# Ketamine
Ketamine is a dissociative anesthetic and non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor, used in human and veterinary medicine for anesthesia and, at subanesthetic doses, as a rapid-acting antidepressant. It was developed in 1962 as a less hallucinogenic and shorter-acting agent than phencyclidine (PCP), given to humans for the first time in 1964, and approved by the U.S. [Food and Drug Administration](https://www.edgepedia.org/food-and-drug-administration) (FDA) in 1970 as a short-acting anesthetic[1](https://pubmed.ncbi.nlm.nih.gov/35764129/) • [2](https://www.nimh.nih.gov/news/science-updates/2023/cracking-the-ketamine-code).
| Key fact | Detail |
|---|---|
| Drug class and mechanism | Non-selective, non-competitive NMDA receptor antagonist; the marketed product Ketalar is a racemic mixture[3](https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/016812s046lbl.pdf) |
| Development | Synthesized in 1962 at Parke-Davis by Calvin Lee Stevens of Wayne State University; first human administration 1964[1](https://pubmed.ncbi.nlm.nih.gov/35764129/) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC4428540/) |
| FDA approval | 1970, as a short-acting anesthetic in humans and animals; given to injured American soldiers during the Vietnam War[2](https://www.nimh.nih.gov/news/science-updates/2023/cracking-the-ketamine-code) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC4428540/) |
| Antidepressant action | First randomized controlled trial of single-dose intravenous ketamine in depression completed at Yale in 2000; effect within hours, sustained up to 72 hours[2](https://www.nimh.nih.gov/news/science-updates/2023/cracking-the-ketamine-code) • [5](https://pmc.ncbi.nlm.nih.gov/articles/PMC13001759/) |
| Approved psychiatric use | Esketamine (Spravato), the S(+) enantiomer delivered as a nasal spray, approved by the FDA in 2019 for treatment-resistant depression, available only at a certified doctor's office or clinic[6](https://www.dea.gov/sites/default/files/2024-12/2024-Drugs-of-Abuse-508.pdf) |
| Duration of antidepressant effect | Effects of a single ketamine treatment last no more than one week and disappear after two weeks (Cochrane, 2021)[7](https://www.cochrane.org/evidence/CD011612_ketamine-and-other-glutamate-receptor-modulators-depression-adults) |
| Common adverse effects | Dissociation, hallucinations, nausea, dizziness, raised blood pressure and intracranial pressure; more frequent than with placebo or midazolam[1](https://pubmed.ncbi.nlm.nih.gov/35764129/) • [8](https://pubmed.ncbi.nlm.nih.gov/41656677/) |
## Pharmacology
Ketamine is a phencyclidine derivative that produces a dissociative anesthetic state, meaning patients feel disconnected from their body and environment[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC4428540/) • [9](https://www.nih.gov/news-events/nih-research-matters/treating-depression). Its mechanism of action is primarily antagonism of NMDA receptors in the central nervous system[3](https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/016812s046lbl.pdf). Unlike most anesthetic agents, it produces potent anesthesia, sedation, and analgesia while maintaining cardiopulmonary stability and airway patency[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC5126726/).
The drug also produces adverse reactions including raised intracranial and blood pressures, seizures, and hallucinations, which have kept patient acceptance low[1](https://pubmed.ncbi.nlm.nih.gov/35764129/). At sufficiently high recreational doses, users may experience the "[K-hole](https://www.edgepedia.org/k-hole)", a state of profound dissociation accompanied by visual and auditory hallucinations[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC13001759/).
## History
Ketamine was created in 1962 out of the need for a better anesthetic, screened among compounds similar to phencyclidine in search of one lacking PCP's unwanted psychotropic effects[2](https://www.nimh.nih.gov/news/science-updates/2023/cracking-the-ketamine-code) • [11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7994242/). Early human testing in 1964 showed few side effects, though subjects described feelings of floating or having no feeling in their limbs[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC4428540/). After FDA approval in 1970 it was used in the [Vietnam War](https://www.edgepedia.org/vietnam-war) and, as new volatile and intravenous anesthetics with favorable side-effect profiles appeared, its use markedly decreased[1](https://pubmed.ncbi.nlm.nih.gov/35764129/) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC4428540/).
