Modulation of THC Effects by CBD: a Dose-ranging Study

Study Overview
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Brief Summary
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The purposes of this study are 1) to determine if CBD modulates THC-induced acute psychoactive effects at different CBD:THC ratios, compared with the control product (0:20, 20:20, 40:20, 80:20, 120:20) and 2) to determine if different doses of CBD modulate other THC induced behavioral effects, compared with the control product and 3)To explore qualitatively whether CBD modulates THC effects by mechanisms that are not detected with standard clinical research tools.

Detailed Description
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Despite more than 40 years of research on the active compounds present in the cannabis plant, the influence of CBD consumption on the metabolism, pharmacology, and behavioral effects of THC remains fragmentary and scarcely documented in vivo in humans. Cannabis users are currently encouraged to choose products containing CBD, but evidence is lacking regarding its potential benefits when consumed jointly with THC across different ratios. Given the recent cannabis legalization in Canada and the widespread use of inhalation as the preferred mode of administration for non-therapeutic cannabis, closing this knowledge gap will help ensure public safety and allow regulatory bodies and public health authorities to elaborate more refined cannabis use guidelines and harm reduction strategies. It will also empower people who use cannabis to make more informed purchasing decisions and will drive the incubation of future research endeavors in the fields of medical and social sciences. The aim of this study is to improve our understanding of the (acute) behavioral and pharmacological effects of different doses of CBD administered concomitantly with THC via inhalation in individuals who engage in occasional cannabis use, taking into consideration multiple factors that can modulate such effects. This study will put to the test conceptions surrounding the interaction between specific cannabinoids by evaluating the role of CBD on the modulation of THC's effects pertaining to cognition, behavior, subjective experience, and physiological parameters.

Official Title
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Modulation of ∆9-tetrahydrocannabinol Acute Psychoactive Effects by Ranging Doses of Cannabidiol in Healthy, Occasional Cannabis Users: a Controlled, Triple Blind, Randomized, Cross-over Study

