THEPSYCHEDELICLIBRARY

Molecule guide

Ketamine: what the research shows

An anaesthetic now used to treat depression. How ketamine works, what it has been studied for, and how strong the evidence is.

ReviewedLast updated September 25, 2026

Also known as Esketamine (Spravato), Arketamine

At a glance

Type
Dissociative anaesthetic. Not a classic psychedelic.
How it acts
Blocks NMDA receptors, part of the brain's glutamate system.
Approved uses
Anaesthesia (since 1970). Esketamine nasal spray for treatment-resistant depression (US 2019, Canada 2020).
How it's given in research
IV infusion, injection, esketamine nasal spray, and oral forms, always under medical supervision.
Legal status
Prescription-only. Schedule I of Canada's Controlled Drugs and Substances Act; Schedule III in the US.
Strongest evidence
Rapid, short-term relief in treatment-resistant depression.
Biggest open question
How to keep benefits going, and the long-term safety of repeated treatment.

Evidence by condition

How strong the research is for each use, on our four-level evidence scale.

Treatment-resistant depression Moderate

Many randomised trials show fast symptom relief, often within a day, and a large 2023 trial found it comparable to ECT. Esketamine is approved. A single dose's effect usually lasts days to about a week, so research now focuses on repeated treatment.

Suicidal thoughts (short term) Moderate

Pooled data from 10 trials (167 people) show a drop in suicidal thoughts within one day, lasting up to a week. Long-term effects on suicide risk are unknown.

PTSD Low

A 30-person trial found six infusions over two weeks improved PTSD symptoms more than an active placebo. Among those who responded, benefits lasted a median of about four weeks. Larger trials are needed.

Alcohol use disorder Low

A 96-person phase 2 trial found three infusions plus therapy led to more days without drinking at six months. Confidence intervals were wide.

Chronic pain Low

A review of 7 randomised trials (211 people) found a small pain reduction lasting up to two weeks after an infusion. Trials are small and differ widely in design.

What it is

Ketamine was developed in the 1960s as a fast, short-acting anaesthetic and approved for medical use in 1970.12 It is still widely used in operating rooms and emergency medicine, partly because it generally preserves breathing better than many other anaesthetics. It is on the World Health Organization’s List of Essential Medicines.13

In 2000, a small randomised, placebo-controlled study of seven people found that one dose of ketamine significantly improved depression within three days.1 That finding launched two decades of psychiatric research. Today, ketamine for mental health is given by intravenous (IV) infusion, by injection, as the esketamine nasal spray, and in some settings orally, always under medical supervision.

How it works in the brain

Ketamine blocks the NMDA receptor, a switch in the brain’s main excitatory chemical system, glutamate. The leading theory is that this sets off a short burst of glutamate activity. That burst triggers growth signals, such as BDNF, which help rebuild connections between brain cells in areas involved in mood. Much of this comes from animal research.

This is different from classic psychedelics, which act mainly on the serotonin 2A receptor. It’s also different from standard antidepressants, which act on serotonin over weeks.

Ketamine is a 50/50 mix of two mirror-image forms. Esketamine (the S-form) is the approved nasal spray. Arketamine (the R-form) is being studied separately in early trials.

Key studies

Ketamine vs electroconvulsive therapy (ECT), 2023. In a trial of 403 adults with treatment-resistant depression (without psychosis), IV ketamine was at least as effective as ECT, the long-standing standard for severe depression. ECT was linked to a drop in memory recall that wasn’t seen with ketamine.3

Esketamine nasal spray, 2019. In the TRANSFORM-2 trial (227 adults), adding esketamine to a new oral antidepressant improved symptoms more than the antidepressant plus a placebo spray.4 In SUSTAIN-1, people who kept taking esketamine were less likely to relapse.5 These trials led to approval in the US and Canada.1415

Suicidal thoughts, 2018. Pooling individual data from 167 participants across ten trials, a single ketamine infusion reduced suicidal thoughts within one day compared with control treatments, with effects lasting up to a week.6

PTSD, 2021. Thirty people with chronic PTSD received six infusions of ketamine or midazolam (an active placebo that also causes noticeable effects) over two weeks. The ketamine group improved significantly more. Among those who responded, the benefit lasted a median of about four weeks.7

Alcohol use disorder, 2022. In a 96-person phase 2 trial, three weekly ketamine infusions, alongside relapse-prevention therapy, led to more days without drinking at six months than placebo.8

Chronic pain, 2019. A meta-analysis of seven randomised trials (211 people) found a small reduction in pain, about 1.8 points on a 10-point scale, lasting up to two weeks after an infusion.9

These results are encouraging, but they come from small studies, so the evidence is rated Low.

Safety and risks reported in research

In clinical trials, the most common side effects are dissociation (feeling detached or unreal), dizziness, nausea and a temporary rise in blood pressure. These usually settle within an hour or two. For this reason, in the US esketamine is only given in certified treatment settings under a safety program (REMS), with patients monitored afterwards.14

  • Canada: Listed in Schedule I of the Controlled Drugs and Substances Act since 2005, and legal when prescribed.16 Health Canada approved esketamine (Spravato) in May 2020, used alongside an SSRI or SNRI antidepressant.15 IV ketamine for depression is prescribed off-label. Provincial colleges of physicians set expectations for how it’s prescribed and monitored.18
  • United States: Schedule III controlled substance. The FDA approved esketamine for treatment-resistant depression in March 2019, alongside an oral antidepressant,14 and in January 2025 as a stand-alone treatment.17 Generic ketamine for depression is off-label.
  • Elsewhere: Esketamine is approved in the European Union and several other regions. Rules for off-label ketamine vary by country.

