Ketamine for Depression: What the Research Actually Shows

Scientifically reviewed by Chana Frenkel, Ph.D. · Edited by Nani Frenkel, chief editor

Ketamine for depression has gone from a surprising lab finding to a treatment people can get in clinics around the world in about 25 years. It can lift symptoms within hours rather than weeks, and one form of it — the esketamine nasal spray Spravato — is approved by the FDA. But the research also has real limits: the benefit from a single dose often begins fading within days and usually does not last beyond one or two weeks, the trials are hard to blind, and a fast-growing market has outrun the evidence in places. This article explains what the treatment involves, what the trials show, how long it lasts, what the risks are, and where it is available as of October 2026.

The short version

• Ketamine is an anesthetic. At lower doses, given under supervision, it can reduce depression symptoms within a day in many people with treatment-resistant depression.
• There are two main forms: esketamine nasal spray (Spravato, FDA-approved) and generic ketamine, usually given by IV infusion (used “off-label,” without FDA approval for depression).
• Single-dose benefits usually fade within one to two weeks. Repeated or maintenance treatment can extend them.
• Because ketamine’s effects are easy to recognize, trials struggle to preserve blinding. Studies using more credible controls have produced mixed results, including some null findings.
• Side effects during treatment (dissociation, a temporary rise in blood pressure, sedation) are common, and ketamine has abuse potential. That is why Spravato must be administered in a certified healthcare setting, and why responsible IV-ketamine programs also provide medical screening and monitoring.

What is ketamine, and why is it used for depression?

Ketamine has been used for decades as an anesthetic in hospitals and veterinary clinics. At anesthetic doses it puts people under. At much lower doses it can produce a short-lived “dissociative” state — a feeling of detachment from the body or surroundings — and, as researchers discovered, a rapid antidepressant effect. Not every patient experiences either effect.

That speed is what makes it different. Standard antidepressants usually take weeks to work, and many people don’t get enough relief from them. For people who have tried several medications without success — what doctors call treatment-resistant depression — a treatment that can work in hours is a significant change.

You will see two forms discussed, and it helps to keep them apart:

• Esketamine (Spravato) is the S-enantiomer of ketamine, delivered as a nasal spray. It is FDA-approved as monotherapy or alongside an oral antidepressant for treatment-resistant depression. With an oral antidepressant, it is also approved for depressive symptoms in adults with major depression and acute suicidal ideation or behavior — although it has not been shown to prevent suicide or reduce suicidal thinking itself.^[1]
• Racemic ketamine is the original, generic drug, usually given as an IV infusion. It is approved as an anesthetic, but its use for depression is off-label. As the FDA puts it, “Ketamine is not FDA approved for the treatment of any psychiatric disorder.”^[2]

How did ketamine become a depression treatment?

The story starts with a tiny study. In 2000, researchers gave seven people with major depression a single low-dose infusion of ketamine or saline. Their symptoms improved significantly within 72 hours after ketamine, but not after saline.^[3]

A larger test followed in 2006 at the U.S. National Institute of Mental Health. Eighteen people with treatment-resistant depression received ketamine and a placebo, one week apart. Ketamine beat placebo within 110 minutes. The day after the infusion, 71% of those who got ketamine had responded and 29% were in remission; about a third still had their response a week later.^[4]

Those results launched two decades of research. For one psychiatrist’s view of why the field got so excited, see our conversation with Dr. Roger McIntyre.

What does a treatment course involve?

It depends on the form.

Esketamine nasal spray. Patients spray the dose themselves, but only in a certified clinic, under direct observation. Spravato is never dispensed for home use.^[5] After each session, patients must be monitored for at least two hours before they can leave, because of the risks of sedation, dissociation, breathing problems and misuse.^[1]

IV ketamine. In research, the standard dose has been 0.5 mg per kg of body weight, infused slowly.^[3][4] Courses of about six infusions over two to three weeks are common in trials.^[6] Private clinics offer similar schedules, but because this use is off-label, protocols, prices and quality of monitoring vary widely.

