The "Cannabidiol for the Treatment of Diabetic Peripheral Neuropathy: Pilot study (CBD-DPN1)" is a double-blinded, placebo-controlled, crossover pilot study evaluating the efficacy of Cannabidiol (CBD) and full-spectrum CBD (fsCBD) tinctures in treating Diabetic Peripheral Neuropathy (DPN)-associated pain. DPN is a common, highly distressing complication of diabetes, characterized by chronic pain and loss of sensory function, for which currently available treatments primarily offer only symptomatic relief. CBD and fsCBD are being investigated for their potential neuroprotective and analgesic effects by regulating inflammation and oxidative stress.

The study aims to recruit 12 to 20 adult participants who have mild to moderate DPN. Subjects will receive either an active treatment (CBD isolate or fsCBD in MCT oil, dosed at 50 mg twice daily for a total of 100 mg daily) or a placebo during two sequential 6-week phases. The overall objective of this pilot phase is primarily methodological: to test and refine the clinical protocol, assess patient compliance and acceptability of the CBD formulations, and generate sufficient data to calculate the necessary sample size for a larger, definitive study. Efficacy will be measured using objective and subjective metrics, including DPN severity (DN4 Assessment Tool and DPNCheck™ for nerve conduction velocity) and pain level (PainDetect Questionnaire). Secondary outcomes include evaluating mood (HADS), sleep quality (MOS Sleep Scale), and quality of life (EQ-5D-5L).

The Cannabidiol for the Treatment of Diabetic Peripheral Neuropathy: Pilot study (CBD-DPN1) is an interventional, double-blinded, placebo-controlled, crossover pilot study investigating the efficacy of cannabidiol (CBD) formulations in treating diabetic peripheral neuropathy (DPN)-associated pain. This study operates under an Investigational New Drug (IND) application cleared by the U.S. Food and Drug Administration (FDA).

Scientific Rationale and Objectives DPN is a widespread and highly distressing complication of Type 2 Diabetes (T2D), leading to chronic pain, numbness, and significant loss of quality of life. Current treatments primarily offer symptomatic relief without halting the disease progression. CBD is a non-psychoactive phytocannabinoid attracting attention for its neuroprotective action and potential therapeutic effect against DPN pain. Mechanistically, CBD is hypothesized to reduce neuropathic and musculoskeletal pain by regulating inflammation and oxidative stress through antagonism of CB1 receptors, agonism of CB2 receptors, and modulation of TRPV1 ion channels. Preclinical data further suggests CBD significantly improves behavioral DPN parameters in diabetic rat models and positively regulates mitochondrial homeostasis pathways (Nrf2-SIRT1 axis) in Schwann cells.

The overall objective is to determine the efficacy of CBD and Full-spectrum CBD delivered as a tincture in treating DPN-associated pain. As a pilot study, the primary objectives are methodological: to evaluate and refine the clinical protocol, assess patient compliance and acceptability of the CBD formulations, test organoleptic acceptability (if participants can discern active agent from placebo), and gather initial data necessary for power size estimates for a future large-scale study.

Study Design and Treatment Protocol The study targets the recruitment of approximately 30 subjects for screening, with a goal of enrolling a minimum of 12 to 20 adults with mild to moderate DPN. The total duration for each participant is about 4 months.

Crossover Design and Blinding: Participants are randomized into four treatment sequences, ensuring each subject receives both an active treatment phase and a placebo phase across the two sequential 6-week treatment periods (Phase I and Phase II). This design ensures that following the enrollment of 4, 8, 12, 16, or 20 participants, there is an equal distribution of subjects across the four treatment combinations. The study is double-blinded, meaning neither the subject nor the clinical investigators will know the assignment of the active agent or placebo during either phase.

