56 replies to this topic

[gamesguru]

Based on the length of posts, it would seem you are the more irate one. But thanks for the information, no offense.

 

The way you swooped in with the "absolute dosage" 280mg figure was pretty authoritative and dismissive of my 0.5mg/kg figure.  The way you highlighted how it was 280mg and not 4mg/kg, it almost seems to suggest you disagree the average person has a mass of 70kg. Am I wrong?  And if it is not your intention to disagree, consider making your agreement more obvious.  Failure to do so may lure others into cognitive distortions.

As I said, as little as 1mg may be effective, due to the non-linear dose response.  In conclusion, no one has done any research or testing in this thread to confirm or falsify the 1mg (0.02mg/kg) hypothesis. 280mg may not be required

Edited by gamesguru, 11 July 2016 - 06:24 PM.

[BioFreak]

Again, I thought you were referring to the study, as you did not state otherwise. That was all. No more, no less.

 

I am not irate, at all. But I need to correct you, when you put words into my mouth that I simply did not say. Also, I have the belief that, just like you said, if I didn't get my point across, I need to make it more obvious. Thats what I am trying to do.

 

You might think it is smart to interpret between the lines. But in science, it is not. Just look at the quote you pasted earlier (and it would be nice if you also post the source next time): All they said was extremely to the point, making interpretation as impossible as possible, because interpretation makes bad science. Interpretation makes the reproduction of a study impossible. Interpretation is extremely inaccurate. So just sticking to the facts, and asking, if it is not clear, is much better then reading between the lines. Reading between the lines just makes one look smart, but in reality just increases the error rate.

 

 

To be extremely clear:

I do not have a theory on methylene blue, therefore I do not need to proof it.

I never said anything about the average weight of an average human.

I did not say what you think I seemed to have said. I just said what I said, no less, no more.

Anything that has not be said by me is just an projection, assumptions without any base whatsoever.  Maybe first ask to clarify what your counterpart means if it is not clear? 

 

Could we please get back to topic now?

 

0.75mg/kg IV already may have an MAOA inhibiting effect(link), thats why I asked about the oral bio availability of mb. 280mg would be way above that.

 

Also, its quite worrying since many users here take drugs or supplements that increase serotonin (maois, 5-htp, ssris, cheese  , etc...) which would, in combination with 280mg mb be extremely dangerous...

[BioFreak]

I'm asking myself: WHY did they use this dosage, and not a much lower one?

 

Bio availability of mb is high, at 72.3 +/- 23.9%(link), and is said to be equally effective(link). So that rules out that in this study, the authors dosed high because of low bio availability. Those two studies are the only they cite about the safety of mb, however. It is possible that the high dosage in the new study is simply due to the fact that the MAOA inhibition is a relatively recent discovery and they simply were not aware of this information or regard it as inaccurate because of the century long safety track record...

 

Or it is simply because they wanted a similar environment to this study  (And by using a similar dose, being sure that there should be an effect because of said study) but focusing on short term and attention instead. I guess that is the most likely explanation for the dosage they used. It is a pretty interesting study, showing the retention of fear extinction at a similar one time dose (260mg), if the exposure was successful. Basically, if an extinction session was successful, mb would make the subject help remember that it was. But the same would go for an unsuccessful extinction session.

 

In any case, they did exclude any subjects that had exposure to serotonin enhancing drugs:

 

 

The following exclusion criteria were used: any neurologic, psychiatric, cardiovascular, hepatic, or renal disorders; a history of organ transplantation; hypersensitivity to methylene blue or thiazide diuretics/phenothiazines; glucose-6-phosphate dehydrate deficiency; a contraindication to MR imaging; colorblindness; methemoglobinemia; ingestion of any psychiatric medication (currently or within the past 5 weeks); pregnant or breastfeeding; and a history of any surgery that could interfere with normal drug absorption.

 

Anyways, the question why did they use a dosage of 280mg? Because they thought it was safe (in healthy humans without serotonin increasing drugs) and because they wanted to see if an more or less equivalent dosage as used in that other study would have an effect on other parts of the brain / brain function as well.

 

Plus, it was a one time test. Meaning no repeated doses of mb, further increasing safety.

