Categories
Life Extension Nootropics Reviews

Cerebramin and the Cytamins – My Experience

Even though the first nootropic, Piracetam, was discovered by a Romanian chemist, we can truly say that Russia is the true motherland of nootropics. From the “oldies”, such as Phenibut and Picamilon, to the newest additions, Russia has always been the bleeding edge of nootropic research. Today we are going to talk about Cerebramin and other compounds of the cytamins family.

Cytamins are nucleoproteins complex isolated from the organs of healthy cattle. These compounds are part of a new family of compounds developed in Russia, and called peptide bioregulators, that are being researched as anti-aging treatments.

Peptide bioregulators

From 1971 to 1996, researchers at the St Petersburg Bioregulation and Gerontology Institute studied and documented the role of peptides in aging. [1] [2] What they discovered is the body releases tissue-specific compounds, of peptide structure, that mediate interactions between cells. As such, they were named peptide bioregulators.

The researchers then isolated and purified those peptides from the organs of healthy cattle and pigs and found out that they had a normalizing effect on the abnormal cells of senescent and/or sick animals. These promising peptides have been developed into a new class of pharmaceuticals, the cytomedins, (e.g. Cortexin, Thymalin and Epithalamin, which has been further developed into Epitalon) as well as para-pharmaceuticals, the cytamins, such as Cerebramin, Vasalamin and Retinalamin.

Cytamins?!

So what’s the difference between the cytamins and the cytomedins?
Cytamins are “interpolymer complexes of tissue-specific proteins with nucleic acids.”[3] Essentially, they are a mixture of compounds such as nucleoproteins, vitamins, peptides and amino acids. The patented technology of cytamins manufacture includes alkaline hydrolysis from tissue cells, consecutive precipitation of nucleoprotein complexes, their purification from ballast substances, and manufacture of the ready form as enterosoluble tablets or capsules.[4]

In the manufacturing of Cytamins only calves and pigs less than 12 months old are employed, and strictly from Russian farms where “no human-endangering infectious diseases including transmissive bovine spongiform encephalopathy has been registered”.[5] Also, Russia is known for “its epizootological and epidemiological safety in respect to prion diseases.”[6] Not only that, but electrophoresis and Congo red staining (the recommended method of testing for Mad Cow disease) are employed to check for the presence of prion proteins.

There are over 17 cytamins on the market, and they are manufactured at “Longvy Farm” in Russia. More information about the cytamins can be found at the official website.

Some of the most famous cytamins are:

  • Brain (Cerebramin)
  • Liver (Hepatamin)
  • Stomach and duodenum (Ventramin)
  • Pancreas (Pancramin)
  • Lungs and respiratory system (Bronchalamin)
  • Heart (Coramin)
  • Circulatory system (Vasalamin)

Dr. A.S. Bashkireva[7] tested the use of Cerebramin and Vasalamin on driving performance, in both healthy subjects as well subjects with depression, anxiety and other mood disorders. The results were that the cytamins were “very effective in the correction of psychoemotional disorders and for attaining stable psychic adaptation”. [8]

[…] 150 professional drivers (men aged 30-59 years) were examined using a clinical questionnaire to identify, estimate and compare neurotic states according to 6 scales of anxiety, neurotic depression, asthenia, hysterical type of reacting, obsessive-phobic disorders and neurovegetative disturbances. The drivers were divided into 5 groups, 30 persons in each: I group received Cerebramin→, II — Vasalamin→, III — Cerebramin→ + Vasalamin→, IV — placebo, V — no preparations. […] The analysis of the incidence of various PES revealed a statistically significant increase in the number of drivers with stable psychic adaptation in Groups I, II, and III after cytamin correction as compared to the baseline level (3.3-, 2.4-, and 2.3-fold, correspondingly, p<0.001-0.05). A statistically relevant decrease in the number of the drivers with unstable psychic adaptation in Groups I, II, and III after a cytamin course was noted in comparison with the baseline level (2.5-, 3.0-, and 3.3-fold, respectively, p<0.001- 0.05). […] A detailed examination of the drivers’ PES according to different scales convincingly demonstrated the efficacy of combined application of Cerebramin and Vasalamin in correction of anxiety (p=0.001), neurotic depression (p=0.0001), asthenia (p=0.0001), hysterical type of reacting (p=0.0004), obsessive-phobic states (p=0.0001), and neurovegetative disorders (p=0.003). […]
The presented results showed the occupational hazards and long driving experience being the risk factors for the development of BMD. The applied parameters of PES and early manifestations of BMD are informative criteria for assessing the life quality and professional suitability of lorry-drivers. Cytamins […] are very effective in the correction of psychoemotional disorders and for attaining stable psychic adaptation. [9]

