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Misc Agmantine Sulfate for Kratom tolerance/potentiation

Okay Uncle Scrof quit scaring the kids now. You signed the non disclosure agreement when you left the agency..
 
Hey, I didn't disclose what those little fuckers really are. Where they come from. Yeah, I know. Hand me the pipe a sec, and I'll tell you everything.

OK, in seriousness, this thread was about agmatine and kratom originally. Well, it is absolutely true that agmatine prevents tolerance and potentiates opioid analgesia:

In chronic studies, agmatine at a low dose (0.1 mg/kg) which does not affect morphine analgesia acutely prevents tolerance following chronic morphine dosing for 10 days. A higher agmatine dose (10 mg/kg) has a similar effect. Agmatine also blocks tolerance to the δ-opioid receptor ligand [d-Pen2,d-Pen5]enkephalin given intrathecally, but not to the κ3-opioid receptor agonist naloxone benzoylhydrazone. Despite its inactivity on κ1-opioid analgesia in the acute model, agmatine prevents κ1-opioid receptor-mediated tolerance. These studies demonstrate the dramatic interactions between agmatine and opioid analgesia and tolerance.
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link

That paper was from 1996, so this has been known for a while. My instincts tell me that the potentiation and tolerance is for the actual pain-fighting use of opiates, in the peripheral nervous system, not the central nervous system, ie., the place you get high.

But, it's then reasonable to ask if agmatine does the same thing to kratom: and the answer is probably something, but no one has any idea. Kratom involves the mu-opioid receptor, which you might notice isn't mentioned in that quote.

Kratom is just not well understood, since it's a whole leaf kind of thing, which means dozens or hundreds of compounds that could be bioactive, all interacting with each other. So agmatine may interact with multiple kratom compounds, some potentiating, some inhibiting.

For now, you'll just have to rely on anecdotes. Is it safe? Probably, at normal doses of each.
 
This is a little allover the place but reinforces your thoughts on both substances and beyond...


Recently it has been revealed that some agents that are not able to interact with opioid receptors play an important role in regulating the pharmacological actions of opioids. Especially, some of them show biphasic modulation on opioid functions, which enhance opioid analgesia, but inhibit tolerance to and substance dependence on opioids. We would like to call these agents which do not interact with opioid receptors, but do have biphasic modulation on opioid functions as biphasic opioid function modulator (BOFM). Mainly based on our results, agmatine is a typical BOFM. Agmatine itself was a weak analgesic which enhanced analgesic action of morphine and inhibited tolerance to and dependence on opioid. The main mechanisms of agmatine were related to inhibition of the adaptation of opioid receptor signal transduction induced by chronic treatment of opioid.
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https://www.ncbi.nlm.nih.gov/pubmed/12852826

You were spot on about agmatine having very poor uptake into the CNS but agmatinase inhibitors are the way:
Like other monoamine transmitter molecules, agmatine is rapidly metabolized in the periphery and has poor penetration into the brain, which limits the use of agmatine itself as a therapeutic agent. However, the development of agmatinase inhibitors will offer a useful method to increase endogenous agmatine in the brain as a possible therapeutic approach to potentiate morphine analgesia and reduce dependence/withdrawal.
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https://www.ncbi.nlm.nih.gov/pubmed/17025265

Although Kratom does hold some serious promise even by itself in regard to interaction with Morphine
In MOR mRNA expression study, cotreatment of morphine with mitragynine significantly reduced the down-regulation of MOR mRNA expression as compared to morphine treatment only.
These finding suggest that mitragynine could possibly avoid the tolerance and dependence on chronic morphine treatment by reducing the up-regulation of cAMP level as well as reducing the down-regulation of MOR at a lower concentration of mitragynine.
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https://www.sciencedirect.com/science/article/pii/S0378874113002481

Looks like Kratom derivatives are the future of less addictive pain meds as well.

