Ketamine and Esketamine: Rapid-Acting Options for Depression
When standard antidepressants don’t work, what’s next?
For nearly one in three people with depression, pills like SSRIs and SNRIs just don’t cut it. After trying two or more medications with no real improvement, the hopelessness doesn’t fade-it deepens. That’s where ketamine and esketamine come in. Unlike traditional antidepressants that take weeks to show effects, these two drugs can lift the fog in hours. They’re not magic. But for people stuck in severe, treatment-resistant depression, they’re one of the few real options left.
What’s the difference between ketamine and esketamine?
Ketamine and esketamine are closely related, but not the same. Ketamine is a racemic mixture-it contains both the (R)- and (S)-molecules. Esketamine is just the (S)-molecule, purified and packaged as a nasal spray under the brand name Spravato. This small chemical difference changes everything: how it works, how it’s given, and how it feels.
Ketamine is given through an IV drip, usually over 40 minutes, in a clinic setting. Esketamine is sprayed into each nostril, and you sit quietly for two hours afterward. The IV route delivers the drug faster and more completely into the bloodstream. The nasal spray? It’s absorbed slower, and a lot of it gets swallowed or lost in the nose.
Which one works better?
A major study from Mass General Brigham, published in September 2025, followed 153 adults with treatment-resistant depression. Half got IV ketamine. The other half got esketamine. The results were clear: ketamine won.
- IV ketamine reduced depression scores by 49.22% after the full treatment course.
- Esketamine? Only 39.55%.
And speed matters. People on IV ketamine often felt better the same day-after just one session. Those on esketamine needed at least two doses before noticing any change. For someone in crisis, that difference isn’t just statistical-it’s life-saving.
But esketamine feels gentler. Is that a plus?
Yes. And that’s why it’s not all about which drug works better. It’s about which one you can tolerate.
Ketamine’s IV dose often causes strong dissociation-feeling detached from your body, blurred vision, dizziness. In the study, 42.3% of patients reported these effects. Esketamine? Only 28.7%. That’s a big drop. And for many, the intensity of ketamine is too much. One patient described it as "feeling like I was floating out of my skin." Another said, "I didn’t know if I’d come back."
Esketamine still causes dissociation, but it’s usually milder. Many users report feeling "dazed" or "spaced out," but not terrified. That’s why, despite lower efficacy, 78.4% of esketamine users rated their overall experience as "good" or "excellent," compared to just 62.9% for ketamine.
Cost and insurance: what you’ll actually pay
Money talks. A full course of eight IV ketamine treatments costs between $4,200 and $5,600. Spravato®? $5,800 to $6,900. At first glance, ketamine looks cheaper. But here’s the catch: insurance coverage.
Commercial insurers cover Spravato® for 67.4% of patients. For IV ketamine? Only 38.2%. That’s because esketamine is FDA-approved for depression. Ketamine isn’t. It’s used off-label, which means most insurers treat it like an experimental treatment.
Even if you pay out-of-pocket, there’s more to consider. IV ketamine requires a nurse, IV access, monitoring equipment, and a provider trained in anesthesia. Esketamine? You can get it in a psychiatrist’s office. Fewer staff, less equipment, lower overhead. That’s why clinics can charge less for ketamine-but still struggle to get paid.
Who gets which treatment?
It’s not one-size-fits-all. Experts split on this.
Dr. John Krystal at Yale says: "If someone is actively suicidal and needs a fast response, IV ketamine is the clear choice." He’s talking about people who can’t wait weeks, who are at risk of ending their lives. In those cases, speed and potency matter more than comfort.
Dr. Christine Denny at Columbia argues the opposite: "For people who’ve tried everything and just need to stay stable, esketamine’s lower side effects make it better for long-term use." She’s thinking about someone who’s not in crisis but can’t function at work or with their kids. They need relief without the scary trips.
Real-world data backs both views. On PatientsLikeMe, 63.2% of IV ketamine users said they felt relief within 24 hours. But 78.4% of esketamine users said they’d recommend it to a friend. One person wrote: "I cried during my first esketamine session-not from sadness, but because I could finally breathe again."
What about safety and risk?
Both drugs are controlled substances. Ketamine has been a Schedule III drug since 1999. Esketamine got the same classification in 2019. That means they’re not addictive like heroin or cocaine-but they can be misused.
IV ketamine carries a higher risk of abuse because it’s more potent and can be snorted or injected recreationally. That’s why clinics require you to stay for two hours after treatment, with trained staff watching you. Esketamine is administered under direct supervision too, but the nasal spray form is harder to divert.
Long-term risks? Still being studied. Both drugs can raise blood pressure temporarily. Ketamine may affect the bladder with frequent use. Esketamine has been linked to mild dizziness and nausea. Neither has shown signs of brain damage in clinical doses.
Access is still a huge problem
Even if you qualify, you might not be able to get treatment.
