HomeBlogConditionsTipsEsketamine vs Ketamine: Which is More Effective for Depression?

Esketamine vs Ketamine: Which is More Effective for Depression?

Depression is the most prevalent mental health disorder. At any point, around 10% of adults are currently struggling with a depressive disorder. Depression also has several forms and can be chronic depression in the form of seasonal affective disorder, acute depression such as postpartum depression, or even severe treatment-resistant depression.

All forms of depressive disorders have a severe impact on mental health, making it difficult for individuals to maintain good quality of life, self-esteem, and physical well-being. It interferes with performance in work or school and can have a detrimental impact on relationships.

The majority of treatments for depression have remained relatively stagnant over the last few decades, with people prescribed the same handful of antidepressants alongside psychotherapy and holistic care but now there are emerging treatments for depression with higher levels of efficacy, including ketamine and esketamine. 

Ketamine is administered in many ways, including:

  • Sublingual like lozenges
  • Intravenously
  • Intramuscularly
  • Subcutaneously
  • Intranasally (in the form of an Esketamine spray)
  • Oral (though this is the least common)

At its face, ketamine is an anesthetic, but esketamine is the nasal spray version, which is sold and used under the brand name “Spravato.” This article will review both ketamine and esketamine side by side as a potential depression treatment. 

Overview of Ketamine

Ketamine has been used as a surgical anesthetic since the 1970s. It, and the subsequent esketamine, derives from PCP or angel dust. In the 1990s, Yale researchers began to investigate its efficacy as a depression treatment and found that those with treatment-resistant depression or those with suicidal ideation saw significant and immediate relief.

Ketamine has been used for major depressive disorder presenting with acute suicidal ideations as well as treatment-resistant depression, particularly with those who struggle to achieve any remission or relief from symptoms using other antidepressant medications. 

Ketamine (or RS-ketamine) is a racemic mixture which has equal levels of:

  1. R-ketamine and 
  2. S-ketamine (or esketamine)

This can be administered in several ways, but an intravenous administration is the most common. This takes place in a clinical setting with an approved doctor over the span of 40 minutes to 60 minutes each session.

esketamine vs ketamine

How ketamine works in the brain

As mentioned, ketamine has arketamine and esketamine in the mixture. These work together to interact with subsets of neurotransmitters. Regular ketamine interacts with NMDA (N-methyl-D-aspartate) receptors. These are the connections that facilitate communication in the brain. Exposure to long-term depression and stress causes the synapses to die, but ketamine is able to regrow these synapses and improve neurological communication.

Ketamine also works by growing new glutamate receptors. Glutamate receptors are located on the ends of your nerve cells, and they help messages be sent and received more effectively. However, long-term depression causes these receptors to deactivate, and we can either die. Ketamine is able to quickly grow new glutamate receptors, which improves mood and brain circuit function and reduces the depression and anxiety symptoms you might experience.

Overview of Esketamine

Esketamine (sold under the brand name Spravato) is a derivative of ketamine. It has received FDA approval for the treatment of major depressive disorder (MDD) and treatment-resistant disorder (TRD). It is administered as a nasal spray in clinical settings and must be used in conjunction with an antipsychotic or antidepressant medication. 

In 2018, phase 2 data was published with new studies that confirmed the efficacy of this nasal spray for treatment-resistant depression and the rapid Improvement of suicidal thoughts. Long-term studies were approved in 2019 for treatment-resistant depression and then in 2020 for major depressive disorder presenting with acute suicidal ideations.

Esketamine nasal spray was developed a few years ago, based on the science of ketamine. 

This is the general name for the intranasal esketamine. The chemical name is (S)-2-(o-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride. This means it does not contain the same two parts as ketamine, just the one. It is also a water soluble powder, which is how it is mixed into the nasal spray liquid and subsequently administered. 

How esketamine works in the brain

Esketamine works similarly but with a primary focus on the glutamate receptors. Studies indicate that the hippocampus shrinks by up to 20% in people who have a major depressive disorder or treatment-resistant depression, and this causes problems with learning and memory. Esketamine improves the connections that depression and stress break because of this damage and helps to boost memory and learning while also growing glutamate receptors. 

Esketamine vs Ketamine: Detailed Comparison

So, which is better, ketamine or esketamine?

Esketamine vs ketamine FDA approval

As of now, esketamine has FDA approval for major depressive disorder and treatment-resistant depression, but it must be used in conjunction with an oral antidepressant or an antipsychotic. FDA approval is still pending for ketamine, but in everyday practice, both are administered at clinical facilities by a qualified professional.

