Written and medically reviewed by Dr. Ladan Eshkevari, CRNA, PhD, FAAN.
The main difference between ketamine and esketamine is that ketamine is a racemic mixture, meaning it includes equal parts (50/50) of two mirror-image molecules. Esketamine (Spravato®) is composed solely of the S-form. For the pharmacology of the two halves on their own, see our guide to s-ketamine vs r-ketamine. This distinction affects the way they target neural receptors, which could influence their impact on treatment-resistant depression. Evaluating esketamine vs ketamine helps clinicians optimize ketamine therapy protocols, and allows patients to make more informed choices for their mental health.
As of July 2026, the comparative evidence still favors neither formulation decisively: the largest pooled analysis suggests racemic ketamine performs better, but it compares trials indirectly rather than head to head.Spravat
Let us investigate.
Ketamine
Ketamine, also called racemic ketamine, is a dissociative anesthetic mixture that is typically administered as a clear liquid solution for intravenous (IV) administration.
Discovery and development
Discovered in 1962 by Dr. Calvin Stevens, ketamine was initially used as a surgical anesthetic due to its rapid onset and short duration of action.[1] However, its unique pharmacological properties quickly caught researchers’ attention outside of anesthesia. Specifically, its ability to modulate glutamate neurotransmission and promote neuroplasticity revealed benefits for treating conditions like depression, PTSD, severe anxiety, OCD, suicidality, and substance use issues.
Pharmacological mechanisms
Ketamine’s efficacy in treating depression is attributed to its ability to modulate the glutamatergic system through interacting with NMDA receptors.[2] By blocking these receptors, ketamine stops the binding of glutamate, the brain’s primary excitatory neurotransmitter.
This blockade triggers downstream effects, including increased release of brain-derived neurotrophic factor (BDNF) and activation of AMPA receptors.[2] These mechanisms strengthen and build new neural connections, enhancing the brain’s ability to adapt and change.
IV ketamine protocol
A typical IV ketamine therapy protocol for depression involves administering a subanesthetic dose of racemic ketamine over a 40-minute infusion period. Treatment often consists of six sessions, typically over three weeks.
- Acute effects during and immediately after ketamine infusions include dissociation, perception changes (detachment and hallucinations), and mild sedation. Other temporary side effects include nausea and dizziness.
- A meta-analysis of IV ketamine trials for treatment-resistant depression found significant improvement in depression measures within the first 24 hours, with the effect tapering over the following week.[3]
- Repeated IV infusions may also ease PTSD symptoms. In one small study of patients with both PTSD and treatment-resistant depression, those whose PTSD went into remission after a six-infusion series stayed in remission for a median of 41 days.[4] Patients who engage in talk therapy alongside infusions may remain in remission longer.
IV ketamine containing a racemic mixture is the most common form of ketamine used for mental health conditions. The first controlled trial of ketamine for depression was published in 2000, and the evidence base has grown steadily since.[5]
Esketamine
Esketamine, also known as S(+)-ketamine, is a dissociative anesthetic. However, it specifically includes only the S(+)-enantiomer of the racemic ketamine mixture and typically comes in a nasal spray formulation.
Discovery and development
Researchers developed esketamine as a pharmaceutical product with the hope of potentially improving racemic ketamine’s pharmacological properties with fewer side effects. Scientists found that ketamine’s S-enantiomer exhibited more potent NMDA receptor antagonism and appeared responsible for many of ketamine’s desirable effects, such as its rapid antidepressant action.[6]
In 2019, the U.S. Food and Drug Administration (FDA) approved esketamine as a breakthrough therapy for treatment-resistant depression. Janssen Pharmaceuticals now markets the compound under the brand name Spravato®.
Pharmacological mechanisms
Both esketamine and racemic ketamine are antagonists at NMDA receptors, which are involved in glutamatergic neurotransmission. Pre-clinical research shows that esketamine has roughly four times the NMDA-receptor affinity of the other enantiomer in the racemic mixture[6]. Some experts believe this more potent and selective binding results in more targeted antidepressant effects.
Esketamine protocol
For treatment-resistant depression, Spravato (esketamine) nasal spray is self-administered under a licensed provider’s supervision and must be used in conjunction with a conventional oral antidepressant.
