Cannabidiol, Morphine, Pain

Study Overview
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Brief Summary
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The purpose of the proposed study is to investigate the interaction of cannabidiol (CBD) and morphine effects on pain sensitivity. Cannabidiol is a cannabinoid (similar to cannabis, or marijuana) present in marijuana that alters some of the effects of marijuana.

Detailed Description
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Eligible participants will be asked to participate in a total of three experimental sessions with each session day separated by at least one week. Each session day will last approximately 6-7 hours. In the morning of each of the three study sessions, participants will be asked to complete baseline assessments which include self-report questionnaires (answering questions about how they feel), vital sign measurements (blood pressure, heart rate, oxygen saturation, temperature, and pupillometry) will be taken using a non-invasive (external) vitals monitor, and lastly thermal (heat and cold) and mechanical sensitivity testing will be done. Participants will be asked to take an oral morphine capsule. Participants will participate in 2 smoking sessions where they will be asked to smoke cigarettes or a vaporizer balloon containing either cannabidiol or a placebo (a blank). Participants will be asked to complete the same battery assessments mentioned above, which include self-report questionnaires (answering questions about how they feel); vital sign measurements (blood pressure, heart rate, oxygen saturation, temperature, and pupillometry) will be taken using a non-invasive (external) vitals monitor; and lastly thermal (heat and cold) and mechanical stimulation will be administered to test pain sensitivity. Participants will be asked to complete subjective questionnaires and have vital signs (blood pressure, heart rate, oxygen saturation, temperature, and pupillometry) measured multiple times throughout the visit; these measurements will be monitored for reasons such as safety. After completing the second round of smoking and battery assessments, participants will be provided with lunch and can relax, watch television, listen to music, or read. Once vital signs and questionnaire ratings have returned to baseline levels; participants can leave the laboratory.

Official Title
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Human Laboratory Model to Screen Drugs With Opioid Analgesic-sparing Effects: Cannabidiol/Morphine Combinations

Conditions
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CBD, Chronic Pain

Intervention / Treatment
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* Drug: Immediate-release Oral Morphine Sulfate Tablets
* Other: Thermal and Pressure Nociceptive Sensitivity


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must report having smoked a cigarette (nicotine or marijuana) AND having taken an opioid on 3 or more occasions in their lifetime. Participants must be in good health to participate; those with certain contraindications will be excluded. All participants will undergo psychiatric evaluation and will be asked to report their substance use history by interview and structured questionnaire methods. Participants will undergo medical evaluations using medical history, physical exam, standard lab tests (complete blood chemistry, urinalysis, urine pregnancy test for females), and 12-lead ECG. Exclusion Criteria: Serious psychiatric illness (e.g. psychotic or bipolar disorder, recent suicide attempts; severe depression) Substance Use Disorders other than Nicotine Use Disorder and Mild Cannabis Use Disorder Neurological diseases; cardiovascular problems (e.g. systolic BP >140 or <95 mmHg, diastolic BP >90 mmHg, abnormal ECG); pulmonary diseases; systemic diseases (e.g. liver, renal, inflammatory) Cognitive impairment (<80 IQ) Past-month medications that increase study risk Women who are pregnant (urine HCG), lactating (self-report), or if heterosexually active and not using (self-report) medically approved birth control (oral or depot contraception, IUD, condom/foam, sterilization, tubal ligation) Individuals unable to give informed consent will be excluded.

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Smoked cannabidiol 0%<br> | Drug: Immediate-release Oral Morphine Sulfate Tablets<br>* 0 mg Immediate release oral morphine; 15 mg Immediate release oral morphine; 30 mg Immediate release oral morphine; Randomized between sessions<br>Other: Thermal and Pressure Nociceptive Sensitivity<br>* Primary outcome measures of pain threshold and tolerance.<br>|
| Active Comparator: Smoked cannabidiol 9.7%<br> | Drug: Immediate-release Oral Morphine Sulfate Tablets<br>* 0 mg Immediate release oral morphine; 15 mg Immediate release oral morphine; 30 mg Immediate release oral morphine; Randomized between sessions<br>Other: Thermal and Pressure Nociceptive Sensitivity<br>* Primary outcome measures of pain threshold and tolerance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CHANGE. PAIN THRESHOLD AND TOLERANCE Pain responses to a range of heat, cold and mechanical pressure stimuli | Change in pain threshold and tolerance is being assessed post each CBD drug use (0%and 9.7%) using Q-Sense Conditioned Pain Modulation™. A randomized series of 7 heat stimuli and 7 cold stimuli will be delivered via a thermode attached to the lower nondominant arm. A series of 7 pressure stimuli will be delivered with a pressure algometer to the opposite arm. | Pain responses measured at the start of the visit, baseline; 15 minutes post CBD 0% drug; 15 minutes post CBD 9.7% drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SAFETY Systolic blood pressure (physiological effects) | Safety is being assessed. | Systolic blood pressure measured at baseline; 15 and 30 minutes post-morphine; 15 minutes post CBD 0% drug; 15, 65, and 90 minutes post 9.7% CBD drug (final drug). | 
| SAFETY Diastolic blood pressure (physiological effects) | Safety is being assessed. | Diastolic blood pressure measured at baseline; 15 and 30 minutes post-morphine; 15 minutes post CBD 0% drug; 15, 65, and 90 minutes post 9.7% CBD drug (final drug). | 
| SAFETY Heart rate | Safety is being assessed. | Heart Rate measured at baseline; 15 and 30 minutes post-morphine; 15 minutes post CBD 0% drug; 15, 65, and 90 minutes post 9.7% CBD drug (final drug). | 
| SAFETY Respiratory rate | Safety is being assessed. | Respiratory rate measured at baseline; 15 and 30 minutes post-morphine; 15 minutes post CBD 0% drug; 15, 65, and 90 minutes post 9.7% CBD drug (final drug). | 
| SAFETY Oxygen saturation | Safety is being assessed. | Oxygen Saturation measured at baseline; 15 and 30 minutes post-morphine; 15 minutes post CBD 0% drug; 15, 65, and 90 minutes post 9.7% CBD drug (final drug). | 
| INDICES OF ABUSE LIABILITY Drug Liking | Indices of abuse liability is being assessed. Visual Analog Scales (0=not at all and 100= extremely): good drug effect, bad drug effect, strength of drug effect, liking, sedated, high and desire to take again. | Drug Liking measured at baseline; 15 and 30 minutes post-morphine; 15 minutes post CBD 0% drug; 15, 65, and 90 minutes post 9.7% CBD drug (final drug). | 
| INDICES OF ABUSE LIABILITY Economic demand (drug purchase task (DPT) | Indices of abuse liability is being assessed. Participants will be asked to make drug purchases based on how they feel at the moment (each DPT assessment is independent from the last CBD cumulative dose received). They will be informed that the amount purchased at each drug unit price (independent observations) must be consumed within 24-hr (i.e., participants cannot save or stockpile drug). Unit prices (UPs) per drug dose will be: $0 (free; no constraint) and $0.01, $0.10, $0.50, $1, $3, $5, $7.50, $10, $12.50, $15, $20, $25, $30, $35, $40, $45, $50, $60, $80 and $100. | Economic demand will be measured at 40 minutes post CBD 0% drug using (1040); 40 minutes post CBD 3.4% drug using (1130); 40 minutes post CBD 12.7% drug using (1210) | 
| SAFETY Pupillometry Measurement | Safety is being assessed. | Pupillometry Measured at baseline; 15 and 30 minutes post-morphine; 15 minutes post CBD 0% drug; 15, 65, and 90 minutes post 9.7% CBD drug (final drug). |