Melatonin for COVID-19: real-time analysis of all 18 studies

Melatonin for COVID-19: real-time meta analysis of 11 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality and recovery. 7 studies from 4 different countries show statistically significant improvements in isolation (6 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 64% [42‑78%] improvement. Results are better for Randomized Controlled Trials, similar after exclusions, and slightly worse for peer-reviewed studies.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 18% of melatonin studies show zero events in the treatment arm.

• Multiple treatments are typically used in combination, and other treatments may be more effective.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. Denying the efficacy of treatments increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.

• All data to reproduce this paper and sources are in the appendix.

	Studies	Early treatment	Late treatment	Prophylaxis	Patients	Authors
All studies	11	78% [25‑94%]	70% [43‑84%]	40% [-11‑67%]	13,517	92
With exclusions	10	78% [25‑94%]	74% [37‑89%]	40% [-11‑67%]	13,069	88
Peer-reviewed	10	78% [25‑94%]	53% [37‑64%]	40% [-11‑67%]	12,569	89
RCTs	5	73% [-5‑93%]	72% [22‑90%]		349	36
Percentage improvement with melatonin treatment

Covid Analysis et al., 1/5/2022, preprint, 1 author.

Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels

Cecon et al., bioRxiv, doi:10.1101/2021.12.30.474561 (Preprint)

K18-hACE2 mouse study showing treatment with melatonin and derived drugs agomelatine and ramelteon inhibited SARS-CoV-2 infection in the brain.

Cecon et al., 1/3/2022, preprint, 14 authors.

CD147-spike protein interaction in COVID-19: Get the ball rolling with a novel receptor and therapeutic target

Behl et al., Science of The Total Environment, doi:10.1016/j.scitotenv.2021.152072 (Review) (Peer Reviewed)

Review of the cluster of differentiation 147 (CD147) transmembrane protein as an entry route for SARS-CoV-2, correlation with observed characteristics of COVID-19, and relevant potential therapeutics including azithromycin, melatonin, statins, beta adrenergic blockers, ivermectin, and meplazumab.

Behl et al., 12/1/2021, peer-reviewed, 9 authors.

The Effect of Melatonin on Thrombosis, Sepsis and Mortality Rate in COVID-19 Patients

Hasan et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.10.012 (Peer Reviewed)

RCT 158 severe condition patients in Iraq, 82 treated with melatonin, showing lower mortality, thrombosis, and sepsis with treatment.

risk of death, 92.9% lower, RR 0.07, p < 0.001, treatment 1 of 82 (1.2%), control 13 of 76 (17.1%), NNT 6.3.

Hasan et al., 10/12/2021, Randomized Controlled Trial, Iraq, Middle East, peer-reviewed, 3 authors.

Therapeutic potential of melatonin and melatonergic drugs on K18-hACE2 mice infected with SARS-CoV-2

Cecon et al., Journal of Pineal Research, doi:10.1111/jpi.12772 (Peer Reviewed)

Study of melatonin and melatonergic compounds with mice expressing the human ACE2 receptor (K18-hACE2). Daily administration of melatonin, agomelatine or ramelteon delayed the occurrence of severe clinical outcome with improvement of survival, especially with high melatonin dose.

Cecon et al., 9/29/2021, peer-reviewed, 11 authors.

Implications for Systemic Approaches to COVID-19: Effect Sizes of Remdesivir, Tocilizumab, Melatonin, Vitamin D3, and Meditation

Castle et al., Journal of Inflammation Research, doi:10.2147/JIR.S323356 (Review) (Peer Reviewed)

Review of the effects of COVID-19 on inflammatory markers, and the effects on those markers of standard treatments vs. vitamin D, melatonin, and meditation, showing comparable or superior effects with the non-standard treatments. The standard treatments in this study were remdesivir and tocilizumab. We note that standard treatments vary widely around the world, for example vitamin D is a standard treatment in many locations.

Castle et al., 9/22/2021, peer-reviewed, 8 authors.

Melatonin effects on sleep quality and outcomes of COVID-19 patients: An open-label, randomized, controlled trial

Mousavi et al., Journal of Medical Virology, doi:10.1002/jmv.27312 (Peer Reviewed)

RCT 96 hospitalized patients in Iran, 48 treated with melatonin, showing improved sleep quality and SpO₂ with treatment. 3mg
oral melatonin daily. Authors recommend studies with a higher dose. IRCT20200411047030N1.

risk of death, 66.7% lower, RR 0.33, p = 0.62, treatment 1 of 48 (2.1%), control 3 of 48 (6.2%), NNT 24, day 10.

risk of ICU admission, 40.0% lower, RR 0.60, p = 0.41, treatment 6 of 48 (12.5%), control 10 of 48 (20.8%), NNT 12, day 10.

