How to use melatonin on COVID-19 patients

MAC19 PRO stands for Melatonin as Adjuvant treatment for COVID-19 Pneumonia Requiring Hospitalization. It is a multipronged initiative consisting of scientific research, clinical trials and advocacies to help mitigate the impact of the new coronavirus disease (COVID-19) on the country and the global population, especially when the health-care system is nearing exhaustion.

The MAC19 PRO group is composed of eminent scientists and clinicians here and abroad who collaborate with various government and nongovernment sectors to consider using high-dose melatonin, particularly among the financially challenged population which could not afford standard medicines and treatments for patients with more advanced COVID-19.

This group includes this author, from the Department of Internal Medicine, Manila Doctors Hospital, Manila, Philippines; Agnes del Rosario, Department of Internal Medicine, Cardinal Santos Memorial Hospital, San Juan, Philippines; Maria Graciela Grayblas-Gonzaga, University of Santo Tomas Hospital, Manila, Philippines; Eugenio Ramos, The Medical City, Pasig City, Philippines; Rafael Bien Guingon, Department of Internal Medicine, Manila Doctors Hospital, Manila, Philippines; Rafaella Giana Javier, clinical research officer, MAC19 PRO study group, Manila, Philippines; Dun-Xian Tan, MD, Ph.D., S.T. Bio-Life, San Antonio, Texas, US; Gregory Brown, MD, Ph.D., Section of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Canada; David Streiner, Ph.D., Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; Harold Pupko, MD, Clinical Community Practice, North York, Ontario, Canada; Paolo Alberto Veronesi, Ph.D., WorphMed, Milan, Italy; and Russell Reiter, Ph.D., Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, Texas, US.

The goal of this initiative is to provide a pragmatic, doable and affordable strategy to reduce the COVID-19 burden on the health-care system by as much as 50 percent.

Reversing moderate to severe cases

The rationale: When given at the right dose and early enough, high-dose melatonin could help prevent worsening of mild coronavirus disease 2019, especially in patients with high-risk features, and help reverse moderate to severe COVID-19 cases.

The MAC19 PRO group felt compelled to make public this recommendation in light of the daily record number of new COVID-19 cases reported by the Department of Health and the overflow of severe cases in hospitals, with many symptomatic patients regrettably being turned away without adequate treatment due to lack of rooms and beds to accommodate them.

This open recommendation for adjuvant high-dose melatonin in COVID-19 patients is based on its well-established antioxidant, anti-inflammatory and immune-system modulating mechanisms published in international journals by the coauthors of this recommendation, the locally conducted case series of patients admitted at Manila Doctors Hospital which was recently published in the Melatonin Research journal in the United States, and some of the group members’ experience as individual clinicians treating COVID-19 cases.

Based on published literature on the benefits of high-dose melatonin in severe viral infections and our clinical experience in actual COVID-19 patients, including those with moderate to borderline severe acute respiratory distress syndrome (ARDS), the MAC19 PRO group believes that if patients with typical COVID-19 symptoms could be started immediately on treatment with high-dose melatonin—without waiting for the results of COVID-19 tests, which take four to five days—many cases would no longer progress or worsen and require critical care in the hospital intensive care unit. This could help ease the burden on the nearly exhausted health-care system.

The MAC19 PRO group’s preliminary clinical experience with high-dose melatonin has shown that it could help accelerate clinical improvement, significantly reduce the need for intubation and mechanical ventilation, shorten hospital stay and possibly reduce mortality.

Our other colleagues in the MAC19 PRO study group hope to validate these observations with the randomized placebo-controlled multicenter clinical trial of high-dose melatonin for symptomatic and hypoxemic moderate to severe COVID-19 cases, funded by the Department of Science and Technology-Philippine Council for Health Research and Development.

Buying precious time

The administration of high-dose melatonin could buy precious time to protect the COVID-19 patients from the dreaded “cytokine storm,” which is the major cause of multiorgan failure and death in COVID-19 patients.

In addition, it is readily available and substantially inexpensive compared to other medicines used in COVID-19; thus, its use will not impose a huge financial burden on patients or the government.

Early intake of high-dose melatonin even before test results are available is a safe measure and is not expected to result in any serious or significant side effect. Its high safety margin is well established, with single doses of 1,000 milligrams to 3,500 mg given in published human clinical trials.

But it has to be clarified—the use of high-dose melatonin for COVID-19 is off-label, just like many current treatments being administered to COVID-19 patients, and not approved by the Food and Drug Administration (FDA), for other indications other than its sleep-enhancing indication.

The MAC19 PRO study group hopes to initiate its randomized clinical trial soon, pending final FDA approval, and have the results available by year’s end.

