Ketamine and Esketamine (Spravato)

What ketamine is and how it works

Ketamine blocks the NMDA receptor, a docking site of the messenger glutamate. At high doses it switches off consciousness; below that, it produces a feeling of detachment from body, thoughts and surroundings, known as dissociation. Esketamine is one of the two mirror-image forms of the molecule and the active ingredient in the approved nasal spray.

The speed is remarkable: the antidepressant effect sets in within hours, not after weeks as with classic antidepressants. Exactly how this effect comes about has not yet been clarified. Blocking the receptor is the beginning of the chain, not its explanation.

What the studies show

Murrough 2013: ketamine versus an active placebo

73 people with treatment-resistant depression received a single infusion, either ketamine or the anesthetic midazolam, which also has noticeable effects and is meant to support blinding. After 24 hours, the depression scale was 7.95 points lower on ketamine, and the response rate was 64 versus 28 percent. The authors themselves wrote that data on duration and safety are lacking.

TRANSFORM-2, 2019: the nasal spray in the approval trial

227 patients switched to a new antidepressant, plus esketamine or a sham spray. After 4 weeks, the difference was 4.0 points on a scale of 0 to 60. 7 percent discontinued on esketamine because of side effects, 0.9 percent on placebo.

SUSTAIN-1, 2019: relapse prevention

Those who had achieved stable remission on esketamine were either kept on treatment or switched to a sham spray. Relapses: 26.7 versus 45.3 percent. Mathematically, 6 people must continue treatment to prevent one relapse. The flip side: the effect apparently does not last on its own after stopping.

ESCAPE-TRD, 2023: esketamine versus quetiapine

676 patients, esketamine or the add-on drug quetiapine. After 8 weeks, 27.1 versus 17.6 percent were in remission. The trial was open-label, only the raters did not know the groups, and the manufacturer funded it.

ELEKT-D, 2023: infusion versus electroconvulsive therapy

403 patients who had been referred for electroconvulsive therapy. On ketamine infusions, 55.4 percent responded, on electroconvulsive therapy 41.2 percent; ketamine was thus not inferior. This trial was also open-label, and 38 people dropped out before the start of treatment, more of them in the electroconvulsive group.

Where the data stop

The trials show a rapid effect, but not one that lasts on its own. In the meta-analysis, the advantage of esketamine was no longer significant during repeated doses and at follow-up, whereas it was for racemic ketamine. For repeated infusions over months, as offered off label, there are far fewer controlled data than for the nasal spray. Blinding is difficult because the dissociation reveals who is receiving the active drug.

For recreational use and microdosing, the data stop entirely: we did not find controlled human studies on ketamine microdosing, only animal experiments. The experience from depression treatment cannot be transferred, because there selected patients are treated under supervision.

Status, approval and legal

In the EU, esketamine nasal spray (Spravato) has been approved since December 18, 2019: together with an SSRI or SNRI for adults with treatment-resistant depression who have not responded to at least two antidepressants, and also as a short-term treatment in a psychiatric emergency. The spray is only administered in the practice or clinic under supervision; blood pressure is checked before and after. In the US it is also approved as sole treatment, as a Schedule III controlled substance, and available only through a safety program.

In Germany, ketamine and esketamine are prescription-only and listed in Annex 1 of the German Prescription Drug Ordinance (Arzneimittelverschreibungsverordnung), not in the German Narcotics Act (Betäubungsmittelgesetz) (as of October 2026). Ketamine infusions for depression are an unapproved use for which physicians take responsibility in the individual case. Recreational use is misuse of a prescription-only medicine.

Safety

On esketamine, dissociation occurs in 27 percent of those treated, severe in fewer than 4 percent, usually over after about an hour and a half. In addition there are nausea, dizziness, headache, drowsiness and a temporary rise in blood pressure. Particular caution is required with a history of psychosis, mania or bipolar disorder.

The prescribing information mentions dependence and tolerance with prolonged ketamine use and, on stopping, craving, anxiety, tremor, sweating and palpitations. The clearest harm is to the bladder: a meta-analysis of 45 studies with 4,921 patients, mostly recreational users, found urinary frequency in 77.1 percent, bladder pain in 60.4 percent and urinary retention in the kidneys in 30.2 percent; the bladder held on average only around 95 milliliters. Improvement occurred only with abstinence. In the esketamine trials there was no interstitial cystitis, but there were more urination complaints than on placebo.

Sources

• EMA, Spravato: product information (EPAR), last updated January 23, 2025
• US prescribing information for Spravato (DailyMed, September 2026 version)
• German Prescription Drug Ordinance (Arzneimittelverschreibungsverordnung), Annex 1 (ketamine, esketamine)
• Popova V et al., Am J Psychiatry 2019 – TRANSFORM-2, esketamine nasal spray plus antidepressant, 227 patients
• Daly EJ et al., JAMA Psychiatry 2019 – SUSTAIN-1, relapse prevention with esketamine
• Reif A et al., N Engl J Med 2023 – ESCAPE-TRD, esketamine versus quetiapine, 676 patients
• Murrough JW et al., Am J Psychiatry 2013 – ketamine infusion versus midazolam, 73 patients
• Anand A et al., N Engl J Med 2023 – ELEKT-D, ketamine versus electroconvulsive therapy, 403 patients
• Nikolin S et al., EClinicalMedicine 2023 – meta-analysis, 49 RCTs on ketamine and esketamine in depression
• Chan EOT et al., Hong Kong Med J 2022 – systematic review and meta-analysis on ketamine uropathy