Cerebramin: My Experience

In my anecdotal, and totally unscientific experience with Cerebramin (the cattle brain extract), I can’t say to have noticed any effect. However, I am 24 years old, and this supplement is to be used in the elderly, so I cannot make any real judgment. That said, I feel that “real drugs” like the cytomedins (eg Epitalon, a pineal gland peptide, and Cortexin, a brain peptide) have a huge potential, and I’d like to try them out in the future.

You can buy Cerebramin, Cortexin and other rare Russian nootropics at RUPharma.

Cerebramin
5
Focus
6
Mood
5.5
Memory
5
Stimulation
5
Relaxation
7
Safety
Reviewer 5.5

References   [ + ]

Categories
Coluracetam Nootropics Racetams Reviews

Coluracetam Review: A Nootropic With Antidepressant Properties

The drug piracetam is often regarded as the first truly nootropic drug, due to its ability to promote healthy brain function and cognition without potentially debilitating side effects. The family of nootropics that are structurally related to piracetam, known as racetams, have also been held in high esteem by the nootropics community. Coluracetam is one of the many members of this nootropic drug class, but it has some unique properties that set it apart from the rest.

Introduction

ColuracetamColuracetam is a fairly new addition to the racetam category of nootropics, being developed and initially researched in the mid-1990s.[1] Coluracetam, known also by its research names of MKC-231 and BCI-540, was initially developed and researched by the Mitsubishi Tanabe Pharma Corporation in Japan as a potential treatment for Alzheimer’s disease. Coluracetam has also seen some limited research concerning its potential use for treating Major Depressive Disorder and Generalized Anxiety Disorder.[2]

Mechanism of Action

When ingested, coluracetam becomes present in nerve tissue within 30 minutes of administration. The concentration in the body begins to decrease about 3 hours after ingestion.[3]
The most definitive mechanism through which coluracetam works is high-affinity choline uptake (HACU). HACU is a crucial step in the process of the body’s converting of choline into acetylcholine, a vital neurotransmitter for cognition processes. [4] In essence, this means that an increase in HACU (caused by coluracetam) will also increase the activity level of acetylcholine in the nervous system. This is the basis for coluracetam’s ability to enhance cognition

My Experience with Coluracetam

My trial run for NootropicsDepot’s coluracetam lasted for one week, due to the fact that coluracetam’s effects seem to all take place rather quickly. In other words, the effects do not appear to be cumulative like some other nootropics. Typically, I took 30 mg orally in the morning, along with another 30 mg in the afternoon. If necessary, I took another dose later on in the day. Dosage recommendations for coluracetam range anywhere from 3 mg up to 100 mg or more, but this dose seemed to work just fine. Having experimented with coluracetam briefly a few months ago, I had a general feel for what dose might work.

Coluracetam powder nootropicDuring the time of this trial, I was not taking any prescription medications. In the morning, I was taking Vitamin B12, Vitamin D, potassium gluconate, fish oil, and turmeric. The effects I experienced from taking coluracetam have been very positive. However, bear in mind that this is only a subjective experience. The placebo effects cannot be ruled out (although I am convinced it was the coluracetam I felt), and experiences will vary between individuals. That being said, I will now go into what I felt are the major benefits of coluracetam:

