What Is the Difference Between Ketamine and Esketamine?
The ketamine molecule exists in two mirror-image forms, called enantiomers. Think of them like your left and right hands: same structure, but not identical. These two forms are the S-enantiomer and the R-enantiomer.
IV ketamine (also called racemic ketamine) contains both the S- and R-enantiomers together. This is the form that has been used in medicine since the 1960s and is what we administer at Music City Ketamine.
Spravato is the brand name for esketamine, which contains only the S-enantiomer. It was developed by Janssen Pharmaceuticals and received FDA approval in 2019 specifically for treatment-resistant depression (TRD).
The S-enantiomer has approximately 2 to 3 times higher affinity for NMDA receptors compared to the racemic mixture. However, higher receptor affinity does not automatically mean better clinical outcomes. The R-enantiomer interacts with additional receptor pathways—including opioid receptors and AMPA receptors—that researchers believe may contribute to the broader antidepressant and anti-inflammatory effects seen with racemic ketamine.
In short: esketamine is a refined version of one part of the ketamine molecule, while IV ketamine uses the complete molecule. Both target the same core mechanism—NMDA receptor modulation and subsequent neuroplasticity—but they do so with different pharmacological profiles.
How Are They Administered Differently?
The treatment experience for IV ketamine and Spravato is quite different, and this matters when choosing between them.
IV ketamine is delivered directly into the bloodstream through an intravenous line. At Music City Ketamine, each infusion is administered by Marla Peterson, CRNA, a Certified Registered Nurse Anesthetist with over 20 years of anesthesia experience. Sessions typically last 40 to 60 minutes for mental wellness, and dosing is adjusted in real time based on your response. You are the only patient in the room. Learn more about what a CRNA brings to ketamine care.
Spravato is delivered as a nasal spray, self-administered under the supervision of a healthcare provider in a certified clinic. Each session involves spraying the medication into each nostril while a clinician monitors you. The administration takes a few minutes, followed by a required two-hour observation period. Sessions typically occur twice weekly for the first month, then weekly or biweekly.
Both treatments require you to remain at the clinic for monitoring after administration. Neither can be taken at home. However, the precision of dosing differs meaningfully: IV delivery allows your provider to control the exact dose reaching your system, while nasal absorption can vary depending on factors like congestion, technique, and individual nasal anatomy.
What Does the Harvard Study Show About Effectiveness?
In 2025, researchers at Harvard published a comparative study examining real-world outcomes for patients receiving either IV ketamine or intranasal esketamine for depression. The study followed 111 IV ketamine patients and 42 intranasal esketamine patients.
The key findings:
- IV ketamine was associated with relatively earlier and greater improvements in depressive symptoms
- IV ketamine patients experienced an average of 49% symptom reduction
- Esketamine patients experienced an average of 40% symptom reduction
- Both treatments produced meaningful clinical improvement
It is important to note what this study does and does not tell us. This was a naturalistic comparison, not a randomized controlled trial, which means the two patient groups may have differed in ways that influenced outcomes. The IV ketamine group was also larger, which gives those results somewhat more statistical weight.
Research suggests that both IV ketamine and intranasal esketamine are effective tools for treatment-resistant depression. The differences in magnitude and onset are meaningful, but they do not mean one treatment is right for everyone. — Harvard Comparative Study, 2025
Yale University is currently conducting a larger comparative study that may provide more definitive answers. We follow this research closely and will update our guidance as new data becomes available.
