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WHAT TO KNOW ABOUT KETAMINE SAFETY: PATIENT MONITORING, NEUROTOXICITY, AND CONSIDERATIONS FOR SPECIAL PATIENT POPULATIONS

Benjamin Brody — Weill Cornell Medical College

2026 ASCP Annual Meeting

Twenty-five years have passed since the publication of the initial report that ketamine hydrochloride has rapid acting antidepressant properties. While initially established as a treatment for refractory depression, ketamine therapy has emerged as a promising intervention for a diverse range of psychiatric conditions, including obsessivecompulsive disorder (OCD), substance use disorders, anxiety disorders, post-traumatic stress disorder among others. Unlike esketamine, racemic ketamine is not regulated by a Risk Evaluation and Mitigation (REMS) program, leaving clinicians far more latitude to use ketamine in varied formulations and settings with limited outcome data to inform their practices. The laissez faire regulatory environment for racemic ketamine also leaves clinicians with limited practical guidance to weight when considering ketamine therapy. In this symposium, clinician investigators with experience leading ketamine services and research groups summarize emerging safety considerations. They will review FDA guidance about unmonitored ketamine use, published and unpublished safety data from their own work, and illustrative case examples that highlight safety risks and opportunities. Dr. Benjamin Brody, Service Chief for Acute Care Services at Weill Cornell Medicine / Psychiatry and founding chief of the ketamine service in the department of Psychiatry, will discuss adverse reactions during ketamine therapy including acute dysphoria, hypertensive urgency, risks associated with unmonitored or remote monitoring of ketamine use, and considerations for individuals with substance use disorders. Dr. Samuel Wilkinson, Medical Director of the Yale Depression Research Program, will review evidence of the potential for neurotoxicity with long term ketamine exposure from both preclinical and human studies, highlighting risks associated with frequent or high-dose use. These studies underscore the potential for neurotoxic effects when ketamine is used at doses or frequencies beyond those utilized in clinical trials, highlighting a critical need for robust longitudinal research. Clinicians are advised to exercise caution, particularly when prescribing ketamine off-label at doses significantly higher than those used in clinical trials. When deviating from this in clinical practice, strong consideration should be given to conducting repeated cognitive assessments. Funding agencies should incentivize preclinical researchers to conduct studies that further elucidate the threshold of ketamine’s neurotoxicity. Dr. Joshua Rosenblat, a staff psychiatrist and clinician-researcher at the Mood Disorders Psychopharmacology Unit at Toronto Western Hospital, will review risks associated with ketamine therapy in special populations including patients with co-occurring depression and PTSD, borderline personality disorder, and older adults and end-of-life cancer. Dr. Cristina Cusin will serve as discussant, contextualizing the issues and emphasizing the importance of team-based collaborative care to prevent burnout and optimize outcomes when taking care of patients with medically and psychiatrically complex, who are at chronic high risk for suicide. Dr. Cusin is the director and founder of the Massachusetts General Hospital Ketamine clinic for treatment-resistant depression, and is involved in numerous research studies on ketamine in treatment-resistant mood disorders at MGH.

Learning Objective 1: Participants will describe the potential for acute and long-term side effects and adverse outcomes associated with ketamine therapy to inform ketamine referrals and informed consent discussions.

Learning Objective 2: Participants will describe psychiatric and general medical comorbidities and concomitant therapies such as PTSD, substance use disorders, personality disorders, hypertension, use of benzodiazepines or naltrexone that should contextualize a decision to refer a patient for ketamine therapy.

References

  1. Brody, B. D., Popeo, D. M., Smetana, R. W., and Kanellopoulos, D. (2025). How Do We Get Ketamine Safety Right? Three Questions From a Clinical Service. The Journal of clinical psychiatry, 86(3), 25com15946.
  2. Li, S. W., Kumpf, K. T., Urrutia, J., Krystal, J. H., Sanacora, G., and Wilkinson, S. T. (2025). Ketamine for depression, but at what cost? a review of ketamine’s neurotoxic effects from preclinical and human studies. American Journal of Psychiatry, 182(10), 903-912.