Bupe Norbupe Theory

[DeathIndustrial88]

So.. Has there been any substantial evidence come out at all yet that norbupe is indeed active in lower dosages of bupe? And if so, can anyone please provide that evidence? Thanks.

 

[DeathIndustrial88]

Also, will long term use of a drug start to make you metabolize that drug at a faster rate once your body is accustomed to it?

 

[4meSM]

So.. Has there been any substantial evidence come out at all yet that norbupe is indeed active in lower dosages of bupe? And if so, can anyone please provide that evidence? Thanks.

Yeah norbupre is thought to have a higher affinity for mu, delta and kappa opioid receptors. Other metabolites could also play a role depending on the dose of buprenorphine administered.

(Lower number = higher affinity)


Also according to this source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560935/

"Norbuprenorphine is a potent opioid agonist, with high affinities for mu, delta, and kappa opioid receptors.22
In rats, norbuprenorphine caused dose-dependent respiratory depression and was 10 times more potent than buprenorphine.8,23
Norbuprenorphine respiratory depression was opioid-receptor mediated, and also antagonized by buprenorphine.8 "

 

[Juniper Bruhmomentius]

Also, will long term use of a drug start to make you metabolize that drug at a faster rate once your body is accustomed to it?

Based on what Ive seen, not necessarily metabolize it faster, but the withdrawals 100% will start faster.

 

[DeathIndustrial88]

Yeah norbupre is thought to have a higher affinity for mu, delta and kappa opioid receptors. Other metabolites could also play a role depending on the dose of buprenorphine administered.

(Lower number = higher affinity)


Also according to this source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560935/

"Norbuprenorphine is a potent opioid agonist, with high affinities for mu, delta, and kappa opioid receptors.22
In rats, norbuprenorphine caused dose-dependent respiratory depression and was 10 times more potent than buprenorphine.8,23
Norbuprenorphine respiratory depression was opioid-receptor mediated, and also antagonized by buprenorphine.8 "

Wow!! Thank you so much for the response, I appreciate it very much!

So theoretically, if one were to take a low enough dose of buprenorphine, the effects felt SHOULD be a combination of norbupe & bupe effects + metabolites? So buprenorphine in low doses would essentially be a pro-drug for a full agonist.

I wonder at what dose buprenorphine would antagonize it's own metabolite then. Thank you for sharing this. I've always wondered why lower doses seemed to feel much better, but I always assumed it had something to with the blood levels spiking up and down from the bupe doses, as I thought norbupe didn't really cross the blood brain barrier.

 

[DeathIndustrial88]

Based on what Ive seen, not necessarily metabolize it faster, but the withdrawals 100% will start faster.

Thanks for the response. I've noticed this with bupe lately. I use to be able to skip a few days in between doses and be just fine. But now, lately, i've noticed that if I try to do this, I won't necessarily feel full blown withdrawal, but I do feel very "blah" and "off" until I finally take my dose for the day.

Thank you both for your responses!!!!

 

[Juniper Bruhmomentius]

Yeah, dont forget its about 50 times stronger than morphine. Its not a good drug but its a really useful "medicine". Basically meant for people who need/want to take something daily but werent so heavy on their past use. I have two friends who both started bupre 5 years ago, one used 30% or something less bupre and he has 200% or more lesser withdrawals. Remember, its closer to fentanyl than morphine. I use 1mg at most per day and its really easy to quit.

Np, I like bupre too.

 

[DeathIndustrial88]

Yeah, dont forget its about 50 times stronger than morphine. Its not a good drug but its a really useful "medicine". Basically meant for people who need/want to take something daily but werent so heavy on their past use. I have two friends who both started bupre 5 years ago, one used 30% or something less bupre and he has 200% or more lesser withdrawals. Remember, its closer to fentanyl than morphine. I use 1mg at most per day and its really easy to quit.

Np, I like bupre too.

I went with bupe cause it was much easier to get than methadone. You practically have to live ontop of a methadone clinic and go in daily in order to get it. With bupe, I can get a months worth at home.

I've been on it a long time now. In the beginning I use to be able to maintain a nice glow reminiscent of full agonists through out the day and this really helped.
But now a days, my doses have escalated and my cravings for heroin and other drugs has started to come back full force, along with some depression.

So I posted this cause I was wondering if there was any merit to the whole norbupe thing and if maybe getting back down to a smaller dose would be worth it to get some of the feelings back. I'm wondering if sticking to micrograms and giving it time to metabolize would have me feeling better than taking 2-8mg a day.

I'm definitely one of those people who needs/wants to take an opioid daily.. probably for the rest of my days. lol But one that I can actually feel.
If I could, I'd just move to Switzerland and get on their pharm grade diacetylmorphine program instead. lol

Thanks again!

