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Research · Medication

Ketamine and esketamine

Ketamine infusions and esketamine nasal spray lowered depression scores within 24 hours in placebo-controlled trials, and esketamine kept more people from relapsing. A single infusion eased suicidal thoughts for up to 3 days. During surgery, ketamine cut pain and opioid use modestly. Dissociation, sedation, dizziness and blood pressure rises were very common, and esketamine carries a boxed warning.

Add to Bio HackChecked 2026-11-13
Status
Prescription drugs in the US and Schedule III controlled substances. Ketamine (Ketalar) is FDA-approved only as an anesthetic. Its use for depression, suicidal thoughts, anxiety and chronic pain is off-label. Esketamine nasal spray (Spravato) is FDA-approved for treatment-resistant depression in adults, alone or with an oral antidepressant, and for depressive symptoms in adults with major depression and acute suicidal thoughts or behavior. Spravato carries a boxed warning and is given only in certified settings under a REMS program.
Also called
ketamine, racemic ketamine, Ketalar, ketamine infusion, IV ketamine, esketamine, Spravato, S-ketamine, esketamine nasal spray, ketamine clinic, ketamine therapy, ketamine troches, oral ketamine
Taken for
treatment-resistant depression, fast relief of depression, suicidal thoughts, anxiety, PTSD, social anxiety, chronic pain, pain after surgery, ketamine clinic infusions, at-home ketamine

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help8

Reported risks10

What people take it for, and what was found

Shown to help8

Strong

Depression, intravenous ketamine

Shown to lower depression scores within 24 hours more than placebo, with racemic ketamine's effect lasting into follow-up in a meta-analysis of 49 trials. Used off-label.

Compared with saline placebo or midazolam [1]; placebo or active control in pooled trials [2][3]

The numbers and sources
Effect
In a Cochrane review, ketamine raised response and remission at 24 hours over placebo (OR 3.94, 95% CI 1.54 to 10.10) and lowered depression scores (SMD -0.87, 95% CI -1.26 to -0.48), in very low-certainty evidence [1]. Across 49 trials, a first high dose of racemic ketamine lowered depression severity by SMD -0.73 (95% CI -0.91 to -0.56) against control. Effects stayed significant during repeated dosing (SMD -0.61) and at follow-up after the last dose (SMD -0.65), and higher doses did more than low doses [2]. An earlier meta-analysis found larger response and remission ratios for racemic ketamine (RR 3.01 and 3.70) than for esketamine (RR 1.38 and 1.47) [3].
Population
31 ketamine trials within 64 studies and 5,299 adults with unipolar depression [1]; 3,299 participants in 49 trials [2]; 1,877 participants in 24 trials [3].
Sources
[1], [2], [3]
Caveats
Most ketamine trials gave one dose and measured hours to days later [1]. Dissociation makes blinding hard, and heterogeneity ran up to 87.6% [2]. Not an FDA-approved use.
Moderate

Treatment-resistant depression, esketamine nasal spray

Shown to lower depression scores in treatment-resistant depression by about 4 to 7 points more than placebo on a 60-point scale after 4 weeks.

Compared with placebo nasal spray, with or without a new oral antidepressant [4]; placebo in pooled trials [1][2]

The numbers and sources
Effect
With a newly started oral antidepressant, esketamine 56 or 84 mg lowered MADRS scores by 19.8 points against 15.8 on placebo spray, a difference of 4.0 (95% CI 0.6 to 7.3), most of it visible at 24 hours. As monotherapy, the differences were 5.1 points at 56 mg and 6.8 at 84 mg [4]. A Cochrane review found esketamine likely raised remission at 24 hours (OR 2.74, 95% CI 1.71 to 4.40, moderate certainty) and raised response (OR 2.11) [1]. A second meta-analysis found effects during repeated esketamine dosing did not differ significantly from control (SMD -0.15 to -0.22) [2].
Population
223 adults aged 18 to 64 in one 4-week trial, and 378 in a monotherapy trial [4]; 894 to 1,071 adults in 5 esketamine trials [1]; esketamine trials within 49 [2].
Sources
[4], [1], [2]
Caveats
The pooled analyses disagree on whether esketamine keeps its edge during repeated dosing [2]. Both arms improved a lot in the label trials, so the difference is smaller than each group's change [4].
Moderate

Staying well on esketamine

Shown to delay relapse in people who had improved on esketamine, about half the hazard of relapse after a switch to placebo spray.