During and shortly after a dose, many people feel dissociated, dizzy or “floaty.” These effects usually pass within a couple of hours. For a fuller description of the experience, see what ketamine feels like.

What do the trials show?

The short answer: across the literature, ketamine and esketamine have often produced rapid improvements, sometimes larger than the comparison treatment — but not every controlled trial has been positive, and blinding is a real problem, covered in the next section.

Trial	What was compared	Main result
Murrough et al., 2013[7]	One IV ketamine infusion vs. midazolam (a sedative used as an “active placebo”), 73 people	Response at 24 hours: 64% vs. 28%
TRANSFORM-2, 2019[8]	Esketamine spray vs. placebo spray, both with a new oral antidepressant	Greater symptom improvement with esketamine over four weeks
ESCAPE-TRD, 2023[9]	Esketamine vs. the antipsychotic quetiapine, both added to an antidepressant, 676 people	Remission at week 8: 27.1% vs. 17.6%
ELEKT-D, 2023[6]	IV ketamine vs. electroconvulsive therapy (ECT), 403 people	Ketamine met the criterion for noninferiority: response was 55.4% vs. 41.2%; ECT produced a larger short-term decline in delayed-recall (memory) scores
KADS, 2023[10]	Twice-weekly ketamine injections under the skin vs. midazolam, 4 weeks	Fixed dose: no difference. Response-guided flexible dosing: remission 19.6% vs. 2.0%

A few things stand out. ESCAPE-TRD favored esketamine over quetiapine, while ELEKT-D found that ketamine was noninferior to ECT for nonpsychotic treatment-resistant depression — at least as good, not proven better, despite its higher response rate. Both were open-label, meaning participants knew which treatment they received, and the ELEKT-D authors note that this “could have influenced response.”^[6] TRANSFORM-2 was the trial that carried esketamine’s original approval, and critics have pointed out it was the only one of three short-term pivotal trials to beat placebo on its main measure; the relapse-prevention trial supplied the other major efficacy evidence the FDA relied on.^[8][11]

Is the effect real, or partly expectation?

This is the hardest question in ketamine research, and it is not settled.

The problem is that ketamine is easy to recognize. Most people who receive it feel dissociated; most people who receive a placebo don’t. Once patients — or the researchers rating them — can tell who got the real drug, hope and expectation can inflate the results. Researchers try to fix this with “active placebos” like midazolam, which causes sedation, but midazolam doesn’t feel like ketamine either. A review of psychedelic and ketamine trials found that masking was rarely measured properly, and in one trial participants correctly identified their ketamine session 88% of the time.^[12]

Two recent trials tried harder to solve the problem — and found less:

• Ketamine under anesthesia (2023). Researchers at Stanford gave ketamine or saline to 40 depressed patients while they were already under general anesthesia for surgery, so no one could feel the difference. Both groups improved, with no significant difference between them. Only 36.8% of participants guessed their group correctly.^[13]
• KARMA-Dep 2 (2025). In a trial of 65 hospital inpatients, serial ketamine infusions added to usual care did not significantly outperform midazolam — and most patients and raters correctly guessed which treatment they got.^[14]

Neither study proves ketamine doesn’t work. The surgery trial is small, and surgery and anesthesia are unusual circumstances; the inpatient trial studied a specific group already receiving intensive care. Together, though, these trials leave real uncertainty about how much of ketamine’s measured advantage comes from its pharmacology and how much comes from expectation, setting and other nonspecific effects — the same blinding problem we describe in our review of psilocybin research and our review of MDMA research.

How long do the benefits last?

After a single dose, not long. A meta-analysis found the antidepressant effect was strong from four hours to seven days after an infusion and possibly lasted up to 14 days; in the authors’ words, “What happens beyond 14 days is unknown.”^[15]

Repeated dosing helps. In one trial, a single infusion’s effect peaked at 24 hours and faded within a week, but after six infusions over two weeks, 59% of patients responded. With weekly maintenance infusions, most responders stayed well — and some who later stopped relapsed.^[16]

For esketamine, the key long-term trial is SUSTAIN-1. People who had done well on esketamine were randomly assigned to keep taking it or switch to placebo. Among those in stable remission, 26.7% relapsed on esketamine versus 45.3% on placebo — about half the relapse risk.^[17] In other words: for many people, ketamine treatment is not a one-time cure but an ongoing therapy.

