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Ketamine Nasal Spray for Treating Depression Symptoms

All About the Esketamine Nasal Spray

Ketamine is a drug that doctors often use as an anesthetic to induce the loss of consciousness in patients. The common effects of using ketamine include a reduced sensation of pain and sedation. Esketamine is chemically almost identical to ketamine. Ketamine, though, is a Schedule III non-narcotic that has been approved by the Food and Drug Administration to be used only as a general anesthetic. However, doctors tend to prescribe it for off-label uses as well, including for the treatment of depression. Off-label means using the medications for treating conditions that the Food and Drug Administration has not approved.(1, 2, 3)

Research published in the American Journal of Psychiatry has shown that esketamine nasal spray is both fast-acting and effective for people with treatment-resistant depression. However, many experts still question the safety of the drug. The phase III clinical trial on this drug was designed to test the efficacy and safety of the drug Spravato, which is the approved esketamine nasal spray by the Food and Drug Administration (FDA). The drug has been developed by Janssen Pharmaceuticals. This was a double-blind and active-controlled study that was carried out on almost 200 patients spread over 39 different outpatient centers from the time period of 2015 to 2017.(4, 5, 6, 7)

During the trials, some patients were administered the esketamine nasal spray along with a traditional oral antidepressant. At the same time, the placebo group was given saline and a traditional oral antidepressant drug. The trial continued for 28 days, during which time the patients were evaluated for symptoms of anxiety depression at both baseline level and throughout the duration of the treatment.

The study found that the group of individuals taking esketamine showed dramatically more improvement than those who were taking the placebo. Furthermore, the improvement in symptoms was observed to start taking place in as little as just 24 hours of taking the first dose. This highlighted one of the most promising aspects of the drug, which is its fast-acting mechanism.(8, 9, 10)

This clinical trial of ketamine is considered to be one of the most important trials during the Food and Drug Administration’s review of this treatment for helping people suffering from treatment-resistant depression. Most important was the discovery of the novel mechanism of action of ketamine combined with the immediate benefit it provided. These factors underpin just how important this medicine can be for patients who face difficulty in the treatment of depression through traditional antidepressants.(11)

Are There Any Side Effects of Esketamine Nasal Spray?

While esketamine showed very promising results, what about any potential side effects? The study addressed the safety concerns related to the drug and also identified some of the most common side effects caused by esketamine.(12, 13) These include:

Most of these common side effects tended to occur just after taking the medication and cleared up within the next one to one and a half hours.

However, nine patients stopped being part of the trial after experiencing adverse side effects that included panic attacks, headaches, and a feeling of being drunk.

Nevertheless, the final consensus of the study was that overall the drug esketamine was deemed to the safe and tolerable.

What About Abuse and Withdrawal Concerns of Esketamine?

Despite the promising results of the study, there have been several questions raised about the safety of the drug. In another editorial published in the same issue of the American Journal of Psychiatry, some of these concerns were discussed. The biggest concern that came up was that there was no clear understanding about the optimal way of using the drug, how much to give, how long to use it for, and what to do when the drug is stopped. (14) While this does not mean that someone should not use esketamine, but medical experts still warn of maintaining a modicum of caution while prescribing this medication.

Another big concern included the potential for abuse and issues with withdrawal once the drug is stopped. Similar to opioids, there could be the potential to experience adverse health effects after discontinuing use. According to Janssen Pharmaceuticals, though, Spravato nasal spray remains the first new mechanism of action for an antidepressant medication to have come to the market in decades. Before this, doctors only had very limited options to help patients who had treatment-resistant depression.

The findings from this study reinforced the effectiveness and safety profile of the drug, along with the significant improvement experienced in depression symptoms in adults with treatment-resistant depression.


Many people often get confused between ketamine and esketamine. Esketamine is chemically almost identical to ketamine, which is a powerful anesthetic and has been used as a recreational drug for many years now. Ketamine is a drug that induces dissociation while providing pain relief and sedation. Though ketamine has been used for many decades as a recreational drug, but it is only recently that medical experts have started exploring ketamine as a treatment option for depression.(15) The dissociative effects of ketamine are believed to be helpful for people who are battling depression.(16)

When administered at the right levels and alongside therapy, ketamine can act as an antidepressant and also help block depressive feelings.

Since over the years, ketamine has developed a reputation of being a potent narcotic club drug, which is capable of leaving users incapacitated.(17, 18, 19) Due to the risks involved with giving esketamine, it is only administered under a doctor’s supervision and within a clinical setting. The dosage is also strictly controlled. Despite the dangers of addiction associated with ketamine and esketamine, as of now, esketamine remains one of the most promising medications for people with treatment-resistant depression.


