Ketamine and esketamine/Spravato are both medications that belong to a class of drugs called dissociative anesthetics. They are both used for similar purposes, such as sedation, pain management, as an anesthetic, and in psychiatry to treat depression and its related behavioral complications.
However, there are some differences between the two drugs. Ketamine is the more well-known and commonly used of the two, and it is available in oral, intravenous, and intramuscular forms. It is also used off-label as a rapid antidepressant in treatment-resistant depression and other mood disorders.
Esketamine was approved by the FDA in 2019 for treatment-resistant depression. Esketamine is the S-enantiomer of ketamine, which means it is one of the two mirror-image forms of the ketamine molecule. It is a nasal spray and is only approved for use in treatment-resistant depression. A person using esketamine for treatment must also be taking another oral antidepressant medication concurrently.
A quick detour into basic chemistry
We often hear the term “racemic ketamine.” What does this mean?
Ketamine is a racemic mix of two enantiomers: esketamine and arketamine. In other words, esketamine is one enantiomer of racemic (generic) ketamine.
A racemic molecule, also known as a racemate, is a mixture of equal amounts of two mirror-image forms of a compound, known as enantiomers. Enantiomers are isomers, which are molecules with the same atoms bonded together in a different arrangement.
Enantiomers are related to each other like left and right hands. They are non-superimposable, which means that they cannot be superimposed or overlaid onto each other. One enantiomer will fit snugly into the shape of the other’s mirror image, but they are not identical.
Racemic molecules can occur naturally or they can be synthesized in the lab. They are often used in the production of drugs, as they can sometimes have different pharmacological effects depending on which enantiomer is present.
In some cases, a racemic mixture may be separated into its individual enantiomers in order to study their effects separately. This process is known as resolution.
Why is esketamine/Spravato rarely used in psychiatry practice?
There are two main reasons why clinicians tend to prefer racemic ketamine over esketamine. One is cost: Esketamine/Spravato is ridiculously expensive. ($850 versus $2 for the generic medication). Second is lack of flexibility:The pharmaceutical company controls the route, the dose, and the frequency of esketamine treatment. This takes away the provider’s ability to utilize their clinical judgment, or to customize the treatment for the individual patient’s needs.
Finally, Spravato is sub-psychedelic by design. In other words, Spravato is not fully dissociative, and would not be useful to achieve the levels of non-ordinary states of consciousness (the “window of plasticity”) that we believe to be highly useful in ketamine assisted psychotherapy (KAP).
Where to learn more about ketamine vs. esketamine
If you’d like to learn more about ketamine vs. esketamine, take a look at this research article from the NIMH team, which compared the clinical efficacy of racemic ketamine and esketamine treatment: Intravenous ketamine appears to be more efficacious than intranasal esketamine for the treatment of depression.
Special thanks to Raquel Bennett, Psy.D. of the KRIYA Institute for citations and consulting for this article.