June 24, 2025 • 19 mins
In this episode of Daily Value, we look at the neurometabolic potential of methylene blue, a synthetic dye first synthesized in the 19th century, for supporting brain energy metabolism during aging. Originally developed for textile use, methylene blue has since demonstrated potential use as a redox-active agent in neuroprotection and memory enhancement (and how exactly it performs these actions).
We look at it’s unique biochemical mechanism as an alternative electron carrier within the mitochondrial electron transport chain, showing how it may bypass dysfunctional complexes to enhance ATP production and reduce oxidative stress.
The episode also discusses findings from animal models and human trials, including the challenges and inconsistencies observed in clinical studies - along with potential risks, contraindications, and the implications for aging-related cognitive decline.
00:00 Introduction to Methylene Blue
00:57 Historical Background and Early Uses
02:31 Methylene Blue in Modern Medicine
04:03 Mechanisms of Action in the Brain
05:59 Dosage and Effects
12:23 Human Studies and Clinical Trials
15:35 Safety Concerns and Contraindications
18:16 Conclusion and Future Directions
PMID: 22067440
PMID: 34943887
PMID: 38022191
PMID: 36803299
Mark as Played
Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:00):
What if a synthetic dye crafted in the bustling
chemical laboratories of 19thcentury Germany might hold
unexpected promise forpreserving your brain's energy
as you age?
Primarily known for itsstriking blue hue, this molecule
once captured the imaginationof medical pioneers, who
famously described it as apotential magic bullet for its
(00:22):
selective affinity toward nervetissue.
Magic bullet for its selectiveaffinity toward nerve tissue.
Today, we're carefullyexamining that claim, not
endorsing it, but exploring theintriguing possibility that
methylene blue could modulatemitochondrial function and
enhance neuronal resilience.
Is there substance behind thiscentury-old promise, or is
methylene blue yet anothermolecule whose therapeutic
(00:42):
legend outpaces reality?
Hello everyone, and welcomeback to Daily Value.
Methylene blue is a relativelywell-established compound,
initially synthesized as atextile dye in 1876.
(01:04):
A decade later, in 1886, apioneering scientist, paul
Ehrlich, injected methylthioninium chloride, now
universally known as methyleneblue, into rodents for
experimental purposes.
Ehrlich coined the term magicbullet due to its very
interesting property ofselectively targeting respiring
tissue of the nervous system.
(01:24):
Initially regarded merely asone among many synthetic dyes,
methylene blue's earlyapplication by Ehrlich catalyzed
a scientific revolution thatextended its use into numerous
novel experimental applications.
Throughout its history spanningover 120 years, methylene blue
has exhibited what can only becharacterized as versatility,
(01:46):
finding roles as diverse as aredox indicator, anti-malarial
agent, photosensitizer, supervital stain, and even as a
chemotherapeutic agent.
In oncology, notably, arenowned neuroscientist named
Santiago Ramon E Cajal employedwhat was known as the Ehrlich
reaction using methylene blue inrodents to verify the existence
(02:09):
of synaptic spines, confirmingthat these structures were not
artifacts of staining techniques.
By the early 20th century,psychiatrists explored methylene
blue as an experimentaltherapeutic for schizophrenia,
due to its affinity for nervoustissue.
This foundational observationhas since been revisited and
expanded into contemporaryresearch, establishing methylene
(02:30):
blue as a potential candidatefor memory enhancement as well
as neuroprotection.
Modern clinical applicationsinclude exploration in mild
cognitive impairment, earlystage Alzheimer's disease,
parkinson's disease, opticneuropathy and various
neurodegenerative disorderslinked by mitochondrial
dysfunction.
(02:51):
At a biochemical level,methylene blue is what's known
as a phenothiazine derivative,capable of undergoing redox
cycling between its oxidizedform, which is blue-colored, and
reduced form known asleukomethylene blue, which is
colorless.
Its unique amphipathic nature,being both hydrophilic and
lipophilic, allows a high degreeof permeability through
(03:14):
biological membranes, notablythe blood-brain barrier.
Its low molecular weightfurther aids rapid tissue
delivery.
Given its extensive history,methylene blue remains FDA
approved as a treatment formethemoglobinemia.
That's a condition where Fe2plus ferrous iron of hemoglobin
gets oxidized to Fe3 plus ferric, iron, reducing the oxygen
(03:37):
carrying capacity of hemoglobin,which impairs oxygen release to
tissues.
All other uses of methyleneblue are considered off-label.
