How Does Spravato Work? Nasal Esketamine Explained

If you've cycled through antidepressants without finding lasting relief, Spravato—a prescription nasal spray containing esketamine—offers a different approach. Rather than targeting serotonin like most antidepressants, it works through the brain's glutamate system, similar to oral ketamine therapy.

Approved by the FDA in 2019, Spravato offers the possibility of rapid improvement where traditional antidepressants have failed. But it also comes with specific requirements—including mandatory clinic visits and observation periods—that shape what treatment actually looks like.

This guide explains how Spravato works, what to expect during treatment, and how it compares to ketamine therapy you can do at home.

What Is Spravato?

Spravato is the brand name for esketamine, a nasal spray approved by the FDA for treatment-resistant depression. Esketamine is chemically related to ketamine—it's one half of the ketamine molecule (the S-enantiomer), isolated and formulated specifically for depression treatment.

Unlike ketamine infusions or oral ketamine, Spravato is self-administered as a nasal spray under medical supervision at certified clinics.

How Does Spravato Work?

Spravato blocks NMDA receptors in the glutamate system—a different set of brain chemicals than traditional antidepressants target. This sets off a chain reaction: a surge of glutamate (the brain's main "activating" chemical), which then activates AMPA receptors and kickstarts rapid mood-lifting signals. The process also releases BDNF, a protein that acts like fertilizer for brain cells, helping them grow and form new connections.

According to neuroplasticity research, these changes can happen within hours to days—a major departure from traditional antidepressants, which work through different mechanisms by gradually adjusting serotonin over weeks.

For some people, this boost in neuroplasticity helps other treatments work better, too. The brain's renewed ability to form connections may create conditions where therapy and lifestyle changes can finally gain traction.

What Does Spravato Treatment Look Like?

Spravato treatment starts with twice-weekly sessions for the first month (8 treatments total), then drops to once weekly for weeks 5–8. After that, you'll typically go every 1–2 weeks, depending on how you're responding.

Each session begins with 56mg (two nasal spray devices) and may increase to 84mg (three devices) based on your response. You'll spray the medication yourself under medical supervision, waiting 5 minutes between each device.

According to Spravato’s Risk and Mitigation Strategy (REMS), you must stay at the clinic for at least 2 hours after each dose. Staff will monitor your blood pressure, sedation levels, and any dissociative symptoms throughout this observation period. You'll also need a ride home—no driving yourself.

The most common side effects from Spravato treatment include dissociation (feeling detached or "floaty"), headache, dizziness, nausea, and sedation. According to clinical studies, most side effects start during or soon after dosing and often improve during the observation period, though some people experience lingering effects or decide to stop treatment.

Does Spravato Work for Treatment-Resistant Depression?

Spravato has proven helpful for many patients with treatment-resistant depression. FDA clinical trials found that 53–69% of people taking Spravato plus an oral antidepressant showed meaningful improvement, compared to 38–52% on placebo plus an oral antidepressant. Results vary, and some people don't respond or relapse after initial benefit, but these numbers offer real hope for those who've tried multiple medications without success.

Because ketamine therapy targets glutamate rather than serotonin, it promotes neuroplasticity in ways that traditional antidepressants don't. Many people notice improvement within hours to days rather than the typical 4–6 week timeline expected from traditional antidepressants.

The trade-off: Spravato requires twice-weekly clinic visits with mandatory 2-hour observation periods after each dose. It's a significant time commitment, but for people whose depression hasn't responded to conventional treatment, that commitment may be worthwhile.

What Makes Treatment-Resistant Depression So Challenging?

Treatment-resistant depression is complex, with multiple factors at play. If you haven't responded to several antidepressants, other brain systems beyond serotonin may be involved.

Research suggests that people with hard-to-treat depression often have impaired glutamate signaling and reduced neuroplasticity—the brain's ability to form new connections and adapt. Studies have also linked depression to lower levels of BDNF, a protein the brain needs to maintain healthy neural networks. These findings help explain why some people don't improve on standard antidepressants that target serotonin alone.

When brain regions responsible for mood, motivation, and decision-making become less connected, traditional treatments may not be enough. That's where NMDA-targeting treatments like ketamine therapy come in—they work through a different pathway that may help when other medications haven't.

What Are the Drawbacks of Spravato?

While Spravato can be effective, it comes with significant practical and safety considerations.

Safety concerns: Spravato carries FDA "black box" warnings—the agency's most serious alerts—for sedation, dissociation, respiratory depression, abuse potential, and suicidal thoughts in young adults. Mixing it with sedatives like benzodiazepines, opioids, or alcohol increases the risk of breathing problems.

Spravato may not be appropriate if you have:

• Blood vessel abnormalities in the brain or history of brain bleeding
• Unstable heart disease or uncontrolled high blood pressure
• History of psychosis
• Active problems with substance use

Time commitment: Between twice-weekly visits and 2-hour observation periods, you're looking at 4+ hours per session once you factor in travel—a significant burden for people with work or family obligations.

