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

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

The overarching goal of this double-blind, placebo-controlled, crossover study is 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. This protocol includes two sub-studies, each randomizing 20 men and women aged 65 years or older to receive two administration routes of THC; oral administration and vaporized administration.

Study Overview

• Status: Recruiting
• Conditions: Pain, Tolerance; Oral vs Vaporized THC; Abuse Liability
• Intervention / Treatment: 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

Detailed Description

This is a double-blind, placebo-controlled, crossover study, with two sub-studies each focusing on different routes of THC administration.

Oral THC Sub-Study: 20 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.

Vaporized THC Sub-Study: 20 men and women aged 65 years or older will be randomized to two doses of vaporized THC (2 mg and 4 mg). Across three 8-hour test sessions, participants will receive a random sequence of 3 conditions: 2 mg vaporized THC; 4 mg vaporized THC; and vaporized placebo.

For both the Oral and Vaporized THC Sub-Studies, 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. General adverse, cardiovascular, and cognitive/psychomotor effects of THC will be thoroughly assessed with behavioral, physiological, and neuropsychological methods.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Julia Meyerovich, M.S.; Phone Number: 203-623-7493; Email: julia.meyerovich@yale.edu

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • Recruiting
      • VA Connecticut Healthcare System
      • Principal Investigator: Joao P. De Aquino, M.D.
      • Contact: Julia Meyerovich; Phone Number: 14805 203-932-5711; Email: julia.meyerovich@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Healthy male and female participants aged 65 ≥ years old
2. 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
3. Capable of providing informed consent in English.

Exclusion Criteria:

1. Meeting DSM-5 criteria for psychiatric/substance use disorders (SUD) other than tobacco use disorder, within the last year
2. Current use of cannabinoid products, as evidenced by a urine drug screen
3. Having a history of treatment for cannabis use disorder
4. History of intent or current intent of abstaining from cannabis use
5. Clinically significant medical disorders (e.g. liver/kidney dysfunction, immunosuppressing conditions, history or presence of epilepsy, seizures, head trauma with loss of consciousness)
6. 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)
7. 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)
8. 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
9. Contraindications for exposure to nociceptive stimuli, such as untreated hypertension
10. 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)
11. Major neurocognitive disorders precluding participation, evidenced by a clinical exam
12. Abnormal EKG, arrythmia, vasospastic disease, chronic heart failure, or presence of a pacemaker
13. Elevation of liver enzymes (ALT, AST) 2x the normal limit or higher
14. Personal or family history of primary psychotic disorders, or mood disorders with psychotic features
15. Current suicidal ideation
16. Allergy or serious adverse reactions to sesame oil, THC, or cannabis
17. Having received any drug as part of a research study within 30 days prior to receiving the study medication in the current study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Drug Abuse (NIDA); VA Connecticut Healthcare System
• Investigators: Principal Investigator: Joao P. De Aquino, M.D., Yale University

Publications and helpful links

General Publications

• Griffiths RR, Troisi JR, Silverman K, Mumford GK. Multiple-choice procedure: an efficient approach for investigating drug reinforcement in humans. Behav Pharmacol. 1993 Feb;4(1):3-13.
• Kaskie B, Ayyagari P, Milavetz G, Shane D, Arora K. The Increasing Use of Cannabis Among Older Americans: A Public Health Crisis or Viable Policy Alternative? Gerontologist. 2017 Nov 10;57(6):1166-1172. doi: 10.1093/geront/gnw166.
• Solomon HV, Greenstein AP, DeLisi LE. Cannabis Use in Older Adults: A Perspective. Harv Rev Psychiatry. 2021 May-Jun 01;29(3):225-233. doi: 10.1097/HRP.0000000000000289.
• Mahvan TD, Hilaire ML, Mann A, Brown A, Linn B, Gardner T, Lai B. Marijuana Use in the Elderly: Implications and Considerations. Consult Pharm. 2017 Jun 1;32(6):341-351. doi: 10.4140/TCP.n.2017.341.
• Gagliese L. What do experimental pain models tell us about aging and clinical pain? Pain Med. 2007 Sep;8(6):475-7. doi: 10.1111/j.1526-4637.2007.00360.x. No abstract available.
• Moore AR, Clinch D. Underlying mechanisms of impaired visceral pain perception in older people. J Am Geriatr Soc. 2004 Jan;52(1):132-6. doi: 10.1111/j.1532-5415.2004.52023.x.
• Lautenbacher S, Kunz M, Strate P, Nielsen J, Arendt-Nielsen L. Age effects on pain thresholds, temporal summation and spatial summation of heat and pressure pain. Pain. 2005 Jun;115(3):410-418. doi: 10.1016/j.pain.2005.03.025.
• Backonja MM, Attal N, Baron R, Bouhassira D, Drangholt M, Dyck PJ, Edwards RR, Freeman R, Gracely R, Haanpaa MH, Hansson P, Hatem SM, Krumova EK, Jensen TS, Maier C, Mick G, Rice AS, Rolke R, Treede RD, Serra J, Toelle T, Tugnoli V, Walk D, Walalce MS, Ware M, Yarnitsky D, Ziegler D. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain. 2013 Sep;154(9):1807-1819. doi: 10.1016/j.pain.2013.05.047. Epub 2013 Jun 3.

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: May 25, 2023
• First Submitted That Met QC Criteria: June 15, 2023
• First Posted (Actual): June 18, 2023

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 19, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Pharmacokinetics THC; Pharmacodynamics THC
• Additional Relevant MeSH Terms: Neurologic Manifestations; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Organic Chemicals; Hydrocarbons; Terpenes; Cannabinoids; Dronabinol
• Other Study ID Numbers: 2000035354; 1R21DA057240-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No