Cannabidiol for Reduction of Brain Neuroinflammation

Study Overview
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Brief Summary
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This study will investigate whether cannabidiol (CBD), the primary centrally and peripherally active non-intoxicating compound in the cannabis plant, exerts anti-neuroinflammatory effects in patients with chronic low back pain (cLBP) with or without mild-to-moderate depression.

Detailed Description
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This is a randomized, double-blind, 2-arm mechanistic trial that seeks to assess the effects of CBD and placebo in patients with cLBP with and without mild-to-moderate depression, using integrated positron emission tomography / magnetic resonance imaging (PET/MRI) scans. The use of integrated PET/MRI will make it possible to simultaneously evaluate neuroinflammation (using [11C]PBR28, a second-generation radioligand for TSPO) and striatal function (using the Monetary Incentive Delay task, a validated fMRI task that probes behavioral and neural responses to rewards and losses).

Official Title
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Evaluation of Cannabidiol for Reduction of Brain Neuroinflammation

Conditions
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Back Pain, Depressive Symptoms

Intervention / Treatment
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* Drug: CBD
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and ≤ 75; The ability to give written, informed consent; Fluency in English; Average worst daily pain of at least 4 on a 0 - 10 scale of pain intensity during a typical day. Pain needs to be present for at least 50% of days during a typical week; On a stable pain treatment (pharmacological or otherwise) for the previous four weeks; Diagnosis of chronic low back pain, ongoing for at least 6 months prior to enrollment. High or mixed affinity binding, as identified by rs6971 polymorphism Exclusion Criteria: Outpatient surgery within 2 weeks and inpatient surgery within 1 month of the time of scanning (this timeframe may be extended if they are not fully recovered from the surgery); Elevated baseline transaminase (ALT and AST) levels above 3 times the Upper Limit of Normal (ULN), accompanied by elevations in bilirubin above 2 times the ULN; Any interventional pain procedures within 6 weeks prior to scanning procedure or at any point during study enrollment; Surgical intervention or introduction/change in opioid regimen at any point during study enrollment; Contraindications to fMRI scanning and PET scanning (including presence of a cardiac pacemaker or pacemaker wires, metallic particles in the body, vascular clips in the head or previous neurosurgery, prosthetic heart valves, claustrophobia); Implanted spinal cord stimulator (SCS) for pain treatment; Any history of neurological illness or major medical illness, unless clearly resolved without long-term consequences; Current or past history of major psychiatric illness (PTSD, depression, and anxiety are exclusion criteria only if the conditions were so severe as to require hospitalization in the past year); Harmful alcohol drinking as indicated by an AUDIT score ≥ 16; Pregnancy or breast feeding; History of head trauma requiring hospitalization; Major cardiac event within the past 10 years; Regular use of recreational drugs in the past 3 months; Any marijuana use, medical or recreational, in the past 2 weeks; Use of immunosuppressive medications, such as prednisone, TNF medications within 2 weeks of the visit; Current bacterial or viral infection likely affecting the central nervous system; Epilepsy or any prescription of an anti-epileptic drug; Use of the medications valproate and clobazam, which may increase risk of hepatic AEs; Safety concerns related to use of any of the following medications will be discussed on an individualized basis with a physician: Strong and moderate CYP3A4 inhibitors including boceprevir, cobicistat, conivaptan, danoprevir, elvitegravir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, paritaprevir and ombitasvir and/or dasabuvir, posaconazole, saquinavir and telaprevir, tipranavir, clarithromycin, diltiazem, idelalisib, nefazodone, nelfinavir, troleandomycin, voriconazole, aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, disulfiram, and verapamil; Strong and moderate inhibitors of CYP2C19 including fluoxetine and ticlopidine; Sensitive and moderately sensitive substrates of CYP2C19 including clobazam, lansoprazole, omeprazole, S-mephenytoin, and rabeprazole; Sensitive and moderately sensitive substrates of CYP1A2 including alosetron, duloxetine, melatonin, ramelteon, tasimelteon, theophylline, tizanidine, pirfenidone, and ramosetron; Sensitive and moderately sensitive substrates of CYP2B6 including bupropion and efavirenz; Sensitive and moderately sensitive substrates of CYP2C8 including repaglinide, montelukast, pioglitazone, and rosiglitazone; Sensitive and moderately sensitive substrates of CYP2C9 including tolbutamide, celecoxib, glimepiride, and warfarin; Sensitive and moderately sensitive substrates of UGT1A9 including diflunisal, propofol, and fenofibrate; Sensitive and moderately sensitive substrates of UGT2B7 including, gemfibrozil, lamotrigine, and morphine; The following CNS depressants including all antipsychotics, benzodiazepines (except for alprazolam, clonazepam, and lorazepam, which have low binding affinity to TSPO), and non-benzodiazepine sleep aids that have a known reaction with CBD; Use of opioids ≥ 30 mg morphine equivalents on average per month; Actively suicidal, history of suicide attempt or an aborted attempt within the last 5 years, or engagement in non-suicidal self-injurious behavior within the last year; Allergy to sesame oil, and any other ingredients of EPIDIOLEX; Any other contraindications to CBD administration noted by the study physician; Any significant change in drug use and pain treatment from screening visit; In the opinion of the investigators, unable to safely participate in this study and/or provide reliable data (e.g., unable to reliably rate pain; unlikely to remain still during the imaging procedures, etc).