Kratom Kratom rapid withdrawal

[Jabberwocky]

In the past when I was dependent on 30g+ per day withdrawal always predictably started around 20-22hr, then would hit me like a ton of bricks around 24-26hr.

I got off it 14 months ago, then started again around 3-4 months ago. However, this time I have kept my usage under 10g per day, only occasionally using up to 12g.

This time the withdrawals are hitting me much more quickly around 8 hours (or even sooner) since last dose, which is annoying because it's making me wake up in the middle of the night. Previously I never used to dose past 2pm, but now I have to dose at 8pm just to be able to sleep for 6hr.

I am frustrated because I am only taking 1/3rd of what I used to but now the withdrawals are impacting me even more than last time.

If I were to guess it's due to kratom's multi stage metabolism, taking higher doses stays in your system longer (obviously), but other opioids don't really seem to work that way...

Wondering other people's experiences. @jasperkent @Xorkoth has this happened to you guys? Just curious.

 

[4meSM]

Tbh it always seemed strange to me that you only needed to take 1-2 doses a day while being dependent. And that you were able to go a full 24 hours without experiencing any withdrawal symptoms.
From what I've read, the majority of people start feeling some withdrawal symptoms about five to eight hours after their last dose. That's usually the way it works out for me at least.

Pharmacokinetics seem to vary between large and small doses. Mitragynine is metabolized into 7-HO-mitragynine by CYP3A4 in the liver, and then it's converted into mitragynine pseudoindoxyl in the plasma. While Mitragynine seems to have a long half-life (I think it's over 20 hours), the two main metabolites, which are much stronger mu agonists, have a much shorter half-life, only around two to three hours at most. It's possible that there's a limit to how much mitragynine can be metabolized at once by CYP3A4 in some people. This could mean that larger single doses might result in a sort of extended-release effect.
But yeah, it's definitely complex since the effects are believed to be due to a mix of these three compounds. And they also each have their own unique effects on the mu opioid receptor...

Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy - PMC

Kratom is widely consumed in the United States for self-treatment of pain and opioid withdrawal symptoms. Mitragynine is the most abundant alkaloid in kratom and is a μ-opioid receptor agonist. 7-Hydroxymitragynine (7-HMG) is a mitragynine ...

www.ncbi.nlm.nih.gov

 

[Jabberwocky]

Maybe it has to due with the fact that kratom inhibits the enzymes which metabolize it, with larger doses making it metabolize more slowly?

"mitragynine gave the strongest inhibitory effect on CYP2D6 with an IC50 value of 0.45±0.33 mM, followed by CYP2C9 and CYP3A4 with IC50 values of 9.70±4.80 and 41.32±6.74 μM respectively"

Although it doesn't seem to be a potent inhibitor of 3a4.

Kava is like that, the more you take the more it inhibits it's own breakdown, leading to it's purported 'reverse tolerance' effect.

 

[4meSM]

Maybe it has to due with the fact that kratom inhibits the enzymes which metabolize it, with larger doses making it metabolize more slowly?

"mitragynine gave the strongest inhibitory effect on CYP2D6 with an IC50 value of 0.45±0.33 mM, followed by CYP2C9 and CYP3A4 with IC50 values of 9.70±4.80 and 41.32±6.74 μM respectively"

Although it doesn't seem to be a potent inhibitor of 3a4.

Kava is like that, the more you take the more it inhibits it's own breakdown, leading to it's purported 'reverse tolerance' effect.

I'd have to check how they measured the inhibition of CYP3A4, because in most cases it just means that it acts as a competitive inhibitor when you have another molecule being metabolized by the same enzyme, and this is solely due to the fact that the enzyme is also busy metabolizing mitragynine (thus impairing the metabolism of the other drug).

But yeah, I always suspected that kratom acted as an inhibitor of CYP2D6 since it doesn't work well with other opioids like codeine, tramadol and even oxycodone which have to be metabolized into their (more) active form.

 

[negrogesic]

I experience quite the opposite; I only experience those rapid onset withdrawal symptoms manifesting when I'm taking higher doses. For instance, if I'm regularly taking kratom and my average re-dose size is 5g, i'll begin noticing the onset of withdrawal symptoms 5-6 hours after dosing. But if im only taking 1.5-2g per dose, I don't really notice much in terms of withdrawal between doses, and can go much longer before feeling a desire to redose.

