114 replies to this topic

[MrHappy]

(chuckle) good to see you back, SRI I still maintain it was your experiments above 2mg that gave you chest pains. I took a break because I was concerned that at 1mg, the MAO-I effect was screwing with my reward perception. I was right. Edit: damn Phone typos

Edited by MrHappy, 05 September 2011 - 09:06 AM.

[MrHappy]

Hmm looks like piracetam is a MAO-I in some parts of the brain and a MAO activator in others.

http://www.banchanid...acetam/004.html

[MrHappy]

I haven't stopped monitoring this thread for other user's progress. I believe you're right about the dosage. Right now I am taking 2-3mg of Deprenyl per day with high dose piracetam and fish oil. I haven't been able to dose at the amounts I want with the piracetam due to only having a 100g pouch.... but I have a kg on the way from Cerebral Health. I am endeavoring to find out just how effective high dose fish oil and piracetam can be, especially after seeing some of kassem's posts around here. I'm thinking about doing about 15g per day of each. I know this seems high and you probably think I have a propensity for extremes but I've only ever tested smaller doses (apart from an initial attack dose).

How does MB impact your reward center? Did you experience pleasure seeking behavior? How have your results been? Is MB something you'll keep in your regimen?

Sorry for the tangential post. I just notice this thread stays right at the top of the forum so I like to pop in and see how MB testers are doing.

Well the increased seratonin levels were the culprit, thanks to the MAO-I effect. Since I was already 'happy/rewarded', I found my libido waning and I wasn't seeking pleasure or comfort from my wife. Instead, I was seeking cognitive stimulation. It was like taking a mild version of amphetamines/adderall without the rush.

Given that I am 99% certain that the delayed senescence is because of the NOS-I effect, I think I will obtain that elsewhere and might reduce my MB intake to perhaps once every few weeks. One thing that I have noticed is that the enhanced cogntive effects have persisted a week after stopping MB, suggesting the effect is obtained from repairing existing cells and pathways. Of course this was not immediately apparent owing to suffering 'empty brain' monoamine withdrawal symptoms for the first 5 days. I think a periodic maintenance dose is the way forward, without generating tolerance issues to elevated monoamine levels.

[MrHappy]

Hmm .. again, I suggest caution about the MAO-I effects. If you are getting on and off it, particularly on a reasonable dosage, you'll certainly see some brain fog and memory issues on the withdrawal cycle.

[Brainbox]

If you would try this stuff, would it be able to identify the cause of a direct noticeable effect? Or would any short term noticeable effect occur due to the MAOI effect?


Edit:

I found this: http://www.springerl...1u/fulltext.pdf

... further corroboration and quantification of methylene blue’s potency (as an MAOI) is in progress.’ That paper has confirmed the prediction by demonstrating experimentally, that it is a potent tight binding MAO-A inhibitor at nanomolar concentrations

I'm a bit confused by this. And no time to further read up on it, so I'll throw it just in here....



I'm not sure, but are the doses advised here ( < 1 mg) resulting in this level of concentration? If I remember correctly, it is. And if it is correct, would the MAOI effect be predominantly present and hence make the mitochondrial optimizing look like a "minor side effect"? Or is the MAOI effect a precondition for the mitochondrial benefits?



I'm pretty sure that chronic use of a MAO-A inhibitor by healthy people would not be good.



But probably I'm just wrong.... it's late.

Edited by Brainbox, 18 September 2011 - 10:43 PM.

[niner]

If you would try this stuff, would it be able to identify the cause of a direct noticeable effect? Or would any short term noticeable effect occur due to the MAOI effect?

Edit:I found this: http://www.springerl...1u/fulltext.pdf

I'm a bit confused by this. And no time to further read up on it, so I'll throw it just in here....

I'm not sure, but are the doses advised here ( < 1 mg) resulting in this level of concentration? If I remember correctly, it is. And if it is correct, would the MAOI effect be predominantly present and hence make the mitochondrial optimizing look like a "minor side effect"? Or is the MAOI effect a precondition for the mitochondrial benefits?

I'm pretty sure that chronic use of a MAO-A inhibitor by healthy people would not be good.