 

[4meSM]

Wow!! Thank you so much for the response, I appreciate it very much!

So theoretically, if one were to take a low enough dose of buprenorphine, the effects felt SHOULD be a combination of norbupe & bupe effects + metabolites? So buprenorphine in low doses would essentially be a pro-drug for a full agonist.

I wonder at what dose buprenorphine would antagonize it's own metabolite then. Thank you for sharing this. I've always wondered why lower doses seemed to feel much better, but I always assumed it had something to with the blood levels spiking up and down from the bupe doses, as I thought norbupe didn't really cross the blood brain barrier.

Well I'm really not sure, once you start looking into it the picture becomes more and more complex haha. I haven't researched it enough.

I believe it's true that norbupe has a hard time crossing the BBB via passive diffusion but, since it has such a high affinity for the opioid receptors, only a very small amount would be needed.
Also there are active transporters which can get opioids in and out of the brain, I think this has been shown for morphine and its active metabolite M-6-G, a protein actuallyhelps them cross the BBB.
I read that norbupe, but apparently not bupe itself, is actually actively excreted out of the brain by P-glycoprotein transporters. Maybe it can also get into the brain with the help of another transporter?
Additionally, while most p450 enzymes are found in the liver, some of them have also been found within the brain so it's possible that bupe could also be metabolized there to some extent, and since it's so potent even a small amount could have an impact in its effects.

 

[Juniper Bruhmomentius]

I just now saw your location. LOL, great one.

I would use more than 1mg a day, but I cant afford that shit since I use it illegally. And bupre works different the each time, well atleast almost. Stopping daily use since the fun is gone at this point.

 

[DeathIndustrial88]

Well I'm really not sure, once you start looking into it the picture becomes more and more complex haha. I haven't researched it enough.

I believe it's true that norbupe has a hard time crossing the BBB via passive diffusion but, since it has such a high affinity for the opioid receptors, only a very small amount would be needed.
Also there are active transporters which can get opioids in and out of the brain, I think this has been shown for morphine and its active metabolite M-6-G, a protein actuallyhelps them cross the BBB.
I read that norbupe, but apparently not bupe itself, is actually actively excreted out of the brain by P-glycoprotein transporters. Maybe it can also get into the brain with the help of another transporter?
Additionally, while most p450 enzymes are found in the liver, some of them have also been found within the brain so it's possible that bupe could also be metabolized there to some extent, and since it's so potent even a small amount could have an impact in its effects.

Interesting. Thank you for your valuable insight.

I guess it's technically still up in the air as to whether norbupe truly elicits an effect or not. Like schizopath said, bupe seems to feel different every time and at varying doses. I would love to be able to find a dose that keeps the opiate-effect and euphoric effect consistent, but have been unable (even after 5 years) to determine what dose this might be. Seems like it's too complex of a drug to really know for sure.

But I do believe the higher doses are almost pointless. Countless times I have actually become very dysphoric after using anywhere from 8-12mg of buprenorphine.

I asked this question as I am on bupe for maintenace, but it is no longer helping with cravings as I don't feel jack shit from it and this is unfortunate because it's effecting me mentally and making me crave heroin again daily. And methadone is not an option for me at the moment, so I'm trying to figure out the best way to utilize what I have and actually feel like my mind is satisfied. I have, in the past achieved very beautiful effects from bupe, so I know it's possible to feel good with this medication. but then again I also had a lower tolerance.

I truly appreciate everyone's input and responses. If anyone else has anything else to add, please feel free.

 

[DeathIndustrial88]

I just now saw your location. LOL, great one.

I would use more than 1mg a day, but I cant afford that shit since I use it illegally. And bupre works different the each time, well atleast almost. Stopping daily use since the fun is gone at this point.

You might actually be doing yourself a favor by sticking to these lower doses (if they're getting you feeling good still that is) as I have practically an unlimited amount of bupe and of course became tempted to go higher and higher, thus leading to a dose where I receive no effects whatsoever.

 

[4meSM]

Interesting. Thank you for your valuable insight.

I guess it's technically still up in the air as to whether norbupe truly elicits an effect or not. Like schizopath said, bupe seems to feel different every time and at varying doses. I would love to be able to find a dose that keeps the opiate-effect and euphoric effect consistent, but have been unable (even after 5 years) to determine what dose this might be. Seems like it's too complex of a drug to really know for sure.

But I do believe the higher doses are almost pointless. Countless times I have actually become very dysphoric after using anywhere from 8-12mg of buprenorphine.

