Using Imaging to Assess Effects of THC on Brain Activity

Study Overview
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Brief Summary
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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
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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.

Official Title
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Using Imaging to Assess Effects of THC on Brain Activity

Conditions
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Intoxication Alcohol, Intoxication THC, Intoxication Combined Alcohol THC

Intervention / Treatment
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* Drug: Dronabinol
* Drug: Ethanol
* Drug: Placebo dronabinol
* Drug: Placebo ethanol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria General Men and women aged 18-55 years, inclusive; (for Phase 2B: men and women aged 21-55 years, inclusive) Competent and willing to provide written informed consent; Able to communicate in English language. Regular, at least monthly, marijuana use, confirmed by positive urine screen for THC Additional Inclusion Criteria For Phase 2B: Past consumption of at least two alcoholic beverages in one occasion. Past co-consumption of alcohol and THC at least once in lifetime with no serious adverse effects. Weigh more than 100 lbs. Exclusion Criteria: General (Phase 2A, 2B 3) Any unstable, serious medical illness, or cardiovascular disease or events. New or unstable psychiatric symptoms, schizophrenia, or bipolar I disorder, Diabetes, cirrhosis, renal failure, Hepatitis C, HIV, History of syncope without an identified situational stressor, migraines >1x/month, head injury with prolonged unconsciousness (> 24 hours); Allergy to sesame oil (contained in Marinol pills) or Marinol capsules Daily use of benzodiazepines or barbiturates, antihistamines, atropine, scopolamine, or other strong anticholinergic agents; Current pregnancy or lactation, or trying to become pregnant (confirmed by urine pregnancy test) In the opinion of the investigator, not able to safely participate in this study. Additional Exclusion Criteria For Phase 2B: Currently seeking treatment, in treatment, or in recovery from an alcohol use disorder.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2A<br>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. | Drug: Dronabinol<br>* Dronabinol at physician determined doses of 10-80mg designed to produce intoxication.<br>* Other names: oral THC;Drug: Placebo dronabinol<br>* Identical in appearance to active dronabinol (overencapsulation of both active and placebo dronabinol)<br>* Other names: placebo oral THC;|
| Experimental: Phase 2B<br>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. | Drug: Dronabinol<br>* Dronabinol at physician determined doses of 10-80mg designed to produce intoxication.<br>* Other names: oral THC;Drug: Ethanol<br>* Oral Ethanol, dosed to obtain a breath alcohol concentration (BrAC) of approximately 0.05 BrAC (equal to 1-2 standard drinks).<br>* Other names: oral ethanol;Drug: Placebo dronabinol<br>* Identical in appearance to active dronabinol (overencapsulation of both active and placebo dronabinol)<br>* Other names: placebo oral THC;Drug: Placebo ethanol<br>* 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.<br>* Other names: oral placebo ethanol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fNIRS, THC, Intoxication