Scientifically speaking, ketamine is a mixture of two compounds that are mirror images of each other but not exactly alike. It’s like your hands – mirror images, but they’re not the same. One such compound is esketamine (also called (S)-ketamine), and the other is racemic ketamine (also called (R)-ketamine, or ketamine). Esketamine is typically administered intranasally – i.e., with a nasal spray – and racemic ketamine most commonly enters a patient via intravenous infusion.
Esketamine Via Nasal Spray
Ketamine is an NMDA receptor antagonist, allowing for ketamine’s antidepressant effects. Of the two compounds within ketamine, previous studies found that esketamine bound better to NMDA receptors than (R)-ketamine.
John Hopkins Medicine explains that for treatment-resistant depression, esketamine nasal treatment is typically self-administered under doctor supervision and must be used in conjunction with a conventional antidepressant. While traditional depression treatments increase naturally occurring brain chemicals like serotonin, norepinephrine, and dopamine, esketamine increases the levels of glutamate, the most abundant chemical messenger in the brain
A 2002 study examined the different effects of each compound on human volunteers and their hemodynamic variables, mood, and cognitive capacities. After 20 minutes, subjects felt better concentration and more bravery after esketamine than racemic ketamine. Esketamine subjects also reported less of a decrease in speed reading and central information flow than the racemic group. Conversely, the racemic group reported feeling less lethargic but also feeling more out of control than their esketamine counterparts. Overall, the researchers found that their subjects had better concentration and memory with esketamine than with racemic ketamine.
Racemic Ketamine via Intravenous Infusion
On the other hand, racemic ketamine in lower doses gives fewer dissociative and psychotomimetic effects. In a randomized, double-blind placebo-controlled trial, researchers from a scientific journal compared the effects of (R)-ketamine, (S)-ketamine, and placebo on ten healthy, male volunteers. Compared to the placebo, both (R)- and (S)-ketamine contributed to notable neurocognitive and psychopathology impairment. They did note, however, that there weren’t any significant differences between the two groups. The researchers found the main difference in the psychological effects on the (S)-ketamine group as participants reported more negative psychological experiences with (S)-ketamine.
Ketamine’s antidepressant effects could depend on the participant’s previous experiences with altered mind-states, which points towards (R)-ketamine as a more suitable treatment for depression. This study reports that preclinical data indicates that (R)-ketamine is a more potent and longer-lasting antidepressant, which contradicts prior studies.
Needless to Say, More Research Needs to Be Conducted
Every study can agree that ketamine research has a long way to go before we can generalize which compound better helps patients. Older studies cite esketamine as the better option for treatment-resistant depression, while newer ones focus on racemic ketamine. Regardless of which is better, ketamine as a whole shows promising results in the depression treatment field.
At Avesta Ketamine and Wellness, we help patients optimize their mental and physical wellness with several high-end ketamine infusion options and ketamine-assisted psychotherapy. More specifically, we tailor our ketamine infusions for patients suffering from treatment-resistant depression. To schedule a consultation, either call one of our locations in Bethesda, McLean, or Washington D.C., or find us online.
Bahji, A., Vazquez, G. H., & Zarate, C. A. (2020, September 23). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders. Retrieved August 3, 2022, from https://www.sciencedirect.com/science/article/abs/pii/S016503272032766X?via%3Dihub
Emamzadeh, A. (2021, February 28). Nasal spray vs. IV ketamine for depression. Psychology Today. Retrieved August 3, 2022, from https://www.psychologytoday.com/us/blog/finding-new-home/202102/nasal-spray-vs-iv-ketamine-depression
Esketamine for treatment-resistant depression. Johns Hopkins Medicine. (2021, October 15). Retrieved August 3, 2022, from https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/esketamine-for-treatment-resistant-depression
Passie, T., Adams, H.-A., Logemann, F., Brandt, S. D., Wiese, B., & Karst, M. (2021, January 21). Comparative effects of (s)-ketamine and racemic (R/s)-ketamine on psychopathology, state of consciousness and neurocognitive performance in Healthy Volunteers. European Neuropsychopharmacology. Retrieved August 3, 2022, from https://www.sciencedirect.com/science/article/abs/pii/S0924977X21000079
Pfenniger, E. G., Durieux, M. E., & Himmelseher, S. (2002). Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology. Retrieved August 3, 2022, from https://pubmed.ncbi.nlm.nih.gov/11818769/
Thase, M., & Connolly, R. (2022, July). Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects. UpToDate. Retrieved August 3, 2022, from https://www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects
Author Dr. Ladan Eshkevari, PhD, CRNA, FAAN Dr. Eshkevari is the lead clinician at Avesta, and is a long time researcher and educator in physiology, biophysics, and anesthesiology. She is passionate about assisting patients with retractable, difficult to treat mood disorders, and relies on the latest research to bring evidence to Avesta’s practice to better understand and serve patients.