Amantadine for COVID‐19

Paweł Grieb PhD Maciej Świątkiewicz PhD Katarzyna Prus MD Konrad Rejdak MD

Shortly after the onset of the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), concerns were raised about the potentially heightened risks of coronavirus disease 2019 (COVID‐19) in patients with Parkinson disease (PD).1 To substantiate these suspicions, we performed a questionnaire‐based study to assess the severity of COVID‐19 in patients suffering PD and multiple sclerosis (MS), whose SARS‐CoV‐2 infection was confirmed by reverse transcriptase polymerase chain reaction of nasopharyngeal swabs. We found that none of them (PD, n = 5; MS, n = 10) developed severe clinical manifestations of infectious disease. Importantly, all patients were taking amantadine.2 Although the aforementioned lack of severe cases among patients taking amantadine could happen by chance, it also provoked hypothesis generation. We suggested that our finding may reflect possible effect of amantadine antiviral activity against SARS‐CoV‐2. Indeed, it has recently been shown that amantadine interferes with the lysosomal milieu and may inhibit the virus’s entry to host cells.3

However, currently amantadine is the foremost neurological drug, used to treat PD and disorders of consciousness and prescribed off‐label to patients suffering from MS. The drug enters the blood‐brain barrier and acts as a weak but unique glutamate/N‐methyl‐D‐aspartate receptor antagonist, which concomitantly activates the cystine/glutamate antiporter and stimulates glutathione synthesis.4

We would like to point to 2 other possible mechanisms by which this drug could contribute to mitigation of COVID‐19 in infected patients. The first relates to the anti‐fatigue effect. Fatigue, a very prevalent symptom in MS (>90% patients), is a multifaceted phenomenon partially related to central mechanisms. Already >3 decades ago a serendipitous observation was made that a patient with MS had a remarkable improvement in fatigue while taking amantadine to prevent influenza, and the effect was soon confirmed in a small double‐blind controlled study. Amantadine is the only drug that seemed to improve fatigue symptoms in MS, although the data were limited,5 and a more recent study did not support such conclusion.6

Fatigue is one of the most prevalent symptoms of COVID‐19 in adults and is more common in patients who require hospitalization. A recent report evidenced that COVID‐19 increased fatigue in a cohort of patients with PD.7 Importantly, patients with MS and PD display blunted respiratory response to hypercapina and hypoxia.89 A connection of depressed responsivity to carbon dioxide and hypoxia with fatigue appears intuitively highly probable.

The second mechanism by which amantadine may benefit patients with COVID‐19 relates to its arousal‐enhancing effect. Impaired consciousness is a frequent central nervous system manifestation of COVID‐19. Since arousal is a normal, physiological response to respiratory stimuli such as hypoxia and hypercapnia, it is plausible to expect that impaired consciousness in patients with COVID‐19 blunt their respiratory response to hypoxia and hypercapnia. Depressed response to hypercapnia and hypoxia may be an important factor in the development of severe forms of COVID‐19, including the so‐called silent, or “happy” hypoxemia, a phenomenon of the absence of dyspnea in patients with COVID‐19 who exhibit severe hypoxemia with considerable risk of death.10

Although it is too early to advocate amantadine as a treatment for COVID‐19, a controlled trial of this drug for postexposure prophylaxis of SARS‐CoV‐2 infection is indicated.

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