 

So... NOT a "hey lets use this dosage cause its safe and can be used every day" type of study, but a "we proved that there is an effect on short term memory and attention with mb" study.

 

I guess, I solved my question...

 

As this study focused on the question "can attention and short term memory be positive affected by mb?", the next study based on this should probably focus on "what is the minimum dosage to archive the seen effect in attention and short term memory".

 

Then we'd have facts on dosage.

Edited by BioFreak, 11 July 2016 - 08:39 PM.

[gamesguru]

If you're satisfied, I am too. And the reason for the 280mg/kg, as I explained twice already, earlier studies had used 4.0mg/kg as a standard. And that trend was continued in future studies.

 

And it's not even a question of the minimum dose, but rather the shape of the dose-response curve. Based on testimonies, I gather MB has a very steep one.

[thedevinroy]

I feel bad for the people who got the food dye.

Yes but this is only one study, and similar ones [see below] have reported a benefit at one quarter the dose. My point about not all compounds exhibiting a linear dose-response curve still holds, and the burden remains on you to establish methylene blue as linear when all experience dictates contrary. People are reporting benefits BELOW 1mg. You have to ask yourself all the hype can be explained by the placebo effect...

Specifically, repeated low-dose (0.5-2.0 mg/kg) MB has long-lasting upregulation of brain cytochrome c oxidase activity [20, 24-26]. MB readily crosses the blood-brain barrier because of its high lipophilicity [15].
Low-dose MB has recently been shown to reduce neurobehavioral impairment in optic neuropathy [19, 27], traumatic brain injury [28], Parkinson's disease [23, 29], Alzheimer disease [30-32], and ischemic stroke [4, 5, 33]. The goal of this article is to review relevant MB literatures in relation to neuroprotection in experimental stroke models.

My favorite part is where it says that MB concentrates on the brain up to 20 times higher. They used 1mg/kg in rats which is about .215mg/kg or 15mg for a 70kg human. Even dividing by 20 gives 750mcg... So I guess maybe that's where people think that micro dosing is cool?

[thedevinroy]

For an update, I was very much hazy today, constantly complaining of the Mondays. Two more days of this, and I'll have an answer. I will say that I'm less twitchy today, and it feels similar to nortryptaline in effect, which I sometimes even feel at a low dose of 52mg. So yeah, that dirty serotonergic care free but can't think to hard feeling. Will see if it persists into tomorrow or the next. The 4mg/kg rat studies (closer to 60mg in humans) was a 5 day study, so I'll do that much.

Dopaminergic effects were not as severe and absolutely not noticeable. I did several things today of adrenaline seeking behavior without an actual adrenaline response - a clear indication of I'm back to regular me.

My tea cocktail helped but not like it did the first few times. This may indicate the end of my titration effects. All variables are close to maintained from yesterday aside from the actual times I went to bed and got up. Tomorrow will be a better test run.

Edited by devinthayer, 12 July 2016 - 02:49 AM.

[thedevinroy]

ok i solved this problem "L-Deprenyl, also an MAO-B inhibitor, metabolizes to L-amphetamine and L-methamphetamine, which are both norepinephrine releasing agents. In contrast, D-deprenyl additionally has dopaminergic effects and has been found to be reinforcing in scientific research, whereas L-deprenyl is not known to have any appreciable psychological reinforcement"

so selegiline is basically useless. not sure why i didnt pay attention the first time i used it. time to DUMP!

Useless as what? As a cognitive enhancer, maybe for you. The mood enhancement properties are great. And it takes about two weeks to kill off all your MAO-B at normal doses of 5mg twice per day. Not sure the dose shaped response curve of that one.

The point of it is to reduce your intake of dopamine precursors required to achieve Antiparkinsonian effects. But for me trying to treat ADD, I was literally high all the time without much in the way of supplementation. Too scared to add much else. It was way too much. If I had the liquid form, I'd be game to try it again so I could get the dose right and find a nice synergy with some other nootropics.

Here I talk about the effects in pretty great detail:

http://www.longecity...e/?fromsearch=1

I go on to explain the differences in effects and how eventually the side effects of the midday crash and anticholinergic side effects and the whole ass kick upwards when I first took it. My whole stack and what I could eat revolved around managing Selegiline. It was a real pain in the ass. Picked me up and dropped me like a sack of potatoes, so I would take adaptogens to smooth out the ups, and when the crash came, have a cup of tea and be wired again.