Ketamine vs esketamine administration methods

The key difference is the administration methods. With esketamine, the administration method is a nasal spray, so a doctor will show you how to use it, which is much the same as any other nasal spray you have ever used, and then watch you as you self-administer each session.

Immediately after using your nasal spray, you’ll remain under supervision for 2 hours so that they can monitor for any negative side effects, such as panic attacks or dissociation.

Traditional ketamine can be received in different ways, although the most common is the intravenous method, whereby a doctor puts a needle into the vein located on the inside of your elbow and provides an IV infusion over the span of 40 to 60 minutes. You’ll remain under supervision not only while it’s happening but also for a few hours afterward for the same monitoring purposes.


Though the administration methods differ, the FDA approval means that esketamine administration has to be done at federally approved programs to monitor for potential abuse or addiction.

esketamine vs ketamine

Esketamine vs. Ketamine treatment lengths

As mentioned, esketamine treatment plans are only available through restricted government programs. The facilities that provide these programs administer your doses over two or three weeks. Blood pressure is taken beforehand and after, but the average individual only uses six doses.

The ketamine infusions work much faster, but you typically have the same treatment length.

In terms of how much time is required to feel a difference in symptoms, the administration of the nasal spray is a much faster administration time because, of course, a spray only takes a few seconds to complete, whereas the ketamine can take up to an hour. However, ketamine alleviates symptoms within 24 hours for many people, and this is especially important for those with suicidal ideations.

Neurobiological difference between ketamine and esketamine

Is esketamine weaker than ketamine? It is not technically weaker; it is just a different mixture. Regular ketamine treatment has equal parts of two things:

  1. Esketamine (s-ketamine)
  2. Arketamine (r-ketamine)

Esketamine nasal spray only has esketamine (hence the name). Science indicates that arketamine has longer-lasting effects in reducing depression. Studies also indicate that esketamine is more likely to produce dissociative effects, so someone considering the esketamine nasal spray alone may not have the longevity of arketamine and may also have higher dissociative effects after each treatment session. 

Ketamine vs esketamine insurance costs

Several insurance companies apply benefits to the cost of esketamine treatment, including:

  • Medicaid
  • United Healthcare
  • Anthem /BCBS
  • Aetna
  • Cigna
  • Medicare 

If you have any of these providers, then you may very well be able to use your insurance benefits to cover the cost of depression treatment. That said, the cost is different depending on your provider and plan. 

For example:

Medicare costs $951 for 56 milligrams and $1,353 for 84 milligrams. 

Note: Most people with treatment-resistant depression will need 84 milligrams. 

Medicare requires individuals to pay 20% of the total cost, which can be around a few hundred dollars. Medicare is one of the few companies that will also cover traditional ketamine with a starting dose of 0.5 mg/kg and a maximum of 1 mg/kg, but you typically have to pay $187 per session.

Private insurance may cover the cost of either option completely, but again, this is based on your provider and your plan.

In most cases, however, ketamine is not covered by insurance, so you have to pay for it out of pocket. The cost can be upwards of a few hundred dollars per session, which may or may not be equal to what you would pay for the nasal spray, even with insurance.

Difference between ketamine and esketamine availability

One difference you need to be aware of is the availability. At present, ketamine for depression treatment is not FDA-approved, which means it can be difficult to find facilities in certain areas that offer these services, and if you do, they will be things you have to pay for out of pocket. By comparison, with FDA approval, esketamine is slightly more widely available depending on where you live.

esketamine vs ketamine

Effectiveness in Treating Depression: ketamine vs esketamine for depression

Clinical trials have not found a difference in effectiveness for ketamine vs. esketamine for depression. Data from Cambridge confirms that both treatment options have similar remission and response rates, particularly among people with treatment-resistant or major depressive disorder.

If you opt for ketamine vs esketamine, it is likely that a change in depression symptoms will begin within 24 hours. The biggest difference between ketamine and esketamine is that regular ketamine, administered in other ways, offers faster relief because it reaches the bloodstream quicker. This directly influences how many sessions you might require, reducing the number of treatment sessions and subsequent costs. 


For most people considering esketamine and ketamine, this can be very important because the cost of esketamine nasal spray is often covered by insurance because it is FDA-approved as a treatment for depression, but the cost of ketamine in an intramuscular or intravenous administration is usually not. As such, those who are paying out of pocket may prefer the faster relief and shorter sessions required for ketamine. 

Safety and Side Effects of Esketamine and Ketamine

So what are the safety and side effects concerns for esketamine and ketamine?

Ketamine and esketamine side effects

Clinical trials for esketamine nasal spray and ketamine have not found any significant difference in terms of side effects. The potential side effects are typically the same regardless of which you choose. 