But probably I'm just wrong.... it's late.

The IC50 for methylene blue inhibition of MAO-A is 164 nM, while the doses used here are aimed at a systemic concentration of ~100 nM. I wouldn't expect a noticeable effect from MAO inhibition at these doses, though if someone were right on the edge of a serotonin overload, maybe they would feel something from it. The instances of serotonin syndrome that have been seen clinically were only observed at MB effective doses that were 100+ times higher than the doses being used here.

The effect I've experienced from an 800 mcg dose doesn't feel like MAO inhibition. I find that on a stationary bike with an ergometer, I'm producing about 10% more watts with MB than without. I'm not seeing anything that I could describe as psychotropic.

[Logan]

I am going to see if my psychiatrist will prescribe me MB. I more hesitant now to try something close to the 15 mg dose used in the bipolar study. If significant MAO A inhibition occurs at a dose like this, it certainly might not be a good idea with the low doses of lexapro and zoloft I'm taking at the moment. But, I need some serious help getting my brain(and body) back to functioning the way it was about 4 or 5 years ago. Hmmm...I wonder what she will say. I wonder if she can prescribe 1 mg, and if the impact of that on MAO A would be mild enough.

[MrHappy]

Morgan - can we get a background on your current symptoms and history? Also, again mixing SSRI + MAOI = foobar.

[Logan]

Morgan - can we get a background on your current symptoms and history? Also, again mixing SSRI + MAOI = foobar.

Not concerned about the MAO A inhibition at the low doses being used here.

In a nutshell im bipolar and have some residual cognitive issues after suffering pretty severely for a few years. I have trouble reading in detail, trouble with focus, trouble with short term memory, and mental and psysical fatigue.

I currently take both Zoloft and Lexapro, but that won't stop me from trying MB at a super low dose. I've taken plenty of other stuff with mild mao a inhibitor action and I was perfectly fine.

[MrHappy]

Bipolar. OK, now out of interest - as statistics for some other research I am working on - do you have HSV-1 or 2?

[MrHappy]

BTW, I've seen lexapro cause some pronounced cognitive issues - inability to focus, memory issues, inability to handle stress.. Typically after a month or so.

[chrono]

Just extracted these posts about MAOI from the two mega-threads, since it seemed to deserve its own topic.

@Mr. Happy: reading this entire thread makes your last dozen or so responses seem a little odd. After niner's very reassuring maths, you still seem to be referring to significant MAOI as the primary mode of action, and warning people of dangers of serotonin toxicity without reference to dosage. What am I missing here?

Edited by chrono, 08 October 2011 - 07:17 PM.

[MrHappy]

@chrono

Theoretical maths are great, however I suggest it is trumped by real-life / subjective experience.

In that light, I can tell you that 750mcg - 1mg of MB, 3 times a day had a very noticeable MAO-I effect on me. I exhibited tolerance and dependance after a few weeks.

However, I can also tell you that 60mcg does not.

This is an interesting margin for dosage and suggests that 1mg doses shouldn't be treated as 'just a low dose, it's fine'.

[niner]

Theoretical maths are great, however I suggest it is trumped by real-life / subjective experience.

In that light, I can tell you that 750mcg - 1mg of MB, 3 times a day had a very noticeable MAO-I effect on me. I exhibited tolerance and dependance after a few weeks.

However, I can also tell you that 60mcg does not.

This is an interesting margin for dosage and suggests that 1mg doses shouldn't be treated as 'just a low dose, it's fine'.

I'm taking the same dose (almost exactly, in fact) and I notice nothing that I could describe as a MAOI effect. What sort of things were you feeling on that dose that you describe as a MAOI effect, anyway? What was the dependence effect?

[chrono]

In that light, I can tell you that 750mcg - 1mg of MB, 3 times a day had a very noticeable MAO-I effect on me. I exhibited tolerance and dependance after a few weeks.

