Now with the psychedelic renaissance underway, Ketamine is being utilized in an increasing number of clinics across the US for healing mental illness. This mixed media coverage and vague headlines about an experimental treatment method can often be confusing for prospective patients seeking information about their treatment options. What news headlines often fail to highlight is that Ketamine is an established compound that has been used in medicine for many decades.

History of Ketamine – Crash Course

Ketamine was first synthesized in 1962 by an established team of chemists looking for a compound that would numb one’s pain and relax one’s muscles during surgery. These compounds, called anesthetics, didn’t suppress vital functions like opiates making them ideal for operations. Unfortunately, the anesthetic compound used prior to Ketamine caused changes in blood pressure and intense hallucinations, making Ketamine a much safer alternative.

Ketamine was then tested for the following seven years for a variety of conditions and was even offered as a prescription medication under the name Ketalar starting in 1969. By 1970 the FDA approved it for human consumption, and it was used extensively in medical operations during the Vietnam War, where it saved countless lives.

Even in 1973, when the DEA was established and US drug policy began to shift, ketamine was recognized for its medical value and remained unscheduled. It wasn’t until 1999 that ketamine and its various forms were made schedule III drugs in the US. Ironically only one year later, the first study covering the antidepressant effects of Ketamine was published in the US. Prior to that point, all studies of this nature had been conducted abroad.

Ketamine Today 

Over the past two decades, the positive clinical results on Ketamine for mental health conditions have been replicated in numerous studies, helping solidify its place as an effective treatment for various mental illnesses. Ketamine has also seen increased attention in part due to the overall “psychedelic renaissance”. More specifically, a marked interest surrounding the medical and healing properties of psychedelic compounds such as Psilocybin, MDMA, and Ayahuasca.

While many of these psychedelic compounds are yielding positive results in clinical trials, they’re still illegal in the US with no federally recognized medical value. This is in contrast to Ketamine which, while considered psychedelic, is readily used in medical treatments and has widely accepted medical value. This unclear distinction between the legal Ketamine and other psychedelic compounds muddies the waters for prospective patients looking to better understand treatment options.

Ketamine Going Forward

The next time you hear Ketamine referred to as an experimental compound or someone jokingly calls it “Horse Tranquilizer”, just remember that Ketamine has been used in medicine for decades and has proven to be safe and effective for a wide variety of conditions. As Ketamine once again gains the attention of mainstream medical communities and the general public, perhaps one day soon, the misconceptions surrounding it will fade.

1. Maddox, V. H. (1965). The synthesis of phencyclidine and other 1-arylcyclohexylamines. Eindhoven University of Technology Research Portal. https://research.tue.nl/en/publications/the-synthesis-of-phencyclidine-and-other-1-arylcyclohexylamines
2. SZAPPANYOS, G. G., BOPP, P., & FOURNET, P. C. (1971). THE USE AND ADVANTAGE OF ???KETALAR??? (CI-581) AS ANAESTHETIC AGENT IN PEDIATRIC CARDIAC CATHETERISATION AND ANGIOCARDIOGRAPHY. Survey of Anesthesiology, 15(1), 63???64. https://doi.org/10.1097/00132586-197102000-00044
3. Domino, E. F., & Warner, D. S. (2010). Taming the Ketamine Tiger. Anesthesiology, 113(3), 678–684. https://doi.org/10.1097/aln.0b013e3181ed09a2
4. Our History. (n.d.). DEA. https://www.dea.gov/about/history
5. 1999 – Placement of Ketamine into Schedule III. (n.d.). Diversion Control Division. https://www.deadiversion.usdoj.gov/fed_regs/rules/1999/fr0713.htm
6. Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47(4), 351–354. https://doi.org/10.1016/s0006-3223(99)00230-9
7. Kokkinou, M. (2017, October 3). The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Nature. https://www.nature.com/articles/mp2017190

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What is S-Ketamine?
Esketamine is a derivative of racemic “regular” ketamine known as an enantiomer. Molecules that are enantiomers are mirror images of each other. Simply put, there is a left and right-handed version of the same base molecule, just at inverse orientations of each other. Esketamine, often known as S-ketamine, differs from regular racemic ketamine in the fact that it is essentially just half of the mixture. Racemic ketamine consists of roughly a 50/50 mix of two enantiomers, S-ketamine and arketamine, also known as R-ketamine. J&J developed a technique to filter out and discard the R-ketamine. This new processing technique is what allowed J&J to patent S-Ketamine as a novel drug formulation.