  1. Motivation enhancement
    Right off the bat, coluracetam seems to provide a decent increase in motivation to engage in productive work. I felt a stronger desire to work on school work that I don’t find very interesting. It made it much easier to push through to get things done, leaving a very satisfactory feeling when things were accomplished.
  2. Stimulation
    This effect goes somewhat hand-in-hand with motivation enhancement. Coluracetam has the effect of making me feel more awake and alert. It seems to help me feel more ready and able to get work done. It didn’t make me feel “jittery” either – I felt quite relaxed the whole time.
  3. Reduction in fatigue
    Coluracetam appears to help alleviate both physical and mental fatigue. There were a few instances when taking it where I went from being exhausted and drained to energized and ready to go.
  4. Enhanced cognition
    This effect is very important for any nootropic compound. After all, it is the main thing that nootropics are purported to influence. Within half an hour of taking coluracetam, I felt much more able to formulate thoughts and translate them into writing. I also felt more able to connect ideas in my mind and get a better idea of the “bigger picture.” I also felt more naturally able to hold conversations with others, feeling much more engaged and fluent.
  5. Music enhancement
    While this is mostly unrelated to the topic of cognitive enhancement, listening to music while on coluracetam was very pleasant. The music itself felt more full, interwoven, and immersive than usual. Individual pieces of melody and minor details became more distinguishable than usual.
  6. Mood Boost
    After taking coluracetam, I can understand why it is being researched as a treatment for depression. It helped me remain more positive and upbeat throughout the day. I also seemed to make things more enjoyable in general.

Drawbacks

Coluracetam seems to be a very promising nootropic in terms of its multiple benefits and few side-effects. I did not experience any apparent increase in tolerance during the week I was taking it, even with multiple doses in one day. Experiments in which rats were given coluracetam for 14 days at a time seems to reinforce this.[5] The only possible side-effect I experience was mild to moderate headaches, which occurred throughout the week. This should be taken with a grain of salt because I am normally fairly prone to headaches in the first place. I’ve also heard that taking choline can alleviate headaches that come with racetam supplementation, so that could be a potential remedy.

Conclusion

All things considered, I was very pleased with the effects of coluracetam. I will certainly be implementing it into my nootropic stacks, as it is one of the most noticeable and useful nootropics I have personally taken. It seemed to have a real impact on my motivation, energy, and cognition. Everyone is bound to react differently to coluracetam, but I strongly encourage nootropics users to give it a try.

You can buy Coluracetam powder and capsules at NootropicsDepot.

Coluracetam
7.5
Focus
8.5
Mood
8
Memory
7.5
Stimulation
7
Relaxation
8
Safety
Reviewer 8.4
Summary
I highly recommend coluracetam for anyone who needs to spend extended periods of time working on demanding mental tasks. The cognitive boost and mental stimulation was extremely useful.

References   [ + ]

Categories
Reviews Stacks

Axon Labs’ NEXUS Nootropic Stack, My Experience (Review)

Formulating nootropic stacks can sometimes be a difficult or time-consuming process. While the research that goes into drug combinations and synergy can be rewarding and even enjoyable, sometimes it’s difficult to find the right information on specific nootropics. Even when the right ratios are figured out, making multiple capsules of a certain stack can be even more time-consuming than the research.

Although pre-made nootropic stacks can be more expensive than buying bulk powder, they are sometimes well worth the price. Nootropic blends can be specially formulated by individuals with a deep understanding of neuroscience, giving the best cognitive benefits possible. Axon Labs’ NEXUS Nootropic Stack is an encapsulated blend of aniracetam, CDP-choline, phosphatidylserine, and Pycnogenol. The serving size is two capsules, and each serving contains 1.250 mg of this nootropic blend. Although the amounts of each component are not specifically listed, we can make a plausible assumption based on standard dosages for these compounds.

nexus-facts_large.jpg

The key component to this blend is aniracetam, a well-respected nootropic that is gaining popularity for its unique ability to improve cognition and reduce anxiety at the same time. A more detailed look at aniracetam’s mechanism can be found here on our site. Essentially, aniracetam modulates the action of glutamate (an excitatory neurotransmitter) by reducing glutamate receptor desensitization. [1] This, in theory, would improve memory and strengthen the connections between neurons. Aniracetam is also unique among racetams in the fact that it has the ability to reduce feelings of anxiety and depression. It most likely accomplishes this by means of serotonergic, dopaminergic, and cholinergic mediation. [2]

CDP-choline (also known as citicoline) is a source of choline that also serves as a prodrug to uridine, another nootropic supplement. Choline is essential for the production of the neurotransmitter acetylcholine in the body, which is the neurotransmitter thought to be closely involved with the regulation of cognitive processes. Aniracetam is partially cholinergic in its mechanism of action, as it potentiates the action of nicotinic acetylcholine receptors.[3] When aniracetam is paired with a choline source, the increase in acetylcholine will theoretically potentiate the cholinergic effects of aniracetam.

