Methylene Blue: Benefits, Dosage and Side Effects 2025
What Is Methylene Blue?
Methylene blue is the parent molecule for hydroxychloroquine and chloroquine,
off-patent drugs commonly used to treat not only malaria but also COVID-19.
Best known as a fish tank antiseptic and textile dye for blue jeans, it was
actually the first synthetic drug in modern history, developed in 1876. Since
then, we’ve discovered it has many really important medicinal benefits.
The first medical application of methylene blue was for malaria. In 1890, Paul Ehrlich, a scientist at the famous Charité Hospital in Berlin, Germany, discovered methylene blue inhibits an enzyme that weakens the malaria parasite.
One of the first antipsychotic medications was also made from methylene blue. Other drugs developed from or with it include antibiotics and antiseptics. In the past, it was commonly used to treat urinary tract infections. It’s also been used as an antiviral agent in blood used for transfusions.
To this day, methylene blue is found in every hospital in the world, as it’s the only known antidote for metabolic poisons (any poison that interferes with oxygen transport or displaces oxygen, either from the blood or from the mitochondria).
For example, if you’re admitted for carbon monoxide poisoning, they’ll give you methylene blue intravenously. Cyanide is another example. The only known antidote for cyanide poisoning is methylene blue. It’s also been speculated that methylene blue might be useful in the treatment of acute lung infections such as SARS-CoV-2.
Importantly, methylene blue is a hormetic drug, which means that low doses have the opposite effect as high doses. For example, it’s primarily used in emergency rooms at the upper dosage limit (3 milligrams to 4 mg per kilo of bodyweight) for methemoglobinemia, which is when a metabolic poison interferes with the transport of oxygen in hemoglobin, by the iron in hemoglobin being oxidized to +3 rather than its normal reduced +2 state.
However, if you take too high a dose, you produce methemoglobinemia. At dosages in between, there’s no effect. Likewise, while low dosages have an antioxidant effect, high doses are pro-oxidative and can kill bacteria and tumor cells.
Basically, as an electron cycler, methylene blue acts like a battery, but unlike other compounds that do the same thing, it doesn’t cause damaging oxidation in the process. If anything interferes with oxygenation or cellular respiration, such as cyanide, methylene blue is able to bypass that point of interference through electron cycling, thus allowing mitochondrial respiration, oxygen consumption and energy production to function as it normally would.
According to a study of two case reports published in Medicine, methemoglobinemia can be treated using methylene blue. Methemoglobinemia is a potentially fatal condition in which hemoglobin loses its ability to carry oxygen to body tissues.
Healthy blood flow is also particularly important for brain function, and many older people have chronic hypoperfusion that contributes to neurodegeneration and memory problems. These issues, Gonzalez-Lima says, can be prevented by methylene blue.
In summary, inside the electron transport chain in your mitochondria are five complexes, the primary purpose of which is to conduct the electrons generated from food, primarily carbohydrates and fat, in the form of acetyl CoA. Sometimes the electron transport chain gets blocked or impaired, and methylene blue is able to bypass such blockages.
In biohacker circles, low-dose methylene blue is used as a nootropic,
meaning a compound that helps improve cognitive function. However, while
some promote sublingual or buccal application (under your tongue or on the
inside of your cheek), the best way is to swallow it, as the acid in your
stomach makes it more bioavailable.
One of the first antipsychotic medications was also made from methylene blue. Other drugs developed from or with it include antibiotics and antiseptics. In the past, it was commonly used to treat urinary tract infections. It’s also been used as an antiviral agent in blood used for transfusions.
To this day, methylene blue is found in every hospital in the world, as it’s the only known antidote for metabolic poisons (any poison that interferes with oxygen transport or displaces oxygen, either from the blood or from the mitochondria).
For example, if you’re admitted for carbon monoxide poisoning, they’ll give you methylene blue intravenously. Cyanide is another example. The only known antidote for cyanide poisoning is methylene blue. It’s also been speculated that methylene blue might be useful in the treatment of acute lung infections such as SARS-CoV-2.
Importantly, methylene blue is a hormetic drug, which means that low doses have the opposite effect as high doses. For example, it’s primarily used in emergency rooms at the upper dosage limit (3 milligrams to 4 mg per kilo of bodyweight) for methemoglobinemia, which is when a metabolic poison interferes with the transport of oxygen in hemoglobin, by the iron in hemoglobin being oxidized to +3 rather than its normal reduced +2 state.
However, if you take too high a dose, you produce methemoglobinemia. At dosages in between, there’s no effect. Likewise, while low dosages have an antioxidant effect, high doses are pro-oxidative and can kill bacteria and tumor cells.
Methylene Blue, an Antioxidant and Energy Producer
Gonzalez-Lima’s research has primarily focused on low-dose benefits for
nonacute purposes over the longer term — such as neuroprotective benefits
and cognitive enhancement. While it has several mechanisms of action, a
unique feature is that it acts on the level of electrons. He explains:
“Our body uses electrons as part of the electron transport chain that happens inside mitochondria, and these electrons, moved along through the mitochondria, are generated from electron donors that we produce by the foods that we eat.
All the foods that we eat, the only way they contribute to energy is by producing electron donors. They donate these electrons to the electron transport inside the mitochondria. The ultimate electron acceptor in nature is oxygen. That's why the process of removing electrons from a compound is referred to as oxidation.
In mitochondria, this process is called oxidative phosphorylation. The electron transport is coupled with the phosphorylation of adenosine to eventually produce the adenosine triphosphate molecule (ATP). Methylene blue is an electron cycler. It's an autooxidizing compound.
So, methylene blue donates its electrons directly to the electron transport chain, it obtains electrons from surrounding compounds, and maintains oxygen consumption and energy production. By doing this, it helps oxygen to be fully reduced into water.