Cost: While Spravato is FDA-approved and often covered by insurance, out-of-pocket costs vary widely. Some patients pay relatively little with good coverage, while others face significant expenses depending on their plan, facility fees, and location.

No therapeutic integration: Spravato's protocol focuses on medication administration and safety monitoring. It doesn't include preparation or integration therapy—the kind of therapeutic support that helps people make sense of their experience and apply insights to daily life.

How Does Spravato Compare to At-Home Ketamine Therapy?

Given these drawbacks, many people wonder whether at-home ketamine therapy might be a better fit. Both treatments work through similar brain pathways—the differences come down to chemistry, delivery, and what happens around the medication.

Spravato contains only esketamine (one half of the ketamine molecule), while sublingual ketamine uses "racemic" ketamine containing both halves—esketamine and arketamine—in equal parts. Esketamine binds more strongly to NMDA receptors, so Spravato uses lower doses. Early research suggests arketamine may have its own antidepressant properties, though scientists are still studying this.

At-home ketamine therapy through Innerwell delivers sublingual lozenges to your door, so you can complete sessions in your own space. Because sublingual ketamine is off-label and doesn't have a REMS program, oversight works differently—virtual check-ins with your care team rather than in-person monitoring. Innerwell maintains safety through comprehensive screening, dosing guidance, and direct access to clinicians.

One major difference: Innerwell pairs ketamine with licensed therapist support. 

Preparation sessions help you set intentions before treatment. Integration therapy afterward helps you make sense of the experience and apply insights to daily life. Research increasingly suggests that ketamine's neuroplasticity window is most valuable when paired with therapeutic work—the medication opens a door, but therapy helps you walk through it.

Innerwell's plans start as low as $54 per treatment.

Is Spravato or At-Home Ketamine Right for You?

If traditional antidepressants haven't worked after multiple tries, you may be a good candidate for NMDA-targeting treatment. Both Spravato and sublingual ketamine offer similar brain-level benefits, so the choice often comes down to lifestyle, preferences, and practical considerations.

Spravato might be better if you prefer taking a nasal treatment, have insurance that covers it well, and can commit to twice-weekly clinic visits during the first month.

At-home ketamine through Innerwell might be better if you want to:

• Skip frequent clinic visits and undergo treatment when it’s most convenient
• Prefer the privacy and comfort of your own space, instead of clinical settings
• Benefit from therapist support throughout your treatment program
• Receive treatment at a lower price point

The ideal candidate for either option wants more than medication alone—someone looking for care that addresses both the biological and psychological sides of depression. 

Not everyone responds to ketamine-based treatments, and benefits can fade over time. These treatments work best when combined with therapy, lifestyle changes, and sometimes maintenance sessions.

Explore Your Ketamine Therapy Options With Innerwell

Spravato and at-home ketamine therapy both offer a different path forward when traditional antidepressants haven't worked. They target the same brain systems and promote the same neuroplasticity. The difference is what happens around the medication.

With Innerwell, you get more than ketamine delivered to your door. You get licensed clinicians who guide your treatment, therapists who help you prepare and integrate, and ongoing monitoring that evolves with your progress. Every step is designed to turn a window of neuroplasticity into lasting change.

Ready to explore what's possible? Take our free assessment.

Frequently Asked Questions

What's the difference between esketamine and racemic ketamine?

Ketamine is made of two mirror-image molecules: esketamine (S-ketamine) and arketamine (R-ketamine). Spravato contains only esketamine, while standard ketamine therapy uses both in equal parts. Esketamine binds more strongly to NMDA receptors. Early research suggests arketamine may have its own mood-lifting effects, but scientists are still studying this. The different compositions may explain why some people respond better to one form than the other.

How quickly does Spravato work compared to regular antidepressants?

Many people notice improvement within hours to days of their first Spravato treatment, compared to 4-6 weeks for traditional antidepressants. This faster timeline reflects how differently these medications work in the brain.

Why does Spravato require clinic visits while sublingual ketamine can be taken at home?

Spravato's FDA approval came with strict safety requirements called REMS that mandate in-clinic administration with 2-hour observation periods. This provides real-time monitoring for side effects like dissociation, sedation, and blood pressure changes. Sublingual ketamine, prescribed off-label, doesn't have these federal requirements—though responsible providers like Innerwell maintain safety through comprehensive screening, virtual monitoring, and direct clinician access.

Is ketamine therapy covered by insurance?

It depends. Spravato often has better coverage as an FDA-approved medication, though your actual costs depend on your specific plan. Innerwell has insurance partnerships in California and New York that bring at-home ketamine therapy costs to as low as $54 per treatment for covered patients. Self-pay options with transparent pricing are also available.