IV Ketamine vs Spravato: Side-by-Side Comparison
| Factor | IV Ketamine | Spravato (Esketamine) |
|---|---|---|
| Active compound | Racemic ketamine (S + R enantiomers) | Esketamine (S-enantiomer only) |
| Administration | Intravenous infusion | Nasal spray |
| Bioavailability | 100% (direct to bloodstream) | ~48% (nasal absorption varies) |
| FDA status | Off-label for depression | FDA-approved for TRD (2019) |
| Insurance coverage | Typically not covered; out-of-pocket | Often covered with prior authorization |
| Cost at MCK | $475 per session | Not offered (see below) |
| Provider type | CRNA (anesthesia specialist) | Varies by clinic (psychiatrist, NP, or PA) |
| Dosing precision | Exact; adjustable in real time | Fixed-dose device (56 mg or 84 mg) |
| Symptom reduction (Harvard 2025) | 49% average | 40% average |
| Onset of improvement | Relatively earlier response | Slightly later onset |
| Research base | Decades of clinical use; extensive off-label data | FDA trial data; growing real-world evidence |
Does Insurance Cover Spravato or Ketamine?
This is one of the most practical differences between the two treatments, and for many patients, it is the deciding factor.
Spravato is FDA-approved for treatment-resistant depression, which means it can be billed through insurance. Many insurance plans cover Spravato, though prior authorization is almost always required, and your out-of-pocket cost depends on your plan's copay and deductible structure. Some patients pay very little; others face significant cost-sharing. Janssen also offers a savings program for eligible patients.
IV ketamine is used off-label for depression, meaning it is not FDA-approved specifically for this indication. As a result, most insurance plans do not cover it. At Music City Ketamine, IV ketamine sessions are $475 per session, paid out of pocket. We provide superbills after each session that you can submit to your insurer for potential out-of-network reimbursement.
We also partner with Advance Care to offer patient financing, allowing you to spread the cost of treatment into monthly payments. You can apply before your first appointment.
Our recommendation: before choosing based on cost alone, calculate your actual out-of-pocket expense for both options. A Spravato treatment covered by insurance may still involve meaningful copays, and an IV ketamine series at $475 per session may be comparable or less expensive depending on your plan.
Why Does MCK Offer IV Ketamine?
We chose to build our practice around IV ketamine for reasons grounded in clinical precision and patient care, not because we believe Spravato is ineffective. Both are legitimate treatments. Here is why we focus on IV administration:
- 100% bioavailability. IV delivery means the full dose reaches your bloodstream. There is no absorption variability from congestion, technique, or individual anatomy.
- Real-time dose control. Marla can adjust your infusion rate during the session based on how you are responding. This level of precision is not possible with a fixed-dose nasal spray.
- CRNA expertise. Marla Peterson brings over two decades of anesthesia experience to every session. IV medication administration and monitoring is core to CRNA training. This is what she has done her entire career.
- Personalized protocols. Because we control the dose precisely, we can tailor each session to your weight, history, and response pattern. Over a treatment series, this allows us to optimize your protocol in ways that fixed-dose administration does not.
- Racemic advantage. The full ketamine molecule engages multiple receptor systems beyond NMDA alone, which may contribute to the broader symptom improvement seen in research.
We respect clinics that offer Spravato, and for some patients—particularly those with strong insurance coverage for it—it may be the more accessible option. We want you to get effective treatment, whichever form that takes.
Which Option Is Right for You?
There is no universal answer. The right choice depends on several personal factors:
- Insurance coverage. If your plan covers Spravato with low cost-sharing, that may make financial sense. If you are paying out of pocket either way, IV ketamine at $475 per session may be the stronger clinical option.
- Severity and urgency. Research suggests IV ketamine may produce faster initial improvement. If speed of response is a priority, this is worth discussing with your provider.
- Prior treatment history. If you have tried one form without adequate results, switching to the other may be worthwhile.
- Preference for precision. If knowing your exact dose and having it adjustable in real time matters to you, IV administration offers that control.
- Comfort with needles vs nasal spray. Some patients prefer the simplicity of a nasal spray. Others are comfortable with an IV and value the consistency it provides.
A consultation is the best way to sort through these factors for your specific situation. We are happy to discuss both options honestly and help you evaluate which path makes the most sense for you. If Spravato is the better fit, we will tell you that.