Ketamine and esketamine are similar, but not the same drugs. Ketamine contains two forms of the drug, called R-ketamine (arketamine) and S-ketamine (esketamine). The combination is called racemic ketamine. Only the S-form of esketamine is used.
In the UK, Ketamine has been found to be useful in the medical field such as anaesthesia and managing pain. In particular cases, at least in adults with treatment resistant major depression, a licensed nasal spray formulation of esketamine is available. Not all medicines that are licensed are routinely recommended or paid for by the NHS, though.
The two medicines therefore need to be considered separately when looking at their medical uses, evidence and monitoring requirements.
What is ketamine?
Ketamine is used as a drug in the health care system for many, many years. It has proven its use in anaesthesia and pain management. Its mechanism of action is primarily on the NMDA receptor within the brain, involved in the glutamate signalling system of the brain.
It is also now being studied and sometimes used for the treatment of depression which has not responded to other treatments in around so some specialist treatments. There are ongoing developments of evidence surrounding this use and there may be variations in clinical practice beyond the licensed indication. The Royal College of Psychiatrists has approved Ketamine for consideration as a treatment for “treatment resistant depression” when administered in a specialist environment with proper care and supervision.
It is not a non-medical use. Ketamine is a controlled substance in the UK and can be used medically for these reasons but also has risks when used outside of medical controls which are not equal to those associated with treatment under the care of a healthcare professional.
What is esketamine?
Esketamine is the S-enantiomer of ketamine. In other words, it’s one of the two mirror image forms that form racemic ketamine. In the UK, a nasal spray containing esketamine (known as Spravato) is licensed for adults with treatment-resistant major depressive disorder who have failed to respond to at least two previous antidepressant medications during this moderate to severe depressive episode. It is used alongside an SSRI or SNRI.
Esketamine is administered by a health care provider. This is significant as this can occur following treatment including sedation, dissociation, or an elevation in blood pressure, so careful clinical observation is necessary.
Racemic ketamine explained
When it comes to ketamine, the term racemic ketamine is used to describe ketamine that is a combination of both enantiomers, R-Ketamine and S-Ketamine. It is the S-enantiomer alone that is called esketamine. The other form is known as Arketamine (R-ketamine).
It’s important to differentiate between the two, because different preparations of the medicine may have different pharmacological properties. But even if you isolate one enantiomer, you might not necessarily think it is more appropriate for one specific person. These should be considered separately with reference to their clinical uses, formulation and evidence.
The Advisory Council on the Misuse of Drugs also identifies the two enantiomers in ketamine and mentions it has approved the use of esketamine for treatment resistant depression in the UK.
How the formulations differ
The primary difference is the composition as well as instructions on which sort of medicine to use and how to administer it. In the traditional medical use, ketamine is administered as a racemic mixture of R- and S-ketamine. It can be found in many medicine formulations including anaesthetics or the treatment of pain.
Esketamine nasal spray is made of esketamine hydrochloride. The licensed product is for nasal administration and must be administered in a healthcare environment.
It should be noted that the different treatments are administered in different ways whenever they are compared. Medicine administered via a nasal spray during the controlled use is not the same as ketamine that may be administered as an anaesthetic or in a different clinical context.
These differences make it important to be careful to have information about one formulation that does not carry over to another.
What each is licensed for
Ketamine is a drug with well-known licensed medical applications, including as an anaesthetic and pain-killing drug. Unfortunately, it is still a significant drug for human health care.
Esketamine is labeled for medical use in the treatment-resistant major depressive disorder under specific circumstances. Product information states that it should be used together with an SSRI or SNRI in adults who have failed the treatment with at least two antidepressant drugs in the current depression.
This is the difference between licensed use and other clinical use. However, a medicine cannot be used by a specialist in a context surrounding its indication that is different from those listed in its authorization but it should not be interpreted that all uses are equally approved or documented.
Ketamine for depression vs esketamine treatment
It has been reported that both ketamine and esketamine have been tested against treatment-resistant depression, but they are not equivalent treatments. Esketamine comes as a nasal spray that is approved for this condition. The use with conventional antidepressant drugs has been studied in clinical trials. The licensed product information provides specifics of who must be given the product, and how it should be given.
Ketamine has also been used to study depression, in specialist psychiatric services as well. But there are some institutions that may not be within usual and authorized indications for the use of ketamine products in depression.
It is therefore more appropriate to consider all ketamine-based treatment as one group, and inspect the specific medicine, formulation, patient population, treatment context and study protocol used rather than the specific type.
Monitoring requirements
It’s important to monitor treatment with esketamine. Spravato cannot be taken without a healthcare professional’s supervision. The patient is observed for the side effects of the drug, changes in blood pressure and mental and physical changes.
Additionally, NICE has pointed out the burden of treatment that supervised esketamine treatment can carry. The assessment material described repeated hospital visits or a suitable community-based environment, observation following treatment, e.g., not driving, and other restrictions.
Medically ketamine must also be used under proper clinical supervision. The intensity and nature of the monitoring will vary depending on the reason for the monitoring, the formulation, and the clinical context.
NHS position
Having a marketing authorisation from the UK does not necessarily mean that NICE recommends it for regular use within the NHS. NICE’s current depression guidance states that esketamine nasal spray is not recommended in its technology appraisal guidance for treating treatment-resistant depression.
Uncertainties in the evidence, treatment pathway, long term outcomes and cost effectiveness were also included as a factor that NICE considered when reviewing esketamine for the NHS. The guidance is thus required to be separated from the UK licence for the medicine.
Position may change as evidence and guidance is reviewed. So anyone thinking about treatment should reach out to a healthcare provider whom they trust and should consult with them instead of using old resources that are found online.
Which one has stronger evidence?
The names of the medicines are not enough to give a simple answer. Esketamine has clinical trial evidence specifically relating to its licensed nasal spray formulation and treatment-resistant major depressive disorder. Ketamine also has a significant research literature in treatment-resistant depression and the studies may differ in terms of formulation, dosing, route of administration and treatment setting.
It is difficult when comparing directly. When evidence for one formulation is presented, it does not automatically stand as evidence in favor of another.
It is also important to separate evidence of a medicine’s clinical effect from questions about whether the treatment is licensed, recommended by NICE or routinely available through the NHS. These are alternate questions.
The appropriate evidence is determined by diagnosis, previous treatments, medical history and actual treatment. A specialist will be able to discuss how those things impact the choices that are available.
Understanding the difference
Ketamine and esketamine are related compounds that are not the same, although they have some similarities. Ketamine is composed of both R-ketamine and S-ketamine, and has medical roles established such as anaesthesia and pain management. Esketamine is supplied as the S-enantiomer, and has a specific UK licence for treatment-resistant major depression disorder under specified conditions.
Rather than that being the only way to look at them, they both have their advantages. It is necessary to generate relevant evidence based on formulation, condition and route of administration and clinical setting.
Educating oneself about the available evidence, monitoring and treatment factors, and the risk associated with treating depression with ketamine should be discussed with a viable health care professional.
References
https://www.gov.uk/government/publications/ketamine-an-updated-review-of-use-and-harms
https://www.ncbi.nlm.nih.gov/books/NBK583074
Evidence last checked: 19 September 2026
