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Melatonin for COVID-19: real-time meta analysis of 16 studies
Covid Analysis, May 27, 2022, DRAFT
https://c19melatonin.com/meta.html
0 0.5 1 1.5+ All studies 49% 16 14,009 Improvement, Studies, Patients Relative Risk Mortality 54% 8 1,828 Ventilation 31% 2 98 ICU admission 6% 5 271 Hospitalization 54% 2 140 Recovery 40% 4 182 Cases 38% 3 11,986 RCTs 55% 7 730 RCT mortality 64% 3 321 Peer-reviewed 36% 15 13,061 Prophylaxis 38% 3 11,986 Early 78% 2 91 Late 53% 11 1,932 Melatonin for COVID-19 c19melatonin.com May 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 49% [33‑62%] improvement. Results are similar 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 49% 16 14,009 Improvement, Studies, Patients Relative Risk Mortality 54% 8 1,828 Ventilation 31% 2 98 ICU admission 6% 5 271 Hospitalization 54% 2 140 Recovery 40% 4 182 Cases 38% 3 11,986 RCTs 55% 7 730 RCT mortality 64% 3 321 Peer-reviewed 36% 15 13,061 Prophylaxis 38% 3 11,986 Early 78% 2 91 Late 53% 11 1,932 Melatonin for COVID-19 c19melatonin.com May 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 and in pooled analysis, high confidence for ventilation and recovery, 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 42 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 Tau​2 = 0.26, I​2 = 84.4%, p = 0.00031 Late treatment 53% 0.47 [0.32-0.71] 64/689 123/1,243 53% 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 49% 0.51 [0.38-0.67] 83/1,425 940/12,584 49% improvement 16 melatonin COVID-19 studies c19melatonin.com May 2022 Tau​2 = 0.14, I​2 = 80.0%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 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 MAY 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 11 11 100% 53% improvement
RR 0.47 [0.32‑0.71]
p = 0.00031
Prophylaxis 3 3 100% 38% improvement
RR 0.62 [0.36‑1.06]
p = 0.081
All studies 16 16 100% 49% improvement
RR 0.51 [0.38‑0.67]
p < 0.0001
Table 2. Results by treatment stage.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 1678% [25‑94%]53% [29‑68%]38% [-6‑64%] 14,009 143
With exclusions 1578% [25‑94%]53% [26‑70%]38% [-6‑64%] 13,561 139
Peer-reviewed 1578% [25‑94%]36% [16‑51%]38% [-6‑64%] 13,061 140
Randomized Controlled TrialsRCTs 773% [-5‑93%]55% [-21‑84%]7% [-1368‑94%] 730 72
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 Tau​2 = 0.26, I​2 = 84.4%, p = 0.00031 Late treatment 53% 0.47 [0.32-0.71] 64/689 123/1,243 53% 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 49% 0.51 [0.38-0.67] 83/1,425 940/12,584 49% improvement 16 melatonin COVID-19 studies c19melatonin.com May 2022 Tau​2 = 0.14, I​2 = 80.0%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 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 May 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 May 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 May 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 May 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 May 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 Tau​2 = 0.09, I​2 = 74.4%, p = 0.023 Late treatment 36% 0.64 [0.43-0.94] 26/77 31/74 36% improvement All studies 40% 0.60 [0.40-0.89] 28/91 40/91 40% improvement 4 melatonin COVID-19 recovery results c19melatonin.com May 2022 Tau​2 = 0.10, I​2 = 69.5%, p = 0.01 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 May 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 Tau​2 = 0.07, I​2 = 59.8%, p = 0.0012 Late treatment 36% 0.64 [0.49-0.84] 64/493 123/491 36% 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 36% 0.64 [0.52-0.78] 83/1,229 940/11,832 36% improvement 15 melatonin COVID-19 peer reviewed trials c19melatonin.com May 2022 Tau​2 = 0.05, I​2 = 57.5%, 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% 0.96 [0.80-1.16] 21mg death 28/33 30/34 Intubated patients Tau​2 = 0.28, I​2 = 85.0%, p = 0.001 Late treatment 53% 0.47 [0.30-0.74] 40/465 70/1,019 53% 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 49% 0.51 [0.38-0.68] 59/1,201 887/12,360 49% improvement 15 melatonin COVID-19 studies after exclusions c19melatonin.com May 2022 Tau​2 = 0.14, I​2 = 80.1%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 CT: study uses combined treatment Favors melatonin Favors control
Figure 14. Random effects meta-analysis for all studies after exclusions. 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.
