IV Ketamine and Spravato (Esketamine)

A physician-led comparison of formulation, bioavailability, dosing, evidence, and the individualized IV ketamine approach at HILLMED.

By Jerron C. Hill, M.D. — Board-Certified Anesthesiologist, Founder of HILLMED

IV ketamine and Spravato are related treatments, but they are not interchangeable. IV ketamine is racemic ketamine delivered directly into the bloodstream and individualized by the treating physician. Spravato is intranasal esketamine, the S-enantiomer of ketamine, delivered in labeled dose levels under a federally required safety program. Both have evidence for rapid improvement in depressive symptoms, yet their formulation, absorption, dosing, regulatory status, and clinical evidence differ in important ways.

HILLMED provides physician-supervised IV ketamine therapy. HILLMED does not provide Spravato.

The short version

IV administration provides 100% systemic bioavailability because the medication enters the circulation directly. The FDA prescribing information reports that Spravato has mean absolute bioavailability of approximately 48% after nasal administration. This does not by itself prove that IV ketamine will work better for every patient, but it does mean that IV delivery is more predictable and avoids variability associated with nasal absorption.

IV ketamine is also racemic, meaning it contains both R-ketamine and S-ketamine molecules. Spravato contains only S-ketamine, or esketamine. The two-enantiomer composition of racemic ketamine gives it a broader stereochemical and pharmacologic profile, but research has not established that this difference alone guarantees a superior clinical response.

What is IV racemic ketamine

Ketamine has been used in medicine for decades as an anesthetic. At lower, subanesthetic doses, IV racemic ketamine has been studied and used off-label for treatment-resistant depression and other psychiatric conditions. Off-label prescribing is common and legal when a licensed clinician judges that the treatment is medically appropriate and discusses its benefits, risks, and alternatives with the patient.

Because the medication is infused into a vein, the physician can select a weight-based dose, control the infusion rate, observe the patient's physiologic and clinical response, and adjust later treatments when appropriate. This dosing flexibility is central to the HILLMED approach.

What is Spravato

Spravato is the brand name for intranasal esketamine. It is FDA-approved for treatment-resistant depression in adults as monotherapy or together with an oral antidepressant. It is also approved, with an oral antidepressant, for depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior. The FDA label notes that its effectiveness in preventing suicide or reducing suicidal behavior has not been demonstrated, and emergency care should not be delayed when hospitalization is clinically warranted.

Spravato must be self-administered under direct supervision in a certified healthcare setting through its Risk Evaluation and Mitigation Strategy. Patients are monitored for at least two hours. The labeled adult dose options are standardized, typically 56 mg or 84 mg after an initial dose, with schedule and frequency adjusted within the prescribing framework.

Key differences at a glance

Medication: IV racemic ketamine — R- and S-ketamine; Spravato — S-ketamine only.

Route: IV racemic ketamine — controlled intravenous infusion; Spravato — patient-administered nasal spray under supervision.

Bioavailability: IV racemic ketamine — 100% by definition for IV delivery; Spravato — approximately 48% mean absolute bioavailability per FDA label.

Dose: IV racemic ketamine — weight-based and physician-titrated; Spravato — labeled dose levels, generally 56 mg or 84 mg after initiation.

Depression status: IV racemic ketamine — off-label; Spravato — FDA-approved for specific indications.

At HILLMED: IV racemic ketamine — provided and personally supervised by Dr. Hill; Spravato — not provided.

What comparative research shows

The science supports both treatments, but it does not support a simple claim that one is best for every patient. Direct randomized head-to-head trials remain limited, and most comparative studies are observational, which means treatment selection and other clinical differences can influence the results.

A 2022 clinical analysis found no statistically significant difference between treatment groups on its primary depression trajectory outcome, although several secondary analyses favored IV ketamine. A 2023 observational study reported that both IV ketamine and intranasal esketamine produced clinically and statistically significant improvement; IV ketamine reached remission with fewer treatment sessions, while response and remission rates were not significantly different between groups.

A 2025 retrospective study of 153 patients with severe treatment-resistant depression found faster and greater symptom reduction with IV racemic ketamine during a four- to five-week induction period. By the eighth treatment, self-reported depression scores had fallen 49.22% in the IV ketamine group and 39.55% in the intranasal esketamine group. These findings are clinically meaningful, but they remain observational and should not be interpreted as proof that every patient will respond better to IV ketamine.

Earlier meta-analyses have also reported larger pooled effects for racemic ketamine than for esketamine. However, many included studies differed in route, dose, design, patient population, and comparator. These indirect comparisons generate useful hypotheses but cannot replace well-designed randomized trials directly comparing the two treatments.

Why dose and personalization matter

Depression is not a one-size-fits-all condition, and IV ketamine should not be delivered as a one-size-fits-all treatment. Dose, infusion rate, treatment frequency, medical history, concurrent medications, tolerability, and symptom trajectory can all influence clinical decisions. More medication is not automatically better; the goal is to identify an effective, well-tolerated treatment plan through careful assessment and monitoring.

For the past nine years, I have personally administered and individualized IV ketamine treatment for every HILLMED patient. I have also treated patients who did not obtain adequate relief with nasal Spravato but later improved with physician-directed IV ketamine. That experience does not prove that every Spravato nonresponder will respond to IV ketamine. It does reinforce an important clinical lesson: route, bioavailability, and especially dose may matter for an individual patient's response.

