Ketamine Therapy for Depression: What You Need to Know

What this article covers

This article explains ketamine as a depression treatment: where it came from, what is known and unknown about how it works, the forms it is given in and their legal status, what a course involves and the risks. Three other pages go further on specific questions:

• The trial evidence, study by study, is on ketamine and esketamine for depression.
• Spravato's REMS rules, its cost and the questions to ask a clinic are in the ketamine and Spravato treatment guide.
• How to find and check a provider is on ketamine and Spravato providers.

From anaesthetic to antidepressant

Ketamine began as CI-581, a chemical derivative of phencyclidine (PCP). In the first human studies, in 20 volunteers from a prison population, it worked as an anaesthetic within a minute of an intravenous dose, with effects lasting 5 to 10 minutes; raised blood pressure, a faster heart rate and "psychic changes" were noted as undesirable, and the researchers proposed calling the mental state it produced "dissociative anesthetic". (Anesthesiology, 2010) The FDA approved ketamine, as Ketalar, on 19 February 1970. (US Food and Drug Administration, 19 Feb 1970) It is still approved only as an intravenous or intramuscular anaesthetic. (U.S. Food and Drug Administration, 10 Oct 2023)

Its antidepressant effect came to light decades later. In 2000, the first placebo-controlled trial gave seven people with major depression a single infusion: depression scores fell within 72 hours after ketamine but not after saline. (Biological Psychiatry, 2000) In 2006 a crossover trial in 18 adults with treatment-resistant depression found ketamine beat placebo within 110 minutes; 71% responded the day after, but only 35% kept that response for at least a week. (Archives of General Psychiatry, 2006)

The speed drew attention; the brevity was the catch, and much of the later research has been about holding the effect.

The evidence in brief

The trials behind Spravato showed modest average gains on top of standard care. In 227 adults whose depression had not responded to at least two antidepressants, esketamine spray plus a newly started antidepressant improved depression scores by 4.0 points more than the antidepressant plus a placebo spray after 28 days. (American Journal of Psychiatry, 2019) For IV ketamine the strongest recent result is the comparison with ECT described below. (New England Journal of Medicine, 2023) A separate trial in 80 depressed adults with suicidal thoughts found one infusion reduced suicidal ideation more than the sedative midazolam within 24 hours, with 55% responding against 30%. (American Journal of Psychiatry, 2018) Even so, the Spravato label states that its effectiveness in preventing suicide has not been demonstrated. (U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026) The condition page lists every study with its size and limits.

How it is thought to work, and what is still open

Ketamine blocks the NMDA receptor, a target for the brain's main excitatory messenger, glutamate. A 2018 review set out several competing explanations of how that turns into an antidepressant effect: blocking particular NMDA receptor types, blocking receptors on inhibitory neurons, quieting burst firing in a small brain region called the lateral habenula, and activating AMPA receptors, with downstream changes in proteins tied to synaptic plasticity such as BDNF and mTOR. (Molecular Psychiatry, 2018) The same review discussed mechanisms that do not involve direct NMDA blockade at all, including ketamine's metabolite (2R,6R)-hydroxynorketamine, and said the proposed mechanisms may work together. (Molecular Psychiatry, 2018)

One small trial complicated the picture. In 12 adults with treatment-resistant depression who completed both conditions, taking the opioid blocker naltrexone before a ketamine infusion markedly reduced the antidepressant effect but not the dissociation, and the trial was stopped at the interim analysis. (American Journal of Psychiatry, 2018) The authors concluded that the acute antidepressant effect seemed to need the opioid system and that dissociation alone was not enough. (American Journal of Psychiatry, 2018) With only 12 completers, that remains an open question rather than a settled one.

The forms of ketamine, and which are approved

Esketamine nasal spray (Spravato). Esketamine is one of ketamine's isomers, its mirror-image forms. (eCFR (Office of the Federal Register), current; U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026) The FDA approved Spravato for treatment-resistant depression on 5 March 2019, under a restricted programme (REMS). (U.S. Food and Drug Administration, Drugs@FDA, 5 Mar 2019; U.S. Food and Drug Administration, Drugs@FDA, 2026) Its label now covers treatment-resistant depression and depressive symptoms in major depressive disorder with acute suicidal thoughts or behaviour, in adults. (U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026) In January 2025 it was approved as a monotherapy for adults who had not responded to at least two oral antidepressants. (Johnson & Johnson (press release), 21 Jan 2025)

Intravenous ketamine. Infusion clinics use racemic ketamine, the ordinary mixture of both forms. That is off-label prescribing, since the FDA has not approved ketamine for any psychiatric disorder. (U.S. Food and Drug Administration, 10 Oct 2023) The best-known recent trial compared it with electroconvulsive therapy (ECT) in 403 patients and found it noninferior: 55.4% responded to ketamine and 41.2% to ECT. (New England Journal of Medicine, 2023)

