Ketamine

• 1. Introduction

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  Ketamine owes its best-known label to a pharmacologist's wife. Researchers testing the drug wanted to call its anesthetic state "dreaming," but the manufacturer, Parke-Davis, would not approve the word. Mrs. Edward F. Domino, whose husband was one of the pharmacologists on the project, heard about the dispute. She also heard how "disconnected" treated people looked. Her suggestion was "dissociative anesthesia."

  The name captures something strange about the drug. One compound puts surgical patients to sleep, eases severe pain, and treats depression that has not responded to other medicines. The same compound is used recreationally, where heavy regular use has damaged the bladder and liver. How did an anesthetic become a treatment for the mind? What does it actually do inside the brain? And why do its medical promise and its dangers keep arriving together?

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• 2. A Safer Cousin

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  In 1962, a chemistry professor at Wayne State University named Calvin L. Stevens first synthesized ketamine. Stevens also worked as a consultant for Parke-Davis. The compound carried the developmental code name CI-581. It was derived from phencyclidine, better known as PCP, in a search for an anesthetic that was safer and caused fewer hallucinations.

  After promising tests in animals, the drug was given to human prisoners in 1964. Those studies showed that ketamine acted for a short time and produced less behavioral toxicity. Those qualities made it a more favorable choice than PCP.

  The United States approved ketamine for use in 1970. After that approval, American soldiers in the Vietnam War were the first to receive ketamine anesthesia. It was used extensively there for surgical anesthesia. Vets have also relied on it regularly in animal medicine.

  Surgery in field conditions in war zones became the proving ground for the drug. The reason lies in how little it disturbs a patient's breathing and blood pressure.

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• 3. Anesthesia That Keeps Breathing

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  Under ketamine, a patient enters a trance-like state of pain relief, sedation and amnesia, yet the body's basic systems keep running. The drug suppresses breathing much less than most other available anesthetics. Protective airway reflexes are preserved, so it is sometimes possible to give it without extra measures to guard the airway. At anesthetic doses it usually stimulates the circulatory system instead of depressing it. These traits make it a drug of choice for short procedures that do not require muscle relaxation.

  Severely injured people are among its most frequent patients, and the drug appears to be safe for them. It is the drug of choice for people in traumatic shock who risk dangerously low blood pressure. Ketamine tends to raise blood pressure and is unlikely to lower it. That makes it useful in severe head injuries, where low blood pressure can be hazardous. A clinical practice guideline from 2011 supports ketamine as a sedative in emergency medicine, including during physically painful procedures.

  Children can receive ketamine as the only anesthetic for minor procedures. It can also be the induction agent before a neuromuscular blocker and a breathing tube are used. Children with cyanotic heart disease or neuromuscular disorders are considered good candidates. A mixture of ketamine and propofol is known as ketofol.

  The drug also relaxes and widens the airways, a property called bronchodilation. That allows doctors to use it for people with asthma, chronic obstructive airway disease and severe reactive airway disease, including active bronchospasm.

  Veterinary medicine relies on the same strengths. Ketamine provides anesthesia and pain relief in cats, dogs, rabbits, rats and other small animals. In horses it is often used to start and maintain anesthesia. It is the primary intravenous anesthetic in equine surgery, often alongside detomidine and thiopental, or sometimes guaifenesin. It is also a key part of the "rodent cocktail," a mixture used to anesthetize rodents. Snails are an exception. In snails, ketamine appears to cause excitement instead of sedation.

  Two more uses rest on thinner evidence. Ketamine is given for status epilepticus that has not responded to standard treatments, but only case studies support this. It has also been suggested for children with severe acute asthma who do not respond to standard care. A 2012 Cochrane review found minimal adverse effects in the limited studies, but no significant benefit.

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• 4. Pain Below Sleep

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  Doses far lower than those used for anesthesia, usually called sub-anesthetic doses, turn ketamine into a pain treatment. Infusions are given in emergency departments and around the time of surgery to people whose pain is refractory or intractable. Alone or added to morphine, ketamine reduces morphine use, pain levels, nausea and vomiting after surgery. It is likely to help most when severe pain is expected after an operation and for patients who are tolerant to opioids.