According to the FDA prescribing information, the starting dose is 56 mg, with adjustments based on individual response and tolerability. Treatment consists of an induction phase of twice-weekly sessions for four weeks, followed by a maintenance phase with sessions occurring weekly or every other week.[7]
- Acute esketamine effects during and immediately after dosing can mimic racemic ketamine, including dissociation, nausea, and dizziness. An early two-patient case report described fewer dissociative effects on S-ketamine than on racemic ketamine, though later controlled work has not borne this out as a general advantage.[8]
- Studies show that esketamine has rapid antidepressant effects, sometimes within mere hours of treatment.[9]
- Additionally, a phase 3 withdrawal study showed that esketamine plus an oral antidepressant can reduce relapse rates. Among patients who achieved stable remission, 73.3% of those who continued esketamine did not relapse over the study period, compared with 54.7% of those switched to a placebo nasal spray alongside their oral antidepressant.[10]
Clinicians have been prescribing esketamine since it received FDA approval in 2019. Spravato is covered by many commercial and government plans, though coverage, prior-authorization requirements, and out-of-pocket cost vary by plan. Our insurance coverage for ketamine and Spravato page explains how we verify benefits.
Esketamine vs. Ketamine for Depression: What Do The Studies Say?
Early research suggested that esketamine may be more effective and better tolerated for treating depression due to its affinity for glutamate NMDA receptors, rapid effects, and reduced hallucinogenic profile. However, the latest comparative analyses point the other way.
Is esketamine less impairing than racemic ketamine?
A 2002 study on 24 healthy volunteers compared equianalgesic intravenous doses of racemic ketamine, esketamine, and R(-)-ketamine on hemodynamic and cognitive measures for 60 minutes following administration.[11]
Researchers found that:
- Subjects experienced similar transient increases in blood pressure, heart rate, and stress hormone levels across all drug administrations.
- Overall, the single-enantiomer preparations, especially esketamine, caused less drowsiness, tiredness, and cognitive impairment over the 60 minutes than equianalgesic racemic ketamine.
- Esketamine specifically caused less decline in concentration capacity and primary memory.
This research suggested that esketamine might work better for patients with concerns about cognitive function directly after treatment. However, later comparative clinical trials did not identify this distinction.
Racemic ketamine may provide the ideal composition for treating depression
In 2021, a study investigated the psychological and cognitive effects of (S)-ketamine compared to racemic (R/S)-ketamine. This randomized, double-blind, placebo-controlled trial involved three groups of 10 healthy male volunteers who received either subanesthetic doses of racemic ketamine, esketamine, or a placebo via continuous IV infusion.[12]
Key findings of the study included:
- Both racemic and (S)-ketamine significantly affected psychopathology and neurocognitive performance compared to placebo, with no significant differences between the two.
- (S)-ketamine was associated with a somewhat more negatively experienced psychopathology.
Researchers concluded that the ideal composition for treating depression might be racemic ketamine, due to its more pleasant altered consciousness experiences and reduced anxiety potential.
Racemic ketamine appears to perform better than esketamine for treatment-resistant depression (TRD)
A systematic review and meta-analysis in 2021 compared racemic ketamine and esketamine for unipolar and bipolar major depression. Researchers pooled data from 24 randomized controlled trials representing 1,877 participants, focusing on outcomes like treatment response, remission, changes in symptom severity, suicidality, and retention in treatment.[13]
The analysis revealed that:
- Racemic ketamine showed a higher overall response (RR = 3.01) and remission rate (RR = 3.70) compared to esketamine (RR = 1.38 for response, RR = 1.47 for remission).[13]
- Racemic ketamine also demonstrated lower dropout rates (RR = 0.76) versus esketamine (RR = 1.37).
An important caveat: these are not head-to-head comparisons. The analysis pooled separate placebo-controlled trials of each formulation and compared them indirectly, and the authors state that direct head-to-head trials are needed to confirm the finding. The results suggest intravenous racemic ketamine may be more effective than intranasal esketamine for treating depression, but that question remains genuinely open.
Esketamine vs. Ketamine at Avesta
Our clinicians in Bethesda and Columbia, Maryland; Washington, DC; and Tysons (Vienna) and Norfolk, Virginia, offer both IV ketamine and esketamine nasal spray treatments based on our patients’ specific needs and situations.
We emphasize IV ketamine’s long history in effectively treating conditions like depression, PTSD, and anxiety with lasting effects. We also recognize Spravato’s rapid antidepressant action, insurance coverage benefits, convenient administration method, and the fact that it is FDA-approved for treatment-resistant depression.