Phosphatidylserine is a naturally-occurring fatty acid derivative that helps comprise cell membranes. In 2003, the Food and Drug Administration (FDA) authorized sellers of phosphatidylserine to label their products with the claim that “consumption of phosphatidylserine may reduce the risk of dementia and cognitive dysfunction in the elderly.” [4] Various studies have indeed confirmed that supplementation of phosphatidylserine can improve cognition[5], memory[6], and processing speed[7], among other factors. Phosphatidylserine also has the potential to increase levels of acetylcholine in the brain, an effect that would work synergistically with aniracetam’s cholinergic mechanisms. [8]

Pycnogenol is a patented extract of pine bark, containing a number of antioxidant flavonoids known as procyanidins. Pycnogenol’s most notable effects include its ability to increase blood flow[9], while also improving attention and cognition.[10] Pycnogenol’s main mechanism seems to be its ability to increase concentrations of nitric oxide (NO). It does this by preventing NO from oxidizing while also inducing the Nitric Oxide Synthase (NOS) enzyme, which catalyzes the production of NO.[11]

My Experience

Note: When dealing with anecdotal experiences, it is difficult to completely rule out the placebo effect as the cause of certain perceived changes in cognition and mood. This is simply my own experience, and it is likely that every individual’s experience with these nootropics will vary. These are simply the effects I perceived.
Previous to this experience, I had taken aniracetam on a few occasions with modest success, taking it with a choline source.

My dosing regimen of Nexus consisted of taking 2 capsules in the morning after I woke up. I took another dose in the afternoon or evening if I was working on tasks that benefit from boosts in cognition (i.e. writing, analysis). During this time period, I was also taking fish oil, bacopa monnieri, and centrophenoxine, which I have been taking regularly for at least a month. I was thus familiar with their effects and would be able to perceive any changes brought on by adding this stack. I took Nexus regularly for about one month.
One of the most marked improvements I noticed was a modest reduction in anxiety that set in about an hour after taking Nexus. I am typically a fairly anxious person, both in general and in social situations. I felt more able to focus on important tasks, rather than focusing on anxious thoughts I was having. I also felt a noticeable clear-headedness and ability to think straight.

There was also a subtle improvement in being able to pick up on new concepts more easily. During college courses, I felt very engaged in the materials being presented, even in the classes, I do not normally find very interesting. I also found it easier to contribute to the discussion.
Taking another dose before working on writing essays and papers seemed to help a great deal with my cognition. Aniracetam has anecdotally been touted to improve holistic and collective thinking, and that seemed to be the case in my experience. It was much easier to weave different concepts and themes together in a way that presented a coherent bigger picture.

Again, when it comes to nootropics, it can be difficult to differentiate legitimate effects from placebo. However, many of the effects I experienced were extreme enough that I am fairly convinced that they were effects of this stack.

Conclusion

Everyone is likely to react differently to a nootropic like aniracetam. There are some people I know who experience little to no effect from taking it. For others, the effects seem to be almost life-changing. However, I do feel like the additional ingredients in Nexus’s blend contribute a good deal to its effects. It seemed to have greater effects than just aniracetam alone.

This being said I can definitely recommend trying Nexus out. It is a good stack for those who are fairly new to nootropics and aren’t sure how to formulate their own stacks, but for the expert nootropic user, it is definitely overpriced. That said, I would definitely like to use it again in the future.

Axon Labs' NEXUS
7.5
Focus
7
Mood
6
Memory
6
Stimulation
7
Relaxation
9
Safety
Reviewer 7.1
Summary
I would recommend this stack to anyone who is into experimenting with nootropics. It gave me a clear cognitive boost while simultaneously reducing anxiety.

References   [ + ]

Categories
Fasoracetam Nootropics Racetams Reviews

Fasoracetam: How This Nootropic May Help You Focus Better

Originally known as NS-105, Fasoracetam is one of the newest nootropics on the market. Besides being the latest racetam to be discovered, it has some unique properties unlike any other racetam on the market. Let’s find out what makes this substance a truly unique nootropic, and why you should (or should not) try it.