So, it becomes two things that are often not found together. It acts as an antioxidant, because oxygen is neutralized into water by donating electrons to the electron transport, and it produces energy, because when the electron transport pumps are moving along oxidative phosphorylation, you have an increase in ATP formation.
Oftentimes, we have things that improve energy metabolism, but then they lead to oxidative stress. In the case of methylene blue, that's not the case.
You can increase oxygen consumption rates, increase ATP production for energy metabolism, and at the same time reduce oxidative stress which, of course, will lead to reduction in oxidative damage at the level of mitochondria, then at the level of the other parts of the cells, and eventually membranes of the cells, and reactions that are cascades of this oxidative damage.”
“Our body uses electrons as part of the electron transport chain that happens inside mitochondria, and these electrons, moved along through the mitochondria, are generated from electron donors that we produce by the foods that we eat.
All the foods that we eat, the only way they contribute to energy is by producing electron donors. They donate these electrons to the electron transport inside the mitochondria. The ultimate electron acceptor in nature is oxygen. That's why the process of removing electrons from a compound is referred to as oxidation.
In mitochondria, this process is called oxidative phosphorylation. The electron transport is coupled with the phosphorylation of adenosine to eventually produce the adenosine triphosphate molecule (ATP). Methylene blue is an electron cycler. It's an autooxidizing compound.
So, methylene blue donates its electrons directly to the electron transport chain, it obtains electrons from surrounding compounds, and maintains oxygen consumption and energy production. By doing this, it helps oxygen to be fully reduced into water.
So, it becomes two things that are often not found together. It acts as an antioxidant, because oxygen is neutralized into water by donating electrons to the electron transport, and it produces energy, because when the electron transport pumps are moving along oxidative phosphorylation, you have an increase in ATP formation.
Oftentimes, we have things that improve energy metabolism, but then they lead to oxidative stress. In the case of methylene blue, that's not the case.
You can increase oxygen consumption rates, increase ATP production for energy metabolism, and at the same time reduce oxidative stress which, of course, will lead to reduction in oxidative damage at the level of mitochondria, then at the level of the other parts of the cells, and eventually membranes of the cells, and reactions that are cascades of this oxidative damage.”
Basically, as an electron cycler, methylene blue acts like a battery, but unlike other compounds that do the same thing, it doesn’t cause damaging oxidation in the process. If anything interferes with oxygenation or cellular respiration, such as cyanide, methylene blue is able to bypass that point of interference through electron cycling, thus allowing mitochondrial respiration, oxygen consumption and energy production to function as it normally would.
Improves Mitochondrial Respiration
Methylene blue can also be helpful in instances where you have impaired blood flow that prevents the delivery of oxygenated hemoglobin to the tissues. In this case, methylene blue helps counteract the reduced blood flow by optimizing the efficiency of mitochondrial respiration.According to a study of two case reports published in Medicine, methemoglobinemia can be treated using methylene blue. Methemoglobinemia is a potentially fatal condition in which hemoglobin loses its ability to carry oxygen to body tissues.
Healthy blood flow is also particularly important for brain function, and many older people have chronic hypoperfusion that contributes to neurodegeneration and memory problems. These issues, Gonzalez-Lima says, can be prevented by methylene blue.
In summary, inside the electron transport chain in your mitochondria are five complexes, the primary purpose of which is to conduct the electrons generated from food, primarily carbohydrates and fat, in the form of acetyl CoA. Sometimes the electron transport chain gets blocked or impaired, and methylene blue is able to bypass such blockages.
When you’re perfectly healthy, low doses of methylene blue will enhance
oxygen consumption, mitochondrial respiration and ATP production above
baseline, basically optimizing the whole system. So, it acts as a
metabolic enhancer and not just an antidote for metabolic poisons and
other inhibitory processes.
The most important complex, Cytochrome c Oxidase, which catalyzes the reaction of oxygen becoming water, is blocked by cyanide. But methylene blue can insert electrons wherever there is a blockage.
What’s more, when you’re perfectly healthy, low doses of methylene blue will enhance oxygen consumption, mitochondrial respiration and ATP production above baseline, basically optimizing the whole system. So, it acts as a metabolic enhancer and not just an antidote for metabolic poisons and other inhibitory processes.
Methylene blue’s action on mitochondrial respiration is also coupled with biochemical upregulation of your oxygen consumption machinery in general, and hemodynamic processes that increase local blood supply to tissues.
And, as detailed by Gonzalez-Lima in the interview, this upregulation remains even after the methylene blue is expelled from your system (primarily through urination unchanged as your body minimally metabolizes it), and over time, it can actually increase the number of mitochondria. In your brain, this will benefit cognition, as your brain is the most energy-dependent organ in your body.
Methylene blue also activates the Nrf2 pathway. Nrf2 is a transcription factor that, when activated, goes into the cell’s nucleus and binds to the antioxidant response element (AREs) in the DNA. It then induces the transcription of further cytoprotective enzymes such as glutathione, superoxide dismutase catalase, glutathione peroxidase, phase II enzymes, heme-1 oxygenase and many others.
“Any process where increasing oxygen-based energy production plays a
major role, methylene blue will have a role to play. One of the first
studies we did that was very impressive [was on] a model in the eye. The
reason we used the eye was because the retina in animals is readily
accessible so that we can inject into the retina. Rotenone [a
broad-spectrum pesticide and Complex 1 inhibitor] inhibits mitochondrial
respiration, subsequently there is atrophy and degeneration of the
retinal layer, which is very dramatic. If methylene blue is on board, we
can prevent this process because the mitochondrial respiration can
continue, so the tissue is not affected.
This was a model called an optic neuropathy due to mitochondrial defects. It’s the most common form of blindness in younger people, so we did this to verify in vivo that [methylene blue] could have this neuroprotective effect. Then we did it in other things like brains. We found a similar phenomenon ...