Over a century after its initialdiscovery, the multifaceted
properties of methylene bluesuggest a renewed revolution in
neurotherapeutics, offeringpromising avenues to address
(03:57):
aging-related cognitive declineand neurodegeneration driven by
mitochondrial dysfunction.
Aging in the brain isn't simplyabout losing cells.
It's also characterized bydeclining cellular energy
production.
Central to this energyproduction are mitochondria, the
microscopic powerhouses withinour neurons.
As we age, mitochondrialefficiency falters, atp
(04:19):
production drops and harmfulreactive oxygen species
accumulate.
This mitochondrial dysfunctionis recognized as a primary
contributor to cognitive declineand neurodegenerative diseases,
such as Parkinson's disease andAlzheimer's disease.
In Parkinson's, mitochondrialimpairment significantly impacts
dopamine-producing neurons,making them susceptible to cell
(04:41):
death due to oxidative stress.
Think of these neurons asfactories with malfunctioning
equipment that produces lessenergy and more pollution,
eventually leading to theirclosure.
Methylene blue seems to offer aunique approach to counteract
this issue, not by traditionaldrug-receptor interactions, but
by acting as an electron shuttlewithin mitochondria.
(05:04):
At low concentrations,methylene blue can directly
accept electrons from NADH atmitochondrial complex 1,
becoming reduced to itscolorless form, leukomethylene
blue then transfers theseelectrons downstream directly to
cytochrome C, effectivelybypassing any blockages or
(05:24):
inefficiencies at complexes 1and 3.
Those are the sites of thehighest reactive oxygen species
production within a mitochondria.
By creating this alternateelectron pathway, methylene blue
enhances activity at complex 4,that's cytochrome C oxidase,
boosting ATP production andreducing reactive oxygen species
formation.
(05:44):
Imagine a blocked highwaycausing traffic jams and
accidents.
Methylene blue provides anefficient detour, allowing
traffic in the form of electronsto flow smoothly again,
restoring efficient energyproduction and reducing harmful
congestion.
However, this beneficial effectseems to be dose-dependent,
following what's called ahormetic response, meaning that
(06:05):
low doses are beneficial, whilehigher doses can be detrimental.
In different animal models,effective low dose methylene
blue ranges from approximatelyone to four milligrams per
kilogram of body weight.
At these doses, methylene blueenhances mitochondrial function
and memory performance, buthigher doses exceeding 10
milligrams per kilogram of bodyweight in rodents can disrupt
(06:28):
mitochondrial function, stealingelectrons from normal
mitochondrial pathways, therebyacting as a pro-oxidant and
making worse oxidative stress.
In humans, clinicalinvestigations have found that
low-dose methylene blue, that'sapproximately 0.5 to 4
milligrams per kilogram bodyweight, orally or intravenously,
to be safe and effective forenhancing mitochondrial
(06:51):
respiration and, in some cases,cognitive function.
Conversely, higher intravenousdoses exceeding 7 milligrams per
kilogram body weight can induceadverse effects such as
paradoxically causingmethemoglobinemia rather than
resolving it.
Thus, dose precision withmethylene blue is important.
Again, methylene blue'sphenothiazine ring grants it
(07:14):
good fat solubility, enhancingrapid penetration across cell
membranes and the blood-brainbarrier.
This permeability allowsmethylene blue to efficiently
reach neuronal mitochondria.
Additionally, methylene blue'schemical structure supports
continuous oxidation reduction,cycling between its two forms
without even losing potency.
(07:34):
This is akin to a batterycontinually recharging itself
within mitochondria.
Now, very interestingly andimportantly, methylene blue's
mitochondrial effects areactivity-dependent.
Neurons actively engaged indemanding cognitive tasks
develop higher mitochondrialmembrane potentials, creating a
(07:54):
stronger attraction point formethylene blue.
Therefore, methylene bluepreferentially accumulates in
metabolically active brainregions.
Animal studies demonstrate thisphenomenon Rodents given
low-dose methylene blue, that's1 to 4 milligrams per kilogram,
exhibit increased cytochrome Cactivity, improved oxygen
(08:15):
utilization and enhancedperformance in learning and
memory tasks, specificallywithin brain regions heavily
involved in these tasks.
Cytochrome C oxidase activityis important to remember, as
that is the best predictingmarker of a neuron's ability to
produce energy.
Previous hypotheses suggestedthat methylene blue's cognitive
(08:37):
benefits were mainly due toimproved oxygen transport via
hemoglobin interactions.
