Misc Kratom's mechanism... Does most of Kratom's WD come from its CA+ ion channel blocking??

[somnilicious]

What in the world is really going on with kratom's mechanism of action? I am a long time opiate addict 20+ yrs. I recently used Kratom after being 10 days clean from Heroin and still very much feeling like shit. I kept using the kratom because it was cheap, allowed me to work and something for me to look forward to everyday, while keeping me clean. By the end of 2mths of use, I was dosing all day long, everyday and going through an ounce of kratom a day. I read a lot about the withdrawal and determined I was taking a fairly large amount, so I braced for the worst upon cessation.

I found myself unable to really taper for various reasons, so I just decided to jump. What I found to my surprise was nothing. I suffered very little if any withdrawal at all. I suffer way more opiate withdrawal from simply dosing heroin, spread out, 2-3X's weekly. I had read report after report that either varied from slight, baby, opiate like withdrawal, to OMG this is worse than heroin withdrawal..... I cannot fathom how this could ever be worse than heroin withdrawal for an opiate addict. I am not doubting the horrible reports as some have come from esteemed and reputable members of this forum.

It has occurred to me that the significant withdrawal from kratom doesn't necessarily come from it's mu agonism at all and that that portion of kratom's effects are over played because I am highly sensitive to mu agonists withdrawal after years of opiate use and would have suffered thus do to kindling.

How could I possibly have avoided withdrawal? I believe that the positive effects from kratom are found from it's entourage effect and that most of its opiate relief comes from its different effects on the opiate receptors coupled with its CA channel blocking and SRA/NERA.

It is already known that gabapentin (NA+ ion channel blocker) increases the subjective effects of opiates when taken co-currently and that it is great for opiate withdrawal. I believe that kratoms mu agonism is minimal but its CA+ ion channel blocking makes the opiate like effects much more pronounced and it is why it is so effective for opiate withdrawal.

I postulate that the horrible withdrawal suffered by some actually has more to do with the CA channel blocking and other effects of kratom and less to do with its Mu agonism.

Gabapentin(another CA ion channel blocker) is known to have horrible withdrawal akin to opiates and benzos and if this was the source of most of the withdrawal effects it would explain the absence of most of the physical aspects of opiate withdrawal and why I didn't suffer opiate like withdrawal. I just hadn't gotten addicted to it's other properties yet, specifically its Calcium ion channel blocking effects.


I am curious to hear what others think about this. When people withdrawal from Kratom are they mostly withdrawing from a CA ion channel blocker, SRA/NERA and just slightly from its opiate effects?

Another related anecdote that came up in another thread is all the reports of Kratom killing the positive effects of other opiates, when one decides to use instead of the daily kratom dose. I have noticed that, while gabapentin increases the subjective effects of opiates when taken co-currently, it dramatically decreases the positive effects of opiates in the days following its use. This also leads me to believe that kratom's CA+ ion channel blocking is a significant part of its mechanism.

Based on my experience. I truly believe Kratom is a miracle plant if used correctly for opiate addicted people. I am simply amazed at it's various activities and effectiveness at handling opiate withdrawal, without causing a withdrawal of its own..... atleast in my case.

If the mods think this would be better suited for N&PD please feel free to move it....

 

[Sertürner]

I actually posted this in N&PD today but as a more generalized question as to how kratom works as a whole. There are so many compounds that contribute to kratoms effects that I don't think one mechanism alone is behind its effects and WD symptoms. I hope to hear from some of the guys on N&PD soon. It is a CA+ channel blocker, mu opioid agonist, and also has SNRI actions so there are tons of factors at play. In my spare time (I have very little right this week) I am investigating this as well. Let's hope we can find something that can find at least a partial answer.

 

[somnilicious]

It looks like I incorrectly, from memory, attributed kratom as a releasing agent instead of a reuptake inhibitor of SA/NE.. Still extremely fascinated. Does this mean the other shoe is going to drop days from now and I'm going to be depressed?

 

[Jekyl Anhydride]

What seems like something that is not only interesting, but will most likely be exploited by pharma companies is the pseudoindoxyl, which hits the mu-opioid receptors but not the kappa, delta, or α2 adrenergic receptors, but even more so it failed to stimulate B-arrestin-2. Failure to stimulate B-arrestin-2 and the delta antagonism seems to provide the pain relief of the classics, without the same level of G coupled protein desensitization. That would be an isolate I'd love to try over some fent analog.

 

[somnilicious]

It is a truly unique substance. The delta antagonism does indeed seem to somewhat help regulate tolerance in my opinion. I've heard all kinds of stuff about what is or is not true in regards to effect predictability and vein color but I have definitely noticed that the reds I've tried seem to have less of the tweeky, stimulant property and more of the classic opiate feeling. I go to a kratom bar and they have a large selection so I rotate very often and I've noticed that when one was working very well but stops working it helps to rotate batches to help bring back positive effects.