We educate patients about both options, including the financial implications and treatment efficacy, so that they can make informed decisions on their treatment journeys.
The Bottom Line: We Need More Research
The latest analyses indicate racemic ketamine may have higher efficacy and better tolerability than esketamine for treatment-resistant depression. However, researchers must conduct more randomized double-masked clinical trials comparing the two directly. Such studies will help determine the optimal ketamine formulation and administration strategy, potentially leading to enhanced protocols for depression and other psychiatric conditions. This approach will help ensure patients and clinicians can make decisions based on solid evidence, aiming to maximize therapeutic benefits and minimize unwanted side effects.
Frequently Asked Questions
Is esketamine the same thing as ketamine?
Not quite. Ketamine is a racemic mixture of two mirror-image molecules in a 50/50 ratio. Esketamine is one of those two halves on its own, the S-enantiomer. It is not a different medicine or a ketamine analog. It is a single component of ketamine, purified and delivered as a nasal spray.
Is esketamine stronger than racemic ketamine?
It binds more tightly, but that does not translate directly into a stronger clinical effect. Pre-clinical work shows esketamine has roughly four times the NMDA-receptor affinity of the other enantiomer. Dosing accounts for that difference, and the two formulations are given by different routes, so binding affinity alone does not tell you which will work better for a given patient.
Which works better for treatment-resistant depression?
The largest pooled analysis to date, covering 24 trials and 1,877 participants, found higher response and remission rates for racemic ketamine than for esketamine. That analysis compared separate trials indirectly rather than testing the two head to head, so it points in a direction rather than settling the question. Our clinicians weigh the evidence alongside route of administration, coverage, and individual history.
Is Spravato covered by insurance when IV ketamine is not?
Often, yes. Spravato is FDA-approved for treatment-resistant depression, so many commercial and government plans cover it, usually with prior authorization. IV ketamine for mental health is prescribed off-label and is less consistently covered. Coverage, authorization requirements, and out-of-pocket cost vary by plan, so we verify benefits before treatment begins.
Contact Avesta, with locations in Bethesda and Columbia, Maryland; Washington, DC; and Tysons (Vienna) and Norfolk, Virginia, for a free consultation about whether IV ketamine or Spravato is the better fit.
References
- Li L, Vlisides PE. “Ketamine: 50 Years of Modulating the Mind.” Frontiers in Human Neuroscience, 2016 (PMC6493431). Accessed July 2026.
- Zanos P, Thompson SM, Duman RS, Zarate CA Jr, Gould TD. “Ketamine: NMDA Receptors and Beyond.” Journal of Neuroscience (PMC5148235). Accessed July 2026.
- Marcantoni WS, Akoumba BS, Wassef M, et al. “A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 to January 2019.” Journal of Affective Disorders, 2020;277:831-841. Accessed July 2026.
- Albott CS, Lim KO, Forbes MK, et al. “Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression.” Journal of Clinical Psychiatry, 2018;79(3):17m11634. Accessed July 2026.
- Berman RM, Cappiello A, Anand A, et al. “Antidepressant effects of ketamine in depressed patients.” Biological Psychiatry, 2000;47(4):351-354. Accessed July 2026.
- Molero P, Ramos-Quiroga JA, Martin-Santos R, et al. “Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review.” CNS Drugs, 2018;32(5):411-420. Accessed July 2026.
- U.S. Food and Drug Administration. “SPRAVATO (esketamine) nasal spray, CIII – Prescribing Information.” Accessed July 2026.
- Paul R, Schaaff N, Padberg F, Moller HJ, Frodl T. “Comparison of racemic ketamine and S-ketamine in treatment-resistant major depression: report of two cases.” World Journal of Biological Psychiatry, 2009;10(3):241-244. Accessed July 2026.
- Popova V, Daly EJ, Trivedi M, et al. “Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression.” American Journal of Psychiatry, 2019;176(6):428-438. Accessed July 2026.
- Daly EJ, Trivedi MH, Janik A, et al. “Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.” JAMA Psychiatry, 2019;76(9):893-903. Accessed July 2026.
- Pfenninger EG, Durieux ME, Himmelseher S. “Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers.” Anesthesiology, 2002;96(2):357-366. Accessed July 2026.
- “Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers.” European Neuropsychopharmacology, 2021 (PMID 33487513). Accessed July 2026.
- Bahji A, Vazquez GH, Zarate CA Jr. “Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis.” Journal of Affective Disorders, 2021;278:542-555. Accessed July 2026.
