Spravato vs. Other Ketamine Therapies

Ketamine, originally developed as an anesthetic, has emerged as a groundbreaking treatment for mental health conditions, particularly treatment-resistant depression (TRD). Its derivative, esketamine (recently approved by FDA and currently marketed as Spravato), along with various administration routes such as intravenous (IV), intramuscular (IM), sublingual, and ketamine-assisted psychotherapy (KAP), offer diverse options for patients. The FDA clearance of Spravato is increasingly leading people who are considering Ketamine Therapy, to consider how it may differ from other forms of Ketamine.    Here, I hope to provide some clarity by comparing Spravato with other ketamine therapies, integrating current research, and clinical and patient perspectives, many from our own Ketamine Clinic in Scottsdale, Arizona, while highlighting the pros and cons of each approach.

Understanding Spravato and Ketamine Therapies

Spravato (Esketamine) is a nasal spray containing S-ketamine, one of the two enantiomers of ketamine, approved by the FDA in 2019 for TRD and in 2020 for major depressive disorder (MDD) with acute suicidal ideation, when used with an oral antidepressant (Janssen Pharmaceuticals, 2025). Its administration requires a Risk Evaluation and Mitigation Strategy (REMS) program, mandating a certified healthcare setting and two-hour post-dose monitoring due to risks like sedation and dissociation (FDA, 2023).

IV Ketamine involves infusions of racemic ketamine (a mix of R- and S-ketamine) administered over 40–60 minutes, typically at 0.5–1 mg/kg. Used off-label for TRD, it offers high bioavailability (100%) and precise dosing control (McIntyre et al., 2021).

Intramuscular (IM) Ketamine delivers racemic ketamine via injection, with bioavailability slightly lower than IV (approximately 93%) but higher than other non-IV routes. It’s less invasive than IV and used in settings emphasizing rapid delivery (Glue et al., 2018).

Sublingual Ketamine involves lozenges or tablets absorbed under the tongue, with bioavailability around 30%. It’s often used in KAP, where lower doses facilitate therapist-patient interaction (Dore et al., 2019).

Ketamine-Assisted Psychotherapy (KAP) integrates ketamine (often sublingual or IM) with psychotherapy to enhance therapeutic outcomes, leveraging the drug’s psychoactive effects to deepen emotional processing (Dore et al., 2019).

Efficacy: What Does the Research Say?

Research suggests both Spravato and IV ketamine are effective for TRD, with subtle differences. A 2023 study presented at the American Psychiatric Association (APA) Annual Meeting found IV ketamine and Spravato had comparable efficacy in reducing depressive symptoms, measured by the Quick Inventory of Depressive Symptomatology (QIDS). However, IV ketamine required fewer treatments to achieve remission (Scott & Gilbert-Bono, 2023). A Cambridge study echoed this, noting similar response and remission rates but fewer sessions needed for IV ketamine (Singh et al., 2022). Yale research further indicated IV ketamine may improve secondary outcomes like mood, sleep, and appetite (Nikayin et al., 2022).

IM ketamine shows promise, particularly for anxiety disorders. Glue et al. (2018) reported that IM doses of 1 mg/kg reduced anxiety by 50% or more in 10 of 12 patients with treatment-refractory anxiety, with effects lasting up to seven days. Sublingual ketamine, often used in KAP, lacks large-scale randomized controlled trials but shows significant reductions in anxiety and depression in smaller studies (Dore et al., 2019).

Spravato’s efficacy is supported by multiple trials. A 2020 study by Papakostas et al. involving 774 patients demonstrated better outcomes with Spravato plus an oral antidepressant compared to placebo (Papakostas et al., 2020). However, Spravato’s dosing (56–84 mg) is constrained by FDA guidelines, potentially limiting flexibility compared to IV or IM ketamine, where doses can be titrated based on response (Banov et al., 2021).

Many clinicians, experience with Ketamine therapy, including us, argue that IV ketamine may be more effective than Spravato in certain cases due to faster onset and fewer required sessions (among other reasons) (Scott & Gilbert-Bono, 2023). However, there is no doubt among scientifically-minded providers, that more research is needed on the long-term efficacy and optimal administration routes of Ketamine (Grinspoon, 2022).

Spravato's FDA approval and REMS (Risk Evaluation and Mitigation Strategy) requirements ensure oversight and accessibility through insurance, a significant benefit for some patients. However, the slower onset, frequent dosing (twice weekly in the induction phase), and lower response rates have led some psychiatrists and patients to prefer IV ketamine despite its off-label status and out-of-pocket costs (Yehuda et al., 2023).

