Mechanisms of Cannabidiol in Persons With MS: the Role of Sleep and Pain Phenotype

Inclusion Criteria: 1. Patients with clinically definite MS (those who are on a disease modifying therapy must be on a stable dose without evidence of liver toxicity for at least 3 months); 2. Presence of chronic pain defined as moderate to severe pain for at least 3 months, based on a 0-10 numeric rating scale (NRS); 3. Willingness to maintain stable analgesic regimen during study period; 4. Recent serum aspartate transaminase, alanine transaminase, and bilirubin testing within 90 days of screening; Exclusion Criteria: 1. Current shift work sleep disorder, or narcolepsy diagnosed with polysomnography and multiple sleep latency test; 2. History of MS relapse within the last 30 days prior to screening (participants will be considered eligible after the 30-day window); 3. Pain due to cancer; 4. Pregnancy or breastfeeding; 5. Current cannabinoid use (participants may be reconsidered for inclusion after 30-day washout) and/or unwillingness to abstain from cannabinoids in any form from 30 days prior to the study of the study drugs and until the last follow up phone call at the end of the study (30 - 37 days after taking the last dose of the study drug). 6. Unwillingness to use contraception from screening until the end of drug treatment 7. Current suicidal ideation (SI) with intent and/or plan; these individuals will be assessed by a study psychologist and referred for urgent mental health treatment as indicated; 8. Current severe depression as indicated by a PHQ-9 score of ≥ 17 that includes indicators of significant depressed mood (sum of items #1 and #2 ≥ 5). 9. History of mania or schizophrenia diagnosis 10. Known hypersensitivity to cannabinoids in general, or Epidiolex® or Dronabinol specifically or its excipients (e.g., sesame oil) 11. History of the following cardiovascular conditions: recent myocardial infarction or stroke (last 6 months prior to screening), unstable angina, left ventricular hypertrophy, mitral valve prolapses, severe coronary artery disease, NYHA class III or IV congestive heart failure. 12. History severe hepatic impairment (must have blood AST ≤ 2.0x ULN, ALT ≤ 2,0x ULN, and bilirubin ≤ 1.5x ULN within the last 90 days (AST, ALT, bilirubin testing will be required within 90 days of screening); 13. History of seizure disorder (recurrent, unprovoked seizures not explained by a known reversible cause) or history of certain types of head injury that could cause an increased risk of seizures; 14. History of prescription or illicit drug abuse (such as cocaine, amphetamine, methamphetamine, heroin); 15. Current risk for alcohol misuse as indicated by a score of ≥ 8 on the Alcohol Use Disorders Identification Test (AUDIT) self-report measure. 16. Current warfarin, valproate or clobazam use. 17. Current use of known moderate or strong inhibitors of CYP3A4 \[topical ketoconazole, and temporary (\<= 4 week) oral courses of clarithromycin, fluconazole and itraconazole will be allowed\]. 18. Current use of strong inducers of CYP3A4 or CYP2C19 (does not include glucocorticoids or modafinil/armodafinil, which are permitted), 19. Current use of moderate or strong inhibitors/inducers of CYP2C9, and narrow therapeutic index drugs (e.g., cyclosporine, amphotericin B). 20. Current use of known non-minor Sensitive CYP2C19 Substrates, with the exception of some proton pump inhibitors (e.g., esoprazole, omeprazole)), periodic self-limited courses of diazepam (e.g., for MRI sedation) and submaximal doses of some antidepressant class medications (e.g., citalopram, and escitalopram), which will be permitted by the discretion of the treating neurologist PI. 21. Refusal to avoid grapefruit or grapefruit products during the study treatment interval. 22. Current use of opioids (tramadol permitted). 23. Employed as a commercial driver or employed in an occupation that involves extreme heights or use of heavy machinery. 24. History of car crashes or near-crashes due to untreated sleepiness that has led to near-misses in the past 6 months. 25. Cognitive dysfunction as indicated by \>=3 errors on the six-item cognitive screener 26. Expanded Disability Status Scale (EDSS) score \>=8.0. 27. Blood pressure at screening above 180 mmHg systolic and/or 120 mmHg diastolic, or below 90 mmHg systolic and or 60 mmHg diastolic, or history of syncope related to orthostatic hypotension; 28. Resting heart rate at screening less than 50 bpm or greater than 100 bpm; 29. Any other treatment or medical, neurological, sleep, or psychiatric condition that, in the opinion of the investigators, could affect participant safety or eligibility.