Methylene blue can be protective in ischemic and hemorrhagic strokes. We’ve also published a study with a hypoxia. In other words, we reduced the amount of oxygen delivered to the animals, and we could use an fMRI, noninvasively, in the animals to see that we were able to increase the amount of cerebral metabolic rate for oxygen consumption in the presence of methylene blue under hypoxic conditions.
With respect to dementia, by the time you see the tau protein inside neurons, those neurons are metabolically, essentially, dead, so it is too late. By acting on that, you cannot recover the metabolic machinery and the health of the neurons.
So, those neurons are not rescued in any way that is functionally meaningful. Generally speaking, biomarkers are not good therapeutic targets because they may or may not have any causal relationship with the disease.”
The most important complex, Cytochrome c Oxidase, which catalyzes the reaction of oxygen becoming water, is blocked by cyanide. But methylene blue can insert electrons wherever there is a blockage.
What’s more, when you’re perfectly healthy, low doses of methylene blue will enhance oxygen consumption, mitochondrial respiration and ATP production above baseline, basically optimizing the whole system. So, it acts as a metabolic enhancer and not just an antidote for metabolic poisons and other inhibitory processes.
Methylene blue’s action on mitochondrial respiration is also coupled with biochemical upregulation of your oxygen consumption machinery in general, and hemodynamic processes that increase local blood supply to tissues.
And, as detailed by Gonzalez-Lima in the interview, this upregulation remains even after the methylene blue is expelled from your system (primarily through urination unchanged as your body minimally metabolizes it), and over time, it can actually increase the number of mitochondria. In your brain, this will benefit cognition, as your brain is the most energy-dependent organ in your body.
Methylene blue also activates the Nrf2 pathway. Nrf2 is a transcription factor that, when activated, goes into the cell’s nucleus and binds to the antioxidant response element (AREs) in the DNA. It then induces the transcription of further cytoprotective enzymes such as glutathione, superoxide dismutase catalase, glutathione peroxidase, phase II enzymes, heme-1 oxygenase and many others.
Methylene Blue for Brain Health
Perhaps one of the most revolutionary benefits of methylene blue is for
the prevention and treatment of dementia, neurodegenerative diseases
such as
Alzheimer’s
and Parkinson’s, and neural injuries caused by stroke and traumatic
brain injuries (TBIs).
A March 2024 review published in Reviews in the Neurosciences explores the use of methylene blue as a therapeutic agent for traumatic brain injury (TBI), which is characterized by damage to brain tissue from an external force. TBI damage leads to a cascade of neurodegenerative processes that continue long after the initial injury.
This is particularly important as the COVID jabs
have radically increased strokes. As explained by Gonzalez-Lima:
This was a model called an optic neuropathy due to mitochondrial defects. It’s the most common form of blindness in younger people, so we did this to verify in vivo that [methylene blue] could have this neuroprotective effect. Then we did it in other things like brains. We found a similar phenomenon ...
Methylene blue can be protective in ischemic and hemorrhagic strokes. We’ve also published a study with a hypoxia. In other words, we reduced the amount of oxygen delivered to the animals, and we could use an fMRI, noninvasively, in the animals to see that we were able to increase the amount of cerebral metabolic rate for oxygen consumption in the presence of methylene blue under hypoxic conditions.
With respect to dementia, by the time you see the tau protein inside neurons, those neurons are metabolically, essentially, dead, so it is too late. By acting on that, you cannot recover the metabolic machinery and the health of the neurons.
So, those neurons are not rescued in any way that is functionally meaningful. Generally speaking, biomarkers are not good therapeutic targets because they may or may not have any causal relationship with the disease.”
The doses used in the trials ranged from 69 to 250 milligrams per day. The “placebos” contained 8 milligrams per day in order to turn the subjects’ urine the same color.
An observational study nested in the two phase III trials plotted the cognitive decline scores at week 65 against the maximum concentration of methylene blue and its metabolites in the plasma of the 8 mg “placebo” members 3.5 hours after their first dose. It found that cognitive decline scores improved in the range of 0.3-0.5 ng/mL and then leveled off.
Mitochondrial-Specific Antioxidants Improve Skin Cell Aging
It’s well-known that antioxidants are potent combatants that help protect the skin and slow aging.
According to a study from the University of Maryland published in the peer-reviewed journal Scientific Reports (Nature 2017), methylene blue was better and safer than mitochondrial-specific antioxidants in reducing mitochondrial dysfunction and promoting new cell generation.
Researchers tested methylene blue using skin cells from healthy middle-aged donors and those diagnosed with a rare genetic disease, progeria, that causes children to age rapidly. Methylene blue outperformed three other antioxidants and improved age-related symptoms in the cells of both progeria patients and healthy donors.
Over the four-week experimental treatment, skin cells had decreased cellular damage due to oxidative stress, a reduced rate of cell death, and increased cell division. According to the researchers, the methylene blue stimulated mitochondrial health and addressed the root cause of skin aging.
“Our work suggests that methylene blue could be a powerful antioxidant for use in skin care products,” Kan Cao, senior study author and associate professor of cell biology and molecular genetics at the University of Maryland, said in a news release. “The effects we are seeing are not temporary. Methylene blue appears to make fundamental, long-term changes to skin cells.”
Not long after the study was published, Ms. Cao launched a line of skin care products based on the research. “Human aging is deeply connected to the function of the mitochondria and our cellular reproduction,” she said in a different press statement. “In fact, mitochondrial mutations [are associated] with many age-related diseases.”
According to a study from the University of Maryland published in the peer-reviewed journal Scientific Reports (Nature 2017), methylene blue was better and safer than mitochondrial-specific antioxidants in reducing mitochondrial dysfunction and promoting new cell generation.
Researchers tested methylene blue using skin cells from healthy middle-aged donors and those diagnosed with a rare genetic disease, progeria, that causes children to age rapidly. Methylene blue outperformed three other antioxidants and improved age-related symptoms in the cells of both progeria patients and healthy donors.