Another benefit that we see with IV Ketamine is that it allows for more precise, weight-based and response-based dosing.  Most Spravato trials used fixed doses (56–84 mg), while IV protocols vary between 0.2–1.0 mg/kg over 40 minutes. There is evidence that lower IV doses may be sufficient for some patients and that higher doses do not always correlate with better outcomes, but like most therapies, having a flexible range generally promotes benefit for a wider population of patients (Acevedo-Diaz et al., 2020).  Adding this layer of personalization and responsiveness, which can also be especially valuable in cases where patients may not tolerate standard dosing, and may have to back off for comfort. Spravato’s fixed dosing and REMS requirements limit flexibility compared to IV or IM ketamine, where clinicians can adjust doses. Sublingual ketamine’s variable bioavailability poses challenges in standardizing protocols (McIntyre et al., 2021).

Administration and Dosing Protocols

One of the key considerations in Ketamine therapy is bioavailability – how much of the medication you are introducing is available to the body.  The method of administration significantly affects ketamine’s bioavailability:

·       IV: 100%

·       IM: ~93%

·       Intranasal (Spravato): ~45–50%

·       Sublingual: ~25–50%

·       Oral: ~16–20% (Andrade, 2017)

Higher bioavailability correlates with greater therapeutic precision, faster onset, and possibly more robust symptom relief, favoring IV and IM over intranasal and oral routes. Spravato: Administered as a nasal spray (56 or 84 mg) twice weekly for four weeks, then weekly or biweekly for maintenance, under strict REMS supervision. The fixed dosing limits personalization, and the two-hour monitoring requirement can be inconvenient (Janssen Pharmaceuticals, 2025).

IV Ketamine: Typically dosed at 0.5–1 mg/kg over 40 minutes, with six infusions over 2–3 weeks, followed by maintenance as needed. Its high bioavailability ensures rapid onset, but it requires IV-line placement, which may deter needle-averse patients (McIntyre et al., 2021).

IM Ketamine: Dosed similarly to IV (0.25–1 mg/kg), IM offers near-equivalent bioavailability with less procedural complexity. It’s suited for rapid delivery in outpatient settings but requires trained staff (Glue et al., 2018).

Sublingual Ketamine: Lower doses (e.g., 10–50 mg) are used, often in KAP, with bioavailability of 30%. It’s less invasive but has variable absorption, making dosing less predictable (Dore et al., 2019).

Pros and Cons for each Ketamine Route

Spravato

Pros:

• FDA-approved for TRD and MDD with suicidal ideation, enhancing insurance coverage (Axis Integrated Mental Health, 2024).

• Non-invasive nasal spray, ideal for needle-averse patients.

• Milder side effects (e.g., nasal discomfort) compared to IV ketamine (Axis Integrated Mental Health, 2024).

Cons:

• Higher cost ($951–$1,353 per session under Medicare) and strict REMS monitoring requirements (Scott & Gilbert-Bono, 2023).

• Fixed dosing limits personalization.

• May require more sessions to achieve remission compared to IV ketamine (Singh et al., 2022).

IV Ketamine

Pros:

• High bioavailability and precise dosing, leading to faster remission (Singh et al., 2022).

• Versatile for conditions like PTSD, OCD, and anxiety.

• Potential for more intense dissociation, which is a double-edged sword: Some people favor this type of experience, while others prefer to avoid it- again emphasizing the value in flexible dosing.

Cons:

• Requires IV line placement, which may considered invasive by some people.

• Not FDA-approved for psychiatric use, limiting insurance coverage.

IM Ketamine

Pros:

• High bioavailability with less procedural complexity than IV.

• In some instances, as effective for anxiety and depression, with durable effects (Glue et al., 2018).

• Suitable for outpatient settings.

Cons:

• Limited research compared to IV or Spravato.

• Some patient feel that the evolution of the experience is to short-lived.

• Not FDA-approved, impacting insurance coverage.

Sublingual Ketamine

Pros:

• Non-invasive and suitable for home or therapy settings.

• KAP enhances therapeutic outcomes through psychotherapy integration (Dore et al., 2019).

• Lower doses reduce side effect intensity.

Cons:

• Variable bioavailability (30%) affects dosing consistency.

• Limited large-scale evidence for efficacy.

• FDA warns of risks with compounded ketamine, including sublingual forms (FDA, 2023).

Clinical and Patient Perspectives

Clinical Perspective: Clinicians, like us, enjoy having IV ketamine in our armatorium, for its rapid response, particularly for suicidal patients, and flexibility in dosing.  Practically speaking, delays in Spravato insurance approval can be critical for some clients (Scott & Gilbert-Bono, 2023). However, Spravato’s FDA approval and insurance coverage make it appealing in settings prioritizing accessibility.  In other words, for many people, having insurance cover it is a higher priority – health insurance generally does not cover Ketamine delivered by IV, IM or sublingual routes.

Patient Perspective: Some patients prefer Spravato for its non-invasive administration and wider insurance coverage. Conversely, IV ketamine offers more responsive dosing (clinician and patient can collaborate on getting dosing “dialed in” for the optimal experience and benefit). KAP patients value the therapeutic support, reporting enhanced emotional breakthroughs, though some find sublingual absorption inconsistent (Dore et al., 2019).

