How sleep distress associated with melatonin imbalance may play a role in the presence, intensity, and severity of anosmia

By Bhavana KunkalikarJul 1 2022Reviewed by Danielle Ellis, B.Sc.

In a recent study published in the International Journal of Developmental Neuroscience, researchers assessed the role of melatonin in coronavirus disease 2019 (COVID-19)-associated anosmia.

Background

Anosmia, or the loss of sense of smell, is often associated with rhinopathies and is a common symptom reported by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals. While there is still no effective drug for the treatment of anosmia, several studies have suggested the role of melatonin in the recovery of olfactory senses.

About the study

In the present study, researchers investigated the association between anosmia and melatonin and the impact of melatonin on sleep and the regulation of the olfactory neurons.

The team conducted a narrative review by searching electronic databases such as Embase, Cochrane, and MEDLINE/PubMed between August 2020 and November 2021. The search was performed using the terms' anosmia and melatonin', 'melatonin and COVID-19 anosmia', 'melatonin and olfactory dysfunction,' 'anosmia and sleep and COVID-19', 'sleep and melatonin and COVID-19', 'olfactory dysfunction and circadian rhythm,' 'olfactory function and melatonin,' and upper airway infections and melatonin. The study included articles that examined and/or referred to: (1) the likely impact of the circadian rhythm and melatonin on anosmia, (2) the olfactory functionality in the upper airway infections such as COVID-19 among patients, and (3) the use of melatonin as a therapeutic agent against COVID-19.

Among the studies reviewed, the clinical trials helped assess the relationship between melatonin and anosmia and estimate the sufficient dose of melatonin that could be used as an adjuvant treatment against chronic anosmia. Furthermore, observational and cross-sectional studies provided data related to human sleep patterns using sleep questionnaires, while epidemiological studies evaluated the incidence of chronic anosmia among COVID-19-infected samples.

Additionally, meta-analyses and systematic reviews provided high-quality evidence that recognized the extent of melatonin's impact on anosmia and assessed any probable correlation of anosmia with circadian imbalance. Animal studies also provided essential information related to sleep patterns and melatonin and the characteristics of the olfactory cells.      

Results

The study results showed that the variation in the human circadian rhythm might be elicited by an imbalance in the melatonin levels, which could lead to sleep impairment and subsequent dysregulation of homeostasis. Melatonin plays an essential role in immunomodulatory, endocrinological, and metabolic processes. The study suggested that the disruption of the circadian rhythm and the incidence of sleep disturbances caused by variations in the melatonin levels could stimulate olfactory symptoms like anosmia.

The team observed that while several fluctuations in the intensity of anosmia experienced by COVID-19 patients, several patients reported chronic and lasting manifestations of the condition. A study also showed that among the COVID-19 patients who had experienced neurological symptoms, 5.1% were diagnosed with anosmia.

The relationship between endogenous melatonin levels and the intensity and severity of anosmia is still not understood. However, since melatonin plays an essential role in circadian rhythm and oxidative stress modulation, the team believes that melatonin could help in the olfactory physiological repair. Other studies also revealed the potential role of melatonin as a protective substrate that assisted in the prevention and recovery of the olfactory neurons by inhibiting oxidative stress. This protective impact might be a result of the inflammatory environment in the olfactory epithelium in a rhinovirus infection which stimulates melatonin levels. The subsequent release of melatonin resulted in a decrease in the proportion of free radicals and inhibition of olfactory neuronal cell apoptosis.

Viral infections like COVID-19 have been known to have a potential impact on the pineal gland. This could lead to a reduction in the functionality of the melatonergic pathway, thus resulting in sleep disturbances and circadian dysregulation. These effects could be correlated to viral replication as well as an impaired immune response. Hence, it is more probable that the treatment of COVID-19-related anosmia with melatonin was more closely related to a systemic response than to any olfactory target.

The team proposed two probable mechanisms of action via which melatonin affected anosmia. The first mechanism was associated with the direct influence of SARS-CoV-2 on the pineal gland, affecting melatonin release and the consequent disruption of sleep and the circadian rhythm. The second mechanism was related to the changes in homeostasis as a result of an injured hypophysis-hypothalamus axis. This could lead to a melatonin imbalance and subsequent sleep disturbances. 

Conclusion

Overall, the study findings showed that the pineal gland and the stimulation of melatonin release might be directly associated with COVID-19 infections and the resulting condition of anosmia. The researchers believe that while further studies are necessary to understand the exact pathway that causes anosmia in COVID-19 patients, melatonin might prove an effective therapeutic drug in treating anosmia.