Interventional Agents and Dosing: The investigational products are administered orally in Medium-Chain Triglyceride (MCT) oil:

1. CBD Isolate Tincture: Pure Cannabidiol isolate in MCT oil. The formulation is a high concentration oral solution of CBD (100 mg/mL), provided by the manufacturer Sunflora.
2. Full-spectrum CBD (fsCBD) Tincture: Cannabidiol hemp extract in MCT oil, containing 85.75 mg of CBD and approximately 13 mg of other cannabinoids (like CBG, CBN, and CBC) per milliliter, and less than 0.3% THC.
3. Placebo: MCT oil formulated identically with natural strawberry flavoring to match the active agents, helping to maintain blinding.

The dose of the active agent (CBD or fsCBD) is 100 mg daily. This daily dose is split, requiring subjects to take 0.5 ml (50 mg) twice daily with a meal (breakfast and supper) to optimize absorption. This dose is relatively low, being less than 2 mg/kg for most participants, which is several-fold lower than doses associated with statistically significant adverse effects observed in epilepsy trials (10-20 mg/kg).

Assessments and Schedule Outline The study involves clinic visits at Day 0, Day 7 (Start of Phase I), Day 49 (End of Phase I/Start of Phase II), and Day 91 (End of Phase II), followed by a phone follow-up at Day 105.

• Objective Neuropathy Measurement: The degree of peripheral neuropathy and the progression of the disease is monitored using a needleless, validated, point-of-care Nerve Conduction Test (NCT) performed with the DPNCheck™ instrument. NCV/SNAP amplitude testing is conducted at baseline (Day 0), mid-study (Day 49), and end-of-study (Day 91). A brief physical exam, including testing for hypoesthesia and allodynia using a nylon filament and a brush, is conducted at baseline and end of phase visits.

• Subjective Metrics: Multiple validated instruments are used to assess DPN symptoms, mood, and quality of life:

  • Pain: PainDetect Questionnaire (slightly modified to quantify changes) to assess allodynia and hyperalgesia.
  • Sleep: MOS Sleep Scale.
  • Mood/Anxiety: Hospital Anxiety and Depression Scale (HADS).
  • Quality of Life: EQ-5D-5L Quality of Life Scale.
  • Subjects are trained to complete these questionnaires at Day 7 under supervision and subsequently complete them at home every two weeks.

• Compliance: Compliance is objectively assessed by measuring the volume of remaining oil in the vials returned by the subject at the end of Phases I (Day 49) and II (Day 91), and by scoring the completeness of the questionnaires. Subjects are also debriefed at the final visit regarding their perception of the active vs. placebo phases.

Safety Management and Withdrawals Given the low anticipated toxicity profile of the low CBD dose, a formal Data Safety Monitoring Board (DSMB) is not warranted for this pilot study; oversight is managed closely by the Principal Investigators (PIs).

• Liver Function Monitoring: Because CBD can interact with cytochrome P450 enzymes (e.g., CYP3A4, CYP2C9) and high doses have been linked to liver enzyme elevations, liver function tests (ALT and AST) are checked before the start of the trial (or current results reviewed) and again at the end of treatment (Day 91). Subjects with severe active liver disease are excluded, although those with Non-Alcoholic Fatty Liver Disease (NAFLD) with only mildly elevated enzymes (ALT or AST the ULN) are permitted due to the high prevalence of NAFLD in the target T2D population.
• Drug-Drug Interactions (DDIs): Patients currently using medications metabolized by key CYP450 enzymes (such as Warfarin, Amiodarone, Cyclosporine, and certain anticonvulsants) are excluded to mitigate the risk of DDIs, as CBD can reduce the activity of these metabolizing enzymes.
• Stopping Criteria: Treatment will be immediately discontinued for any participant exhibiting worsening cardiovascular symptoms (e.g., hypotension, tachycardia, syncope, worsening hypertension) or neuropsychiatric symptoms (anxiety, paranoia). Participants are withdrawn for non-compliance, new exclusion criteria (such as pregnancy), or any adverse event severe enough to require hospitalization and reasonably attributed to the treatment.