How does it work?

Nobody knows for sure. Most of what we know comes from animal studies, so treat these as leading theories rather than established facts.

Ketamine blocks NMDA receptors, part of the brain’s main excitatory (glutamate) system. In rats, this triggered a chain of signals that rapidly grew new connections between neurons in the prefrontal cortex — and blocking that chain also blocked the antidepressant-like effect.^[18]

A 2016 mouse study suggested a twist: that a breakdown product of ketamine, called (2R,6R)-hydroxynorketamine, produces antidepressant effects without blocking NMDA receptors at all.^[19] Other researchers disputed this, reporting that the metabolite does block NMDA receptors at higher doses.^[20] That debate is still unresolved.

What are the risks?

During treatment. Side effects are common but usually short-lived. In Spravato’s trials, dissociation was reported by 41% of patients versus 9% on placebo. Blood pressure rises temporarily, peaking about 40 minutes after a dose and lasting about four hours. Dizziness, nausea, sedation and vertigo each affected roughly a quarter to a third of patients.^[21] At the end of 2024, the FDA also added respiratory depression — slowed breathing — to the risks clinics must monitor for.^[22]

Misuse and overdose. Ketamine can be abused, and people with a history of substance misuse may be at greater risk.^[21] This is a major reason both forms are given under supervision. For what happens at high doses, see can you overdose on ketamine.

Bladder damage. Heavy recreational ketamine use can seriously damage the bladder. A Hong Kong series of 59 regular street users described a painful condition resembling interstitial cystitis, and half had kidney swelling from blocked urine flow.^[23] The risk rises with dose and frequency; stopping ketamine usually helps, though advanced cases may need surgery.^[24] These findings come from heavy, frequent recreational use — a very different pattern from supervised clinical dosing — but they are one reason long-term treatment needs monitoring.

At-home and compounded ketamine. During the pandemic, telehealth companies began prescribing ketamine lozenges and tablets for use at home. In 2023, the FDA warned that “home use of compounded ketamine products presents additional risk,” because no provider is present to monitor patients. It described a case of respiratory depression in a patient taking compounded oral ketamine.^[2] In 2026, the FDA sent warning letters to online sellers of unapproved ketamine products.^[25]

The dangers of unsupervised use became widely known after actor Matthew Perry’s death in October 2023. The medical examiner identified the acute effects of ketamine as the primary cause, with drowning, coronary artery disease and buprenorphine also contributing. Five people who supplied or administered the ketamine later pleaded guilty and were sentenced in federal court.^[26][27]

Is clinic ketamine the same as street ketamine?

Chemically, racemic ketamine is the same molecule whether it comes from a hospital pharmacy or a street dealer. What differs is everything around it: a known dose and purity, a medical screening beforehand, monitoring during and after each session, and a treatment plan. Street ketamine comes with none of these, may be contaminated or mixed with other drugs, and is often used at higher doses and much more frequently — the pattern linked to bladder damage and dependence.

Where is treatment available?

United States. Spravato is available only at certified healthcare settings enrolled in its safety program (called a REMS).^[1] Since January 2025 it can be prescribed on its own, without an oral antidepressant, for treatment-resistant depression.^[1] IV ketamine is widely offered off-label at private clinics, usually at the patient’s own expense.

Telehealth prescribing of ketamine depends on federal rules for controlled substances. The pandemic-era flexibilities that allow prescribing without an in-person visit have been extended through December 31, 2026.^[28] A permanent rule was under final review as of October 2026, so this may change soon — check the current rules before relying on a telehealth service.