Compared with switching to placebo nasal spray, with the oral antidepressant continued [4]

The numbers and sources
Effect
In adults in stable remission after at least 16 weeks of esketamine plus an oral antidepressant, continuing esketamine lengthened time to relapse (HR 0.49, 95% CI 0.29 to 0.84). In stable responders not in remission, the HR was 0.30 (95% CI 0.16 to 0.55) [4].
Population
Adults aged 18 to 64 who had remitted or responded on esketamine, in one randomized withdrawal trial [4].
Sources
[4]
Caveats
The label notes the hazard ratio did not appear constant over the trial [4]. Only people who had already responded were enrolled.
LimitedVery common

Esketamine against quetiapine

One trial found 27% in remission at 8 weeks on esketamine against 18% on quetiapine, each added to an SSRI or SNRI, in treatment-resistant depression.

Compared with extended-release quetiapine, each added to an SSRI or SNRI [5]

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Remission at week 8 occurred in 91 of 336 (27.1%) on esketamine against 60 of 340 (17.6%) on quetiapine. Remission at week 8 with no relapse through week 32 occurred in 21.7% against 14.1% [5].
Population
676 adults with treatment-resistant depression [5].
Sources
[5]
Caveats
Open-label, with raters blinded. Funded by the maker of esketamine [5].
LimitedVery common

Against electroconvulsive therapy

One trial found ketamine infusions no worse than electroconvulsive therapy for treatment-resistant depression without psychosis, with 55% responding against 41%.

Compared with electroconvulsive therapy [6]

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Response occurred in 55.4% on ketamine and 41.2% on ECT, a difference of 14.2 percentage points (95% CI 3.9 to 24.2), meeting the noninferiority test. Delayed recall fell more after ECT (T-score -9.7 vs -0.9). Quality of life improved similarly. Ketamine was linked to dissociation and ECT to musculoskeletal effects [6].
Population
403 patients referred for ECT, 365 treated, at five clinical sites [6].
Sources
[6]
Caveats
Open-label. More people withdrew before starting ECT than ketamine [6].
Strong

Suicidal thoughts

Shown to reduce suicidal thoughts within a day of a single ketamine infusion, an effect lasting up to 3 days. The esketamine label states no reduction in suicide was shown.

Compared with saline or midazolam [7]; control infusions [8]; placebo spray added to standard care [4]

The numbers and sources
Effect
In individual data from 10 trials, one infusion reduced suicidal ideation within 1 day and for up to 1 week, with effect sizes of d = 0.48 to 0.85, partly independent of mood changes [7]. Across 15 trials, suicidal ideation scores fell at 4 hours (SMD -0.51) and 24 to 72 hours (SMD -0.57), but not after, with almost no data on suicidal behavior [8]. In two esketamine trials in people with active suicidal intent, depression scores fell 3.8 to 3.9 points more than placebo at 24 hours, but clinician-rated suicidality did not differ [4].
Population
167 adults with suicidal ideation at baseline [7]; 572 adults in 15 trials [8]; 449 hospitalized adults with major depression and suicidal intent [4].
Sources
[7], [8], [4]
Caveats
Short follow-up and marked heterogeneity [8]. The esketamine label states effectiveness in preventing suicide or reducing suicidal ideation or behavior has not been demonstrated [4].
Moderate

Pain after surgery

Shown to cut pain after surgery by about 19% and opioid use by about 8 mg morphine over 24 hours, when given around the operation.

Compared with placebo, or a basic pain reliever alone [10]

The numbers and sources
Effect
Perioperative intravenous ketamine reduced opioid use over 24 hours by 8 mg morphine equivalents (19% of 42 mg on placebo) and over 48 hours by 13 mg. Pain at rest fell 5 points on a 100 mm scale at 24 hours (19% lower) and 48 hours, and pain on movement 6 points. Time to first pain relief request lengthened by 54 minutes. Nausea and vomiting fell from 27% to 23% [10].
Population
8,341 adults in 130 trials across many operations [10].
Sources
[10]
Caveats
Most trials had fewer than 50 people per arm, with small-study effects. No analysis by dose was possible [10].
ModerateVery common

Chronic pain

Shown to lower chronic pain scores by about 1.8 points on a 10-point scale for up to 2 weeks after an infusion, with 51% responding against 19%.

Compared with placebo infusions [11]

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Up to 2 weeks after an infusion, pain scores fell 1.83 points more than placebo on a 0 to 10 scale (95% CI 1.31 to 2.35). In 3 studies reporting responders, 51.3% on ketamine and 19.4% on placebo responded (RR 2.43, 95% CI 1.10 to 5.40) [11].
Population
211 patients with neuropathic, mixed or other chronic pain in 7 trials [11].
Sources
[11]
Caveats
All but one trial had high risk of bias, and follow-up was short [11].

