronabinol + placebo ethanol (31 subjects), placebo dronabinol + ethanol (28 subjects) and placebo dronabinol + placebo ethanol (34 subjects)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2A: Dronabinol Only | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Peak | -0.00000000043 Δ mol/L | Standard Deviation 1.0544e-7 |
| Phase 2A: Dronabinol Only | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Predose | -0.00000000056 Δ mol/L | Standard Deviation 1.4233e-7 |
| Phase 2A: Placebo Dronabinol Only | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Predose | 0.00000000009 Δ mol/L | Standard Deviation 1.1881e-7 |
| Phase 2A: Placebo Dronabinol Only | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Peak | 0.00000000115 Δ mol/L | Standard Deviation 1.4174e-7 |
| Phase 2B: Dronabinol and Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Peak | 0.00000000025 Δ mol/L | Standard Deviation 8.717e-8 |
| Phase 2B: Dronabinol and Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Predose | 0.00000000198 Δ mol/L | Standard Deviation 1.0153e-7 |
| Phase 2B: Dronabinol and Placebo Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Predose | 0.00000000021 Δ mol/L | Standard Deviation 1.5753e-7 |
| Phase 2B: Dronabinol and Placebo Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Peak | 0.00000000190 Δ mol/L | Standard Deviation 1.3848e-7 |
| Phase 2B: Placebo Dronabinol and Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Peak | 0.00000000195 Δ mol/L | Standard Deviation 1.1273e-7 |
| Phase 2B: Placebo Dronabinol and Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Predose | 0.00000000144 Δ mol/L | Standard Deviation 1.7047e-7 |
| Phase 2B: Placebo Dronabinol and Placebo Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Peak | -0.00000000014 Δ mol/L | Standard Deviation 8.289e-8 |
| Phase 2B: Placebo Dronabinol and Placebo Ethanol | Change in Concentration of Oxygenated Hemoglobin Between Pre-drug and Post-drug Scans During Resting State. | Predose | -0.00000000051 Δ mol/L | Standard Deviation 1.1795e-7 |
Comparison: The mean difference in average HbO levels (converted to z-scores) between the pre and post-dose scans for conditions where a participant was dosed with dronabinol (i.e., a main effect for dronabinol dose), estimated via a linear model with with a subject-varying intercept and covariates for (a) overall differences between pre and post-dose scans and (b) visit order.p-value: 0.9495% CI: [-0.384, 0.057]Regression, Linear
Comparison: The mean difference in average HbO levels (converted to z-scores) between the pre and post-dose scans for conditions where a participant was dosed with ethanol (i.e., a main effect for ethanol dose), estimated via a linear model with with a subject-varying intercept and covariates for (a) overall differences between pre and post-dose scans and (b) visit order.p-value: 0.9495% CI: [-0.588, 0.237]Regression, Linear
Comparison: The mean difference in average HbO levels (converted to z-scores) between the pre and post-dose scans for conditions where a participant was dosed with both dronabinol and ethanol (i.e., the interaction between dronabinol and ethanol doses), estimated via a linear model with with a subject-varying intercept and covariates for (a) overall differences between pre and post-dose scans and (b) visit order.p-value: 0.9495% CI: [-0.354, 0.728]Regression, Linear