In the 1990s, clinical interest revived when high-dose opioid anesthesia was found to cause [hyperalgesia](https://www.edgepedia.org/hyperalgesia) and acute tolerance, problems that low-dose ketamine's anti-hyperalgesic action could counter[1](https://pubmed.ncbi.nlm.nih.gov/35764129/).
## Antidepressant development
A 1990 study by researchers under [Phil Skolnick](https://www.edgepedia.org/phil-skolnick) at the National Institute of Diabetes and Digestive and Kidney Diseases showed that NMDA antagonists reduced depression-like signs in mice, suggesting a new class of antidepressants[2](https://www.nimh.nih.gov/news/science-updates/2023/cracking-the-ketamine-code). At Yale, John Krystal and Dennis Charney then pursued ketamine itself, and in 2000 the team completed the first randomized, controlled trial of single-dose intravenous ketamine in people with depression. While established antidepressants could take over a month to work, intravenous ketamine worked within hours[2](https://www.nimh.nih.gov/news/science-updates/2023/cracking-the-ketamine-code).
In that trial, Berman and colleagues showed that a single intravenous injection of 0.5 mg/kg produced rapid antidepressant effects in patients with major depressive disorder, sustained for up to 72 hours after treatment[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC13001759/). A 2006 trial by [Carlos Zarate](https://www.edgepedia.org/carlos-a-zarate)'s team at the [National Institute of Mental Health](https://www.edgepedia.org/national-institute-of-mental-health) replicated and expanded the finding, with 71% of participants who received intravenous ketamine reporting feeling better[2](https://www.nimh.nih.gov/news/science-updates/2023/cracking-the-ketamine-code).
Ketamine is an equal mixture of two mirror-opposite compounds, R-ketamine and S-ketamine. Husseini Manji's team developed esketamine, the isolated S-ketamine, for intranasal delivery; in 2019, nearly 60 years after ketamine's creation, the FDA fully approved esketamine for treatment-resistant depression[2](https://www.nimh.nih.gov/news/science-updates/2023/cracking-the-ketamine-code).
## Evidence in depression and suicidality
A 2021 Cochrane review of glutamate receptor modulators included 64 studies with 5299 people and 16 different medications. Only ketamine and esketamine were more effective than placebo at reducing depressive symptoms, and most participants had treatment-resistant depression, meaning depression that had not responded to two or more medications[7](https://www.cochrane.org/evidence/CD011612_ketamine-and-other-glutamate-receptor-modulators-depression-adults). Ketamine's effects lasted no more than one week after treatment and disappeared after two weeks, while esketamine's effects appeared at 24 hours and could last up to four weeks with repeated doses[7](https://www.cochrane.org/evidence/CD011612_ketamine-and-other-glutamate-receptor-modulators-depression-adults).
Against electroconvulsive therapy (ECT), a meta-analysis of eight studies found no evidence supporting ketamine's superiority for depressive symptom severity (Hedges' g = -0.12, p = 0.68) or response to therapy, though ketamine carried a lower risk of muscle pain[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC10497186/). A network meta-analysis of ketamine-assisted ECT, covering 2322 patients from 17 randomized trials, found that ketamine as the anesthetic agent reduced depressive symptoms more than propofol (pooled SMD -2.21, 95% CI -3.79 to -0.64), but a sensitivity analysis showed worse cognitive performance than propofol (SMD -0.18, 95% CI -0.28 to -0.09)[13](https://www.nature.com/articles/s41380-023-02366-8).
For acute suicidality, a meta-analysis of ten randomized trials with 649 adults compared ketamine with midazolam, an active sedative used to preserve blinding. Ketamine reduced suicidal ideation more than midazolam, with mean differences of -1.23 points on the MADRS-SI item (95% CI -2.14 to -0.32) and -4.30 points on the Beck Scale for Suicide Ideation (95% CI -8.01 to -0.59), and reduced depressive symptoms by -6.23 points on the MADRS total score. Adverse events such as nausea, emotional disturbance, derealization, and dizziness were much more frequent in the ketamine group[8](https://pubmed.ncbi.nlm.nih.gov/41656677/).