Remember how it reduces ferriciron to ferrous iron.
However, research does showthat methylene blue enhances
cognitive performance evenwithout significantly changing
oxygen transport capacity.
The true benefit of methyleneblue lies not in delivering more
(08:58):
oxygen, but rather in improvinghow effectively neurons use
existing oxygen supplies.
Think of methylene blue asupgrading the engine rather than
simply providing more fuel.
Ultimately, methylene blue'sstrength resides in its nuanced
mechanism.
It isn't a generalizedantioxidant or cognitive
enhancer, but rather a precisemitochondrial metabolic
(09:19):
optimizer.
It supports neuronal functionby enhancing intrinsic
mitochondrial capacity,particularly valuable under
conditions of aging-relatedmitochondrial dysfunction.
Animal research has shown robustevidence that methylene blue
accumulates preferentially inbrain tissue.
For instance, studies reportbrain concentrations of
(09:40):
methylene blue approximately 100times higher than plasma within
four hours following oral orintravenous administration in
rodents.
Interestingly, methylene bluetreatment resulted in a notable
enhancement of brain cytochromeC oxidase activity,
approximately 70% highercompared to untreated controls.
Such elevation of cytochrome Coxidase is directly correlated
(10:04):
with improved pneumonic capacityduring tasks involving
discrimination learning.
Now, memory processingencompasses several critical
phases.
Those are encoding,consolidation and retrieval,
each facilitated by distinctneural mechanisms.
Seminal research by Martinez Jrand colleagues demonstrated the
(10:26):
timing-specific nature ofmethylene blue's effects
administering one milligram perkilogram body weight of
methylene blue immediately aftertraining, and that
significantly improved memoryretention in animals performing
an inhibitory avoidance taskmeasured 24 hours later.
However, administering the samedose either 15 minutes before
training, six hourspost-training or immediately
(10:49):
before testing showed nobeneficial effects, clearly
indicating that methylene blueenhances memory specifically
during the consolidation phase.
This phase-dependenteffectiveness as a consolidative
enhancer is likely mediatedthrough its action in brain
mitochondria rather than generalneurochemical interactions.
Even more interestingly,methylene blue's
(11:11):
memory-enhancing effects, asseen primarily in animal models,
are not limited to one type ofmemory, but can affect
consolidation of any memoriesthat are being processed during
the time that methylene blue ispresent as a redox agent in
brain mitochondria.
This has been shown in bothnormal conditions and in those
associated with abnormalmitochondrial function.
(11:31):
Interestingly, high doses ofmethylene blue around 50
milligrams per kilogram of bodyweight administered before
training in animals impairedmemory retention, suggesting a
dose-dependent and, again,hormetic effect.
Lower doses around 1 to 4 mgper kg reliably enhanced memory
without adverse side effects,whereas higher concentrations
(11:53):
disrupted cognitive processes.
This paradoxical dose-responserelationship is consistent with
methylene blue's redoxproperties.
Optimal low doses likelyfacilitate electron transport in
mitochondria, enhancingcellular energetics and
antioxidant capacity, whereasexcessive doses could disrupt
electron flow, creatingoxidative stress as well as
(12:15):
metabolic imbalance.
As it comes to methylene blue'spotential for helping aging
brains, especially inAlzheimer's disease.
Human data does show some veryinteresting yet complex results.
Recent clinical trials havesuggested benefits, although
findings have been mixed,largely dependent on the dosage
(12:36):
used and condition it's beenused.
In In a major analysisconducted in 2019 by Schefter
and colleagues, researchersexplored the impact of a
methylene blue derivative.
This was a stabilizedpharmaceutical grade form of
methylene blue in its reducedform.
Surprisingly, they found thatlower doses, specifically around
(12:57):
eight milligrams per day, didin fact provide cognitive
benefits slowing cognitivedecline and reducing brain
atrophy compared tosignificantly higher doses like
150 or 250 mg per day.
Interestingly, the lower doseused in this study was initially
intended only as a positivecontrol and not actually as an
experimental arm, yet itunexpectedly emerged as the most
(13:21):
therapeutically beneficial dose, suggesting that when it comes
to methylene blue, more mightnot necessarily be better.
This finding was supported byWilcock and colleagues in 2018.
Their study demonstrated thatAlzheimer's patients who
received low doses of thispharmaceutically stabilized form
methylene blue just fourmilligrams twice a day had
(13:47):
consistently better cognitiveoutcomes than patients receiving
the same drug at higher dosesor even alongside standard
Alzheimer's medications likecholinesterase inhibitors and
memantine.
