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Esketamine vs. Ketamine: What is the Difference?

illustration portraying Esketamine vs Ketamine

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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: S-ketamine and R-ketamine. Esketamine (Spravato®) is composed solely of the S-ketamine form. 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.

Let’s investigate.


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. 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.

IV Ketamine infusions for depression anxiety ptsd chronic pain fibromyalgia CRPS Bethesda MD McLean VA Washington DC

Pharmacological mechanisms

Ketamine’s efficacy in treating depression is attributed to its ability to modulate the glutamatergic system through interacting with NMDA receptors. 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. These mechanisms strengthen and build new neural connections, enhancing the brain’s ability to adapt and change.

IV ketamine protocol

avesta ketamine therapy patient infusion

A typical IV protocol for depression involves administering a subanesthetic dose of racemic ketamine ranging 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. 
  • Clinical trials show that IV ketamine improves depression symptoms within hours or days after a single injection.
  • Repeated IV infusions alone can alleviate PTSD symptoms for at least 41 days. Patients who engage in talk therapy alongside infusions can remain in remission even longer.

IV ketamine containing a racemic mixture is the most common form of ketamine for mental health conditions. More than two decades of clinical research confirms its rapid and sustaining effects.


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.

Spravato® nasal spray

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 discovered 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.

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®.

Ketamine Infusions in Bethesda, MD, McLean, VA and Washington, DC

Pharmacological mechanisms 

Both esketamine and racemic ketamine are antagonists at NMDA receptors, which are involved in glutamatergic neurotransmission. However, pre-clinical research shows that esketamine binds four times more efficiently to these receptors than ketamine. Some experts believe this potent and selective binding results in more targeted antidepressant effects. 

Esketamine protocol

John Hopkins Medicine explains that for treatment-resistant depression, esketamine nasal treatment is typically self-administered under a licensed provider’s supervision and must be used in conjunction with a conventional antidepressant. 

The initial dose of esketamine is 56 mg, with adjustments based on individual response and tolerability available. Treatment consists of an initial phase of twice-weekly sessions for four weeks, followed by a maintenance phase with sessions occurring weekly or every other week.

  • Acute esketamine effects during and immediately after the infusion can mimic racemic ketamine, including dissociation, nausea, and dizziness. However, research suggests Spravato® is less prone to causing hallucinations
  • Studies show that esketamine has rapid antidepressant effects, sometimes within mere hours of treatment. 
  • Additionally, a phase 3 withdrawal study showed that esketamine plus an oral antidepressant can reduce relapse rates. Of the patients who achieved stable remission and continued treatment, 73.3% did not relapse after a 16-week period. This contrasts with the group treated with an oral antidepressant and placebo nasal spray, where 54.7% did not relapse.

Clinicians have been prescribing esketamine since it received FDA approval in 2019. Today, most insurance plans cover treatment with a standard co-pay.  

Esketamine vs. Ketamine for Depression: What Do The Studies Say?

infographic on Esketamine vs. Ketamine for Depression

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 indicate standard ketamine may be superior.

Is Esketamine Less Impairing Than Racemic Ketamine?

A 2002 study on 24 healthy volunteers compared intravenous doses of racemic ketamine, esketamine, and R(-)-ketamine on blood flow measurements, mood, and cognitive capacities for 60 minutes following administration. 

Researchers found that:

  • Subjects experienced similar transient increases in blood pressure, heart rate, and stress hormone levels across all drug administrations.
  • Esketamine made subjects feel braver compared to racemic ketamine 20 minutes after injection.
  • Overall, ketamine isomers, especially esketamine, caused less drowsiness, lethargy, and impairment in subjective cognitive capacities over the 60 minutes than racemic ketamine.

This research suggested that esketamine might work better for patients with concerns about cognitive function directly after the treatments. 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. 

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.

Ketamine Infusions in Bethesda, MD, McLean, VA and Washington, DC

Racemic ketamine appears to be more productive than esketamine for Treatment-resistant Depression (TRD)

A systematic review and meta-analysis in 2021 compared racemic ketamine vs esketamine for unipolar and bipolar major depression. Researchers compiled data from 24 randomized controlled trials representing 1,877 participants, focusing on primary outcomes like treatment response and remission from depression, changes in symptom severity, suicidality, and retention in treatment. 

The analysis revealed that:

  • Racemic ketamine showed a higher overall response (RR = 3.01) and remission rates (RR = 3.70) compared to esketamine (RR = 1.38 for a response, RR = 1.47 for remission).
  • Additionally, racemic ketamine demonstrated lower dropout rates (RR = 0.76) versus esketamine (RR = 1.37), indicating patients preferred this form.

The results suggest that intravenous racemic ketamine may be more effective than intranasal esketamine for treating depression. Racemic mixtures may also be preferable for severe cases that require rapid and effective intervention.

Esketamine vs. Ketamine at Avesta

Avesta ketamine clinic

Avesta’s ketamine clinicians in Washington D.C., McLean, Virginia, and Bethesda, Maryland, offer both IV ketamine and esketamine nasal spray treatments based on their patients’ specific needs and situations. 

Its team emphasizes IV ketamine’s long history in effectively treating mental health conditions like TRD, PTSD, and anxiety with lasting effects. However, Avesta also recognizes Spravato’s® rapid antidepressant action, insurance coverage benefits, convenient administration method, and the fact that it is FDA-approved for TRD. 

Avesta educates 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 a higher efficacy and better tolerability than esketamine for treatment-resistant depression. However, researchers must conduct more randomized double-masked clinical trials comparing the two. 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 ensure patients and clinicians can make decisions based on solid evidence, aiming to maximize therapeutic benefits and minimize unwanted side effects.

At Avesta Ketamine and Wellness, we help patients optimize their mental and physical wellness with esketamine nasal spray and racemic IV ketamine options. Call for a free consultation with providers at one of our locations in Bethesda, McLean, or Washington DC to learn more. 

Ketamine Infusions in Bethesda, MD, McLean, VA and Washington, DC

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