Esketamine (Spravato): Compound Guide

If someone is in danger right now

After a treatment session, serious drowsiness, trouble breathing, very high blood pressure symptoms or thoughts of suicide need emergency help: call 911 in the United States, or call or text 988 for a mental health crisis. US Poison Help is 1-800-222-1222. [1]

What esketamine is

Esketamine is the S-enantiomer (one of two mirror-image forms) of ketamine. The US label calls it a non-competitive antagonist of the NMDA receptor, a glutamate receptor. [2] The brand-name nasal spray is Spravato. It is a medicine made by a drug company and approved by regulators; it is not a natural product or a classic psychedelic. NIDA calls esketamine a ketamine derivative and groups ketamine with dissociative drugs. [3]

It is not the same as ketamine. Ketamine (a mixture of two forms) is approved as an anesthetic, while the FDA says Spravato, which contains only esketamine, is approved as a nasal spray for depression. [4] See Ketamine: Compound Guide and Ketamine vs Esketamine.

Regulatory category

Evidence labels used on this page: approved medicine, promising but limited, mixed, evidence of harm.

• United States (FDA label revised 04/2025, as read). Spravato is indicated for treatment-resistant depression (TRD) in adults, alone or with an oral antidepressant, and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior, together with an oral antidepressant. The label says its effectiveness in preventing suicide or reducing suicidal ideation has not been shown, and that it is not approved as an anesthetic or for pediatric patients. [2] Check the current label, as labels are updated.
• European Union. The European Medicines Agency lists Spravato as authorized for adults with major depression resistant to treatment, in combination with an SSRI or SNRI when at least two other treatments have failed. [5] Other countries: not verified here.
• United States (federal control). The label describes esketamine as a Schedule III controlled substance. [2] Read 2026-10-22. Laws change; this is not legal advice.

The safety program

The Spravato label has a boxed warning for sedation, dissociation, respiratory depression, abuse and misuse, and suicidal thoughts and behaviors in young people taking antidepressants. [2] It is available only through a restricted program, the Spravato REMS (Risk Evaluation and Mitigation Strategy). Healthcare settings must be certified, and the label says to monitor patients for at least two hours after administration. [2] The EMA likewise says it is used in a clinic or doctor's office under direct supervision. [5] This is a medical safety system, and treatment decisions belong with the prescriber.

What research shows (treatment-resistant depression)

Short-term, with an oral antidepressant: approved medicine; the measured difference from placebo was 4 points. In the label's Study 1, 223 adults with TRD under 65 received esketamine or placebo nasal spray, each with a newly started oral antidepressant. After four weeks, the MADRS (a 0 to 60 depression scale) improved by 19.8 points with esketamine and 15.8 with placebo, a difference of 4.0 points (95% CI 0.6 to 7.3). [2]

Versus quetiapine: promising but limited. In ESCAPE-TRD, 676 people with TRD on an SSRI or SNRI were randomized to esketamine nasal spray or extended-release quetiapine. The trial was open-label with raters unaware of group, and it was funded by Janssen EMEA. At week 8, 27.1% had remission with esketamine against 17.6% with quetiapine. [6] Side effects were more frequent with esketamine (91.9% vs 78.0%) but were typically mild or moderate and short; fewer people stopped treatment because of them (4.2% vs 11.0%). [7]

Comparisons with ketamine: insufficient evidence. I did not find a head-to-head randomized trial of intranasal esketamine and ketamine; a network meta-analysis made indirect comparisons and had few patients on intravenous ketamine. [8]

Long-term: A 2026 systematic review reported no evidence of cumulative organ toxicity over 3 to 12 months of typical follow-up, with heterogeneous safety monitoring in the studies. [9]

Risks and adverse effects

• Common reactions in TRD trials: dissociation, dizziness, nausea, sedation, vertigo, numbness, anxiety, lethargy, increased blood pressure, vomiting, feeling drunk and headache. [2]
• Dissociation: 61% to 84% of treated patients developed dissociative or perceptual changes. [2]
• Blood pressure: it raises blood pressure at all recommended doses, peaking around 40 minutes and lasting about 4 hours. [2]
• Thinking and driving: the label warns of impaired attention and judgment and says not to drive or operate machinery until the next day after a restful sleep. [2]
• Bladder: cystitis has been reported with long-term off-label ketamine use; lower urinary tract symptoms were more frequent with esketamine than placebo in trials. [2]
• Abuse and misuse: the label calls for assessing each patient's risk before prescribing. [2]

Special groups and interactions

Contraindicated: aneurysmal vascular disease, arteriovenous malformation, intracerebral hemorrhage, or known hypersensitivity to esketamine or ketamine. [2] Pregnancy: not recommended; breastfeeding: not recommended during treatment. [2] Alcohol, benzodiazepines and opioids may increase sedation, and stimulants may increase blood pressure. [2] Do not stop or change any medicine because of this page; talk with your prescriber. See Treatment-Resistant Depression: Psilocybin, Ketamine and Esketamine Evidence.