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Melatonin for COVID-19: real-time meta analysis of 11 studies
DRAFT
PLEASE SUBMIT FEEDBACK
Covid Analysis, November 18, 2021
https://c19melatonin.com/meta.html
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 64% 11 13,517 Improvement, Studies, Patients Relative Risk, 95% CI With exclusions 66% 10 13,069 Mortality 79% 4 1,650 ICU admission 7% 3 160 Hospitalization 91% 1 60 Progression 33% 1 20 Recovery 50% 3 115 Cases 40% 2 11,672 RCTs 72% 5 349 Peer-reviewed 52% 10 12,569 Prophylaxis 40% 2 11,672 Early 78% 2 91 Late 70% 7 1,754 Melatonin for COVID-19 c19melatonin.com Nov 18, 2021 Favors melatonin Favors control
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.
Statistically significant improvements are seen for mortality and recovery. 7 studies show statistically significant improvements in isolation (6 for the most serious outcome).
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 64% 11 13,517 Improvement, Studies, Patients Relative Risk, 95% CI With exclusions 66% 10 13,069 Mortality 79% 4 1,650 ICU admission 7% 3 160 Hospitalization 91% 1 60 Progression 33% 1 20 Recovery 50% 3 115 Cases 40% 2 11,672 RCTs 72% 5 349 Peer-reviewed 52% 10 12,569 Prophylaxis 40% 2 11,672 Early 78% 2 91 Late 70% 7 1,754 Melatonin for COVID-19 c19melatonin.com Nov 18, 2021 Favors melatonin Favors control
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 PatientsAuthors
All studies 1178% [25‑94%]70% [43‑84%]40% [-11‑67%] 13,517 92
With exclusions 1078% [25‑94%]74% [37‑89%]40% [-11‑67%] 13,069 88
Peer-reviewed 1078% [25‑94%]53% [37‑64%]40% [-11‑67%] 12,569 89
Randomized Controlled TrialsRCTs 573% [-5‑93%]72% [22‑90%] 349 36
Percentage improvement with melatonin treatment
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Lissoni 91% 0.09 [0.01-1.57] hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Treatment Control Alizadeh (SB RCT) 73% 0.27 [0.07-1.05] no recov. 2/14 9/17 Tau​2 = 0.00; I​2 = 0.0% Early treatment 78% 0.22 [0.06-0.75] 2/44 14/47 78% improvement Ramlall 87% 0.13 [0.08-0.22] death 196 (n) 752 (n) Improvement, RR [CI] Treatment Control Darban (RCT) 33% 0.67 [0.14-3.17] progression 2/10 3/10 CT​1 Hosseini 48% 0.52 [0.36-0.77] recov. time 20 (n) 20 (n) Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] ICU 0/24 2/20 Sánchez-González 54% 0.46 [0.28-0.71] death 24/224 53/224 Mousavi (RCT) 67% 0.33 [0.04-3.09] death 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] death 1/82 13/76 Tau​2 = 0.37; I​2 = 72.9% Late treatment 70% 0.30 [0.16-0.57] 28/604 74/1,150 70% improvement Jehi 58% 0.42 [0.26-0.68] cases 16/529 802/11,143 Improvement, RR [CI] Treatment Control Zhou (PSM) 21% 0.79 [0.65-0.94] cases Tau​2 = 0.17; I​2 = 83.5% Prophylaxis 40% 0.60 [0.33-1.11] 16/529 802/11,143 40% improvement All studies 64% 0.36 [0.22-0.58] 46/1,177 890/12,340 64% improvement 11 melatonin COVID-19 studies c19melatonin.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.37; I​2 = 83.7%; Z = 4.15 Effect extraction pre-specified, see appendix 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.
Results
Figure 3, 4, 5, 6, 7, 8, 9, and 10 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, ICU admission, hospitalization, progression, recovery, cases, and peer reviewed studies. Table 1 summarizes the results by treatment stage.
