Don’t Sleep On Melatonin's Potential For Helping Prevent COVID-19 – Study

Immunity boosting nutrients have been the rage among dietary supplements during the COVID-19 pandemic but an analysis of data from nearly 27,000 patients shows an ingredient promoted for sleep, melatonin, has potential for helping prevent infections.

Analysis of patient data in Cleveland Clinic’s COVID-19 registry revealed that use of melatonin, a physiologic hormone in humans, was associated with a 28% reduced likelihood of testing positive for SARS-CoV-2, the virus that causes COVID-19, adjusting for age, race, smoking history and comorbidities for diabetes, hypertension, coronary artery disease and chronic obstructive pulmonary disease.

The researchers in the study published online in the journal PLOS Biology noted that the reduced likelihood of testing positive for the virus increased to 52% for African Americans when adjusted for the variables.

Although melatonin is available in the US in dietary supplements, the researchers referred to the ingredient as a drug when discussing its potential use to prevent SARS-CoV-2. However, Food and Drug Administration has noted melatonin among the dietary ingredients it has warned firms about marketing with claims for preventing or treating COVID-19. (Also see "CBD Firm Targeting Veterans, Military Takes Broadside On COVID Claims From US Agencies" - HBW Insight, 21 Oct, 2020.)

"Large-scale observational studies and randomized controlled trials are critical to validate the clinical benefit of melatonin for patients with COVID-19, but we are excited about the associations put forth in this study and the opportunity to further explore them,” said Feixiong Cheng, a researcher at Cleveland Clinic's Genomic Medicine Institute and lead author on the study.

AI Platform, Electronic Health Records

Cheng and his colleagues conducted their analysis with an artificial intelligence platform developed by Lerner Research Institute and using large-scale electronic health records from Cleveland Clinic patients to identify clinical manifestations and pathologies common between COVID-19 and other diseases, according to a 10 November release.

They established an integrative network medicine platform that quantified the association of COVID-19 with other diseases across six categories, autoimmune, malignant cancer, cardiovascular, metabolic, neurological, and pulmonary. They analyzed across those categories because the proteins that functionally associate with a disease, such as COVID-19, are localized in the corresponding subnetwork within the comprehensive human protein–protein interaction network, and proteins that are associated with a specific disease may be directly targeted by the virus or are in the close vicinity of the target host proteins.

They measured the proximity between host genes/proteins and those well-associated with 64 other diseases across malignant cancer and autoimmune, cardiovascular, metabolic, neurological and pulmonary diseases. Closer proximity indicates a higher likelihood of pathological associations between the diseases.

Overall, they determined that autoimmune, pulmonary, and neurological diseases showed significant network proximity to SARS-CoV-2 genes/proteins. From their network medicine findings and data from the Cleveland Clinic COVID-19 patient registry database, they identified 34 FDA-approved drugs for repurposing as potential COVID-19 drug candidates.

RCTs 'Urgently Needed'

Applying their subject matter expertise to the drugs, the analysis identified the drug carvedilol, a beta blocker that stops norepinephrine and epinephrine from binding to beta receptors on nerves and is approved for both hypertension and heart failure, as well as melatonin as a potential ingredient for preventing SARS-CoV-2 (see table).

Cheng and the other researchers also conducted a retrospective COVID-19 cohort analysis to validate the potential prevention effect of melatonin and carvedilol. Among 26,779 patients tested for COVID-19 in the Cleveland Clinic Health System in Ohio and Florida, 8,274 were diagnosed as SARS-CoV-2 positive between March 8 and July 27.

Overall, network-based prediction and multiple observational analyses suggest melatonin usage offers a potential prevention and treatment strategy for COVID-19, though randomized controlled clinical trials “are urgently needed to test meaningfully the effect” the ingredient may have, the researchers said.

They said carvedilol use “was significantly associated with a reduced likelihood of a positive laboratory test result for SARS-CoV-2 adjusting for age, sex, race, smoking history and disease comorbidities, but it didn’t show a significant advantage compared” to angiotensin II receptor blockers (ARBs), a type of drug indicated for treatment of hypertension.

Analysis Shows Results Differ Among Subgroups

Testing whether a clinically meaningful effect of melatonin and carvedilol can be observed in patient subgroups, Cheng and his colleagues analyzed data from asthma patients, hypertension patients, diabetes patients, black Americans and white Americans.

While showing an overall 28% reduced likelihood of testing positive for SARS-CoV-2, melatonin usage by white consumers was not significantly associated with a reduced likelihood of a positive result compared to the use of ARBs and a second a type of drug indicated for treatment of hypertension, angiotensin-converting enzyme inhibitors (ACEIs). The reduction, adjusting for age, race, smoking history and comorbidities for diabetes, hypertension, coronary artery disease and COPD, was 23% for the subgroup comparing melatonin to no therapy; 20% comparing melatonin to ARBs; and 15% comparing melatonin to ACEIs.

The researchers added that melatonin supplementation may be of benefit for older COVID-19 patients due to aging-related reduction of hormonal melatonin and the greater vulnerability of older persons to mortality from SARS-CoV-2.

As well, melatonin suppresses activation of nucleotide-binding domain-like receptor protein 3 inflammasome, a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines in response to microbial infection and cellular damage, induced by cigarette smoking and attenuates pulmonary inflammation.

Cheng and his colleagues cautioned that observational studies and RCTs needed to validate the clinical benefit of melatonin for patients with COVID-19 should be “designed with the understanding of the mechanism of the drug to be repurposed.”

They say it “would be obvious that drugs that decrease viral entry, “ such as melatonin’s effect, “would be beneficial in preventing infection or very early in the COVID-19 course, but may be inconsequential when utilized in severe or end-stage infection.”