The acute effects of ketamine nasal spray (sold as Spravato) typically last about 1.5 to 2 hours, with dissociative symptoms peaking around 40 minutes after administration. The antidepressant benefits, however, follow a completely different timeline, beginning within 2 to 4 hours of the first dose and persisting for days to weeks depending on the dosing schedule.
These two timelines cause a lot of confusion, so it helps to break them down separately.
How Long the Immediate Effects Last
After you spray esketamine into your nose, the drug reaches peak blood levels within 20 to 40 minutes. This is also when the dissociative side effects are strongest. You might feel spacey, detached, or like things around you aren’t quite real. In clinical studies, these sensations typically resolved within 1.5 hours of the dose. One detailed case report found that dissociative symptoms started about 23 minutes after administration and lasted roughly 43 minutes.
Blood pressure also rises temporarily, peaking at about 40 minutes and returning to normal within approximately 4 hours. This is the main reason you’re required to stay at the clinic for at least 2 hours after each dose. A healthcare provider monitors you until your blood pressure is stable and you’re alert enough to leave safely. You also can’t drive for the rest of the day after a session.
Once the drug clears the initial peak, blood levels drop rapidly over the first 2 to 4 hours. After that, a much smaller amount lingers in the body with a terminal half-life of about 7 to 12 hours, meaning trace amounts may take a day or more to fully clear your system. But the noticeable psychoactive effects are largely gone well before that.
How Long the Antidepressant Effect Lasts
The mood-lifting benefits operate on a different clock entirely. A meta-analysis of clinical trials found that esketamine produced measurable improvement in depression scores starting 2 to 4 hours after the very first dose. That improvement was still significant at 24 hours, remained detectable at one week, and held through the end of study periods at 3 to 4 weeks.
This rapid onset is the whole reason ketamine nasal spray exists as a treatment. Traditional antidepressants take 4 to 6 weeks to build up effectiveness. Esketamine can begin working the same day, which is particularly important for people in crisis or those who haven’t responded to other medications.
That said, a single dose doesn’t produce permanent relief. The antidepressant effect fades over days, which is why the treatment follows a structured dosing schedule designed to build and sustain the benefit over time.
The Dosing Schedule Over Time
Treatment is divided into phases, and the frequency decreases as your mood stabilizes.
- Induction (weeks 1 through 4): You receive the nasal spray twice per week. The starting dose is 56 mg, which your provider may increase to 84 mg based on how you respond and how well you tolerate the side effects.
- Optimization (weeks 5 through 16): Frequency drops to once per week. If your depression scores drop low enough by week 8, your provider may reduce sessions further to once every two weeks.
- Maintenance (week 17 onward): Most people settle into either a weekly or every-two-weeks schedule. Your provider reassesses roughly every four weeks and adjusts the frequency based on whether symptoms stay in remission.
The goal of this tapering approach is to find the minimum dosing frequency that keeps depression at bay. Some people do well at every two weeks. Others need to stay on weekly doses long term. If symptoms start creeping back on a biweekly schedule, the frequency gets bumped back up to weekly.
What Affects How Long It Stays in Your System
The drug is processed primarily by the liver. According to FDA pharmacology data, the terminal half-life of esketamine is about 11 hours, while its main breakdown product (noresketamine) has a half-life of about 7.5 hours. In practical terms, the drug is mostly cleared from your body within 2 to 3 days after a single dose.
People with significant liver problems may process the drug more slowly, which could extend both the duration of side effects and how long the drug remains detectable. Nasal congestion at the time of dosing can also affect absorption, since the medication needs to be absorbed through the lining of your nose. If you have a cold or severe allergies, your provider may adjust timing accordingly.
What to Expect at Each Session
Each visit follows a predictable pattern. You self-administer the spray under supervision (it’s two or three sprays depending on your dose, with a five-minute gap between each device). The dissociative effects build over the next 20 to 40 minutes, then gradually fade. During this time you’ll be in a comfortable setting, typically seated, and asked not to eat for at least two hours beforehand.
The two-hour monitoring period is a minimum. If your blood pressure is still elevated or you’re still feeling sedated at the two-hour mark, you stay longer. Most people feel close to normal by the time they’re discharged, though grogginess can linger for some. Plan for the appointment to take about two and a half to three hours total, and arrange a ride home since you won’t be cleared to drive until the following day.