Ketamine in psychiatry: a systematic review of clinical applications, safety considerations, and emerging challenges
Matthew M. Kinney, Zackary L. Bowers
Frontiers in Psychiatry October 1, 2026 DOI: 10.3389/fpsyt.2026.1949261 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Key findings | The review consolidates evidence that ketamine acts as an NMDA receptor antagonist with downstream effects on glutamate transmission, AMPA receptors, BDNF, synaptogenesis, and mTOR signaling, and alters large-scale brain networks including the default mode network. It reports clinical use for anesthesia, treatment-resistant depression, and pain, with off-label use for PTSD, anxiety, and bipolar disorder, while highlighting challenges around recreational use, safety, monitoring, and telehealth prescribing. |
Abstract
Ketamine has progressed from solely being an anesthetic agent to a drug of rising clinical and research interest due to its distinctive pharmacological properties. Its dissociative properties and rapid-acting antidepressant effects have made it a prominent area of investigation across many medical and psychiatric applications. This systematic review examines ketamine’s history, mechanisms of action, clinical uses, and significant challenges. A systematic search of PubMed, SCOPUS, PsycINFO, and other sources, generated peer-reviewed publications that addressed the history of ketamine, its pharmacology, clinical applications, recreational use, safety considerations, and societal consequences. Overall, 106 articles were identified for inclusion in this study. At the receptor level, ketamine is an antagonist of NMDA receptors that triggers a number of downstream effects ranging from heightened glutamate transmission, AMPA receptor activation, increased BDNF expression, synaptogenesis, and mTOR pathway signaling. At the network level, it alters activity within large-scale brain circuits including the default mode network, affecting cognition, mood, and perception. Clinically, ketamine is used for anesthesia, treatment-resistant depression, and pain, with off-label uses for PTSD, anxiety disorders, and bipolar disorder. The review also examines current challenges related to ketamine’s recreational use, associated risks, sociocultural factors, and key clinical and ethical considerations, including safety, monitoring, and telehealth prescribing of oral and sublingual formulations. It integrates previously fragmented research from anesthesiology, neuroscience, pharmacology, psychiatry, and public health, consolidates clinical and ethical guidance, identifies critical gaps in current knowledge, and proposes directions for future research.
Comparable studies
Other systematic reviews and meta-analyses on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis Depressed patients with suicidal ideation at baseline | 2017 | Systematic review and individual participant data meta-analysis | n = 167 |
| Ketamine use: a review Ketamine users | 2011 | Systematic review | |
| Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression Participants with major depression in placebo-controlled, double-blind, randomized... | 2015 | Systematic review and meta-analysis | |
| Ketamine and postoperative pain – a quantitative systematic review of randomised trials Surgical patients from 25 countries | 2004 | Systematic review | n = 2,839 |
| Side-effects associated with ketamine use in depression: a systematic review. Patients with depression | 2018 | Systematic review |
Citations in the library
Cites 79
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
and 74 more in the library