The proposed study is a single-center, phase II, randomized, double-blind, parallel-group, active-placebo-controlled trial of intravenous low-dose ketamine in patients with MS 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.

After completion of the study and publication of key findings, the study investigators will make Final Research Data available to researchers upon written request. Researchers must adhere to a data sharing agreement. This agreement requires users to:

(1) use the data only for research purposes; (2) not share the data with unauthorized users; (3) ensure that the data are protected from unauthorized persons; (4) require that the data be returned or destroyed at the end of the analysis; (5) provide certification of IRB review and approval.