I asked this question as I am on bupe for maintenace, but it is no longer helping with cravings as I don't feel jack shit from it and this is unfortunate because it's effecting me mentally and making me crave heroin again daily. And methadone is not an option for me at the moment, so I'm trying to figure out the best way to utilize what I have and actually feel like my mind is satisfied. I have, in the past achieved very beautiful effects from bupe, so I know it's possible to feel good with this medication. but then again I also had a lower tolerance.

I truly appreciate everyone's input and responses. If anyone else has anything else to add, please feel free.

Yeah there's the old saying "less is more" with bupe, but of course it also depends on your previous opioid use. Seems bupe has a ceiling where high doses stop acting like a pleasurable opioid and only keep WD away and block other opioids, I've heard it stops being "recreational" after 1-2mg.
For example the standard dose for pain relief is around 0.2-0.4mg
The problem is that once your tolerance is high enough a low dose won't be enough to cover the WD symptoms...

I've never been on opioid maintenance but I'm sure more experienced bluelighters will share some practical tips/insight, it might help you decide which path to take.

 

[DeathIndustrial88]

"Notably, of the four compounds tested, norbuprenorphine is the only one that causes respiratory depression and also does not have affinity for the nociceptin receptor. This may suggest a role for nociceptin activation in attenuation of mu receptor mediated respiratory depression. This hypothesis is supported by recent work with experimental compounds having activity at both mu and nociceptin receptors.2 That inhibition of locomotion was observed only with norbuprenorphine and N3G, and yet these two compounds had very different receptor affinity profiles, is intriguing. As before mentioned, inhibition of locomotion could be mediated by activation of the nociceptin receptor, yet N3G and not norbuprenorphine has affinity for that receptor. This suggests that either the same effect is mediated through different pathways activated by the different receptors, or that the effect is mediated through a receptor for which the two compounds both have affinity, such as the kappa receptor. Conversely, it is also intriguing that B3G and buprenorphine, both with moderate affinity for the nociceptin receptor, do not elicit sedative effects."


I'm no expert, but based on what is said here, norbupe must be active somewhat in the brain, since "respiratory depression" can be a side effect of Suboxone treatment.
And I have definitely been buzzed on low doses of bupe where it felt like my breathing was slowed, so I wonder if this does mean norbupe crosses the blood brain barrier.

So much conflicting information. Can't think of a more complex pharmaceutical!

I'm gonna try with all my might to adjust back down to a smaller dose, possibly even microgram dosages to see if I can get more consistent daily craving relief and perceptible effects. I can't live this way of feeling absolutely nothing daily.

 

[MDPV_Psychosis]

Yea buprenorphine gets kinda bleak and blah feeling after awhile when taking larger doses (for me, 4mg per day and up). Just started to feel depressed, unmotivated, and not interested in anything.

Once I tapered down again (slowly) things improved. It really started to feel much better again once I got to down to like 1-2mg a day. Each dose actually started to feel better, like I was actually getting high again. Just so much better overall. More energy/motivation, better mood, better sleep, etc

 

[DeathIndustrial88]

"Drugs that in vitro inhibited P-gp or BCRP were tested in hMDR1- and hBCRP-MDCKII bidirectional transport studies. Human P-gp was significantly inhibited in a concentration-dependent manner by norbuprenorphine>buprenorphine>methadone>ibogaine and THC. Similarly, BCRP was inhibited by buprenorphine>norbuprenorphine>ibogaine and THC. None of the other tested compounds inhibited either transporter, even at high concentration (100 microm). Norbuprenorphine (transport efflux ratio approoximately 11) and methadone (transport efflux ratio approoximately 1.9) transport was P-gp-mediated; however, with no significant stereo-selectivity regarding methadone enantiomers. BCRP did not transport any of the tested compounds. However, the clinical significance of the interaction of norbuprenorphine with P-gp remains to be evaluated. "


Maybe some one who understands what is said here better can chime in, but from what I understand, norbuprenorphine & buprenorphine inhibit P-gp, so that should allow norbupe to cross the blood brain barrier right? Wouldn't this also allow drugs like loperamide to cross the blood brain barrier?

Of course this info was taken from something about breast cancer, so maybe I'm misunderstanding something.

Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) - PubMed

Drug interaction with P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) may influence its tissue disposition including blood-brain barrier transport and result in potent drug-drug interactions. The limited data obtained using in-vitro models indicate that methadone...

pubmed.ncbi.nlm.nih.gov

 

[albatross]

Put aside the Norbupe thing for a minute. If you have a 2mg dose and take 2mg 24hrs later, you're accumulating the drug. At that rate you never really have time coming down from the high so you'll never really be high. Lower doses seem to prevent that buildup.

Thru trial and error I found my bupe ceiling was around 2mg. More would do nothing. So I decided to stick to .5-1mg a day and if I really needed a buzz I could bump it up to 1-2mg and truly get twice the effect.