I always figured this was because those lower doses don't activate the MOR profoundly enough to make those receptors "raw" and downregulated to the extent that say 5g does, thus producing less of a rebound. The higher doses seem to make my opioid receptors scream, "hey asshole! where did that stuff go?!!", whereas the lower doses don't.

 

[SpiralusSancti]

Could it be also that like with some drugs (paracetamol is an example), when you take higher dose BA increases? Taking 1g vs. 500mg of paracetamol significantly increases BA (I think it goes up about 20%) and given there’s more than one active alkaloid in kratom that might be the case for some and cause unusual differences in high and WDs between small and big doses..

 

[4meSM]

I experience quite the opposite; I only experience those rapid onset withdrawal symptoms manifesting when I'm taking higher doses. For instance, if I'm regularly taking kratom and my average re-dose size is 5g, i'll begin noticing the onset of withdrawal symptoms 5-6 hours after dosing. But if im only taking 1.5-2g per dose, I don't really notice much in terms of withdrawal between doses, and can go much longer before feeling a desire to redose.

Well I'd say 1.5-2g are very low doses, how many times a day do you redose at those levels? In that case it might indeed not be enough to cause a "strong" opioid dependency (relatively speaking).

When I say high doses I'm thinking about 8-20g at once. A regular dose for me is about 3-4g of high quality powder, 5 to 7 times a day.

 

[negrogesic]

Well I'd say 1.5-2g are very low doses, how many times a day do you redose at those levels? In that case it might indeed not be enough to cause a "strong" opioid dependency (relatively speaking).

When I say high doses I'm thinking about 8-20g at once. A regular dose for me is about 3-4g of high quality powder, 5 to 7 times a day.

If I'm only taking 1.5g-2g per dose, I'll only redose a few times during the day. Only very recently have I even tried taking these kinds of doses because for years I was under the impression that doses like 1.5g to 2g had no perceptible effects. Turns it does have perceptible effects at these doses, having some motivating and pain relieving effects.

But when i actually get "hooked" on kratom, i generally wind up on 5g every 5-6 hours. Which sucks because even if you take it right before bed you wake up in some degree of withdrawal.

 

[4meSM]

If I'm only taking 1.5g-2g per dose, I'll only redose a few times during the day. Only very recently have I even tried taking these kinds of doses because for years I was under the impression that doses like 1.5g to 2g had no perceptible effects. Turns it does have perceptible effects at these doses, having some motivating and pain relieving effects.

But when i actually get "hooked" on kratom, i generally wind up on 5g every 5-6 hours. Which sucks because even if you take it right before bed you wake up in some degree of withdrawal.

Yeah I agree, I've had a very similar experience.

Right now I have to dose right before bed and upon waking up, but I'm still able to get at least 6h of continuous sleep (sometimes I manage to sleep a bit more right after redosing in the morning). But this is also because I recently transitioned to kratom again after binging on stronger opioids so my receptors are still a bit fried...
In the past I've managed to sleep for longer and not wake up fully WDing, while still being dependent on kratom. It probably depends on the total daily amount as well (plus some varieties/batches seem to last longer).

 

[jasperkent]

I really can't provide an honest assessment since the longest I've abstained from kratom (28 days) was during my recent stint in detox/rehab to recover from a 2-month alcohol binge.

I'd been taking 25-30g of kratom daily for a couple years but during that bender I was also drinking 500ml or more of 90-proof vodka and washing it down with 6 to 8 24oz Steel Reserves (8.1%) every day. My detox was pretty rough. They were giving me the maximum allowable doses of Librium but my tremors were still pretty severe and I couldn't eat or sleep at all.

I was doing a lot better after the first week but I still couldn't sleep worth a shit. For three weeks I averaged about 2hrs of sleep per night even though I was taking melatonin, diphenhydramine, and baclofen every evening. Despite the sleep deprivation I felt pretty good and my mood was positive.

The other weird thing about me is that I find all kratom stimulating. Red/green, low dose/high dose, any source, it doesn't matter. I never take kratom within 4hrs of bedtime or I won't be able to sleep. In the past I generally found any opiate or opioid to be more stimulating than most folks. I used oxys/hydros much more heavily on work days than on off days and it's the same with kratom.

 

[Jabberwocky]

The other weird thing about me is that I find all kratom stimulating. Red/green, low dose/high dose, any source, it doesn't matter. I never take kratom within 4hrs of bedtime or I won't be able to sleep. In the past I generally found any opiate or opioid to be more stimulating than most folks. I used oxys/hydros much more heavily on work days than on off days and it's the same with kratom.

