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Ketamine vs. Esketamine: 3 Important Differences Explained

ketamine vs. esketamine
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Ketamine treatments are a revolutionary force in the journey towards healing and relief for a multitude of chronic mental health disorders. Ketamine gained popularity as a sedative in the 1970s. But today, health professionals use it as a treatment for people previously unable to find relief from chronic ailments. In March of 2019, the FDA approved esketamine, a type of ketamine derivative, as a treatment for refractory depression. Health officials are now exploring the benefits of ketamine vs. esketamine to discover which form can provide the most benefits for people with treatment-resistant mental illnesses, like ketamine for depression and anxiety.

What is Ketamine?

Before getting into ketamine vs. esketamine, let’s get into a few basics. Ketamine is classified as an NMDA receptor antagonist, meaning it blocks the flow of electrical communication in the brain by way of the glutamate signaling system. Glutamate is one the most abundant excitatory neurotransmitters in the brain, and by blocking its ability to bind to NMDA receptors, ketamine can trigger new or regenerative neural growth. Chronic illness affects these neural connections, causing some to die off while others are strengthened.

Ketamine-induced neural growth helps patients foster neural communication outside of their illness. Higher doses of ketamine can induce a state of dissociative anesthesia and has potent psychedelic effects. Ketamine comes in three forms: injectable liquid, crystalline powder and nasal spray. It can be consumed intravenously in liquid form through an IV or intranasally through a nasal spray.

Most recreational use of ketamine is intranasal consumption of crystalline powder, though this can damage the respiratory tract and nasal cavity due to impurities. Some recreational ketamine comes as pressed pills, but these can often contain other substances and pose significant risks. Legal ketamine and the standard of care for ketamine treatments can be found through ketamine clinics, ketamine-assisted psychotherapy and ketamine infusion therapy. 

Ketamine was first seen as a possible treatment for depression in the early 21st century. Since then, it has been used to treat numerous chronic health conditions, including but not limited to: chronic pain, depression, eating disorders, PTSD, OCD and anxiety.

What is Esketamine?

Ketamine is a chiral molecule meaning that it has two molecular forms that are perfect mirror images. Chemists distinguish between the two molecules as left-handed and right-handed. Esketamine is simply the left-handed version of ketamine. It is sometimes referred to as S-ketamine, whereas generic ketamine — the right-handed version — is referred to as R-ketamine.

As a derivative of ketamine, esketamine has a very similar effect on the brain’s NMDA receptors. Esketamine blocks glutamate from binding to NMDA receptors, thus causing a surge that triggers rapid neural growth. Johnson & Johnson developed a nasal spray as the only prescription form of esketamine on the market. The nasal spray, called Spravato, is prescribed to patients with treatment-resistant depression.

Experts themselves still have a hard time defining what treatment-resistant depression is. However, most experts see treatment-resistant depression as a type of depression that does not respond to two or more antidepressant treatments. Some experts label a case of depression as treatment-resistant only after a person fails to respond to at least four different treatments. Of course, this will vary from person to person, and only a patient and their doctor can agree on where they stand. Treatment-resistant is not limited to depression and can include other mental illnesses.

Although ketamine and esketamine treatments can only take place in a doctor’s office or other healthcare facilities, due to COVID-19 social distancing guidelines, some generic ketamine clinics began allowing patients to self-administer via this nasal spray.

What Are the Differences Between Ketamine and Esketamine?

When thinking of ketamine vs. esketamine, a few key differences come to mind. The two vary in potency, number of treatments and the current therapeutic uses.


Generic ketamine treatments can come in a variety of potencies based on the amount of liquid ketamine medical practitioners administer. Esketamine is only available in two dosages as a nasal spray. The route of administration and limited dosage options make esketamine much less likely to induce the level of dissociation found with generic ketamine. 

Dosages aside, at the molecular level, esketamine is much more potent than generic ketamine. This means that if ketamine and esketamine were both infused intravenously, esketamine would be much more powerful. Currently, intravenous ketamine infusions, or ketamine IV therapy, are only available at ketamine treatment centers or clinics.

Number of Treatments

Ketamine infusions begin with six one-hour infusions within the first two to three weeks. After the initial infusions, patients undergo hour-long infusions for the following three to six weeks. Esketamine treatments begin with a month of bi-weekly hour-long applications of the nasal spray followed by weekly applications and then tapering off to twice a month. 

Both have been found to produce rapid antidepressant effects, with patients feeling relief from symptoms mere hours after treatment. Some research also suggests there may be a delay in symptom relief and how long ketamine stays in your system, but further research needs to be conducted to have more conclusive answers.

Therapeutic Uses

The FDA has approved generic ketamine infusions as treatments for a myriad of mental health issues, including depression, anxiety and chronic pain, amongst other things. Esketamine has only been approved as an augmenting agent for treatment-resistant cases. 

Ketamine infusion treatments can be both psychedelic and sub-psychedelic, depending on dosage levels. Esketamine nasal sprays are not intended to produce psychedelic effects. Instead, they work to harness esketamine’s biochemical effect on the brain, providing a boost in neural growth that can help reduce symptoms of depression.

Which Substance is Right for You: Ketamine vs. Esketamine

The success rate of ketamine treatments is nearly double those of traditional refractory depression treatments. This means patients are reporting greater and more rapid relief from depressive symptoms. So, ketamine vs. esketamine, which one is right for you? Both treatments are now FDA-approved but have some crucial differences that people seeking treatment have to consider. A few things to keep in mind include:

  • There is currently only one prescription form of esketamine on the market: medicated nasal spray.
  • Medical professionals primarily prescribe esketamine as a supplement to traditional SSRI treatments for patients seeking greater relief from refractory depression.
  • Ketamine infusions are not recommended for patients already using neurotropic medications like SSRIs.

At this time, ketamine treatments cannot be accessed as the first resource for those suffering from mental illness. It’s important to remember that to be able to receive ketamine or esketamine treatments, patients need to be categorized as treatment-resistant. This is an individual discussion that should happen between patients and their doctors.

People should always discuss their medical history with a healthcare professional before undergoing ketamine or esketamine therapy to see if it’s right for them. Whatever treatment path one chooses, it is important to be educated about the current research on ketamine and its derivatives. One thing is clear, numerous reports state that both provide relief and hope to people who previously had been unable to find recovery and manage symptoms of their mental illness.

Psychonaut Thoughts?

We want to hear from our readers! Ketamine vs esketamine? If you feel comfortable sharing your stories and experiences with ketamine and esketamine treatments, we invite you to leave a comment below.

Disclaimer: Ketamine is potentially categorized as an illegal drug. Reality Sandwich is not encouraging the use of these drugs where prohibited. However, we believe that providing information is imperative for the safety of those who choose to explore these substances. This guide is intended to give educational content and should in no way be viewed as medical recommendations.


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    Haley is a writer, artist, and musician based in Southern California. She is passionate about discovering new avenues toward compassion and understanding for self and others. With an academic background in psychology, she hopes to reduce the stigma surrounding plant medicine so more people can find healing and relief, allowing them to tap into the expansiveness of human existence. In her free time she loves eating breakfast foods, taking in a sunset over the ocean, and laughing with friends.

1 thought on “Ketamine vs. Esketamine: 3 Important Differences Explained”

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    Generic ketamine, otherwise known as racemic ketamine, is a 50/50 blend of R and S-ketamine.
    Racemic ketamine has been shown to be effective in the treatment of bipolar depression and for some substance abuse disorders e.g. alcohol and opiate addiction.

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