However, other studies exploringhigher doses tell a different
story.
For example, gothier andcolleagues in 2016 found no
significant cognitiveimprovements in patients who
were given higher daily doses ofmethylene blue, ranging from 75
(14:09):
to 125 milligrams twice a day.
Similarly, research by Baddeleyand colleagues in 2015 showed
that, although intermediatedoses of methylene blue around
138 milligrams daily, showedthat, although intermediate
doses of methylene blue around138 milligrams daily initially
seemed promising, althoughhigher doses quickly lost
effectiveness, suggesting acomplex relationship between
(14:30):
dosage and therapeutic outcome.
Further complicating the story,a recent study by Sing and
colleagues in 2023 directlymeasured how methylene blue
affects the human brain's energymetabolism using advanced
neuroimaging techniques.
Contrary to expectations, theyfound that intravenous doses
between 0.5 and 1 mg per kg ofbody weight actually reduced
(14:54):
both cerebral blood flow andoxygen consumption in healthy
volunteers.
These reductions weredose-dependent, suggesting an
inhibitory rather thanstimulating effect on brain
metabolism at these clinicallyrelevant doses.
Taken together, these humanstudies show the complexity of
methylene blue's action in thebrain.
(15:16):
They indicate that possiblebeneficial effects, especially
for cognitive aging, may beachievable, but only within a
narrow dosing window.
Clearly, the future ofmethylene blue in clinical
practice will depend on carefuldose selection, targeted patient
groups and, of course, furtherresearch.
Before summarizing today'sepisode, it's important to
(15:38):
discuss some concerns andcautions associated with the use
of methylene blue.
The most common adverse effectseen with methylene blue is the
bluish-green discoloration ofurine.
Another frequently reportedside effect, especially
following intravenousadministration, can be limb pain
.
Additionally, methylene bluehas notable monoamine oxidase
(16:00):
inhibiting properties, meaningit can potentially interact with
other medications affectingserotonin.
Combining methylene blue withserotonergic medications such as
selective serotonin reuptakeinhibitors, serotonin
norepinephrine reuptakeinhibitors, monoamine oxidase
inhibitors or tricyclicantidepressants can lead to
(16:21):
serotonin syndrome if the doseof methylene blue is high enough
.
In humans, methylene blueadministration has been shown to
cause central nervous systemsymptoms such as dizziness,
confusion and headaches.
Special care must also be takenwith children, where methylene
blue administration has beenlinked to serious conditions
like hyperbilirubinemia has beenlinked to serious conditions
(16:45):
like hyperbilirubinemia,respiratory depression,
pulmonary edema, phototoxicityand also hemolytic anemia.
There are knowncontraindications with methylene
blue use.
It should not be used inpatients who have a known
hypersensitivity or a history ofanaphylaxis following its
previous administration.
Additionally, it'scontraindicated in patients with
(17:05):
glucose 6-phosphatedehydrogenase deficiency, due to
the risk of developinghemolytic anemia.
Very importantly, methyleneblue is also contraindicated in
pregnancy.
The FDA has assigned it apregnancy class X rating due to
the potential fetalcomplications.
A pregnancy class X rating dueto the potential fetal
(17:27):
complications At therapeuticdoses of 2 milligrams per
kilogram of body weight in anadult.
With no contraindications,methylene blue is generally
considered safe.
However, significant adverseeffects typically occur when
doses exceed 7 milligrams perkilogram of body weight.
Serotonin syndrome has beenspecifically associated with
methylene blue doses, as well as5 milligrams per kg of body
weight.
Serotonin syndrome has beenspecifically associated with
methylene blue doses, as well as5 mg per kg of body weight when
(17:48):
combined with otherserotonergic agents.
Additionally, caution isrequired for patients with renal
impairment, as methylene bluecan reduce renal blood flow.
Thus, people using serotonergicmedications should probably
avoid methylene blue.
Currently, no antidote existsfor methylene blue toxicity.
(18:09):
In the rare event ofanaphylactic shock, the drug
must be discontinued immediately.
In today's episode, we'veexplored fascinating yet complex
role of methylene blue insupporting brain health and
potentially combating brainaging.
Methylene blue appears capableof enhancing mitochondrial
function, offeringneuroprotective benefits and
(18:31):
potentially slowing cognitivedecline, particularly at very
specific lower doses.
However, the clinical evidenceremains nuanced, suggesting the
need for careful dosing andpatient selection.