The metrics of S-Ketamine (esketamine) therapy
When S-ketamine was first approved by the FDA, many people were excited about the prospect of on-label ketamine treatment, yet the execution and accessibility issues that plague this new treatment dampened that initial optimism. S-ketamine comes solely in the form of a nasal spray dosed at either 56 or 84mgs, which costs a patient or their insurance $590 or $885 per dose. Since most patients are advised to seek treatment twice a week for their first month, the cost of the medication alone can range from $4720-$6785 for just one month.4  In contrast, the entire price of a racemic ketamine session, that is both the price of the drug and the medical treatment, can be as low as $350 and can be administered in a variety of ways, Lozenge, and nasal spray just to name a few.5 Given the steep price per dose, one would assume that S-ketamine is more effective or possesses noteworthy qualities when compared to racemic ketamine, however, this is not the case. 6 In fact, studies suggest that R-ketamine, the compound J&J discards in their formulation of S-ketamine, is actually a longer-lasting and more potent antidepressant than S-ketamine.7 This makes sense when you also consider that studies found racemic “regular” ketamine to be a higher efficacy treatment for depression than S-ketamine alone. 8 Keeping this in mind, it’s no surprise researchers ruled S-ketamine an ineffective treatment at its current cost, citing that only after a 40% reduction in price would S-ketamine become a cost-effective treatment method.9 With a staggering price per dose and questionable efficacy compared to well-established racemic ketamine treatment, one begins to question the motives of those who produce and push so heavily for S-ketamine treatment. If regular racemic ketamine has effective, reliable results and is more affordable, why make the switch?

References

1. Mental Health America. (2021). The State of Mental Health in America | Mental Health America.Mhanational.org.https://mhanational.org/issues/state-mental-health-america
2. ‌Martínez-Alés, G., Jiang, T., Keyes, K. M., & Gradus, J. L. (2021). The Recent Rise of
Suicide Mortality in the United States. Annual Review of Public Health, 43(1).
https://doi.org/10.1146/annurev-publhealth-051920-123206
3. ‌Eichelbaum, M. (1992). Enantiomers: implications and complications in developmental
pharmacology. Developmental Pharmacology and Therapeutics, 18(3-4), 131–134.
https://pubmed.ncbi.nlm.nih.gov/1306801/
4. ‌NPR Choice page. (2019). Npr.org. https://www.npr.org/sections/health-
shots/2019/03/05/700509903/fda-clears-esketamine-nasal-spray-for-hard-to-treat-
depression
5. ‌Ziegler, L., Peters, E., Wanson, A., & Halpape, K. (2021). Compounded intranasal
racemic ketamine for major depressive disorder: A case report. Experimental and
Clinical Psychopharmacology, 29(6), 750–754. https://doi.org/10.1037/pha0000437
6. Gastaldon, C., Papola, D., Ostuzzi, G., & Barbui, C. (2019). Esketamine for treatment
resistant depression: a trick of smoke and mirrors? Epidemiology and Psychiatric
Sciences, 29. https://doi.org/10.1017/s2045796019000751
7. ‌Yang, C., Shirayama, Y., Zhang, J-c., Ren, Q., Yao, W., Ma, M., Dong, C., &
Hashimoto, K. (2015). R-ketamine: a rapid-onset and sustained antidepressant without
psychotomimetic side effects. Translational Psychiatry, 5(9), e632–e632.
https://doi.org/10.1038/tp.2015.136

8. Bahji, A., Vazquez, G. H., & Zarate, C. A. (2020). Comparative efficacy of racemic
ketamine and esketamine for depression: a systematic review and meta-analysis. Journal
of Affective Disorders, 12473. https://doi.org/10.1016/j.jad.2020.09.071
9. ‌Ross, E. L., & Soeteman, D. I. (2020). Cost-Effectiveness of Esketamine Nasal Spray for
Patients With Treatment-Resistant Depression in the United States. Psychiatric Services,
71(10), 988–997. https://doi.org/10.1176/appi.ps.201900625

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