This is a pilot, prospective, randomized study evaluating the feasibility and acceptability of incorporating hemp-derived cannabidiol (CBD) supplementation to prevent oxaliplatin-induced peripheral neuropathy (OIPN) in patients receiving oxaliplatin-based chemotherapy for colorectal cancer (CRC). Participants will be randomized to receive either CBD capsules in addition to standard therapy or standard therapy alone.

Patients with metastatic colorectal cancer (mCRC) scheduled to receive at least 3 months of oxaliplatin-based chemotherapy will be enrolled on this prospective, randomized, open-label pilot study. A total of 30 patients will be randomized 2:1, with 20 patients assigned to the CBD supplementation arm and 10 patients assigned to the standard of care arm. Patients with pre-existing neuropathy, prior oxaliplatin exposure, or active cannabinoid use will be excluded.

Patients in the intervention arm will receive hemp-derived CBD capsules at a dose of 150 mg orally twice daily (following a titration during Cycle 1) starting the day before oxaliplatin and continuing through 7 days after each chemotherapy cycle. Standard oxaliplatin-based chemotherapy will be administered every 2-3 weeks per NCCN guidelines. Compliance will be monitored through pill counts, patient reporting, and scheduled check-ins. Dose adjustments to 100 mg or 50 mg twice daily will be permitted for treatment-related adverse events at investigator discretion.

Neuropathy will be assessed using both physician grading (CTCAE v5) and patient-reported outcomes (FACT-GOG NTx-13). Safety monitoring will include laboratory tests, neurological and physical examinations, and psychiatric evaluation with the Columbia Suicide Severity Rating Scale (C-SSRS). Exploratory analyses will measure circulating inflammatory cytokines (IL-6, TNF-α) and neuropathy-associated microRNAs (miR-155, miR-146a).

A total of 30 patients (20 intervention, 10 control) will be enrolled at Fox Chase Cancer Center over a 2-year period.

Inclusion Criteria:

1. Patients with metastatic, locally advanced unresectable colorectal cancer patients planned to receive Ox based chemotherapy in metastatic setting (at least 3 months planned).

2. Subjects are allowed to have one cycle of Ox based chemotherapy before enrollment.

3. ECOG PS 0-2

4. No prior platinum exposure

5. No evidence of ongoing neuropathy of any grade at the time of enrollment

6. Patients must have marrow and organ function appropriate for systemic therapy, as per physician's discretion, but liver function should meet criteria below:

   1. Total Bilirubin: less than and/or equal to 1.5 X ULN
   2. AST(SGOT)/ALT(SGPT): less than and/or equal to 3 X ULN (5 X ULN in patients with liver metastases

7. Ability to understand and willingness to sign a written informed consent and HIPAA consent document.

   Exclusion Criteria:

8. Family history of genetic/familial neuropathy and personal history of ongoing neuropathy (any grade) or nervous system disease with the potential to affect cognition, Parkinson's disease, or multiple sclerosis.

9. Routine use of recreational marijuana products (defined as > 4 times per month) or illicit drug use per self-reported history within the last 90 days. If using medical cannabis products, it should be stopped at least 1 week prior to inclusion.

10. Known underlying liver disease (Child-Pugh B or C) or baseline elevation of total bilirubin greater than and/or equal to 1.5 x upper limit of normal based on screening laboratory values.

11. 1Untreated brain metastases (can increase seizure risk), or treated brain metastases on anti-seizure medications.

12. Patients being treated with anti-seizure or anti-psychotic medications. Patients with a prior history of anti-seizure medication use, who have been off treatment for more than 3 months, are eligible. Use of Selective Serotonin Reuptake Inhibitors (SSRIs) is permitted.

13. Concomitant treatment with strong inducers of CYP3A4 and/or strong inducers of CYP2C19.

14. Underlying history of epilepsy/recurrent seizure disorder or unexplained seizure within past 6 months.

15. Patients with current or lifetime diagnosis of schizophrenia spectrum disorder, psychotic disorder, bipolar disorder type I & II, cluster B personality disorders (antisocial, borderline, narcissistic, histrionic), eating disorders, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revised (DSM-5-TR, APA 2022)

16. Recent history or clinical concern for major depression with suicidal ideation as determined by investigator assessment at baseline

17. Currently taking medications known to be contraindicated with Epidiolex -FDA-approved CBD (buprenorphine, leflunomide, levomethadyl acetate, lomitapide, mipomersen, pexidartinib, propoxyphene, sodium oxybate, teriflunomide, clobazam, lamotrigine, valproate).

18. Women who are pregnant or breastfeeding, and individuals of any sex who are capable of reproduction and unwilling to use an effective form of birth control (e.g., condoms, diaphragm, birth control pills, or IUD).

19. Patients may not be receiving any other investigational agents.