Inclusion Criteria:

• 1. Have chronic, persistent fatigue for at least 6 months;
• 1. Intensity greater than or equal to 50 mm using fatigue VAS (on a 0-100 mm horizontal fatigue scale).
• 2. Chronicity greater than or equal to six months total in the past year using the first item of the revised Piper Fatigue Scale.
• 2. Be a cancer survivor with a documented medical report of completing primary cancer treatment \> 6 months ago (except hormone and vaccine therapies) OR diagnosed with complex syndromes like ME/CFS, CFS, chronic fatigue, fibromyalgia; OR autoimmune disorder such as SLE, or Sjogren s disease;
• 3. Able to provide written informed consent;
• 4. Able to have an accompanying responsible adult for drug infusion study visits;
• 5. 18-70 years of age at the time of signing the informed consent form;
• 6. Participants may be NIH employees/staff (see below for some exclusion);
• 7. Individuals of childbearing potential must use adequate contraception, as defined below, prior to study entry and for the duration of study participation. Sexually active subjects must agree to use at least one medically accepted barrier method of contraception during the study. For example:
• * Condoms
• * Prescribed hormonal oral contraceptives, vaginal ring, or transdermal patch.
• * Intrauterine device (IUD).
• * Intrauterine hormone-releasing system (IUS).
• * Depot/implantable hormone (e.g., Depo-provera , Implanon).
• * Bilateral tubal occlusion/ligation.
• * Sexual abstinence: refraining from intercourse during the entire period of risk associated with the study requirements or if the participant decides to become sexually active during the study, then one of the highly effective birth control methods must be used.
• 8. Individuals of non-childbearing potential; as defined by the following criteria:
• * Postmenopausal defined as 12 months of spontaneous amenorrhea or follicle-stimulating hormone (FSH) serum level \> 40mIU/mL;. appropriate documentation is required.
• * Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure.
• * Has a congenital condition resulting in no uterus. OR
• * Is sterile
• * Has documentation confirming vasectomy
• EXCLUSION CRITIERIA:
• 1. Total body irradiation or cranial irradiation for cancer;
• 2. Has a diagnosis of progressive or unstable disease to any body system causing clinically significant fatigue (e.g., class IV congestive heart failure, end-stage renal disease, liver failure, stage IV chronic obstructive pulmonary disease) including patients with active systemic infections (e.g., human immunodeficiency virus (HIV), active hepatitis, COVID-19 - screened using NIH Clinical Center questionnaire);
• 3. Individuals with comorbid conditions other than clinically stable cardiovascular, metabolic conditions, and rheumatologic/systemic autoimmune diseases;
• 4. Current or past psychiatric disorders including medically documented depression with psychosis, bipolar disorder, schizophrenia;
• 5. Clinically documented post-traumatic stress syndrome and/or traumatic brain injury because of the high risk for ketamine to exacerbate symptoms including hallucinations;
• 6. Categorized as a high-risk drinker (\>=5 drinks/day and \>=15 drinks/week for men, \>=4 drinks/day and \>=8 drinks/week for women). ("Dietary Guidelines for Americans 2015-2020," U.S. Department of Health and Human Services and U.S. Department of Agriculture);
• 7. Detectable alcohol content \>1 mg/dL using either breath test or using other biologic samples (e.g., urine);
• 8. Current substance use disorder within the last five years as diagnosed on the Structured Clinical Interview for DSM-5 (SCID-5) or positive urine toxicology results at enrollment;
• 9. Participants with clinical hypothyroidism or hyperthyroidism defined by abnormal thyroid stimulating hormone TSH;
• 10. Poorly controlled hypertension as judged by the Principal Investigator and confirmed by repeat assessment during the screening period (SBP \>160 and DBP \> 100 in all readings);
• 11. Any medical condition causing impairment in mobility (e.g., stroke with residual neuromuscular weakness). This may prohibit the assessment of study outcomes, such as physical activity;
• 12. Any change in dose of regularly scheduled medication or initiation of a new medication (excluding PRN medications) within four weeks prior to signing the informed consent form and throughout the entire duration of the study;
• 13. Untreated sleep condition.
• 14. Medically diagnosed kidney disease (except for chronic stable kidney disease with eGFR\>45);
• 15. Medically diagnosed acute narrow-angle glaucoma;
• 16. Allergic to ketamine, benzodiazepines, flumazenil;
• 17. With poor IV access;
• 18. NINR employees or subordinates, relatives, and/or co-workers of NINR employees/staff or study investigators;
• 19. Pregnant or lactating individuals;
• 20. Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study or safety of the participant.
• 21. Taking concomitant medication known to interact with ketamine and/or midazolam 14 days prior to study drug administration and during the study. The medications are shown in the tables below:
• * List of Psychiatric Medications Allowed and Not Allowed During the Study\*
• * Drug Class: Antidepressants;
• * Episodic Use (as needed): No; Chronic Use: No;
• * Restrictions: SSRI, SNRI, and serotonin modulators, including Buproprion are allowed if on low maintenance doses, and no history of seizure if taking SNRI.
• * Drug class: Antipsychotics;
• --- Episodic Use (as needed): No; Chronic Use: No
• * Drug class: Anxiolytics;
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: Mood Stabilizers;
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: Psychotropic drugs not otherwise specified (including herbal products);
• * Episodic Use (as needed): No; Chronic Use: No;
• * Restrictions: No drugs with psychomotor effects or with anxiolytic, stimulant, antipsychotic, or sedative properties are allowed.