I'm the same. I can't sleep for a few hours after dosing. Other opioids also gave me insomnia as well, I'd be tired and feel like I could easily sleep but it just doesn't happen.

Were you generally able to sleep through the night on higher doses of kratom? That's what is bothering me now.

I'm considering using some loperamide to help taper but I'd rather avoid that.

I enjoyed kratom more when I didn't have to dose every 6hr.

 

[jasperkent]

Were you generally able to sleep through the night on higher doses of kratom?

Yeah, as long as I didn't dose within 4hrs or so of bedtime. My pattern almost always is that I fall asleep easily but wake up earlier than I need to. I can usually get back to sleep but not every time.

 

[Jabberwocky]

Man this sucks. I'm trying to taper a bit but when I drop my dose down from 5g to 3g withdrawal hits even faster by 4hr.

It's mainly just body and muscle aches/minor mental symptoms, not debilitating, just annoying.

I never understood when people said they had a difficult time tapering kratom, but now I do....

I just don't understand why kratom is this way for me now when it never used to be.

 

[4meSM]

Man this sucks. I'm trying to taper a bit but when I drop my dose down from 5g to 3g withdrawal hits even faster by 4hr.

It's mainly just body and muscle aches/minor mental symptoms, not debilitating, just annoying.

I never understood when people said they had a difficult time tapering kratom, but now I do....

I just don't understand why kratom is this way for me now when it never used to be.

The thing I'd like to figure out is wether most of the effects come from mitragynine or from the more potent metabolites. From my own personal experience it seems like they come from 7-Hydroxy and maybe pseudoindoxyl as well, mainly due to the short duration which seems to be somewhat aligned with their half-life and peak plasma concentrations.

If that's the case for you then I'd be inclined to think that the big difference you're experiencing now might be due to pharmacokinetics instead of receptor adaptations (but I could be wrong, or partly wrong).
Do you know if you might have been consuming some kind of CYP3A4 inhibitor in the past? Did you stop or start taking another drug/medication since then?
And the bonus question. What do you think about codeine?

 

[Jabberwocky]

The thing I'd like to figure out is wether most of the effects come from mitragynine or from the more potent metabolites. From my own personal experience it seems like they come from 7-Hydroxy and maybe pseudoindoxyl as well, mainly due to the short duration which seems to be somewhat aligned with their half-life and peak plasma concentrations.

If that's the case for you then I'd be inclined to think that the big difference you're experiencing now might be due to pharmacokinetics instead of receptor adaptations (but I could be wrong, or partly wrong).

I've basically chalked it up to the kratom batch I've been using. Indeed it is very potent, particularly it has unusually pronounced opioid effects that I don't get from other batches that have even higher mit%. It definitely feels like it has a special amount of indoxyl or 7-OH. Best kratom I've had in several years TBH, but definitely not laced or anything.

This strain is a yellow blend 1.72% mit. 7-OH test is vague like every other COA and says <0.01%. Does not test for any other alkaloids, except paynantheine which is a normal 0.3-0.4%.

Comparing it to a premium green strain I have which is 1.93% mit, the yellow has significantly more opioid feeling to it, and is more sedating.

However, I've also sort of confirmed my other theory about higher doses delaying withdrawal onset. Yesterday I took a lot more than I usually do, 23g over the day, and withdrawal didn't significantly show up until 12 hours. (Dosed at 4:45pm, woke up at 5am). I probably could have even slept more had my cat not insisted on waking me up by spilling the water next to my bed.

Do you know if you might have been consuming some kind of CYP3A4 inhibitor in the past? Did you stop or start taking another drug/medication since then?
And the bonus question. What do you think about codeine?

Haven't taken anything new that would alter enzymes, unless it's one of these alt cannabinoids, but that's a stretch.

My last 2 codeine experiences (that I can remember) doses of 200-300mg produced quite strong effects, but I was also taking powerful antibiotics, some of which are very potent 3a4 inhibitors. But I've always been a normal/standard metabolizer in my experience, but never been tested.

 

[4meSM]

However, I've also sort of confirmed my other theory about higher doses delaying withdrawal onset. Yesterday I took a lot more than I usually do, 23g over the day, and withdrawal didn't significantly show up until 12 hours. (Dosed at 4:45pm, woke up at 5am). I probably could have even slept more had my cat not insisted on waking me up by spilling the water next to my bed.