Over the four-week experimental treatment, skin cells had decreased cellular damage due to oxidative stress, a reduced rate of cell death, and increased cell division. According to the researchers, the methylene blue stimulated mitochondrial health and addressed the root cause of skin aging.
“Our work suggests that methylene blue could be a powerful antioxidant for use in skin care products,” Kan Cao, senior study author and associate professor of cell biology and molecular genetics at the University of Maryland, said in a news release. “The effects we are seeing are not temporary. Methylene blue appears to make fundamental, long-term changes to skin cells.”
Not long after the study was published, Ms. Cao launched a line of skin care products based on the research. “Human aging is deeply connected to the function of the mitochondria and our cellular reproduction,” she said in a different press statement. “In fact, mitochondrial mutations [are associated] with many age-related diseases.”
Methylene Blue for Cancer
Methylene Blue in Glioblastoma (Brain Cancer)
Dr William Makis shared on X/Twitter in Feb 2025:
2013 Poteet et al - Reversing the Warburg Effect as a Treatment for Glioblastoma (PubMed).
"Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in Glioblastoma cell lines"
"Methylene Blue decreases Glioblastoma cell proliferation and halts the cell cycle in S phase."
Methylene Blue inhibits cell proliferation in both temozolomide-sensitive and -insensitive GBM cell lines (wow!!!)
Methylene Blue
Methylene blue (MB), synthesized in 1876, has been in clinical application for more than a century in diagnostic procedures and as a treatment of multiple disorders such as methemoglobinemia, malaria, ifosfamide neurotoxicity, and cyanide poisoning
There is mounting evidence that MB enhances brain metabolism and exerts neuroprotective effects in multiple neurodegenerative disease models including Parkinson, Alzheimer, and Huntington disease
In the current study we tested the hypothesis that reversal of the Warburg effect by MB inhibits GBM cell proliferation.
More than 90 years ago, Warburg hypothesized that cancers may be caused by increased glycolysis and impaired respiration based on observations that tumor tissue actively metabolizes glucose and produces excessive lactic acid while exhibiting a comparably low respiratory rate
Recent findings suggest that reinstating normal oxidative phosphorylation in cancer cells may not only inhibit cell growth and proliferation but also impair the metastatic capacity of malignant cells
Acute Methylene Blue treatment dramatically increases oxygen consumption rate (OCR) and decreases extracellular acidification rate (ECAR) in U87 Glioblastoma cells.
Reversal of the Warburg effect was associated with a reduction of U87 cell proliferation, evidenced by the cell growth curve, liquid colony formation, and soft agar colony formation assays
CANCER NEEDS:
Glioblastoma cells, like other cancers, face two major metabolic challenges, bioenergetic and biosynthetic demands of rapid cell proliferation
It has been proposed that the fundamental metabolic switch may confer to cancer cells a selective advantage during growth and proliferation
Glucose not only provides the major fuel for ATP synthesis through glycolysis and mitochondrial oxidative phosphorylation
but glucose also provides the backbone for intermediates needed in biosynthetic pathways, including ribose sugars for nucleotides, glycerol and citrate for lipids, nonessential amino acids, and NADPH through the oxidative pentose phosphate pathway
Besides serving as the major bioenergetic hub, mitochondria also provide metabolites for macromolecule synthesis to meet the biosynthetic demand of a proliferating cancer cell
We predict that Methylene Blue reverses the Warburg effect and switches mitochondria from a biosynthetic hub back to a predominantly bioenergetic hub in GBM cells, thus decreasing metabolic intermediates and inhibiting cancer proliferation. This notion is supported by our data that MB increases ATP production, decreases NADPH, and arrests cancer cells in S phase (!!!)
MB enhances oxygen consumption rate and extracellular acidification rate in glioma cells immediately after treatment
TEMOZOLOMIDE
TMZ is currently one of the primary chemotherapies for GBM
TMZ is a prodrug that decomposes into a drug which disrupts GBM cell division by heavily alkylating and methylating DNA
Resistance to TMZ develops when cells increase expression of certain enzymes.
We tested the effect of MB on both TMZ-sensitive and TMZ-resistant GBM cell lines, U87 and T98G, respectively.
As predicted, TMZ arrests U87 cell cycle at M phase.
Methylene Blue induced cell cycle arrest in S phase and inhibited cell proliferation of both U87 and T98G cells.
Similarly, Methylene Blue increased OCR, decreased ECAR, and activated the AMPK signaling pathway in T98G cells.
These data suggested that Methylene Blue might be effective in both TMZ-sensitive and -resistant GBMs.
Our study indicated that MB and TMZ arrest GBM cells at different stages of the cell cycle; thus, an additive effect on GBM proliferation might be achievable with a combination therapy of MB and TMZ.
A slight additive action was indeed observed in the combination therapy of MB and TMZ in the liquid colony formation assay; therefore, we predict that combination therapy of MB and TMZ might be able to decrease the necessary dose of each drug, reducing the side effects while still achieving the maximal inhibitory effect on GBM progression.
CONCLUSION:
Our current study demonstrated that Methylene Blue exerts profound action on GBM bioenergetics.
Methylene Blue inhibits GBM cells proliferation and arrests the cell cycle in S phase
The effect of MB on GBM proliferation intertwined with the activation of AMPK and its downstream signaling of ACC and cyclin expression
By reversing the Warburg effect, Methylene Blue switches the mitochondria from a biosynthetic hub to bioenergetic hub and inhibits GBM cell proliferation.
Although the inhibitory action of Methylene Blue on cancer proliferation needs further verification in vivo using different treatment paradigms, our in vitro data provide the proof of concept that reversal of Warburg effect might be a novel therapy for Glioblastoma (!)
