Esketamine (Spravato) and Generic Ketamine: Two Names, One Core Pathway
If you’re researching ketamine-based treatments for depression, you’ve likely come across two versions: ketamine (often delivered by IV or IM) and Spravato, the brand name for intranasal esketamine.
They sound similar — because they are. But their differences matter when it comes to how they’re used, where they’re covered by insurance, and what a treatment journey may look like.
In this post, we’ll clarify:
- Why both versions work on the same core glutamate pathway, as well as other pathways relevant to ketamine’s and Spravato’s mechanism of action.
- How their delivery routes and regulatory approval differ
- What to consider when choosing between off-label ketamine and FDA-approved Spravato
No Difference in the Mechanism of Action for Ketamine and Spravato (Esketamine)
At the biological level, both ketamine and esketamine (Spravato - you may see these terms used interchangeably) target the NMDA receptor, part of the brain’s glutamate signaling system. By blocking this receptor on GABAergic interneurons, they trigger a cascade that:
- Loosens feedback inhibition
- Leads to a temporary glutamate surge
- Engages AMPA receptors
- Opens a window for neuroplasticity and healing
“Ketamine and esketamine share the same upstream mechanism — they shift how the brain regulates glutamate, which changes how signals get sent and received.” — Dr. Ben Yudkoff
In other words: the therapeutic engine is the same. What differs is the vehicle — how the medicine is delivered and regulated.
Logistics: Delivery Routes, Absorption, and Insurance
Here’s where the story diverges.
💉 Ketamine (Intravenous infusions/Intramuscular injections/Lozenge/Nasal Spray)
- Form: Racemic ketamine – a 50/50 mix of R-ketamine and S-ketamine; which are mirror images of the same molecule
- Route: Commonly IV or intramuscular in clinics; sometimes lozenges for at-home or maintenance dosing
- Approval status: Off-label for depression
- Absorption: IV is direct; nasal and oral forms can vary
- Insurance: Often not covered
🌬️ Esketamine (Spravato) Nasal Spray
- Form: Isolated S-ketamine (one of the mirror-image molecules of ketamine), delivered as a nasal spray
- Route: Intranasal in clinic, supervised
- Approval status: FDA-approved for treatment-resistant depression and major depressive disorder (MDD) with suicidal ideation
- Absorption: Reliable through mucous membranes
- Insurance: Often covered under REMS-certified programs
“Spravato’s nasal format wasn’t chosen for convenience — it was chosen for consistency and regulatory approval. That makes it more accessible for many patients.” — Dr. Ben Yudkoff
Approved Contexts for Spravato
Spravato is approved under specific conditions:
- Diagnosed treatment-resistant depression (TRD) or MDD with suicidal thoughts.
- Aged 18+
- Failure of two or more prior antidepressant trials
- Administered in a certified clinic
- Supervised for 2+ hours post-dose
Because of this formal approval, Spravato is covered by many insurers—an important factor for patients seeking long-term treatment with financial support.
What “Off-Label” Means in Medicine and How That Applies to Ketamine Therapy
The term off-label can sound risky, but in medicine, it simply means a drug is being used for a non-FDA-approved indication.
This is common — especially in psychiatry. For example:
- Many antidepressants are used off-label for anxiety
- Antipsychotic medications are used off-label for sleep
- Ketamine (originally approved as an anesthetic) is used off-label for depression
Off-label use is legal, evidence-based, and often guided by strong clinical consensus — even if not officially approved. Something important to note is that despite generic ketamine being “off-label” that doesn’t necessarily mean it is less safe for use than Spravato.
“Off-label doesn’t mean unsafe. It means the responsibility for safety falls more on the clinician, rather than the FDA framework.” — Dr. Ben Yudkoff
Why Approval Focused on S-Ketamine Nasal Spray
So why was S-ketamine, and not the full blend of both sides of the ketamine molecule, chosen for FDA approval?
A few factors:
- S-ketamine (the “active half”) has slightly higher NMDA affinity
- The nasal spray allowed for non-invasive, repeatable dosing
- Regulatory bodies favored the lower abuse potential of this tightly controlled setting
Still, the core mechanism is identical. The approval is about formulation, consistency, and access — not a fundamentally different antidepressant effect.
Frequently Asked Questions
Q: Why is Spravato FDA-approved and Generic(/Racemic) Ketamine isn’t?
A: Esketamine (Spravato) was approved because of its standardized nasal formulation, repeatable clinical protocol, and demonstrated safety data in structured trials. Racemic ketamine wasn’t submitted for approval for depression in the same context.
Q: Which is “stronger”; Esketamine or Racemic Ketamine?
A: Mechanistically, both work through the same pathways. The difference lies in delivery, metabolism, and logistical support—not clinical “strength.”
Q: Is off-label use of Ketamine Unsafe?
A: Not inherently. Off-label ketamine can be safe and effective when administered by experienced providers. The key is oversight, making sure a patient is healthy enough for the treatment and has a psychiatric disorder that might be improved by the treatment, and mechanism of delivery.
Q: Why not approve racemic ketamine?
A: Approval requires extensive data, consistent delivery, and regulatory sponsorship. S-ketamine (aka esketamine) met those thresholds first—via the intranasal format and formal trials.
How the Differences Between Spravato and Ketamine Affects Patients
Ketamine and Spravato aren’t different treatments. They’re different formats of the same biological tool. Choosing between them is less about “which works better” and more about access, comfort, oversight, and coverage.
At Lumin Health, we help patients navigate both options—off-label ketamine when appropriate, and Spravato when insurance access or safety monitoring makes it the right fit.
Either path can be the right one. What matters most is clarity, support, and the belief that your brain can change.