Mixed results2

Moderate

Racemic ketamine against esketamine

Mixed results: two meta-analyses found larger effects for intravenous racemic ketamine than intranasal esketamine, but only by comparing separate trials, not head to head.

Compared with each other, indirectly, across trials against placebo [2][3]

The numbers and sources
Effect
Racemic ketamine had larger pooled response (RR 3.01 vs 1.38) and remission ratios (RR 3.70 vs 1.47) and fewer dropouts [3]. Effect sizes were numerically larger for racemic ketamine at first dose, during repeated dosing and at follow-up [2].
Population
1,877 participants in 24 trials [3]; 3,299 in 49 trials [2].
Sources
[3], [2]
Caveats
No trial compared the two directly. Racemic trials were mostly single-dose and smaller, and routes differ.
Limited

Anxiety disorders

Small trials found mixed results: ketamine raised response in social anxiety disorder, but not significantly in PTSD.

Compared with control infusions in randomized trials [9]

The numbers and sources
Effect
Four of six trials found anxiety scores fell more on ketamine than control. Response was more likely in social anxiety disorder (OR 28.94, 95% CI 3.45 to 242.57) but not in PTSD (OR 2.03, 95% CI 0.67 to 6.15). Doses of 0.5 mg/kg or more reduced social anxiety more than lower doses [9].
Population
6 acute randomized trials: 2 in social anxiety disorder, 3 in PTSD, 1 in OCD [9].
Sources
[9]
Caveats
Very small trials, shown by the very wide intervals [9]. Not an FDA-approved use.

Doses studied

The depression and suicidal-thought trials mostly gave racemic ketamine 0.5 mg/kg intravenously over 30 to 45 minutes, usually once [8]. The ECT comparison gave 0.5 mg/kg over 40 minutes twice a week for 3 weeks [6]. The esketamine label gives 56 or 84 mg by nasal spray twice a week in weeks 1 to 4, weekly in weeks 5 to 8, then weekly or every 2 weeks, and 84 mg twice a week for 4 weeks in people with suicidal intent [4]. Surgical trials used bolus doses of 0.25 to 1 mg, as the review reports them, and infusions of 2 to 5 µg/kg a minute [10]. Anesthetic doses on the Ketalar label are far higher, 6.5 to 13 mg/kg into a muscle [12]. Oral ketamine and troches sold through some clinics were not tested in the trials above.

Risks

Reported risks10

ModerateVery common

FDA boxed warning: sedation, dissociation and breathing

FDA states esketamine causes sedation in 48% to 61% and dissociation in 61% to 84% of patients, and respiratory depression after approval, requiring 2 hours of observation.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
The boxed warning covers sedation, dissociation, respiratory depression, abuse and misuse, and suicidal thoughts in young people. In trials, 48% to 61% developed sedation on an observer scale and 0.3% to 0.4% lost consciousness. 61% to 84% developed dissociative or perceptual changes on a clinician scale. Adverse-event reports of dissociation were 41% against 9% on placebo, and sedation 23% against 9%. Respiratory depression and rare respiratory arrest were reported after approval. Patients must be watched by a healthcare provider for at least 2 hours, with pulse oximetry [4].
Population
346 adults on esketamine with an oral antidepressant and 222 on placebo spray, within 1,709 adults in safety studies [4].
Sources
[4]
Caveats
Rates are for esketamine. Racemic ketamine trials report dissociation as well [6].
ModerateVery common

Dizziness, nausea and vertigo

Shown to raise dizziness to 29% against 8%, nausea to 28% against 9%, and vertigo to 23% against 3% in esketamine trials.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
On esketamine with an oral antidepressant, dizziness occurred in 29% vs 8% on placebo, nausea 28% vs 9%, vertigo 23% vs 3%, numbness 18% vs 2%, anxiety 13% vs 6%, vomiting 9% vs 2% and feeling drunk 5% vs 0.5%. 4.6% of adults under 65 stopped for adverse reactions against 1.4% on placebo [4].
Population
346 on esketamine and 222 on placebo [4].
Sources
[4]
Caveats
Effects mostly occur on treatment days.
LimitedVery common

Emergence reactions at anesthetic doses

The Ketalar label reports confusion or agitation on waking from ketamine anesthesia in about 12% of patients, from dream-like states to hallucinations.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Emergence delirium occurred in about 12% during recovery, usually lasting a few hours, ranging from pleasant dream-like states to vivid imagery, hallucinations and confusion [12]. At the lower doses used around surgery, central nervous system adverse events occurred in 5% on ketamine against 4% on control (RR 1.2, 95% CI 0.95 to 1.4) [10].
Population
Patients given anesthetic doses [12]; 6,538 participants in 105 surgical trials [10].
Sources
[12], [10]
Caveats
Anesthetic doses are far higher than depression or pain doses.
ModerateCommon