This is a very interesting study from a mechanistic view point of how Methylene Blue works on Cancer!
METHYLENE BLUE and Ovarian Cancer
According to Dr William Makis (X/Twitter):
"2024 Moreira - Methylene Blue Metabolic Therapy Restrains In Vivo Ovarian Tumor Growth" (source)
"Ovarian cancer remains a significant challenge, especially in platinum-resistant cases where treatment options are limited."
"In this study, we investigated the potential of methylene blue (MB) as a metabolic therapy and complementary treatment approach for ovarian cancer"
Methylene blue (MB), a well-known dye agent, has shown promising effects in stimulating mitochondrial electron transfer chain and oxidative phosphorylation (OXPHOS), leading to increased mitochondrial respiration and ATP production
MB has also been reported to have direct effects on cell and mitochondrial metabolism
Methylene blue metabolic therapy exerted a strong inhibitory effect on the proliferation of the TOV112D ovarian cancer cell line, where the cell proliferation reached 16% of the control
addition of carboplatin to MB-50 exhibited a slight impact on TOV112D proliferation compared to MB-50 alone, but this effect was not significant (adding chemo to methylene blue makes little difference)
DISCUSSION:
The anticancer effect of methylene blue has been known for over a century.
In 1893, Louis Rambaud published data on a series of end-stage patients who responded to a high-dose treatment of methylene blue. This was confirmed by Pursell in cancer treatments on dogs
The results presented in this study demonstrate the potential of methylene blue (MB) metabolic therapy as an effective treatment approach for ovarian cancer
“stronger reduction in proliferation observed in TOV112D (platinum resistant cancer) cells compared to ARPE-19 (normal ovarian) cells in response to the MB-50 treatment highlights the potential of methylene blue as a therapeutic agent that specifically targets ovarian cancer cells”
"addition of carboplatin to MB-50 exhibited a slight impact on the TOV112D proliferation compared to MB-50 alone, suggesting a potential additive effect of carboplatin in combination with methylene blue, albeit to a limited extent."
modest enhancement of the in vivo tumor response observed to the combination of MB and carboplatin (MB + carboplatin) raises the possibility of a synergistic effect between methylene blue and carboplatin
“it would be highly relevant to identify the metabolic pathways as well as the signaling pathways involved in the inhibition of cancer cell growth by methylene blue”
“In conclusion, this study provides crucial insights into the potential of methylene blue-guided metabolic therapy for treating ovarian cancer. The results underscore the promise of metabolic therapy in reducing tumor growth by addressing the mitochondria redox potential, akin to its role as an oxidative agent in bacterial diseases. However, there is a pressing need for further investigations into the specific impact of methylene blue on apoptotic signaling and metabolic pathways within cancer cells. These molecular mechanisms must be thoroughly elucidated to optimize the application of metabolic therapy and enhance the treatment outcomes, particularly in the context of chemoresistant ovarian cancers.
My Take…
I will be writing a series of articles on Methylene Blue and Cancer over the coming days.
In this paper, methylene blue had a dramatic effect on ovarian cancer cell proliferation, oxygen consumption rate in tumor cells and on tumor growth.
However, the pathways are unknown.
Interestingly, while MB slowed the tumor growth rate significantly (much better than chemo), it didn’t stop the tumor growth.
The authors admit they don’t really know exactly how methylene blue works against ovarian cancer."
METHYLENE BLUE in PROSTATE CANCER (androgen-dependent and androgen-independent)
According to Dr William Makis (X/Twitter):
A few years ago there was an abstract presentation at the 2019 AACR Annual Meeting - American Association for Cancer Research
Shanti et al, looked at Methylene Blue in Prostate Cancer (source).
Highlights:
Methylene Blue effectively reduced the viability of androgen-dependent (LNCaP) and androgen-independent (PC3 and DU145) Prostate Cancer cells
Methylene Blue inhibited the colony forming ability of Prostate Cancer cells in-vitro suggesting its tumor suppressive potential
Methylene Blue treatment disrupted the migration potential of Prostate Cancer cells in a wound healing assay indicating the anti-metastatic function of MB
Methylene Blue effectively targeted the Prostate Cancer cell lines by inducing apoptotic cell death
Key apoptotic molecules such as Bax, TRAIL R2/D5, and phospho p53 (Serine 15, Serine 46, Serine 392) were robustly upregulated in androgen-dependent LNCaP cells following MB treatment.
“In conclusion, our findings suggest that MB induces apoptosis in Prostate Cancer cells and thus could serve as a potential anticancer agent for treating both hormone-dependent and -independent Prostate Cancer”
My Take…. Although this was an abstract presentation, it was nonetheless a very interesting one. We are still learning about the mechanisms of action of methylene blue on cancer cells but as we’ve seen with Ivermectin and Fenbendazole, it appears that numerous mechanisms are in play.
Read More: Methylene Blue for Cancer
Urinary Tract Infections in the Elderly
In my mind, this is one of the most important uses: It is a highly effective agent against urinary tract infections (UTIs). Many elderly are put on antibiotics, which disrupts their microbiome. Methylene blue was used for many decades at a dose of 65 mg per day and was even sold in pharmacies as Urolene Blue.
Methylene blue does make an effective antimicrobial, and it is probably safer than most antibiotics in the sense that most of them are mitochondrial toxins and methylene blue is an antidote to some mitochondrial toxins.
Since your body doesn’t really metabolize it, it is excreted by your kidneys into your bladder where it reaches very high concentrations over time and becomes a potent oxidant stress that kills virtually any pathogen in the bladder. Plus, it has the additional “side effect” of improving brain health and reducing dementia. In my mind, it is reprehensible medical malpractice not to use methylene blue in UTIs in the elderly. It clearly is the safest and most effective drug of choice.