As research continues, it'sessential to approach methylene
blue with caution, understandingboth its therapeutic potential
(18:51):
as well as its risks.
Clearly, optimizing its use forbrain health will depend on
further clinical studies, betterunderstanding of dosing windows
and heightened awareness of itsinteractions and
contraindications.
Thank you for joining me todayon Daily Value.
Remember aging biology isn'tjust about magic bullets, but
(19:12):
targeted and informed strategiesto support our body's energy
systems.
Be sure to subscribe and joinme here next time as we continue
exploring the science behindhealth.
Stay sharp and stay healthy.
What if a synthetic dye crafted in the bustling
chemical laboratories of 19thcentury Germany might hold
unexpected promise forpreserving your brain's energy
as you age?
Primarily known for itsstriking blue hue, this molecule
once captured the imaginationof medical pioneers, who
famously described it as apotential magic bullet for its
(00:22):
selective affinity toward nervetissue.
Magic bullet for its selectiveaffinity toward nerve tissue.
Today, we're carefullyexamining that claim, not
endorsing it, but exploring theintriguing possibility that
methylene blue could modulatemitochondrial function and
enhance neuronal resilience.
Is there substance behind thiscentury-old promise, or is
methylene blue yet anothermolecule whose therapeutic
(00:42):
legend outpaces reality?
Hello everyone, and welcomeback to Daily Value.
Methylene blue is a relativelywell-established compound,
initially synthesized as atextile dye in 1876.
(01:04):
A decade later, in 1886, apioneering scientist, paul
Ehrlich, injected methylthioninium chloride, now
universally known as methyleneblue, into rodents for
experimental purposes.
Ehrlich coined the term magicbullet due to its very
interesting property ofselectively targeting respiring
tissue of the nervous system.
(01:24):
Initially regarded merely asone among many synthetic dyes,
methylene blue's earlyapplication by Ehrlich catalyzed
a scientific revolution thatextended its use into numerous
novel experimental applications.
Throughout its history spanningover 120 years, methylene blue
has exhibited what can only becharacterized as versatility,
(01:46):
finding roles as diverse as aredox indicator, anti-malarial
agent, photosensitizer, supervital stain, and even as a
chemotherapeutic agent.
In oncology, notably, arenowned neuroscientist named
Santiago Ramon E Cajal employedwhat was known as the Ehrlich
reaction using methylene blue inrodents to verify the existence
(02:09):
of synaptic spines, confirmingthat these structures were not
artifacts of staining techniques.
By the early 20th century,psychiatrists explored methylene
blue as an experimentaltherapeutic for schizophrenia,
due to its affinity for nervoustissue.
This foundational observationhas since been revisited and
expanded into contemporaryresearch, establishing methylene
(02:30):
blue as a potential candidatefor memory enhancement as well
as neuroprotection.
Modern clinical applicationsinclude exploration in mild
cognitive impairment, earlystage Alzheimer's disease,
parkinson's disease, opticneuropathy and various
neurodegenerative disorderslinked by mitochondrial
dysfunction.
(02:51):
At a biochemical level,methylene blue is what's known
as a phenothiazine derivative,capable of undergoing redox
cycling between its oxidizedform, which is blue-colored, and
reduced form known asleukomethylene blue, which is
colorless.
Its unique amphipathic nature,being both hydrophilic and
lipophilic, allows a high degreeof permeability through
(03:14):
biological membranes, notablythe blood-brain barrier.
Its low molecular weightfurther aids rapid tissue
delivery.
Given its extensive history,methylene blue remains FDA
approved as a treatment formethemoglobinemia.
That's a condition where Fe2plus ferrous iron of hemoglobin
gets oxidized to Fe3 plus ferric, iron, reducing the oxygen
(03:37):
carrying capacity of hemoglobin,which impairs oxygen release to
tissues.
All other uses of methyleneblue are considered off-label.
Over a century after its initialdiscovery, the multifaceted
properties of methylene bluesuggest a renewed revolution in
neurotherapeutics, offeringpromising avenues to address
(03:57):
aging-related cognitive declineand neurodegeneration driven by
mitochondrial dysfunction.
Aging in the brain isn't simplyabout losing cells.
It's also characterized bydeclining cellular energy
production.
Central to this energyproduction are mitochondria, the
microscopic powerhouses withinour neurons.
As we age, mitochondrialefficiency falters, atp
(04:19):
production drops and harmfulreactive oxygen species
accumulate.