The DPNCheck™ instrument performs a needleless nerve conduction test, which involves placing electrodes on the skin and running a small current, minimizing risks of infection or injury associated with venipuncture. Subjects are instructed on side effects of the interventional agents , which are generally expected to be mild and self-limiting, such as drowsiness, diarrhea, or dry mouth.

Inclusion Criteria

1. Adult aged 40 to 70 years
2. Diagnosis of Type 2 Diabetes
3. Ambulatory and independently living adult
4. Minimum body weight of 50 kg (to ensure daily dose ≤2 mg/kg)
5. Physical exam completed within the previous 6 months
6. Liver Function Studies (ALT and AST) completed within the previous six months showing normal values
7. If NAFLD is present, ALT and AST levels are ≤2 times the Upper Limit of Normal (ULN)
8. DN4 questionnaire results indicate mild to moderate DPN
9. Nerve Conduction Test (NCT) confirms at least mild DPN
10. Signed ICF/Screening Consent
11. Able to complete required questionnaires (adequate vision)

Exclusion Criteria:

1. High-risk or severely ill individuals (e.g., high risk for general anesthesia, significant limitations due to heart/lung disease, ascites, renal failure, loss of limbs from diabetic complications)
2. Uncontrolled or severe cardiovascular disease (e.g., unstable angina, uncontrolled heart failure, recent myocardial infarction)
3. History of atrial fibrillation, dysrhythmias, MI within the previous 2 years, or stroke
4. Severe respiratory illness (e.g., uncontrolled asthma, COPD with frequent exacerbations, oxygen dependence)
5. Severe or uncontrolled liver disease (e.g., cirrhosis, active viral hepatitis A, B, or C, autoimmune hepatitis, uncontrolled primary biliary cholangitis or primary sclerosing cholangitis)
6. Elevation of liver enzymes (ALT or AST) exceeding 2 times the ULN, or bilirubin exceeding the ULN
7. Severe or uncontrolled kidney disease (e.g., end-stage renal disease requiring dialysis, uncontrolled nephrotic syndrome)
8. History of malignancy within the past 5 years (excluding certain low-risk non-melanoma skin cancers)
9. History of a seizure disorder
10. Blindness (poor vision preventing questionnaire completion)
11. Known allergy or previous adverse reaction to any ingredient, including natural strawberry flavoring
12. Reproductive Health (Women Only)
13. Currently pregnant or lactating
14. Women who can get pregnant who are not using acceptable methods of birth control
15. Current uncontrolled mental health conditions (e.g., major depressive episode with active suicidal ideation, bipolar disorder with current manic/hypomanic episode, or psychosis)
16. Diagnosis of a major depressive episode with active suicidal ideation and/or a plan to attempt suicide within the previous 5 years
17. Attempted suicide in the last 10 years
18. C-SSRS Suicide Ideation Subscore ≥5 at study onset
19. HADS-D score ≥15 at study onset
20. Used cannabis products in the past 30 days
21. Current use or history of illicit drug use or misuse of prescription medications within the previous 5 years
22. Heavy drinking (≥8 drinks/week for women; ≥15 drinks/week for men)
23. Taking medications that are known to cross-reacting with CBD or Cannabiods

Data will be shared primarily with the Sponsor and their designated agents/collaborators for the purposes of study monitoring, data analysis, protocol evaluation, and generating initial data for power size estimates needed for a larger, definitive study. Regulatory agencies, including the Food and Drug Administration (FDA), may also inspect and copy the information.

The data will be compiled and prepared for analysis following the completion of the trial and the final follow-up visit (Day 105). The sponsor will reveal the treatment labeling data after the trial for data analysis

Access to the coded IPD will be limited to the study team, the Sponsor (Florida A&M University), and its agents or collaborators (e.g., the funder, Consortium for Medical Marijuana Clinical Outcomes Research (CCORC)) necessary for study conduct, oversight, and data analysis.