  In the pre-hospital setting, the drug is especially useful because it works well and carries a low risk of respiratory depression. In a hospital emergency department it has similar efficacy to opioids for acute pain and for the pain of procedures. It may also prevent opioid-induced hyperalgesia and shivering after anesthesia.

  For chronic pain, ketamine is given as an intravenous analgesic, mainly when the pain is neuropathic. It has the added benefit of counteracting spinal sensitization, also called wind-up, which people with chronic pain experience. In multiple clinical trials, infusions brought short-term relief in neuropathic pain, pain after a traumatic spine injury, fibromyalgia and complex regional pain syndrome, known as CRPS.

  Consensus guidelines on chronic pain in 2018 were more cautious. They found weak evidence for spinal injury pain and moderate evidence for CRPS. For mixed neuropathic pain, fibromyalgia and cancer pain, they found weak or no evidence. Only for CRPS did they find evidence of relief lasting into the medium or longer term.

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• 5. The Depression Breakthrough

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  The year 2000 changed ketamine's reputation. That was when its rapid antidepressant effects were discovered, a finding later described as the single most important advance in treating depression in more than 50 years. It sparked interest in drugs that block the NMDA receptor and shifted the direction of antidepressant research and development.

  Regulators moved first on esketamine, one of ketamine's two mirror-image forms. In 2019, the European Medicines Agency approved it as an antidepressant. That same year it was approved as a nasal spray for treatment-resistant depression in the United States and elsewhere. The Canadian Network for Mood and Anxiety Treatments recommends it as a third-line treatment. In February 2022, the US Food and Drug Administration issued an alert to healthcare professionals about compounded nasal sprays containing ketamine that were intended to treat depression.

  Whether the single form beats the mixture is a live question. The antidepressant effect appears stronger and more sustained for racemic ketamine, the equal mixture of both forms. The effects of esketamine are smaller and may fade after treatment ends. A 2023 meta-analysis found racemic ketamine, particularly at higher doses, more effective than esketamine at reducing depression severity, with more sustained benefits.

  Maintenance therapy appears effective and generally safe for treatment-resistant depression. Outcomes improve with regular dosing, early intervention and concurrent psychotherapy. Standardized protocols and careful patient selection are crucial. In 2026, the French drug regulatory agency approved intravenous racemic ketamine for severe suicidal crisis. It is the first official rapid-acting pharmacological option for imminent suicide risk. Most systematic reviews suggest short-term benefit against suicidality with mostly mild side effects. The evidence is largely low quality, however, and the long-term effect is unclear.

  For bipolar depression the picture is thinner still. A single intravenous dose added to mood stabilizers may produce a rapid but transient effect. Certainty about that finding is low to very low.

  Researchers are testing other uses. Ketamine appears to reduce anxiety within 12 hours, with relief lasting up to 1-2 weeks. Those improvements track improvements in depression, not the peak of dissociation. For obsessive-compulsive disorder, relief appears rapid and tolerable, but evidence is limited and inconsistent. For post-traumatic stress disorder, reviews suggest symptoms fall for about 24 hours, though the evidence quality is low. In substance use disorders, ketamine shows short-term reductions in withdrawal and cravings, especially alongside therapy. Evidence for reducing alcohol and cocaine use is limited, mixed and low quality, and results for opioids are inconclusive. No biomarker has been validated to predict who will respond.

  The British critical psychiatrist Joanna Moncrieff has challenged the enthusiasm. She points to excessive hype, questionable biological theories of benefit, flawed trial findings, financial conflicts of interest, strong expectancy effects and large placebo responses. She also notes that benefits over placebo are small and short-term, that difficult experiences are possible, and that the lines between medical and recreational use have blurred.

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• 6. Brain and Body

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  Ketamine is an equal mixture of two mirror-image molecules, esketamine, also called S-ketamine, and arketamine, also called R-ketamine. Esketamine is a far more potent blocker of the pore of the NMDA receptor. It binds the receptor's dizocilpine site with roughly 3- to 4-fold greater affinity. Blocking that pore produces the anesthetic, analgesic and psychotomimetic effects. For pain, the block prevents central sensitization in neurons of the spinal cord's dorsal horn, which interferes with pain transmission there. Esketamine is sold for medical use under the brand name Ketanest S. Arketamine has never been marketed as a pure single form.