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 7 7 100% 70% improvement
RR 0.30 [0.16‑0.57]
p = 0.00024
Prophylaxis 2 2 100% 40% improvement
RR 0.60 [0.33‑1.11]
p = 0.1
All studies 11 11 100% 64% improvement
RR 0.36 [0.22‑0.58]
p < 0.0001
Table 1. Results by treatment stage.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Lissoni 91% 0.09 [0.01-1.57] hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Treatment Control Alizadeh (SB RCT) 73% 0.27 [0.07-1.05] no recov. 2/14 9/17 Tau​2 = 0.00; I​2 = 0.0% Early treatment 78% 0.22 [0.06-0.75] 2/44 14/47 78% improvement Ramlall 87% 0.13 [0.08-0.22] death 196 (n) 752 (n) Improvement, RR [CI] Treatment Control Darban (RCT) 33% 0.67 [0.14-3.17] progression 2/10 3/10 CT​1 Hosseini 48% 0.52 [0.36-0.77] recov. time 20 (n) 20 (n) Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] ICU 0/24 2/20 Sánchez-González 54% 0.46 [0.28-0.71] death 24/224 53/224 Mousavi (RCT) 67% 0.33 [0.04-3.09] death 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] death 1/82 13/76 Tau​2 = 0.37; I​2 = 72.9% Late treatment 70% 0.30 [0.16-0.57] 28/604 74/1,150 70% improvement Jehi 58% 0.42 [0.26-0.68] cases 16/529 802/11,143 Improvement, RR [CI] Treatment Control Zhou (PSM) 21% 0.79 [0.65-0.94] cases Tau​2 = 0.17; I​2 = 83.5% Prophylaxis 40% 0.60 [0.33-1.11] 16/529 802/11,143 40% improvement All studies 64% 0.36 [0.22-0.58] 46/1,177 890/12,340 64% improvement 11 melatonin COVID-19 studies c19melatonin.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.37; I​2 = 83.7%; Z = 4.15 Effect extraction pre-specified, see appendix Favors melatonin Favors control
Figure 3. 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 87% 0.13 [0.08-0.22] 196 (n) 752 (n) Improvement, RR [CI] Treatment Control Sánchez-González 54% 0.46 [0.28-0.71] 24/224 53/224 Mousavi (RCT) 67% 0.33 [0.04-3.09] 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] 1/82 13/76 Tau​2 = 0.60; I​2 = 78.9% Late treatment 79% 0.21 [0.08-0.56] 26/550 69/1,100 79% improvement All studies 79% 0.21 [0.08-0.56] 26/550 69/1,100 79% improvement 4 melatonin COVID-19 mortality results c19melatonin.com Nov 18, 2021 Tau​2 = 0.60; I​2 = 78.9%; Z = 3.14 Favors melatonin Favors control
Figure 4. Random effects meta-analysis for mortality results.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Darban (RCT) 6% 0.94 [0.84-1.06] 10 (n) 10 (n) CT​1 Improvement, RR [CI] Treatment Control Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] 0/24 2/20 Mousavi (RCT) 40% 0.60 [0.24-1.52] 6/48 10/48 Tau​2 = 0.00; I​2 = 0.6% Late treatment 7% 0.93 [0.81-1.06] 6/82 12/78 7% improvement All studies 7% 0.93 [0.81-1.06] 6/82 12/78 7% improvement 3 melatonin COVID-19 ICU results c19melatonin.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.00; I​2 = 0.6%; Z = 1.09 Favors melatonin Favors control
Figure 5. 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] hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment 91% 0.09 [0.01-1.57] 0/30 5/30 91% improvement All studies 91% 0.09 [0.01-1.57] 0/30 5/30 91% improvement 1 melatonin COVID-19 hospitalization result c19melatonin.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.00; I​2 = 0.0%; Z = 1.65 Favors melatonin Favors control
Figure 6. 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] 2/10 3/10 CT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% 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 Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.00; I​2 = 0.0%; Z = 0.51 Favors melatonin Favors control
Figure 7. 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] no recov. 2/14 9/17 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment 73% 0.27 [0.07-1.05] 2/14 9/17 73% improvement Hosseini 48% 0.52 [0.36-0.77] recov. time 20 (n) 20 (n) Improvement, RR [CI] Treatment Control Farnoosh (DB RCT) 49% 0.51 [0.32-0.81] recov. time 24 (n) 20 (n) Tau​2 = 0.00; I​2 = 0.0% Late treatment 48% 0.52 [0.39-0.70] 0/44 0/40 48% improvement All studies 50% 0.50 [0.38-0.67] 2/58 9/57 50% improvement 3 melatonin COVID-19 recovery results c19melatonin.com Nov 18, 2021 Tau​2 = 0.00; I​2 = 0.0%; Z = 4.68 Favors melatonin Favors control
