Cannabidiol for Reduction of Brain Neuroinflammation

Depressive Symptoms Clinical Trial

— CBD  

Official title:

Evaluation of Cannabidiol for Reduction of Brain Neuroinflammation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05066308
• Other study ID #: 2021P002617
• Status: Recruiting
• Phase: Phase 2
• Start date: January 4, 2022
• Est. completion date: December 15, 2026

Study information

• Verified date: February 2024
• Source: Massachusetts General Hospital
• Contact: Jodi M Gilman, PhD
• Phone: 617-643-7293
• Email: jgilman1[@]mgh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: December 15, 2026
• Est. primary completion date: September 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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).

Related Conditions & MeSH terms

• Back Pain
• Depression
• Depressive Symptoms

Intervention

Drug:
• CBD
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.

Other:
• Placebo
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.

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Functional Brain Reward Circuitry [Exploratory]	The Monetary Incentive Delay task will be used to assess striatal response to the anticipation and/or consumption of rewards/losses.	Change from Baseline to Week 4
Other	Change in Pain Severity & Interference with Daily Functioning [Exploratory]	The full Brief Pain Inventory - Short Form will be used to assess pain severity and its interference with daily functioning. Pain severity is assessed on a scale from 0 - 10, with a higher score indicating more severe pain. Daily functioning is also assessed on a scale from 0 - 10, with a higher score indicating that pain more greatly interferes with functioning.	Change from Baseline to Week 4
Other	Change in Pain Catastrophizing [Exploratory]	The Pain Catastrophizing Scale will be used to assess pain catastrophizing. The scale ranges from 0 - 52, with a higher score indicating greater catastrophic thinking.	Change from Baseline to Week 4
Other	Change in Neuropathic Pain Components [Exploratory]	The PainDETECT questionnaire will be used to assess neuropathic components of pain. The scale ranges from -1 to 38, with a higher score indicating more neuropathic-like symptoms.	Change from Baseline to Week 4
Other	Change in Disability Related to Low Back Pain [Exploratory]	The Oswestry Disability Index will be used to assess disability related to low back pain. The scale ranges from 0 - 50, with a higher score indicating greater disability.	Change from Baseline to Week 4
Other	Change in Widespread Pain and Fibromyalgia Symptom Severity [Exploratory]	The American College of Rheumatology's fibromyalgia survey will be used to assess widespread pain and fibromyalgia symptom severity. The widespread pain subscale ranges from 0 - 19, with a higher score indicating more widespread pain. The fibromyalgia symptom severity subscale ranges from 0 - 12, with a higher score indicating more severe symptoms.	Change from Baseline to Week 4
Other	Change in Depression [Exploratory]	In addition to the secondary outcome which uses the BDI-II to assess change in depression, depression will also be assessed daily on a scale from 0 - 10, with a higher score indicating greater depression.	Change from average score of the 7 days prior to initiation of treatment to average score of the 7 days of Week 4
Other	Change in Health-Related Quality of Life [Exploratory]	The Patient-Reported Outcomes Measurement Information System(PROMIS)-29 will be used to assess health-related quality of life, including physical, mental, and social health. The scale uses a t-score metric. For positively worded measures, a higher t-score indicates greater health within that domain; for negatively worded measures, a higher t-score indicates poorer health within that domain.	Change from Baseline to Week 4
Other	Change in Sleep Quality [Exploratory]	The Pittsburgh Sleep Quality Index will be used to assess sleep quality. The scale ranges from 0 - 21, with a higher score indicating less healthy sleep quality.	Change from Baseline to Week 4
Other	Change in Widespreadness of Pain Sensation [Exploratory]	The SymptomMapper app, a digital tablet-based application where patients can mark where on the body they are experiencing pain, will be used to assess widespreadness of pain sensation.	Change from Baseline to Week 4
Other	Change in Spinal Cord TSPO Signal [Exploratory]	The investigators will test whether reductions in spinal cord [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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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