Cannabidiol for Reduction of Brain Neuroinflammation

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 atypical day. Pain needs to be present for at least 50% of days during a typicalweek;

5. On a stable pain treatment (pharmacological or otherwise) for the previous fourweeks;

6. Diagnosis of chronic low back pain, ongoing for at least 6 months prior toenrollment.

7. High or mixed affinity binding to [11C]PBR28 identified by the Ala147Thr TSPOpolymorphism in the TSPO gene (rs6971)

Exclusion Criteria:

1. Outpatient surgery within 2 weeks and inpatient surgery within 1 month of the timeof scanning (this timeframe may be extended if they are not fully recovered from thesurgery);

2. Elevated baseline transaminase (ALT and AST) levels above 3 times the Upper Limit ofNormal (ULN), accompanied by elevations in bilirubin above 2 times the ULN;

3. Any interventional pain procedures within 6 weeks prior to scanning procedure or atany point during study enrollment;

4. Surgical intervention or introduction/change in opioid regimen at any point duringstudy enrollment;

5. Contraindications to fMRI scanning and PET scanning (including presence of a cardiacpacemaker or pacemaker wires, metallic particles in the body, vascular clips in thehead 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 clearlyresolved without long-term consequences;

8. Current or past history of major psychiatric illness (PTSD, depression, and anxietyare exclusion criteria only if the conditions were so severe as to requirehospitalization 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 overthe-counter or dispensary CBD, for 2 weeks prior to starting the study medicationand during the 4 weeks of taking the study medication;

15. Use of immunosuppressive medications, such as prednisone, TNF medications within 2weeks 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 hepaticAEs;

19. Safety concerns related to use of any of the following medications will be discussedon 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, andverapamil;

• 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, andramosetron;

• Sensitive and moderately sensitive substrates of CYP2B6 including bupropion andefavirenz;

• 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 foralprazolam, clonazepam, and lorazepam, which have low binding affinity toTSPO44-48), and non-benzodiazepine sleep aids that have a known unsafe reaction withCBD;

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 studyand/or provide reliable data (e.g., unable to reliably rate pain; unlikely to remainstill during the imaging procedures, etc).