Project Summary/Abstract US suicide rates rose more than 30% from 1999 – 2017. Individuals who visit an emergency department (ED) for deliberate self-harm or suicidal thoughts have suicide rates within a year that are 57 and 31 times greater, respectively, than age-, sex-, and race/ethnicity-adjusted general population groups. This targets the ED as a key setting to intervene to reduce suicide risk. Yet, there is no U.S. Food and Drug Administration (FDA) approved treatment for rapid relief of suicidal thoughts in depressed patients. This is even though randomized clinical trials, including ours, show relief of suicidal thoughts within hours of treatment with sub-anesthetic ketamine. Our published, controlled clinical trials in bipolar and unipolar suicidal depressed patients found that ketamine reduced suicidal thoughts within hours and the improvement persisted for up to six weeks with optimized, standard pharmacotherapy. During the two years 2017-18 there were more than 2 million ED visits for suicidal ideation, self-directed violence, or both. Patients are at greater risk for suicide attempts and suicide after an ED visit. A rapid, safe, and easy-to-use treatment for patients presenting to an ED with severe suicidal thoughts or behavior would advance public health. There has not yet been a definitive study of readily available generic ketamine for rapid reduction of suicidal thoughts in ED patients. A key military recommendation for battlefield analgesia is ketamine 50-100 mg intramuscular (im) injection, similar to effective intravenous (iv) doses used for depression. Onset of clinical effects is about 1 minute with iv and 5 minutes with im injection. IM ketamine is 93% bioavailable in adult humans and has a plasma half-life similar to iv administration. A clinical trial demonstrating feasibility, safety, and effectiveness of im, generic ketamine for rapid reduction of suicidal thoughts in ED patients would support a novel, scalable, easy-to-use treatment for this population. We propose to conduct a trial of im ketamine versus im midazolam (an active comparator used in our prior ketamine trials) in ED patients presenting with severe suicidal ideation or behavior requiring psychiatric hospitalization. The primary outcomes will be feasibility, safety, and reduction of suicidal thoughts within 24 hours. Secondary outcomes will include effects on length of stay, cognitive function, and suicidal thoughts and behavior during the month after hospital discharge, a known high-risk period for suicide.