When administered orally, the antinociceptive effect of MGM-9 was seven to 22 times more potent than that of morphine. The antinociceptive effects of MGM-9 were mediated by both μ- and κ-opioid receptors. Subcutaneous administration of MGM-9 twice daily for 5 days led to antinociceptive tolerance. In the gastrointestinal transit study, MGM-9 inhibited gastrointestinal transit, but its effect was weaker than that of morphine at equi-antinociceptive doses. Furthermore, MGM-9 induced less hyperlocomotion and fewer rewarding effects than morphine. The rewarding effect of MGM-9 was blocked by a μ antagonist and enhanced by a κ antagonist. Taken together, the results suggest that MGM-9 is a promising novel analgesic that has a stronger antinociceptive effect and weaker adverse effects than morphine.
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https://www.sciencedirect.com/science/article/pii/S0028390808001305
 
Thanks for digging those up.

I was thinking agmatine could help with some of the physical symptoms of opiate abuse or withdrawal, like muscle pains. But then I noticed it does not interact with the receptor that makes you poop. So no relief for opiate constipation, or the shits you get with withdrawal, unfortunately.

Still, any relief is good, right?

And from those links, RC Kratom isolates, coming to a vendor near you.
 
It would be cool if MGM-9 ~[(E)-methyl 2-(3-ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-methoxyindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate~ became the next methadone or suboxone. Although there's no metric for less desirable like 22x as potent as Morphine.
 
The thing is, for Bluelighters who no longer use opiates as pain-killers, but because they've fired up reinforcement pathways, I wonder if putative drugs like this are helpful.

The researchers are looking for a pain-killer that doesn't get people hooked. But would something like that help with opiate withdrawals (other than possibly helping with shits and body aches), when it's the "hook" that's the problem? Or did I just miss it, and that is the whole idea behind kratom?
 
It's kind of like acetylating the morphine after stripping it from the opium. Opium's not so bad, Morphine is worse and H is the devil. Seems like they're headed down the same path with Kratom and MGM-9. After all Heroin was a non-addictive substitute for Morphine, Alcohol and Cocaine. If C.R. Alder Wright would have studied nothing more than salicyclic acid who knows how different things might be.
 
Tonight will start my regimen of a gram a day. I am going to alternate between taking it with kratom and before /after kratom. Next week I will add memantine to the equation. Will report back at the end of the week.
 
Mycophile said:
I found is link on Agmantine on Reddit but I don't understand it. Anyone wanna translate?
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Nothing too profound, it's a hyperspecialized study that, far as I know, didn't shatter any paradigms. NO signalling in the brain? Weird, but they must not have been the first to find that, or that would have been the title.

They had a totally expected result. They showed that agmatine modulation in this tiny brain region uses nitric oxide, and the enzyme nitric oxide synthase, to do it's business. It sounds like agmatine promotes NO production, instead of inhibit it, like the graph up this thread says. I don't want to read it all to check. Or look up why the locus correolus is interesting.

And that's because this doesn't matter for the supplement people, because it doesn't get into your brain (they shot the rats up in their brain-veins). Even if the chart at the top of this thread is wrong, and agmatine promotes NO synthesis, it's still not how things work to make your bicep veins poofy.

More interesting to BL'ers is that it involves imidazoline receptors, which are kind of newish and where the clonidine magic is thought to happen. Agmatine would be a very interesting drug if it could get into your brain.

It's like GABA supplements, basically.
 
I think it would definitely help w/d as it has a slight glowing effect that accompanies most ndma antagonis. Noticeable potentiation when taking 1gram with 5 grams of kratom. It does not affect duration like GFJ or Tagamet but it definitely seems to increase mood lift/euphoria, similar to 100mgs of dxm without the nasty side effects. From a nootropic perspective it stacks very well with coluracetam and phenylpiracetam.
 