Conditions
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Cannabis, THC

Intervention / Treatment
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* Drug: ∆9-tetrahydrocannabinol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 21 and 49 years of age, inclusively; Have used cannabis at least once in their lifetime and have used cannabis three days or less in the 30 days prior to enrollment; Be able to provide a signed informed consent; Willing to comply with study procedures and requirements as per protocol; Have a forced expiratory volume in first second (FEV) less than or equal to 90 %; Able to communicate and understand English or French language; For female participants: a. No childbearing potential, defined as: i. postmenopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age); or ii. Documented surgically sterilized (i.e., tubal ligation, hysterectomy, or bilateral oophorectomy); or b. For female of childbearing potential: i. Must have negative pregnancy test result at screening and at subsequent visits. ii. AND have no pregnancy plan while on the study iii. AND must agree to use a medically accepted method of birth control throughout the study. Exclusion criteria Participants will be excluded if any of the following criteria are met: Any disabling medical condition, as assessed by medical history, physical exam, vital signs and/or laboratory assessments that, in the opinion of the study physician, precludes safe participation in the study or the ability to provide fully informed consent; Severe psychiatric condition (history of schizophrenia, schizoaffective disorder or bipolar disorder; current acute psychosis, mania or current suicidality based on the Mini International Neuropsychiatric Interview); Any other disabling, unstable or acute mental condition that, in the opinion of the study physician, precludes safe participation in the study or ability to provide fully informed consent; Known chronic liver disease or aspartate transaminase/alanine transaminase (AST/ALT) two times higher than upper limit of normal values at screening visit; Blood pressure higher than 130/80 mmHg; Kidney disorders; Bleeding disorders; Current moderate or severe DSM-5 substance use disorder (except nicotine) according to SCID-V; Currently pregnant, breastfeeding or planning to become pregnant either at screening or while enrolled in the study; Pending legal action or other reason that, in the opinion of the study physician, might prevent study completion; Use of medication within 7 days of experimental sessions; which, in the opinion of the Investigator, may interact with cannabis. Participation in clinical studies or undergoing other investigational procedure involving cannabis or cannabinoids administration within 30 days prior to randomization. Resting heart rate over 100 beats per minute. Current body mass index (BMI) over 29.9 kg/m2. Any clinically significant electrocardiogram abnormalities at screening visit.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 49 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: In this crossover design, participants will be administered all phytocannabinoid doses contained in the four CBD:THC products and the control product (THC only) during participation in the study. Participant will be randomly assigned to one of the predetermined sequences with a CBD:THC product or control product at 5 dosages (CBD:THC of 0:20 mg, 20:20 mg, 40:20 mg, 80:20 mg and 120:20 mg). Participants will be randomized based on a balanced 5 by 5 Latin square.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CBD:THC Group 1<br>Group will receive four doses of CBD:THC ratio (20:20 mg, 40:20 mg, 80:20 mg and 120:20 mg) and a control product CBD:THC ratio (0:20 mg). Group will attend a total of five study visits (one for each study product) with at least 1 week between each visit. The order in which the study products will be administered depend on the randomization sequence. | Drug: ∆9-tetrahydrocannabinol<br>* Phytocannabinoids from plant inflorescences (CBD and THC dominant) - inhaled<br>* Other names: Cannabidiol;|
| Experimental: CBD:THC Group 2<br>Group will receive four doses of CBD:THC ratio (20:20 mg, 40:20 mg, 80:20 mg and 120:20 mg) and a control product CBD:THC ratio (0:20 mg). Group will attend a total of five study visits (one for each study product) with at least 1 week between each visit. The order in which the study products will be administered depend on the randomization sequence. | Drug: ∆9-tetrahydrocannabinol<br>* Phytocannabinoids from plant inflorescences (CBD and THC dominant) - inhaled<br>* Other names: Cannabidiol;|
| Experimental: CBD:THC Group 3<br>Group will receive four doses of CBD:THC ratio (20:20 mg, 40:20 mg, 80:20 mg and 120:20 mg) and a control product CBD:THC ratio (0:20 mg). Group will attend a total of five study visits (one for each study product) with at least 1 week between each visit. The order in which the study products will be administered depend on the randomization sequence. | Drug: ∆9-tetrahydrocannabinol<br>* Phytocannabinoids from plant inflorescences (CBD and THC dominant) - inhaled<br>* Other names: Cannabidiol;|
| Experimental: CBD:THC Group 4<br>Group will receive four doses of CBD:THC ratio (20:20 mg, 40:20 mg, 80:20 mg and 120:20 mg) and a control product CBD:THC ratio (0:20 mg). Group will attend a total of five study visits (one for each study product) with at least 1 week between each visit. The order in which the study products will be administered depend on the randomization sequence. | Drug: ∆9-tetrahydrocannabinol<br>* Phytocannabinoids from plant inflorescences (CBD and THC dominant) - inhaled<br>* Other names: Cannabidiol;|
