The purpose of this study is to study new ways to treat post-traumatic stress disorder (PTSD). Current treatments for PTSD do not work for everyone and it can take time to determine whether a person responds to a chosen treatment. The purpose of this study is to see whether ketamine, when given repeatedly intravenously can produce a quick and persistent improvement in PTSD symptoms. At higher doses, ketamine has been used for many years as an anesthetic for medical procedures, and at lower doses may be an effective treatment in patients with major depression and PTSD. Ketamine given for PTSD is investigational, which means that the FDA has not yet approved the drug for treating this condition. In this study, the effects of ketamine will be compared to those of midazolam. Midazolam has similar acute anesthetic effects compared to ketamine but has not been shown to treat or alleviate any symptoms of PTSD. This makes midazolam an appropriate substance to gauge whether ketamine can treat or alleviate PTSD symptoms thereby acting as what we call an active control.

Ketamine is an approved medication in several countries for the induction of general anesthesia and for use as adjunct to other anesthetics. Intravenous ketamine is being developed and tested for the treatment of posttraumatic stress disorder (PTSD).

All subjects will be administered the study medication by the study anesthesiologists and under the direct supervision of the investigator or designee. On all dosing days, all subjects must remain at the clinical site until at least 4 hours post-dose (or longer if required for study procedures) and will be accompanied by a responsible adult when discharged from the clinical site. The end of study will occur when the last subject in the trial completes his/her last study assessment.

Inclusion Criteria:

• Men or women, 18-65 years of age;
• Participants must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign a written informed consent document;
• Participants must fulfill DSM-5 criteria for current civilian or combat-related PTSD
• Women must be using a medically accepted reliable means of contraception (if using an oral contraceptive medication, they must also be using a barrier contraceptive) or not be of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year);
• Women of childbearing potential must have a negative pregnancy test at screening and prior to each intravenous infusion;
• Participants must be able to identify a family member, physician, or friend (i.e. someone who knows them well) who will participate in a Treatment Contract (and e.g. contact the study physician on their behalf in case manic symptoms or suicidal thoughts develop).

Exclusion criteria:

• Women who plan to become pregnant, are pregnant or are breast-feeding
• Serious, unstable medical illnesses such as hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease, including gastro-esophageal reflux disease, obstructive sleep apnea, history of difficulty with airway management during previous anesthetics, ischemic heart disease and uncontrolled hypertension, and history of severe head injury;
• Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG;
• Renal impairment, as reflected by a BUN >20 mg/dL, and/or creatinin clearance of >1.3 mg/dL;
• Thyroid impairment, as reflected by TSH> 4.2 mU/L Patients with uncorrected hypothyroidism or hyperthyroidism;
• Hormonal treatment (e.g., estrogen) started in the 3 months prior to the first infusion day;
• Use of evidence-based individual psychotherapy (such as prolonged exposure) during the study;
• History of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome; History of one or more seizures without a clear and resolved etiology;
• History of (hypo)mania;
• Past or current presence of psychotic symptoms, or diagnosis of a lifetime psychotic disorder including schizophrenia or schizoaffective disorder;
• Drug or alcohol abuse or dependence within the preceding 3 months
• Previous recreational use of ketamine or PCP;
• Current diagnosis of bulimia nervosa or anorexia nervosa;
• Diagnosis of schizotypal or antisocial personality disorder
• Patients judged clinically to be at serious and imminent suicidal or homicidal risk.
• A blood pressure of one reading over 160/90 or two separate readings over 140/90 at screen or baseline visits
• Patients who report current treatment with a benzodiazepine, an opioid medication, or a mood stabilizer (such as valproic acid or lithium) within 2 weeks prior to randomization

up to 21 weeks

Exclusion of patients with comorbid psychotic, bipolar, or current alcohol or substance use disorders to protect against worsening of psychotic symptoms or abuse potential, which may limit generalizability of our findings to individuals with PTSD and these comorbid disorders.