Quick answer: esketamine (Spravato) and ketamine are closely related but not the same. Ketamine is the original ("racemic") compound — a 50/50 mix of two mirror-image molecules, R-ketamine and S-ketamine — and it is used off-label for depression. Spravato is the brand name for esketamine, the isolated S-ketamine molecule, delivered as a nasal spray and FDA-approved for treatment-resistant depression (TRD) and major depressive disorder with acute suicidal ideation. They share the same core mechanism in the brain; the practical differences are molecule, delivery route, regulatory status, and insurance coverage.
Medically reviewed by Benjamin Yudkoff, MD — Co-Founder and Chief Medical Officer at Lumin Health, and Instructor in Psychiatry at Harvard Medical School. Bio. Last reviewed June 15, 2026. Lumin Health offers both esketamine (Spravato) and IM ketamine injections across our Boston and DC-area locations.
What is ketamine?
Ketamine is a medication first approved by the FDA decades ago as an anesthetic, now widely studied for its rapid effects in depression. Chemically it is a racemic compound: an equal mix of two mirror-image versions of the same molecule — R-ketamine and S-ketamine. (Think of your reflection in a mirror or a left-hand and right-hand pair: it's the same object, just reversed.) For mental health conditions, ketamine is used off-label — prescribed for an indication the FDA hasn't formally approved, which is legal, common, and provably safe in psychiatry. Ketamine can be delivered intravenously (IV), intramuscularly (IM), or as a compounded lozenge or nasal spray, and clinicians point to evidence across major depression, bipolar depression, OCD, PTSD, and anxiety.
What is esketamine (Spravato)?
Spravato is the brand name — developed by Janssen (Johnson & Johnson) — for esketamine, the isolated S-ketamine molecule. It is the only form of ketamine that is FDA-approved specifically for mental health conditions like depression, with two indications: treatment-resistant depression (TRD) and major depressive disorder with acute suicidal ideation or behavior. Spravato is a nasal spray you self-administer under direct medical supervision at a certified site, where you're monitored for two hours or more after each dose. Because of those safety requirements it is dispensed through a federal REMS program and cannot be taken home.
The mirror-image science: R- vs. S-ketamine
The single biggest difference is the molecule. S-ketamine (the Spravato form) is the more pharmacologically active orientation at the brain's NMDA receptor, and it absorbs reliably across the nasal mucosa — part of why a nasal-spray formulation was viable for esketamine specifically.[1] R-ketamine is not absorbed the same way. Isolating S-ketamine is what made a standardized, FDA-reviewable nasal product possible. Check out more at our blog specifically about the differences between S-ketamine and R-ketamine.
At a glance: Spravato vs. ketamine
- Molecule — Spravato: isolated S-ketamine. Ketamine: a 50/50 mix of R- and S-ketamine.
- FDA status — Spravato: FDA-approved for TRD and MDD with suicidal ideation. Ketamine: used off-label for depression (FDA-approved as an anesthetic).
- Delivery route — Spravato: nasal spray, self-administered under supervision. Ketamine: IV, IM, or compounded lozenge/nasal spray.
- Setting & monitoring — Spravato: certified site, monitored two hours or more after each dose (REMS). Ketamine: medical setting with monitoring appropriate to the route.
- Insurance — Spravato: often covered, including Medicare, subject to plan and prior authorization. Ketamine: generally not covered, usually out-of-pocket.
- Evidence base — Spravato: TRD and MDD-with-suicidality (the approval indications). Ketamine: broader off-label use studied across MDD, bipolar depression, OCD, PTSD, and anxiety.
Is the mechanism of action different between ketamine and Spravato (esketamine)?
No — at the level of the brain, the mechanism is essentially the same. Both esketamine and racemic ketamine act on the glutamate/NMDA system, a pathway distinct from traditional antidepressants that target serotonin. Research links the rapid antidepressant effects of NMDA-receptor antagonists like ketamine to fast synapse formation in the brain (Li et al., Science, 2010[2]). The meaningful differences between Spravato and ketamine are practical — molecule, delivery, regulation, and access — not mechanistic.