Europe. The European Commission authorized esketamine in December 2019 for treatment-resistant depression, together with an antidepressant.^[29] In England, however, NICE does not recommend it for treatment-resistant depression on the NHS.^[30]

Australia and Canada. Australia approved esketamine in 2021 and added it to the Pharmaceutical Benefits Scheme, which subsidizes the cost, from May 2025.^[31] It is also approved in Canada.^[32] For one Canadian province’s approach to regulating psychedelic and ketamine therapy, see our report on Alberta.

The bottom line

Ketamine for depression is a real advance with real limits. It can help some people with treatment-resistant depression faster than anything else available, and esketamine has passed the FDA’s bar for approval. But the benefit of a single dose fades quickly, keeping it going usually means ongoing treatment, and recent trials using more credible controls have produced smaller or null differences, leaving uncertainty about how much expectancy contributes to the measured effect. It is a medicine to take seriously — in both directions — and to use under medical supervision, not at home.

This article is for information only and is not medical advice. If you are struggling with depression or thoughts of suicide, please contact a doctor or a local crisis line.

References

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2. US Food and Drug Administration. FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. October 10, 2023. fda.gov
3. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.
4. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864. doi:10.1001/archpsyc.63.8.856
5. SPRAVATO REMS. Information for healthcare settings. spravatorems.com
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7. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142. doi:10.1176/appi.ajp.2013.13030392
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13. Lii TR, Smith AE, Flohr JR, et al. Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nat Ment Health. 2023;1(11):876-886. doi:10.1038/s44220-023-00140-x
14. Jelovac A, McCaffrey C, Terao M, et al. Serial ketamine infusions as adjunctive therapy to inpatient care for depression: the KARMA-Dep 2 randomized clinical trial. JAMA Psychiatry. 2025;82(12):1216-1224. doi:10.1001/jamapsychiatry.2025.3019
15. Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. 2015;30(3):152-163. doi:10.1002/hup.2475
16. Phillips JL, Norris S, Talbot J, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176(5):401-409. doi:10.1176/appi.ajp.2018.18070834
17. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903. doi:10.1001/jamapsychiatry.2019.1189
18. Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-964. doi:10.1126/science.1190287
19. Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481-486. doi:10.1038/nature17998
20. Suzuki K, Nosyreva E, Hunt KW, Kavalali ET, Monteggia LM. Effects of a ketamine metabolite on synaptic NMDAR function. Nature. 2017;546(7659):E1-E3. doi:10.1038/nature22084
21. US Food and Drug Administration. SPRAVATO (esketamine) nasal spray: prescribing information, revised 02/2020 (sections 5.2, 5.3, 6, 9.2). accessdata.fda.gov
22. US Food and Drug Administration. Supplement approval letter, SPRAVATO REMS modification (respiratory depression), NDA 211243/S-013. accessdata.fda.gov
23. Chu PS, Ma WK, Wong SC, et al. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int. 2008;102(11):1616-1622.
24. Anderson DJ, Zhou J, Cao D, et al. Ketamine-induced cystitis: a comprehensive review of the urologic effects of this psychoactive drug. Health Psychol Res. 2022;10(3):38247. doi:10.52965/001c.38247
25. US Food and Drug Administration. Warning letter to ketaminetroches.com, June 23, 2026. fda.gov
26. NPR. Matthew Perry died from the acute effects of ketamine, autopsy finds. December 15, 2023. npr.org (via HPR)
27. US Attorney’s Office, Central District of California. Matthew Perry’s former live-in personal assistant sentenced to nearly 3½ years in federal prison. May 27, 2026. justice.gov
28. Drug Enforcement Administration. Fourth temporary extension of COVID-19 telemedicine flexibilities for prescription of controlled medications. Federal Register. December 31, 2025;90 FR 61301. federalregister.gov
29. European Medicines Agency. Spravato: EPAR. ema.europa.eu
30. National Institute for Health and Care Excellence. Esketamine nasal spray for treatment-resistant depression (TA854). nice.org.uk
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32. Health Canada. Approved in 2020: Drugs for Human Use — Spravato. Notice of Compliance issued May 20, 2020. health-products.canada.ca

Published October 2026. This article will be updated as new research and regulatory decisions appear.