duration of treatment

[Val Koganski]

How long does it take to see the benefits on fatigue? What is the best way to take it: once a day in am, twice a day, daily, 5 days a week? How fast can it be titrated?

Thank you.

[Anthony Castore]

When using methylene blue to address fatigue, the timeline for seeing benefits can vary depending on the individual. Some may experience improvements within days, while others might take weeks. This variability often depends on genetic factors, underlying health conditions, and lifestyle habits. Before administering methylene blue, it’s essential to test for specific genetic variants, such as G6PD deficiency (glucose-6-phosphate dehydrogenase), to avoid the risk of hemolysis. Additionally, consider variations in nitric oxide-related genes like NOS3, as methylene blue inhibits nitric oxide synthase, which can reduce vasodilation and impair endothelial function. This is a critical factor when weighing its pros and cons, especially for individuals with cardiovascular concerns.

Methylene blue works by enhancing mitochondrial function, bypassing complexes I and II of the electron transport chain, improving ATP production, and reducing oxidative stress. However, one of the most exciting aspects of methylene blue is its synergy with red and near-infrared (NIR) light therapy, which can further expedite results.

Here’s how it works: methylene blue is a photosensitizer, meaning it absorbs light, particularly in the red and NIR spectrum (around 630–660 nm and 800–850 nm). When exposed to these wavelengths, methylene blue generates reactive oxygen species (ROS) in a controlled manner that signals the body to repair and optimize cellular function. Simultaneously, red and NIR light enhance mitochondrial activity by stimulating cytochrome c oxidase in complex IV, boosting ATP production. Together, these therapies amplify each other’s effects, leading to enhanced energy metabolism, reduced inflammation, and accelerated recovery.

This synergy is particularly helpful for individuals dealing with fatigue because it targets multiple mechanisms simultaneously. For example, methylene blue provides the biochemical support for mitochondrial efficiency, while red light therapy enhances cellular energy and blood flow, mitigating the potential negative impact methylene blue has on nitric oxide production.

The best protocol often involves starting methylene blue at a low dose—such as 0.5–1 mg/kg body weight—once daily in the morning, as it can have mild stimulating effects. For red light therapy, sessions of 10–20 minutes using a device with the appropriate wavelengths (red: 630–660 nm, NIR: 800–850 nm) can be done 3–5 times per week, ideally following methylene blue administration for optimal absorption and effects.

Titration of methylene blue should be done cautiously, increasing the dose over one to two weeks to find the minimum effective dose while monitoring for side effects. When combined with red light therapy, the results may be expedited, with some individuals noticing significant improvements in fatigue, recovery, and cognitive clarity within a shorter timeframe.

By leveraging the powerful combination of methylene blue and red light therapy, while being mindful of genetic predispositions and potential nitric oxide impacts, you can maximize the benefits and achieve faster, more effective outcomes for fatigue and overall cellular health. Regular monitoring and individualized adjustments are key to optimizing this synergistic approach.

[Val Koganski]

Thank you for the advice.

Do you take it daily or take 1-2 days off in a week?

Do you add NO supplements to minimize vasoconstriction?

[Anthony Castore]

When using methylene blue, the approach really depends on the individual and their situation. For someone dealing with long COVID, where their capacity for intense training is limited due to ongoing inflammation and mitochondrial dysfunction, I typically start with daily methylene blue for a couple of weeks. After that, I transition to using it every three days, avoiding workout days entirely. This schedule provides mitochondrial support without risking overuse or interference with other physiological processes.

Methylene blue enhances mitochondrial function by improving the efficiency of the electron transport chain. It bypasses damaged Complex I and II, donating electrons directly to Complex IV (cytochrome c oxidase), which increases ATP production and reduces harmful reactive oxygen species. It also helps balance the redox system by enhancing the NAD+/NADH ratio, further supporting cellular energy and repair.

On training days, I avoid methylene blue to prioritize nitric oxide production, which is critical for exercise performance. Instead, I incorporate BPC 157, which helps reduce inflammation by modulating cytokines like TNF-α and IL-6, while also promoting nitric oxide production for improved blood flow and recovery. Additionally, I use Beet It Sport, a product rich in dietary nitrates, which boosts nitric oxide through the nitrate-nitrite-NO pathway. Taken about two hours before training, this ensures peak plasma nitrate levels during exercise. Dr. Seeds introduced me to this product, and it’s been a game-changer.

I also supplement with arginine alpha-ketoglutarate (AAKG) and citrulline, taking 7 grams of citrulline with AAKG about 30 minutes before training. Citrulline is converted to arginine in the kidneys, providing a sustained boost to nitric oxide production. This combination enhances muscle blood flow, reduces fatigue, and improves endurance during workouts.

A simple and sustainable addition to this protocol is Ketone Aid KE4 ketone ester BHB, which provides multiple benefits, particularly on the inflammatory side. Ketone esters work as HDAC inhibitors, reducing pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which are key players in chronic inflammation. By inhibiting these pathways, ketones significantly decrease systemic inflammation, improving recovery and cellular efficiency.