Only 12.4% of U.S. counties have certified Spravato® centers. For IV ketamine? Even fewer. Most clinics are in big cities. Rural areas? Forget it. And even if there’s a clinic nearby, waitlists can be months long.
Insurance denials add another layer. One woman in Ohio spent six months appealing her insurer before they finally covered ketamine. She said, "I almost gave up. I didn’t think I’d live to see my daughter’s graduation."
What’s coming next?
The field is moving fast. In September 2025, the FDA accepted a new, higher-dose version of Spravato® (112 mg) for review. If approved, it could mean fewer treatments and better results.
Researchers are also testing intramuscular ketamine-injections into the muscle. It’s faster than nasal spray, less invasive than IV, and could bridge the gap between the two. Early trials look promising.
And then there’s brain science. A November 2025 study in Nature Mental Health found that people who responded to ketamine showed a clear spike in gamma brain waves right after treatment. That pattern might one day help doctors predict who will benefit-before they even start.
Is this the future of depression treatment?
Not alone. Ketamine and esketamine aren’t cures. They’re tools. Most people need ongoing maintenance-doses every few weeks. Many still take oral antidepressants alongside them. Therapy helps too.
But for the first time in decades, we have something that works fast for people who had no hope. That’s huge.
If you’ve tried everything and still feel broken, this isn’t a last resort. It’s a new path. Talk to a psychiatrist who knows these treatments. Ask about IV ketamine vs. esketamine. Ask about costs. Ask about waitlists. Don’t assume you’re out of options. You’re not.
Is ketamine FDA-approved for depression?
No, ketamine itself is not FDA-approved for depression. It was approved in 1970 as an anesthetic. Its use for depression is "off-label," meaning doctors can prescribe it for that purpose, but it’s not officially labeled for it. Esketamine, the nasal spray version (Spravato®), is FDA-approved specifically for treatment-resistant depression and acute suicidal ideation.
How quickly do ketamine and esketamine work?
Ketamine often works within hours-many patients report feeling better after the first IV session. Esketamine usually takes two doses before noticeable improvement. Both are much faster than traditional antidepressants, which can take 4-8 weeks to kick in.
Do I need to stay at the clinic after treatment?
Yes. Both treatments require a mandatory 2-hour monitoring period after each dose. This is because of the risk of dissociation, dizziness, or elevated blood pressure. You cannot drive yourself home. You’ll need someone to pick you up.
Can I use ketamine or esketamine if I have high blood pressure?
Both drugs can temporarily raise blood pressure. If you have uncontrolled hypertension, you may not be eligible. Your provider will check your blood pressure before and after treatment. Stable, well-managed high blood pressure is usually okay, but you’ll need close monitoring.
Are these drugs addictive?
They have potential for misuse, but addiction is rare when used medically under supervision. Recreational users who abuse ketamine regularly can develop dependence. In clinical settings, with controlled dosing and monitoring, the risk is low. Esketamine’s nasal spray form is harder to misuse than IV ketamine.
How long do the effects last?
After a full course of 6-8 treatments, most people feel better for weeks to months. Maintenance doses-usually every 1-3 weeks-are often needed to keep symptoms away. One study found that 56% of IV ketamine responders stayed in remission at six months with regular maintenance.
Can I take other antidepressants with ketamine or esketamine?
Yes. In fact, esketamine is only approved when used with an oral antidepressant. Many people continue taking SSRIs, SNRIs, or other meds while receiving ketamine or esketamine. The combination often works better than either alone.
Is there a difference in side effects between IV ketamine and nasal esketamine?
Yes. IV ketamine causes stronger dissociation, hallucinations, and dizziness more often-about 42% of patients report these effects. Esketamine causes milder versions in about 29% of users. Nausea is more common with esketamine. Both can raise blood pressure temporarily.
What happens if I don’t respond to either treatment?
If neither ketamine nor esketamine helps, other options exist: transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), or newer experimental treatments like psilocybin-assisted therapy. Your psychiatrist can help you explore these next steps. Response rates aren’t 100%, but many people find relief after trying multiple approaches.
Can I get ketamine or esketamine from my regular doctor?
No. Both require administration in certified clinics under strict supervision. Ketamine must be given by providers trained in anesthesia. Esketamine can be given in psychiatric offices, but only if they’re certified under the FDA’s Risk Evaluation and Mitigation Strategy (REMS) program. Your primary care doctor can refer you, but they can’t prescribe or administer it.
What’s the bottom line?
Both ketamine and esketamine offer real, rapid relief for people who’ve run out of options. Ketamine works faster and stronger. Esketamine is easier to take and gentler on the mind. Cost and insurance play a huge role. Access is still limited. But for the first time, there’s real hope for those who’ve been told there’s nothing else left.
If you’re struggling and nothing else has worked, don’t give up. Ask your psychiatrist about these treatments. Ask about the research. Ask about your options. You deserve to feel better-and now, there’s a path forward.
