Does serotonin deficiency lead to anosmia, ageusia, dysfunctional chemesthesis and increased severity of illness in COVID-19?
Authors: Sen Amarnath 
Published: February 2021

Anosmia, ageusia and impaired chemesthetic sensations are quite common in coronavirus patients. Different mechanisms have been proposed to explain the anosmia and ageusia in COVID-19, though for reversible anosmia and ageusia, which are resolved quickly, the proposed mechanisms seem to be incomplete. In addition, the reason behind the impaired chemesthetic sensations in some coronavirus patients remains unknown. It is proposed that coronavirus patients suffer from depletion of tryptophan (an essential amino acid), as ACE2, a key element in the process of absorption of tryptophan from the food, is significantly reduced due to the attack of coronavirus, which use ACE2 as the receptor for its entry into the host cells. The depletion of tryptophan should lead to a deficit of serotonin (5-HT) in SARS-COV-2 patients because tryptophan is the precursor in the synthesis of 5-HT. Such 5-HT deficiency can give rise to anosmia, ageusia and dysfunctional chemesthesis in COVID-19, given the fact that 5-HT is an important neuromodulator in the olfactory neurons and taste receptor cells and 5-HT also enhances the nociceptor activity of transient receptor potential channels (TRP channels) responsible for the chemesthetic sensations. In addition, 5-HT deficiency is expected to worsen silent hypoxemia and depress hypoxic pulmonary vasoconstriction (a protective reflex) leading to an increased severity of the disease and poor outcome. Melatonin, a potential adjuvant in the treatment of COVID-19, which can tone down cytokine storm, is produced from 5-HT and is expected to decrease due to the deficit of 5-HT in the coronavirus patients. In addition, niacin (vitamin B3), which is synthesized from tryptophan (and also can be obtained from niacin rich diet), may decline resulting in lower production of nicotinamide adenine dinucleotide (NAD+, oxidized form), which has anti-inflammatory effect. Hence, 5-HT deficiency state in coronavirus patients arising from tryptophan depletion can explain reversible anosmia and ageusia (and also a wide variation in the incidence rate of anosmia and ageusia and female predominance), chemesthetic dysfunction as well as increased severity of the disease because of worsening of silent hypoxemia, near-absence of protective hypoxic pulmonary vasoconstriction and impaired synthesis of melatonin and niacin. Therefore, correcting 5-HT deficiency in SARS-CoV-2 patients should be of utmost importance and the priority should be to fix the tryptophan depletion as selective serotonin reuptake inhibitors (SSRIs) work poorly when there is depletion of tryptophan in the system. Accordingly, clinical trials of tryptophan supplementation (both oral and parenteral) should be conducted on coronavirus patients to find out how tryptophan administration benefits the patients at different stages of the disease. In addition, different selective serotonin reuptake inhibitors (SSRIs) and 5-HT agonists should be studied to find out whether they can be of any help in preventing or alleviating the aforementioned disorders of coronavirus patients. Based on the results of clinical trials, proper measures taken are expected to cure, relieve or prevent the olfactory, gustatory and chemesthetic dysfunctions and to lessen the severity of COVID-19 by mitigating the consequences of hypoxemia and by stimulating the protective hypoxic pulmonary vasoconstriction as well as melatonin and niacin synthesis.