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Melatonin for COVID-19: real-time meta analysis of 17 studies
Covid Analysis, August 19, 2022, DRAFT
https://c19melatonin.com/meta.html
0 0.5 1 1.5+ All studies 47% 17 14,075 Improvement, Studies, Patients Relative Risk Mortality 54% 8 1,828 Ventilation 31% 2 98 ICU admission 6% 5 271 Hospitalization 54% 2 140 Recovery 35% 5 248 Cases 38% 3 11,986 RCTs 32% 8 796 RCT mortality 64% 3 321 Peer-reviewed 34% 16 13,127 Prophylaxis 38% 3 11,986 Early 78% 2 91 Late 49% 12 1,998 Melatonin for COVID-19 c19melatonin.com Aug 2022 Favorsmelatonin Favorscontrol after exclusions
Statistically significant improvements are seen for mortality, ventilation, and recovery. 8 studies from 8 independent teams in 5 different countries show statistically significant improvements in isolation (6 for the most serious outcome).
Meta analysis using the most serious outcome reported shows 47% [31‑59%] improvement. Results are slightly worse for Randomized Controlled Trials, similar after exclusions, and slightly worse for peer-reviewed studies. Early treatment is more effective than late treatment.
0 0.5 1 1.5+ All studies 47% 17 14,075 Improvement, Studies, Patients Relative Risk Mortality 54% 8 1,828 Ventilation 31% 2 98 ICU admission 6% 5 271 Hospitalization 54% 2 140 Recovery 35% 5 248 Cases 38% 3 11,986 RCTs 32% 8 796 RCT mortality 64% 3 321 Peer-reviewed 34% 16 13,127 Prophylaxis 38% 3 11,986 Early 78% 2 91 Late 49% 12 1,998 Melatonin for COVID-19 c19melatonin.com Aug 2022 Favorsmelatonin Favorscontrol after exclusions
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 12% of melatonin studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments may be more effective.
No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.
All data to reproduce this paper and sources are in the appendix. Other meta analyses for melatonin can be found in [Lan, Pilia, Tan], showing significant improvements for recovery and mortality.
Highlights
Melatonin reduces risk for COVID-19 with very high confidence for mortality, recovery, and in pooled analysis, high confidence for ventilation, low confidence for cases, and very low confidence for ICU admission.
We show traditional outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor in COVID-19 studies.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 43 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Lissoni 91% 0.09 [0.01-1.57] 20mg hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Dose (1d) Treatment Control Alizadeh (SB RCT) 73% 0.27 [0.07-1.05] 6mg no recov. 2/14 9/17 Tau​2 = 0.00, I​2 = 0.0%, p = 0.016 Early treatment 78% 0.22 [0.06-0.75] 2/44 14/47 78% improvement Ramlall (ICU) 87% 0.13 [0.08-0.22] n/a death 196 (n) 752 (n) Intubated patients Improvement, RR [CI] Dose (1d) Treatment Control Darban (RCT) 33% 0.67 [0.14-3.17] 24mg progression 2/10 3/10 ICU patients CT​1 Hosseini 48% 0.52 [0.36-0.77] 9mg recov. time 20 (n) 20 (n) Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] 9mg ICU 0/24 2/20 Sánchez-González 54% 0.46 [0.28-0.71] varies death 24/224 53/224 Mousavi (RCT) 67% 0.33 [0.04-3.09] 3mg death 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] 10mg death 1/82 13/76 Bologna 50% 0.50 [0.13-1.86] 2mg death 3/40 6/40 Sánchez-Rico 19% 0.81 [0.61-1.08] 2mg death Karimpour-.. (ICU) 39% 0.61 [0.21-1.76] 15mg death 5/12 13/19 ICU patients Alizadeh (DB RCT) 4% 0.96 [0.80-1.16] 21mg death 28/33 30/34 Intubated patients Fogleman (DB RCT) 17% 0.83 [0.55-1.25] recovery 32 (n) 34 (n) Tau​2 = 0.23, I​2 = 83.0%, p = 0.00028 Late treatment 49% 0.51 [0.36-0.73] 64/721 123/1,277 49% improvement Jehi 58% 0.42 [0.26-0.68] n/a cases 16/529 802/11,143 Improvement, RR [CI] Dose (1d) Treatment Control Zhou (PSM) 21% 0.79 [0.65-0.94] n/a cases García-G.. (DB RCT) 7% 0.93 [0.06-14.7] 2mg symp. case 1/163 1/151 Tau​2 = 0.13, I​2 = 67.2%, p = 0.081 Prophylaxis 38% 0.62 [0.36-1.06] 17/692 803/11,294 38% improvement All studies 47% 0.53 [0.41-0.69] 83/1,457 940/12,618 47% improvement 17 melatonin COVID-19 studies c19melatonin.com Aug 2022 Tau​2 = 0.13, I​2 = 78.7%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 CT: study uses combined treatment Favors melatonin Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Lissoni 91% hospitalization CT​1 Improvement Relative Risk [CI] Alizadeh (SB RCT) 73% recovery Tau​2 = 0.00, I​2 = 0.0%, p = 0.016 Early treatment 78% 78% improvement Ramlall (ICU) 87% death Intubated patients Darban (RCT) 33% progression ICU patients CT​1 Hosseini 48% recovery Farnoosh (DB RCT) 81% ICU admission Sánchez-González 54% death Mousavi (RCT) 67% death Hasan (RCT) 93% death Bologna 50% death Sánchez-Rico 19% death Karimpour-.. (ICU) 39% death ICU patients Alizadeh (DB RCT) 4% death Intubated patients Fogleman (DB RCT) 17% recovery Tau​2 = 0.23, I​2 = 83.0%, p = 0.00028 Late treatment 49% 49% improvement Jehi 58% case Zhou (PSM) 21% case García-G.. (DB RCT) 7% symp. case Tau​2 = 0.13, I​2 = 67.2%, p = 0.081 Prophylaxis 38% 38% improvement All studies 47% 47% improvement 17 melatonin COVID-19 studies c19melatonin.com Aug 2022 Tau​2 = 0.13, I​2 = 78.7%, p < 0.0001 Protocol pre-specified/rotate for details1 CT: study uses combined treatment Favors melatonin Favors control
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the distribution of effects reported in studies. C. History of all reported effects (chronological within treatment stages).
Introduction
We analyze all significant studies concerning the use of melatonin for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, for studies within each treatment stage, for individual outcomes, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Mechanisms of Action
CD147SARS-CoV-2 may enter host cells via the cluster of differentiation 147 (CD147) transmembrane protein. Melatonin inhibits the CD147 signalling pathway [Behl, Su, Wang].
Heme oxygenaseCOVID-19 risk may be related to low intracellular heme oxygenase (HO-1). Melatonin increases HO-1 and HO-1 has cytoprotective and anti-inflammatory properties [Anderson, Anderson (B), Hooper, Hooper (B), Shi].
Inhibiting brain infectionMelatonin has been shown to inhibit SARS-CoV-2 brain infection in a K18-hACE2 mouse model via allosteric binding to ACE2. [Cecon].
Limiting type I and III interferonsIn a K18-hACE2 mouse model, melatonin improved survival which may be associated with limiting lung production of type I and type III interferons [Cecon (B)].
MucormycosisMelatonin deficiency may increase the risk of mucormycosis by providing favorable conditions for growth [Sen].
GlutathioneMelatonin increases glutathione levels, and glutathione deficiency may be associated with COVID-19 severity [Morvaridzadeh, Polonikov].
Cytokine levelsMelatonin may lower pro-inflammatory cytokine levels [Zhang].
Immune regulationMelatonin has immune regulatory properties, enhancing the proliferation and maturation of natural killing cells, T and B lymphocytes, granulocytes, and monocytes [Miller, Zhang].
Sleep improvementMelatonin improves the quality of sleep which may be beneficial for COVID-19 [Lewis, Zhang].
Anti‑inflammatoryMelatonin shows anti-inflammatory effects [Zhang].
Anti‑oxidationMelatonin shows anti-oxidative effects which may be beneficial for COVID-19 [Gitto, Gitto (B), Reiter, Wu, Zhang].
Table 1. Melatonin mechanisms of action. Submit updates.
Preclinical Research
2 In Vivo animal studies support the efficacy of melatonin [Cecon, Cecon (B)].
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Results
Figure 3 shows a visual overview of the results, with details in Table 2 and Table 3. Figure 4, 5, 6, 7, 8, 9, 10, 11, and 12 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, and peer reviewed studies.
