Ketamine and esketamine are closely related, but they are not the same medicine. Ketamine is a mixture of two mirror-image molecules. Esketamine, sold as Spravato, is one of those two molecules, made into a nasal spray that the FDA has approved for specific kinds of depression in adults.
Part of our guide: A Patient’s Guide to Ketamine and Spravato
The biggest practical difference is regulation. Ketamine is not FDA-approved for any psychiatric disorder, so using it for depression is off-label. Spravato has approved depression uses, boxed warnings and a required safety program that controls where and how it is taken.
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The two side by side
| Spravato (esketamine) | Ketamine (racemic) | |
|---|---|---|
| What it is | The S form of the molecule | A mixture of the R and S forms |
| FDA-approved use | Treatment-resistant depression in adults, alone or with an oral antidepressant; depressive symptoms in adults with major depression and acute suicidal thoughts or behavior, with an oral antidepressant | General anesthesia only |
| Use for depression | On-label for the uses above | Off-label |
| FDA-approved form | Nasal spray | Intravenous or intramuscular injection |
| Other forms in use | None approved | Compounded oral, lozenge and nasal products exist; these are not FDA-approved |
| Safety program | Required REMS with certified settings | The Spravato REMS does not cover it |
| Monitoring | At least 2 hours at every session, by requirement | Set by the clinician and the setting; practices vary |
| Controlled substance | Schedule III | Schedule III |
Sources: the Spravato label, the Ketalar label and an FDA warning letter from June 2026 that summarizes both.
What "off-label" does and does not mean
The FDA explains that healthcare providers generally may prescribe an approved drug for an unapproved use when they judge it medically appropriate. Off-label use also means the FDA has not determined the drug is safe and effective for that use.
For ketamine, this has real consequences. A 2017 consensus statement from an American Psychiatric Association task force pointed to small studies, little longer-term efficacy data and limited safety data, while still noting that ketamine may benefit some patients. That statement is several years old, and research has grown since, but a 2026 expert panel reached consensus on only 35 of 105 practical questions about ketamine and esketamine care.
What they share and how they act
Both are Schedule III controlled substances, and both can raise blood pressure and cause dissociation and sedation. Esketamine is one half of the ketamine mixture, so the overlap is expected. The Spravato label describes esketamine as blocking the NMDA receptor, a glutamate receptor, and says the way it produces an antidepressant effect is unknown. Claims that either drug "resets" the brain go beyond what the label can support.
Who should not use them
The Spravato label rules it out for people with aneurysmal vascular disease, an arteriovenous malformation, a history of bleeding in the brain, or an allergy to esketamine, ketamine or the other ingredients. It is not recommended during pregnancy. The Ketalar label rules out use when a significant rise in blood pressure would be a serious hazard, and in people with a known allergy to ketamine. Those Ketalar rules were written for anesthesia, so a clinician still has to judge the risks of any off-label plan for you.
How they differ in evidence
Both have research support, and the two research bases look different.
- Spravato went through the trial program required for FDA approval. Those trials and their limits are summarized in the label and in this overview of Spravato.
- Intravenous ketamine has been studied in many smaller trials and in head-to-head trials against ECT, with mixed results: one large trial found ketamine noninferior, and another in hospitalized patients favored ECT. A 2023 international review describes intravenous ketamine and intranasal esketamine as established treatments for treatment-resistant depression.
- Other ketamine forms have less evidence, as this comparison of routes explains.
Is one stronger than the other?
This is a common question without a settled answer. A 2023 meta-analysis of 49 randomized trials found effect sizes numerically greater for racemic ketamine than esketamine. That result needs caution for several reasons:
- It compares across separate trials with different doses, routes and study designs.
- The word "numerically" matters, because a bigger number across different studies does not prove one drug beats the other in the same people.
- A 2021 Cochrane review called for long-term non-inferiority trials comparing repeated ketamine and esketamine, along with rigorous real-world monitoring.
Be cautious of any website that says one is simply better. The honest answer for now is that direct long-term comparisons are still needed.
How they differ in safety rules
The same core risks appear for both drugs, since they are so closely related. The difference lies in how much the rules specify.
Spravato's boxed warning covers:
- Sedation, dissociation and respiratory depression. Patients can become sleepy, feel disconnected, or have slowed or stopped breathing after a dose, so they must be monitored for at least 2 hours at each session and then assessed before they can leave.
- Abuse and misuse. Spravato is a Schedule III controlled substance. Risk should be weighed before prescribing and watched for during treatment.
- Suicidal thoughts and behaviors in young people. Antidepressants increased these risks in pediatric and young adult patients in short-term studies. All antidepressant-treated patients should be watched closely for worsening or new suicidal thoughts. Spravato is not approved for anyone under 18.
Under the REMS, Spravato must be taken in a certified healthcare setting with a prescriber onsite and a pulse oximeter available. It may not be dispensed for use elsewhere.
For ketamine, the FDA has listed known safety concerns that include abuse and misuse, psychiatric events, increases in blood pressure, slowed breathing, and lower urinary tract and bladder symptoms. The FDA has also warned about compounded ketamine used without a clinician monitoring for sedation, dissociation and changes in vital signs, and said that because these products have no REMS monitoring requirement, they may be less safe. More detail is in this article on at-home ketamine.
Off-label ketamine is not automatically unsafe, and a labeled drug is not risk-free. The difference is how much of the safety framework comes from a regulator and how much depends on the individual clinician and setting. That is worth asking about directly.
What a session may look like
A Spravato session follows the label: you use the spray yourself under observation, have blood pressure checks, and stay for at least 2 hours. Ketamine sessions vary with the route, the setting and whether therapy is built into the visit. Some people prefer a therapy-linked format, and others prefer a standard medical protocol. The research on whether added psychotherapy changes outcomes is still thin, as this article on maintenance and integration describes.
Questions that help you compare
- Which option has the stronger evidence for this diagnosis, and how sure is that evidence?
- Is the recommended treatment on-label or off-label?
- What is the exact product and route, and is it FDA-approved or compounded?
- Who is present during and after dosing, and what is monitored?
- Which medical conditions or medicines would rule this out?
- How will progress be judged, and what would lead to stopping?
- What will the insurance plan do? Coverage often differs between the two.
Where to learn more
Mind Body Seven describes each treatment on its own page: Spravato and ketamine therapy. Which forms are appropriate is a question for an evaluation with a clinician.
FAQs
If one gave no benefit, could the other still help?
There is not enough good research for a general answer. Bring your full treatment history to a psychiatric evaluation so a clinician can weigh it with your other options.
Can ketamine and Spravato be used together?
This is not something to arrange on your own. Tell every prescriber about any ketamine or esketamine product you use, including compounded products bought online or through a telehealth platform.
Is Spravato just a brand name for ketamine?
No. It contains esketamine, one of the two molecules in ketamine, in a specific nasal spray with its own label. A compounded ketamine nasal spray is a different product and is not the same as Spravato.