This mitochondrial dysfunctionis recognized as a primary
contributor to cognitive declineand neurodegenerative diseases,
such as Parkinson's disease andAlzheimer's disease.
In Parkinson's, mitochondrialimpairment significantly impacts
dopamine-producing neurons,making them susceptible to cell
(04:41):
death due to oxidative stress.
Think of these neurons asfactories with malfunctioning
equipment that produces lessenergy and more pollution,
eventually leading to theirclosure.
Methylene blue seems to offer aunique approach to counteract
this issue, not by traditionaldrug-receptor interactions, but
by acting as an electron shuttlewithin mitochondria.
(05:04):
At low concentrations,methylene blue can directly
accept electrons from NADH atmitochondrial complex 1,
becoming reduced to itscolorless form, leukomethylene
blue then transfers theseelectrons downstream directly to
cytochrome C, effectivelybypassing any blockages or
(05:24):
inefficiencies at complexes 1and 3.
Those are the sites of thehighest reactive oxygen species
production within a mitochondria.
By creating this alternateelectron pathway, methylene blue
enhances activity at complex 4,that's cytochrome C oxidase,
boosting ATP production andreducing reactive oxygen species
formation.
(05:44):
Imagine a blocked highwaycausing traffic jams and
accidents.
Methylene blue provides anefficient detour, allowing
traffic in the form of electronsto flow smoothly again,
restoring efficient energyproduction and reducing harmful
congestion.
However, this beneficial effectseems to be dose-dependent,
following what's called ahormetic response, meaning that
(06:05):
low doses are beneficial, whilehigher doses can be detrimental.
In different animal models,effective low dose methylene
blue ranges from approximatelyone to four milligrams per
kilogram of body weight.
At these doses, methylene blueenhances mitochondrial function
and memory performance, buthigher doses exceeding 10
milligrams per kilogram of bodyweight in rodents can disrupt
(06:28):
mitochondrial function, stealingelectrons from normal
mitochondrial pathways, therebyacting as a pro-oxidant and
making worse oxidative stress.
In humans, clinicalinvestigations have found that
low-dose methylene blue, that'sapproximately 0.5 to 4
milligrams per kilogram bodyweight, orally or intravenously,
to be safe and effective forenhancing mitochondrial
(06:51):
respiration and, in some cases,cognitive function.
Conversely, higher intravenousdoses exceeding 7 milligrams per
kilogram body weight can induceadverse effects such as
paradoxically causingmethemoglobinemia rather than
resolving it.
Thus, dose precision withmethylene blue is important.
Again, methylene blue'sphenothiazine ring grants it
(07:14):
good fat solubility, enhancingrapid penetration across cell
membranes and the blood-brainbarrier.
This permeability allowsmethylene blue to efficiently
reach neuronal mitochondria.
Additionally, methylene blue'schemical structure supports
continuous oxidation reduction,cycling between its two forms
without even losing potency.
(07:34):
This is akin to a batterycontinually recharging itself
within mitochondria.
Now, very interestingly andimportantly, methylene blue's
mitochondrial effects areactivity-dependent.
Neurons actively engaged indemanding cognitive tasks
develop higher mitochondrialmembrane potentials, creating a
(07:54):
stronger attraction point formethylene blue.
Therefore, methylene bluepreferentially accumulates in
metabolically active brainregions.
Animal studies demonstrate thisphenomenon Rodents given
low-dose methylene blue, that's1 to 4 milligrams per kilogram,
exhibit increased cytochrome Cactivity, improved oxygen
(08:15):
utilization and enhancedperformance in learning and
memory tasks, specificallywithin brain regions heavily
involved in these tasks.
Cytochrome C oxidase activityis important to remember, as
that is the best predictingmarker of a neuron's ability to
produce energy.
Previous hypotheses suggestedthat methylene blue's cognitive
(08:37):
benefits were mainly due toimproved oxygen transport via
hemoglobin interactions.
Remember how it reduces ferriciron to ferrous iron.
However, research does showthat methylene blue enhances
cognitive performance evenwithout significantly changing
oxygen transport capacity.
The true benefit of methyleneblue lies not in delivering more
(08:58):
oxygen, but rather in improvinghow effectively neurons use
existing oxygen supplies.
Think of methylene blue asupgrading the engine rather than
simply providing more fuel.
Ultimately, methylene blue'sstrength resides in its nuanced
mechanism.
It isn't a generalizedantioxidant or cognitive
enhancer, but rather a precisemitochondrial metabolic
(09:19):
optimizer.