One of the primary effects of Fasoracetam is the modulation of metabotropic glutamate receptors II and III (mGluR).[1] mGlu receptors have been shown to be involved in synaptic plasticity and neuroprotection. In addition, LY354740, am mGlu2/3 agonist, has been shown to be effective in generalized anxiety disorder.[2]

Fasoracetam is also the only racetam that significantly enhances cAMP formation[3] and that has been shown to be potentially effective in individuals with glutamatergic gene variants that are suffering from ADHD[4]. A Phase III clinical trial is near completion, but the drug is not currently listed as an ADHD treatment by the FDA.

Fasoracetam has also shown to have antidepressant effects[5] and to counteract learned helplessness, an avoidance behavior typically associated with depression. Fasoracetam, however, does not act on serotonin and other monoamines, and researchers think the antidepressant effect may stem from its ability to upregulate GABA-B receptors.[6]

Generally speaking, Fasoracetam has shown to be more effective with chronic use, and, in the ADHD study, most benefits were felt at week five onward.[7]
Fasoracetam ADHD

Mechanism of Action

In rat studies, fasoracetam restores the function of key receptors, glutamate mGluR II and III[8].  It also upregulates GABA-B receptors through receptor antagonism[9], a fact which may be related to its ability to reverse phenibut tolerance (which is one of the few supplements reported to relieve anhedonic depression). The GABA-B receptor is very important and has been found to play a role in cognition[10], anxiety and mood.

Alcohol, a very disinhibiting and fog-inducing compound (with pleasurable effects similar to phenibut) is thought to achieve its activity by activating GABA-B and A receptors (as well as dopamine).  However, because it downregulates these receptors, prolonged use may cause anxiety and cognitive disruptions.  Phenibut binds in a similar fashion to GABA-B.

FasoracetamBecause of its relatively narrow range of receptor targets, fasoracetam does not feel like a classic stimulant nor does it alter one’s feeling of wakefulness.  It lacks clinical dopamine activity but remarkably still managed to address ADHD symptoms, according to the study.  It is not clear how fasoracetam has such a specific utility in treating ADHD, more research on other neurotransmitters may be turned up in coming years, but judging on present evidence, it seems that Fasoracetam could reduce ADHD symptoms by modulating glutamatergic receptors.

That being said, the FDA does not list Fasoracetam as an ADHD medication and it should not be used as such. Only a professional can prescribe medications for ADHD and you should not self medicate.

Although it is a newer supplement without much of a user-base, it does appear to be well-tolerated even in large doses or extended periods. Among college students, it may soon become a mainstay, alongside other trusted nootropics such as Bacopa, Modafinil, and Noopept.

Acetylcholine

In addition to the findings surrounding glutamate and ADHD, rat studies have also revealed fasoracetam to have profound cholinergic activity.  Many common nootropics work by controlling acetylcholine, including several drugs used in the treatment of Alzheimer’s.

It increases the uptake of choline at sites in key brain regions involved in intelligence and mood, the hippocampus and cerebral cortex.  This, in turn, results in increased production and release of acetylcholine.[11]
This, similarly to what has been commonly reported with piracetam, may explain a need for choline supplementation in the case of symptoms such as low mood, headache or brain-fog.

Although I personally have only ever tried piracetam and aniracetam (and found, despite a slight cognitive boost, that they both caused a slightly lowered mood, with piracetam being more stimulating and anxiety-prone while aniracetam was calm and relaxing), I haven’t read any complaints of fasoracetam and depression (on the contrary it appears to be a robust antidepressant nootropic, similar to tianeptine). This is remarkable because excessive acetylcholine production is typically associated with low mood and depression. Even with something as mild as bacopa, reports of moodiness are easy to pin down.

Since all three of the mentioned racetams seem to operate through a shared mechanism of acetylcholine, it’s not clear how fasoracetam achieves a similar cognitive boost without side effects on mood.  Perhaps it has been less trialed and as more users sample it, more negative reports will pour in.  This seems unlikely, however, given multiple reports of antidepressant effects, and at higher doses, near euphoria.

Fasoracetam and coluracetam are interesting racetams with multiple mechanisms of action compared to piracetam. Although they both share a cholinergic effect, the former modulates mGlu receptors (as well as GABA-B receptors) while the latter interacts with a process named high-affinity choline uptake.  This may explain their calm, clear effects when compared with the more bland effects of piracetam.

