Ketamine and esketamine are related but not interchangeable — one is an FDA-approved, REMS-controlled nasal spray, the other a 60-year-old anesthetic used off-label. Here's how they differ.
People use "ketamine" and "esketamine" almost interchangeably, and clinics sometimes blur them on purpose. They are closely related molecules, but the practical differences — approval, insurance, protocol, and cost — are large.
The chemistry in one paragraph
Ketamine is a mixture of two mirror-image molecules, called enantiomers. Esketamine is just one of them — the "S" enantiomer — isolated and concentrated. Because that enantiomer binds the NMDA receptor more tightly, esketamine is roughly twice as potent by weight, so doses are measured in milligrams delivered by nasal spray rather than infusion rates in a vein.
Approval status: the difference that drives everything else
Ketamine (as racemic ketamine) is FDA-approved as a general anesthetic. Using it for depression, anxiety, PTSD, OCD, or chronic pain is off-label. Esketamine, marketed as SPRAVATO®, is the only ketamine-based medicine FDA-approved for a psychiatric indication: treatment-resistant depression in adults (as monotherapy or with an oral antidepressant) and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior (with an oral antidepressant) 1. Its effectiveness in preventing suicide or reducing suicidal ideation or behavior has not been demonstrated 1.
Practical consequence #1: insurance. SPRAVATO® for an approved use is frequently covered, though prior authorization is standard — see what to ask before starting SPRAVATO®. IV, IM, and oral ketamine for psychiatric conditions are almost always self-pay; our cost guide has the details.
Practical consequence #2: the REMS program. SPRAVATO® is dispensed only through a restricted program in certified settings, with at least two hours of observation after each dose, because of boxed warnings for sedation, dissociation, respiratory depression, abuse and misuse, and suicidal thoughts and behaviors 1. IV ketamine clinics are not part of REMS — which does not mean they are unregulated, but it does mean the oversight framework differs and you are relying on the clinic's own standards. That makes vetting the clinic more important, not less.
Route and session shape
IV ketamine is delivered over 40–60 minutes in a recliner, usually in a series of six or so infusions over two to three weeks, sometimes followed by maintenance sessions. SPRAVATO® is a nasal spray the patient self-administers under supervision, twice a week at first, tapering to weekly or biweekly, with the same two-hour observation window each time. Our what-to-expect guide to a first ketamine session describes the infusion experience; the esketamine experience is milder and shorter but the monitoring routine is stricter.
Evidence
Both routes have randomized-trial support for treatment-resistant depression. IV racemic ketamine has the larger and longer research base; esketamine has the label. For anxiety, PTSD, OCD, and chronic pain, no ketamine-based medicine is approved, and evidence ranges from promising (PTSD, pain) to early (OCD) — our condition guides break that down per condition.
How to choose between them
That is a question for a prescriber who knows your history, not a directory. What a directory can do is show you who offers what: our provider directory lists clinics with their treatment details, and our complete 2026 ketamine guide maps the whole landscape.
Sources
- FDA Prescribing Information for SPRAVATO® (esketamine), revised January 2025: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf. Editorial interpretation: comparisons of cost, protocol shape, and clinic practice outside the label reflect publicly reported patterns, not a clinical recommendation.
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This report is educational and is not medical advice. Coverage, availability and eligibility can change; verify details with the named source or your care team.