  1. Sinner, B. and Graf, B.M., 2008. Ketamine. Modern anesthetics, pp.313-333.
  2. Wolff, K. and Winstock, A.R., 2006. Ketamine. CNS drugs, 20(3), pp.199-218.
  3. Morgan, C.J., Curran, H.V. and Independent Scientific Committee on Drugs (ISCD), 2012. Ketamine use: a review. Addiction, 107(1), pp.27-38.
  4. Popova, V., Daly, E.J., Trivedi, M., Cooper, K., Lane, R., Lim, P., Mazzucco, C., Hough, D., Thase, M.E., Shelton, R.C. and Molero, P., 2019. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. American Journal of Psychiatry, 176(6), pp.428-438.
  5. Daly, E.J., Singh, J.B., Fedgchin, M., Cooper, K., Lim, P., Shelton, R.C., Thase, M.E., Winokur, A., Van Nueten, L., Manji, H. and Drevets, W.C., 2018. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA psychiatry, 75(2), pp.139-148.
  6. Daly, E.J., Trivedi, M.H., Janik, A., Li, H., Zhang, Y., Li, X., Lane, R., Lim, P., Duca, A.R., Hough, D. and Thase, M.E., 2019. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA psychiatry, 76(9), pp.893-903.
  7. Schatzberg, A.F., 2019. A word to the wise about intranasal esketamine. American Journal of Psychiatry, 176(6), pp.422-424.
  8. Molero, P., Ramos-Quiroga, J.A., Martin-Santos, R., Calvo-Sánchez, E., Gutiérrez-Rojas, L. and Meana, J.J., 2018. Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. CNS drugs, 32(5), pp.411-420.
  9. Singh, J.B., Fedgchin, M., Daly, E., Xi, L., Melman, C., De Bruecker, G., Tadic, A., Sienaert, P., Wiegand, F., Manji, H. and Drevets, W.C., 2016. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biological psychiatry, 80(6), pp.424-431.
  10. Canuso, C.M., Singh, J.B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., Pinter, C., Hough, D., Sanacora, G., Manji, H. and Drevets, W.C., 2018. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. American Journal of Psychiatry, 175(7), pp.620-630.
  11. Anon, Study supports effectiveness of new fast-acting antidepressant, esketamine nasal spray. EurekAlert! Available at: https://www.eurekalert.org/news-releases/656971 [Accessed February 1, 2022].
  12. Hashimoto, K., 2016. Detrimental side effects of repeated ketamine infusions in the brain. American Journal of Psychiatry, 173(10), pp.1044-1045.
  13. Ceban, F., Rosenblat, J.D., Kratiuk, K., Lee, Y., Rodrigues, N.B., Gill, H., Subramaniapillai, M., Nasri, F., Lui, L.M., Lipsitz, O. and Kumar, A., 2021. Prevention and Management of Common Adverse Effects of Ketamine and Esketamine in Patients with Mood Disorders. CNS drugs, 35(9), pp.925-934.
  14. Schatzberg, A.F., 2019. A word to the wise about intranasal esketamine. American Journal of Psychiatry, 176(6), pp.422-424.
  15. Jonkman, K., Dahan, A., van de Donk, T., Aarts, L., Niesters, M. and van Velzen, M., 2017. Ketamine for pain. F1000Research, 6.
  16. Ezquerra-Romano, I.I., Lawn, W., Krupitsky, E. and Morgan, C.J.A., 2018. Ketamine for the treatment of addiction: Evidence and potential mechanisms. Neuropharmacology, 142, pp.72-82.
  17. Gahlinger, P.M., 2004. Club drugs: MDMA, gamma-hydroxybutyrate (GHB), Rohypnol, and ketamine. American family physician, 69(11), pp.2619-2626.
  18. Smith, K.M., Larive, L.L. and Romanelli, F., 2002. Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate. American Journal of Health-System Pharmacy, 59(11), pp.1067-1076.
  19. Liao, Y., Tang, Y.L. and Hao, W., 2017. Ketamine and international regulations. The American journal of drug and alcohol abuse, 43(5), pp.495-504.

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Team PainAssist
Team PainAssist
Written, Edited or Reviewed By: Team PainAssist, Pain Assist Inc. This article does not provide medical advice. See disclaimer
Last Modified On:February 7, 2022

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