FlawedByDesign said:
I think it would definitely help w/d as it has a slight glowing effect that accompanies most ndma antagonis. Noticeable potentiation when taking 1gram with 5 grams of kratom. It does not affect duration like GFJ or Tagamet but it definitely seems to increase mood lift/euphoria, similar to 100mgs of dxm without the nasty side effects. From a nootropic perspective it stacks very well with coluracetam and phenylpiracetam.
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Agreed, I was being a smart ass and going off topic with single sentences about DL Phenylalanine. Please keep reporting how your regimen is going as it is quite interesting.
 
Will report back in about a week after the accumulative effects present themselves. Will also add memantine to the mix. Thanks for digging up all that info. Very interesting indeed.
 
FlawedByDesign said:
I think it would definitely help w/d as it has a slight glowing effect that accompanies most ndma antagonis. Noticeable potentiation when taking 1gram with 5 grams of kratom. It does not affect duration like GFJ or Tagamet but it definitely seems to increase mood lift/euphoria, similar to 100mgs of dxm without the nasty side effects. From a nootropic perspective it stacks very well with coluracetam and phenylpiracetam.
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Do grape fruit juice and tagamet help Kratom to last longer or are you saying they make withdrawal last less long?

I tried drinking grape fruit juice with Kratom several times and felt it did not potentiate it.

Is the jury out on whether or not GPF does potentiate Kratom?

And I've never tried Tagamet but maybe I should.

People also keep saying that Tumeric and black pepper corns reduce tolerance but I don't know if that is true.
 
Grapefruit juice almost certainly causes something in kratom to last longer. That's just because there are hundreds of compounds in organic matter, and grapefruit juice is such a potent inhibitor of liver enzymes.

Whole extracts inhibit the usual major players, 3A4, 1A2 and 2D6. WGJ inhibits 3A4. Mitragynine is metabolized by the liver to an active metabolite; which enzyme? Don't know yet, or it's behind a paywall. How it all plays out you'll just have to try and let us know.

And the curcumin in turmeric cures every disease known in test tubes, no word on what it does for opiates or kratom. Black pepper only increases the curcumin bioavailability, from zero to like 0.1%.

mycophile said:
So what this guy is saying is just bullshit.

It's annoying when people go around spreading misinformation like this though I don't think he's doing it on purpose because he's not selling Phenylalanine supplements (to the best of my knowledge) so I don't think he has anything to gain there.
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Well, you can look through my post history here and find some misinformation. Fortunately not many read that stuff, so it didn't spread. I think the guy could be sincere and got the wrong big picture reading about addiction.

It's the problem with trying to simplify and generalize, you say dopamine is the "pleasure" chemical, released by "drugs" and causes "addiction". Well yes and no to all but addiction, and only things like amphetamines make your brain release enough stores that you could consider a supplement. The dopamine release from a gambler walking into a casino is different from the dopamine deluge forced by drugs like meth. The gambler doesn't run out of anything but money.

And I like the idea of tapering caffeine with a standardized dose like that. Coffee could be pretty variable. I'd watch yourself with the theobromine and xanthines, since they all have the same MOA. There's a lot of theobromine in cocoa, and it's more potent than you think--it kills dogs and black bears. Only difference is inter-animal metabolism.
 
It may be placebo but since taking 1 gram of agmantine with my first and last dose of the day I have effectively lowered my dose from 6gs ~6 Times a day to 5gs ~5 Times a day. I have also started supplementing CBD isolate which has probably helped as well. The vasodilation is pretty apparent during workouts and intercourse. This effect also Seems to cause angina when mixed with stimulating nootropics such as phenylpiracetam and coluracetam(keep in mind I get angina from moderate doses of caffeine as I am sensitive to stimulants)
 
Lol if you read closely the chest pain only occurred when mixing with stims(which is why I take it at a time where it doesn?t interact with any other substances). Unfortunately I?m unable to function without at least a bit of caffeine as my job is pretty demanding. Since 200 mg of caffeine causes angina where any reasonable amount of phenylpiracetam/coluracetam doesn?t I am effectively tapering off of caffeine by using the two aforementioned substances,(which seem to be the lesser evils ime) but thanks for the concern I suppose.
 
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