Safety and Considerations

All ketamine therapies carry risks of dissociation, sedation, and blood pressure changes. Spravato’s REMS mitigates these through mandatory monitoring, but compounded ketamine (sublingual or IM) lacks such oversight, raising safety concerns (FDA, 2023). IV and IM ketamine require trained staff to manage adverse events, while KAP demands experienced therapists to guide psychoactive experiences (McIntyre et al., 2021).  This is why all ketamine applications are supervised and conducted by suitably trained professionals from A-Z!

Conclusion

Spravato and ketamine therapies offer hope for TRD, but their suitability depends on patient needs, cost, and clinical goals. IV ketamine appears slightly more effective, generally requiring fewer sessions, is more adaptive, and is cost-effective, but its invasiveness and lack of FDA formal approval are drawbacks.  To be clear, it is legal to receive Ketamine when administered by appropriately trained professionals, but there is no Ketamine IV product that has ever been presented to the FDA for approval.  Spravato’s FDA approval and insurance coverage enhance accessibility, though its fixed dosing and monitoring requirements limit flexibility. Patients should consult providers to weigh these factors, considering integrative programs like those at Neuregen in Scottsdale for personalized care.

About the Author

David George, founder of Neuregen in Scottsdale, Arizona, has substantial clinical experience in both ketamine therapy and neurorehabilitation. The integrative program at Neuregen Scottsdale leverages ketamine therapy for conditions like treatment-resistant depression, anxiety, PTSD, and chronic pain. Neuregen’s approach combines IV ketamine infusions, intramuscular ketamine, and ketamine-assisted psychotherapy (KAP) in a carefully designed, patient-centered environment. At Neuregen, Scottsdale ketamine therapy is tailored to enhance neuroplasticity and mental health outcomes, offering hope through evidence-based, innovative treatments. Dr. George’s expertise ensures Neuregen Scottsdale remains a trusted destination for integrative mental health care and up-to-date Ketamine Therapy.

References

Axis Integrated Mental Health. (2024, February 7). Which is better: Ketamine infusions vs. Spravato. https://www.axismh.com

Avesta Ketamine & Wellness. (2024, June 23). Which is better for depression? Spravato vs. ketamine. https://avestaketaminewellness.com

Banov, M. D., Young, J. R., Dunn, M., & Szabo, S. T. (2021). A retrospective case series assessing the antidepressant effects of switching from IV ketamine to intranasal esketamine. Journal of Affective Disorders Reports, 6, 100204. https://doi.org/10.1016/j.jadr.2021.100204

Dore, J., Turnipseed, B., Dwyer, S., Turnipseed, A., Andries, J., & Ascani, G. (2019). Ketamine assisted psychotherapy (KAP): Patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. Journal of Psychoactive Drugs, 51(2), 189–198. https://doi.org/10.1080/02791072.2019.1587556

FDA. (2023, October 10). FDA warns about compounded ketamine for psychiatric disorders. https://www.fda.gov

Glue, P., Medlicott, N. J., Harland, S., Neehoff, S., Anderson-Fahey, B., & Le Nedelec, M. (2018). Ketamine’s dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders. Journal of Psychopharmacology, 32(10), 1088–1094. https://doi.org/10.1177/0269881118798619

Grinspoon, P. (2022, August 9). Ketamine for treatment-resistant depression: When and where is it safe? Harvard Health Publishing. https://www.health.harvard.edu

Janssen Pharmaceuticals. (2025). Spravato (esketamine) nasal spray, CIII [package insert]. Johnson & Johnson.

McIntyre, R. S., Carvalho, I. P., Lui, L. M. W., Majeed, A., Masand, P. S., & Gill, H. (2021). Ketamine for the treatment of mental health and substance use disorders: Comprehensive systematic review. BJPsych Open, 8(1), e19. https://doi.org/10.1192/bjo.2021.1061

Nikayin, S., Murphy, E., Krystal, J. H., & Wilkinson, S. T. (2022). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders, 287, 347–355. https://doi.org/10.1016/j.jad.2021.03.054

Papakostas, G. I., Salloum, N. C., Hock, R. S., Jha, M. K., Murrough, J. W., & Mathew, S. J. (2020). Efficacy of esketamine augmentation in major depressive disorder: A meta-analysis. Journal of Clinical Psychiatry, 81(4), 19r12889. https://doi.org/10.4088/JCP.19r12889

Scott, T., & Gilbert-Bono, B. (2023, May). Study: Intravenous ketamine vs. intranasal esketamine. Presented at the American Psychiatric Association 2023 Annual Meeting. https://www.psychiatrist.com

Singh, B., Kung, S., Pazdernik, V., Schak, K. M., Geske, J., & Schulte, P. J. (2022). Comparative effectiveness of intravenous ketamine and intranasal esketamine in clinical practice among patients with treatment-refractory depression. Journal of Clinical Psychiatry, 83(3), 21m14108. https://doi.org/10.4088/JCP.21m14108