Long-term safety of ketamine and esketamine in treatment of depression

Expert Opin Drug Saf. 2022 Jun;21(6):777-787. doi: 10.1080/14740338.2022.2066651. Epub 2022 Apr 19.


Introduction: Ketamine can produce rapid-acting antidepressant effects. Esketamine (Spravato), the S-enantiomer of racemic ketamine, was approved by the FDA for treatment-resistant depression in 2019. Here we review what is known about the long-term safety of both racemic ketamine and esketamine as therapies for psychiatric disorders.

Areas covered: In this article, we conducted a safety review of ketamine and esketamine. In looking at ketamine and esketamine long-term safety effects, we considered data available from experimental studies and several phase-three clinical trials.

Expert opinion: Based on available data, the most common side effects of ketamine/esketamine are generally transient, mild, and self-limited. These include dissociation, nausea, headache, elevated heart rate, and blood pressure. Treatment with esketamine may lead to an increased risk of lower urinary tract symptoms, such as dysuria or urgency. However, severe bladder pathology has not been reported among patients receiving doses of esketamine/ketamine in line with prescribing guidelines for depression. There is considerable data that ketamine at high doses can lead to long-term impairments in cognition. However, the esketamine clinical trials found that cognition generally remains stable or improves over time, suggesting that when used appropriately, there is no increased risk of cognitive impairment.

Keywords: Ketamine; depression; esketamine; safety.

Publication types

  • Review

MeSH terms

  • Antidepressive Agents / adverse effects
  • Depression / drug therapy
  • Depressive Disorder, Treatment-Resistant* / drug therapy
  • Humans
  • Ketamine* / adverse effects


  • Antidepressive Agents
  • Esketamine
  • Ketamine