Ketamine is an old anesthesia drug (a medicine used to put people to sleep for surgery). Researchers found that it can ease depression within a day in some people.9 Esketamine is a close chemical cousin made from ketamine. It comes as a nasal spray with the brand name Spravato.8
These two are not the same thing, legally or medically. Esketamine is approved by the FDA for depression and is given only in certified clinics. Ketamine is FDA-approved only for anesthesia. When clinics use it for depression, it is "off-label" (used in a way the FDA has not approved).8 This page explains how each is used, the safety rules, the side effects, and what the research shows.
Key points
- Esketamine (Spravato) is FDA-approved for adults with depression that has not gotten better after other treatment. Since January 2025, it can be used alone or with an antidepressant pill.1,3
- You use the spray yourself, but only in a certified clinic. Staff watch you for at least 2 hours after each dose, and you cannot drive until the next day.1,6
- Common side effects include feeling disconnected or unreal, dizziness, nausea, sleepiness and a short rise in blood pressure.1
- Ketamine for depression (often by IV) is not FDA-approved for this use. Its benefit in studies was short-lived, and the research is less certain.8,9
- Neither drug is a first choice. A major U.S. guideline suggests them only after several other medicines have not worked.10
Who these treatments are for
Doctors call depression "treatment-resistant" when a person does not get better after trying at least two antidepressants.11 If this sounds like you or someone you love, our page When depression doesn't get better walks through all the options.
Esketamine is FDA-approved for adults in two situations:1
- Treatment-resistant depression (TRD). It can be used alone or with an antidepressant pill.
- Major depression with current, serious suicidal thoughts or actions. In this case, it is used with an antidepressant pill.
The label states clearly that esketamine has not been shown to prevent suicide.1 It is a treatment for the depression, not a replacement for crisis care, a safety plan or close support.
The VA and Department of Defense depression guideline (2022) suggests against using ketamine or esketamine as the first medicine. It suggests them as an option to add on for people who have not improved after several good tries of other medicines.10
The January 2025 change: esketamine alone
The FDA first approved Spravato on March 5, 2019. At first, it had to be used together with an antidepressant pill.2
On January 17, 2025, the FDA expanded the approval. Adults with treatment-resistant depression can now use esketamine as their only antidepressant (called monotherapy).3
The approval was based on a 4-week study of 378 adults. Depression was measured with a standard rating scale, where a lower score is better.4
| After 4 weeks | Esketamine (two dose groups) | Placebo spray |
|---|---|---|
| Average drop in depression score | 11.4 and 13.0 points | 6.3 points |
| Extra improvement over placebo | about 5 to 7 points | — |
Source for the table: FDA label for Spravato.4
What this means in daily life. People on placebo (a look-alike spray with no medicine) improved too. People on esketamine improved more, on average. The extra benefit was real but moderate. Some people feel much better. Others notice little change.
What the other esketamine studies showed
In an earlier 4-week study of 223 adults, all of whom started a new antidepressant pill, the group that also got esketamine improved by about 4 more points than the placebo group.4
A longer study looked at people who had already done well on esketamine. Those who kept using it were about half as likely to relapse (have the depression come back) as those switched to a placebo spray.4
A 2021 Cochrane review (a careful summary of all the trials) found moderate-quality evidence that esketamine helps more people reach remission (few or no symptoms) within 24 hours. The benefit could last up to four weeks with repeated doses. Esketamine also caused far more side effects than placebo.9 Moderate evidence
The Spravato REMS: safety rules for every dose
Because esketamine can cause strong sleepiness, a disconnected feeling and misuse, the FDA requires a safety program called a REMS (Risk Evaluation and Mitigation Strategy).1,6 What it means for you:
- Certified clinics only. The spray is given only in health care settings certified in the program. It is never handed out for use at home.6
- You enroll in a registry. Every patient is signed up in a registry (a list that helps the FDA track safety). You will be told about the risks first.6
- You use the spray yourself, with staff watching. A nurse or doctor supervises each dose.5
- At least 2 hours of monitoring. Staff check your blood pressure, breathing and alertness. They decide when you are stable enough to leave.1,5
- No driving until the next day. You may not drive or run machinery until you have had a full night of restful sleep. Someone else must take you home.1,5
Your clinic will also tell you not to eat for 2 hours before a dose, or drink for 30 minutes before.5
In 2026, the FDA approved Spanish translations of the REMS materials on the program website.7 If English is not your first language, ask the clinic for materials in your language and a free medical interpreter. The REMS program's phone line is 1-855-382-6022.6
To find a certified clinic, ask your psychiatrist. You can also see finding geriatric mental health care.