0 0.5 1 1.5+ ALL STUDIES MORTALITY VENTILATION ICU ADMISSION HOSPITALIZATION RECOVERY CASES RANDOMIZED CONTROLLED TRIALS RCT MORTALITY PEER-REVIEWED After Exclusions ALL STUDIES All Prophylaxis Early Late Melatonin for COVID-19 C19MELATONIN.COM AUG 2022
Figure 3. Overview of results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Early treatment 2 2 100% 78% improvement
RR 0.22 [0.06‑0.75]
p = 0.016
Late treatment 12 12 100% 49% improvement
RR 0.51 [0.36‑0.73]
p = 0.00028
Prophylaxis 3 3 100% 38% improvement
RR 0.62 [0.36‑1.06]
p = 0.081
All studies 17 17 100% 47% improvement
RR 0.53 [0.41‑0.69]
p < 0.0001
Table 2. Results by treatment stage.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 1778% [25‑94%]49% [27‑64%]38% [-6‑64%] 14,075 150
With exclusions 1678% [25‑94%]48% [24‑65%]38% [-6‑64%] 13,627 146
Peer-reviewed 1678% [25‑94%]33% [15‑47%]38% [-6‑64%] 13,127 147
Randomized Controlled TrialsRCTs 873% [-5‑93%]25% [-14‑51%]7% [-1368‑94%] 796 79
Table 3. Results by treatment stage for all studies and with different exclusions.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Lissoni 91% 0.09 [0.01-1.57] 20mg hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Dose (1d) Treatment Control Alizadeh (SB RCT) 73% 0.27 [0.07-1.05] 6mg no recov. 2/14 9/17 Tau​2 = 0.00, I​2 = 0.0%, p = 0.016 Early treatment 78% 0.22 [0.06-0.75] 2/44 14/47 78% improvement Ramlall (ICU) 87% 0.13 [0.08-0.22] n/a death 196 (n) 752 (n) Intubated patients Improvement, RR [CI] Dose (1d) Treatment Control Darban (RCT) 33% 0.67 [0.14-3.17] 24mg progression 2/10 3/10 ICU patients CT​1 Hosseini 48% 0.52 [0.36-0.77] 9mg recov. time 20 (n) 20 (n) Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] 9mg ICU 0/24 2/20 Sánchez-González 54% 0.46 [0.28-0.71] varies death 24/224 53/224 Mousavi (RCT) 67% 0.33 [0.04-3.09] 3mg death 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] 10mg death 1/82 13/76 Bologna 50% 0.50 [0.13-1.86] 2mg death 3/40 6/40 Sánchez-Rico 19% 0.81 [0.61-1.08] 2mg death Karimpour-.. (ICU) 39% 0.61 [0.21-1.76] 15mg death 5/12 13/19 ICU patients Alizadeh (DB RCT) 4% 0.96 [0.80-1.16] 21mg death 28/33 30/34 Intubated patients Fogleman (DB RCT) 17% 0.83 [0.55-1.25] recovery 32 (n) 34 (n) Tau​2 = 0.23, I​2 = 83.0%, p = 0.00028 Late treatment 49% 0.51 [0.36-0.73] 64/721 123/1,277 49% improvement Jehi 58% 0.42 [0.26-0.68] n/a cases 16/529 802/11,143 Improvement, RR [CI] Dose (1d) Treatment Control Zhou (PSM) 21% 0.79 [0.65-0.94] n/a cases García-G.. (DB RCT) 7% 0.93 [0.06-14.7] 2mg symp. case 1/163 1/151 Tau​2 = 0.13, I​2 = 67.2%, p = 0.081 Prophylaxis 38% 0.62 [0.36-1.06] 17/692 803/11,294 38% improvement All studies 47% 0.53 [0.41-0.69] 83/1,457 940/12,618 47% improvement 17 melatonin COVID-19 studies c19melatonin.com Aug 2022 Tau​2 = 0.13, I​2 = 78.7%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 CT: study uses combined treatment Favors melatonin Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Lissoni 91% hospitalization CT​1 Improvement Relative Risk [CI] Alizadeh (SB RCT) 73% recovery Tau​2 = 0.00, I​2 = 0.0%, p = 0.016 Early treatment 78% 78% improvement Ramlall (ICU) 87% death Intubated patients Darban (RCT) 33% progression ICU patients CT​1 Hosseini 48% recovery Farnoosh (DB RCT) 81% ICU admission Sánchez-González 54% death Mousavi (RCT) 67% death Hasan (RCT) 93% death Bologna 50% death