Widely used as a battlefield anesthetic in the later stages of the Vietnam War, ketamine has emerged as a key player in the unfolding drama over psychedelic drugs as last-ditch treatments for severe depression. A tenacious coalition of researchers and patient advocates has defended ketamine’s anti-depressant effects for many years, and their efforts finally began to pay off with FDA approval of esketamine (Spravato) nasal spray in 2019 for treatment-resistant depression (TRD). Off-label use of the drug accelerated during the COVID pandemic as distraught Americans, confined to their homes and denied access to normal life, began experiencing anxiety and depression at alarming rates; some 41 percent of adults reported experiencing high levels of psychological distress in the wake of COVID-19. While preliminary studies suggest ketamine could reduce—or perhaps even eliminate—depressive symptoms in some patients, critics emphasize its significant risks. As a powerful anesthetic with a history of recreational abuse, ketamine carries high addiction potential, especially for those with substance use histories. Side effects include dissociation, elevated blood pressure and potential long-term issues like bladder damage. Its benefits may be short-lived, necessitating repeated infusions of IV ketamine therapy, and long-term safety data remains limited, raising concerns about unknown effects from prolonged use. While it reduces suicidal thoughts acutely, evidence for sustained protection is unclear. Accessibility is another hurdle: treatments are costly, require clinic supervision and are not universally licensed for depression. Proponents rebuff these criticisms, noting that traditional medications can also have serious side effects and often take weeks or even months to relieve depression, if they work at all. If ketamine can help even a relatively small group of people, including those at greatest risk for suicide, then why not allow them to use it? Some patients report life-transforming outcomes, including reduced anxiety and PTSD symptoms after just a few sessions. For individuals unresponsive to standard therapies, ketamine could offer relief where few other treatment options exist, proponents say. Follow the latest news and policy debates on sustainable agriculture, biomedicine, and other ‘disruptive’ innovations. Subscribe to our newsletter. SIGN UP The controversy underscores the tenuous balance between innovation and caution. Advocates push for expanded research and access, viewing ketamine as a breakthrough for TRD, while skeptics call for rigorous studies on risks and ethical guidelines to prevent misuse. As of today, ongoing trials aim to clarify its role, but the debate persists on whether benefits outweigh hazards for vulnerable populations. Join Dr. Liza Lockwood and Cam English on this episode of Facts and Fallacies as they take a closer look at ketamine’s promising benefits and alarming risks: Dr. Liza Lockwood is a medical toxicologist and the medical affairs lead at Bayer Crop Science. Follow her on X @DrLizaMD Cameron J. English is the director of bio-sciences at the American Council on Science and Health. Follow him on X @camjenglish