Mousavi et al., 8/30/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 7 authors.

NLRP3 inflammasome activation and oxidative stress status in the mild and moderate SARS-CoV-2 infected patients: impact of melatonin as a medicinal supplement

Ghaleh et al., Zeitschrift für Naturforschung C, doi:10.1515/znc-2021-0101 (Peer Reviewed)

Study of melatonin treatment in COVID-19 hospitalized patients showing anti-oxidative and anti-inflammatory activity, and beneficial impacts on lung cytokine storm.

Ghaleh et al., 8/5/2021, peer-reviewed, 9 authors.

The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy

Ramos et al., Antioxidants, doi:10.3390/antiox10071152 (Review) (Peer Reviewed)

Review of melatonin for COVID-19 discussing mechanisms of action and ongoing trials.

Ramos et al., 7/20/2021, peer-reviewed, 10 authors.

What if melatonin could help COVID-19 severe patients?

Sánchez-González (Peer Reviewed)

Retrospective 2,463 hospitalized patients in Spain, 265 treated with melatonin, showing lower mortality with treatment in PSM analysis, however these results are subject to immortal time bias. Authors excluded from the sample patients that died during the first 72 hours of admission without taking melatonin, and patients that started on melatonin in the last 7 days of their admittance, having completed 75% of their stay.

risk of death, 54.4% lower, RR 0.46, p < 0.001, treatment 24 of 224 (10.7%), control 53 of 224 (23.7%), NNT 7.7, OR converted to RR, PSM.

Excluded in after exclusion results of meta analysis: immortal time bias may significantly affect results.

Sánchez-González et al., 7/20/2021, retrospective, Spain, Europe, peer-reviewed, 4 authors.

Melatonin interferes with COVID-19 at several distinct ROS-related steps

Camp et al., Journal of Inorganic Biochemistry, doi:10.1016/j.jinorgbio.2021.111546 (Review) (Peer Reviewed)

Review discussing how melatonin may improve COVID-19 prognosis by acting to reduce oxygen deficiency and hypoxia, vitamin B12 deficiency, NO deficiency, oxidative stress, and sleep disturbance.

Camp et al., 7/17/2021, peer-reviewed, 5 authors.

Deficient synthesis of melatonin in COVID-19 can impair the resistance of coronavirus patients to mucormycosis

Sen, A., OSF Preprints, doi:0.31219/osf.io/xw3np (Preprint) (Theory)

Proposal that melatonin deficiency plays a significant role in COVID-19 associated mucormycosis.

Sen et al., 7/2/2021, preprint, 1 author.

The Effect of Melatonin as an Adjuvant Therapy on COVID-19: A Randomized Clinical Trial

Davoodian et al., SSRN, doi:10.2139/ssrn.3878090 (Preprint)

RCT 81 hospitalized patients in Iran, showing significantly improved oxygen saturation with treatment. Melatonin 3mg, 3x daily for 2 weeks. IRCT20200408046988N1.

Davoodian et al., 7/1/2021, preprint.

Efficacy of a Low Dose of Melatonin as an Adjunctive Therapy in Hospitalized Patients with COVID-19: A Randomized, Double-blind Clinical Trial

Farnoosh et al., Archives of Medical Research, doi:10.1016/j.arcmed.2021.06.006 (Peer Reviewed)

RCT 44 hospitalized patients in Iran, 24 treated with melatonin, showing faster recovery with treatment. There was no mortality.

risk of ICU admission, 81.5% lower, RR 0.19, p = 0.20, treatment 0 of 24 (0.0%), control 2 of 20 (10.0%), NNT 10.0, relative risk is not 0 because of continuity correction due to zero events.

recovery time, 49.0% lower, relative time 0.51, p = 0.004, treatment 24, control 20.

risk of no hospital discharge, 44.4% lower, RR 0.56, p = 0.65, treatment 2 of 24 (8.3%), control 3 of 20 (15.0%), NNT 15.

time to discharge, 42.9% lower, relative time 0.57, p = 0.02, treatment 24, control 20.

Farnoosh et al., 6/23/2021, Double Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 12 authors.

Melatonin for the Early Treatment of COVID-19: A Narrative Review of Current Evidence and Possible Efficacy

Cross et al., Endocrine Practice, doi:10.1016/j.eprac.2021.06.001 (Review) (Peer Reviewed)

Review of the potential benefits of melatonin for COVID-19.