Figure 8. 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] 16/529 802/11,143 Improvement, RR [CI] Treatment Control Zhou (PSM) 21% 0.79 [0.65-0.94] Tau​2 = 0.17; I​2 = 83.5% Prophylaxis 40% 0.60 [0.33-1.11] 16/529 802/11,143 40% improvement All studies 40% 0.60 [0.33-1.11] 16/529 802/11,143 40% improvement 2 melatonin COVID-19 case results c19melatonin.com Nov 18, 2021 Tau​2 = 0.17; I​2 = 83.5%; Z = 1.62 Favors melatonin Favors control
Figure 9. 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] hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Treatment Control Alizadeh (SB RCT) 73% 0.27 [0.07-1.05] no recov. 2/14 9/17 Tau​2 = 0.00; I​2 = 0.0% Early treatment 78% 0.22 [0.06-0.75] 2/44 14/47 78% improvement Darban (RCT) 33% 0.67 [0.14-3.17] progression 2/10 3/10 CT​1 Improvement, RR [CI] Treatment Control Hosseini 48% 0.52 [0.36-0.77] recov. time 20 (n) 20 (n) Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] ICU 0/24 2/20 Sánchez-González 54% 0.46 [0.28-0.71] death 24/224 53/224 Mousavi (RCT) 67% 0.33 [0.04-3.09] death 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] death 1/82 13/76 Tau​2 = 0.00; I​2 = 0.0% Late treatment 53% 0.47 [0.36-0.63] 28/408 74/398 53% improvement Jehi 58% 0.42 [0.26-0.68] cases 16/529 802/11,143 Improvement, RR [CI] Treatment Control Zhou (PSM) 21% 0.79 [0.65-0.94] cases Tau​2 = 0.17; I​2 = 83.5% Prophylaxis 40% 0.60 [0.33-1.11] 16/529 802/11,143 40% improvement All studies 52% 0.48 [0.33-0.68] 46/981 890/11,588 52% improvement 10 melatonin COVID-19 peer reviewed trials c19melatonin.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.13; I​2 = 62.4%; Z = 4.06 Effect extraction pre-specified, see appendix Favors melatonin Favors control
Figure 10. Random effects meta-analysis for peer reviewed studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
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 11 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] hosp. 0/30 5/30 CT​1 Improvement, RR [CI] Treatment Control Alizadeh (SB RCT) 73% 0.27 [0.07-1.05] no recov. 2/14 9/17 Tau​2 = 0.00; I​2 = 0.0% Early treatment 78% 0.22 [0.06-0.75] 2/44 14/47 78% improvement Ramlall 87% 0.13 [0.08-0.22] death 196 (n) 752 (n) Improvement, RR [CI] Treatment Control Darban (RCT) 33% 0.67 [0.14-3.17] progression 2/10 3/10 CT​1 Hosseini 48% 0.52 [0.36-0.77] recov. time 20 (n) 20 (n) Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] ICU 0/24 2/20 Mousavi (RCT) 67% 0.33 [0.04-3.09] death 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] death 1/82 13/76 Tau​2 = 0.66; I​2 = 75.6% Late treatment 74% 0.26 [0.11-0.63] 4/380 21/926 74% improvement Jehi 58% 0.42 [0.26-0.68] cases 16/529 802/11,143 Improvement, RR [CI] Treatment Control Zhou (PSM) 21% 0.79 [0.65-0.94] cases Tau​2 = 0.17; I​2 = 83.5% Prophylaxis 40% 0.60 [0.33-1.11] 16/529 802/11,143 40% improvement All studies 66% 0.34 [0.19-0.59] 22/953 837/12,116 66% improvement 10 melatonin COVID-19 studies after exclusions c19melatonin.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.45; I​2 = 84.7%; Z = 3.77 Effect extraction pre-specified, see appendix Favors melatonin Favors control
Figure 11. 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 12 and 13 show forest plots for a random effects meta-analysis of all Randomized Controlled Trials and RCT mortality results. Table 2 summarizes the results.
RCTs have a bias against finding an effect for interventions that are widely available — patients that believe they need the intervention are more likely to decline participation and take the intervention. This is illustrated with the extreme example of an RCT showing no significant differences for use of a parachute when jumping from a plane [Yeh]. RCTs for melatonin are more likely to enroll low-risk participants that do not need treatment to recover, making the results less applicable to clinical practice. This bias is likely to be greater for widely known treatments. Note that this bias does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable.
