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What’s the difference between ketamine and esketamine?
Esketamine is the S-enantiomer of ketamine; standard racemic ketamine contains both the S- and R-enantiomers. The Drug Enforcement Administration describes the S-enantiomer as more potent, but that chemical distinction alone does not show that esketamine works better for depression.
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In the depression-treatment context, the products also differ in their FDA status, route, and access requirements. Esketamine is an intranasal spray with specific adult indications. Ketamine hydrochloride injection is labeled for anesthesia, while its use at subanesthetic intravenous doses for depression is off-label. “Off-label” means a clinician is prescribing or administering an FDA-approved medicine for a use that is not among the uses in its FDA-approved labeling; it does not mean the medicine is the same product or follows the same care pathway as esketamine.
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| Comparison | Esketamine (SPRAVATO) | Ketamine |
|---|---|---|
| Composition | S-enantiomer of ketamine (DEA). | Racemic ketamine contains both enantiomers (DEA). |
| Depression-use status in the cited sources | FDA-labeled for specified adult indications (FDA prescribing information, 2025). | Subanesthetic IV use for depression is off-label (NIH, 2019); the injection label is for anesthesia (DailyMed). |
| Route in the depression context described | Intranasal spray (FDA prescribing information, 2025). | Intravenous use in depression research; the cited injection label describes anesthesia (NIH, 2019; DailyMed). |
| Access and monitoring | Restricted SPRAVATO REMS, supervised administration, and observation (FDA prescribing information, 2025; DailyMed). | The sources cited here do not establish one universal protocol across off-label providers. |
| Which is more effective? | Not established by the sources cited here. | Not established by the sources cited here. |
Is esketamine FDA-approved for depression?
Yes. The 2025 FDA prescribing information lists two indications for adults:
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- Treatment-resistant depression, either as monotherapy or in conjunction with an oral antidepressant.
- Depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior, in conjunction with an oral antidepressant.
The second indication concerns depressive symptoms in a defined clinical setting. It should not be described as proof that esketamine prevents suicide or reduces suicidal behavior.
Why treatment access is restricted
SPRAVATO is a Schedule III controlled substance with potential for abuse and diversion. It is available only through the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS), which requires the treatment to be administered under supervision with observation safeguards. The restriction is part of how the treatment is provided, not an optional convenience or a take-home-use recommendation.
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What is ketamine used for?
Ketamine hydrochloride injection is FDA-labeled for induction and maintenance of anesthesia. The NIH describes subanesthetic IV ketamine treatment for depression as off-label. That distinction matters when discussing a clinician’s proposal: approval of ketamine injection as an anesthetic is not FDA approval of IV ketamine as a depression treatment.
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Ketamine and esketamine are clinician-directed controlled medicines, not consumer products. This comparison is not a guide to selecting a dose, obtaining a product, or administering either medicine without qualified medical supervision.
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What effects and side effects can occur?
Esketamine
FDA and DailyMed labeling warns of sedation, dissociation, respiratory depression, abuse or misuse, and increased blood pressure, among other risks. Dissociation can involve feeling detached from oneself or one’s surroundings, or experiencing altered perception. The label also warns that attention, judgment, thinking, reaction speed, and motor skills can be impaired. Patients must not drive or operate machinery until the next day after a restful sleep.
The label advises clinicians to assess patients with psychosis. Individual risks and precautions require discussion with the treating clinician; a simple description such as a “brief high” would leave out important safety information.
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IV ketamine
Ketamine is a dissociative drug with hallucinogenic effects, according to the DEA. In a 2019 summary of research involving 163 people with major depressive disorder or bipolar disorder and 25 healthy controls across five placebo-controlled trials over 13 years, the NIH reported that the most common short-term side effect after a single antidepressant dose of IV ketamine was feeling “strange or loopy.” That is a reported study observation—not a prediction for every patient or a complete account of long-term risks.
Both medicines can cause altered perception or dissociation and sedation. The presence, intensity, and course of effects vary; an individual response cannot be inferred from the chemical relationship between the medicines.
Which works better for depression?
The evidence cited here does not support a universal efficacy ranking between IV racemic ketamine and intranasal esketamine. There is no matched head-to-head comparison in these sources that would justify a claim that one is more effective, faster, or longer-lasting. Results from separate studies should not be treated as a direct contest when their formulations, routes, patient groups, comparators, schedules, or measured outcomes may differ.
A clinician can discuss how the treatment choice relates to a person’s diagnosis, prior treatment, health risks, and available care. The sources cited here do not establish a general price comparison, insurance-coverage rate, or access advantage; those depend on the payer, location, provider, indication, and current rules. Confirm expected costs and coverage with the insurer and treating clinician.
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