Sánchez-Rico 19% death Karimpour-.. (ICU) 39% death ICU patients Alizadeh (DB RCT) 4% death Intubated patients Fogleman (DB RCT) 17% recovery Tau​2 = 0.23, I​2 = 83.0%, p = 0.00028 Late treatment 49% 49% improvement Jehi 58% case Zhou (PSM) 21% case García-G.. (DB RCT) 7% symp. case Tau​2 = 0.13, I​2 = 67.2%, p = 0.081 Prophylaxis 38% 38% improvement All studies 47% 47% improvement 17 melatonin COVID-19 studies c19melatonin.com Aug 2022 Tau​2 = 0.13, I​2 = 78.7%, p < 0.0001 Protocol pre-specified/rotate for details1 CT: study uses combined treatment Favors melatonin Favors control
Figure 4. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Ramlall (ICU) 87% 0.13 [0.08-0.22] n/a 196 (n) 752 (n) Intubated patients Improvement, RR [CI] Dose (1d) Treatment Control Sánchez-González 54% 0.46 [0.28-0.71] varies 24/224 53/224 Mousavi (RCT) 67% 0.33 [0.04-3.09] 3mg 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] 10mg 1/82 13/76 Bologna 50% 0.50 [0.13-1.86] 2mg 3/40 6/40 Sánchez-Rico 19% 0.81 [0.61-1.08] 2mg Karimpour-.. (ICU) 39% 0.61 [0.21-1.76] 15mg 5/12 13/19 ICU patients Alizadeh (DB RCT) 4% 0.96 [0.80-1.16] 21mg 28/33 30/34 Intubated patients Tau​2 = 0.31, I​2 = 88.4%, p = 0.0016 Late treatment 54% 0.46 [0.28-0.74] 62/635 118/1,193 54% improvement All studies 54% 0.46 [0.28-0.74] 62/635 118/1,193 54% improvement 8 melatonin COVID-19 mortality results c19melatonin.com Aug 2022 Tau​2 = 0.31, I​2 = 88.4%, p = 0.0016 Favors melatonin Favors control
Figure 5. Random effects meta-analysis for mortality results.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Karimpour-.. (ICU) 43% 0.57 [0.28-1.18] 15mg 12 (n) 19 (n) ICU patients Improvement, RR [CI] Dose (1d) Treatment Control Alizadeh (DB RCT) 27% 0.73 [0.51-1.05] 21mg 33 (n) 34 (n) Intubated patients Tau​2 = 0.00, I​2 = 0.0%, p = 0.028 Late treatment 31% 0.69 [0.50-0.96] 0/45 0/53 31% improvement All studies 31% 0.69 [0.50-0.96] 0/45 0/53 31% improvement 2 melatonin COVID-19 mechanical ventilation results c19melatonin.com Aug 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.028 Favors melatonin Favors control
Figure 6. Random effects meta-analysis for ventilation.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Darban (RCT) 6% 0.94 [0.84-1.06] 24mg 10 (n) 10 (n) ICU patients CT​1 Improvement, RR [CI] Dose (1d) Treatment Control Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] 9mg 0/24 2/20 Mousavi (RCT) 40% 0.60 [0.24-1.52] 3mg 6/48 10/48 Bologna 50% 0.50 [0.13-1.86] 2mg 3/40 6/40 Karimpour-.. (ICU) 2% 0.98 [0.81-1.19] 15mg 12 (n) 19 (n) ICU patients Tau​2 = 0.00, I​2 = 0.0%, p = 0.23 Late treatment 6% 0.94 [0.85-1.04] 9/134 18/137 6% improvement All studies 6% 0.94 [0.85-1.04] 9/134 18/137 6% improvement 5 melatonin COVID-19 ICU results c19melatonin.com Aug 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.23 1 CT: study uses combined treatment Favors melatonin Favors control
Figure 7. Random effects meta-analysis for ICU admission.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Lissoni 91% 0.09 [0.01-1.57] 20mg hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Dose (1d) Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.099 Early treatment 91% 0.09 [0.01-1.57] 0/30 5/30 91% improvement Bologna 9% 0.91 [0.83-1.00] 2mg hosp. time 40 (n) 40 (n) Improvement, RR [CI] Dose (1d) Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.054 Late treatment 9% 0.91 [0.83-1.00] 0/40 0/40 9% improvement All studies 54% 0.46 [0.06-3.62] 0/70 5/70 54% improvement 2 melatonin COVID-19 hospitalization results c19melatonin.com Aug 2022 Tau​2 = 1.60, I​2 = 60.2%, p = 0.47 1 CT: study uses combined treatment Favors melatonin Favors control
