When patients start researching ketamine therapy, they often encounter two distinct options: IV ketamine infusions, offered at clinics like ours, and Spravato® (esketamine), a nasal spray approved by the FDA in 2019 and sometimes covered by insurance. The two are related (esketamine is derived from ketamine) but they differ in meaningful ways that matter clinically.
Here’s a clear-eyed comparison of both.
What Are They, Exactly?
Ketamine is a racemic mixture, meaning it contains two mirror-image molecular forms (called enantiomers): S-ketamine and R-ketamine. Both forms are pharmacologically active, and both contribute to its therapeutic effects.
Esketamine (Spravato®) is the isolated S-enantiomer of ketamine. It was developed by Janssen Pharmaceuticals, received FDA approval for treatment-resistant depression in 2019, and became the first truly novel antidepressant mechanism approved in decades.
Both target NMDA glutamate receptors. Both produce dissociative effects. But how they’re delivered, how much reaches the brain, and how precisely the dose can be controlled differ significantly.
The Bioavailability Gap
This is the most clinically important difference, and it’s often underappreciated.
When ketamine is delivered intravenously, 100% of the administered dose enters the bloodstream directly. There’s no absorption step; the drug goes exactly where it’s intended, in exactly the amount prescribed.
Esketamine is administered intranasally, as a nasal spray. Nasal bioavailability is approximately 48%. This means that roughly half of the administered dose is absorbed; the rest is lost to mucosal tissue, swallowing, or other factors. Additionally, nasal absorption varies depending on nasal congestion, technique, and individual anatomy. What a patient receives from a given dose of Spravato® is inherently less predictable than what they receive from IV ketamine.
For a medication that works on a dose-dependent mechanism, where getting the right amount to the brain is the whole point, this matters.
Dose Precision and Titration
IV ketamine dosing is calculated based on body weight (typically 0.5 mg/kg for an initial infusion) and can be adjusted precisely up or down based on clinical response. The rate of infusion, total dose, and duration can all be modulated in real time during the session.
Spravato® comes in fixed-dose devices: 56 mg or 84 mg per session. There’s limited ability to titrate based on response; you can go from 56 mg to 84 mg, but that’s essentially the range available.
For patients who need careful dose adjustment, either because they’re sensitive to the dissociative effects or because they need a higher-than-standard dose for therapeutic response, IV ketamine offers substantially more clinical flexibility.
The Full Ketamine Molecule vs. One Enantiomer
This is an area of active research, but it’s worth noting. IV ketamine contains both S-ketamine (the enantiomer in Spravato®) and R-ketamine. Emerging research suggests that R-ketamine may have distinct and potentially advantageous properties, including longer-lasting antidepressant effects and, in some animal models, a better side effect profile.
By using only the S-enantiomer, esketamine may be leaving some of ketamine’s therapeutic potential on the table. This is not yet proven in large human trials, but the preclinical and early clinical data are interesting enough to note.
The Evidence Base
Both have solid research support, but the evidence bases are different in character.
IV ketamine has been studied for depression since the early 2000s, beginning with the landmark Berman et al. 2000 study in Biological Psychiatry and replicated in Zarate et al. 2006 in Archives of General Psychiatry. Multiple subsequent randomized controlled trials, meta-analyses, and real-world outcome studies have followed. The effect sizes in TRD are robust, and response rates of 50–70% in treatment-resistant patients have been consistently replicated.
Esketamine’s FDA approval was based on a clinical trial program specifically designed for regulatory approval, adequate for that purpose but with some notable limitations: relatively short follow-up periods, and the requirement that patients continue standard antidepressant therapy alongside Spravato®. In practice, Spravato® is approved as an adjunctive therapy, not a standalone treatment.
Neither has strong evidence from head-to-head trials directly comparing IV ketamine to esketamine. The honest answer is that we don’t have a definitive “which is better” comparison, but clinical experience and mechanistic reasoning favor IV ketamine for patients who can access it.
Cost and Insurance
This is where Spravato® has a real advantage for many patients.
Spravato® has FDA approval for TRD, which means some commercial insurance plans cover it (often with strict prior authorization requirements). For patients who can navigate the coverage process, out-of-pocket costs may be substantially lower than IV ketamine.
IV ketamine is not FDA-approved for depression (it’s used off-label, which is legal and common in medicine). Most insurance plans do not cover it for mental health indications. At Mosaic, our pricing is $400–$450 per infusion, substantially lower than the $800–$1,000+ per session that Spravato® can cost out-of-pocket when insurance doesn’t cover it.
The insurance situation can shift; coverage for IV ketamine may expand as evidence continues to accumulate.
Why We Offer IV Ketamine
At Mosaic Infusions & Wellness, we offer IV ketamine infusions rather than esketamine administration for several reasons:
- Bioavailability certainty: Every patient receives exactly the dose we prescribe.
- Titration precision: We can adjust dose and rate in real time based on how each individual responds.
- Clinical flexibility: We can customize the protocol to the patient, not the other way around.
- Evidence depth: The IV ketamine evidence base for TRD is the deepest available for any ketamine-based intervention.
- Cost transparency: Our flat-rate pricing is often more affordable than out-of-pocket Spravato® for patients without insurance coverage.
This doesn’t mean Spravato® is without value; for patients who have insurance coverage and for whom IV infusion is inaccessible, it may be the right option. But when we’re designing a treatment protocol for a patient sitting across from us, IV ketamine gives us more tools to work with.
The Bottom Line
Esketamine got the brand name, the FDA approval, and the insurance coverage. IV ketamine got the deeper evidence base, the full molecular profile, and the clinical precision. Neither is the right choice for every patient, but for patients who can access IV ketamine under proper clinical supervision, it remains the gold standard for treatment-resistant depression.
Curious about whether IV ketamine is right for your depression? Schedule a free consultation with our team; we’ll give you an honest assessment of your options.