In reading through the nootropic thread, it struck me that several people assumed any subjective effect was proof of MAOI activity, even at very low dosages. But do we know for sure that MAO is the only way in which this substance might affect neurochemistry? Was MAO-A inhibition confirmed by reactions unique to that mechanism? Keep in mind that several people have mentioned a dose close to 1mg didn't feel like MAO inhibition, as well. (edit: like niner ^^)

I agree that theoretical calculations based on in vitro studies are not 100% proof of safety, and it's probably more of an issue at 1mg than it is at 60mcg (though calculations suggest it still might not be that strong). But I don't think that means one should attribute all its effects to that mechanism in advance of better evidence, and maybe when warning someone of the danger, to highlight the fact that it's highly dose dependent?


I've been persevarating for a year or so about whether to take this myself. I'm on a moderate dose of tramadol (for chronic neck pain), which is a downstream SSRI and probable serotonin releasing agent. If I was going to try it, I'd probably start at an even lower dose than 60mcg, just to be cautious, but I think a pretty good case has been made for the safety of that dose.

Edited by chrono, 09 October 2011 - 01:12 AM.

[MrHappy]

The effects I noticed were virtually identical to the seratonin imbalance caused by experimentation with certain popular party drugs in my youth.

The 'need' to keep dosing was apparent.
The withdrawal symptoms after stopping cold turkey were pronounced. I was unhappy/mildly depressed, brain fogged and unable to complete my work efficiently.

Difficult tasks that should have taken eg 1 hr ended up taking 6 or more. I had trouble with short term memory loss and difficulty following multiple step tasks without constantly referring to documentation or notes.

This was really bad for about a week and gradually rebalanced over about 3 weeks or so.

Can't think if any other obvious chemistry changes that would cause these effects, but I'm always open to ideas.

[lourdaud]

MrHappy: Don't mean to be rude but you seem to be a bit dramatic. Like in the other thread "SSRI + MB WILL kill you" and now about these drastic WD symptoms. Sure you're not exaggerating a little bit?

I'm taking MB at ~250 mcg 4 times per day and I'm on escitalopram (5 mg) and dexamphetamine (15 - 20 mg), and the effects from MB are barely noticable. The best improvement, I think, has been that I don't seem to get mentally drained as quickly as before, now I can still read a book etc late at night, even when the dex has weared off.

[MrHappy]

Nope.

After withdrawing, I didn't want to touch the stuff again, but nearly 2 months later, curiosity overcame trepidation, I tried the lower dose at 60mcg and have had a much better experience thus far.

With MAO-Is, seratonin toxicity is a real issue. Tyramine, too.. it's why MAO-Is were banned originally. People died.

Not the most technical link, but I am typing this on my phone, so it'll do for now:
http://atheism.about...stjohnswort.htm

MB's MAO-I IC50 is 164nM. I had been reading earlier that day from another post that between 1-2mg orally equated to 100nM. Obviously, this concerned me at the time. There has since been another post with a PDF detailing MB distribution amongst organs, so I am somewhat more relaxed, but still cautious about doses in the higher range.

[thedevinroy]

That IC-50 is of concern to some... not me, but possibly to those on SSRI's. It is a reversible inhibitor, is it not? That definitely ramps down the danger at 1-2mg for foods contain tyramine and such, but it still might be of concern for those on SSRI or MAOi treatment. 60mcg is not much to worry about. Some report nootropic effects as low as 5mcg.

[chrono]

@klantskalle: thanks for that report, it's pretty indicative. How long have you been taking all three of those together?

Can't think if any other obvious chemistry changes that would cause these effects, but I'm always open to ideas.

I'm sorry to say I don't have any more solid explanation, but I still suggest that it doesn't make sense as an MAOI effect. Even if this effect is stronger at 1mg, a slight and transient increase in 5HT seems very unlikely to result in what you experienced. For MAO inhibition to have a similar aftereffect as, say, the cognitive consequences of heavy MDMA usage, and for 3 weeks, it seems like it would have to be a) irreversible inhibition, and b) so strong (to replicate a drug which floods your brain with supraphysiological levels of 5HT) that the effect would be obvious from tyramine, and people reporting combos with any serotonin agents would have been hospitalized.

Rather, in the presence of these fairly strong discrepancies, it seems more likely to me that MB has other actions on the brain (which seems reasonable, given reports of noticeable effects at <100mcg dosages), which did not agree with your chemistry at higher dosages. There are examples of this for every non-5HT/MAOI drug discussed here.