It supports neuronal functionby enhancing intrinsic
mitochondrial capacity,particularly valuable under
conditions of aging-relatedmitochondrial dysfunction.
Animal research has shown robustevidence that methylene blue
accumulates preferentially inbrain tissue.
For instance, studies reportbrain concentrations of
(09:40):
methylene blue approximately 100times higher than plasma within
four hours following oral orintravenous administration in
rodents.
Interestingly, methylene bluetreatment resulted in a notable
enhancement of brain cytochromeC oxidase activity,
approximately 70% highercompared to untreated controls.
Such elevation of cytochrome Coxidase is directly correlated
(10:04):
with improved pneumonic capacityduring tasks involving
discrimination learning.
Now, memory processingencompasses several critical
phases.
Those are encoding,consolidation and retrieval,
each facilitated by distinctneural mechanisms.
Seminal research by Martinez Jrand colleagues demonstrated the
(10:26):
timing-specific nature ofmethylene blue's effects
administering one milligram perkilogram body weight of
methylene blue immediately aftertraining, and that
significantly improved memoryretention in animals performing
an inhibitory avoidance taskmeasured 24 hours later.
However, administering the samedose either 15 minutes before
training, six hourspost-training or immediately
(10:49):
before testing showed nobeneficial effects, clearly
indicating that methylene blueenhances memory specifically
during the consolidation phase.
This phase-dependenteffectiveness as a consolidative
enhancer is likely mediatedthrough its action in brain
mitochondria rather than generalneurochemical interactions.
Even more interestingly,methylene blue's
(11:11):
memory-enhancing effects, asseen primarily in animal models,
are not limited to one type ofmemory, but can affect
consolidation of any memoriesthat are being processed during
the time that methylene blue ispresent as a redox agent in
brain mitochondria.
This has been shown in bothnormal conditions and in those
associated with abnormalmitochondrial function.
(11:31):
Interestingly, high doses ofmethylene blue around 50
milligrams per kilogram of bodyweight administered before
training in animals impairedmemory retention, suggesting a
dose-dependent and, again,hormetic effect.
Lower doses around 1 to 4 mgper kg reliably enhanced memory
without adverse side effects,whereas higher concentrations
(11:53):
disrupted cognitive processes.
This paradoxical dose-responserelationship is consistent with
methylene blue's redoxproperties.
Optimal low doses likelyfacilitate electron transport in
mitochondria, enhancingcellular energetics and
antioxidant capacity, whereasexcessive doses could disrupt
electron flow, creatingoxidative stress as well as
(12:15):
metabolic imbalance.
As it comes to methylene blue'spotential for helping aging
brains, especially inAlzheimer's disease.
Human data does show some veryinteresting yet complex results.
Recent clinical trials havesuggested benefits, although
findings have been mixed,largely dependent on the dosage
(12:36):
used and condition it's beenused.
In In a major analysisconducted in 2019 by Schefter
and colleagues, researchersexplored the impact of a
methylene blue derivative.
This was a stabilizedpharmaceutical grade form of
methylene blue in its reducedform.
Surprisingly, they found thatlower doses, specifically around
(12:57):
eight milligrams per day, didin fact provide cognitive
benefits slowing cognitivedecline and reducing brain
atrophy compared tosignificantly higher doses like
150 or 250 mg per day.
Interestingly, the lower doseused in this study was initially
intended only as a positivecontrol and not actually as an
experimental arm, yet itunexpectedly emerged as the most
(13:21):
therapeutically beneficial dose, suggesting that when it comes
to methylene blue, more mightnot necessarily be better.
This finding was supported byWilcock and colleagues in 2018.
Their study demonstrated thatAlzheimer's patients who
received low doses of thispharmaceutically stabilized form
methylene blue just fourmilligrams twice a day had
(13:47):
consistently better cognitiveoutcomes than patients receiving
the same drug at higher dosesor even alongside standard
Alzheimer's medications likecholinesterase inhibitors and
memantine.
However, other studies exploringhigher doses tell a different
story.
For example, gothier andcolleagues in 2016 found no
significant cognitiveimprovements in patients who
were given higher daily doses ofmethylene blue, ranging from 75
(14:09):
to 125 milligrams twice a day.
Similarly, research by Baddeleyand colleagues in 2015 showed
that, although intermediatedoses of methylene blue around
138 milligrams daily, showedthat, although intermediate
doses of methylene blue around138 milligrams daily initially
seemed promising, althoughhigher doses quickly lost
effectiveness, suggesting acomplex relationship between
(14:30):
dosage and therapeutic outcome.