## Anesthetic and critical care use
Ketamine is frequently chosen for induction of anesthesia in critically ill adults perceived to be at high risk of hemodynamic instability, but a meta-analysis of ten trials with 4673 patients found a greater risk of postinduction hemodynamic instability with ketamine compared with etomidate (risk ratio 1.28, 95% CI 1.13-1.45), driven mainly by early vasopressor requirement. Against a midazolam-sufentanil regimen, ketamine performed better (risk ratio 0.51, 95% CI 0.29-0.89), and no differences in mortality, ventilator-free days, or ICU-free days were shown[14](https://doi.org/10.1016/j.bja.2026.02.023).
Beyond the operating room, reported beneficial effects include analgesia, anti-shock actions in hemorrhagic and septic insults, anti-inflammatory and anti-tumor effects, neuroprotection, and bronchodilation[1](https://pubmed.ncbi.nlm.nih.gov/35764129/).
## Off-label use and misuse
Ketamine's rapid onset has driven growth in off-label use for conditions including chronic pain, anxiety, post-traumatic stress disorder, and alcohol addiction, most of it paid in cash because insurers generally do not cover non-surgical uses, none of which are FDA approved[15](https://apnews.com/article/2c67eeac1932962a7b0affc07d24c09a). Prescriptions rose more than 500% since 2017 according to Epic Research, with pain the leading condition each year, and the prescribing boom contributed to shortages of manufactured ketamine[15](https://apnews.com/article/2c67eeac1932962a7b0affc07d24c09a). Pain society guidelines note some evidence for complex regional pain but found weak or no evidence for many other conditions, including back pain, migraines, fibromyalgia, and cancer pain[15](https://apnews.com/article/2c67eeac1932962a7b0affc07d24c09a).
Recreational use, where the drug is known as "Special K", has been documented since the 1970s, and between 2019 and 2023 approximately 11,500 ketamine exhibits were submitted to DEA forensic laboratories[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC13001759/) • [16](https://www.dea.gov/sites/default/files/2025-07/2025NationalDrugThreatAssessment.pdf). High-frequency use is associated with bladder toxicity, including urothelial barrier disruption and inflammation[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC10497186/).
## References
1. [Hirota K, Lambert DG (2022). Ketamine; history and role in anesthetic pharmacology. Neuropharmacology.](https://pubmed.ncbi.nlm.nih.gov/35764129/)
2. [Cracking the Ketamine Code, National Institute of Mental Health (2023)](https://www.nimh.nih.gov/news/science-updates/2023/cracking-the-ketamine-code)
3. [KETALAR FDA label (2020)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/016812s046lbl.pdf)
4. [A brief history of the development of antidepressant drugs: From monoamines to glutamate, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4428540/)
5. [Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC13001759/)
6. [Drugs of Abuse: A DEA Resource Guide, 2024 Edition](https://www.dea.gov/sites/default/files/2024-12/2024-Drugs-of-Abuse-508.pdf)
7. [Ketamine and other glutamate receptor modulators for depression in adults, Cochrane (2021)](https://www.cochrane.org/evidence/CD011612_ketamine-and-other-glutamate-receptor-modulators-depression-adults)
8. [Comparative Efficacy and Safety of Ketamine Versus Midazolam for Suicidality, PubMed](https://pubmed.ncbi.nlm.nih.gov/41656677/)
9. [Treating depression, National Institutes of Health](https://www.nih.gov/news-events/nih-research-matters/treating-depression)
10. [Ketamine: 50 Years of Modulating the Mind, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5126726/)
11. [Ketamine—50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7994242/)
12. [Efficacy and adverse effects of ketamine versus electroconvulsive therapy for major depressive disorder, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10497186/)
13. [Efficacy and safety of ketamine-assisted electroconvulsive therapy in major depressive episode, Molecular Psychiatry (2024)](https://www.nature.com/articles/s41380-023-02366-8)
14. [Ketamine versus alternate agents to prevent postinduction haemodynamic instability during tracheal intubation of critically ill adults, British Journal of Anaesthesia](https://doi.org/10.1016/j.bja.2026.02.023)
15. [Mind-altering ketamine becomes latest pain treatment, despite little research or regulation, AP News](https://apnews.com/article/2c67eeac1932962a7b0affc07d24c09a)
16. [2025 National Drug Threat Assessment, DEA](https://www.dea.gov/sites/default/files/2025-07/2025NationalDrugThreatAssessment.pdf)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Medicines and therapeutics › Pharmacology and drug action › Pharmacodynamics and drug action*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license