I'm certainly not trying to invalidate your experience in any way, but I think the reasons for it deserve more scrutiny. As niner said earlier, it's important to aim for a realistic assessment of risk.

I think it's pretty conservative to say that a 60mcg dose is of no concern even with SSRIs/etc. As for 1mg doses, it looks like it was established earlier that something like 25% inhibition could be reached transiently (in some organs?). Is there any good human data to suggest what levels of inhibition need to be reached (and for how long) to pose a risk of toxicity when combined with serotonergics?

Edited by chrono, 09 October 2011 - 02:29 PM.

[maxwatt]

...
I think it's pretty conservative to say that a 60mcg dose is of no concern even with SSRIs/etc. As for 1mg doses, it looks like it was established earlier that something like 25% inhibition could be reached transiently (in some organs?). Is there any good human data to suggest what levels of inhibition need to be reached (and for how long) to pose a risk of toxicity when combined with serotonergics?

No, not to my knowledge. I do know for me 60 mcg indistinguishable from placebo, and at 1.4 mg I felt brain fog, lack of energy. 350 to 700 mg has mild nootropic effect, and improves exercise poiwer output., But also take nuvigil (an enantiomer of provigol=modafinal).As far as I know, modafinal is a norepinephrine reuptake inhibitor, not involved with the serotonic system. Something else may be going on here than serotonin toxicity.

[thedevinroy]

...
I think it's pretty conservative to say that a 60mcg dose is of no concern even with SSRIs/etc. As for 1mg doses, it looks like it was established earlier that something like 25% inhibition could be reached transiently (in some organs?). Is there any good human data to suggest what levels of inhibition need to be reached (and for how long) to pose a risk of toxicity when combined with serotonergics?

No, not to my knowledge. I do know for me 60 mcg indistinguishable from placebo, and at 1.4 mg I felt brain fog, lack of energy. 350 to 700 mg has mild nootropic effect, and improves exercise poiwer output., But also take nuvigil (an enantiomer of provigol=modafinal).As far as I know, modafinal is a norepinephrine reuptake inhibitor, not involved with the serotonic system. Something else may be going on here than serotonin toxicity.

Armodafinil and Modafinil are Dopamine Reuptake Inhibitors as well as a D2 partial agonist and Orexin receptor agonist. Thus, it has a combined dopaminergic effect. The Orexin receptor agonism creates increased levels of dopamine, norepinephrine, and histamine. It also is glutamatergic, though not sure how, possibly Orexin related. I loved it, but it's dopamine reuptake inhibition required too high of a dose to be effective long term for ADHD.

I would never advise anyone to dose over 60mg of MB. I got twitching after that dose.

[MrHappy]

Twitching as in dyskinesia?

The only other noticable side-effect I had at 1mg was a sore neck from the vasoconstrictor aspect. Perhaps there was some additional / accumulative effect from that?

It's that or I have some genetic perculiarity that makes me more sensitive to MB, I guess. I'm extremely unlikely to be G6PD deficient.

Has anyone else here taken 1mg x3 for a few weeks and stopped cold-turkey?

[niner]

The only other noticable side-effect I had at 1mg was a sore neck from the vasoconstrictor aspect. Perhaps there was some additional / accumulative effect from that?

MB isn't actually a vasoconstrictor that I know of, but at doses far higher than we are using, it has been used to interrupt an abnormal vasodilation that sometimes occurs after cardiac surgery and is refractory to the usual agents like catecholamines. This is a good survey of the effect. The doses used here were 1.5 to 2 mg/kg delivered intravenously. That's effectively five hundred to a thousand times greater than what we're using, so I really doubt that this would cause a sore neck, which is a possible symptom of a hypertensive crisis. You could try checking your blood pressure with and without MB. This is interesting to me, because one of the effects I've noticed from MB may be related to vasodilation. If I crouch down for a while, then stand up quickly, I get a lightheaded, hypotensive feeling. I've found that MB reduces this phenomenon, even at 800 mcg. I'm trying to figure out what's going on there; I actually checked my bp at the gym today with both MB and a large coffee on board. I was 138/78, which is a little high for me, but certainly not a "hypertensive crisis". I'm going to do some more checking of this and see if I can figure anything out. The MOA that I'm leaning toward is improved mitochondrial output both in the brain and in the heart leading to improved cardiac output and reduced oxygen demand, but I want to try to rule pressor effects in or out. It's fairly tricky to measure transient hypotensive effects like I seem to experience without MB, so I don't know if I'll be able to put a number on that unless I hook up with someone who has the technology to do it.