  The antidepressant action is a puzzle. Esketamine was developed as an antidepressant because of the hypothesis that NMDA blocking explains the effect. Yet memantine, lanicemine, rislenemdaz, rapastinel and 4-chlorokynurenine, all NMDA antagonists, have so far failed to show significant benefit for depression. Animal research suggests that arketamine, the weaker NMDA blocker, may have antidepressant action, as may a metabolite called (2R,6R)-hydroxynorketamine. That metabolite barely touches the NMDA receptor but potently blocks the alpha-7 nicotinic receptor. In the R form, the antidepressant effects are also longer lasting.

  Other proposals abound. One is the acute inhibition of the lateral habenula, a brain region that inhibits the mesolimbic reward pathway and is called the "anti-reward center." Another begins with a paradoxical burst of glutamate, released when ketamine blocks inhibitory GABAergic neurons. That surge activates AMPA receptors and sets off downstream changes in the limbic system. They include more brain-derived neurotrophic factor, activation of its receptor TrkB, activation of the mTOR pathway, deactivation of GSK-3, and inhibition of the kinase that phosphorylates eEF2. It remains unclear whether ketamine alone is enough or whether its metabolites also matter.

  Some mechanisms have been ruled doubtful. Ketamine is a very weak ligand of the monoamine transporters, and no functional inhibition appeared at concentrations up to 10,000 nM. Animal studies and at least three human case reports found no interaction with the MAOI tranylcypromine, a pairing that could cause serotonin syndrome or hypertensive crisis if reuptake were blocked. Whether ketamine activates D2 dopamine receptors is controversial. The Philip Seeman group found partial agonism, but later researchers found affinity weaker than 10 micromolar.

  The body handles the drug quickly. Intravenous bioavailability is 100% by definition, intramuscular is 93% and epidural is 77%. The intranasal route is highest among the less invasive ones, at 45-50%, and oral is lowest, at 16-20%. Sublingual and rectal fall at about 25-50%. In the liver, the enzymes CYP3A4 and CYP2B6 convert ketamine into norketamine. That is converted onward into hydroxynorketamine and dehydronorketamine. After an intravenous dose of tritium-labelled ketamine, 91% of the radioactivity was recovered from urine and 3% from feces, with only 2% unchanged.

  Blood levels tell the story of its effects. Dissociation appears at plasma concentrations of about 100 to 250 ng/mL. The typical intravenous antidepressant dose peaks at 70 to 200 ng/mL. In a study of pure ketamine anesthesia, people began to wake when the level fell to about 2,600 ng/mL and became oriented in place and time at about 1,000 ng/mL.

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• 7. The Price of Use

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  At anesthetic doses, 10-20% of adults and 1-2% of children have adverse psychiatric reactions as they emerge, ranging from dreams and dysphoria to hallucinations and delirium. Adding lamotrigine and nimodipine reduces these psychotomimetic effects, and pretreatment with a benzodiazepine or propofol counteracts them. More than 10% of patients show tonic-clonic movements. Vomiting is expected in 5-15%, and propofol mitigates it. Laryngospasm is rare. In the first 2-3 minutes of a rapid high-dose intravenous injection, breathing may be transiently depressed.

  At sub-anesthetic doses, the psychiatric effects dominate. The most common are dissociation, visual distortions and numbness. Between 20% and 50% of patients report difficulty speaking, confusion, euphoria, drowsiness and trouble concentrating. Hallucinations occur in 6-10%. Effects peak by the end of the injection, drop sharply after 40 minutes and disappear completely within 4 hours.

  Some people should not receive the drug. The major contraindications include severe cardiovascular disease, poorly controlled psychosis, severe liver disease such as cirrhosis, pregnancy, active substance use disorder for serial injections, and age under 3 months. Increased pressure inside the skull or eye is also listed, though recent studies call that controversial.