At the cellular level, ketone esters enhance mitochondrial function by providing a direct, efficient energy source that bypasses glycolysis and reduces oxidative stress. This not only improves ATP production but also minimizes the accumulation of damaging free radicals, which are often linked to fatigue and inflammation. The improved energy efficiency at the cellular level reduces fatigue, accelerates recovery, and contributes to overall health by maintaining a healthier inflammatory profile.

On non-training days, I always pair methylene blue with red light therapy. Red light activates cytochrome c oxidase in the mitochondria, amplifying the effects of methylene blue and further boosting ATP production. Avoiding methylene blue on training days ensures it doesn’t interfere with nitric oxide pathways, while the addition of ketone esters offers a sustainable solution to combat inflammation and support mitochondrial function.

 

[Anthony Castore]

I wanted to share some thoughts and invite feedback on an ongoing discussion we’ve been having in our clinic and research group about methylene blue—specifically its impact on nitric oxide (NO) signaling—and whether the mitochondrial benefits outweigh potential vascular drawbacks.

To simplify things for those newer to the topic: mitochondria are like the power plants of your cells. Methylene blue acts as a backup generator or shortcut wire that keeps the lights on when part of the system fails. However, it might interfere with nitric oxide, which functions like a traffic cop for blood flow and oxygen delivery. The question becomes whether this backup power source unintentionally causes a traffic jam.

Methylene blue is a redox-active molecule that donates electrons directly to cytochrome c, bypassing complexes I and III of the mitochondrial electron transport chain. This is particularly useful when complex I is impaired, which is common in aging, chronic inflammation, and neurodegenerative diseases. By improving electron flow, methylene blue enhances ATP production and reduces upstream reactive oxygen species. This has been demonstrated in various models and summarized in a 2022 review in the journal Antioxidants (PMID: 35268034), which highlighted methylene blue’s role in restoring mitochondrial function.

However, methylene blue also inhibits nitric oxide synthase—particularly the inducible and neuronal isoforms—and it binds directly to nitric oxide, reducing its bioavailability. It also blocks soluble guanylate cyclase, thereby preventing the conversion of GTP to cyclic GMP, a key second messenger for smooth muscle relaxation and vasodilation. This introduces a fundamental trade-off.

On one hand, in inflammatory states or neurodegeneration, nitric oxide is often produced in excess, especially via iNOS. This excessive NO reacts with superoxide to form peroxynitrite, which damages proteins, lipids, and DNA while inhibiting mitochondrial respiration by blocking cytochrome c oxidase. In these cases, methylene blue’s suppression of NO may be beneficial, protecting mitochondrial function and reducing oxidative stress. This protective role is supported by studies such as one on septic shock where methylene blue reversed hypotension and improved cellular respiration (PMID: 16502415).

On the other hand, in healthy individuals, especially athletes, nitric oxide is vital for vascular function, neuroplasticity, and exercise adaptation. It enhances vasodilation via cyclic GMP signaling, improving blood flow, oxygen delivery, and glucose uptake. Chronic suppression of NO can impair endothelial health and blunt the adaptive response to training. A 2021 paper in Free Radical Biology & Medicine (PMID: 34126247) emphasized the critical role of NO in maintaining vascular responsiveness.

Mark Sloan has suggested an interesting hypothesis: the increase in mitochondrial activity from methylene blue leads to increased CO2 production, which may help compensate for the loss of NO. CO2, far from being just a waste product, plays a significant role in vasodilation by causing local acidosis and triggering the Bohr effect, which enhances oxygen unloading from hemoglobin. A 2022 study in Cell Metabolism (PMID: 35462385) supports the idea that increased CO2 production during elevated mitochondrial respiration improves local oxygen delivery and tissue perfusion.

In this model, even if methylene blue reduces NO, the increase in CO2 could still support tissue oxygenation and blood flow. Think of NO and CO2 as two different types of road signs that direct blood traffic. If methylene blue removes some NO signs, CO2 may step in with alternative directions to keep traffic (blood flow) moving efficiently.

In clinical practice, I use low-dose methylene blue intermittently—typically 0.5 to 2 mg/kg—for patients with cognitive decline, neuroinflammation, or post-viral fatigue. These individuals often show signs of mitochondrial inefficiency and excessive iNOS activity. In these cases, MB improves cognition, mood, and energy. However, we are more cautious with athletes or individuals with vascular issues, as NO suppression could impair performance or recovery. In those cases, we might co-administer red light therapy, citrulline, or dietary nitrates to support NO pathways while using MB in a pulsed, short-duration protocol. We also monitor markers like blood pressure, HRV, and endothelial function to guide ongoing use.

Some open questions remain. Does CO2 production from MB reliably offset NO inhibition in all populations? What is the long-term cardiovascular impact of suppressing cGMP signaling?

Until we have more definitive answers, I see methylene blue as a powerful but context-specific tool. Used properly, it offers significant benefits. Used indiscriminately, it could disrupt critical signaling networks.

I’d love to hear how others are integrating methylene blue into practice, especially in performance settings or with vascular-compromised patients.

Looking forward to your insights.

[Author]

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