Spravato is not the same as ketamine, though the two are closely related. Spravato (brand name for esketamine) contains only one half of the ketamine molecule, specifically the S-enantiomer. Standard ketamine is a 50/50 mix of two mirror-image molecules, the S-form and the R-form. That molecular difference leads to meaningful differences in how each drug is approved, administered, and experienced.
The Molecular Difference
Ketamine exists as two mirror-image versions of the same molecule, called enantiomers. Think of them like left and right hands: identical in composition but not interchangeable. Traditional ketamine (sometimes called “racemic ketamine”) contains equal parts of both versions. Spravato isolates just the S-enantiomer, which binds to receptors in the brain about four times more strongly than the R-enantiomer.
That stronger binding doesn’t necessarily translate to better antidepressant effects. Animal research has found that the R-enantiomer, despite weaker receptor binding, actually produces longer-lasting antidepressant responses in rodents. This is one reason researchers continue studying all forms of ketamine rather than assuming the most potent version at the receptor level is automatically the best treatment.
FDA Approval and Legal Status
Spravato is FDA-approved for two specific conditions: treatment-resistant depression in adults (either alone or alongside an oral antidepressant), and depressive symptoms in adults with major depressive disorder who have acute suicidal thoughts or behavior. It’s classified as a Schedule III controlled substance.
Standard ketamine, by contrast, has no FDA approval for depression. It was originally approved decades ago as an anesthetic. When clinics offer IV ketamine infusions for depression, they’re using it “off-label,” meaning a doctor is prescribing an approved drug for a purpose the FDA hasn’t formally evaluated. This distinction matters for insurance coverage. Spravato, as an FDA-approved treatment, is more likely to be covered by insurance plans, while IV ketamine for depression typically comes out of pocket.
How Each One Is Given
Spravato is a nasal spray administered in a certified healthcare setting. You cannot pick it up at a pharmacy and use it at home. The FDA requires it to be dispensed through a restricted program called a REMS (Risk Evaluation and Mitigation Strategy), which means every dose happens under medical supervision. After each session, you’re monitored for at least two hours while a healthcare provider checks your blood pressure, watches for sedation and dissociation, and confirms you’re stable enough to leave. You cannot drive for the rest of the day.
For treatment-resistant depression, the typical schedule starts with twice-weekly sessions for the first four weeks (the induction phase) at either 56 mg or 84 mg per spray. After that, sessions drop to once weekly for about a month, then taper to every two weeks or once weekly depending on how well you’re responding. The goal is to find the least frequent dosing that maintains your improvement. For patients with MDD and active suicidal ideation, the dose is 84 mg twice weekly for four weeks.
IV ketamine, on the other hand, is delivered through an infusion, typically over 40 minutes. Clinics set their own protocols since there’s no standardized FDA-approved regimen for depression. Most follow a common pattern of six infusions over two to three weeks, but this varies by provider.
How They Compare for Depression
A meta-analysis of seven observational studies covering 915 patients found no statistically significant difference in overall response or remission rates between IV ketamine and intranasal esketamine. However, IV ketamine appears to work faster. In one detailed analysis, the median number of treatments needed to achieve a response was 2 for IV ketamine versus 4 for intranasal esketamine. For remission, the gap was wider: 2 treatments for IV ketamine compared to 7 for esketamine. Another study found that 47% of IV ketamine patients responded by week one, compared to just 7% of those on intranasal esketamine.
That speed difference likely reflects the route of administration as much as the drug itself. IV delivery puts the full dose directly into the bloodstream, while nasal absorption is less complete and more variable.
Spravato does have strong trial data on its own merits. In the ESCAPE-TRD trial comparing esketamine nasal spray to quetiapine (a commonly used add-on medication for treatment-resistant depression), 55.7% of esketamine patients achieved remission by week 32, compared to 36.3% on quetiapine. The difference was already visible by week 8, with remission rates of 28.3% versus 18.6%. Patients on esketamine were also more likely to stay relapse-free through the study period.
Side Effects
Both drugs share a core set of side effects tied to their shared mechanism: dissociation (feeling detached from yourself or your surroundings), sedation, and temporary increases in blood pressure. These effects tend to peak within the first hour or two after a dose and resolve on their own, which is why the two-hour monitoring window exists for Spravato.
Real-world safety data suggests esketamine may produce fewer overall side effects than racemic ketamine, though dissociation and sedation remain the most commonly reported issues with Spravato by a wide margin. Ketamine activates the sympathetic nervous system, causing brief cardiovascular stimulation in both forms, so blood pressure monitoring is standard with either treatment.
One practical difference: because Spravato is always given under medical supervision through the REMS program, side effects are caught and managed in real time. IV ketamine clinics also monitor patients, but standards vary since the treatment isn’t regulated through a comparable federal program.
Cost and Access
Spravato’s FDA approval gives it a clearer path through insurance, but that doesn’t always mean it’s cheap. Copays, prior authorization requirements, and coverage limits vary widely by plan. Many insurers require documented failure of two or more antidepressants before approving Spravato, which aligns with the definition of treatment-resistant depression.
IV ketamine clinics typically charge per infusion, often between $400 and $800, and most insurance plans don’t cover it at all since it’s off-label. A full induction course of six infusions can run $2,400 to $4,800 or more. Some patients find the faster response with IV ketamine worth the out-of-pocket cost, while others prefer the insurance pathway and standardized monitoring that comes with Spravato.
Which One Is Right for You
The choice between Spravato and IV ketamine often comes down to access, insurance, and how quickly you need relief. If your insurance covers Spravato and you meet the criteria for treatment-resistant depression, it offers a well-studied, federally regulated treatment path with structured monitoring. If speed of response is a priority and cost isn’t a barrier, IV ketamine’s faster onset may be more appealing, though you’ll be navigating a less standardized treatment landscape. Both deliver the core antidepressant mechanism of ketamine. Neither is clearly superior to the other in overall effectiveness based on current evidence.