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BMJ 2020; 368 doi: (Published 31 January 2020) Cite this as: BMJ 2020;368:m406

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Nicotine and COVID-19

Dear Editor
Nicotine and COVID-19
Dear Editor
While SARS-CoV-2 is known to use angiotensin converting enzyme 2 (ACE2) as a receptor for cell entry [2], an intriguing hypothesis was recently presented about a potential interaction between SARS-CoV-2 and nicotinic acetylcholine receptors (nAChRs) [2]. It was initially observed that smokers were under-represented among hospitalized patients with COVID-19. While several limitations apply to this analysis, data from retrospective case series from China, the US, Italy and the UK have consistently shown that the proportion of hospitalized patients who were current smokers was substantially lower compared to the expected prevalence based on population smoking rates [3-8]. This represents a “paradox” considering that smoking increases the risk for respiratory infections susceptibility and severity [9].
Smoking was immediately and justifiably rejected as a viable protective measure for COVID-19 due to its well-established adverse health effects [4]. However, a protective role for nicotine was suggested based on the fact that cytokine storm is a hallmark of severe COVID-19 [10] while the cholinergic anti-inflammatory pathway, mediated mainly through nAChRs, can suppress the hyper-inflammatory response and promote immune homeostasis [11]. Nicotine is a cholinergic agonist that has been found to inhibit the release of pro-inflammatory cytokines, preventing the development of acute respiratory distress syndrome and sepsis in animal models [12,13]. Subsequently, an analysis of the clinical manifestations of COVID-19 identified that they could be linked to dysfunction of the nicotinic cholinergic system [2]. Additionally, an amino acid sequence on the receptor binding domain of SARS-CoV-2 spike glycoprotein was found to be homologous to a sequence of a snake venom neurotoxin [14]. In silico molecular modelling and docking experiments showed that this sequence may interact with the alpha9 and alpha7 subtypes of nAChRs [15]. These findings indicate that there may be a potential direct, adverse effect of SARS-CoV-2 on the nicotinic cholinergic system.
Studies have found that, once hospitalized, current smokers have higher risk for adverse outcome [16-18]. This is not contradictory to the above-mentioned hypothesis. Besides the higher likelihood for comorbidities that are risk factors for adverse COVID-19 outcome, such as cardiovascular and respiratory disease, smokers experience abrupt cessation of nicotine intake once hospitalized since it is highly unlikely that they would receive nicotine replacement therapies during hospitalization. As a result, their plasma nicotine levels would be reduced to non-detectable levels within hours from hospital admission. Therefore, although smokers should still be encouraged to quit as a general measure to reduce their health risk, physicians should consider prescribing pharmaceutical nicotine products as smoking substitutes. Additionally, pharmaceutical nicotine products could be considered for smokers hospitalized for COVID-19. Nicotine can be administered in the form of a patch, but could also be considered for inhalation through a nebulizer, which would deliver nicotine directly to the lungs and, thus, better address the local immunological cascade.
Another aspect of the interaction between nicotine and COVID-19 relates to its effects on ACE2. While previous studies have shown that smoking and nicotine down-regulate ACE2 [19], recent genetic studies report that smoking up-regulates ACE2 [20,21]. While this has been suggested to be detrimental in terms of susceptibility for infection and viral invasion, evidence suggests that ACE2 down-regulation has detrimental effects resulting due to unopposed activity of angiotensin II to AT1 receptors, which cause vasoconstriction, enhanced inflammation and thrombosis [22]. Studies on SARS-CoV also show that viral entry to the cells results in rapid depletion of ACE2 and severe inflammation [23]. Finally, common risk factors for severe COVID-19, such as age, male gender, diabetes and cardiovascular disease, are associated with lower levels of ACE2 [24-27]. Recently, an in vitro study found that nicotine increases ACE2 through the alpha7 subtype of nAChRs [28]. Still, it is currently unclear how ACE2, an enzyme which by definition has protective properties, affects SARS-CoV-2 virulence and disease severity.
In conclusion, the evidence suggests that nicotine or other nicotinic agonists could have beneficial effects against severe COVID-19. Potential mechanisms include modulation of the immune response through activation of the cholinergic anti-inflammatory pathway or prevention of an interaction between SARS-CoV-2 and nAChRs. Considering that pharmaceutical nicotine products have been available for years and have been administered for months, even in non-smoking patients, without significant side-effects [29,30], it is perhaps timely to propose a clinical trial of pharmaceutical nicotine in COVID-19 patients.

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Competing interests: No competing interests

30 May 2020
Konstantinos Farsalinos
Konstantinos Poulas, PhD
Laboratory of Molecular Biology and Immunology, Department of Pharmacy, University of Patras
Rio, 26500, Greece