Raised blood pressure

Shown to raise blood pressure after each dose, peaking at 40 minutes. Rises of 40 mmHg systolic or 25 diastolic occurred in 3% to 19% against 1% to 4%.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Esketamine raised systolic and diastolic pressure at all doses, peaking about 40 minutes after dosing and lasting about 4 hours. Rises of at least 40 mmHg systolic or 25 mmHg diastolic occurred at least once in 3% to 19% against 1% to 4% on placebo. Blood pressure increase was reported as an adverse event in 10% against 3%. The label contraindicates esketamine where a rise in blood pressure or skull pressure is a serious risk, such as aneurysm [4].
Population
346 on esketamine and 222 on placebo, plus other label trials [4].
Sources
[4]
Caveats
The band above is the adverse-event rate.
LimitedCommon

Bladder and urinary symptoms

Limited evidence: esketamine raised urinary frequency slightly, 3% against 0.5%. Severe bladder damage is described mainly in long-term recreational ketamine users.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Urinary frequency occurred in 3% on esketamine vs 0.5% on placebo, and no esketamine-related interstitial cystitis was seen in trials up to a year. The label reports ulcerative or interstitial cystitis with long-term off-label use or misuse of ketamine [4]. A review of psychiatric treatment studies found urinary symptoms in 0% to 24.5% of patients, mostly mild, with no change in urinary measures [13]. In recreational users with ketamine uropathy, frequency affected 77.1%, urgency 69.9% and hydronephrosis 30.2%, and bladder capacity averaged 95 mL [14].
Population
Label trials [4]; 27 studies of ketamine for psychiatric disorders [13]; 4,921 patients with ketamine-associated uropathy in 45 studies [14].
Sources
[4], [13], [14]
Caveats
The uropathy rates are among people who already had the condition, not a rate of harm in users [14]. Most treatment studies did not assess long-term use [13].
LimitedHow often is not known

Spravato REMS

The label states esketamine is given only in certified healthcare settings, taken under direct observation, with at least 2 hours of monitoring.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Because of sedation, dissociation, respiratory depression, abuse and misuse, Spravato is dispensed only to certified healthcare settings. Patients self-administer under a provider's observation and are monitored for at least 2 hours. Outpatients must be enrolled. Patients must arrange a ride home and not drive until the next day after restful sleep [4].
Population
Labeling statement [4].
Sources
[4]
Caveats
A regulatory program, not a measured harm. Compounded racemic ketamine given at clinics or at home is outside this program.
LimitedHow often is not known

Abuse, misuse and dependence

The label warns of abuse and misuse. In recreational users, drug liking for esketamine matched intravenous ketamine and exceeded placebo. Dependence is reported with prolonged ketamine use.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Ketamine and esketamine are Schedule III. In 34 recreational polydrug users, "drug liking" and "take drug again" scores for esketamine 84 and 112 mg matched intravenous ketamine 0.5 mg/kg and exceeded placebo. Physical dependence has been reported with prolonged ketamine use. No withdrawal symptoms were captured up to 4 weeks after esketamine stopped [4].
Population
34 recreational drug users in an abuse study, and trial participants [4].
Sources
[4]
Caveats
The label gives no rate of misuse in treated patients.
LimitedHow often is not known

Suicidal thoughts in young people

FDA states antidepressants raised suicidal thoughts and behaviors in people under 25 in pooled trials, 14 more per 1,000 under 18. Esketamine is not approved for children.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The esketamine label carries the antidepressant class warning: in pooled trials of other antidepressants, suicidal thoughts or behaviors rose by 14 per 1,000 under age 18 and 5 per 1,000 at 18 to 24, and fell at 25 and older [4].
Population
About 77,000 adults and 4,500 children in trials of other antidepressants [4].
Sources
[4]
Caveats
The data are from other antidepressant classes, not from esketamine itself.
LimitedHow often is not known

Thinking, memory and driving

The label reports slower thinking 40 minutes after an esketamine dose, back to placebo levels by 2 hours, and stable cognition over 1 to 3 years in open-label studies.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In healthy volunteers, a single dose impaired cognitive performance at 40 minutes but matched placebo at 2 hours. In 1-year and 3-year open-label studies, cognition stayed stable. Driving at 6 and 18 hours after 84 mg matched placebo, but two people stopped a driving test at 8 hours due to side effects. Long-term memory impairment is reported with repeated ketamine misuse [4].
Population
Healthy volunteers and open-label study participants [4].
Sources
[4]
Caveats
Long-term data are uncontrolled.
LimitedHow often is not known

