By Dr. Dina Seif, MD | OC Ketamine Therapy | May 2026
I get this question every week. A patient calls — sometimes frustrated, sometimes relieved to have options — and they say something like: “My psychiatrist mentioned Spravato, but I’ve also been reading about IV ketamine. How do I know which one is right for me?”
It’s a genuinely important question, and I want to answer it the way I would in my clinic: honestly, without a sales pitch, because both treatments have legitimate roles. I offer IV ketamine at OC Ketamine Therapy, and while I don’t administer Spravato, I regularly discuss it with patients and refer when it’s the better fit. In my view, IV ketamine remains the most flexible and clinically effective option for many of the patients I see — largely because it allows for real-time customization, including individualized dosing and rate adjustments, rather than fixed dosing. That level of control can make a meaningful difference in both tolerability and response. IV ketamine also provides the ability to thoughtfully incorporate adjunctive medications like oxytocin that can support the experience. At the same time, there are situations where Spravato makes more sense, and I’ll always be transparent about that.
Let’s get into it.
The Basics: What Are These Two Treatments?
Ketamine was developed in the 1960s as an anesthetic. For decades, emergency medicine physicians like me used it for procedural sedation, especially in children. Its antidepressant effects were an unexpected discovery — first noted formally in 2000 — and the field of psychiatric ketamine has grown rapidly since then.
IV ketamine is the original formulation. It’s racemic ketamine (a mixture of two molecular mirror images, R and S), administered intravenously in a monitored clinical setting, typically over 40 minutes. The dose is titrated to each patient based on weight and tolerance. If you’d like a deeper look at the fundamentals, our post on what ketamine is covers the background in plain language.
Spravato (esketamine) is FDA-approved for treatment-resistant depression and major depressive disorder with suicidal ideation. It’s a nasal spray using only the S-ketamine isomer — hence the name “es-ketamine.” It received FDA approval in 2019. Crucially, it can only be administered in a certified healthcare setting, where patients must be monitored for at least two hours after each dose. It’s not something you take home.
Same family. Different pharmacology, different delivery, different evidence bases. The differences matter.
How the Pharmacology Differs
Here’s something that doesn’t get discussed enough: IV ketamine and intranasal esketamine don’t behave identically in the brain, even though they act on the same receptor family.
IV ketamine delivers racemic ketamine directly into the bloodstream, bypassing the gastrointestinal system entirely. Bioavailability is essentially 100%. The drug reaches therapeutic plasma levels within minutes, crosses the blood-brain barrier efficiently, and the clinical team has precise, real-time control over dosing. If a patient needs the dose adjusted — up or down — we can do that immediately.
Spravato’s bioavailability via intranasal delivery is approximately 48%. You lose roughly half the dose to mucosal absorption variability. The S-ketamine isomer is more potent at the NMDA receptor than R-ketamine in isolation, which partially compensates, but the kinetics are different. Some patients absorb intranasally well; others don’t. And you can’t adjust mid-session the way you can with IV.
The clinical implication: IV ketamine tends to produce more consistent and predictable infusion experiences, and in my clinical observation, more reliable initial response rates — particularly in patients with severe or chronic treatment-resistant depression (TRD). Studies confirm that IV ketamine response rates in treatment-resistant depression typically range from 60–70% (Jha et al., 2024). The data on Spravato shows response in approximately 50–65% of patients, with more variability across trials (Yavi et al., 2022). For a broader look at what the evidence says about ketamine for depression in Orange County, our treatment page summarizes the current clinical picture.
Where Spravato Has Real Advantages
I want to be fair, because there are patients for whom Spravato is the better choice.
Insurance coverage. This is the single biggest practical advantage Spravato has. Because Spravato is FDA-approved for TRD and MDD with suicidal ideation, many commercial insurance plans and Medicare now cover it — with significant prior authorization requirements, but coverage nonetheless. IV ketamine is almost never covered by insurance. If cost is a prohibitive barrier and a patient meets Spravato’s diagnostic criteria, I’ll absolutely talk through that option and provide a referral if appropriate. We do offer financing options for IV ketamine to help make treatment more accessible.
Established regulatory pathway. For psychiatrists working within a medication management framework, Spravato fits more naturally into a standard of care workflow. Some patients find the structure reassuring.
That said — I want to be honest about a frustration I have. The fact that Spravato requires monitored in-office administration anyway makes the “convenience” argument partially moot. Spravato patients still come to a clinical setting, still spend 2+ hours per session, and still require supervision. The key difference is the FDA approval — and the insurance coverage that follows from it.
My Clinical Opinion
I’ll tell you what I actually think. For patients with severe, treatment-resistant depression — especially those who’ve failed multiple antidepressants — IV ketamine offers what I consider the most potent, most clinically well-characterized neurobiological reset available in outpatient psychiatry. The full-spectrum pharmacology of racemic IV ketamine appears to engage the brain’s neuroplasticity machinery more completely than the isolated S-isomer, at least based on what I observe clinically and what the emerging literature suggests (Fava et al., 2020). Our post on the superiority of IV ketamine therapy over esketamine explores this topic in further depth if you’d like the full analysis.
If you’re trying to decide, the honest answer is: talk to a provider who offers both, knows the literature, and isn’t financially incentivized to push one over the other. I offer IV ketamine, and I believe it’s the better first-line option for most patients with TRD. But if cost is the determining factor, Spravato’s insurance coverage changes the calculus, and I’ll always help a patient navigate that.
Have questions about which might be right for you? I’d genuinely love to have that conversation. Contact us to schedule a consultation and we’ll help you find the path forward that makes the most sense for your situation.
References
1. Jha MK et al. (2024). Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open. https://doi.org/10.1001/jamanetworkopen.2024.17786
2. Yavi M et al. (2022). Ketamine treatment for depression: a review. Discover Mental Health. https://doi.org/10.1007/s44192-022-00012-3
3. Fava M et al. (2020). Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0256-5
About Dr. Dina Seif
Dina Seif, MD, believes that with the right mindset and support, every one of us has the potential to transform and heal our minds. She specializes in creating a personalized plan for each patient and is committed to providing a supportive healing environment for your journey. Dr. Seif is a member of the American Society of Ketamine Physicians and was recognized as a Physician of Excellence by the Orange County Medical Association. Dr. Seif has 15+ years of experience with ketamine in the emergency setting and founded one of the first ketamine practices in Orange County in 2019. She has administered thousands of infusions and cared for hundreds of patients from around the world. Dr. Seif is board-certified in Emergency Medicine and is a graduate of the University of California, Irvine, where she attended college, medical school, and business school. After an internship in Internal Medicine at St. Vincent’s Medical Center in New York, she returned to California for Emergency Medicine residency at LAC+USC Medical Center where she also completed a fellowship in Emergency Ultrasound and was a Professor of Clinical Emergency Medicine at Keck School of Medicine of USC for 5 years.
Medical Disclaimer
This content is for informational purposes only and does not constitute medical advice, diagnosis, or treatment. If you are experiencing a mental health crisis or having thoughts of self-harm, please call or text 988 (Suicide and Crisis Lifeline) or go to your nearest emergency room immediately. Always consult with a qualified healthcare provider before starting any new treatment or making changes to your existing treatment plan. Individual results may vary, and no outcomes are guaranteed.