Meanwhile, countless lives hang in the balance. Hence, the MAC19 PRO group hopes this open recommendation could help guide physicians and health-care workers in proactively managing with high-dose melatonin the imminent life-threatening consequences of COVID-19, to prevent the serious and potentially fatal complications in the latter stages of the disease.

This recommendation is intended for both primary care physicians managing suspected, asymptomatic and mild COVID-19 cases, as well as specialists managing symptomatic, hypoxemic, advanced cases of COVID-19.

Dosage recommendation

For outpatient care

1. Suspected, asymptomatic but with strong direct exposure to a COVID-19-positive patient: Melatonin 3 mg 3 caps 3x daily for 10 days, then 2 caps (6 mg) at bedtime subsequently.

2. Asymptomatic or mild COVID-19: Above patients (in No. 1) if confirmed COVID-19-positive still with none or mild symptoms (no hypoxemia), no lung findings in chest X-ray: increase dose to 4 caps 4x daily for 14 days then 3 caps 3x daily for another 14 days, then 2 caps (6 mg) at bedtime subsequently.

For inpatient care (hospitalized patients)

1. Symptomatic COVID-19 or COVID-19-suspect on admission to hospital, with hypoxemia but no ARDS: Even if still unconfirmed but if with moderate symptoms (with hypoxemia, but no ARDS—ratio of partial pressure of oxygen to oxygen support given, or PFR, less than 300): Give 100 mg ASAP initially then 4 mg/kbw/day (200-400 mg/day) in 3-4 divided doses for 1 week, then reduce to 2 mg/kbw/day (100-200 mg/day) in 3-4 divided doses for another week, then further reduce to 1 mg/kbw/day (50-100 mg/day) in 3-4 divided doses for another 2 weeks (total of 4-week treatment), then reduce to a maintenance dose of 2 caps (6 mg) at bedtime.

2. COVID-19 or COVID-19-suspect on admission to hospital with mild ARDS (PFR less than 300 but more than 200): Even if still unconfirmed for COVID-19 but if with moderate symptoms and mild ARDS: Give 150 mg ASAP initially then 6 mg/kbw/day (300-600 mg/day) in 3-4 divided doses for 1 week, then reduce to 3 mg/kbw/day (150-300 mg/day) in 3-4 divided doses for another week, then further reduce to 1 mg/kbw/day (50-100 mg/day) in 3-4 divided doses for another 2 weeks (total of 4-week treatment), then reduce to a maintenance dose of 2 caps (6 mg) at bedtime.

3. COVID-19 or COVID-19-suspect on admission to hospital with moderate to severe ARDS (PFR less than 200): Even if still unconfirmed for COVID-19 but if with severe symptoms and moderate to severe ARDS and not intubated yet: Give 200 mg ASAP initially then 8 mg/kbw/day (480-800 mgs/day) in 3-4 divided doses for 1 week, then reduce to 4 mg/kbw/day (200-400 mg/day) in 3-4 divided doses for another week, then further reduce to 1 mg/kbw/day (50-100 mg/day) in 3-4 divided doses for another 2 weeks (total of 4-week treatment), then reduce to a maintenance dose of 2 caps (6 mg) at bedtime.

Important notes

High-dose melatonin is to be taken by mouth. Doses for confined patients with symptomatic COVID-19 are to be compounded by hospital pharmacist with usual available dosage form of 3 mg/capsule. The melatonin powder may be mixed with patient’s preferred juice or drink if taken orally, or it may be given by nasogastric tube or mixed with feeding if patient is intubated. (Success so far with high-dose melatonin has been observed mainly in unintubated patients.)

Only pure melatonin preparations which are FDA-approved must be used. Severe headache has been experienced with fixed-drug preparations which combine melatonin with other vitamins. Same with some non-FDA registered preparations available online or in supermarkets and health stores.

Usual side effects with high-dose melatonin are sleepiness (but easily awaken) with tendency to oversleep, headache, nausea. But all side effects are relatively mild and tolerable with pure melatonin preparations.

Survival in unintubated patients with moderate to severe ARDS is 100 percent so far, based on preliminary experience, but it also didn’t save one intubated patient where melatonin was given 4 days after intubation.

The key is to give it ASAP, as soon as patient is seen and not to wait for patient to deteriorate further. A common pitfall is to wait for results of the COVID-19 swab which may cause a 4- to 5-day delay in treatment, during which time the patient could rapidly deteriorate.

Give also: vitamin C, 3-6 g/day; zinc, 50-100 mg/day; vitamin D, 5000-10,000 u/day; virgin coconut oil, 15 cc TID (three times a day).

(Early high dose of melatonin intake even before test result is available is a safe measure, and will not result in any additional adverse effect due to its high safety margin, but could buy time to save a life.

In addition, it is substantially inexpensive compared to other medicines used in COVID-19, and thus, its use will not become a financial burden on patients or government.) INQ

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