Cannabis Derivatives for Diabetic Neuropathy

Recruiting at3 trial locations

Overseen by Donald McGeary, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: VA Office of Research and Development

Must not be taking: Cannabis, Opioids

Disqualifiers: Cannabis use disorder, Psychiatric disorders, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests if cannabis derivatives (THC, CBD, and their combination) can reduce chronic diabetic nerve pain in Veterans. Veterans often don't get enough relief from standard treatments, so this study aims to find out if cannabis can help. The trial will test if these cannabis compounds are effective. Cannabis has been studied for its potential to alleviate pain in various conditions, including diabetic neuropathy, but its long-term safety and efficacy remain uncertain.

Do I have to stop taking my current medications for the trial?

The trial requires that you do not change your current pain medications by more than 20% from 4 weeks before the screening until the study ends. So, you can continue your current medications as long as they remain stable.

What data supports the effectiveness of the drug for diabetic neuropathy?

Research shows that a cannabis-based drug called Sativex, which contains THC and CBD, has been effective in reducing pain in people with diabetic neuropathy. In a study, patients using this drug reported a significant decrease in pain levels over time, and it was well tolerated with no major safety concerns. ^{1 2 3 4 5}

Is the cannabis-based treatment Sativex safe for humans?

Sativex, a cannabis-based spray containing THC and CBD, has been studied for multiple sclerosis symptoms and is generally well-tolerated with mild to moderate side effects like dizziness and sleepiness. Long-term safety and potential for dependence are not fully known. ^{1 6 7 8 9}

How does this drug differ from other treatments for diabetic neuropathy?

This drug is unique because it combines THC and CBD in an oromucosal spray, which is absorbed through the mouth, offering a novel way to manage pain associated with diabetic neuropathy. Unlike traditional treatments, it targets the endocannabinoid system, which may provide relief for patients who have not responded well to other pain medications. ^{1 2 4 5 10}

Research Team

Deepak D'Souza, MD MBBS

Principal Investigator

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Donald McGeary, PhD

Principal Investigator

South Texas Health Care System, San Antonio, TX

Eligibility Criteria

This trial is for Veterans aged 21+ with diabetic neuropathic pain who can consent to participate. They must have allodynia, meet NEURODIAB criteria for painful diabetic peripheral neuropathy, and experience persistent high-impact pain. Excluded are federal employees, those needing psychiatric hospitalization, pregnant or breastfeeding women, individuals using cannabis products or with a recent history of Cannabis Use Disorder.

Inclusion Criteria

You experience pain when touched lightly with a brush during a screening test.

I experience constant, severe pain.

Able to provide written consent

Exclusion Criteria

You need to be hospitalized for psychiatric reasons right away.

You have been diagnosed with Cannabis Use Disorder in the past 6 months according to DSM-5.

Unwilling to refrain from using cannabis or cannabis-based products through the entire duration of the study

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cannabis derivatives (THC, CBD, or THC+CBD) or placebo to assess efficacy in reducing neuropathic pain

8 weeks

Weekly visits (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CBD (Epidolex) (Cannabinoid)
• Placebo (Other)
• THC + CBD (Nabiximols) (Cannabinoid)
• THC (Dronabinol) (Cannabinoid)

Trial Overview The study tests the effects of THC (Dronabinol), CBD (Epidolex), their combination (Nabiximols), and placebo on chronic diabetic neuropathic pain in Veterans. It's a phase II trial with four groups randomly assigned in a double-blind manner to determine potential benefits and adverse effects.

Participant Groups

Group I: THC (Syndros) Active Control 2 Interventions

Target dose of 10mg per day.

Group II: CBD (Epidolex) Active Control 2 Interventions

Target dose of 800 mg per day.

Group III: THC + CBD (Nabiximols) Active Control 2 Interventions

Target dose of 10.8 mg / 10 mg per day.

Group IV: Placebo Placebo Group 1 Intervention

Identical in appearance to the three active comparators.

CBD (Epidolex) is already approved in Canada for the following indications:

Approved in Canada as Epidiolex for:

• Seizures associated with Lennox-Gastaut syndrome
• Seizures associated with Dravet syndrome

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Dr. Grant Huang

VA Office of Research and Development

Acting Chief Research and Development Officer

PhD in Medical Psychology and Master of Public Health from the Uniformed Services University of Health Sciences

Dr. Erica M. Scavella

VA Office of Research and Development

Chief Medical Officer since 2022

MD from University of Massachusetts School of Medicine

Findings from Research

Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in the form of Sativex has shown therapeutic effects on refractory spasticity, central neuropathic pain, and bladder dysfunction in multiple sclerosis patients, addressing common symptoms that current oral medications struggle to effectively manage.

The use of THC/CBD is generally well-tolerated, with most adverse effects being mild to moderate, and a low rate of discontinuation suggests good long-term safety for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the tolerability and efficacy of Sativex in multiple sclerosis. Moreno Torres, I., Sanchez, AJ., Garcia-Merino, A.[2017]

In a randomized controlled trial with 30 subjects, Sativex, a cannabis-based extract, did not show significant efficacy compared to placebo in reducing pain scores for painful diabetic peripheral neuropathy (DPN).

