Ketamine for Multiple Sclerosis Fatigue

Inclusion Criteria:

* Subject must be a man or woman, 18 to 65 years of age, inclusive.
* Subject must be medically stable based on physical examination, medical history, and vital signs
* Subject must meet McDonald 2017 diagnostic criteria for multiple sclerosis based on the PI review of the medical records
* Subject must complain from fatigue as one of their main symptoms and have a screening MFIS score equal or higher than the cutoff based on gender, age, and education displayed in Table-226
* Subject must be ambulatory (able to walk at least 20 feet using bilateral assistance)
* Subject must have internet and email access and ability to use a computer or tablet or smartphone
* Subjects that are currently taking medication for alleviating fatigue (such as amantadine, modafinil and armodafinil, and amphetamine-like psychostimulants) at Screening are eligible to participate unless the medication is one of the disallowed therapies (Table 3). Subjects taking a fatigue medication at the Screening visit must have been receiving a stable dose for at least four weeks before the Screening visit and be willing to continue the medication at the same dose for the duration of the study.

Exclusion Criteria:

* BDI-II score of more than 29 (indicating severe depression)
* Having a known clear cause for secondary fatigue, such as untreated sleep apnea, untreated hypothyroidism, chronic liver disease, history of moderate to severe anemia (hemoglobin concentration of less than 9 gr/dl in men or less than 8 gr/dl in women).
* Neurodegenerative disorders other than relapsing or progressive MS
* Breastfeeding or pregnant
* History of coronary artery disease or congestive heart failure
* Uncontrolled hypertension at Screening (history of high blood pressure and screening systolic blood pressure \>160 or diastolic blood pressure\>100)
* History of severe liver disease, including cirrhosis
* Terminal medical conditions
* Currently treated for active malignancy
* Alcohol or substance abuse in the past year (except marijuana or other cannabinoids)
* A history of intolerance or allergic or anaphylactic reaction to ketamine or midazolam
* Clinically unstable medical or psychiatric disorders that require acute treatment as determined by the PI
* History of severe or untreated coronary artery disease or history of congestive heart failure
* History of prior ischemic or hemorrhagic stroke and cerebral vascular aneurysms.
* History of recurrent seizures or epilepsy
* Taking any disallowed therapy(ies), as noted in the protocol.