What does "off-label" ketamine mean?
"Off-label" means a medication is prescribed for a use the FDA hasn't formally approved. It does not mean experimental or unsafe — off-label prescribing is legal, common, and especially routine in psychiatry. Generic ketamine for depression is off-label; Spravato for TRD is on-label. Both are administered by clinicians under medical supervision.
Why was only esketamine FDA-approved?
FDA approval follows a sponsor running the clinical-trial program for a specific molecule and indication. Janssen (Johnson & Johnson) developed and submitted esketamine — the S-ketamine nasal spray — and pursued approval for that formulation. S-ketamine's higher NMDA-receptor affinity and reliable intranasal absorption made it a practical candidate for a standardized, supervised product. Racemic ketamine has long been generic, so there has been less commercial incentive for any single company to fund the trials an FDA approval for depression would require — which is why it remains off-label despite extensive clinical use.
Which one is "better"; ketamine or Spravato?
There is no single "better" option — the right choice depends on your clinical situation: your diagnosis, treatment history, medical history, and insurance coverage. Spravato's FDA-approved status and insurance coverage make it a primary path for people who meet the TRD criteria. In Dr. Yudkoff's clinical experience, ketamine delivered IM (or, at other practices, IV) can sometimes be titrated across a wider dose range, which may matter for certain patients; Spravato offers a standardized, insurance-covered, FDA-approved option. A comprehensive psychiatric assessment is the only way to determine what fits.
How Lumin Health delivers ketamine treatment and esketamine (Spravato)
Lumin Health — a medical practice based in the Boston Metro area and expanding to other states — offers insurance-covered Spravato (esketamine) and intramuscular (IM) ketamine therapy, delivered at our sites under clinician supervision. (We do not offer IV ketamine.) If you're weighing your options, start with our Spravato & esketamine treatment overview or see the insurance plans we accept.
For more first-hand experience, read the patient reviews of Spravato and ketamine treatment at Lumin Health.
References
- Zhang Y, Ye F, Zhang T, et al. Structural basis of ketamine action on human NMDA receptors. Nature. 2021;596(7871):301-305. PubMed
- Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-64. PubMed
- Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects?. J Affect Disord. 2014;159:56-61. PubMed
- Medeiros GC, Demo I, Goes FS, Zarate CA Jr, Gould TD. Personalized use of ketamine and esketamine for treatment-resistant depression. Transl Psychiatry. 2024;14(1):481. PubMed
Frequently Asked Questions
Is Spravato the same as ketamine?
Not exactly, though they're closely related. Ketamine is the original compound, an even mix of two mirror-image molecules, while Spravato is the brand name for esketamine, the isolated, more active half of that molecule, delivered as a nasal spray. They share the same core mechanism in the brain, but differ in molecule, delivery, regulatory status, and insurance coverage.
Why is Spravato FDA-approved but generic ketamine isn't?
FDA approval is granted to a specific molecule and indication that a sponsor has taken through clinical trials. The manufacturer developed esketamine as a nasal spray and pursued approval for treatment-resistant depression, while generic racemic ketamine has no single sponsor funding equivalent depression trials, so it remains off-label.
Which is stronger, esketamine or racemic ketamine?
S-ketamine is the more active orientation of the molecule, but strength isn't quite the right lens. Dose, route, and your individual situation matter more than the formulation alone, so the more useful question is which approach and dose fits you.
Is off-label ketamine unsafe?
No. Off-label simply means a use the FDA hasn't formally approved, and it's legal and common in psychiatry. Both Spravato and ketamine can affect blood pressure, heart rate, and perception, which is why both are given only in certified medical settings with trained monitoring.
Is a 'bad trip' a common concern with medical ketamine or Spravato?
That idea comes from recreational, unsupervised use. In a monitored medical setting, dissociative effects are expected, anticipated, and managed as part of treatment, and dissociation itself is not something to chase.
