Safety and Effects on Responses to Stress and Pain of Natural Medical Marijuana Products

Safety of Acute and Repeated Doses of Natural Medical Marijuana Products and Effects on Subjective and Physiological Responses to Stress and Pain

This proposal aims to systematically examine the safety and pharmacokinetic/pharmacodynamic profile and the physiologic, neuroendocrine and behavioral stress and pain responses to acute single doses and repeated dosing of oral tablet formulation of natural Cannabidiol (CBD) alone and in combination with Tetrahydrocannabinol and matched Placebo (PLA).

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Drug: Active CBD/THC Dose 1; Drug: matched placebo comparator; Drug: Active CBD/THC Dose 2

Detailed Description

This proposal aims to systematically examine the safety and pharmacokinetic/pharmacodynamic (PK/PD) profile and the physiologic, neuroendocrine and behavioral stress and pain responses to acute single doses and repeated dosing of oral tablet formulation of natural Cannabidiol (CBD) at 40 mg and 100 mg alone and in combination with Tetrahydrocannabinol (THC) at 10, 20 and 30 mg, and matched Placebo (PLA) under the following specific aims:

Aim 1: To assess the safety and PK/PD profile of acute single doses of natural oral tablet of CBD (40 mg, 100 mg), and the CBD/THC combination (40/10, 40/20 and 100/30 mg) and matching placebo (PLA) over six separate sessions one week apart in healthy adult men and women who are current recreational cannabis users (STUDY 1).

Aim 2: To examine the effects of separate CBD, THC, CBD/THC combination vs. PLA on subjective, physiological, neuroendocrine, cognitive and behavioral measures of stress, pain and anxiety at baseline and under acute pain provocation using an adapted Cold Pressor Test (CPT) in STUDY 1.

Aim 3: To examine the safety and tolerability of the two specific doses of CBD/THC, selected on the basis of best PK/PD and tolerability profile from Study 1 vs. PLA on baseline and CPT provoked pain in individuals with chronic pain over a 7-day repeated dosing (STUDY 2).

Study 1:

Eight 21-45-year-old men and women , who are recreational marijuana users but do not meet criteria for moderate-severe cannabis use disorder will be recruited to complete six separate inpatient laboratory sessions one week apart during which they will be assigned to receive an acute dose of either 40 mg CBD or 100 mg CBD alone, a CBD/THC combination of 40/10, 40/20 or 100/30 or PLA, in a random, counter-balanced, double-blind, cross-over design over a 6-week period. Sessions will be completed one -week apart to allow for an adequate washout period between sessions.

Study 2:

Adult men and women ages 21-60 (N=24) with chronic pain (not fully controlled by opioid pain medication), will be recruited and randomly assigned to receive the two most tolerable CBD/THC doses (two active doses of n=8 in each) or PLA (n=8) repeated dosing for 7 days. On day 1 and day 6/7 of the 7-day dosing, subjects will complete laboratory sessions. For 14 days after the 7-day dosing, subjects will complete daily ratings of pain and other patient-related outcomes. Subjects cannot meet criteria for moderate to severe levels of cannabis use disorder or other substance use disorders.

This registration will focus on Study 2.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • The Yale Stress Center: Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Able to read and write English;
2. Recreational cannabis use with a minimum history recent use of at least one joint of smoked marijuana or marijuana edible or other equivalent form;
3. Current chronic pain, as defined by the International Classification of Diseases (ICD)-10, and stabilized for a minimum of 2 weeks on pain medication, (minimum pain ratings of 4 on a 10-point scale) and agree to not change pain medication during course of the study;
4. Body Mass Index (BMI) in the 18-36 range;

Exclusion Criteria:

1. Any psychotic disorder or current psychiatric symptoms requiring specific attention, including active symptoms of psychosis or suicidal/homicidal ideation.
2. Any Current moderate/severe Substance Use Disorder, including alcohol and cannabis.
3. Women who are nursing or have premenstrual dysphoric disorder;
4. Women who are pregnant as determined by the urine pregnancy test at each assessment period;
5. Inability to give informed consent;
6. Traumatic brain injury or loss of consciousness;
7. Individuals with current or past history of seizure disorders;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Dose 1; Participants will receive the most tolerable CBD/THC dose with repeated dosing for 7 days. On day 1 and 6/7 of the 7-day dosing, subjects will complete laboratory sessions.	Drug: Active CBD/THC Dose 1; Subjects will self-administer the assigned study medication daily at home after pickup and will be tested using medication compliance procedures. Subjects will visit the center 2 times in the 7-day period on days 1 and 7 for blood draws to assess medication compliance.; Other Names: Medical marijuana medicine
Placebo Comparator: Matching Placebo; Participants will receive a placebo with repeated dosing for 7 days. On day 1 and 6/7 of the 7-day dosing, subjects will complete laboratory sessions.	Drug: matched placebo comparator; Subjects will self-administer the assigned study medication daily at home after pickup and will be tested using medication compliance procedures. Subjects will visit the center 2 times in the 7-day period on days 1 and 7 for blood draws to assess medication compliance.; Other Names: Placebo
Experimental: Active Dose 2; Participants will receive the second most tolerable CBD/THC dose with repeated dosing for 7 days. On day 1 and 6/7 of the 7-day dosing, subjects will complete laboratory sessions	Drug: Active CBD/THC Dose 2; Subjects will self-administer the assigned study medication daily at home after pickup and will be tested using medication compliance procedures. Subjects will visit the center 2 times in the 7-day period on days 1 and 7 for blood draws to assess medication compliance.; Other Names: Medical marijuana medicine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Ratings	Change in provoked pain ratings on day 1 and day 7 on visual analog scale of pain (range 0-10)	Day 1 and 7 provocation during 7-day treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anxiety Ratings	Change in provoked anxiety ratings on day 1 and day 7 on visual analog scale of anxiety (range 0-10)	Day 1 and 7 provocation during 7-day treatment period

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Intensity Ratings	Pain intensity ratings from Brief Pain Inventory (intensity range: 0-10)	Baseline, 7-day treatment period and during 2 week follow-up
Sleep disturbance Ratings	Sleep disturbance T score from PROMIS29 sleep questions (standardized T score distribution)	Baseline, 7-day treatment period and during 2 week follow-up

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Connecticut Pharmaceutical Solutions

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2022
• Primary Completion (Actual): December 15, 2023
• Study Completion (Actual): December 15, 2023

Study Registration Dates

• First Submitted: January 9, 2020
• First Submitted That Met QC Criteria: January 9, 2020
• First Posted (Actual): January 13, 2020

Study Record Updates

• Last Update Posted (Actual): July 19, 2024
• Last Update Submitted That Met QC Criteria: July 17, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Marijuana Abuse; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Psychotropic Drugs; Hallucinogens; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; Dronabinol
• Other Study ID Numbers: 2000020896; No NIH funding (Other Identifier: 11.09.23)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No