Side effects of esketamine
Most side effects start soon after the dose and go away the same day.5 In the main studies of esketamine with an antidepressant pill, these were the most common:1
| Side effect | How often |
|---|---|
| Feeling disconnected from yourself or your surroundings (dissociation) | about 2 in 5 people (41%) |
| Dizziness | 29% |
| Nausea | 28% |
| Sleepiness (sedation) | about 1 in 4 people (23%) |
| A spinning feeling (vertigo) | 23% |
| Numbness | 18% |
| Anxiety | 13% |
| Higher blood pressure | 10% |
Source for the table: FDA label for Spravato.1
Blood pressure. Esketamine raises blood pressure for a few hours. It peaks about 40 minutes after the dose. In the first month, a large jump happened in about 3% to 19% of people, compared with 1% to 4% on placebo.1 Staff check your blood pressure before each dose and recheck it afterward.1
Thinking. Thinking slowed a little about 40 minutes after a dose, then was back to normal by 2 hours. In studies lasting 1 and 3 years, thinking stayed stable.1
Bladder. Some people have to urinate more often or more urgently, or feel pain when urinating. Tell your doctor if this happens.1,5
Misuse. Esketamine is a controlled substance because it can be misused. People with a past alcohol or drug problem have a higher risk.1 Tell your doctor about any past substance use.
Who should not use esketamine: people with an aneurysm or other weak, bulging blood vessel, an abnormal tangle of blood vessels (arteriovenous malformation), a past bleed in the brain, or an allergy to esketamine or ketamine.1
Tell your doctor first if you have high blood pressure, heart disease, a past stroke, a brain injury, liver problems, a history of psychosis, or are pregnant or breastfeeding. It should not be used in pregnancy.5 Bring a full list of your medicines, including supplements.
Get help right away for chest pain, shortness of breath, a sudden severe headache, vision changes or a seizure. Call 911 for these signs at home.5
Ketamine clinics: what to know
Ketamine clinics often give ketamine by IV (a drip through a vein) for depression. Some offer shots, lozenges or nasal sprays. Because ketamine is FDA-approved only for anesthesia, this use is off-label. No ketamine nasal spray is FDA-approved.8
What the research shows. The Cochrane review found that IV ketamine may help some people within 24 hours. But the evidence was very uncertain. The benefit faded within about a week and was gone by two weeks.9 All the trials were short, so little is known about repeated treatment over months or years.9 Promising
In some studies, people may have been able to tell whether they got the real drug, since its effects are easy to notice. The Cochrane authors noted this may have made the drugs look better than they are.9
Risks. Ketamine's label warns about swings in blood pressure and heart rate, vivid dreams or hallucinations when waking, slowed breathing and liver injury.8 Ketamine is also sold illegally as a street drug.12 Long-term misuse has been linked to bladder damage and lasting memory problems.1
At-home ketamine. In 2022, the FDA warned about compounded ketamine nasal sprays (made by a pharmacy, not FDA-approved). It found reports of hallucinations, panic attacks, misuse and abuse. Most of these people used the spray at home without monitoring, often at higher strengths than esketamine.8 Limited research
Esketamine (Spravato)
- FDA-approved for depression in adults
- Nasal spray, used in a certified clinic
- REMS rules: registry, at least 2 hours of monitoring, no driving until the next day
- Several large trials, plus longer follow-up studies; moderate-quality evidence
- Insurance coverage varies by plan
Ketamine for depression
- FDA-approved only for anesthesia; off-label for depression
- Usually IV; some clinics offer other forms
- No REMS; safety steps depend on the clinic
- Mostly short studies; benefit often fades within a week
- Ask about the full cost before starting
Questions to ask a ketamine clinic:
- Who checks whether this is right for me? Will a psychiatrist review my history and medicines?
