When standard antidepressants fail, people with severe depression often face months-or years-of trial and error. For many, the wait is too long. That’s where ketamine and esketamine come in. Unlike traditional pills that take weeks to work, these drugs can lift depression within hours. They’re not magic, but they’re among the fastest-acting tools we have today for people who’ve run out of options.
How They Work (And Why They’re Different)
Both ketamine and esketamine target the brain’s glutamate system, not serotonin like most antidepressants. Glutamate is a key chemical for brain communication, and when it’s out of balance, it can lock people into deep depressive states. These drugs help reset that system, sparking new connections between brain cells. It’s not just chemistry-it’s like rebooting a frozen computer.
But here’s the catch: they’re not the same drug. Ketamine is a racemic mixture-it contains two mirror-image molecules: (R)-ketamine and (S)-ketamine. Esketamine is just the (S)-version, purified and packaged as Spravato®. That small difference changes everything. The full ketamine mix seems to pack a stronger punch, but it also brings more side effects. Esketamine is milder, but sometimes less effective.
How They’re Given
IV ketamine is delivered through an IV drip over about 40 minutes. You’re in a quiet room, monitored by a nurse, and you might feel like you’re floating or seeing colors. It’s intense, but it usually wears off in under an hour. Most patients get six to eight treatments over three weeks, then maintenance doses every few weeks.
Esketamine is a nasal spray. You sit in a doctor’s office, spray one or two doses into each nostril, and wait under supervision for two hours. It’s less invasive, no needles, and you can go home afterward. But you need to do it twice a week during the first month. That’s a lot of trips to the clinic.
Which One Works Better?
A major 2025 study from Mass General Brigham tracked 153 people with treatment-resistant depression. 111 got IV ketamine. 42 got nasal esketamine. The results were clear: ketamine won.
- IV ketamine reduced depression scores by 49.22% after the full course.
- Esketamine dropped scores by 39.55%.
Ketamine also worked faster. Some patients felt better after just one session. Esketamine users needed at least two doses before they noticed any change. A 2020 meta-analysis of over 20 studies backed this up: IV ketamine consistently outperformed nasal esketamine across all time points-from 24 hours to eight weeks.
But numbers don’t tell the whole story. On patient forums, 63% of IV ketamine users said they felt relief within 24 hours. For esketamine, it was 52%. Still, 78% of esketamine users rated their overall experience as good or excellent. Why? Because the side effects were less scary.
Safety and Side Effects
Both drugs can cause dissociation-feeling detached from your body or surroundings. With IV ketamine, it happened in 42.3% of patients. For esketamine? 28.7%. That’s a big difference.
Hallucinations, dizziness, nausea, and elevated blood pressure are common with both. But because esketamine is a single molecule and given in controlled doses, it’s less likely to trigger severe reactions. That’s why the FDA approved it for people with acute suicidal thoughts. It’s safer to monitor in an outpatient setting.
IV ketamine carries a higher risk of abuse. It’s been used recreationally for decades. That’s why clinics require strict screening and follow-up. Esketamine is tightly controlled-only available through certified centers, and you can’t take it home.
Cost and Insurance
This is where things get messy.
A full course of eight IV ketamine infusions costs between $4,200 and $5,600. Spravato®? Around $5,800 to $6,900. At first glance, esketamine is more expensive. But here’s the twist: 67.4% of commercial insurers cover Spravato®. Only 38.2% cover IV ketamine.
So if you have insurance, esketamine might cost you less out of pocket. Without insurance? IV ketamine is cheaper. A 2025 JAMA Psychiatry analysis found IV ketamine delivers more value per dollar-$14,327 per quality-adjusted life year gained versus $18,764 for esketamine.
Who Gets Which Treatment?
Experts don’t agree on one-size-fits-all. Dr. John Krystal from Yale says: “IV ketamine’s superior efficacy makes it preferable for life-threatening depression.” If someone is actively suicidal and needs a fast response, IV ketamine is often the go-to.
Dr. Christine Denny from Columbia puts it differently: “Esketamine’s safety and convenience make it better for maintenance therapy.” If you’ve already stabilized with IV ketamine, switching to nasal esketamine for ongoing care is common.
For many, it comes down to personal tolerance. If you can handle a strong dissociative experience, IV ketamine might be worth it. If you’re anxious about needles, or you’ve had bad reactions before, esketamine is a gentler path.
Access Is Still a Big Problem
Even though ketamine clinics have exploded-from 142 in 2020 to over 1,000 in 2025-most of them are in big cities. Only 12.4% of U.S. counties have a certified Spravato® center. Rural areas? Almost none. And even if you live near one, wait times can be months.
Insurance hurdles make it worse. If your plan doesn’t cover ketamine infusions, you’re paying thousands out of pocket. Some clinics offer payment plans, but not all. And Medicare? It doesn’t cover IV ketamine for depression at all.
What About Long-Term Results?
Neither drug is a cure. Both require maintenance. A 2024 study followed patients for six months. Of those who responded to IV ketamine, 56.3% stayed in remission with monthly or biweekly sessions. For esketamine? 48.7%.
That’s not bad. But it means most people need ongoing treatment. There’s no evidence yet that either drug permanently rewires the brain. They’re tools-not fixes.
The Future Is Coming
The FDA just accepted Janssen’s application for a higher-dose Spravato® (112 mg), which could improve effectiveness. Researchers are also testing intramuscular ketamine-injections into the muscle-as a middle ground between IV and nasal. Early results suggest it’s as effective as IV, with fewer side effects.
And there’s exciting brain research. Scientists found that people who respond to ketamine show increased gamma wave activity in certain brain regions after treatment. That might one day let doctors predict who will benefit-before they even start.
Final Thoughts
Ketamine and esketamine aren’t for everyone. They’re not first-line treatments. You need to have tried at least two antidepressants without success. But if you’re stuck in deep depression and time is running out, they offer something no pill does: speed.
IV ketamine works faster and stronger. Esketamine is easier to tolerate and easier to access-if your insurance covers it. Neither is perfect. But for the right person, either one could mean the difference between surviving and starting to live again.