Both groups experienced improvements in pain, but the lack of significant differences suggests that Sativex may not provide additional benefits, and the presence of depression in patients could influence pain outcomes in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Selvarajah, D., Gandhi, R., Emery, CJ., et al.[2021]

The combination of synthetic cannabidiol (CBD) and tetrahydrocannabivarin (THCV) significantly improved symptoms of paclitaxel-induced peripheral neuropathy in mice, showing a twofold enhancement in neurobehavioral outcomes compared to individual treatments.

This combination therapy effectively reversed harmful changes in protein expression caused by paclitaxel, suggesting a protective mechanism that involves the 5-HT1A and CB1 receptors, which are crucial for neuronal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Cannabidiol and Tetrahydrocannabivarin on Paclitaxel-induced neuropathic pain in rodents. Kumar Kalvala, A., Bagde, A., Arthur, P., et al.[2023]

In a 38-week study involving 380 patients with peripheral neuropathic pain (PNP), the THC/CBD oromucosal spray significantly reduced pain severity, with average scores dropping from 6.9 to 4.2 on a 0-10 scale, and over half of the patients reported at least a 30% improvement in pain.

The THC/CBD spray was well tolerated over the study duration, with no new safety concerns and no increase in dosage sought by patients, indicating its long-term safety and efficacy in managing PNP associated with diabetes or allodynia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. Hoggart, B., Ratcliffe, S., Ehler, E., et al.[2021]

KLS-13019, a structural analogue of CBD, not only prevented the development of chemotherapy-induced mechanical sensitivity in mice but also effectively reversed established sensitivity, unlike CBD.

KLS-13019 showed potential in reducing reinforcing behaviors related to food and morphine, indicating it may have unique therapeutic benefits compared to CBD, which did not exhibit this effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Behavioural and pharmacological effects of cannabidiol (CBD) and the cannabidiol analogue KLS-13019 in mouse models of pain and reinforcement. Foss, JD., Farkas, DJ., Huynh, LM., et al.[2021]

In a study of 297 patients with moderate to severe MS-related spasticity, nabiximols (Sativex) demonstrated significant effectiveness, with a mean reduction in spasticity scores from 7.6 to 5.5 over 12 weeks.

Patients undergoing physiotherapy alongside nabiximols treatment had a higher likelihood of achieving clinically relevant improvement and were less likely to discontinue treatment, indicating that combining PT with nabiximols may enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of physiotherapy intervention on patients with multiple sclerosis-related spasticity treated with nabiximols (THC:CBD oromucosal spray). Grimaldi, AE., De Giglio, L., Haggiag, S., et al.[2020]

A retrospective study involving 34 pediatric patients showed that nabiximols, a cannabinoid buccal spray, was primarily used to treat pain and nausea/vomiting, with a median treatment duration of 3.8 days.

Half of the patients reported perceived effectiveness, but the most common side effects were drowsiness and tachycardia in 9% of cases, highlighting the need for further research to establish the safety and efficacy of nabiximols in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterizing the Use of Nabiximols (Δ9-Tetrahydrocannabinol-Cannabidiol) Buccal Spray in Pediatric Patients. Hagg, L., Leung, S., Carr, R.[2023]

In a study of 12 multiple sclerosis patients treated with nabiximols (Sativex®), 58.3% showed a significant reduction in spasticity, indicating its potential efficacy in managing MS-related symptoms.

Functional MRI analysis revealed that nabiximols treatment was linked to increased global brain connectivity, particularly in responders, and changes in connectivity in motor areas and the cerebellum, suggesting a possible mechanism of action for its therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resting-state functional connectivity in multiple sclerosis patients receiving nabiximols for spasticity. Gajofatto, A., Cardobi, N., Gobbin, F., et al.[2023]

Sativex, a cannabis-based oromucosal spray containing THC and CBD in a 1:1 ratio, has shown significant effectiveness in reducing neuropathic pain and other symptoms like spasticity in patients with multiple sclerosis, based on five randomized controlled trials involving 368 patients.

While Sativex is effective for managing certain neurological symptoms, common side effects include dizziness, sleepiness, and fatigue, and the long-term safety and potential for dependence remain uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sativex for the management of multiple sclerosis symptoms. Perras C, .[2016]

References

1. England pubmed.ncbi.nlm.nih.gov

Evaluation of the tolerability and efficacy of Sativex in multiple sclerosis. [2017]

2. United States pubmed.ncbi.nlm.nih.gov

Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Role of Cannabidiol and Tetrahydrocannabivarin on Paclitaxel-induced neuropathic pain in rodents. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Behavioural and pharmacological effects of cannabidiol (CBD) and the cannabidiol analogue KLS-13019 in mouse models of pain and reinforcement. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

The influence of physiotherapy intervention on patients with multiple sclerosis-related spasticity treated with nabiximols (THC:CBD oromucosal spray). [2020]

7. Canada pubmed.ncbi.nlm.nih.gov

Characterizing the Use of Nabiximols (Δ9-Tetrahydrocannabinol-Cannabidiol) Buccal Spray in Pediatric Patients. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Resting-state functional connectivity in multiple sclerosis patients receiving nabiximols for spasticity. [2023]

9. Canada pubmed.ncbi.nlm.nih.gov

Sativex for the management of multiple sclerosis symptoms. [2016]

10. New Zealand pubmed.ncbi.nlm.nih.gov

An Update of Current Cannabis-Based Pharmaceuticals in Pain Medicine. [2020]