Further complicating the story,a recent study by Sing and
colleagues in 2023 directlymeasured how methylene blue
affects the human brain's energymetabolism using advanced
neuroimaging techniques.
Contrary to expectations, theyfound that intravenous doses
between 0.5 and 1 mg per kg ofbody weight actually reduced
(14:54):
both cerebral blood flow andoxygen consumption in healthy
volunteers.
These reductions weredose-dependent, suggesting an
inhibitory rather thanstimulating effect on brain
metabolism at these clinicallyrelevant doses.
Taken together, these humanstudies show the complexity of
methylene blue's action in thebrain.
(15:16):
They indicate that possiblebeneficial effects, especially
for cognitive aging, may beachievable, but only within a
narrow dosing window.
Clearly, the future ofmethylene blue in clinical
practice will depend on carefuldose selection, targeted patient
groups and, of course, furtherresearch.
Before summarizing today'sepisode, it's important to
(15:38):
discuss some concerns andcautions associated with the use
of methylene blue.
The most common adverse effectseen with methylene blue is the
bluish-green discoloration ofurine.
Another frequently reportedside effect, especially
following intravenousadministration, can be limb pain
.
Additionally, methylene bluehas notable monoamine oxidase
(16:00):
inhibiting properties, meaningit can potentially interact with
other medications affectingserotonin.
Combining methylene blue withserotonergic medications such as
selective serotonin reuptakeinhibitors, serotonin
norepinephrine reuptakeinhibitors, monoamine oxidase
inhibitors or tricyclicantidepressants can lead to
(16:21):
serotonin syndrome if the doseof methylene blue is high enough
.
In humans, methylene blueadministration has been shown to
cause central nervous systemsymptoms such as dizziness,
confusion and headaches.
Special care must also be takenwith children, where methylene
blue administration has beenlinked to serious conditions
like hyperbilirubinemia has beenlinked to serious conditions
(16:45):
like hyperbilirubinemia,respiratory depression,
pulmonary edema, phototoxicityand also hemolytic anemia.
There are knowncontraindications with methylene
blue use.
It should not be used inpatients who have a known
hypersensitivity or a history ofanaphylaxis following its
previous administration.
Additionally, it'scontraindicated in patients with
(17:05):
glucose 6-phosphatedehydrogenase deficiency, due to
the risk of developinghemolytic anemia.
Very importantly, methyleneblue is also contraindicated in
pregnancy.
The FDA has assigned it apregnancy class X rating due to
the potential fetalcomplications.
A pregnancy class X rating dueto the potential fetal
(17:27):
complications At therapeuticdoses of 2 milligrams per
kilogram of body weight in anadult.
With no contraindications,methylene blue is generally
considered safe.
However, significant adverseeffects typically occur when
doses exceed 7 milligrams perkilogram of body weight.
Serotonin syndrome has beenspecifically associated with
methylene blue doses, as well as5 milligrams per kg of body
weight.
Serotonin syndrome has beenspecifically associated with
methylene blue doses, as well as5 mg per kg of body weight when
(17:48):
combined with otherserotonergic agents.
Additionally, caution isrequired for patients with renal
impairment, as methylene bluecan reduce renal blood flow.
Thus, people using serotonergicmedications should probably
avoid methylene blue.
Currently, no antidote existsfor methylene blue toxicity.
(18:09):
In the rare event ofanaphylactic shock, the drug
must be discontinued immediately.
In today's episode, we'veexplored fascinating yet complex
role of methylene blue insupporting brain health and
potentially combating brainaging.
Methylene blue appears capableof enhancing mitochondrial
function, offeringneuroprotective benefits and
(18:31):
potentially slowing cognitivedecline, particularly at very
specific lower doses.
However, the clinical evidenceremains nuanced, suggesting the
need for careful dosing andpatient selection.
As research continues, it'sessential to approach methylene
blue with caution, understandingboth its therapeutic potential
(18:51):
as well as its risks.
Clearly, optimizing its use forbrain health will depend on
further clinical studies, betterunderstanding of dosing windows
and heightened awareness of itsinteractions and
contraindications.
Thank you for joining me todayon Daily Value.
Remember aging biology isn'tjust about magic bullets, but
(19:12):
targeted and informed strategiesto support our body's energy
systems.
Be sure to subscribe and joinme here next time as we continue
exploring the science behindhealth.
Stay sharp and stay healthy.
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