cannabidiol for reduction of brain neuroinflammation

Conditions: Back Pain; Depressive Symptoms

Summary: 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.

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).

Eligibility criteria:
inclusion criteria: 1. age ≥ 18 and ≤ 75; 2. the ability to give written, informed consent; 3. fluency in english; 4. 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; 5. on a stable pain treatment (pharmacological or otherwise) for the previous four weeks; 6. diagnosis of chronic low back pain, ongoing for at least 6 months prior to enrollment. 7. high or mixed affinity binding to \[11c\]pbr28 identified by the ala147thr tspo polymorphism in the tspo gene (rs6971) exclusion criteria: 1. 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); 2. 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; 3. any interventional pain procedures within 6 weeks prior to scanning procedure or at any point during study enrollment; 4. surgical intervention or introduction/change in opioid regimen at any point during study enrollment; 5. 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); 6. implanted spinal cord stimulator (scs) for pain treatment; 7. any history of neurological illness or major medical illness, unless clearly resolved without long-term consequences; 8. 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); 9. harmful alcohol drinking as indicated by an audit score ≥ 16; 10. pregnancy or breast feeding; 11. history of head trauma requiring hospitalization; 12. major cardiac event within the past 10 years; 13. regular use of recreational drugs in the past 3 months; 14. use of cannabis-containing products, such as products containing thc or over the-counter or dispensary cbd, for 2 weeks prior to starting the study medication and during the 4 weeks of taking the study medication; 15. use of immunosuppressive medications, such as prednisone, tnf medications within 2 weeks of the visit; 16. current bacterial or viral infection likely affecting the central nervous system; 17. epilepsy; 18. use of the medications valproate and clobazam, which may increase risk of hepatic aes; 19. 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, 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; 20. cns depressants including all antipsychotics, benzodiazepines (except for alprazolam, clonazepam, and lorazepam, which have low binding affinity to tspo44-48), and non-benzodiazepine sleep aids that have a known unsafe reaction with cbd; 21. use of opioids ≥ 30 mg morphine equivalents on average per month; 22. 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; 23. allergy to sesame oil, and any other ingredients of epidiolex; 24. any other contraindications to cbd administration noted by the study physician; 25. any significant change in drug use and pain treatment from screening visit; 26. 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).

Keywords: back pain depression depressive symptoms cannabis cannabidiol