Cross et al., 6/10/2021, peer-reviewed, 4 authors.

A Pilot Study on Controlling Coronavirus Disease 2019 (COVID-19) Inflammation Using Melatonin Supplement

Alizadeh et al., Iranian Journal of Allergy, Asthma and Immunology (Peer Reviewed)

Small RCT 31 mild/moderate COVID-19 outpatients in Iran, 14 treated with melatonin, showing improved recovery with treatment.

risk of no recovery, 73.0% lower, RR 0.27, p = 0.06, treatment 2 of 14 (14.3%), control 9 of 17 (52.9%), NNT 2.6, day 14.

Alizadeh et al., 5/29/2021, Single Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 6 authors.

Evaluation of Th1 and Th2 mediated cellular and humoral immunity in patients with COVID-19 following the use of melatonin as an adjunctive treatment

Hosseini et al., European Journal of Pharmacology, doi:10.1016/j.ejphar.2021.174193 (Peer Reviewed)

40 hospitalized patients in Iran, 20 treated with melatonin, showing faster recovery and attenuated inflammatory cytokines with treatment.

recovery time, 47.6% lower, relative time 0.52, p = 0.001, treatment 20, control 20.

Hosseini et al., 5/17/2021, prospective, Iran, Middle East, peer-reviewed, 9 authors.

Melatonin may decrease risk for and aid treatment of COVID-19 and other RNA viral infections

DiNicolantonio et al., Open Heart, doi:10.1136/openhrt-2020-001568 (Review) (Peer Reviewed)

Review of melatonin for COVID-19 and the result of Ramlall et al., suggesting that vitamin D, zinc, and melatonin supplementation may have general utility for the prevention and treatment of RNA virus infections, such as COVID-19 and influenza.

DiNicolantonio et al., 3/19/2021, peer-reviewed, 3 authors.

Case Cluster of RT-PCR COVID-19 Positive Patients with an Unexpected Benign Clinical Course With Vitamin D, Melatonin, Vitamin C, and Viscum Album

Hancock et al., SSRN, doi:10.2139/ssrn.3779211 (Preprint)

Case series of 24 COVID-19 patients (12 confirmed PCR+) treated with vitamin D, vitamin C, and melatonin, showing positive outcomes with no patient having worse than a mild case, including 7 high risk patients.

Hancock et al., 2/9/2021, preprint, 4 authors.

COVID-19 Disease as an Acute Angiotensin 1-7 Deficiency: A Preliminary Phase 2 Study with Angiotensin 1-7 in Association with Melatonin and Cannabidiol in Symptomatic COVID19 -Infected Subjects

Lissoni et al., Journal of Infectiology, doi:10.29245/2689-9981/2018/2.1162 (Peer Reviewed)

Small study with 30 patients treated with melatonin, cannabidiol, and for 14 patients angiotensin 1-7, compared with an age/sex matched control group during the same period, showing lower hospitalization with treatment.

risk of hospitalization, 90.9% lower, RR 0.09, p = 0.05, treatment 0 of 30 (0.0%), control 5 of 30 (16.7%), NNT 6.0, relative risk is not 0 because of continuity correction due to zero events.

Lissoni et al., 12/30/2020, prospective, Italy, Europe, peer-reviewed, 14 authors, this trial uses multiple treatments in the treatment arm (combined with cannabidiol and angiotensin 1-7) - results of individual treatments may vary.

Efficacy of melatonin in non-intensive care unit patients with COVID-19 pneumonia and sleep dysregulation

Brusco et al., Melatonin Research, doi:10.32794/mr11250089 (Peer Reviewed)

Review of melatonin for COVID-19 along with preliminary data suggesting efficacy of melatonin for COVID-19 pneumonia patients.

Brusco et al., 12/23/2020, peer-reviewed, 6 authors.

Efficacy of High Dose Vitamin C, Melatonin and Zinc in Iranian Patients with Acute Respiratory Syndrome due to Coronavirus Infection: A Pilot Randomized Trial

Darban et al., Journal of Cellular & Molecular Anesthesia, doi:10.22037/jcma.v6i2.32182 (Peer Reviewed)

Small RCT in Iran with 20 ICU patients, 10 treated with high-dose vitamin C, melatonin, and zinc, not showing significant differences. IRCT20151228025732N52.

risk of progression, 33.3% lower, RR 0.67, p = 1.00, treatment 2 of 10 (20.0%), control 3 of 10 (30.0%), NNT 10.

ICU time, 6.0% lower, relative time 0.94, p = 0.30, treatment 10, control 10.