Glutamate

Of the eight known metabotropic glutamate receptors, only one and five are believed to increase NMDA receptor activity and neural excitation (these two are postsynaptic).  The other six receptors all function to lower NMDA (and are presynaptic), lessen excitation and thus reduce potential neurotoxicity.

By slightly lowering glutamate activity and at the same time boosting GABA-B levels, fasoracetam offers a collected state of mind compared to piracetam’s more scattered one.  Normal tasks would flow much easier, and performance would be improved without adverse effect.
While OCD and more recently schizophrenia have been described as hyperglutamatergic, ADHD has always been thought of as a condition of low glutamate.[12]

However, fasoracetam may very well regulate the metabotropic receptors in both directions and benefit everyone equally (restoring both high and low activity of the receptors to normal).

It is not clear how to explain the remarkable improvements reported in samples of both schizophrenia and ADHD. An explanation may be the selectiveness for the presynaptic mGluRs (mGluR1 and mGluR5) coupled with the fact that these receptors both elevate cAMP and lower NMDA activity. Levels of these receptors in the body are both altered in schizophrenia (so fasoracetam would produce two favorable alterations for the schizophrenic patient).

Despite all this fine talk about schizophrenia and glutamate, most of the reports surrounding fasoracetam are concerned with ADHD symptoms, specifically motivation and focus.  It is not widely known for its use as psychiatric medicine, and it may be considered by ADHD patients who have not responded well to conventional treatments. Again, it is not approved by the FDA as an ADHD treatment, and we are not suggesting people suffering from that disease to use it without a medical prescription.

GABA

As stated above fasoracetam appears to have GABA-B antagonistic properties[13], and it may upregulate these receptors and thus diminish the tolerance to GABA-B agonists like Phenibut, Baclofen, and Alcohol, and may even act as an “antidote” to a Phenibut overdose.

Before many of the newer designer supplements hit the market and much was known about fasoracetam, Noopept was one of the more recommended supplements for alcoholics to recover cognitive capacities. But in light of this newer evidence, fasoracetam may address the issue more directly. Because of its activity here, fasoracetam may eventually find use in treating age-related memory decline, dementia, and even depression. For now, the research and hype seem to surround the potential treatment of ADHD symptoms.

Dosage and half-life

Buy Fasoracetam CapsulesNo dependence potential was noted in the rhesus monkey over the course of four weeks.[14]  However. users cannot be completely absolved of concern, due to interspecies differences and the possibility of an only mildly addictive substance requiring an exceptionally long habituation period.

If its use is not completely discouraged in elderly patients, significant caution and close monitoring are recommended.  Its metabolism and clearance depend heavily on the kidneys and at least one studied has reported significant accumulation in the elderly (whose renal function is typically compromised).[15]

It is typically taken at 10mg twice daily, but it is probably best to start with 5 mg and taper up. Even though the dosage is very low, bitterness is still a problem and the use of capsules or parachuting is recommended.

Although some work their way up to 30 mg in one dose, this may not be the most effective strategy (due to a short half-life of the compound) and this pattern of use is more likely to be helped along by a large meal.  A potent nootropic with a half-life of around 90 minutes, taking it even once a day may be enough for active levels to build up in your system, but tolerance will be close behind.

You can buy Fasoracetam capsules and powder at Nootropics Depot. Fasoracetam is not approved by the FDA as an ADHD treatment.

Fasoracetam
8.5
Focus
7.5
Mood
7.5
Memory
7.5
Stimulation
7.5
Relaxation
8
Safety
Reviewer 8.8

References   [ + ]

Categories
Methylene Blue Nootropics Reviews

Methylene Blue as a Nootropic? (Review)

Since its initial synthesis in 1886, the phenothiazine derivative methylene blue (MB) has been established as a highly versatile chemical agent with a diverse span of uses, ranging from treating malaria to dying textiles[1]. Within the past few years, preclinical research has suggested a possible neuroprotective benefit from MB administration. MB is believed to promote neuronal cell health by supporting mitochondrial function. Animal studies have yielded promising results in neurocognitive tests[2][3]. Here is what you need to know if you’re interested in using methylene blue.

How does Methylene Blue work?

