Ketamine vs. Spravato: what's different

The short version: Spravato® is a nasal spray containing esketamine, one of the two mirror-image forms that make up ketamine. It's FDA-approved for treatment-resistant depression, which makes insurance coverage possible. Many plans cover it with prior authorization, but whether yours does depends on the plan. IV ketamine is the full (racemic) molecule, given by infusion. It's prescribed off-label for depression and almost always paid out of pocket. Neither is "the fake one." The choice usually comes down to coverage, logistics, and how your care team wants to dose and adjust.

One of ketamine's two mirror-image forms

Ketamine is a mix of two mirror-image molecules, called S-ketamine and R-ketamine. Spravato is the S half alone (hence "esketamine"). Janssen developed it as a nasal spray, ran the clinical trials, and won FDA approval. The first approval, in 2019, was for treatment-resistant depression alongside an oral antidepressant. In 2020, again alongside an oral antidepressant, it was approved for depressive symptoms in adults with major depression and acute suicidal thinking or behavior. In early 2025 it was approved as a standalone treatment for TRD. For the suicidal-thinking use, the label says it has not been shown to prevent suicide or reduce suicidal thoughts, and it does not replace hospital care when that is needed; our conditions page covers what else the label says.

IV ketamine skips all of that regulatory history. Ketamine itself has been an FDA-approved anesthetic since 1970. That lets licensed clinicians prescribe it off-label for depression. Off-label prescribing is a legal and common practice across medicine, but insurers rarely reimburse it for this use.

How you receive each one

An IV ketamine session means a monitored infusion, typically around 40 minutes. Dosing is based on your body weight and can be adjusted session to session. You'll be observed until the dissociative effects fade, and you'll need a ride home. Our what-to-expect guide walks through a full session, including the driving rules for both treatments.

Spravato is self-administered as a nasal spray, but not at home. It's dispensed only through a federal safety program (a REMS). The program requires you to take each dose at a certified treatment center, and then you stay under observation for at least two hours. In practice, a Spravato appointment often takes longer than an infusion appointment. That surprises people who assume a nasal spray is the quick option.

Cost and coverage: where the real fork is

This is the difference that decides it for most people.

• Spravato: because it's FDA-approved, many insurers cover it for treatment-resistant depression after prior authorization. They often require documentation that you've tried at least two antidepressants. Check your own plan. Our Spravato insurance page compares the published rules of eight commercial insurers, Medicare, and East Coast Medicaid programs. Your cost depends on whether your plan covers it under the medical or pharmacy benefit, plus any office fees. Without insurance, the drug alone runs from several hundred dollars to more than a thousand dollars per session, depending on the dose. That's before the clinic's own fees, so coverage is doing heavy lifting here.
• IV ketamine: off-label means insurers generally won't pay for the infusion itself. Clinics charge roughly $300–$800 per infusion depending on market, according to a commercial clinic directory. A typical induction series is six infusions. Some patients get partial reimbursement for the office visit or monitoring codes, but plan on cash. Our cost and insurance page breaks the math down.

If your budget is the constraint and your insurance covers Spravato, that's often the practical answer, even if you would have preferred infusions. If you have Medicaid, our East Coast guide shows what each state's drug list says about Spravato®.

Does one work better?

Nobody can tell you this with certainty. Be wary of anyone who does. Both have real evidence behind them. Esketamine has the large, FDA-reviewed trials. IV ketamine has decades of studies. An older 2021 meta-analysis that compared results across separate trials suggested infusions performed somewhat better. But a 2025 review looked at the studies that compared the two directly, almost all of them observational. It found no significant difference in response or remission, with infusions possibly working faster. Those comparisons are not randomized head-to-head trials, and study populations differ. The fair summary: both help a meaningful share of people with hard-to-treat depression. Neither helps everyone. Individual response is hard to predict either way.

One genuine clinical difference: infusion dosing is weight-based and adjustable, while Spravato comes in two fixed doses. Some prescribers value that flexibility, particularly when the first sessions produce side effects or no response.

How to think about the choice

• Insurance covers Spravato and money matters: start there. It's a closely related drug with a payer behind it. Our Spravato coverage guide shows what plans ask for, and Finding programs to compare lists where to look for a certified center.
• You've tried Spravato without benefit: some people respond to racemic ketamine anyway. Talk it through with a prescriber rather than assuming either way.
• You want dosing flexibility or IV access matters clinically: infusions give the care team more room to adjust.
• Neither is available nearby: check both clinic types before settling for an at-home program. The supervision trade-offs are real, and we cover them in our at-home ketamine article.

Whichever route you're leaning toward, the quality of the program matters more than the molecule. A Spravato center that rushes evaluation is a worse choice than an infusion clinic that screens carefully, and vice versa. Our guide to choosing a clinic lists the questions that separate the two.