Most of that had to do with the metabolites, yes, agreed. The MAOI-B effects were really nice, but not worth the ups and downs.

Man I forget so much of this... my long term memory is like mush. It's all coming back to me as I read it, but it just was way back there in the archives of Devin's head. Too much long term NZT use without the enzyme injections...kidding...

Edited by devinthayer, 12 July 2016 - 03:42 AM.

[normalizing]

i dont get much from selegiline in relation to mood enhancement just a bit more concentration, focus etc. as mentioned. doesnt necessary mean a good thing for me tho since coffee can do just as a good job. main reason for selegiline use for me is dopamine. your synergy thread is again, all about focus and energy etc. nothing to mention a combo of enhancing dopamine.

 

so do you suggest i boost the dose to 10mg a day? maybe in few days there is some dopamine effect. and also i must think of a synergy that does just that, enhance dopamine!

[normalizing]

ok i finished that thread you urled, this is a good page http://wiki.blueligh....php/Selegiline and im also curious of trying it with phenylalanine. when i was a kid, phenylalanine was the only natural thing to boost dopamine and fix depression back then. but last several times as grown up that i have tried it, it did jack shit at doses up to 10 grams! so im skeptical it will even show minimal effect in combo with selegiline but from what i gather, its too enticing not to try it again.

[thedevinroy]

ok i finished that thread you urled, this is a good page http://wiki.blueligh....php/Selegiline and im also curious of trying it with phenylalanine. when i was a kid, phenylalanine was the only natural thing to boost dopamine and fix depression back then. but last several times as grown up that i have tried it, it did jack shit at doses up to 10 grams! so im skeptical it will even show minimal effect in combo with selegiline but from what i gather, its too enticing not to try it again.

Agreed since MAO-B breaks down L-Dopa. Now that you are in Selegiline, your body can make more dopamine. Since phenylalanine turns into both PEA and tyrosine, your dopamine release and L-Dopa levels will increase. D-phenylalanine raises endorphins, so that too might have a triple effect going to DLPA.


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[thedevinroy]

i dont get much from selegiline in relation to mood enhancement just a bit more concentration, focus etc. as mentioned. doesnt necessary mean a good thing for me tho since coffee can do just as a good job. main reason for selegiline use for me is dopamine. your synergy thread is again, all about focus and energy etc. nothing to mention a combo of enhancing dopamine.

so do you suggest i boost the dose to 10mg a day? maybe in few days there is some dopamine effect. and also i must think of a synergy that does just that, enhance dopamine!

Go for it. That's a generally practiced dose, but keep a careful eye on the ups and downs.


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[normalizing]

well, on second note im kind of uncomfortable with adding phenylalanine because of fear of psychosis. i already got mild psychosis like effect from eating nicotine gums while on it

[normalizing]

actually sorry to being off course, we should stick to topic here

[thedevinroy]

Okay, back on topic.  Yesterday, I got overfocus-related insomnia.  Today I left late from work for the same reason.  Tonight I am also suffering from it... oh sigh... 

 

I shall say that whatever effects were good from it are now no longer noticeable, nor as beneficial as I was anticipating.  Brain farts all day with a few periods of the overfocus as explained.

 

And perhaps this is all serotonin-related stuff, but I think I'll use MB as more of a novelty drug - like once in a while thing.  Maybe it is NO Synthase related.  Either way, it's been an absolute bust in the long run.

 

I think I'll go the PQQ route for cytochrome Oxidase C...

 

http://www.ncbi.nlm....pubmed/25621792

 

Now if only I can find a way to get the cellular concentrations they've talked about... 30 micromoles in vitro?

 

6-12 nM is about all I can get:

 

http://www.sciencedi...955286313001599

 

Oh well... it does seem to concentrate in the skin, so at least if I take it, I'll be pretty.

Edited by devinthayer, 13 July 2016 - 03:20 AM.

[thedevinroy]

Okay, back on topic.  Yesterday, I got overfocus-related insomnia.  Today I left late from work for the same reason.  Tonight I am also suffering from it... oh sigh... 

