Bupe "Less is More" ... not so fast

As many if not all of you know about the "less is more" theory surrounding norbuprenorphine ..

but I get how there is a ceiling per say, and how taking suboxone in doses of 8mg + is a waste, because the scientific facts behind that make sense, but not so much with the less is more theory

now don't get me wrong I'm not denying that 2mg can bring or will bring the same effect as 16mg...BUT

how can less be MORE if the full agonist norbuprenorphine doesn't really, if at all, cross the BBB cuz of PGP...??

and even with that said wouldn't 4mg blow 2mg< out the water?? But I don't really know for sure? I just took about an hour ago a dose of 1.5 mg and though I feel a bit better from PAWS with slight euphoria , I don't feel a difference between this dose and let's say 4mg, so I do realize that a smaller dose can have the same effect, which I don't understand for the purpose of science since I'm taking less bupe, but it seems to be true

BUT the bigger question lays with how is it MORE?

P.S. Even if you DO cause the norbuprenorphine to cross the BBB fully and completely activate it with the help of other substances , where is the scientific backing that bupe still wouldn't fight to block the active norbupe trying to attach to the receptors?? I couldnt find one source.

I think this theory is interesting, and people seem to back it and I'm never one of those people to say what there feeling is placebo, but it truly doesn't make sense for the fact that norpube technically is not active? Or am I wrong? Idk... and if it was, wouldn't bupe still do what it was meant to? Or no?

Im no doctor, that is why I'm asking you guys who might have a little more insight to educate me, and don't just look at the title and say because norbupe, I want to know how....
if your even one of those that truly believe "less is more"

Thanks - The best coast; The East Coast

https://www.ncbi.nlm.nih.gov/pubmed/18997874

The buprenorphine dose-response curve is sometimes submaximal, or even bell-shaped, in nociceptive assays, depending upon the nature and intensity of the noxious stimulus. Moreover, buprenorphine, when administered with full agonists, such as morphine, antagonizes the action of these drugs. Partial agonism at the mu opioid receptor and, in some cases, antagonism at the kappa or delta opioid receptor have been considered as possible underlying mechanisms for the ceiling effect and bell-shaped dose-response curve of buprenorphine. While ceiling effects can be explained by partial agonist activity of buprenorphine, the bell-shaped dose-response curve cannot be a consequence of this property of the drug. Recently, buprenorphine has been shown to activate the opioid receptor-like (ORL-1; also known as NOP) receptor. Supraspinal activation of the ORL-1 receptor counteracts the antinociceptive and rewarding actions of morphine, raising the possibility that these actions of buprenorphine can also be altered by its ability to concomitantly activate the ORL-1 receptor. The use of molecular biological techniques has advanced our knowledge regarding the role of opioid receptors in modulation of pain and reward. In particular, generation of opioid receptor knockout mice has proven useful in this regard. Indeed, using knockout mice, we have recently shown that the antinociceptive effect of buprenorphine mediated primarily by the mu opioid receptor is attenuated by the ability of the drug to activate the ORL-1 receptor.

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So maybe agonism of ORL-1 with high doses makes it less effective than small doses that don't agonise ORL-1 ?

And yes, I did search the forum before asking, but there's so many different kind of questions, (that don't really point what I pointed out), with many answers swinging from left to right....

**Also I forgot to mention, I did read somewhere that norbup was metabolized through the liver not the stomach , like how Lop does. But other readings I see it's metabolized through stomach.. so there is so many different answers floating around the internet including this form, and I think it should be put to rest, with one solid answer lol!

What is pgp i dont recognize so im guessnother might now either.

What is the exact theory your trying to provide evidence for and against


Ie 2 mg of will cause more activation at the mu opioid receptors than 16 mg of buprenorphine a mu opioid partial agonist due to higher doses interfering with the secondary metabolite norbuprenorphines bility to bind at the mu opioids as a full agonist.

Nociceptin is thought to be an endogenous antagonist of dopamine transport that may act either directly on dopamine or by inhibiting GABA to affect dopamine levels.[8]

I read this on the orl 1 receptor page and dopamine transport is strongly related to almost every reinforcing drug i take .

kleinerkiffer said:

So maybe agonism of ORL-1 with high doses makes it less effective than small doses that don't agonise ORL-1 ?

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Interesting?

Could be a theory of truth
and good read, and also a quick knowledgeable jump at the question, I should look more into it...

but if it is, where does it say low doses of bupe or norbuprenorphine itself doesn't agonise ORL-1? (NOP) ..which I've read about, just today actually because I was looking this up lol.. and there is many other receptors involved as well that I find interesting, but none of which even maybe show why less is more , in the fact of being "more active or just as active while not working the way bupe typically does on the receptors "and causing euphoria and well again making less, well, More??

d1nach said:

What is pgp i dont recognize so im guessnother might now either.

What is the exact theory your trying to provide evidence for and against


Ie 2 mg of will cause more activation at the mu opioid receptors than 16 mg of buprenorphine a mu opioid partial agonist due to higher doses interfering with the secondary metabolite norbuprenorphines bility to bind at the mu opioids as a full agonist.

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Im trying to see if you guys evidence that the less is more theory, has scientific backing to where it actually causes more euphoria and acts as a full agonist , though it is a full agonist that's not what I'm getting at..

PGP is a compound called P-glycoprotein I believe it's spelled, and A lot like loperamide , norbup does not exactly cross the BBB because it has a very high affinity to PGP..(p-glycoproteins)
so how could norbupe technically bind to such receptors at a rate where the less is more theory is true, like though it's a full agonist , it doesn't seem to even work though it metabolizes... even at low doses it seems that bupe does what it's supposed to wether norbup is metabolized or not....