Since your body doesn’t really metabolize it, it is excreted by your kidneys into your bladder where it reaches very high concentrations over time and becomes a potent oxidant stress that kills virtually any pathogen in the bladder. Plus, it has the additional “side effect” of improving brain health and reducing dementia. In my mind, it is reprehensible medical malpractice not to use methylene blue in UTIs in the elderly. It clearly is the safest and most effective drug of choice.
Methylene Blue Side Effects
While methylene blue has an impressive safety profile when used appropriately, there are some important considerations:- Blue discoloration — Methylene blue will temporarily turn urine and sometimes your tongue blue. This is harmless but can be startling if unexpected. This typically occurs when the dose is larger than 30 to 50 mg which is a dose about ten times higher than I recommend for most.
- Interference with pulse oximeters — High doses of methylene blue can affect pulse oximeter readings.
- Serotonin syndrome risk — I would advise strong caution for anyone ever to take an SSRI drug. I don’t believe anyone benefits from them and would encourage you to read my last article on SSRIs. Taking methylene blue only worsens this risk as they increase serotonin levels even further. This typically only occurs at high doses that are used to treat life threatening situations and is likely rarely, if ever, occur at lower doses that I recommend of 3 to 5 mg. This mostly occurs in those on SSRI drugs and taking doses of methylene blue over 100 mg.
- Kidney concerns — Those with severe renal insufficiency should use caution and work closely with a health care provider.
- G6PD deficiency — Methylene blue is contraindicated in patients with this genetic disorder.
Neurological effects such as headaches and confusion can occur, with high doses potentially triggering serotonin syndrome, especially in patients taking serotonergic medications. For individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, methylene blue can cause hemolytic anemia, making it crucial to screen for this genetic condition before administration.
Cardiovascular effects, though less common, may include increased blood pressure and palpitations. Importantly, methylene blue can interact with various medications, particularly antidepressants and antimalarials, altering their efficacy or causing adverse reactions.
To my knowledge, there’s never been more than five cases, where the patients were anesthetized, and they still had SSRIs [in their system], and they did repeated flushing in the open neck with methylene blue, which exceeded these doses that we have been talking about.
The U.S. FDA reacted with this warning. But this has been reviewed by both surgeons and pharmacologists at the Mayo Clinic, and they wrote a rebuttal paper where they indicate that there is no evidence to suggest oral methylene blue has any interaction with the therapeutic dosing of serotonergic compounds, especially SSRIs, and that this was something that happened under these specific [surgical] conditions.
Canada limits the warning to that particular application, but our FDA went beyond that to any kind of serotonergic drug. I think there is absolutely no evidence for oral methylene blue having interactions in this low-dose range with any SSRIs.
And when they talk about the MAO inhibitor function, it really only works as an MAO inhibitor in the higher concentration of the higher dose range, not the low-dose range. So, the effects of methylene blue as an antidepressant — only to a very limited extent, if you repeat it cumulative treatments — can be due to any kind of a MAO inhibitor role. In addition, it is due to its metabolic enhancing function, so it antagonizes some of the depression symptoms like the low energy that is experienced with depression. So yes, it is effective to reduce symptoms of depression. Unfortunately, this warning is going to make some physicians scared of using it in combination with SSRIs.”
For an acute treatment, the upper limit is between 3 mg to 4 mg per kg, which is typically the range given as an IV antidote for methemoglobinemia. For nonacute, more long-term treatment, 0.5 mg to 1 mg per kg per day works better. It has a half-life of 12 to 13 hours, so once-a-day dosing is fine. He gives the following example of how methylene blue has been used in the treatment of fears and phobias:
“One of the processes in which a memory formation can be used therapeutically is when you form a memory to extinguish fear. Individuals who have a phobia, you can expose them to the specific situation that is involved in the phobia, and there is a learning called extinction learning that happens that you extinguish your response.
In that situation, we only give methylene blue once after this extinction learning to facilitate the process of memory consolidation. What happens after you go through the learning is the process of consolidation, which requires energy.
So, by facilitating the energy availability during the consolidation phase, which happens over a number of hours, then the next time [you’re exposed to fear-evoking stimuli, you’ve] consolidated that extinction memory more effectively.
We’ve done this also with post-traumatic stress disorder (PTSD), where you use prolonged exposure therapy. In that situation, you can give the methylene blue after different sessions where you see that there is a good extinction learning.
In other words, where people are learning through exposure to reduce their fear levels, that’s when you want to reinforce that therapeutic learning by giving them the methylene blue right after the session.”
For brain health, nootropic effects and the prevention or treatment of dementia, 0.5 mg to 1 mg per kg per day (or when needed) is the dose Gonzalez-Lima recommends and uses.
The doses they advise are 0.5 milligram (mg) to 1 mg per kilogram of body weight. I believe these doses are highly excessive and unnecessary. Please understand that doses of more than 3 to 5 mg are likely never needed unless you are undergoing treatment for some life-threatening conditioning like carbon monoxide or cyanide poisoning or a resistant urinary tract infection.
Selecting the right product is also important, and there are three types typically sold — industrial-grade, chemical-grade (laboratory-grade) and pharmaceutical-grade. The only one you should use is the pharmaceutical-grade variety. Other types of methylene blue, such as the one found in pet stores, are meant for keeping aquariums clean. Industrial-grade methylene blue contains impurities, and should never be used for any biological purposes.
There are several important considerations to consider when using methylene blue. Firstly, while you can easily and cheaply purchase methylene blue online, this is rarely a pharmaceutical grade product, and I strongly recommend never using these products because of the risk of heavy metal contamination.
Secondly, it is a prescription drug and can only be used with a prescription from a doctor. If you’re considering it, I encourage you to speak with your doctor about whether it might be appropriate for your needs.
Thirdly, it’s best to get your prescription filled by a compounding pharmacy. The only form of methylene blue available at conventional pharmacies is for IV use and a 10 ml vial contains 100 mg and costs over $200.
