Methylene blue attracted attention early in the COVID-19 pandemic as a potential low-cost, repurposed therapy. Several open-label randomized controlled trials were run in Iran in 2020, mostly in hospitalized patients with severe disease, and laboratory researchers separately found a plausible antiviral mechanism. Neither line of evidence turned methylene blue into a standard-of-care treatment, but both are worth understanding on their own terms rather than through pandemic-era headlines.
Key Takeaways
- A phase 2 randomized, controlled, open-label trial in 80 hospitalized COVID-19 patients found methylene blue added to standard care significantly improved oxygen saturation and respiratory rate within 3 to 5 days.
- In that trial, hospital stay was significantly shorter in the methylene blue group, and mortality was 12.5% versus 22.5% in the standard-care-only group.
- Separate laboratory research found methylene blue inhibits the interaction between the SARS-CoV-2 spike protein and the ACE2 receptor that the virus uses to enter human cells, a plausible antiviral mechanism distinct from its clinical trial results.
- Nearly all of the clinical trials were open-label and conducted at a small number of hospitals in Iran, which limits how confidently the findings generalize.
- Methylene blue is not an approved or recommended treatment for COVID-19 in the United States; this remains hypothesis-generating research, not a basis for self-treatment.
What the Phase 2 Hospitalized-Patient Trial Actually Tested
The most-cited methylene blue COVID-19 trial was a randomized, controlled, open-label phase 2 study conducted at hospitals affiliated with Mashhad University of Medical Sciences in Iran. Eighty hospitalized patients with severe COVID-19 were randomly assigned to receive either oral methylene blue added to standard of care, or standard of care alone[1]. The primary outcomes were oxygen saturation (SpO2) and respiratory rate on day 3 and day 5 of treatment.
The methylene blue group showed a significant improvement in both measures at both time points, while the standard-care-only group showed no significant improvement on day 3 and only modest improvement by day 5. Researchers reported the rate ratio of SpO2 improvement was more than 13 times higher in the methylene blue group on day 3. Secondary outcomes followed the same direction: hospital stay was significantly shorter in the methylene blue group, and 28-day mortality was 12.5% in the methylene blue group compared to 22.5% in the standard-care group. A related, larger open-label trial from the same research group, run with 223 hospitalized patients, reported a similar pattern, average hospital stay of roughly 6 days in the methylene blue group versus roughly 11 days in the standard-care group.
The Antiviral Mechanism: Blocking Spike-ACE2 Binding
Separately from the clinical trials, laboratory researchers screened a panel of compounds for the ability to block the interaction between the SARS-CoV-2 spike protein and ACE2, the receptor on human cells that the virus binds to as the first step of infection. Methylene blue inhibited this protein-protein interaction in a concentration-dependent way, with a half-maximal inhibitory concentration (IC50) of roughly 3 micromolar in a cell-free binding assay[2]. In a follow-up cell-based experiment, methylene blue also reduced entry of a pseudovirus carrying the SARS-CoV-2 spike protein into ACE2-expressing cells at a similar concentration.
This is a genuinely different line of evidence from the clinical trials above. The clinical trials measured real-world outcomes in sick, hospitalized patients; this laboratory work identifies a specific molecular mechanism that could plausibly contribute to an antiviral effect, tested in isolated proteins and cell culture rather than in people. Neither study alone proves the other, but together they offer a coherent, if still incomplete, picture of why researchers investigated methylene blue for COVID-19 in the first place.
Why Open-Label and Small Sample Size Matter for How Seriously to Take This
Open-label means both patients and treating clinicians knew who received methylene blue, which introduces the possibility that care decisions, patient reporting, or outcome assessment were subtly influenced by that knowledge, even without anyone intending bias. This is a materially weaker design than a blinded, placebo-controlled trial. A smaller phase II trial did run with proper blinding and a placebo capsule, focused primarily on viral load kinetics rather than the oxygenation and mortality outcomes reported above, and its detailed published results are less widely cited than the open-label hospitalized-patient trials.
The trials were also run at a limited number of hospitals within one country’s healthcare system during a specific, early phase of the pandemic, before vaccination, before the emergence of later variants, and before many current standard-of-care treatments existed. Results from that setting do not automatically transfer to COVID-19 as it presents today, in a vaccinated population, treated with modern standard-of-care protocols.
Where This Leaves Anyone Considering Methylene Blue for COVID-19
Methylene blue is not an FDA-approved or clinically recommended treatment for COVID-19, and no major treatment guideline currently lists it as standard or adjunct therapy. The existing trials are best understood as hypothesis-generating: promising enough to justify further, better-controlled research, not strong enough to establish methylene blue as an effective COVID-19 treatment on their own. Methylene blue also carries real contraindications, most notably G6PD deficiency, MAOI and serotonergic drug interactions, and the need for medical supervision at any but the lowest doses, all of which matter more, not less, in someone who is already acutely ill.
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Frequently Asked Questions
Is methylene blue an approved treatment for COVID-19?
No. Methylene blue is not FDA-approved or included in standard COVID-19 treatment guidelines. The clinical trials described here are early-phase, open-label research, not the basis for an approved indication.
Did the clinical trials show methylene blue reduces COVID-19 mortality?
The phase 2 hospitalized-patient trial reported lower mortality in the methylene blue group (12.5%) compared to standard care alone (22.5%), but the trial was open-label and conducted at a small number of hospitals, which limits how confidently that finding can be generalized.
How is methylene blue thought to work against SARS-CoV-2?
Laboratory research found methylene blue can block the binding between the SARS-CoV-2 spike protein and the ACE2 receptor human cells use for viral entry, a mechanism separate from its use in treating methemoglobinemia or its proposed mitochondrial effects.
Should someone take methylene blue if they have COVID-19?
This is a medical decision that should involve a physician, particularly because methylene blue has significant contraindications (including G6PD deficiency and serotonergic drug interactions) that are especially important to screen for in someone who is acutely ill.
References
- Methylene Blue for Treatment of Hospitalized COVID-19 Patients: A Randomized, Controlled, Open-Label Clinical Trial, Phase 2. PMID 34019535
- Methylene Blue Inhibits the SARS-CoV-2 Spike-ACE2 Protein-Protein Interaction-a Mechanism that can Contribute to its Antiviral Activity Against COVID-19. PMID 33519460
These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease. Content is for informational purposes only and is not medical advice; consult a qualified healthcare provider before starting any supplement. As an Amazon Associate we earn from qualifying purchases.