Figure 8. Random effects meta-analysis for hospitalization.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Darban (RCT) 33% 0.67 [0.14-3.17] 24mg 2/10 3/10 ICU patients CT​1 Improvement, RR [CI] Dose (1d) Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.62 Late treatment 33% 0.67 [0.14-3.17] 2/10 3/10 33% improvement All studies 33% 0.67 [0.14-3.17] 2/10 3/10 33% improvement 1 melatonin COVID-19 progression result c19melatonin.com Aug 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.62 1 CT: study uses combined treatment Favors melatonin Favors control
Figure 9. Random effects meta-analysis for progression.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Alizadeh (SB RCT) 73% 0.27 [0.07-1.05] 6mg no recov. 2/14 9/17 Improvement, RR [CI] Dose (1d) Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.058 Early treatment 73% 0.27 [0.07-1.05] 2/14 9/17 73% improvement Hosseini 48% 0.52 [0.36-0.77] 9mg recov. time 20 (n) 20 (n) Improvement, RR [CI] Dose (1d) Treatment Control Farnoosh (DB RCT) 49% 0.51 [0.32-0.81] 9mg recov. time 24 (n) 20 (n) Alizadeh (DB RCT) 14% 0.86 [0.70-1.06] 21mg no recov. 26/33 31/34 Intubated patients Fogleman (DB RCT) 17% 0.83 [0.55-1.25] recovery 32 (n) 34 (n) Tau​2 = 0.05, I​2 = 63.0%, p = 0.0099 Late treatment 32% 0.68 [0.51-0.91] 26/109 31/108 32% improvement All studies 35% 0.65 [0.48-0.88] 28/123 40/125 35% improvement 5 melatonin COVID-19 recovery results c19melatonin.com Aug 2022 Tau​2 = 0.06, I​2 = 60.9%, p = 0.0055 Favors melatonin Favors control
Figure 10. Random effects meta-analysis for recovery.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Jehi 58% 0.42 [0.26-0.68] n/a cases 16/529 802/11,143 Improvement, RR [CI] Dose (1d) Treatment Control Zhou (PSM) 21% 0.79 [0.65-0.94] n/a cases García-G.. (DB RCT) 7% 0.93 [0.06-14.7] 2mg symp. case 1/163 1/151 Tau​2 = 0.13, I​2 = 67.2%, p = 0.081 Prophylaxis 38% 0.62 [0.36-1.06] 17/692 803/11,294 38% improvement All studies 38% 0.62 [0.36-1.06] 17/692 803/11,294 38% improvement 3 melatonin COVID-19 case results c19melatonin.com Aug 2022 Tau​2 = 0.13, I​2 = 67.2%, p = 0.081 Favors melatonin Favors control
Figure 11. Random effects meta-analysis for cases.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Lissoni 91% 0.09 [0.01-1.57] 20mg hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Dose (1d) Treatment Control Alizadeh (SB RCT) 73% 0.27 [0.07-1.05] 6mg no recov. 2/14 9/17 Tau​2 = 0.00, I​2 = 0.0%, p = 0.016 Early treatment 78% 0.22 [0.06-0.75] 2/44 14/47 78% improvement Darban (RCT) 33% 0.67 [0.14-3.17] 24mg progression 2/10 3/10 ICU patients CT​1 Improvement, RR [CI] Dose (1d) Treatment Control Hosseini 48% 0.52 [0.36-0.77] 9mg recov. time 20 (n) 20 (n) Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] 9mg ICU 0/24 2/20 Sánchez-González 54% 0.46 [0.28-0.71] varies death 24/224 53/224 Mousavi (RCT) 67% 0.33 [0.04-3.09] 3mg death 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] 10mg death 1/82 13/76 Bologna 50% 0.50 [0.13-1.86] 2mg death 3/40 6/40 Sánchez-Rico 19% 0.81 [0.61-1.08] 2mg death