As COVID-19 cases continue to climb in the United States and globally, the need to identify effective treatment options becomes more dire. Researchers at Beaumont Hospital, Royal Oak are currently investigating the efficacy of a treatment protocol involving ketamine in the treatment of SARS-CoV-2. The project, which has been looking at the efficacy of two common drugs—naltrexone and ketamine—in modulating the immune systems of infected patients, is appropriately called Study of Immunomodulation using Naltrexone and Ketamine for COVID-19 or SINK COVID-19. In this article, I’ll discuss the details of the study that’s currently underway, how these drugs are believed to work on the immune system in general and specifically in cases of COVID-19, and why this research is so important to the medical sector on a global scale.
What is Project SINK COVID-19 all about?
Inflammation plays a critical role in the pathogenesis of COVID-19 infection. Earlier this year, we learned about a multisystem inflammatory syndrome that we were seeing as a rare but serious complication in children infected with COVID-19. Symptoms of this syndrome include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6.  To add to this growing body of research, the CDC released an update earlier this month stating that a similar multisystem inflammatory syndrome has also been observed in adults. 
Needless to say, the need to identify additional available and affordable treatment options in order to reduce the likelihood of progression to more severe stages of the disease cannot be overemphasized.
Project SINK COVID-19 appears to be an attempt to meet this growing need. According to Dr. Annas Aljassem, a co-investigator of the SINK COVID-19 project at Beaumont Hospital, the goal of SINK COVID-19 is to “interrupt the inflammation that causes the worst COVID-19 symptoms.” 
The study, which has an estimated completion date of August 2021, is a single-center, randomized trial. Participants currently include patients 18 years old and older who are hospitalized at Beaumont, Royal Oak. To be included, potential participants must meet additional criteria.
What effect does low-dose naltrexone have on the immune system?
Naltrexone is a drug traditionally used to treat alcohol dependence and to help prevent relapse in cases of opioid dependence. Low doses of naltrexone, referred to as low-dose naltrexone or LDN, have been used off-label to regulate dysfunctional immune systems, particularly in cases of autoimmunity and related chronic pain. It is believed that LDN exhibits its anti-inflammatory properties within the central nervous system by acting on microglial cells. 
Microglial cells head the innate immune response in the central nervous system. These immune cells are responsible for viral clearance and for activating the appropriate systemic antiviral response. 
Recent research has demonstrated that in more severe cases COVID-19, there appears to be a problem with overactivation of microglial cells. This leads to detrimental effects, which can include T-lymphocyte-mediated neurotoxicity, synapse loss, neuronal degeneration in response to viral infection, and microglia-induced cytokine storm, leading to increased permeability of the blood-brain barrier and other neurological symptoms of severe COVID-19 infection. 
Researchers at Beaumont are likely utilizing LDN in the treatment of COVID-19 because of its modulatory effects on microglial cells.
What effect does ketamine have on the immune system?
Ketamine is a phencyclidine dissociative amnestic that serves as an N-methyl-D-aspartate receptor antagonist.  Ketamine exhibits anti-inflammatory properties. Research demonstrates that interleukin-6 and C-reactive protein are significantly reduced after administration of ketamine, [7,8] which is one reason why ketamine has been suggested as a drug that should be studied as part of a sedation regimen in a double-blind, randomized trial geared toward patients with respiratory failure due to COVID-19. 
Researchers at Beaumont are using ketamine in the treatment of COVID-19 because of its ability to modulate the immune system.
What’s next with SINK COVID-19?
The SINK COVID-19 trial is still underway and is estimated to be completed by August 2021. It is estimated that researchers will enroll 500 participants by the conclusion of the study. As long as things go as anticipated, researchers will continue to enroll patients into the clinical trial. Results of the study should be publicized upon completion of the trial.
In closing, there is currently a clinical trial underway that is investigating the efficacy of low-dose naltrexone and ketamine in the treatment of COVID-19. The trial, which is being conducted with patients at Beaumont Hospital, is set to continue until August 2021. Both low-dose naltrexone and ketamine are being used in this trial because of their modulatory effects on the immune system. The SINK COVID-19 trial is an attempt to utilize available drugs in the treatment of COVID-19, and specifically to reduce the occurrence of the long-term complications that we’ve seen with COVID-19 infection to date.
 Godfred-Cato, S., Bryant, B., Leung, J., Oster, M. E., Conklin, L., Abrams, J., Roguski, K., Wallace, B., Prezzato, E., Koumans, E. H., Lee, E. H., Geevarughese, A., Lash, M. K., Reilly, K. H., Pulver, W. P., Thomas, D., Feder, K. A., Hsu, K. K., Plipat, N., Richardson, G., … California MIS-C Response Team (2020). COVID-19-Associated Multisystem Inflammatory Syndrome in Children - United States, March-July 2020. MMWR. Morbidity and mortality weekly report, 69(32), 1074–1080. https://doi.org/10.15585/mmwr.mm6932e2
 Morris SB, Schwartz NG, Patel P, et al. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020. MMWR Morb Mortal Wkly Rep 2020;69:1450–1456. DOI: http://dx.doi.org/10.15585/mmwr.mm6940e1
 Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical rheumatology, 33(4), 451–459. https://doi.org/10.1007/s10067-014-2517-2
 Vargas, G., Medeiros Geraldo, L. H., Gedeão Salomão, N., Viana Paes, M., Regina Souza Lima, F., & Carvalho Alcantara Gomes, F. (2020). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and glial cells: Insights and perspectives. Brain, behavior, & immunity - health, 7, 100127. https://doi.org/10.1016/j.bbih.2020.100127
 Mazzeffi M, Johnson K, Paciullo C. Ketamine in adult cardiac surgery and the cardiac surgery intensive care unit: An evidence-based clinical review. Ann Card Anaesth. 2015;18:202–209.
 Dale O, Somogyi AA, Li Y, Sullivan T. Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesth Analg. 2012;115:934–943
 Hudetz JA, Iqbal Z, Gandhi SD. Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol Scand. 2009;53:864–872.
 Ortoleva J. (2020). Consider Adjunctive Ketamine in Mechanically Ventilated Coronavirus Disease-2019 Patients. Journal of cardiothoracic and vascular anesthesia, 34(10), 2580. https://doi.org/10.1053/j.jvca.2020.04.037