| Experimental: CBD:THC Group 5<br>Group will receive four doses of CBD:THC ratio (20:20 mg, 40:20 mg, 80:20 mg and 120:20 mg) and a control product CBD:THC ratio (0:20 mg). Group will attend a total of five study visits (one for each study product) with at least 1 week between each visit. The order in which the study products will be administered depend on the randomization sequence. | Drug: ∆9-tetrahydrocannabinol<br>* Phytocannabinoids from plant inflorescences (CBD and THC dominant) - inhaled<br>* Other names: Cannabidiol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective and subjective measures of cannabinoids effect | Based on the scores obtained on the observer items (objective) and the participant-rated items (subjective) from the Clinician Administered Dissociative State Scale (CADSS). The CADSS is a 28-item validated instrument, includes 5 observer items and 23 participant self-report items rated on a 5-point scale, ranging from 0 (not at all) to 4 (extremely) on eight items. The score will reflect the extent to which participants were observed to be under the effect of cannabinoids, i.e., in adissociative state. | Prior to the Product administration ,10 minutes and 60 minutes after inhalation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive and Negative Affect | Will be measured by the Positive and Negative Affect Schedule (PANAS). The PANAS is a 20-item validated questionnaire, used in both non-clinical and clinical populations. | Prior to the Product administration , 10 minutes and 60 minutes post inhalation | 
| Neural oscillations | Auditory oscillations, using an electroencephalogram (EEG), will be probe in response to 40-Hz FM and ascending/descending AM stimuli, using a 16-channel system with 250-Hz sampling rate and 24-bit resolution (model g.Nautilus PRO 16 g.SAHARA, g.tec, Schiedlberg, Austria). | Prior to the Product administration, 50 minutes post inhalation and at the end of the study visit, approximatively 120 minutes after inhalation | 
| Anxiety Symptoms | Symptoms of anxiety will be assessed using the States-Trait-Anxiety-Inventory (STAI). It consists of two 20-item self-report scales (trait and state anxiety) that measure the severity of anxiety in adults. Both subscales are composed of 20 statements rated on a 4-point Likert scale ranging from 1 (not at all and almost never for the state and trait subscales, respectively) to 4 (very much and almost always for the state and trait subscales, respectively). | Prior to the Product administration, 10 minutes and 60 minutes after inhalation | 
| Subjective Drug Effects | Drug Effect Questionnaire (twenty-three-item) will be use to assess participant's physical signs, symptoms associated with cannabis inhalation and desire to use the product. The Drug Effects Questionnaire uses visual analogue scale, ranging from 0 (not at all) to 100 (extremely). | 10 minutes and 60 minutes after inhalation | 
| Experience with Study Products | Subjective effects of cannabis will be assessed using the Cannabis Experience Questionnaire (CEQ), The CEQ measures participants' subjective experiences with cannabis consumption and consists of two subscales: pleasurable experiences (18 items), psychosis-like experiences (25 items), and after-effect experiences measuring the consequences of cannabis after use (12 items). Each item of each subscale is rated on a 5-point Likert scale, ranging from 1 (not at all) to 5 (extremely). | 120 minutes after inhalation | 
| Social Exposition Challenge | This will help determine if different doses of CBD can modulate the feeling of paranoia and/or anxiety triggered by social interactions, in comparison to the control product. The research staff will give to the participant five dollars in cash. The participant will then be escorted out of the research center by a member of the research staff for a 10-minute walk to the hospital pharmacy with the instruction of purchasing an item of their choosing with the money. Once the task is completed, the participant will be escorted back to the research center. The research staff will walk approximately two meters behind the participant during the whole procedure and will be instructed not to engage in any conversation, unless the participant needs assistance or feels abnormally anxious. | 50 minutes after inhalation | 
| Change on cognition | The Cambridge Neuropsychological Test Automated Battery tests will be used for the rapid assessment of multiple cognitive components. | Prior to the Product administration (only at Visite 1) and 10 minutes after inhalation at each visit | 
| Success of Blinding Questionnaire | To assess the success of the blind iwith the Blinding Success Questionnaire (BSQ). The specific aims of testing the blind are to a) determine which research product participants think they received and b) examine the associations between the research product participants think they received and their expectations, subjective cannabis perceptions, treatment outcomes, and side effects. | 10 minutes and 120 minutes after inhalation | 
| Inhalation Adherence | When the participant inhales the investigational product, research staff will fill a questionnaire assessing participant compliance. | During inhalation procedure | 
| Change in Safety | Adverse events will be collected prior to administration of the study product (T0) and following administration of the study product (T1, T2 and T3). | Baseline,10 minutes, 60 minutes and 120 minutes after inhalation | 
| Visit Intoxication Assessment | Signs of intoxication will be assess using the modified Standardized Field Sobriety Test. | Through study visit completion, approximatively 120 minutes after product inhalation |