Cannabidiol for Reduction of Brain Neuroinflammation

Phase 2

Recruiting

• Conditions: Depressive Symptoms; Back Pain
• Interventions: Other: Placebo; Drug: CBD

• Registration Number: NCT05066308
• Lead Sponsor: Massachusetts General Hospital

Brief 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.

Detailed Description

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).

Study Timeline

• Study First Submitted: 2021-09-23
• Study First Submitted QC: 2021-09-23
• Study First Posted: 2021-10-04
• Study Start: 2022-01-04
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-28
• Last Update Posted: 2025-03-30
• Primary Completion: 2026-09-01
• Study Completion: 2026-12-15

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 80

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	The placebo will be taken at identical doses to the active drug condition.
Cannabidiol (CBD)	CBD	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.

Primary Outcome Measures

Name	Time	Method
Changes in Neuroinflammation in the Thalamus	Change from Baseline to Week 4	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.

Secondary Outcome Measures

Name	Time	Method
Correlation Between Reductions in Thalamic [11C]PBR28 PET Signal and Reductions in Clinical Pain Ratings	Change from Baseline to Week 4	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.
Changes in Neuroinflammation in Limbic Regions	Change from Baseline to Week 4	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 in Clinical Pain Ratings	Change from average score during the 7 days prior to treatment (Baseline) to average score during the final week of treatment	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 in Pain Bothersomeness	Change from average score during the 7 days prior to treatment (Baseline) to average score during the final week of treatment	Pain bothersomeness will be assessed daily on a scale from 0 - 10, with a higher score indicating greater bothersomeness.
Correlation Between Reductions in Limbic [11C]PBR28 PET Signal and Reductions in Depressive Symptoms	Change from Baseline to Week 4	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 in Depressive Symptoms	Change from Baseline to Week 4	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.
Patient Global Impression of Change	Week 4	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.

Trial Locations

Locations (1)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States