I see, so it does look like there's some kind of extended release effects with higher doses. Unless you only increased the total daily amount but not the amount per dose?

In the EU it's kind of hard to get kratom with a certificate of analysis unfortunately... And there aren't many good vendors with good products on stock, which kind of sucks. But at least I still have some decent green vein left.

 

[Jabberwocky]

So I've been doing some experiments and playing with my dose to confirm what's going on.

If I dose 5g withdrawal starts in about 8 hours.

If I dose 10g withdrawal starts in about 12 hours.

If I dose 15g withdrawal starts in about 15 hours.

(Those are single doses, not total daily consumption. Cumulative daily dose during all of those has been about 12-22g)

Also I am defining withdrawal as when the symptoms can't be ignored and become bothersome.

So there is definitely some sort of "extended release" effect going on here, and explains why when I used to take 30g per day withdrawal didn't start until +20 hours.

Still not sure why, but it definitely feels like it might have to do with metabolism rates.

 

[GetMeOutOfThisCRAP]

In the past when I was dependent on 30g+ per day withdrawal always predictably started around 20-22hr, then would hit me like a ton of bricks around 24-26hr.

I got off it 14 months ago, then started again around 3-4 months ago. However, this time I have kept my usage under 10g per day, only occasionally using up to 12g.

This time the withdrawals are hitting me much more quickly around 8 hours (or even sooner) since last dose, which is annoying because it's making me wake up in the middle of the night. Previously I never used to dose past 2pm, but now I have to dose at 8pm just to be able to sleep for 6hr.

I am frustrated because I am only taking 1/3rd of what I used to but now the withdrawals are impacting me even more than last time.

If I were to guess it's due to kratom's multi stage metabolism, taking higher doses stays in your system longer (obviously), but other opioids don't really seem to work that way...

Wondering other people's experiences. @jasperkent @Xorkoth has this happened to you guys? Just curious.

Its difficult to say and you'll probably drive yourself insane trying to calculate why...

I think if I had to guess the body just adjusts to dependent use. For example, opioids and kratom just hit different for me if I'm coming back from a vacation. They aren't as strong as I'd like probably each time, but it does feel like my metabolism is slower/faster in some regards than when I'm physically forced to wake up daily and take it to not withdraw. Its a bit different when your body isn't fully convinced its going to get a repeated substance over and over without fail.

But idk, if you're back on kratom you might as well just take doses that prevent withdrawals in between doses. If you're back on it and probably going to stay on it from now on, I don't see the point in avoiding mini withdrawals *unless you don't want to go back to your old doses.* In which case, your body would in time be dependent on the new lower dose fine and you would stop withdrawing slightly like you are now.

 

[jmr777]

I

Tbh it always seemed strange to me that you only needed to take 1-2 doses a day while being dependent. And that you were able to go a full 24 hours without experiencing any withdrawal symptoms.
From what I've read, the majority of people start feeling some withdrawal symptoms about five to eight hours after their last dose. That's usually the way it works out for me at least.

Pharmacokinetics seem to vary between large and small doses. Mitragynine is metabolized into 7-HO-mitragynine by CYP3A4 in the liver, and then it's converted into mitragynine pseudoindoxyl in the plasma. While Mitragynine seems to have a long half-life (I think it's over 20 hours), the two main metabolites, which are much stronger mu agonists, have a much shorter half-life, only around two to three hours at most. It's possible that there's a limit to how much mitragynine can be metabolized at once by CYP3A4 in some people. This could mean that larger single doses might result in a sort of extended-release effect.
But yeah, it's definitely complex since the effects are believed to be due to a mix of these three compounds. And they also each have their own unique effects on the mu opioid receptor...

Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy - PMC

Kratom is widely consumed in the United States for self-treatment of pain and opioid withdrawal symptoms. Mitragynine is the most abundant alkaloid in kratom and is a μ-opioid receptor agonist. 7-Hydroxymitragynine (7-HMG) is a mitragynine ...

www.ncbi.nlm.nih.gov

Was taking extract everyday at worst point. The kinda shitty feeling started the next morning when id wake up

 

[Droppersneck]

I’ve been through the waking up with restless legs and sweat a million time. There is a magic substance, that gets rid of all of it and let’s you sleep, but since it isn’t abusable itself no one ever even tries it lol. I got a big jar of dlpa from liftmode and any time I’m in those situations I take like half a gram in a scoop and am able to pass right out. It does a bunch of other stuff too, pretty amazing shit tbh