Evidence shows that non-RCT trials can also provide reliable results. [Concato] find that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. [Anglemyer] summarized reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. [Lee] shows that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or Internet survey bias could have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see [Deaton, Nichol].
Figure 14. Randomized Controlled Trials. The distribution of results for RCTs and other studies.
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] no recov. 2/14 9/17 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment 73% 0.27 [0.07-1.05] 2/14 9/17 73% improvement Darban (RCT) 33% 0.67 [0.14-3.17] progression 2/10 3/10 CT​1 Improvement, RR [CI] Treatment Control Farnoosh (DB RCT) 81% 0.19 [0.01-3.65] ICU 0/24 2/20 Mousavi (RCT) 67% 0.33 [0.04-3.09] death 1/48 3/48 Hasan (RCT) 93% 0.07 [0.01-0.53] death 1/82 13/76 Tau​2 = 0.02; I​2 = 2.1% Late treatment 72% 0.28 [0.10-0.78] 4/164 21/154 72% improvement All studies 72% 0.28 [0.12-0.63] 6/178 30/171 72% improvement 5 melatonin COVID-19 Randomized Controlled Trials c19melatonin.com Nov 18, 2021 1 CT: study uses combined treatmentTau​2 = 0.00; I​2 = 0.0%; Z = 3.09 Effect extraction pre-specified, see appendix Favors melatonin Favors control
Figure 12. 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] 1/48 3/48 Improvement, RR [CI] Treatment Control Hasan (RCT) 93% 0.07 [0.01-0.53] 1/82 13/76 Tau​2 = 0.02; I​2 = 1.5% Late treatment 86% 0.14 [0.03-0.64] 2/130 16/124 86% improvement All studies 86% 0.14 [0.03-0.64] 2/130 16/124 86% improvement 2 melatonin COVID-19 RCT mortality results c19melatonin.com Nov 18, 2021 Tau​2 = 0.02; I​2 = 1.5%; Z = 2.54 Favors melatonin Favors control
Figure 13. Random effects meta-analysis for RCT mortality results. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Randomized Controlled Trials 5 5 100% 72% improvement
RR 0.28 [0.12‑0.63]
p = 0.002
RCT mortality results 2 2 100% 86% improvement
RR 0.14 [0.03‑0.64]
p = 0.011
Table 2. 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]. Other medications might be beneficial for late stage complications, while early use may not be effective or may even be harmful. Figure 15 shows an example where efficacy declines as a function of treatment delay.
Figure 15. Effectiveness may depend critically on treatment delay.
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 thousands of different variants of SARS-CoV-2 and efficacy may depend critically on the distribution of variants encountered by the patients in a study.
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 a negative bias for inexpensive treatments for COVID-19. Both negative and positive results are very important for COVID-19, media in many countries prioritizes negative results for inexpensive treatments (inverting the typical incentive for scientists that value media recognition), and there are many reports of difficulty publishing positive results [Boulware, Meeus, Meneguesso]. For melatonin, there is currently not enough data to evaluate publication bias with high confidence.
One method to evaluate bias is to compare prospective vs. retrospective studies. Prospective studies are more likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For example, researchers may perform preliminary analysis with minimal effort and the results may influence their decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and adjustments to influence results.
The median effect size for retrospective studies is 56% improvement, compared to 73% for prospective studies, consistent with a negative publication bias. 100% of retrospective studies report a statistically significant positive effect, compared to 43% of prospective studies, consistent with a bias toward publishing positive results. Figure 16 shows a scatter plot of results for prospective and retrospective studies.
Figure 16. Prospective vs. retrospective studies.
Conflicts of interest.
Pharmaceutical drug trials often have conflicts of interest whereby sponsors or trial staff have a financial interest in the outcome being positive. Melatonin for COVID-19 lacks this because it is off-patent, has multiple manufacturers, and is very low cost. In contrast, most COVID-19 melatonin trials have been run by physicians on the front lines with the primary goal of finding the best methods to save human lives and minimize the collateral damage caused by COVID-19. While pharmaceutical companies are careful to run trials under optimal conditions (for example, restricting patients to those most likely to benefit, only including patients that can be treated soon after onset when necessary, and ensuring accurate dosing), not all melatonin trials represent the optimal conditions for efficacy.