The dose of methylene blue that Dr Joseph Mercola recommends is 3 to 5 mg once a day (regardless of your weight). It has a half-life of 12 to 13 hours, so taking it once a day is sufficient and will increase your levels over time. It’s also best to take a day off once a week if you are taking it long term.
First, ask your healthcare provider if they have any that they prefer to use. They may be able to direct you to a compounding pharmacy that they’ve worked with in the past or like to use. They may also refer you to a compounding pharmacy that specializes in a certain area.
From sharper thinking to stronger cells, Methylene Blue enhances how your brain and body perform by enhancing mental clarity and focus, supporting blood flow, and increasing ATP production.Methylene Blue Adverse Events - Clinical Trials
In the first phase III trial, there was a dose-dependent effect on people dropping out of the trial:
24% of the 8 mg “placebo,” 31.3% of the 150 mg group, and 38.3% of the 250 mg group.
Gastrointestinal and urinary problems were the most common side effects driving this.
In the second phase III trial, five times as many people dropped out in the 200 mg treatment
group as in the 8 mg “placebo.” Again the most common increased side effects were
gastrointestinal and urinary.
The earlier phase II trial had four times as many treatment subjects drop out (31.4%) as 8 mg
“placebo” subjects (7.6%) over 24 weeks. Consistent with the phase III trials, gastrointestinal
side effects, mainly diarrhea, and urinary side effects, mainly an alteration of urinary output,
were the prime drivers.
However, the phase III trials found no difference in injuries from falls,
while the phase II trial found a large increase. Only 1.1% of the 8 mg “placebo” group
participants reported an injury from falling, while this rate was 8.5% in the 60 mg group, 5% in
the 120 mg group, and 5.6% in the 200 mg group. Altogether, the injuries from falling were
reported in 6.1% of the treatment group participants, 5.6-fold greater than in the 8 mg “placebo”
group.
The problem with these trials is they tried treating a common disease — Alzheimer’s — rather
than looking specifically for people with respiratory chain disorders that could be treated with
methylene blue.
Contraindications
While methylene blue is safe, there are some contraindications. One is
G6PD deficiency, which is also a contraindication for high-dose ascorbic
acid treatments, which could be deadly.
Methylene blue is also a mild
monoamine oxidase (MAO) inhibitor, so taking high doses with a selective
serotonin reuptake inhibitor (SSRI) antidepressant could potentially lead to
serotonin syndrome, which is not good. The risk of this, however, is very
small.
Other contraindications include hydroxylamine toxicity and renal failure.
Gonzalez-Lima explains:
“With respect to the warning about the SSRIs, the problem is not
methylene blue but the amount of SSRI. The problem was in a specific
application of methylene blue where they use it for parathyroid surgery as
a stain ...
To my knowledge, there’s never been more than five cases, where the patients were anesthetized, and they still had SSRIs [in their system], and they did repeated flushing in the open neck with methylene blue, which exceeded these doses that we have been talking about.
The U.S. FDA reacted with this warning. But this has been reviewed by both surgeons and pharmacologists at the Mayo Clinic, and they wrote a rebuttal paper where they indicate that there is no evidence to suggest oral methylene blue has any interaction with the therapeutic dosing of serotonergic compounds, especially SSRIs, and that this was something that happened under these specific [surgical] conditions.
Canada limits the warning to that particular application, but our FDA went beyond that to any kind of serotonergic drug. I think there is absolutely no evidence for oral methylene blue having interactions in this low-dose range with any SSRIs.
And when they talk about the MAO inhibitor function, it really only works as an MAO inhibitor in the higher concentration of the higher dose range, not the low-dose range. So, the effects of methylene blue as an antidepressant — only to a very limited extent, if you repeat it cumulative treatments — can be due to any kind of a MAO inhibitor role. In addition, it is due to its metabolic enhancing function, so it antagonizes some of the depression symptoms like the low energy that is experienced with depression. So yes, it is effective to reduce symptoms of depression. Unfortunately, this warning is going to make some physicians scared of using it in combination with SSRIs.”
Dosing Suggestions
As mentioned, methylene blue is a hormetic, so low dosages have the opposite effect of high dosages. While every possible dose response has not been tested, as a general guideline, the benefits Gonzalez-Lima discusses in this interview are based on dosages between 0.5 milligram per kilogram of bodyweight to 4 mg per kg. He admits lower doses may work but he hasn’t tested them.
For an acute treatment, the upper limit is between 3 mg to 4 mg per kg, which is typically the range given as an IV antidote for methemoglobinemia. For nonacute, more long-term treatment, 0.5 mg to 1 mg per kg per day works better. It has a half-life of 12 to 13 hours, so once-a-day dosing is fine. He gives the following example of how methylene blue has been used in the treatment of fears and phobias:
“One of the processes in which a memory formation can be used therapeutically is when you form a memory to extinguish fear. Individuals who have a phobia, you can expose them to the specific situation that is involved in the phobia, and there is a learning called extinction learning that happens that you extinguish your response.
In that situation, we only give methylene blue once after this extinction learning to facilitate the process of memory consolidation. What happens after you go through the learning is the process of consolidation, which requires energy.
So, by facilitating the energy availability during the consolidation phase, which happens over a number of hours, then the next time [you’re exposed to fear-evoking stimuli, you’ve] consolidated that extinction memory more effectively.
We’ve done this also with post-traumatic stress disorder (PTSD), where you use prolonged exposure therapy. In that situation, you can give the methylene blue after different sessions where you see that there is a good extinction learning.
In other words, where people are learning through exposure to reduce their fear levels, that’s when you want to reinforce that therapeutic learning by giving them the methylene blue right after the session.”
For brain health, nootropic effects and the prevention or treatment of dementia, 0.5 mg to 1 mg per kg per day (or when needed) is the dose Gonzalez-Lima recommends and uses.