[thedevinroy]

Twitching as in dyskinesia?

The only other noticable side-effect I had at 1mg was a sore neck from the vasoconstrictor aspect. Perhaps there was some additional / accumulative effect from that?

It's that or I have some genetic perculiarity that makes me more sensitive to MB, I guess. I'm extremely unlikely to be G6PD deficient.

Has anyone else here taken 1mg x3 for a few weeks and stopped cold-turkey?

Twitching as in muscle spasms. No shaking or uneasiness or restlessness. The penile ones were awkward.

I took it pretty religiously at 5mg and dropped to 1mg then infrequently. I suppose I could have got depression from that, but there were plenty of other things going on in my life at the time.

[unregistered_user]

I experimented with MB at varying doses (60mcg - 7mg) and noticed no apparent withdrawal symptoms after cessation. Perhaps I didn't take it long enough? Who knows really. Just figured I'd toss my subjective account of things into the conversation.

[MrHappy]

Hmm. Well, my wife also had neck tightness and pain on MB and I still get it to a much, much lesser degree at 60mcg.

S-R-I had chest pains, as I recall, at higher doses.

On the positive side, my vision is much sharper on MB and libido and sensory perception (skin) much improved at 60mcg. Additional bloodflow to my nether regions has also been most welcome.

However, at 1mg, my libido disappeared.

My only obvious difference is that I've premixed ascorbic acid with my MB. Not enough to change the colour.

[niner]

Dang, MrHappy, you get all kinds of cool effects from this stuff. I like what it does for me, but I'd like all the fun stuff too. I tried the ascorbic acid thing. I let it sit overnight, and got most of the color to go away. Maybe I should have used more ascorbic acid. Anyway, I didn't notice anything different from it. Could it be that some of these effects (or lack of effects) are due to contaminants? I'm using Kordon fish medicine. When I first started playing around with MB, I noticed a fairly subtle 'tightness' that felt like it was in my head, rather than neck. That was with low doses, like 60 mcg; it went away with higher doses. That's the opposite dose response to what you've felt. I could have been imagining it, I suppose.

[MrHappy]

(chuckle)

Well I am quite happy to send you a sample of my current batch and see if you have different or amusing results?

Maybe there is an impurity in what I am taking. I am also using fish-grade, but not Kordon's. It's from Aristopet.

[manic_racetam]

I've been taking MB for a couple weeks now... starting with around 1mg and slowly increasing up to 55mg (just one day). I've finally started noticing some effects from it. There is a definite mood-lift that happens but it is very short lived.

I've been dosing just in the morning and at night and didn't notice any effects for 2 weeks. Then today after a morning dose of 20mgs or so I noticed a moderately improved mood. The sun was shining and I was able to appreciate the beauty of the morning. Then just at about 4-5 hours after the morning dose I felt a dramatic drop in mood. (not earth-shattering but an easily noticeable contrast from the morning).

Tomorrow I'm going to go ahead and prepare 40mgs with ascorbic acid and keep it in a bottle. I'll just drink it in three doses. How should I eventually get off of this stuff though? Taper down for two weeks?

At these doses I haven't noticed any nootropic benefit, or really anything at all until this morning. If anything right now I feel a bit emotionally dull and there seems to be a lack of verbal fluency in my writing. Hmmm, tricky subjective experience.

As a side note I've stopped all other nootropics 2 days ago due to worries over interactions. I was worried a bit about energy drinks interaction with the MB but checked my blood pressure and it was 110/68... an actual great improvement for me. I'm rambling, I'm gonna end the post now

Edited by manic_racetam, 14 October 2011 - 12:12 AM.