Early/late vs. mild/moderate/severe.
Some analyses classify treatment based on early/late administration (as we do here), while others distinguish between mild/moderate/severe cases. We note that viral load does not indicate degree of symptoms — for example patients may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing of treatment is critical — late administration may be less helpful regardless of severity.
Notes.
2 of 11 studies combine treatments. The results of melatonin alone may differ. 1 of 5 RCTs use combined treatment.
Conclusion
Melatonin is an effective treatment for COVID-19. 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. Statistically significant improvements are seen for mortality and recovery. 7 studies show statistically significant improvements in isolation (6 for the most serious outcome).
Study Notes
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Recovery 73% Imp. Relative Risk, 95% CI Alizadeh: A Pilot Study on Controlling Coronavirus Disea.. c19melatonin.com/alizadeh.html Favors melatonin Favors control
[Alizadeh] Small RCT 31 mild/moderate COVID-19 outpatients in Iran, 14 treated with melatonin, showing improved recovery with treatment. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Disease progression 33% Imp. Relative Risk, 95% CI ICU time 6% Darban: Efficacy of High Dose Vitamin C, Melatonin and.. c19melatonin.com/darban.html Favors melatonin Favors control
[Darban] Small RCT in Iran with 20 ICU patients, 10 treated with high-dose vitamin C, melatonin, and zinc, not showing significant differences. IRCT20151228025732N52. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ ICU admission 81% Imp. Relative Risk, 95% CI Recovery time 49% Hospital discharge 44% Time to discharge 43% Farnoosh: Efficacy of a Low Dose of Melatonin as an Adju.. c19melatonin.com/farnoosh.html Favors melatonin Favors control
[Farnoosh] RCT 44 hospitalized patients in Iran, 24 treated with melatonin, showing faster recovery with treatment. There was no mortality. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mortality 93% Imp. Relative Risk, 95% CI Hasan: The Effect of Melatonin on Thrombosis, Sepsis .. c19melatonin.com/hasan.html Favors melatonin Favors control
[Hasan] RCT 158 severe condition patients in Iraq, 82 treated with melatonin, showing lower mortality, thrombosis, and sepsis with treatment. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Recovery time 48% Imp. Relative Risk, 95% CI Hosseini: Evaluation of Th1 and Th2 mediated cellular an.. c19melatonin.com/hosseini.html Favors melatonin Favors control
[Hosseini] 40 hospitalized patients in Iran, 20 treated with melatonin, showing faster recovery and attenuated inflammatory cytokines with treatment. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Case 58% Imp. Relative Risk, 95% CI Case (b) 100% Jehi: Individualizing Risk Prediction for Positive C.. c19melatonin.com/jehi.html Favors melatonin Favors control
[Jehi] Retrospective 11,672 patients tested for COVID-19, 818 that tested positive, showing significantly lower risk with melatonin use. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Hospitalization 91% Imp. Relative Risk, 95% CI Lissoni: COVID-19 Disease as an Acute Angiotensin 1-7 D.. c19melatonin.com/lissoni.html Favors melatonin Favors control
[Lissoni] 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. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mortality 67% Imp. Relative Risk, 95% CI ICU admission 40% Mousavi: Melatonin effects on sleep quality and outcome.. c19melatonin.com/mousavi.html Favors melatonin Favors control
[Mousavi] 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. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mortality 87% Imp. Relative Risk, 95% CI Ramlall: Melatonin is significantly associated with sur.. c19melatonin.com/ramlall.html Favors melatonin Favors control
[Ramlall] Retrospective 948 intubated patients, 196 treated with melatonin, showing lower mortality with treatment. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mortality 54% Imp. Relative Risk, 95% CI Sánchez-González: What if melatonin could help COVID-19 severe p.. c19melatonin.com/sanchezgonzalez.html Favors melatonin Favors control
[Sánchez-González] 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. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Case 21% Imp. Relative Risk, 95% CI Zhou: A network medicine approach to investigation a.. c19melatonin.com/zhou2.html Favors melatonin Favors control
[Zhou] PSM observational study with a database of 26,779 patients in the USA, showing significantly lower risk of PCR+ with melatonin usage. Submit Corrections or Updates.