Tapering to 2mg was no problem at all for me, going to 1mg was a little weird but nothing that bad.

 

[DeathIndustrial88]

Put aside the Norbupe thing for a minute. If you have a 2mg dose and take 2mg 24hrs later, you're accumulating the drug. At that rate you never really have time coming down from the high so you'll never really be high. Lower doses seem to prevent that buildup.

Thru trial and error I found my bupe ceiling was around 2mg. More would do nothing. So I decided to stick to .5-1mg a day and if I really needed a buzz I could bump it up to 1-2mg and truly get twice the effect.

Tapering to 2mg was no problem at all for me, going to 1mg was a little weird but nothing that bad.

Thank for sharing your experience!

I am having THE STRANGEST time with bupe the past few days.
Yesterday I experimented and only took .5mg and waited an hour and suddenly I was feeling an effect I haven't felt in years. I was stimulated, yet sedated. Had that "lovey dovey" type effect (heroin & other opiates always turned me into a very soft spoken, romantic dreamy person) and nice tingles through out my body. This lasted about 5-6 hours. But strangely, the day before, I had literally taken about 8-12mg. So I thought for sure a half a milligram wouldn't have done squat yesterday. Especially considering I've been taking bupe daily for 5 years now.

And so then today, I tried to repeat it and took another .5mg. Waited 2 hours and still no perceptible effects. So I took another 1mg and about an hour later I got an effect, but it's nowhere near what I felt yesterday. It's a sedated/noddy type of effect. But not in a pleasurable way. Almost an annoying type of feeling. Like a heroin nod, minus the euphoria, body tingles and lovey dovey effect.

It's incredibly odd to have such drastic different experiences and this inconsistency is what innevitably makes my dosages jump around all over the place and then I end up on higher doses. It makes no sense to me. Perhaps I ate something yesterday that inhibited an enzyme or something weird like that, I have no idea how this happens. Logically, I shouldn't have felt anything from that .5 yesterday.

 

[4meSM]

Maybe some one who understands what is said here better can chime in, but from what I understand, norbuprenorphine & buprenorphine inhibit P-gp, so that should allow norbupe to cross the blood brain barrier right? Wouldn't this also allow drugs like loperamide to cross the blood brain barrier?

Of course this info was taken from something about breast cancer, so maybe I'm misunderstanding something.

Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) - PubMed

Drug interaction with P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) may influence its tissue disposition including blood-brain barrier transport and result in potent drug-drug interactions. The limited data obtained using in-vitro models indicate that methadone...

pubmed.ncbi.nlm.nih.gov

I don't think so because the primary role of P-gp is to get molecules/drugs out of the cell. I guess in this case they're talking about breast cells (maybe cancer cells in general) but P-gp is expressed in almost every cell and it can also get drugs OUT of the blood brain barrier as far as I know. So a P-gp inhibitor would essentially prevent certain drugs from being thrown out (which is kinda like a natural defence mechanism of the cell), thus increasing their intracellular concentration which often means a stronger effect.

At least that's the case with some anticancer drugs, P-gp is often overactive in cancer cells so the drugs don't work as well because the fucked up cell is constantly getting rid of them. Inhibiting P-gp makes those drugs more efficient.

 

[DeathIndustrial88]

I don't think so because the primary role of P-gp is to get molecules/drugs out of the cell. I guess in this case they're talking about breast cells (maybe cancer cells in general) but P-gp is expressed in almost every cell and it can also get drugs OUT of the blood brain barrier as far as I know. So a P-gp inhibitor would essentially prevent certain drugs from being thrown out (which is kinda like a natural defence mechanism of the cell), thus increasing their intracellular concentration which often means a stronger effect.

At least that's the case with some anticancer drugs, P-gp is often overactive in cancer cells so the drugs don't work as well because the fucked up cell is constantly getting rid of them. Inhibiting P-gp makes those drugs more efficient.

Aaah okay. So what exactly do they mean when they say norbuprenorphine inhibited P-gp? I always thought that meant is stopped P-gp from working. If norbupe inhibits it, wouldn't that mean norbupe could get through? Or if P-gp much more apparent and stronger in the blood-brain-barrier perhaps?

I guess they do say "However, the clinical significance of the interaction of norbuprenorphine with P-gp remains to be evaluated."
So maybe no one knows quite yet.

I had quite an interesting experience with a .5mg dose that I wrote above your last response. Bupenorphine seems to display wildly different effects dependent on dose and possibly what you've eaten/active liver enzymes, etc..

It's probably too complex to really know or for laymen like me to fully understand. I am however going to try and stick to these lower doses from now on.