• * Drug class: Sedatives/Hypnotics;
• * Episodic Use (as needed): No; Chronic Use: No
• * List of Non-Psychiatric Medications Allowed and Not Allowed During the Study\*
• * Drug class: Analgesics;
• * Episodic Use (as needed): Yes; Chronic Use: No;
• * Restrictions: Non-narcotic analgesics only
• * Drug class: Anorexics (sibuteramine);
• --- Episodic Use (as needed): No; Chronic Use: No
• * Drug class: Antacids;
• --- Episodic Use (as needed): Yes; Chronic Use: Yes;
• * Drug class: Antianginal Agents;
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: Antiarrhythmics;
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: Antiasthma Agents;
• * Episodic Use (as needed): Yes; Chronic Use:Yes
• * Restrictions: Systemic corticosteroids are not allowed if taking more than \> 10 mg /day of prednisone or glucocorticoid equivalent.
• * Drug class: Antibiotics;
• * Episodic Use (as needed): Yes; Chronic Use: No;
• * Except erythromycin (see P450-3A4 enzyme inhibitors below)
• * Drug class: Anticholinergics;
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: Anticoagulants;
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: Anticonvulsants;
• * Episodic Use (as needed): No; Chronic Use: No;
• * Restrictions: Carbamazepine, phenytoin, and oxcarbazepine are 3A4 inducers and significantly decrease perampanel levels. Topiramate may increase perampanel levels up to 20%
• * Drug class: Antidiarrheal Preparations;
• --- Episodic Use (as needed): Yes; Chronic Use: No;
• * Drug class: Analgesics-Systemic;
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: Analgesics-Topical;
• --- Episodic Use (as needed): Yes; Chronic Use: Yes;
• * Drug class: Antihistamines-Nonsedating;
• --- Episodic Use (as needed): Yes; Chronic Use: Yes;
• * Drug class: Antihistamines-Sedating;
• --- Episodic Use (as needed): N; Chronic Use: No;
• * Drug class: Antihypertensives;
• * Episodic Use (as needed): Yes; Chronic Use: Yes;
• * Restrictions: Non-narcotic analgesics only
• * Drug class: Anti-inflammatory Drugs;
• * Episodic Use (as needed): Yes; Chronic Use: Yes(a);
• * Restrictions: Systemic corticosteroids are not allowed if taking more than \> 10 mg /day of prednisone or glucocorticoid equivalent.
• * Drug class: Antinauseants;
• --- Episodic Use (as needed): Yes; Chronic Use: Yes;
• * Drug class: Antineoplastics;
• * Episodic Use (as needed): No; Chronic Use: No;
• * Restrictions: Agents used in low maintenance doses as immunosuppressive agents (not as antineoplastics) such as Azathioprine, Methotrexate, Mycophenolate mofetil, and Belimumab are allowed.
• * Drug class: Antiobesity;
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: Antivirals;
• * Episodic Use (as needed): No; Chronic Use: No;
• * Restrictions: Except for treatment of HSV with agents without CNS activity e.g. acyclovir, ganciclovir, famciclovir, valacyclovir
• * Drug class: Cough/Cold Preparations;
• * Episodic Use (as needed): Yes; Chronic Use: No;
• * Restrictions: Dextromethorphan preps- N/N, Guaifenesin - Y/Y, Pseudoephedrine- N/N
• * Drug class: Diuretics;
• * Episodic Use (as needed): Yes; Chronic Use: Yes(b);
• * Restrictions: Non-narcotic analgesics only
• * Drug class: H2-Blockers/ PPI;
• * Episodic Use (as needed): Yes; Chronic Use: Yes(b);
• * Restrictions: Except cimetidine (see P450-3A4 enzyme inhibitors below)
• * Drug class: Hormones;
• * Episodic Use (as needed): N; Chronic Use: Yes(b);
• * Restrictions: Only thyroid hormone replacement, oral contraceptives, and estrogen replacement therapy are allowed.
• * Drug class: Hypoglycemic Agents;
• * Episodic Use (as needed): No; Chronic Use: Yes(b);
• * Restrictions: Only oral hypoglycemic agents are allowed.
• * Drug class: Antihyperlipidemics
• --- Episodic Use (as needed): No; Chronic Use: No(b);
• * Drug class: Insulin
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: Laxatives
• --- Episodic Use (as needed): Yes; Chronic Use: Yes;
• * Drug class: Muscle Relaxants
• --- Episodic Use (as needed): No; Chronic Use: No;
• * Drug class: P450-3A4 enzyme inhibitors
• * Episodic Use (as needed): No; Chronic Use: No;
• * Restrictions: Including cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole (topical ketoconazole allowed)
• * Drug class: Protease Inhibitor
• * Episodic Use (as needed): No; Chronic Use: No;
• * Restrictions: Including Saquinavir
• a Allowed only if being taken prior to enrolling in the study.
• b Allowed only if being taken for at least 2 months prior to enrolling in the study and the dose has been stable for at least 1 month.
• \*Some medications in the above table may be indicated for exclusionary conditions; therefore, it would be unlikely that participants meeting inclusion will be taking them.