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cannabidiol (CBD)<br>The recommended starting dosage is 2.5mg/kg taken twice daily. The titration schedule recommended in the EPIDIOLEX label will be followed, with 2.5 mg/kg twice daily in week 1, 5 mg/kg twice daily in week 2, 7.5 mg/kg twice daily in week 3, and 10 mg/kg twice daily in week 4 with the second PET scan conducted after one week at the maximum labeled dose. Any participant not tolerating a given dose can either go back down to the next lowest dose or delay uptitration at any week in the protocol. Participants will be instructed to take Epidiolex with a meal rather than in a fasted state. Participants will be treated for 4 weeks in total. | Drug: CBD<br>* Epidiolex, an agent within the anti-epileptic drug class, will be used. Epidiolex, Greenwich Biosciences Inc.'s CBD formulation, is a 100 mg/mL purified oral solution, dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring. The drug is formulated from extracts prepared from Cannabis sativa L. plants that have a defined chemical profile and contain consistent levels of CBD as the principal phytocannabinoid. Extracts from these plants are processed to yield pure (>95%) CBD that typically contains less than 0.5% (w/w) THC. Cannabidiol is the active ingredient in Epidiolex; inactive ingredients include dehydrated alcohol, sesame seed oil, strawberry flavor, and sucralose. Of note, CBD has no psychoactive properties.<br>* Other names: Epidiolex;|
| Placebo Comparator: Placebo<br>The placebo will be taken at identical doses to the active drug condition. | Other: Placebo<br>* Placebo CBD will be identical to the active CBD, a 100 mg/mL purified oral solution, dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring, but with no CBD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Neuroinflammation in the Thalamus | The investigators will test for the presence of a significant treatment effect in the brain [11C]PBR28 signal in the thalamus, in order to test whether patients in the CBD arm will demonstrate significantly larger treatment-related reductions in neuroinflammation, compared to patients in the placebo arm. | Change from Baseline to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Neuroinflammation in Limbic Regions | The investigators will test for the presence of a significant treatment effect in the brain [11C]PBR28 in limbic regions (pgACC, aMCC), in order to test whether patients in the CBD arm will demonstrate significantly larger treatment-related reductions in neuroinflammation, compared to patients in the placebo arm. | Change from Baseline to Week 4 | 
| Correlation Between Reductions in Thalamic [11C]PBR28 PET Signal and Reductions in Clinical Pain Ratings | The investigators will test whether reductions in thalamic [11C]PBR28 PET signal correlate with reductions in clinical pain ratings, as assessed by the worst pain item of the Brief Pain Inventory - Short Form. The worst pain item's scale ranges from 0 - 10, with a higher score indicating worse pain intensity. | Change from Baseline to Week 4 | 
| Correlation Between Reductions in Limbic [11C]PBR28 PET Signal and Reductions in Depressive Symptoms | The investigators will test whether reductions in pgACC/aMCC [11C]PBR28 PET signal (as measured by Standardized Uptake Value Ratio) correlate with reductions in depressive symptoms, as measured by the Beck Depression Inventory-II. The Beck Depression Inventory-II scale ranges from 0 - 63, with a higher score indicating greater depression. | Change from Baseline to Week 4 | 
| Change in Clinical Pain Ratings | The worst pain item of the Brief Pain Inventory - Short Form will be used daily to assess pain intensity. The scale ranges from 0 - 10, with a higher score indicating worse pain intensity. | Change from average score during the 7 days prior to treatment (Baseline) to average score during the final week of treatment | 
| Change in Pain Bothersomeness | Pain bothersomeness will be assessed daily on a scale from 0 - 10, with a higher score indicating greater bothersomeness. | Change from average score during the 7 days prior to treatment (Baseline) to average score during the final week of treatment | 
| Change in Depressive Symptoms | The Beck Depression Inventory-II will be used to assess symptoms of depression. The scale ranges from 0 - 63, with a higher score indicating greater depression. | Change from Baseline to Week 4 | 
| Patient Global Impression of Change | The Patient Global Impression of Change scale will be used to assess participants' perceptions about their global improvement related to their low back pain. The scale ranges from 0 - 7, with a higher score indicating greater overall improvement. | Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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back pain, depression, depressive symptoms, cannabis, cannabidiol