For both ketamine and esketamine, physical side effects can include:

  • Headaches
  • Panic attacks
  • Nausea
  • Vomiting

One difference between ketamine and esketamine is the administration methods and, therefore, the side effects of that. If, for example, you receive esketamine nasal spray, the potential side effects from the administration method include:

  • A runny nose
  • Nasal discomfort

If, instead, you opt for an intravenous ketamine treatment, you might have:

  • Swelling at the IV site
  • Pain
  • Blurred vision
  • Allergic reactions 

Patients who have completed both describe traditional ketamine as a more aggressive and immediate resolution to their depression symptoms, while the nasal spray is more of a gentler, slower resolution. 

Potential risks for esketamine and ketamine

With ketamine vs. esketamine, there are safety considerations. Esketamine is FDA-approved for treatment and that means that you can only access the nasal spray through approved Federal programs. Any treatment center or clinic that provides this nasal spray must be a part of the FDA Risk Evaluation and Mitigation Strategies (REMS) program. 

The reason for this is the high risk of addiction and abuse associated with this drug. To alleviate some of these potential risks, as the patient, you have to register with the program and fill out paperwork when you first arrive that acknowledges your understanding of subsequent requirements, including the monitoring.

After each session where you have to use the nasal spray in front of a doctor, you still have to remain at the facility for an additional 2 hours while they monitor you for potential side effects.

Traditional ketamine, outside of surgical procedures where it’s used as an anesthetic, and you remain monitored the entire time. There are slightly fewer FDA requirements, which means it’s incumbent upon you to find reputable facilities and be aware of the risks of addiction and abuse. 

Long-term risks for ketamine vs. esketamine

The FDA has only approved the use of this nasal spray in conjunction with a combination of traditional antidepressant medications or antipsychotic medications.

Suppose you struggle with a depressive disorder and you have previously taken antidepressants with serious side effects. In that case, you may be required to take those antidepressants again in order to use esketamine. This could pose long-term safety risks for you and your overall health.

Additionally, even if you don’t have severe reactions to traditional antidepressants, they come with a wide range of significant side effects like metabolic changes, blood pressure problems, weight gain, and the risk of suicidal ideations.

By comparison, ketamine administration does not require that you also take an antipsychotic or antidepressant medication at the same time. However, it is up to you to consider whether or not this might be worth the investment or whether you might want to consider additional treatment like therapy at the same time.

esketamine vs ketamine

The Benefits of Ketamine and Esketamine for Depression

Studies have found that with ketamine vs. esketamine for depression, the results are almost exactly the same, with both options presenting with complete remission in around 30% of people, with the remainder experiencing a significant drop in depression and anxiety symptoms. 


  • Research has found that an average of 38% of participants using esketamine go into remission.
  • Esketamine produces reduced depression symptoms in 70% of participants, many of whom experience a 50% reduction in depression. 
  • Studies show that 62% of those who take esketamine enjoy better social functioning.
  • 53% of those who take esketamine have a better quality of life
  • Of those who take esketamine, 41% are better able to work or complete school requirements.
  • Of those who take esketamine, 30% say they are better able to take care of themselves. 
  • 34% of those who take esketamine saw general improvements in their overall health


  • 63% of those with MDD or TRD with suicidal ideations who used ketamine no longer experience suicidal thoughts after just three days of treatment.  
  • There is a 70% success rate for both TRD and MDD with ketamine. 
  • 90% of patients who used ketamine for depression saw a significant drop in depression symptoms after just two weeks. 
  • Many with ketamine saw improvements in symptoms after their first or second session. 
  • Studies indicate that of those patients who used ketamine, 35% had complete remission after their full treatment. 

This would indicate that, in general, both methods are relatively similar in their success. But there are some key differences.

People who are struggling with suicidal ideations and depression get a much faster response from traditional ketamine, and this can be the difference between life and death. Similarly, complete remission and improvements take place much faster overall with traditional ketamine.

That said, complete remission is 3% higher comparatively with esketamine. There are also noted improvements in other areas, including social function, anxiety symptoms, and overall physical health.


Which is better, ketamine or esketamine? These two treatments are similarly derived with almost the exact same positive impact on depression and anxiety symptoms. Ketamine is faster than the other in terms of efficacy but is also a treatment you might have to pay for out-of-pocket. Esketamine is a better option for anyone with a fear of needles or who wants to utilize insurance coverage. 

Overall, the effectiveness of esketamine vs. ketamine is comparable, and it’s important to consult with healthcare providers to create personalized treatment plans based on your needs.

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