Mitochondria are organelles within cells that play the key role of energy production. Cellular energy is stored in the form of adenosine triphosphate (ATP), one of the most important molecules in the cell. As the name suggests, ATP contains three linked phosphate groups. Removal of each group releases a large amount of energy, which is expended in supporting cellular function. Subsequent removal of ATP produces ADP (adenosine diphosphate) & AMP (adenosine monophosphate). ATP is produced within mitochondria as a final product of respiration, a series of biochemical reactions that extract energy from glucose. These biochemical reactions require oxygen & electron carriers (e.g. NADH).

Poteet E, Winters A, Yan L, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue & its derivatives. PLoS One. 2012;7(10):e48279-.
Methylene blue acts as an artificial electron carrier, promoting mitochondrial respiration. The net outcome is more energy available as ATP for cellular processes.[4]
Methylene blue supports mitochondrial respiration by functioning as an additional electron carrier[5]. MB receives electrons from NADH through mitochondrial complex I, itself being reduced to leuco-MB (MBH2). Leuco-MB then donates the electrons to cytochrome C, upon which it is recycled back to MB. These reactions serve to create a high proton (H+) concentration in the space between the inner & outer mitochondrial membranes. This leads to the passage of H+ down the concentration gradient, through mitochondrial complex V. In doing so, ADP & a phosphate (Pi) are joined to form ATP. Leuco-MB can also act as a free radical scavenger, neutralising superoxides by accepting electrons & itself becoming oxidized back to MB[6]. In this way, leuco-MB acts to prevent direct oxidative damage caused by free radicals.

Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
Methylene blue preferentially accumulates in more active neurones (A), & potentiates mitochondrial & synaptic activity (B). These processes result in increased & improved neurotransmission (C), which is thought to be the mechanism behind the neurocognitive benefits associated with MB.[7]
MB has been observed to preferentially localise in neurones that are more active[3]. Stimulated mitochondria in these neurones modulate genomic expression of proteins that further potentiate mitochondrial respiration via nuclear respiratory transcription factor (NRF-1), resulting in increased expression of cytochrome oxidase (COX), nitric oxide synthase (NOS-1), NMDA receptors, & AMPA receptors. Strengthened synaptic connections as a result of these processes result in improved memory.

The pharmacologic mechanism behind the neuroprotective activity of methylene blue is unique in that it does not involve a receptor-ligand interaction, as do most drugs. In addition, MB also exhibits an atypical dose-response curve– one that has been described as hormetic[8]. Hormesis is a phenomenon where lower doses produce optimum responses while higher doses or exposures may actually produce the opposite effect. Hormesis is an intriguing pattern that may explain the dose-responses associated with exercise & oxidative stress, where the right amount of exercise-induced oxidative stress induces a cascade of favourable physiologic adaptations that can mitigate more severe stressors[9].

Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
An example hormetic dose-response curve. Note the inverse response caused with higher doses.[10]
As previously mentioned, metabolism of MB involves reduction to leukomethylene blue (MBH2). MB is primarily eliminated in the urine (75%)[11].

What is it like?

I have tested BlueBrainBoost’s formulation with the following results. I have noticed increased energy and decreased fatigue, with an onset of up to 1 hour and duration of 2-4 hours. The only adverse effects were discolouration of the mouth and urine. I used a dosage of 10 mg (20 drops) in the morning sublingually before brushing my teeth. During this time, I was also taking 30 mg/day coluracetam, 500 mg/day ashwagandha, & 600 mg/day NAC. I suspect that coadministration of CoQ10 and creatine may have a synergistic effect based on the pharmacologic site and mechanism of action.

Is it safe?

methylene blue nootropicMethylene blue is associated with a very favourable safety profile. It is generally well-tolerated at doses lower than 2 mg/kg.[12] The most noticeable side effect of MB is blue discolouration of the oral cavity and blue or blue-green discoloration of the urine. These effects are reversible and not harmful. [13] Staining of the teeth can be removed with repeated tooth-brushing, and discolouration of the urine ceases after the drug is fully removed from the system. Other reported adverse effects include a mild headache and dizziness[14].

MB does exhibit some serotonergic activity. This is due to its inhibition of enzymatic degradation of serotonin by MAO-A. Intravenous doses higher than 5 mg/kg have led to the development of serotonin syndrome. This risk is increased in individuals already taking other serotonergic agents (e.g. tianeptine, St. John’s Wort, common antidepressants, dextromethorphan, tramadol). For these reasons, individuals at risk should avoid coadministration of MB with serotonergic agents by at least 2 weeks (or more depending upon the agent), start at low doses, & increase carefully to an effective dose.