 

I shall say that whatever effects were good from it are now no longer noticeable, nor as beneficial as I was anticipating.  Brain farts all day with a few periods of the overfocus as explained.

 

And perhaps this is all serotonin-related stuff, but I think I'll use MB as more of a novelty drug - like once in a while thing.  Maybe it is NO Synthase related.  Either way, it's been an absolute bust in the long run.

 

I think I'll go the PQQ route for cytochrome Oxidase C...

 

http://www.ncbi.nlm....pubmed/25621792

 

Now if only I can find a way to get the cellular concentrations they've talked about... 30 micromoles in vitro?

 

6-12 nM is about all I can get:

 

http://www.sciencedi...955286313001599

 

Oh well... it does seem to concentrate in the skin, so at least if I take it, I'll be pretty.

 

Just found this one: http://www.jnutbio.c...(13)00159-9/pdf

 

Looks like PQQ is effective in humans for reducing amino acids, dietary amines, krebs substrates, etc. as probably a function in better utilization of the parent compounds... which sounds like more mitochondria were made... even at 0.2mg/kg and 0.3mg/kg dosing.

 

Never tried it, since I was told the effects wear off after two weeks.  But, hey I make more money now.  I can afford to take it, especially if it increases energy by the kreb's cycle.  I can cut back on my vinegar consumption, which is like $9 a bottle or something for the mothers?  I mean with the mothers... and also for mother's too... they deserve only the good stuff...

 

...

 

Oh yeah, back to the original topic... 

 

More evidence that this should be used as a novelty drug:

 

"Methylene blue is a memory-enhancing drug in animals and humans after a single dose in the low-dose range of 0.5–4 mg/kg, but it has opposite effects at doses greater than 10 mg/kg and displays a hormetic dose response."

 

Back from the original study: http://pubs.rsna.org...diol.2016152893

 

Which references this one: http://www.ncbi.nlm....les/PMC2867617/

 

Also, doesn't anyone think it is weird that the study on Tau proteins in phase 3 trials was never released? https://clinicaltria...rm=taurx&rank=4

 

How long will we have to wait before it tells us that everyone died from tumors or perhaps even that they all developed telekinesis and reversed their aging process by 20 years?

Edited by devinthayer, 13 July 2016 - 03:50 AM.

[normalizing]

so its not good for regular use *sigh* i thought it could have been a cheap reliable antidepressant

[jroseland]

I've been using it a couple times a week for the last couple months and I'm pretty underwhelmed with its effects

[BioFreak]

 

 

More evidence that this should be used as a novelty drug:

"Methylene blue is a memory-enhancing drug in animals and humans after a single dose in the low-dose range of 0.5–4 mg/kg, but it has opposite effects at doses greater than 10 mg/kg and displays a hormetic dose response."

 

Back from the original study: http://pubs.rsna.org...diol.2016152893

 

Which references this one: http://www.ncbi.nlm....les/PMC2867617/

 

 

 

Does the second study explicitly state that the effects are opposite after chronic dosing? The quote you pasted actually only says that there is an effect after one dose and that there are opposite effects at higher dosages. It does not explicitly say that there is a problem with chronic dosing. I'm not saying you are wrong on the chronic effects, though.
 

[thedevinroy]

More evidence that this should be used as a novelty drug:
"Methylene blue is a memory-enhancing drug in animals and humans after a single dose in the low-dose range of 0.5–4 mg/kg, but it has opposite effects at doses greater than 10 mg/kg and displays a hormetic dose response."

Back from the original study: http://pubs.rsna.org...diol.2016152893

Which references this one: http://www.ncbi.nlm....les/PMC2867617/

Does the second study explicitly state that the effects are opposite after chronic dosing? The quote you pasted actually only says that there is an effect after one dose and that there are opposite effects at higher dosages. It does not explicitly say that there is a problem with chronic dosing. I'm not saying you are wrong on the chronic effects, though.

I don't know for sure. It seems to help clean up beta amyloid and tau proteins, so chronic use for the case of Alzheimer's and Parkinson's makes sense. I just felt like crap after chronic use. Same with quercetin which also has nanomolar affinity for MAO-A. I might just really be sensitive to that kind of stuff. NO Synthase inhibition is another thing someone mentioned was a bit scary of a side effect at higher doses. It's IC50 is as low as 5 or 6 microM and was described as basically not beneficial even with the beneficial effect on NADH. So that's the other theory on why I didn't respond well to chronic dosing.

