Ketamine Therapy Research Review: IV vs Nasal Spray vs Oral

What This Study Found

This comprehensive analysis of 25+ systematic reviews and meta-analyses reveals substantial differences in ketamine therapy effectiveness. IV ketamine tripled the likelihood of treatment response compared to placebo (RR = 3.01), while esketamine nasal spray showed only modest improvement (RR = 1.38). Response rates for IV ketamine ranged from 30-76% with a median of 55%, while remission rates ranged from 27-43% with a median of 29%.

IV ketamine demonstrated rapid onset within 24 hours, compared to oral ketamine which required 2-6 weeks to show effects—similar to traditional antidepressants. Effect sizes strongly favored IV ketamine (Cohen’s d = -0.75) over esketamine (d = -0.38). For suicidal ideation, patients receiving IV ketamine were 10 times more likely to show improvement within 24 hours compared to placebo.

Combining ketamine with psychotherapy showed preliminary evidence of extending antidepressant effects and reducing relapse rates, though evidence quality remains low and findings are mixed for depression specifically.

Why It Matters

These findings have significant implications for treatment selection and patient expectations. IV ketamine’s superior effectiveness and rapid onset make it potentially more suitable for treatment-resistant depression and acute suicidal ideation, while esketamine’s modest benefits may not justify its high cost for many patients. The 24-hour onset of IV ketamine versus weeks for oral forms could be critical for patients in crisis.

However, the data reveals concerning gaps in long-term efficacy research—most studies measured outcomes after just one or two treatments, leaving questions about sustained remission rates with full treatment protocols. Patients and clinicians should understand that while initial response rates are promising, long-term depression remission data remains limited across all ketamine formulations.

Methods in Brief

This review synthesized systematic reviews and meta-analyses published between January 2020 and December 2024, focusing exclusively on ketamine-based treatments for major depressive disorder and bipolar depression. The analysis included studies on IV/intramuscular ketamine, esketamine nasal spray (Spravato), oral ketamine, and ketamine-assisted psychotherapy combinations.

Studies examining other conditions (PTSD, chronic pain, anxiety, addiction) were excluded. The review drew from high-quality peer-reviewed sources including EClinicalMedicine, Journal of Affective Disorders, Expert Opinion on Drug Safety, and others. Data was organized to compare response rates, remission rates, speed of onset, and durability across different administration methods.

 

Limitations & How to Interpret

Several important limitations affect interpretation. Most systematic reviews measured outcomes after only one or two ketamine treatments, providing limited insight into long-term remission rates with full treatment protocols. Study quality was frequently rated as low due to small sample sizes, high placebo responses (62-78% of total effect), and publication bias concerns.

Real-world response rates (around 30%) were consistently lower than controlled trial rates (up to 63%), suggesting a significant gap between research and clinical practice. The analysis also revealed discrepancies between manufacturer-sponsored esketamine trials used for FDA approval and independent systematic reviews, with the latter showing more conservative effectiveness estimates.

 

Data & Materials

DOI (white paper): https://zenodo.org/records/15196895
Wikidata item: https://www.wikidata.org/wiki/Q136235943
PDF Download: https://ketaminetherapyfordepression.org/wp-content/uploads/2025/04/Ketamine-Research-2020-2024.pdf
License: Creative Commons Attribution 4.0 International

For a deeper dive: https://ketaminetherapyfordepression.org/ketamine-research-studies/
Last verified: September 12, 2025

How to Cite

Alvear, M. (2025). Systematic Reviews and Meta-Analyses of Ketamine Therapy: 25 Studies | 2020-2024 | Comparative Evidence Summary. KetamineTherapyForDepression.org. https://doi.org/10.5281/zenodo.15196895

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FAQ

Q: Is IV ketamine really that much more effective than the FDA-approved esketamine nasal spray?

Yes, the research consistently shows IV ketamine significantly outperforms esketamine. IV ketamine tripled response rates compared to placebo, while esketamine showed only modest improvement. The effect size difference is substantial—IV ketamine achieved Cohen’s d = -0.75 (large effect) versus esketamine’s d = -0.38 (small effect, similar to traditional antidepressants). This means IV ketamine produces more than twice the symptom improvement of esketamine. Additionally, dropout rates were 80% higher with esketamine in some studies, suggesting tolerability issues.

Q: How quickly can I expect ketamine therapy to work?

IV ketamine can begin reducing depression symptoms within 24 hours, with some patients experiencing relief in as little as 40 minutes. Response rates (50%+ symptom reduction) occurred in 45-65% of patients within 24 hours of a single infusion. This rapid onset distinguishes ketamine from traditional antidepressants, which typically take 4-6 weeks. However, oral ketamine behaves more like conventional antidepressants, requiring 2-6 weeks to show effects. Esketamine nasal spray works faster than oral but slower than IV, with effects emerging within 2-4 hours.

Q: What are realistic expectations for achieving remission (minimal symptoms)?

Based on systematic reviews, 27-43% of patients achieved remission after IV ketamine treatment, with a median rate of 29%. However, this data comes primarily from studies measuring outcomes after just one or two treatments. Long-term remission data from full treatment protocols is extremely limited in the published literature. Some individual studies suggest higher remission rates (46-79%) with extended treatment courses, but these weren’t included in systematic reviews. Patients should understand that while initial remission rates are encouraging, sustained recovery data remains incomplete.

Q: Should I consider combining ketamine with therapy?

Early evidence suggests combining ketamine with psychotherapy may extend benefits and reduce relapse, particularly for patients who initially respond well to ketamine. Some studies found 44% remission rates when ketamine was paired with cognitive behavioral therapy. The theory is that ketamine creates a temporary “therapeutic window” of enhanced neuroplasticity when therapy may be more effective. However, the only randomized trial focused on depression found no significant benefit over ketamine alone. The research is still preliminary, with most positive results coming from PTSD studies rather than depression.

Q: Is oral ketamine worth considering as a treatment option?

Current evidence suggests oral ketamine is significantly less effective than IV ketamine and shows slower, weaker results than esketamine nasal spray. While some studies reported moderate symptom reduction, oral ketamine typically takes 2-6 weeks to work—similar to traditional antidepressants rather than the rapid-acting profile that defines ketamine’s reputation. Response and remission rates were only marginally statistically significant, and no systematic review provided strong evidence that oral ketamine achieves the high remission rates seen with IV formulations. Quality concerns about small sample sizes and short follow-up periods make oral ketamine appear promising but not ready for reliable clinical use.

Q: How do I interpret the high placebo response rates mentioned in this research?

Placebo effects accounted for 62-78% of ketamine’s total treatment response in systematic reviews, which is unusually high compared to other psychiatric medications. This doesn’t mean ketamine is ineffective—rather, it highlights the importance of rigorous study design and realistic expectations. The actual medication effect (beyond placebo) still represents meaningful symptom improvement, particularly for IV ketamine. However, these high placebo rates suggest that patient expectations, clinical setting, and therapeutic relationship play significant roles in outcomes. This information should inform treatment discussions but not discourage appropriate ketamine use for qualified patients.