Intramuscular injection. Ketamine is approved for intramuscular use only as an anaesthetic, so injections for depression are also off-label. (U.S. Food and Drug Administration, 10 Oct 2023)

Oral ketamine, lozenges and at-home telehealth. In October 2023 the FDA said compounded ketamine products, including oral forms, have not been evaluated for safety, effectiveness or quality, and that using them without monitoring by a health care provider may put patients at risk of serious adverse events. (U.S. Food and Drug Administration, 10 Oct 2023)

All ketamine, including esketamine, is a Schedule III controlled substance in the US, so it is lawful only on a prescription. (eCFR (Office of the Federal Register), current; U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026)

What a course is like

Spravato. For treatment-resistant depression the label sets an induction phase of two doses a week for weeks 1 to 4, then weekly doses in weeks 5 to 8, then every two weeks or weekly, at the least frequent schedule that keeps the response. (US National Library of Medicine, DailyMed, 24 Sep 2026) Patients are told to avoid food for 2 hours beforehand because of nausea, and not to drive until the next day after a restful sleep, so they need a lift home. (US National Library of Medicine, DailyMed, 24 Sep 2026) In the 28-day trial, dissociation, nausea, vertigo, altered taste and dizziness were more common with esketamine, generally appearing shortly after a dose and settling within 1.5 hours; 7% stopped because of a side effect, against 0.9% on placebo spray. (American Journal of Psychiatry, 2019) Each dose is taken in a certified setting, with monitoring for at least 2 hours for sedation, dissociation, breathing problems and changes in vital signs. (U.S. Food and Drug Administration, REMS@FDA, 24 Jun 2026; U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026) In a relapse-prevention trial, people in stable remission who kept taking esketamine relapsed less often than those switched to placebo, 26.7% against 45.3%. (JAMA Psychiatry, 2019)

IV ketamine. There is no approved schedule. In the ketamine versus ECT trial, patients received 0.5 mg per kilogram over 40 minutes, twice a week for three weeks. (New England Journal of Medicine, 2023) Clinics set their own courses and maintenance plans, so ask for the plan, the monitoring and the full cost in writing; the guide's list of questions is a good starting point.

Risks

• Dissociation, sedation and blood pressure. Spravato carries a boxed warning for sedation, dissociation, respiratory depression, abuse and misuse, and suicidal thoughts and behaviours in younger people. (U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026) It raises blood pressure at all recommended doses, peaking about 40 minutes after a dose, and is contraindicated in people with certain vascular conditions such as aneurysms. (U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026)
• Misuse. The FDA lists abuse and misuse among the known safety concerns of all ketamine products, along with psychiatric events, raised blood pressure, slowed breathing and urinary tract symptoms. (U.S. Food and Drug Administration, 10 Oct 2023)
• Bladder damage with heavy use. A Hong Kong case series of 59 people who regularly used street ketamine found all had moderate to severe urinary symptoms, and 51% had swelling of one or both kidneys on ultrasound; the authors described a syndrome of cystitis and a contracted bladder. (BJU International, 2008) The Spravato label notes cases of ulcerative or interstitial cystitis with long-term off-label use or misuse of ketamine. (US National Library of Medicine, DailyMed, 24 Sep 2026)
• Interactions. Benzodiazepines, opioids and alcohol add to sedation, and MAO inhibitors and stimulants can raise blood pressure further. (Janssen Pharmaceuticals, via DailyMed (US National Library of Medicine), 24 Sep 2026; Journal of Clinical Psychiatry, Veraart JKE, Smith-Apeldoorn SY, Kutscher M, et al., 2022) Check your medicines in the interaction checker, and never stop or change a prescribed medicine without talking to the prescriber.

Cost and finding a provider

In 2019 an independent cost review judged esketamine low value for money at its announced list price. (Institute for Clinical and Economic Review, 20 Jun 2019) The FDA publishes no list of certified Spravato settings; the manufacturer runs a search tool and the REMS lists certified pharmacies. (Janssen Pharmaceuticals (manufacturer's website), current page; U.S. National Library of Medicine, DailyMed (Janssen label), 24 Sep 2026; U.S. Food and Drug Administration, REMS@FDA, 24 Jun 2026) For both, and for what no official source says about infusion prices, see the ketamine and Spravato treatment guide. If you would rather take part in research, search recruiting depression trials.

If you are thinking about suicide or are in crisis, call or text 988 in the US. (988 Suicide & Crisis Lifeline)