History in brief

  • 1962: Ketamine first made, as a shorter-acting alternative to the anaesthetic PCP.12
  • 1970: Approved as an anaesthetic in the US.12
  • 2000: First controlled study showing rapid antidepressant effects.1
  • 2005: Canada lists ketamine in Schedule I of the Controlled Drugs and Substances Act.16
  • 2006: A randomised trial at the US National Institute of Mental Health confirms rapid effects in treatment-resistant depression.2
  • 2019–2020: Esketamine approved in the US (2019) and Canada (2020).
  • 2021–2022: Early randomised trials in PTSD and alcohol use disorder.
  • 2023: Large trial finds ketamine comparable to ECT.3
  • 2025: US approves esketamine as a stand-alone treatment.17

Myths vs evidence

The claim“Ketamine is just a horse tranquilizer.”

What the evidence says Misleading

Ketamine is used in veterinary medicine, but it was developed for people. It has been a human anaesthetic since 1970 and is on the World Health Organization's List of Essential Medicines.13

The claim“One ketamine treatment cures depression.”

What the evidence says False

In an early randomised trial, a single dose improved symptoms within about two hours, and the difference from placebo lasted around a week.2 For most people, one dose isn't a lasting fix. Research now focuses on repeated treatment, maintenance, and combining ketamine with therapy.

The claim“Ketamine is completely safe because it's a prescribed medicine.”

What the evidence says Misleading

In monitored clinical settings, trials report mostly short-lived side effects such as dissociation and raised blood pressure. Frequent, high-dose non-medical use is linked to serious bladder damage,11 and regulators require supervised use partly because of the potential for misuse.14 The setting and supervision matter.

See all myths vs evidence →

Frequently asked questions

Is ketamine a psychedelic?

Not in the classic sense. Classic psychedelics like psilocybin and LSD act mainly on serotonin 2A receptors. Ketamine is a dissociative that acts on the glutamate system. It's often grouped with psychedelics because it can change perception and is studied in similar mental health settings.

What is the difference between ketamine and esketamine?

Ketamine is a mix of two mirror-image molecules. Esketamine (brand name Spravato) is one of them, the S-form, given as a nasal spray. Esketamine is the version formally approved for treatment-resistant depression. Generic ketamine given by infusion for depression is used off-label.

How quickly does ketamine work for depression?

In trials, many participants improved within hours to a day. In one early study, 71% of participants met the response criteria the day after a single infusion.2 That speed is the main difference from standard antidepressants, which usually take weeks.

Is ketamine therapy legal in Canada?

Yes, when prescribed and supervised by a licensed physician. Esketamine is approved by Health Canada. Ketamine infusions for depression are legal but off-label, and provincial medical regulators set expectations for how physicians prescribe and monitor it. Talk to a qualified health professional about your own situation.

What is arketamine?

Arketamine is the other mirror-image half of ketamine, the R-form. Animal studies suggested it might have antidepressant effects with less dissociation, so it is now being tested in early human trials. It is not approved for any use.

Who is usually excluded from ketamine trials?

Trials commonly exclude people with a history of psychosis, active substance use problems, or certain heart and blood vessel conditions, because ketamine can raise blood pressure and affect perception. That means results may not apply to everyone.

Clinical trials

Showing 8 of 122 active trials in our tracker.

See all trials in the tracker →

References

  1. Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry. 2000;47(4):351–354. Source
  2. Zarate CA Jr, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry. 2006;63(8):856–864. Source
  3. Anand A, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. New England Journal of Medicine. 2023;388(25):2315–2325. Source
  4. Popova V, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression (TRANSFORM-2). American Journal of Psychiatry. 2019;176(6):428–438. Source
  5. Daly EJ, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in treatment-resistant depression (SUSTAIN-1). JAMA Psychiatry. 2019;76(9):893–903. Source
  6. Wilkinson ST, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. American Journal of Psychiatry. 2018;175(2):150–158. Source
  7. Feder A, et al. A randomized controlled trial of repeated ketamine administration for chronic PTSD. American Journal of Psychiatry. 2021;178(2):193–202. Source
  8. Grabski M, et al. Adjunctive ketamine with relapse prevention-based psychological therapy in the treatment of alcohol use disorder. American Journal of Psychiatry. 2022;179(2):152–162. Source
  9. Orhurhu V, et al. Ketamine infusions for chronic pain: a systematic review and meta-analysis of randomized controlled trials. Anesthesia & Analgesia. 2019;129(1):241–254. Source
  10. Williams NR, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. American Journal of Psychiatry. 2018;175(12):1205–1215. Source
  11. Chu PS, et al. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU International. 2008;102(11):1616–1622. Source
  12. Domino EF. Taming the ketamine tiger. Anesthesiology. 2010;113(3):678–684. Source
  13. World Health Organization. Model List of Essential Medicines. Source
  14. Janssen. U.S. FDA approval of SPRAVATO (esketamine) CIII nasal spray for adults with treatment-resistant depression. Press release, March 5, 2019. Source
  15. Health Canada. Regulatory Decision Summary: Spravato (esketamine). 2020. Source
  16. Health Canada. Ketamine (controlled and illegal drugs). Source
  17. AJMC. Esketamine approved by FDA as first monotherapy for treatment-resistant depression. January 2025. Source
  18. College of Physicians & Surgeons of Alberta. Ketamine prescribing, administration and oversight expectations. March 2026. Source