We performed ongoing searches of PubMed, medRxiv, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Collabovid, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19melatonin.com. Search terms were melatonin, filtered for papers containing the terms COVID-19, SARS-CoV-2, or coronavirus. Automated searches are performed every few hours with notification of new matches. All studies regarding the use of melatonin for COVID-19 that report a comparison with a control group are included in the main analysis. Sensitivity analysis is performed, excluding studies with major issues, epidemiological studies, and studies with minimal available information. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in calculations for that study. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days are used. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms were not used (the next most serious outcome is used — no studies were excluded). For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcome is considered more important than PCR testing status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available (after most or all patients have recovered there is no room for an effective treatment to do better). If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we computed the relative risk when possible, or converted to a relative risk according to [Zhang]. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported including propensity score matching (PSM), the PSM results are used. When needed, conversion between reported p-values and confidence intervals followed [Altman, Altman (B)], and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 1 [Sweeting]. Results are expressed with RR < 1.0 favoring treatment, and using the risk of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time for the control group is used. Calculations are done in Python (3.9.7) with scipy (1.7.1), pythonmeta (1.23), numpy (1.21.2), statsmodels (0.13.0), and plotly (5.3.1).
Forest plots are computed using PythonMeta [Deng] with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case) and inverse variance weighting. None
We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.
We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment, and treatment started within 5 days of the onset of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time of patients contributing most to the events (for example, consider a study where most patients are treated early but late treatment patients are included, and all mortality events were observed with late treatment patients). We note that a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective [McLean, Treanor].
A summary of study results is below. Please submit updates and corrections at the bottom of this page.
A summary of study results is below. Please submit updates and corrections at https://c19melatonin.com/meta.html.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in calculations, which may differ from the effect a paper focuses on.
[Alizadeh], 5/29/2021, Single Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 6 authors. 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%), day 14.
[Lissoni], 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. risk of hospitalization, 90.9% lower, RR 0.09, p = 0.05, treatment 0 of 30 (0.0%), control 5 of 30 (16.7%), relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in calculations, which may differ from the effect a paper focuses on.
[Darban], 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. risk of disease progression, 33.3% lower, RR 0.67, p = 1.00, treatment 2 of 10 (20.0%), control 3 of 10 (30.0%).
ICU time, 6.0% lower, relative time 0.94, p = 0.30, treatment 10, control 10.
[Farnoosh], 6/23/2021, Double Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 12 authors. 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%), relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
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%).
time to discharge, 42.9% lower, relative time 0.57, p = 0.02, treatment 24, control 20.
[Hasan], 10/12/2021, Randomized Controlled Trial, Iraq, Middle East, peer-reviewed, 3 authors. risk of death, 92.9% lower, RR 0.07, p < 0.001, treatment 1 of 82 (1.2%), control 13 of 76 (17.1%).
[Hosseini], 5/17/2021, prospective, Iran, Middle East, peer-reviewed, 9 authors. recovery time, 47.6% lower, relative time 0.52, p = 0.001, treatment 20, control 20.
[Mousavi], 8/30/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 7 authors. risk of death, 66.7% lower, RR 0.33, p = 0.62, treatment 1 of 48 (2.1%), control 3 of 48 (6.2%), 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%), day 10.
[Ramlall], 10/18/2020, retrospective, USA, North America, preprint, 3 authors. risk of death, 86.9% lower, RR 0.13, p < 0.001, treatment 196, control 752, multivariate model Cox proportional hazards.
[Sánchez-González], 7/20/2021, retrospective, Spain, Europe, peer-reviewed, 4 authors, excluded in exclusion analyses: immortal time bias may significantly affect results. risk of death, 54.4% lower, RR 0.46, p < 0.001, treatment 24 of 224 (10.7%), control 53 of 224 (23.7%), odds ratio converted to relative risk, PSM.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in calculations, which may differ from the effect a paper focuses on.
[Jehi], 6/10/2020, retrospective, USA, North America, peer-reviewed, 8 authors. 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%), 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%), relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), Florida validation cohort.
[Zhou], 11/6/2020, retrospective, propensity score matching, USA, North America, peer-reviewed, 18 authors. 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%), odds ratio converted to relative risk, PSM.
References
Please send us corrections, updates, or comments. Vaccines and treatments are both extremely valuable and complementary. All practical, effective, and safe means should be used. Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. Denying the efficacy of any method increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. Treatment protocols for physicians are available from the FLCCC.
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