I was primarily taking reds and at one point they stopped working and I switched to some of the greens that were known to be more stimulating and the buzz was very effective again but it got progressively more tweaky and less pleasant. Some of the greens would often start to actually feel like an antagonists at higher doses. The weird part was that I switched back over to my original red and it was amazing again... Strange.... I wish I could have known exactly what was going on pharmacologically.

Fortunately the positive effects have just stopped working and I don't wish to chase it anymore and so I will be quitting. I just get more negative effects than positive now no matter the dose or color. It's seems that its self regulating properties are perfect for my goals of abstinence.

I've heard the color could have something to do with the curing process and i believe this could be true and that it helps to change the alkaloid profile... Although a study showed no composition differences by color.... I don't know how that can be true because something is definitely going on.

My friend has a couple of kratom trees and the fresh leaves are extremely tweaky but the leaves that fall off and turn reddish brown are a lot more sedating but you have to take more of them to get desirable effects. The fresh leaves are more uncomfortable at higher doses.... The composition obviously changes.

 

[Sertürner]

The alkaloid content varies from strain to strain, and even within strains. It does indeed help to rotate to avoid a tolerance build up but I do not quite understand why. As for your question about different colors from curing, this is true to only an extent. According to some very reliable sources, there are three types of leaves: Red Green and White, and there are only a few actual "pure" strains out there. These strains will be from the region they are grown in i.e. green Hulu, Red Bali, etc. There are also the Horned strains that use only horned leaves and Super strains that use large leaves. Then there are Maeng Da strains which are grown near rivers and mossy areas. The color difference as well as the name of the strain is actually just a blend of the 3 colors of leaves at certain ratios. So hundreds of strains can be made using just the 3 colors of veins grown from different regions of Indonesia (primarily). There are exceptions to the rule though, Bentuangie kratom is a great example, it is fermented during its drying process and this changes the color and alkaloid profile of the kratom.

These different factors allow a ton of difference among strains, which is why rotating every so often will bring new life to your kratom usage. As far as how the alkaloids work together though, I'm still learning everyday about it through my own studies and you guys. I would like to keep this thread going as there has been MANY threads about this recently and the some of the best people to answer these questions are already posting on it. It willl be very interesting to see what we can dig up. It seems JA has a decent grasp on some of the more specific questions involving the pharmacodynamics so I'm sure he will be able to enlighten us further.

 

[Sertürner]

It looks like I incorrectly, from memory, attributed kratom as a releasing agent instead of a reuptake inhibitor of SA/NE.. Still extremely fascinated. Does this mean the other shoe is going to drop days from now and I'm going to be depressed?

Eh not in my experience. The WD is not terrible and I am a 30-50g a day user. I get a little irritable and restless with some recurring pain and restlessness but that is about it. Think a smoking habit with a caffeine addiction. Hard to quit but the WD is not terrible. No real depression or lethargy that I have experienced. Take in mind I have no scientific data to back this up for the population as a whole at the moment though.

 

[somnilicious]

I wound up taking10g today split in 2 doses an hr apart. I have a total of 10g left that I am allowing myself over the next 2 days. I will probably take 6g, at happy hour(4pm) tomorrow and then 4gm(4pm Wed) and that will be it for me. I skipped 2 days after basically taking 30gm a day for a week at the end. I just took a weewee test for probi and will have a couple of days to smoke. I got 2gms of higher, mid grade buds for the next couple of days for my quick taper. I am starting to enjoy being more clearheaded lately and every substance seems to get in the way of that and have a downside..

I'm ready to be done and moving on....

 

[Sertürner]

What seems like something that is not only interesting, but will most likely be exploited by pharma companies is the pseudoindoxyl, which hits the mu-opioid receptors but not the kappa, delta, or α2 adrenergic receptors, but even more so it failed to stimulate B-arrestin-2. Failure to stimulate B-arrestin-2 and the delta antagonism seems to provide the pain relief of the classics, without the same level of G coupled protein desensitization. That would be an isolate I'd love to try over some fent analog.

I couldn't find much on mitragynine pseudoindoxyl, except this

Kratom and its Alkaloids - Pyxis Labs

March 2017 Francisco J. Rojas, Ph.D. In August 2016, the US Drug Enforcement Administration (DEA) announced plans to designate mitragynine and 7-hydroxymitragynine, two alkaloid compounds that naturally occur in the leaves of kratom, as a schedule 1 substances. The classification was a de facto...

www.pyxislabs.com

There were a few article that I couldn't fully access and/or had very limited information on, but I'm excited to learn about this.
This might be why the Bentuangie Kratom is so different from other strains. It is by far the most analgesic of any of the kratom I have tried, but it does not cause very much of a euphoric effect at all. Can you find any info on the pseudoindoxyl and ORL-1 activity?