Karimpour-.. (ICU) 39% 0.61 [0.21-1.76] 15mg death 5/12 13/19 ICU patients Alizadeh (DB RCT) 4% 0.96 [0.80-1.16] 21mg death 28/33 30/34 Intubated patients Fogleman (DB RCT) 17% 0.83 [0.55-1.25] recovery 32 (n) 34 (n) Tau​2 = 0.06, I​2 = 55.5%, p = 0.00089 Late treatment 33% 0.67 [0.53-0.85] 64/525 123/525 33% improvement Jehi 58% 0.42 [0.26-0.68] n/a cases 16/529 802/11,143 Improvement, RR [CI] Dose (1d) Treatment Control Zhou (PSM) 21% 0.79 [0.65-0.94] n/a cases García-G.. (DB RCT) 7% 0.93 [0.06-14.7] 2mg symp. case 1/163 1/151 Tau​2 = 0.13, I​2 = 67.2%, p = 0.081 Prophylaxis 38% 0.62 [0.36-1.06] 17/692 803/11,294 38% improvement All studies 34% 0.66 [0.55-0.79] 83/1,261 940/11,866 34% improvement 16 melatonin COVID-19 peer reviewed trials c19melatonin.com Aug 2022 Tau​2 = 0.04, I​2 = 54.7%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 CT: study uses combined treatment Favors melatonin Favors control
Figure 12. Random effects meta-analysis for peer reviewed studies. [Zeraatkar] analyze 356 COVID-19 trials, finding no significant evidence that peer-reviewed studies are more trustworthy. They also show extremely slow review times during a pandemic. Authors recommend using preprint evidence, with appropriate checks for potential falsified data, which provides higher certainty much earlier. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Dose Response
Melatonin trials for COVID-19 use a very wide range of dosage, from 2mg/day to 500mg/day [Reiter (B)]. Figure 13 shows a mixed-effects meta-regression for efficacy as a function of dose from studies to date, excluding very late stage ICU studies.
Figure 13. Mixed-effects meta-regression showing efficacy as a function of dose, excluding very late stage ICU studies.
Exclusions
To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which may underemphasize serious issues not captured in the checklists, overemphasize issues unlikely to alter outcomes in specific cases (for example, lack of blinding for an objective mortality outcome, or certain specifics of randomization with a very large effect size), or be easily influenced by potential bias. However, they can also be very high quality.
The studies excluded are as below. Figure 14 shows a forest plot for random effects meta-analysis of all studies after exclusions.
[Sánchez-González], immortal time bias may significantly affect results.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Lissoni 91% 0.09 [0.01-1.57] 20mg hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Dose (1d) Treatment Control Alizadeh (SB RCT) 73% 0.27 [0.07-1.05] 6mg no recov. 2/14 9/17 Tau​2 = 0.00, I​2 = 0.0%, p = 0.016 Early treatment 78% 0.22 [0.06-0.75] 2/44 14/47 78% improvement Ramlall (ICU) 87% 0.13 [0.08-0.22] n/a death 196 (n) 752 (n) Intubated patients Improvement, RR [CI] Dose (1d) Treatment Control Darban (RCT) 33% 0.67 [0.14-3.17] 24mg progression 2/10 3/10 ICU patients CT​1 Hosseini 48% 0.52 [0.36-0.77] 9mg recov. time 20 (n) 20 (n) Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] 9mg ICU 0/24 2/20 Mousavi (RCT) 67% 0.33 [0.04-3.09] 3mg death 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] 10mg death 1/82 13/76 Bologna 50% 0.50 [0.13-1.86] 2mg death 3/40 6/40 Sánchez-Rico 19% 0.81 [0.61-1.08] 2mg death Karimpour-.. (ICU) 39% 0.61 [0.21-1.76] 15mg death 5/12 13/19 ICU patients Alizadeh (DB RCT) 4%