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. 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). 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.
Frequently asked questions
Why is Spravato FDA-approved but generic ketamine isn't?
Because FDA approval is granted to a specific molecule and indication that a sponsor has taken through clinical trials. Janssen (Johnson & Johnson) developed esketamine (S-ketamine) as a nasal spray and pursued approval for treatment-resistant depression. 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 molecule-for-molecule, but "stronger" is the wrong lens — dose, route, and the individual patient matter more than the formulation alone. The clinically relevant question is which approach, at which dose and route, fits your situation.
Is off-label ketamine unsafe?
No. Off-label simply means a use the FDA hasn't formally approved; it is legal and common in psychiatry. Both Spravato and ketamine carry real effects on blood pressure, heart rate, and perception, which is why both are administered only in certified medical settings with trained monitoring.
Is a "bad trip" a common concern?
The "bad trip" idea comes from recreational, unsupervised use. In a monitored medical setting the experience is different: dissociative effects are expected, anticipated, and managed as part of treatment. In fact, dissociation may represent a ceiling dosage — beyond the dissociative window, additional dose does not necessarily add benefit — which is one reason careful, supervised dosing matters.
Why is medical supervision so important?
Both esketamine and ketamine can temporarily raise blood pressure and heart rate and produce dissociative effects. For that reason, administration of either is limited to certified medical sites where you're monitored by trained staff — consistent with FDA guidelines and safety protocols described by the National Institutes of Health.
Which treatment is right for me?
That requires a comprehensive psychiatric assessment. Factors include your diagnosis, prior treatments, medical comorbidities, and insurance. A clinician can map those to the most appropriate option.
