








key: cord-306146-i4a74j3r
authors: Fitzgerald, Paul J.
title: Noradrenergic and serotonergic drugs may have opposing effects on COVID-19 cytokine storm and associated psychological effects
date: 2020-06-09
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.109985
sha: 
doc_id: 306146
cord_uid: i4a74j3r

nan

Funding sources: None that directly supported this letter.

In previous publications I have suggested that the neurotransmitters norepinephrine (NE) and serotonin (5HT), which are engaged in a wide range of physiological processes outside the brain as well, are largely functionally opposed to one another 1,2 . In addition to its role in various psychiatric, neurologic, and cardiovascular functions, there is increasing evidence that NE plays a role in the symptomatology associated with serious systemic infections such as influenza, including activation of cytokine signaling such as IL-6 as well as the manifestation of psychological effects associated with infection 3 .

It has also been suggested that catecholamines, including NE, play a role in producing the potentially lethal "cytokine storm" associated with coronavirus disease 2019 (COVID-19) 4 . I suggest here that this cytokine storm may be counteracted by a range of clinically used drugs that reduce NE transmission (but that may not act through direct effects on viral replication or viral entry into cells) 5 : alpha2 agonists such as clonidine, guanfacine, dexmedetomidine; various beta blockers such as propranolol, nebivolol, carvedilol, atenolol; and various alpha1 antagonists such as prazosin 4 . Since HDAC inhibitors like valproic acid and vorinostat may also decrease NE transmission 6 , they may also be therapeutic in COVID-19.

Since 5HT may be functionally opposed to NE, drugs that facilitate 5HT transmission may also dampen the cytokine storm associated with COVID-19: SSRIs (fluoxetine, citalopram, sertraline, paroxetine, fluvoxamine; TCA (clomipramine); MAOIs (phenelzine, tranylcypromine); and the 5HT2C agonist lorcaserin.

There are also theoretical underpinnings supporting functional opposition between NE and the neurotransmitter acetylcholine 7 , where the latter molecule participates in the cholinergic antiinflammatory pathway 8 . In this scenario, clinically available cholinesterase inhibitors (pyridostigmine, donepezil, rivastigamine, galantamine, physostigmine) may also counteract the cytokine storm associated with COVID-19.

There are already several ongoing clinical trials, in various countries, testing whether some of the above pharmacological agents reduce morbidity and mortality accompanying COVID-19. I suggest that all of the above compounds are promising candidates for additional prospective clinical trials, and they can also be examined immediately through retrospective epidemiological investigation of the medical records of individuals who were taking these drugs for various indications and were hospitalized and had pneumonia or acute respiratory distress, where their clinical outcomes may be relevant to treating today's ongoing COVID-19 pandemic 4 . If COVID-19 is accompanied by systemically elevated NE signaling, the various drugs listed above may also counteract deleterious psychological effects associated with this infection 3 .

The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Gamma oscillations as a biomarker for major depression: an emerging topic

In vivo electrophysiological recordings of the effects of antidepressant drugs

Serious infection may systemically increase noradrenergic signaling and produce psychological effects

COVID-19 using α-1 adrenergic receptor antagonists

Can beta-adrenergic blockers be used in the treatment of COVID-19? Med Hypotheses

Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems

The Neuro-Immuno-Senescence Integrative Model (NISIM) on the negative association between parasympathetic activity and cellular senescence

Conflicts of interest The author reports no conflicts of interest, and no funding source directly supported this work