The HILLMED approach

At HILLMED, treatment begins with a detailed medical and psychiatric review, appropriate screening, and a discussion of realistic expectations. When IV ketamine is appropriate, I personally supervise the infusion and tailor the plan to the patient's response rather than applying one identical protocol to everyone.

Ketamine is not treated as a stand-alone cure. The HILLMED wellness program integrates stress management, mindfulness, restorative sleep, nutrition, movement, and coordination with the patient's mental-health and medical professionals. This whole-person framework is designed to support more sustainable improvement, although no program can guarantee that benefits will persist or that every patient will respond.

Safety and monitoring

Both IV ketamine and Spravato require careful patient selection and medical monitoring. Temporary effects may include dissociation, sedation, dizziness, nausea, anxiety, perceptual changes, and increased blood pressure. Patients need transportation home and should not drive until the next day after a restful sleep, consistent with their clinician's instructions. Certain cardiovascular conditions, uncontrolled hypertension, pregnancy, substance-use concerns, psychotic disorders, or other medical and psychiatric factors may require additional caution or make treatment inappropriate.

Frequently asked questions

Are IV ketamine and Spravato the same medication? No. IV ketamine is racemic ketamine containing both R- and S-enantiomers. Spravato contains S-ketamine only and is delivered intranasally.

Does IV ketamine have greater bioavailability? Yes. IV administration has 100% bioavailability, while the FDA label reports approximately 48% mean absolute bioavailability for Spravato nasal spray. Greater bioavailability does not guarantee a better outcome for every patient.

Is Spravato a fixed dose? Spravato is supplied in standardized 28 mg devices and administered in labeled dose levels, generally 56 mg or 84 mg after initiation. Its treatment frequency and choice between labeled dose levels can be individualized. IV ketamine allows more granular weight-based dose and infusion-rate adjustments.

Does HILLMED provide Spravato? No. HILLMED provides personalized, physician-supervised IV ketamine therapy and does not provide Spravato.

Can IV ketamine help after Spravato has not? Some patients may respond to IV ketamine after an inadequate response to Spravato, and this has occurred in Dr. Hill's clinical practice. Individual outcomes vary, and a prior Spravato response does not predict the result with certainty.

When to seek support

If depression is disrupting sleep, relationships, work, or daily functioning, contact a qualified healthcare professional. If you are in crisis or thinking about harming yourself, call or text 988 in the United States to reach the Suicide and Crisis Lifeline. Ketamine treatment is not a substitute for emergency evaluation, hospitalization, or comprehensive psychiatric care when those services are needed.

Selected scientific references

1. U.S. Food and Drug Administration. Spravato prescribing information. 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf

2. Meisner R, Li S, Boyle B, et al. Comparative effects of repeated ketamine infusion versus intranasal esketamine in patients with treatment-resistant depression: a retrospective chart review. Journal of Clinical Psychiatry. 2025;86(4):25m15789. doi:10.4088/JCP.25m15789.

3. Nikayin S, Rhee TG, Cunningham ME, et al. Evaluation of the trajectory of depression severity with ketamine and esketamine treatment in a clinical setting. JAMA Psychiatry. 2022;79(7):736-738. doi:10.1001/jamapsychiatry.2022.1074.

4. Singh B, Kung S, Pazdernik V, et al. Comparative effectiveness of intravenous ketamine and intranasal esketamine in clinical practice among patients with treatment-refractory depression: an observational study. Journal of Clinical Psychiatry. 2023;84(2):22m14548. doi:10.4088/JCP.22m14548.

5. Gutierrez G, Swainson J, Ravindran N, et al. IN esketamine and IV ketamine: results of a multi-site observational study assessing effectiveness and tolerability in treatment-resistant depression. Psychiatry Research. 2024;340:116125. doi:10.1016/j.psychres.2024.116125.

6. Bahji A, Zarate CA Jr, Vazquez GH. Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. Expert Opinion on Drug Safety. 2022;21(6):853-866.

Final thoughts

IV racemic ketamine and intranasal esketamine are related rapid-acting treatments, but their differences are clinically relevant. IV ketamine offers complete systemic bioavailability, a two-enantiomer formulation, and flexible physician-directed dosing. Spravato offers an FDA-approved intranasal pathway with standardized labeled doses and REMS oversight. The best decision depends on diagnosis, medical history, prior treatments, access, preferences, and a careful clinical evaluation.

To learn more or schedule a consultation, visit hillmedstressmanagement.com or call the HILLMED Plano practice at (972) 212-4341.

This article is for general educational purposes only and is not medical advice. IV ketamine for depression is an off-label use. Spravato is FDA-approved for specific indications. Individual results vary, neither treatment helps everyone, and neither is a cure. Please consult a qualified healthcare professional regarding your own care.

About the author

Jerron C. Hill, M.D. is a board-certified anesthesiologist and the founder of HILLMED, a physician-led wellness practice in Plano, Texas. Drawing on decades of experience administering intravenous medications and managing complex physiology in the operating room, Dr. Hill brings a rigorous, safety-first approach to IV ketamine therapy, IV vitamin therapy, and physician-formulated CBD. At HILLMED, he pairs advanced, doctor-supervised treatments with the fundamentals of whole-person wellness — nutrition, movement, restorative sleep, and stress management — to help patients function and feel better. To learn more or schedule a consultation, visit hillmedstressmanagement.com or call the Plano practice at (972) 212-4341.