Methylene blue low dose works particularly well for those who have reductive stress. However, an easier to find and safer to use alternative would be molecular hydrogen. Learn more: Why Molecular Hydrogen Is a Superior Antioxidant.
The only version you’ll want to use medicinally is pharmaceutical-grade. Do not ingest methylene blue from the pet store that is meant for fish tanks. Industrial-grade methylene blue has lots of impurities, and typically contain only 10% to 25% methylene blue.
Chemical or laboratory grade, which is used for staining purposes on laboratories, has a much higher purity, but it’s still not suitable for medicinal purposes as it typically has heavy metal contaminants like lead, cadmium and arsenic. Over time, the impurities can accumulate in your body, resulting in toxicity.
Pharmaceutical grade is 99%+ pure. This is the kind used when injected intravenously for antidote purposes, or used orally. These products will be marked USP, which stands for United States Pharmacopeia.
According to Gonzalez-Lima, USP is better in terms of purity than the European pharmaceutical grade, which has fewer requirements. Taking the methylene blue with some ascorbic acid (vitamin C) facilitates absorption. You won’t find methylene blue at your local pharmacy but many compounding pharmacies can obtain the pharmaceutical grade.
“Ascorbic acid is a way to facilitate the cycling of methylene blue by promoting its reduction,” he explains. Considering the importance of mitochondrial health, methylene blue appears to be a simple and remarkably effective way to improve your overall health and cognitive function.
How to Select a High-Quality Product
Last but not least, selecting the correct product is of crucial importance, in addition to getting the dosing right. There are three basic types of methylene blue: industrial, chemical and pharmaceutical-grade.The only version you’ll want to use medicinally is pharmaceutical-grade. Do not ingest methylene blue from the pet store that is meant for fish tanks. Industrial-grade methylene blue has lots of impurities, and typically contain only 10% to 25% methylene blue.
Chemical or laboratory grade, which is used for staining purposes on laboratories, has a much higher purity, but it’s still not suitable for medicinal purposes as it typically has heavy metal contaminants like lead, cadmium and arsenic. Over time, the impurities can accumulate in your body, resulting in toxicity.
Pharmaceutical grade is 99%+ pure. This is the kind used when injected intravenously for antidote purposes, or used orally. These products will be marked USP, which stands for United States Pharmacopeia.
According to Gonzalez-Lima, USP is better in terms of purity than the European pharmaceutical grade, which has fewer requirements. Taking the methylene blue with some ascorbic acid (vitamin C) facilitates absorption. You won’t find methylene blue at your local pharmacy but many compounding pharmacies can obtain the pharmaceutical grade.
“Ascorbic acid is a way to facilitate the cycling of methylene blue by promoting its reduction,” he explains. Considering the importance of mitochondrial health, methylene blue appears to be a simple and remarkably effective way to improve your overall health and cognitive function.
How to Use Methylene Blue
Most experts recommend relatively high doses for longer-term treatments, including dementia prevention and treatment, post-stroke care, cognitive enhancement and overall health optimization.The doses they advise are 0.5 milligram (mg) to 1 mg per kilogram of body weight. I believe these doses are highly excessive and unnecessary. Please understand that doses of more than 3 to 5 mg are likely never needed unless you are undergoing treatment for some life-threatening conditioning like carbon monoxide or cyanide poisoning or a resistant urinary tract infection.
Selecting the right product is also important, and there are three types typically sold — industrial-grade, chemical-grade (laboratory-grade) and pharmaceutical-grade. The only one you should use is the pharmaceutical-grade variety. Other types of methylene blue, such as the one found in pet stores, are meant for keeping aquariums clean. Industrial-grade methylene blue contains impurities, and should never be used for any biological purposes.
There are several important considerations to consider when using methylene blue. Firstly, while you can easily and cheaply purchase methylene blue online, this is rarely a pharmaceutical grade product, and I strongly recommend never using these products because of the risk of heavy metal contamination.
Secondly, it is a prescription drug and can only be used with a prescription from a doctor. If you’re considering it, I encourage you to speak with your doctor about whether it might be appropriate for your needs.
Thirdly, it’s best to get your prescription filled by a compounding pharmacy. The only form of methylene blue available at conventional pharmacies is for IV use and a 10 ml vial contains 100 mg and costs over $200.
The dose of methylene blue that Dr Joseph Mercola recommends is 3 to 5 mg once a day (regardless of your weight). It has a half-life of 12 to 13 hours, so taking it once a day is sufficient and will increase your levels over time. It’s also best to take a day off once a week if you are taking it long term.
How do I find a compounding pharmacy in US?
You won’t find methylene blue at your local pharmacy but many compounding pharmacies can obtain the pharmaceutical grade. There are a few ways to locate a compounding pharmacy in your local area.First, ask your healthcare provider if they have any that they prefer to use. They may be able to direct you to a compounding pharmacy that they’ve worked with in the past or like to use. They may also refer you to a compounding pharmacy that specializes in a certain area.
Another way is by utilizing the Alliance for Pharmacy Compounding’s website. Enter your city and state, and their directory will point you to nearby compounding pharmacies.
You can also find a compounding pharmacy by using the Professional Compounding Centers of America’s website. Enter your zip code or your city and state to find one.
And remember, your local community pharmacy may be able to compound your medication. If you’re unsure, ask your pharmacist.
Urolithin A promotes healthy aging by activating mitophagy. Mitophagy helps the body to recycle and rebuild mitochondria (the powerhouses of your cells) and enhances the benefits of Methylene Blue.
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Studies show that doses higher than 5 mg are needed for depression and bipolar illness, for example. I’m wondering why your recommendations are so much lower, as they used 15 mg/day for depression and 300 mg/day to prevent manic episodes and provide anti-depressant relief. Have read about higher doses for other conditions.
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