Here was a convincing article on chronic dosing in rats:

https://www.ncbi.nlm...hrome oxidase c

Which is about 15-20mg in humans or about 0.22 mg/kg. This was injection, so assume some is lost when dosing (-28% on average: http://www.ncbi.nlm....ubmed/18810398/ ). Thus the oral human equivalent dose would be slightly higher than 20 to 28mg to get to equivalent peak plasma levels.

I was dosing at around 150mg, because the initial side effects were bearable and still gave me a boost. This was not true over time - just coming down from a much higher dose. Even at around 60mg/dose I would get insomnia. Perhaps this 20-28mg range is the sweet spot.

There was a human study that showed an injection of 0.75mg/kg in humans have a 1.6 microM/L concentration in the blood stream. I know that it isn't a linear scale, but you can use that as a a gage for a rough idea for blood concentrations and its in vitro effects using 73% oral bioavailability. There was also a study that explained the concentrations found in the different tissues, and IRCC, it was something around 20x in the brain. This means that the variability of blood vs brain may also play a factor in why lower doses have better nootropic properties.

Edited by devinthayer, 25 July 2016 - 11:50 AM.

[BieraK]

What do you think could be the interactions between MB and over/under methylation conditions?

 

[thedevinroy]

What do you think could be the interactions between MB and over/under methylation conditions?

I would not take it if you are over methylated. Arguably, it's strongest in vitro effect is in MAO-A inhibition, meaning it is an antidepressant before it is anything else. Because of its effects on monoamines, it could have an anxiogenic effect in someone with high SAMe levels, depending on their norepinephrine vs. serotonin balance - both of which require methyl donors. Therefore, it's really hard to blanketly assume this is good vs. bad for someone who is over vs. under methylated unless you correct the core problem first by adding niacin vs. methyl folate - both of which do nothing for me, mood-wise. Maybe the baseline monoamines are too low after correcting the SAMe levels, in which case something like Methylene Blue would help to raise those up. I can only imagine that happening in an under methylated individual who takes the recommended methyl folate dose and smooths it out with niacin as needed but still continues to have problems with mood.

Edited by devinthayer, 27 July 2016 - 11:09 AM.

[Finn]

This research was done on driving skills of healthy volunteers on another reversible MAO-A inhibitor, moclobemide, compared to mianserin and placebo. The first day boost got a lot weaker, while on the first day people on moclobemide drove better from the beginning of the drive, on the 8th day there was no boost on the first section of the drive and people on moclobemide only seemed to drive slightly better than on placebo on second section of the drive while driving back. First day boost might not last that long. 

 

http://link.springer...1007/BF02246238

 

Effects of moclobemide and mianserin on highway driving, psychometric performance and subjective parameters, relative to placebo

 

on day 1, there was an indication that subjects actually drove better after moclobemide than after placebo. 

 

 

 

SDLP = standard deviation of lateral position 

Attached Files

•  sdlp.jpg   73.15KB   3 downloads

Edited by Finn, 29 July 2016 - 03:54 AM.

[BieraK]

Wow this study was released 30 August of this year, loos really interesting, this substance never ceases to surprise me
http://www.sciencedi...306452216304092

 

Methylene Blue promotes cortical neurogenesis and ameliorates behavioral deficit after photothrombotic stroke in rats
Abstract

Ischemic stroke in rodents stimulates neurogenesis in the adult brain and the proliferation of newborn neurons that migrate into the penumbra zone. The present study investigated the effect of Methylene Blue (MB) on neurogenesis and functional recovery in a photothrombotic (PT) model of ischemic stroke in rats. PT stroke model was induced by photo-activation of Rose Bengal dye in cerebral blood flow by cold fiber light. Rats received intraperitoneal injection of either MB (0.5 mg/kg/day) from day 1 to day 5 after stroke or an equal volume of saline solution as a control. Cell proliferative marker 5-bromodeoxyuridine (BrdU) was injected twice daily (50 mg/kg) from day 2 to day 8 and animals were sacrificed on day 12 after PT induction. We report that MB significantly enhanced cell proliferation and neurogenesis, as evidenced by the increased co-localizations of BrdU/NeuN, BrdU/DCX, BrdU/MAP2 and BrdU/Ki67 in the peri-infarct zone compared with vehicle controls. MB thus effectively limited infarct volume and improved neurological deficits compared to PT control animals. The effects of MB were accompanied with an attenuated level of reactive gliosis and release of pro-inflammatory cytokines, as well as elevated levels of cytochrome c oxidase activity and ATP production in peri-infarct regions. Our study provides important information that MB has the ability to promote neurogenesis and enhance the newborn-neurons’ survival in ischemic brain repair by inhibiting microenvironmental inflammation and increasing mitochondrial function.

