In this post
- How is Esketamine / Spravato® Different from Ketamine?
- How are Esketamine / Spravato® and Ketamine Similar?
- How Esketamine / Spravato® vs Ketamine is Administered
- Esketamine / Spravato® vs Ketamine: Side Effects Compared
- Esketamine / Spravato® vs Ketamine: Cost Comparison
- Is Esketamine / Spravato® or Ketamine Better for Depression?
- Does Esketamine / Spravato® Work for Pain Like Ketamine?
- The Bottom Line: Which Should You Choose?
Esketamine and ketamine are closely related but not identical. Ketamine is a racemic mixture of two mirror-image molecules: R-ketamine and S-ketamine. Esketamine is just the S-ketamine half. Esketamine is FDA-approved for treatment-resistant depression and sold as the nasal spray Spravato®. Generic ketamine is FDA-approved as an anesthetic and used off-label, typically as an IV infusion, to treat depression and chronic pain.
| Factor | Esketamine (Spravato®) | Ketamine (IV infusion) |
|---|---|---|
| Chemical form | S-enantiomer only | Racemic (R + S enantiomers) |
| FDA approval | Approved for treatment-resistant depression (2019) | Approved as anesthetic; used off-label for depression |
| Route | Nasal spray, self-administered under supervision | IV infusion, clinician-administered |
| Session length | ~2 hours (including monitoring) | 45–60 minutes |
| Typical schedule | 2x/week for 4 weeks, then weekly | 6 infusions over 2–3 weeks, then maintenance |
| Insurance coverage | Often covered after 2 failed antidepressants | Usually out-of-pocket; some clinics in-network |
| Out-of-pocket cost (uninsured) | $800–$1,200 per session | $400–$600 per session |
| Approved for ages | 18+ only | Used in teens off-label |
| Other indications | MDD with TRD only | PTSD, OCD, anxiety, chronic pain, SUD |
How is Esketamine / Spravato®Different from Ketamine?
Esketamine is one half of the ketamine molecule. Ketamine is a racemic mixture of two mirror-image molecules — R-ketamine (arketamine) and S-ketamine. Esketamine is the S-ketamine half isolated and sold as the nasal spray Spravato®. In preclinical studies, esketamine binds NMDA receptors with 2–3x the affinity of R-ketamine, but more recent animal research suggests R-ketamine may produce more potent and longer-lasting antidepressant effects.
How are Esketamine / Spravato® and Ketamine Similar?
Esketamine and ketamine share the same mechanism of action and produce similar effects in the brain. Both activate glutamate-related NMDA receptors, which supports neuroplasticity — the brain’s ability to rewire and adapt. Both produce dissociative psychedelic effects during dosing, with patients reporting altered perceptions and a feeling of detachment from their surroundings. Both deliver rapid antidepressant relief, often within hours, compared to the weeks required by traditional SSRI antidepressants.
How Esketamine / Spravato® vs Ketamine Is Administered
Esketamine is given as a nasal spray; ketamine is given as an IV infusion. Both must be administered in a monitored clinical setting. Spravato® sessions involve 2–3 nasal doses spaced 5 minutes apart, followed by 2 hours of monitoring — typically twice weekly for 4 weeks, then weekly or biweekly during maintenance. IV ketamine is delivered through a vein over 45–60 minutes, usually as 6 infusions across 2–3 weeks with booster sessions as needed.
Intranasal Spravato® is administered through the nose, twice weekly
Spravato® delivers a low esketamine dose through the nose in a quick burst. Most patients receive two to three doses about five minutes apart, using them twice weekly for the first four weeks and once every week or two in the maintenance phase. Each session requires two hours of monitoring after administration, side effects can last a few hours.
IV Ketamine is administered through the vein
IV Ketamine infusions are administered through the vein and directly into the bloodstream under controlled doses via an IV line. Most patients receive six treatments over two to three weeks, with maintenance and booster sessions for those who need them. Sessions last 45 minutes to an hour, and side effects can linger for several hours post-infusion.
Esketamine / Spravato® vs Ketamine: Side Effects Compared
Esketamine and ketamine produce nearly identical short-term side effects. Both can cause dissociation (a sense of detachment from reality), disorientation, nausea or vomiting, and anxiety during the session. Studies suggest esketamine causes less drowsiness and cognitive impairment after dosing, while IV ketamine more often produces a mood-elevating, mildly euphoric experience. Side effects from both typically resolve within a few hours, and serious adverse events are rare when administered in a supervised clinical setting.
Esketamine / Spravato® vs Ketamine: Cost Comparison
With insurance, esketamine is usually cheaper; without insurance, IV ketamine is significantly cheaper. Spravato® (esketamine) is FDA-approved for treatment-resistant depression, so most insurance plans cover it after a patient has failed two prior antidepressants — out-of-pocket cost can be near zero. IV ketamine is off-label for depression and rarely covered, with uninsured patients typically paying $400–$600 per infusion. Uninsured Spravato® sessions can run $800–$1,200 each — up to 6x the cost of IV ketamine.
Is Esketamine / Spravato® or Ketamine Better for Depression?
Both treatments work, but head-to-head meta-analyses show IV ketamine produces slightly higher response and remission rates for treatment-resistant depression. A 2021 meta-analysis by Bahji et al. reported a 60% response rate and 43% remission rate for IV ketamine, compared to 57% response and 27% remission for esketamine. A 2022 Cambridge study (Singh et al.) found IV ketamine required fewer total treatments to reach remission. No prospective, randomized head-to-head trial has been conducted to date.
Here are key findings from available research:
Correia-Melo et al. (2020): This randomized, double-blind study involving 63 participants showed that esketamine was non-inferior to ketamine, indicating similar efficacy in treating TRD.
Bahji et al. (2021): This meta-analysis found IV ketamine had a 60.0% response rate and 42.6% remission rate, compared to 57.4% response and 26.7% remission for esketamine — concluding ketamine may be more effective overall.
Singh et al. (2022): This Cambridge study concluded that ketamine and Spravato® showed similar response and remission rates. However, IV ketamine required significantly fewer treatments compared to intranasal esketamine.
Nikayin et al. (2022): A Yale study indicated ketamine had better secondary outcomes than esketamine, meaning greater improvements in depression symptoms such as mood, sleep, and appetite.
Does Esketamine / Spravato® Work for Pain Like Ketamine?
No — esketamine is not used for pain, while IV ketamine has substantial evidence for treating acute and chronic pain.
- A 2019 systematic review of randomized controlled trials concluded that ketamine provides significant short-term pain relief.
- A 2014 study showed that low-dose ketamine produces potent relief for neuropathic pain states during administration, with some long-term effects lasting up to three months following infusion.
- The American Society of Hematology reported that ketamine worked well in patients with severe pain not responsive to standard opioid analgesics, such as sickle cell disease and cancer-related pain.
The Bottom Line: Which Should You Choose?
Choose esketamine (Spravato®) if you have insurance, qualify for coverage, and prefer a non-invasive nasal spray; choose IV ketamine if you are uninsured, need treatment for a condition other than treatment-resistant depression, or want the option with the strongest research base for depression and chronic pain.
Avesta Ketamine and Wellness offers both protocols at our Bethesda, Washington DC, Tysons, Columbia, and Norfolk locations — book a free consultation to discuss which is right for you.