  Other drugs change its effects. Ketamine potentiates the sedative effects of propofol and midazolam. Naltrexone potentiates its psychotomimetic effects at a low dose. Clonidine reduces the rise in salivation, heart rate and blood pressure during anesthesia and cuts the incidence of nightmares. Benzodiazepines may diminish the antidepressant effect, while most conventional antidepressants can be safely combined with it.

  Regular heavy use harms the urinary tract. Of frequent users, 20-30% have bladder complaints, ranging from cystitis to hydronephrosis to kidney failure. Symptoms include frequent urination, painful urination, urgency and blood in the urine. The bladder wall thickens, and functional capacity can fall as low as 10-150 mL. Studies indicate that ketamine and its metabolites directly damage the epithelial cells of the bladder lining and make it more permeable.

  Treatment starts with stopping ketamine. NSAIDs and anticholinergics follow, then tramadol if the response is insufficient. Second-line options include oral pentosan polysulfate, hyaluronic acid placed in the bladder, and intravesical botulinum toxin. Some research suggests that epigallocatechin-3-gallate, or EGCG, may help restore storage capacity.

  The liver is also at risk with higher doses and repeated use. In a group of chronic high-dose users, about 10% had liver injury. Chronic abuse has also been linked to biliary colic, cachexia, gastrointestinal disease and acute kidney injury.

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• 8. Special K

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  Users call it "Ket," "Special K" or simply "K." Recreationally it appears as crystals, powder or liquid. At sub-anesthetic doses it produces a sense of detachment from the body and the outside world, known as depersonalization and derealization. At sufficiently high doses users may reach the "K-hole," a state of dissociation with visual and auditory hallucinations.

  John C. Lilly, Marcia Moore and D. M. Turner, among others, wrote extensively about their own entheogenic and psychonautic experiences with the drug. Turner died by drowning during presumed unsupervised ketamine use.

  Some of the strangest accounts involve death itself. Most people who remember dreams during ketamine anesthesia report near-death experiences, when the broadest definition is used. A large-scale study in 2019 found that written reports of ketamine experiences resembled written reports of near-death experiences more closely than reports of other drug experiences did.

  There is no evidence that ketamine causes physical dependence, but some regular users develop an addiction, and animal experiments confirm the risk of misuse. Fast onset after snorting and short duration promote bingeing. Tolerance develops rapidly, even with repeated medical use, which pushes doses higher. Some users report anxiety, tremor, sweating and palpitations when they try to stop, though these have never been measured objectively like opioid or benzodiazepine withdrawal. Long-term abuse is known to cause brain damage, including reduced white and grey matter on MRI and atrophy on CT scans. Frequent recreational users show cognitive deficits and more dissociation and delusions.

  The toll has been counted. More than 90 deaths in England and Wales between 2005 and 2013 involved recreational ketamine use, including accidental poisonings, drownings, traffic accidents and suicides. Most of the dead were young. In October 2023, the actor Matthew Perry was found dead in his hot tub. Months later, his apparent drowning was revealed to have been caused by a ketamine overdose, ruled the primary cause even though other factors were present. Because it causes confusion and amnesia, ketamine has also been used for date rape.

  Laboratories can measure it. Blood or plasma levels are usually 0.5-5.0 mg/L in people receiving it under general anesthesia, 1-2 mg/L in those arrested for impaired driving, and 3-20 mg/L in victims of fatal overdose. Urine is often preferred for routine monitoring, and the metabolite norketamine helps confirm ingestion.

  Laws vary, though the drug is on the World Health Organization's List of Essential Medicines and is available as a generic. Australia lists it as a Schedule 8 controlled drug under the Poisons Standard as of October 2015. Canada has classified it as a Schedule I narcotic since 2005. In August 1999, rising recreational use led the United States to place it in Schedule III. In December 2013, India added it to Schedule X, citing recreational use and its use as a date rape drug, which requires a special license and two years of sales records. The United Kingdom made it a Class B drug on the 12th of February 2014. In 2025, the Home Office requested a review of the classification with a view to making it Class A, citing more recreational use and worse health consequences.

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