- Who gives the treatment, and who watches me afterward? For how long?
- How do you check my blood pressure and breathing? What happens in an emergency?
- How many sessions do you expect, and what is the total cost?
Be cautious of any clinic that promises a cure, skips a full health check, or does not involve your other doctors. Never buy ketamine online or from a friend.
Older adults
Esketamine's label notes no overall safety differences between people 65 and older and younger adults. But older adults had more short-term effects. In the TRD studies, about half of people 65 and older (49%) became very sleepy, compared with 19% on placebo. A large blood pressure jump happened in 17%, compared with 2%.1
A 4-week study just in people 65 and older did not show a clear benefit over placebo plus a new antidepressant pill.1 That does not mean it never helps older adults. It means the evidence is weaker.
If you are older, talk with your doctor about:
- Blood pressure, heart disease and past strokes
- Falls, because dizziness and sleepiness are common
- Getting a ride to and from every visit
- Other medicines that cause sleepiness
Ask about other options for hard-to-treat depression too, such as ECT or TMS. See depression in later life.
Paying for treatment
Insurance rules for esketamine vary by plan. Ask whether your plan needs prior approval, and ask the clinic to check your coverage before your first visit, including the clinic visit and monitoring time. Off-label ketamine may not be covered. For Medicare basics, see what Medicare covers for mental health.
For families and caregivers
You can help in practical ways:
- Plan rides. The person cannot drive home after any dose.1
- Keep a simple log of mood, sleep and side effects to bring to the doctor.
- Watch for changes in mood, especially early in treatment. The label warns that thoughts of suicide can rise in young people on antidepressants.5
- Look after yourself too. See supporting someone in treatment.
Do not start, stop or change any medicine on your own. Talk with the doctor or pharmacist first.
If someone is thinking about suicide or is in danger, call or text 988 (the Suicide and Crisis Lifeline) any time, day or night. If there is immediate danger, call 911. See when a family member is in a mental health crisis. Depression can get better, even after many tries. Help is available.
Common questions
Is esketamine the same as street ketamine?
How fast does it work?
Can I do this at home?
Is it a psychedelic?
Ketamine can change how you sense reality, and some people feel detached from their surroundings.12 It is different from psilocybin. See psilocybin and psychedelic research.
Sources
- U.S. Food and Drug Administration. SPRAVATO (esketamine) nasal spray prescribing information, revised March 2026. DailyMed, 2026. DailyMed
- U.S. Food and Drug Administration. Drugs@FDA: SPRAVATO, NDA 211243, approval history. FDA, 2026. Drugs@FDA
- U.S. Food and Drug Administration. Supplement approval letter, NDA 211243/S-016 (monotherapy for treatment-resistant depression). FDA, January 17, 2025. FDA letter
- U.S. Food and Drug Administration. SPRAVATO prescribing information, revised January 2025 (Section 14, Clinical Studies). FDA, 2025. FDA label
- U.S. Food and Drug Administration. SPRAVATO Medication Guide, revised September 2026. FDA, 2026. FDA Medication Guide
- SPRAVATO REMS Program. About the SPRAVATO REMS. FDA-required REMS program, 2026. SPRAVATO REMS
- U.S. Food and Drug Administration. REMS modification approval letter, NDA 211243/S-028 (Spanish translations). FDA, 2026. FDA letter
- U.S. Food and Drug Administration. FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray. FDA, 2022. FDA
- Dean RL, et al. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev, 2021. Cochrane
- U.S. Department of Veterans Affairs and Department of Defense. VA/DoD clinical practice guideline for the management of major depressive disorder, version 4.0. VA/DoD, 2022. VA
- National Institute of Mental Health. Depression. NIMH. NIMH
- National Institute on Drug Abuse. Ketamine. NIDA. NIDA
Education only. This page is general information written from the sources listed. It is not medical, legal or financial advice and does not replace a doctor, therapist or lawyer who knows your situation. How we write and check pages.
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