Randomized Controlled Trials (RCTs)
Figure 15 shows the distribution of results for Randomized Controlled Trials and other studies, and a chronological history of results. The median effect size for RCTs is 67% improvement, compared to 50% for other studies. Figure 16 and 17 show forest plots for a random effects meta-analysis of all Randomized Controlled Trials and RCT mortality results. Table 4 summarizes the results.
Figure 15. The distribution of results for Randomized Controlled Trials and other studies, and a chronological history of results.
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 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 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 Alizadeh (DB RCT) 4% 0.96 [0.80-1.16] 21mg death 28/33 30/34 Intubated patients Tau​2 = 0.62, I​2 = 53.0%, p = 0.11 Late treatment 55% 0.45 [0.16-1.21] 32/197 51/188 55% improvement García-G.. (DB RCT) 7% 0.93 [0.06-14.7] 2mg symp. case 1/163 1/151 Improvement, RR [CI] Dose (1d) Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.96 Prophylaxis 7% 0.93 [0.06-14.7] 1/163 1/151 7% improvement All studies 55% 0.45 [0.20-1.00] 35/374 61/356 55% improvement 7 melatonin COVID-19 Randomized Controlled Trials c19melatonin.com May 2022 Tau​2 = 0.46, I​2 = 48.2%, p = 0.049 Effect extraction pre-specified(most serious outcome, see appendix) 1 CT: study uses combined treatment Favors melatonin Favors control
Figure 16. Random effects meta-analysis for all Randomized Controlled Trials. 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+ Mousavi (RCT) 67% 0.33 [0.04-3.09] 3mg 1/48 3/48 Improvement, RR [CI] Dose (1d) Treatment Control Hasan (RCT) 93% 0.07 [0.01-0.53] 10mg 1/82 13/76 Alizadeh (DB RCT) 4% 0.96 [0.80-1.16] 21mg 28/33 30/34 Intubated patients Tau​2 = 1.53, I​2 = 72.2%, p = 0.22 Late treatment 64% 0.36 [0.07-1.87] 30/163 46/158 64% improvement All studies 64% 0.36 [0.07-1.87] 30/163 46/158 64% improvement 3 melatonin COVID-19 RCT mortality results c19melatonin.com May 2022 Tau​2 = 1.53, I​2 = 72.2%, p = 0.22 Favors melatonin Favors control
Figure 17. Random effects meta-analysis for RCT mortality results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Randomized Controlled Trials 7 7 100% 55% improvement
RR 0.45 [0.20‑1.00]
p = 0.049
RCT mortality results 3 3 100% 64% improvement
RR 0.36 [0.07‑1.87]
p = 0.22
Table 4. Randomized Controlled Trial results.
Heterogeneity
Heterogeneity in COVID-19 studies arises from many factors including:
Treatment delay.
The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours [McLean, Treanor]. Figure 18 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 42 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
Figure 18. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 42 treatments. Early treatment is critical.
Patient demographics.
Details of the patient population including age and comorbidities may critically affect how well a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to improve results (as in [López-Medina]).
Effect measured.
Efficacy may differ significantly depending on the effect measured, for example a treatment may be very effective at reducing mortality, but less effective at minimizing cases or hospitalization. Or a treatment may have no effect on viral clearance while still being effective at reducing mortality.
Variants.
There are many different variants of SARS-CoV-2 and efficacy may depend critically on the distribution of variants encountered by the patients in a study. For example, the Gamma variant shows significantly different characteristics [Faria, Karita, Nonaka, Zavascki]. Different mechanisms of action may be more or less effective depending on variants, for example the viral entry process for the omicron variant has moved towards TMPRSS2-independent fusion, suggesting that TMPRSS2 inhibitors may be less effective [Peacock, Willett].
Regimen.
Effectiveness may depend strongly on the dosage and treatment regimen.
Treatments.
The use of other treatments may significantly affect outcomes, including anything from supplements, other medications, or other kinds of treatment such as prone positioning.
The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though the treatment may be very effective when used earlier.
In general, by combining heterogeneous studies, as all meta analyses do, we run the risk of obscuring an effect by including studies where the treatment is less effective, not effective, or harmful.
When including studies where a treatment is less effective we expect the estimated effect size to be lower than that for the optimal case. We do not a priori expect that pooling all studies will create a positive result for an effective treatment. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations.
Discussion
Publication bias.
Publishing is often biased towards positive results, however evidence suggests that there may be