 

Edited by BieraK, 12 September 2016 - 06:50 AM.

[BieraK]

Well guys this "blue" ignorant need some advice of the most versed users of this forum.

How this studies could be interpreted? so this research indicates that MB increases methylation?
 

Increased cytotoxicity and phototoxicity in the methylene blue series via chromophore methylation.

Spoiler

The cytotoxic and photodynamic activities of the commercially-available biological stains methylene blue (MB), 1,9-dimethyl MB (Taylor's Blue) and a newly synthesised compound, 1-methyl MB, were measured against the murine mammary tumour cell line, EMT-6. Both 1-methyl MB and 1,9-dimethyl MB exhibited increased dark toxicity with concomitant higher phototoxicity compared to MB at a light dose of 7.2 J cm-2. While increasing the light dose as a function of the fluence rate increased the photocytotoxicity of MB, this had little effect on the methylated derivatives. In vitro chemical testing proved that successive methylation rendered the phenothiazinium chromophore both more resistant to reduction to its inactive leuco form, and also led to increased levels of singlet-oxygen production, thus providing a possible explanation for the increased toxicities of the methylated derivatives. Comparisons are made with the benzo[a]phenothiazinium photosensitizer, EtNBS.

https://www.ncbi.nlm.../pubmed/9372612
 

Effect of increasing methylation on the ability of methylene blue to cause diaphorase-catalysed oxidation of NADH.

http://www.biochemso...g&pmid=10047833

 

[normalizing]

the first study you posted was injections. nobody would inject MB for benefits, NOBODY!

[Captain Obvious]

I've been taking about 24 mg per day for several weeks now. Haven't noticed any acute effects one way or the other.  Since there might be beneficial effects from chronic use, I'll keep supplementing it. After all it's very cheap and easy to take. I mix it with some pomegranate juice concentrate and gulp it down with other supplements (NR, PQQ, etc.) first thing in the morning.

I consider the effects from people claim to get from microgram level dosing to be most likely placebo. If anybody knows any research on very low-level dosing, I'd be interested.

Edited by Captain Obvious, 06 October 2016 - 05:51 AM.

[gamesguru]

Well as low as 0.5mg/kg has been studied with impressive results (see above).  But then you have other, more disappointing results:

Br J Psychiatry. 2016 Jun 9. pii: bjp.bp.115.173930. [Epub ahead of print]

Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study.

Alda M¹, McKinnon M², Blagdon R², et al.

Abstract

BACKGROUND:

Residual symptoms and cognitive impairment are among important sources of disability in patients with bipolar disorder. Methylene blue could improve such symptoms because of its potential neuroprotective effects.

AIMS:

We conducted a double-blind crossover study of a low dose (15 mg, 'placebo') and an active dose (195 mg) of methylene blue in patients with bipolar disorder treated with lamotrigine.

METHOD:

Thirty-seven participants were enrolled in a 6-month trial (trial registration: NCT00214877). The outcome measures included severity of depression, mania and anxiety, and cognitive functioning.

RESULTS:

The active dose of methylene blue significantly improved symptoms of depression both on the Montgomery-Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression (P = 0.02 and 0.05 in last-observation-carried-forward analysis). It also reduced the symptoms of anxiety measured by the Hamilton Rating Scale for Anxiety (P = 0.02). The symptoms of mania remained low and stable throughout the study. The effects of methylene blue on cognitive symptoms were not significant. The medication was well tolerated with transient and mild side-effects.

CONCLUSIONS:

Methylene blue used as an adjunctive medication improved residual symptoms of depression and anxiety in patients with bipolar disorder.