Neurotoxicity has been associated with some preparations of MB as a result of chemical impurities. The presence of heavy metals used in the synthesis of MB can have adverse effects on neurones. Thus, only pharmaceutical grade formulations are recommended for human consumption – not lab grade, & not aquarium grade. These formulations may not meet USP standards and may contain up to 11% contaminants.

How should I take it?

Because MB’s role as a neuroprotective agent in humans is still being studied, there is as yet no recommended dosage. The animal doses used in preclinical trials roughly converts to a human equivalent dose of 0.16–0.64 mg/kg administered sublingually. Sublingual administration may produce higher bioavailability than oral administration, but causes more staining of the mouth. I calculated my dose like so:

  1. 0.16 to 0.64 mg/kg × 54.43 kg = 8.71 mg to 34.84 mg per dose
  2. 10 mg/1 mL = 8.71 mg/x mL → 0.87 mL × 20 gtt/1 mL = 17 gtt to 3.5 mL per dose SL (gtt = drops)

It should be noted that due to the hormetic dose-response curve, the response to MB may decrease with higher doses. MB is typically formulated as a 10 mg/mL solution, where 1 drop = 0.05 mL = 0.5 mg. The bottle should be shaken well before administration.

Summary

Overall, I would recommend methylene blue to individuals looking for an inexpensive extra boost in energy. I have not tested MB long enough to notice changes in cognition or memory, but the pre-clinical studies & pharmacologic literature seem to support this benefit.

  • Methylene blue supports mitochondrial respiration & strengthens synaptic connections, which may lead to decreased fatigue and enhanced cognition & recall. MB exhibits a hormetic dose-response curve.
  • The safety profile has been well-characterised, and MB has generally been shown to be well-tolerated. I believe the most important warnings are those concerning serotonin syndrome and chemical impurities.
  • The best-estimated dosage is only an approximation from animal studies. MB is not yet recommended for human consumption for the purpose of improving cognition and memory.
  • Only pharmaceutical grade formulations of MB should be used.
Methylene Blue
7.5
Focus
8
Mood
7.5
Memory
8
Stimulation
5.5
Relaxation
6.5
Safety
Reviewer 8.3
Summary
Methylene Blue improves mood, memory and energy levels, as well as mitochondrial function (and may also delay aging). I think it is a powerful tool to have in your arsenal, and the BBB solution is cheap and convenient, therefore I highly recommend it to anyone.

References   [ + ]

1. Ginimuge PR, Jyothi SD. Methylene blue: revisited. J Anaesthesiol Clin Pharmacol.
2. Callaway NL, Riha PD, Bruchey AK, Munshi Z, Gonzalez-Lima F. Methylene blue improves brain oxidative metabolism & memory retention in rats. Pharmacol. Biochem. Behav. 2004; 77:175–181.
3, 7. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement & neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
4. Poteet E, Winters A, Yan L, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue & its derivatives. PLoS One. 2012;7(10):e48279-.
5. Gonzalez-Lima F, Barksdale BR, Rojas JC. Mitochondrial respiration as a target for neuroprotection & cognitive enhancement. Biochem Pharmacol. 2014 Apr 15;88(4):584-93.
6. Miclescu A, Basu S, Wiklund L. Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest. Crit. Care Med. 2006; 34:2806–2813.
8. Bruchey AK, Gonzalez-Lima F. Behavioral, physiological, and biochemical hormetic responses to the auto-oxidizable dye methylene blue. Am. J. Pharm. & Toxicol. 2008; 3:72–79.
9. Ji LL, Gomez-Cabrera MC, Vina J. Role of free radicals & antioxidant signaling in skeletal muscle health and pathology. Infect Disord Drug Targets. 2009;9(4):428–444.
10. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
11. Medscape® 5.1.2, (electronic version). Reuters Health Information, New York, New York.
12, 14. Ginimuge PR, Jyothi SD. Methylene blue: revisited. J Anaesthesiol Clin Pharmacol. 2010 Oct;26(4):517-20.
13. Gillett MJ, Burnett JR. Medications and green urine. Intern Med J. 2006 01;36(1):64-6.