Use with sedatives, opioids, stimulants and MAOIs

The label warns that benzodiazepines, opioids and alcohol may add to sedation, and that stimulants and MAOIs may raise blood pressure further.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label states CNS depressants such as benzodiazepines, opioids and alcohol may increase sedation, and that psychostimulants such as amphetamines, methylphenidate, modafinil and armodafinil, and MAO inhibitors, may increase blood pressure [4].
Population
Labeling statement [4].
Sources
[4]
Caveats
Predicted from how the drugs act. No rate is given.

Possible, not studied in people1

Untested

Pregnancy

Not studied in people. In animal studies, ketamine-type drugs raised nerve cell death in the developing primate brain, and the label states esketamine may cause fetal harm.

No study in people. This rests on animal studies.

The numbers and sources
Effect
The label states there are insufficient data in pregnant women. Drugs that block NMDA receptors raised nerve cell death in the developing brain of offspring when given to pregnant primates. Intranasal ketamine caused skeletal malformations in rabbits at doses toxic to the mother, and esketamine delayed development in rat pups. On these animal findings, the label states esketamine may cause fetal harm [4].
Population
Pregnant primates, rabbits and rats (animal) [4].
Sources
[4]
Caveats
No human pregnancy outcome data are given in the label.

Claims tested and not found

  1. That esketamine reduces suicide or suicidal behavior. The label states this has not been demonstrated, and in two trials clinician-rated suicidality did not differ from placebo at 24 hours [4].
  2. That one ketamine infusion relieves suicidal thoughts for weeks. Pooled trials found the effect from 4 to 72 hours, but not after [8].
  3. That ketamine eases every anxiety disorder. Pooled PTSD trials did not show a significant rise in response [9].

Related

SSRIsSNRIs

Sources

  1. Dean RL, Hurducas C, Hawton K, et al. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database of Systematic Reviews. 2021. https://doi.org/10.1002/14651858.CD011612.pub3
  2. Nikolin S, Rodgers A, Schwaab A, et al. Ketamine for the treatment of major depression: a systematic review and meta-analysis. eClinicalMedicine. 2023. https://doi.org/10.1016/j.eclinm.2023.102127
  3. Bahji A, Vazquez GH, Zarate CA. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders. 2021. https://doi.org/10.1016/j.jad.2020.09.071
  4. U.S. Food and Drug Administration. SPRAVATO (esketamine) nasal spray, prescribing information. 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d81a6a79-a74a-44b7-822c-0dfa3036eaed
  5. Reif A, Bitter I, Buyze J, et al. Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. New England Journal of Medicine. 2023. https://doi.org/10.1056/NEJMoa2304145
  6. Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. New England Journal of Medicine. 2023. https://doi.org/10.1056/NEJMoa2302399
  7. Wilkinson ST, Ballard ED, Bloch MH, 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. https://doi.org/10.1176/appi.ajp.2017.17040472
  8. Witt K, Potts J, Hubers A, et al. Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials. Australian & New Zealand Journal of Psychiatry. 2020. https://doi.org/10.1177/0004867419883341
  9. Whittaker E, Dadabayev AR, Joshi SA, et al. Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders. Therapeutic Advances in Psychopharmacology. 2021. https://doi.org/10.1177/20451253211056743
  10. Brinck EC, Tiippana E, Heesen M, et al. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database of Systematic Reviews. 2018. https://doi.org/10.1002/14651858.CD012033.pub4
  11. Orhurhu V, Orhurhu MS, Bhatia A, et al. Ketamine Infusions for Chronic Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Anesthesia & Analgesia. 2019. https://doi.org/10.1213/ANE.0000000000004185
  12. U.S. Food and Drug Administration. KETALAR (ketamine hydrochloride) injection, prescribing information. 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14e8f864-8b8a-4e7e-8439-e510d3107063
  13. Kerr-Gaffney J, Tröger A, Caulfield A, et al. Urological symptoms following ketamine treatment for psychiatric disorders: A systematic review. Journal of Psychopharmacology. 2025. https://doi.org/10.1177/02698811251350267
  14. Chan EOT, Chan VWS, Tang TST, et al. Systematic review and meta-analysis of ketamine-associated uropathy. Hong Kong Medical Journal. 2022. https://doi.org/10.12809/hkmj209194

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