Darban et al., 12/15/2020, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 8 authors, this trial uses multiple treatments in the treatment arm (combined with vitamin C and zinc) - results of individual treatments may vary.

A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19

Zhou et al., PLOS Biology, doi:10.1371/journal.pbio.3000970 (Peer Reviewed)

PSM observational study with a database of 26,779 patients in the USA, showing significantly lower risk of PCR+ with melatonin usage.

risk of case, 21.1% lower, RR 0.79, p = 0.01, treatment 222 of 1,055 (21.0%), control 8,052 of 25,724 (31.3%), NNT 9.7, OR converted to RR, PSM.

Zhou et al., 11/6/2020, retrospective, propensity score matching, USA, North America, peer-reviewed, 18 authors.

Melatonin is significantly associated with survival of intubated COVID-19 patients

Ramlall et al., medRxiv, doi:10.1101/2020.10.15.20213546 (Preprint)

Retrospective 948 intubated patients, 196 treated with melatonin, showing lower mortality with treatment.

risk of death, 86.9% lower, RR 0.13, p < 0.001, treatment 196, control 752, multivariate model Cox proportional hazards.

Ramlall et al., 10/18/2020, retrospective, USA, North America, preprint, 3 authors.

Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): a case series

Castillo et al., Melatonin Research, doi:10.32794/mr11250063 (Peer Reviewed)

Report on the use of high-dose melatonin in 10 pneumonia patients, showing clinical stabilization and/or improvement for all patients within 4-5 days. All patients survived, including 3 with moderately severe ARDS and one with mild ARDS. None required mechanical ventilation.

Castillo et al., 6/15/2020, retrospective, Philippines, Asia, peer-reviewed, 10 authors.

Individualizing Risk Prediction for Positive Coronavirus Disease 2019 Testing

Jehi et al., Chest, doi:10.1016/j.chest.2020.05.580 (Peer Reviewed)

Retrospective 11,672 patients tested for COVID-19, 818 that tested positive, showing significantly lower risk with melatonin use.

risk of case, 58.0% lower, RR 0.42, p < 0.001, treatment 16 of 529 (3.0%), control 802 of 11,143 (7.2%), NNT 24, development cohort.

risk of case, 99.7% lower, RR 0.003, p = 0.09, treatment 0 of 18 (0.0%), control 290 of 2,005 (14.5%), NNT 6.9, relative risk is not 0 because of continuity correction due to zero events, Florida validation cohort.

Jehi et al., 6/10/2020, retrospective, USA, North America, peer-reviewed, 8 authors.

COVID-19 and heme oxygenase: novel insight into the disease and potential therapies

Hooper, P., Cell Stress and Chaperones, doi:10.1007/s12192-020-01126-9 (Peer Reviewed) (Theory)

Proposal that COVID-19 risk is related to low intracellular heme oxygenase (HO-1), and that therapies that raise HO-1 may be beneficial, which includes fluvoxamine, certain anesthetics (sevoflurane or isoflurane), hemin, estrogen, statins, curcumin, resveratrol, and melatonin. Authors note that cigarette smoke is associated with increased HO-1 in lung fibroblasts and vascular endothelial cells, which may help explain the lower risk for smokers seen in several studies.

Hooper et al., 6/4/2020, peer-reviewed, 1 author.

Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19

Reiter et al., Frontiers in Medicine, doi:10.3389/fmed.2020.00226 (Review) (Peer Reviewed)

Review of melatonin's action as an antiinflammatory, antioxidant, and antiviral (against other viruses) agent, and proposed therapeutic algorithm for use with COVID-19.

Reiter et al., 5/15/2020, peer-reviewed, 4 authors.

Prophylactic Treatment Protocol against the Severity of COVID-19 Using Melatonin

Charaa et al., SSRN, doi:10.2139/ssrn.3601861 (Review) (Preprint)

Review of the potential benefits of melatonin for COVID-19, and a proposed prophylactic treatment protocol.

Charaa et al., 5/4/2020, preprint, 4 authors.

Can melatonin reduce the severity of COVID-19 pandemic?

Shneider et al., International Reviews of Immunology, doi:10.1080/08830185.2020.1756284 (Review) (Peer Reviewed)

Review of the potential benefits of melatonin for COVID-19.

Shneider et al., 4/29/2020, peer-reviewed, 3 authors.

COVID-19: Melatonin as a potential adjuvant treatment

Zhang et al., Life Sciences, doi:10.1016/j.lfs.2020.117583 (Review) (Peer Reviewed)

Review of the potential benefits of melatonin for COVID-19.

Zhang et al., 3/23/2020, peer-reviewed, 8 authors.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption