Kratom Isolated 7-OH-Mitragynine products are beginning to hit the market (!...?)

[SpiralusSancti]

Don't forget that tolerance is a word used for a reason. Developing tolerance to drugs is fundamentally not that different to developing tolerance to any inner or outside factors, be it tolerance to cold or tolerance to spicy food or tolerance to pleasures...

 

[Hexenstahl]

Except that tolerance to opioids can actually be effectively blocked by the application of microdoses of Naltrexone. Not only studies and numerous anecdotal user reports exist on the effectivity of ultra low dose naltrexone in lowering opioid tolerance and potentiating its effects, but an entire chapter was devoted to this exact mechanism by the german pain medicine pundit Enno Freye in his book "Opioide in der Medizin" (there is also an english translation but only up to the 6th edition and I'm not sure if that chapter exists in that edition). I'm using ULDN myself since the beginning of 2022 and have kept my tolerance to opioids at a stable level ever since then (I only increase when I want a stronger high but can decrease with no problems afterwards). It literally hasn't increased since then. There is even an american documentary about the effectiveness of ULDN. One of the doctors who was interviewed in that documentary told a story about a patient of one of his colleagues who was on a daily dose of 3.000mg Oxy and reduced to ZERO in just 10 days without any withdrawal symptoms. It works and it's amazing...

 

[someguyontheinternet]

Maybe @AlsoTapered knows where to find some papers related to filamin A, beta arrestin, mu receptors, membrane insertion and regulation?

 

[Snafu in the Void]

My favorite thing about 7-OH so far is that it comes with significantly less side effects than kratom itself. I've been having really bad side effects from kratom lately, which was becoming very problematic because I'm dependent on it so I can't just stop taking it. Side effects like horrible dehydration, chronic headaches (especially when waking up in the morning), and anxiety.

I've been taking 3.75-11mg along with 2-3g of leaf powder, twice per day. Overall doing a lot better and no more of those problems.

It's great stuff. Definitely very addictive, though. Not much more psychologically addictive than kratom itself, but I bet the physical withdrawals are bad.

It has this very unique physical relaxation/euphoria to it. It relaxes your muscles and makes your whole body tingle, very pleasurable sensation that I have not felt from any other opioid before.

 

[AlsoTapered]

Maybe @AlsoTapered knows where to find some papers related to filamin A, beta arrestin, mu receptors, membrane insertion and regulation?

Those are all HUGE topics. If I search for papers with any of those terms in them, I get hundreds of hits. Unless someone has a couple of years to read them and really understand them, it's not practical to just post hotlinks since I don't know what the best index papers would be.

 

[someguyontheinternet]

Those are all HUGE topics. If I search for papers with any of those terms in them, I get hundreds of hits. Unless someone has a couple of years to read them and really understand them, it's not practical to just post hotlinks since I don't know what the best index papers would be.

I guess I meant more along the intersection of those, specifically around signaling pathways involving filimin and the mu receptor membrane insertion

 

[Hexenstahl]

Yeah I just realized that the Filamin A and µOR correlation is a huge rabbit hole to go down to. It's something I will need to research in little bits and pieces. Actually I plan on first studying the topic of neuropharmacology, then chemistry and perhaps then I will look into individual aspects like Filamin A and its interaction with the µOR because I'll be better equipped intellectually speaking, to understand these topics. But right now I feel more confused than educated, except that I just know superficially how tiny doses of Naltrexone change the modulation of the binding affinity of µOR. That's it really. I think it will be a long but fun journey...

 

[someguyontheinternet]

I don't think its changing affinity is it? Rather more likely inserting more receptors into the membrane? I'm not aware of there being subunits or splice variants of the mu receptor which would increase affinity

 

[Hexenstahl]

I don't think its changing affinity is it? Rather more likely inserting more receptors into the membrane? I'm not aware of there being subunits or splice variants of the mu receptor which would increase affinity

Unfortunately I can't quite remember where exactly I have read that information, but I'm pretty sure that paper talked about modulation of µOR's binding affinity and if I'm not mistaken it also talked about glial cell modulation (and how an inflammation of the latter is what causes many of the wd symptoms). But I'm not entirely sure about the latter.

 

[Snafu in the Void]

These pills are very unevenly dosed. Sometimes they hit hard, other times it's meh. Sometimes they hit in 45 minutes, other times they hit after 90 minutes. I suppose uneven dosing is the only real answer, or maybe how they are pressed? IDK.

