key: cord-0686382-pkr5iqen
authors: Pitt, Bertram; Tate, Ashley M; Gluck, David; Rosenson, Robert S; Goonewardena, Sascha N
title: Repurposing low-dose naltrexone (LDN) for the prevention and treatment of immunothrombosis in COVID-19
date: 2022-02-18
journal: Eur Heart J Cardiovasc Pharmacother
DOI: 10.1093/ehjcvp/pvac014
sha: 4db41e041874668f5e0d5efded370a44d990b3b9
doc_id: 686382
cord_uid: pkr5iqen

Coronavirus disease 2019 (COVID-19) is characterized by striking dysregulation of the immune system, with evidence of hyperinflammation, an impaired induction of interferons, and delayed adaptive immune responses. In addition to dysfunctional immune responses, thrombosis is a hallmark of severe COVID-19. Because traditional anticoagulation strategies are associated with increased bleeding, novel strategies that address both the immune and thrombotic dysfunction associated with COVID-19 would be of tremendous benefit. In this commentary, we discuss the unique properties of low dose naltrexone (LDN) which could be leveraged to reduce the immune-mediated thrombotic complications in COVID-19. Mechanistically, LDN can blunt innate immune responses and Toll-like receptor (TLR) signaling, reducing interleukin1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interferon (IFN) levels. Because of the immune-mediated thrombotic mechanisms that underlie COVID-19, we hypothesize that the immune-modulating and known pharmacologic properties of LDN could be leveraged as a novel therapeutic strategy in COVID-19.

In addition to immune dysregulation, SARS-CoV-2 infections are associated with an increased 

Naltrexone (NTX), a competitive opioid receptor antagonistic, has primarily been used in the management of alcohol dependence and opioid addiction. At typical doses (50 mg), NTX inhibits activity at mu-and delta-opioid receptors, suppressing β-endorphin activity. (7) However, at low doses (between 1-5 mg) NTX has analgesic and anti-inflammatory properties.

Because of these properties, LDN has recently been used in several chronic inflammatory diseases including inflammatory bowel disease (IBD) and multiple sclerosis, and has been shown to blunt pathologic inflammation and reduce the incidence of clinical thrombosis. (7, 8) Importantly, LDN is well tolerated and its adverse effects are rare, mild, and self-limited. It is believed that LDN can also modulate other, non-opioid receptors. Perhaps the most compelling data for LDN is its use in Crohn's disease, a type of inflammatory bowel disease (IBD) that affects the GI tract. 

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention

and the Parker Institute for Cancer Immunotherapy. N.B. receives research support from the Parker Insitute, Novocure, Celldex, Genentech, Oncovir, and Regeneron. M.M. serves as an advisor/board member for Celsius, Pionyr, Compugen, Myeloids and Innate pharma and ad hoc for Takeda. M.M. receives research support from Regeneron, Takeda, and Genentech. A.M. has equity in Gilead Sciences and Regeneron Pharmaceuticals

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