PK/PD of Oral and Vaporized Delta-9-Tetrahydrocannabinol (THC) in Older Adults

Study Overview
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Brief Summary
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This double-blind, placebo-controlled, crossover study aims to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) effects of the main analgesic and psychoactive constituent of cannabis, delta-9 tetrahydrocannabinol (THC), among older adults - the fastest growing population of cannabis consumers, and the most likely age cohort to use cannabinoids to relieve pain.

Detailed Description
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This is a double-blind, placebo-controlled, crossover study, commencing with an oral THC Sub-Study. Following the completion of this sub-study, the Primary Study will commence. Oral THC Sub-Study: 10 men and women aged 65 years or older, will be randomized to two doses of oral THC (5 mg and 10 mg). Across three, 8-hour test sessions, participants will receive a random sequence of 3 conditions: 5 mg oral THC; 10 mg oral THC; oral placebo. Primary Study: 20 men and women aged 65 years or older will be randomized to two doses of oral THC (5 mg and 10 mg) and vaporized THC (2 mg and 4 mg). Across six 8-hour test sessions, participants will receive a random sequence of 6 conditions: 5 mg oral THC; 10 mg oral THC; oral placebo; 2 mg vaporized THC; 4 mg vaporized THC; and vaporized placebo. For both the sub-study and primary study, blood samples will be regularly collected from an intravenous line, up to 8 hours post-dose, and at 24 hours post-dose, to assess the PK of THC and its phase I and II metabolites. PD effects of THC on pain will be measured with Quantitative Sensory Testing (QST), a psychophysical technique used to reliably measure pain sensitivity and investigate pain modulatory mechanisms. The abuse liability of THC will be measured using an established drug reinforcement paradigm.

Official Title
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Pharmacokinetics and Pharmacodynamics of Oral and Vaporized Delta-9-Tetrahydrocannabinol (THC) in Older Adults

Conditions
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Pain, Tolerance, Oral vs Vaporized THC, Abuse Liability

Intervention / Treatment
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* Drug: Dronabinol 5 MG
* Drug: Dronabinol 10 MG
* Drug: 2mg Purified THC in an ethanolic solution
* Drug: 4mg Purified THC in an ethanolic solution
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and female participants aged 65 ≥ years old Prior exposure to THC or cannabis least once in the last 10 years; 1-10 times in the last 20 years; or more than 20 times in their lifetime Capable of providing informed consent in English. Exclusion Criteria: Meeting DSM-5 criteria for psychiatric/substance use disorders (SUD) other than tobacco use disorder, within the last year Current use of cannabinoid products, as evidenced by a urine drug screen Having a history of treatment for cannabis use disorder History of intent or current intent of abstaining from cannabis use Clinically significant medical disorders (e.g. liver/kidney dysfunction, immunosuppressing conditions, history or presence of epilepsy, seizures, head trauma with loss of consciousness) Medical conditions that increase the risk of respiratory problems (e.g. COPD, asthma, recuring bronchitis, reactive airway disorder)* (does not apply to the Oral THC Sub-Study) History of environmental sensitivities (e.g. bronchospastic allergies, multiple chemical sensitivities) or other airway sensitivities that require the use of an epi pen*(does not apply to the Oral THC Sub-Study) Neurological conditions that may change the response to nociceptive stimuli (e.g., stroke, neuropathy), or that lead to loss of balance, evidenced by a neuro-sensory exam Contraindications for exposure to nociceptive stimuli, such as untreated hypertension Current regular use of drugs known to affect pain, or that are prominent inducers or inhibitors of CYP2C9, CYP3A4, or UGTA19 (e.g., carbamazepine, valproate, fluvoxamine, and paroxetine) Major neurocognitive disorders precluding participation, evidenced by a clinical exam Abnormal EKG, arrythmia, vasospastic disease, chronic heart failure, or presence of a pacemaker Elevation of liver enzymes (ALT, AST) 2x the normal limit or higher Personal or family history of primary psychotic disorders, or mood disorders with psychotic features Current suicidal ideation Allergy or serious adverse reactions to sesame oil, THC, or cannabis Having received any drug as part of a research study within 30 days prior to receiving the study medication in the current study.

Ages Eligible for Study
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Minimum Age: 65 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: This is a double-blind, placebo-controlled, crossover study, randomizing 20 men and women aged 65 years or older to two doses of oral THC and vaporized THC. The research will commence with a sub-study focusing on oral THC administration, randomizing 10 men and women aged 65 years or older to two doses of oral THC.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dronabinol 5mg<br>Dronabinol 5 mg | Drug: Dronabinol 5 MG<br>* Dronabinol 5 mg<br>* Other names: Marinol;|
| Placebo Comparator: Dronabinol 10mg<br>Dronabinol 10 mg | Drug: Dronabinol 10 MG<br>* Dronabinol 10mg<br>* Other names: Marinol;|
| Active Comparator: Vaporized THC 2mg<br>Vaporized THC 2mg | Drug: 2mg Purified THC in an ethanolic solution<br>* 2mg Purified THC in an ethanolic solution<br>|
| Active Comparator: Vaporized THC 4mg<br>Vaporized THC 4 mg | Drug: 4mg Purified THC in an ethanolic solution<br>* 4mg Purified THC in an ethanolic solution<br>|
| Placebo Comparator: Placebo<br>Masked oral placebo or vaporized saline | Drug: Placebo<br>* Oral placebo and/or vaporized saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak concentration (Cmax) | Serial blood samples will be collected for plasma levels of THC; its phase I metabolite 11-hydroxy-THC (OH-THC); phase II metabolite 11-nor-9-carboxy-THC (THC-COOH); and THC-COOH glucuronide. For THC and all other analytes, the peak concentration (Cmax) will be derived using a linear noncompartmental analysis. | Up to 8 hours | 
| Time to attain Cmax concentration (Tmax) | Serial blood samples will be collected for plasma levels of THC; its phase I metabolite 11-hydroxy-THC (OH-THC); phase II metabolite 11-nor-9-carboxy-THC (THC-COOH); and THC-COOH glucuronide. For THC and all other analytes, the time to attain Cmax concentration (Tmax) will be derived using a linear noncompartmental analysis. | Up to 8 hours | 
| Area under the plasma concentration-time curve (AUC0-8h) | Serial blood samples will be collected for plasma levels of THC; its phase I metabolite 11-hydroxy-THC (OH-THC); phase II metabolite 11-nor-9-carboxy-THC (THC-COOH); and THC-COOH glucuronide. For THC and all other analytes, the area under the plasma concentration-time curve (AUC0-8h) will be derived using a linear noncompartmental analysis. | Up to 8 hours | 
| Nociception | Multimodal quantitative sensory testing (QST) will be used ensure that various types of afferent fibers are engaged, so that the analgesic efficacy of THC can be comprehensively investigated. A composite pain sensitivity measure as a Z-score (ranging from -1 to +1) will be derived from the QST battery, with greater scores indicating a higher sensitivity to pain. | Up to 8 hours | 
| Abuse Liability | A modified Multiple-Choice Procedure (MPC) will be used to measure abuse liability. The MCP was developed and validated by Roland Griffiths to efficiently assess drug reinforcement - including cannabinoid-induced reinforcement. In each of the 6 experimental sessions, participants will choose between forfeiting or receiving escalating sums of money, on a scale of values between -$20.00 and $20.00; or re-receiving the study medication assigned for that day. The primary outcome will be the crossover point, the value at which the participant chooses money rather than the study medication, which will be determined for each session. | Up to 8 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics THC, Pharmacodynamics THC