Anyways, they are definitely addictive, but not tremendously more than kratom itself. It still has some forgiving qualities in comparison to true opioids. Some guy on reddit says they "ruined" regular kratom for him, and he can never go back after he got addicted to taking 4-5 of these pills every day (which is a lot...). I disagree with him. I still crave regular kratom, especially in the morning. 7-OH is heavily sedataing and not great for work or in the morning. It's not a good coffee replacement like kratom.

They also seem to have "stabilized" me. I can now easily sleep through the night and get a solid 8 hours, and when I wake up I'm not immediately in intense withdrawal like I used to be with regular kratom. I'm also recovering from a lot of the physical and mental side effects heavy kratom use had been giving me lately.

These pills have been somewhat of a blessing for me.

 

[someguyontheinternet]

I've switched to extract to try and get off leaf recently and I feel similarly to you about reducing the dependence on leaf. There are other alkaloids that give me tons of energy but the withdrawal from those was what I felt like was making leaf hard to quit

Something to be aware of is that 7-OH does cause respiratory depression btw

The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine - PubMed

Both the anti-nociceptive effects and the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7-OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built-in ceiling effect of the mitragynine-induced...

pubmed.ncbi.nlm.nih.gov

 

[Doctor Steve Brule]

I'd try the 7-oh with the mit extracts available. Never enjoyed the mit extracts as the 7-oh ratio gets even worse. I guess people are too lazy to buy applesauce and would rather catch a shittier buzz as long as you get to down less powder.

 

[Snafu in the Void]

Something to be aware of is that 7-OH does cause respiratory depression btw

The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine - PubMed

Both the anti-nociceptive effects and the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7-OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built-in ceiling effect of the mitragynine-induced...

pubmed.ncbi.nlm.nih.gov

I definitely suspected this. 7-OH levels from mitragynine conversion are rate limited, maybe that's why withdrawal onset seems extremely variable to me based on dose.

With high levels of pure 7-OH introduced, this would lead to much much higher levels of mitragynine pseudoindoxil, which is apparently a full mu agonist compared to a partial agonist. I suspect pseudoindoxil does cause significant respiratory depression. The nods from this stuff are much closer to real opioids, I can definitely feel respiratory depression too. Luckily I have not felt any need to take more than 15mg every 5-6 hours, probably because there isn't a reinforcing mental euphoria to it. "Less is more" seems to also apply to 7-OH somewhat.

 

[someguyontheinternet]

I definitely suspected this. 7-OH levels from mitragynine conversion are rate limited, maybe that's why withdrawal onset seems extremely variable to me based on dose.

With high levels of pure 7-OH introduced, this would lead to much much higher levels of mitragynine pseudoindoxil, which is apparently a full mu agonist compared to a partial agonist. I suspect pseudoindoxil does cause significant respiratory depression. The nods from this stuff are much closer to real opioids, I can definitely feel respiratory depression too. Luckily I have not felt any need to take more than 15mg every 5-6 hours, probably because there isn't a reinforcing mental euphoria to it. "Less is more" seems to also apply to 7-OH somewhat.

"Inhibition of CYP3A reduced mitragynine-induced respiratory depression and anti-nociception without affecting the effects of 7-OH mitragynine" - This is fairly curious. If 3a4 is the only pathway for mitragynine -> 7-OH in vivo, why wouldn't inhibition lead to lower levels of conversion? Also, this implies there is some other respiratory depressant in kratom other than mitragynine or 7-OH

From the discussion

"In this study, we report the respiratory depressant effects of the kratom alkaloid mitragynine and its oxidised derivative 7‐OH mitragynine. We also showed that the respiratory depressant effects of mitragynine were partly due to its metabolic conversion to 7‐OH mitragynine by CYP3A. These results are in line with previous reports suggesting that mitragynine‐induced anti‐nociception can be mediated by its active metabolite"

I think the statement you posted was worded strangely. If you look at figure 4, inhibition of 3a4 prevents mitragynine associated nocicpetion but not 7-OH. The figure is labeled poorly but the lines you see separation in are green for vehicle and mit and dark purple for keto and mit

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the μ opioid receptor. CYP3A‐dependent oxidation of mitragynine yields the metabolite 7‐OH mitragynine, a more efficacious μ receptor ...

www.ncbi.nlm.nih.gov

 

[AlsoTapered]

What they don't mention is that their are at least 3 different subtypes of MOR and each one has a unique endorphin.

Physiology, Opioid Receptor - StatPearls - NCBI Bookshelf

The NOP was previously referred to as the ORL-1 (opiate receptor-like 1) but now it looks like the target for effective analgesics. Previously (in the 1990s) it was noted that duel MOR/DOR ligands (like 14-methoxymetopon) were extremely active as analgesics but had much higher TIs. BUT they still produced tolerance and dependence.

I have yet to be convinced that 'biased' opioids are of use. I think they are merely low efficacy ligands. The Chinese work that brought us brorphine turned out to be interesting but not useful.

For acute pain at least, the euphoria mediated by dopamine is key to how the brain perceives pain. So while KORs were seen as the way forward in the 1970s, the dysphoria and hallucinations limited utility. Non-selective opiates don't do this as, seemingly MOR activity also removes those side-effects.

 

[someguyontheinternet]

For acute pain at least, the euphoria mediated by dopamine is key to how the brain perceives pain. So while KORs were seen as the way forward in the 1970s, the dysphoria and hallucinations limited utility. Non-selective opiates don't do this as, seemingly MOR activity also removes those side-effects.

I thought there was mu opioid inhibitory signaling in the descending pain pathway and that wasn't necessarily related to euphoria

Are you talking about the dopaminergic modulation referenced in this paper?

Mu Opioid Receptor Modulation of Dopamine Neurons in the Periaqueductal Gray/Dorsal Raphe: A Role in Regulation of Pain - Neuropsychopharmacology

The periaqueductal gray (PAG) is a brain region involved in nociception modulation, and an important relay center for the descending nociceptive pathway through the rostral ventral lateral medulla. Given the dense expression of mu opioid receptors and the role of dopamine in pain, the recently...

www.nature.com

 

[Doctor Steve Brule]

I keep hearing about this but it might just be outlets peddling old news on repeat:

Nonaddictive drug compound could replace opioids for chronic pain sufferers

A new nonaddictive drug compound discovered by Purdue University researchers could lead to the treatment of chronic pain without the need to rely on opioids, just as a bipartisan package of bills moves through the U.S. House and Senate to battle the nation’s opioid epidemic.

www.purdue.edu

 

[AlsoTapered]

I thought there was mu opioid inhibitory signaling in the descending pain pathway and that wasn't necessarily related to euphoria

Are you talking about the dopaminergic modulation referenced in this paper?

Mu Opioid Receptor Modulation of Dopamine Neurons in the Periaqueductal Gray/Dorsal Raphe: A Role in Regulation of Pain - Neuropsychopharmacology

The periaqueductal gray (PAG) is a brain region involved in nociception modulation, and an important relay center for the descending nociceptive pathway through the rostral ventral lateral medulla. Given the dense expression of mu opioid receptors and the role of dopamine in pain, the recently...

www.nature.com

I wasn't referring to a specific paper. But yes, that 'circuit' concept.

It's worth noting that several NOP selective ligands and a few MOP/NOP ligands are known. In fact, one of them is sufentanil which is about x10 fentanyl in analgesic activity but whose TI is some x140 larger.

There is even an etonitazine derivative (actually the most potent of the series and x4 more potent than the parent compound) that I actually discovered to be a NOP using a large training set. And guess what? It's TI is also much higher than the parent compound so NOP activity seems to reverse or at least limit respiratory depression.

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

The =O of that chiral carboxamide overlays the O of the 4-methoxymethyl group in sufentanil and the 14-methoxy of 14-methoxymetopon. Obviously I used a training set with known selective NOPs and dropped in one other opiate at a time to see if it overlaid and that the software recognized it as part of the pharmacore.

I've already posted hotlinks to all the papers including the training-sets on that 'useful links...' thread.

 

[Snafu in the Void]

I think the statement you posted was worded strangely.

Yeah, I was pretty high on this stuff when I posted that.

I'm gonna take a break from these pills. They're making me higher than I realized.

Unlike kratom, it absolutely tanks my endurance and running performance (as an opioid should...), even with super high doses of kratom I could go for 7 mile jogs, and it actually increased my performance plus made running very enjoyable. This stuff is the opposite. It's really heavy shit.

Its been making me somewhat depressed, too. Just zoned out. I feel like I'm back on hard drugs again after taking this stuff for a week. It has none of the benefits kratom provides.

 

[thurston]

I've switched to extract to try and get off leaf recently and I feel similarly to you about reducing the dependence on leaf. There are other alkaloids that give me tons of energy but the withdrawal from those was what I felt like was making leaf hard to quit

Something to be aware of is that 7-OH does cause respiratory depression btw

The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine - PubMed

Both the anti-nociceptive effects and the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7-OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built-in ceiling effect of the mitragynine-induced...

pubmed.ncbi.nlm.nih.gov

I recently quit after a run on extracts and I found the extract way easier to quit than pure leaf.