Investigator decided not to do study, due to insufficient funding.

With this study, the investigators will address the following scientific aims:

1. Demonstrate the antidepressant effects of CBD in human adults with treatment refractory MDD as measured by standard rating scales.
2. Confirm CBD's safety profile in human adult patients with MDD.

Participants will be medically stable and historically failed to respond to one or more adequate trials of commercially available antidepressant drugs during the current depressive episodes. We plan to administer Epidiolex (CBD) or placebo in double blind, randomized, cross-over fashion to 10 depressed adults with MDD over 16 weeks. The study will use a cross-over design so that each participant serves as their own control. The dosage of CBD or placebo CBD will automatically be titrated up and down during the dosing period. Participants first randomized to CBD will automatically be tapered from CBD and switched to placebo CBD after eight weeks. Participants first randomized to placebo CBD will automatically have an equivalent reduction in placebo CBD and be switched to CBD after eight weeks. During the first week after randomization, participants will receive 125mg of CBD or placebo CBD taken twice daily (250mg/day). During the second week after randomization, the dosage will be increased to 250mg of CBD or placebo CBD taken twice daily (500mg/day) for one week. During the third week after randomization, the dosage will be increased to 500mg of CBD or placebo CBD taken twice daily (1000mg/day). Participants will remain on 1000mg/day of CBD or placebo CBD for four more weeks, at which point they will be stepped down to 500mg/day of CBD or placebo CBD for one week, followed by 250mg/day of CBD or placebo CBD for one week.

Study drug and matching placebo will be prepared by the UAB Investigational Pharmacy. Sesame oil will be used to create the placebo. Both the placebo and the active CBD will be flavored with strawberry flavoring. Study medications will be dispensed at weekly visits and each participant will be given 14 single dose syringes to be taken orally twice a day.

At screening participants will undergo a MINI interview, physical examination, and ECG, vital signs, HDRS-17, MADRS, CSSR-S, ATRQ, SF-36 and CGI-S. Laboratory assessment including CBC with differential, TSH with reflex T4, CMP, UA, and UDS will be done at screening.. At screening, the investigators will also administer the following self-report questionnaires to characterize reward sensitivity and other personality features relevant to anhedonia: Social Anhedonia Scale, the Motivation and Energy Inventory and the Physical Anhedonia Scale. The screening period will last up to one week, at which point subjects will present for a baseline randomization visit.

Participants will be seen on site weekly during the study. Drug effect will be measured using standard rating scales including the HDRS-17, MADRS, SF36, CSSR-S, CGI-I, CGI-S, which will be completed at each visit. The following scales will be completed at every other visit following the screening visit: Social Anhedonia Scale, the Motivation and Energy Inventory and the Physical Anhedonia Scale. At each study visit safety assessments including vital sign assessment and adverse event assessment will be completed. Subjects will also undergo physical examination and an ECG for safety during screening, after 8 weeks of treatment and at the end of 16 weeks of treatment. Laboratory assessment including CBD with differential, CMP, and UA will be done at the 8 week and 16 week visit.

To assess potential changes in cognition while on the study drug/placebo, three computerized tests of cognition will the administered at baseline, Week 8, and Week 16. The Relational & Item Specific Encoding task (RISE) will probe any potential neural abnormalities. The Probabilistic Learning Task will be used to examine neural circuits related to reward processing in major depression disorder. For the working memory task, participants will be shown two images with objects and asked to decide whether the two images differ or not.

Inclusion Criteria:

1. Age 18-65 years old

2. Sufficient fluency in English to understand testing procedures and provide written informed consent

3. A Hamilton Depression Rating Scale total score greater than 18

4. A DSM 5 diagnosis of MDD based on the MINI.

5. No evidence of alcohol or other substance use disorder in the past 3 months

6. For females: no current pregnancy or lactation (women of reproductive potential must have a negative urine pregnancy test at screening).

7. Depressed patients who have failed at least one adequate antidepressant trial during the current depressive episode based on the ATRQ.

   Exclusion Criteria:

8. No diagnosis of other primary psychiatric disorder (defined in this case as being the main focus of treatment) as determined by the MINI, such as: bipolar disorder, personality disorders, psychotic disorders, post-traumatic stress disorder, obsessive-compulsive disorder, dissociative disorders, eating disorder, or cognitive task due to neurological conditions

9. Systolic blood pressure < 150 and/or diastolic blood pressure < 90 at screening

10. A QTc F< 480 as determined by an ECG

11. No post-partum state (being within 2 months of delivery or miscarriage)

12. Imminent suicide or homicide risk as determined by the investigator

13. No history of using prescription Epidiolex for any indication.

14. Not being treated with one of the following medications: benzodiazepines or other CNS depressants.

15. Not using concomitant medications that are moderate or strong CYP3A4 or CYP2C19 inhibitors.

16. None of the following clinically-significant medication condition or therapy that would preclude treatment with ketamine, to include: Recent myocardial infarction, unstable angina, malignant neoplasm in the past 6 months, immunosuppressive or corticosteroid therapy within the last month, with the following exceptions: any inhaled, intranasal, topical or vaginal corticosteroids are allowed, chemotherapy.

17. No clinically significant neurological disease based on medical history (e.g., epilepsy) or significant head injury.

18. Any of the following disorders: Rheumatoid arthritis; Lupus erythematosus; Autoimmune hepatitis; Autoimmune peripheral neuropathy; Autoimmune pancreatitis; Behcet's disease; Crohn's disease; Autoimmune glomerulonephritis; Grave's disease; Guillain-Barre syndrome; Hashimoto's thyroiditis; Autoimmune polymyositis or polymyalgia; Myasthenia gravis; Narcolepsy; Polyarteritis nodosa; Scleroderma; Sjogren's syndrome; Transverse myelitis; Wegener's granulomatosis; History of seizures (only childhood febrile seizures are allowed)

19. The presence of clinically significant laboratory findings in the opinion of the investigator including, but not limited to, clinically significant anemia or transaminase elevation.

20. If the UDS is positive, the subject would be excluded if, in the opinion of the investigator, the positive UDS meant the subject has an active substance use disorder.

Plan to share protocol, consent, SAP,and CRS. Do not plan to share IPD,

3 years

Will share with public

Double-blind