Ive never even heard of this receptor till like 5 minutes ago lol so i dont think this is even part of most peoples ideas with low dose burp.

I have absolutely zero idea what im talking about im just asking questions

So, based on that then a pglycoprotein inhibitor would make burp 2 mg alot stronger then 2mg alone.

It's not a receptor, it's a ATP-dependent efflux pump

d1nach said:

Nociceptin is thought to be an endogenous antagonist of dopamine transport that may act either directly on dopamine or by inhibiting GABA to affect dopamine levels.[8]

I read this on the orl 1 receptor page and dopamine transport is strongly related to almost every reinforcing drug i take .

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i did read up on Nociceptin (NOP or ORL-1) -and how it can inihibit GABA to affect dopamine levels, I was also reading on how people believe taking small amount of sub/bupe with xanax and or DXM will make the lower dose efficiently More efficient to say? If I worded that correctly to where it makes sense lol

but where does this prove that less will still cause a better result... especially if it's technically the NorBup that does that job wen it's metabolized but still it does not even cross the BBB at a rate to where it would even be recognizable to the person consuming the buprenorphine

kleinerkiffer said:

It's not a receptor, it's a ATP-dependent efflux pump

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Im saying there is also many other receptors as well that play a part very similar to how NOP does... and thank you I did not know what it technically was ..

anyways I'm saying that Norbup as a high affinity to the protein, hence the reason it doesn't cross the blood barrier, some of it does though, but most of it does not, almost all of it does not. Or at least not at a faste enough rate

How much dxm are we talking about?

If you take xanax im willing to bet yes it does increase the subjective effects but i dont think that proves there theory.

And sorry to keep jumping in front, but I am also hoping the Less is more theory, to be true, I am not neglecting the idea..I just think there needs to be more questions to be answered,

though it it seems that 1mg, 2mg etc.. works just as good as let's say 6-8mg , it still does not show any evidence that taking again let's say .75-1mg will actually be more powerful then 5mg; in the sense of euphoria and working as a full agonist...because many people stand by that theory, and I'm NOT knocking it

i just want to be educated on HOW...because the science does not show that, but the science does show that a fairly small dose (when your habitats not Huge OR coming off ur first day of opiates) seems to work just as good as 8mg and science proves that day in and day out, but these pharm. company's and doctors are lying to us and making us spend money and catch a bigger habitat it seems...

but where is the backing that norbup is in fact active at smaller doses, hence causing euphoria and working as a full agonist instead of partial...

d1nach said:

How much dxm are we talking about?

If you take xanax im willing to bet yes it does increase the subjective effects but i dont think that proves there theory.

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Yes I completely agree, I'm just saying what people say , and DXM comes up a lot in that theory, especially with small doses of bupe, and idk about the dosage I would have to go back and look at some articles to see if they mention the amount...and yes xanax may increase the effects, but I think it would in the same way many drugs combined can increase each other's effects

i personally don't see or maybe just understand how there theories on xanax w/ bupe could and would help the activation in the bupe / norbup process of again making less more... but Im open to anything, I just want to understand how

most people seem to make there own scientific assumptions because it would make sense, which is fine, but, they make it out to be a fact lol smh

its like they put the pieces together, and make sense of it, and say this is how it's done, instead of saying I THINK this is how it may work ...or In my opinion etc.. 8)

I'm just adding a few quotes, not sure what to think about them yet
http://jpet.aspetjournals.org/content/321/2/598.long (mostly about rats and respiratory depression)

Following i.v. administration of buprenorphine, only a small fraction of buprenorphine is converted into norbuprenorphine. The values of these norbuprenorphine concentrations are well below the values causing an effect on respiration. Therefore, norbuprenorphine does not contribute to the overall respiratory depressant effect of buprenorphine.

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Only following the administration of highdose 30 mg/kg buprenorphine does the peak concentration exceed that of the estimated EC50 value for norbuprenorphine of 72.8 ng/ml. The lower buprenorphine doses yield maximum norbuprenorphine concentrations that are much lower than the EC50 value.

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The results of these in vitro studies show that norbuprenorphine is a full agonist at the μ-opioid receptor with an in vitro EC50 value of 1.5 nM. It should be noted that the in vivo EC50 is estimated based on total plasma concentrations. Correction for the free fraction in plasma will result in a close similarity to the in vitro EC50 value.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581407/

EC50 buprenorphine mu-receptor 0.08 +/-0,01 nM

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http://jpet.aspetjournals.org/content/297/2/688.long

Buprenorphine (BUP) is an oripavine analgesic that is beneficial in the maintenance treatment of opiate-dependent individuals. Although BUP has been studied extensively, relatively little is known about norbuprenorphine (norBUP), a major dealkylated metabolite of BUP. We now describe the binding of norBUP to opioid and nociceptin/orphanin FQ (ORL1) receptors, and its effects on [35S]guanosine-5′-O-(γ-thio)triphosphate ([35S]GTPγS) binding mediated by opioid or ORL1 receptors and in the mouse acetic acid writhing test. Chinese hamster ovary cells stably transfected with each receptor were used for receptor binding and [35S]GTPγS binding. NorBUP exhibited high affinities for μ-, δ-, and κ-opioid receptors withK i values in the nanomolar or subnanomolar range, comparable to those of BUP. NorBUP and BUP had low affinities for the ORL1 receptor with K i values in the micromolar range. In the [35S]GTPγS binding assay, norBUP displayed characteristics distinct from BUP. At the δ-receptor, norBUP was a potent full agonist, yet BUP had no agonist activity and antagonized actions of norBUP and DPDPE. At μ- and κ-receptors, both norBUP and BUP were potent partial agonists, with norBUP having moderate efficacy and BUP having low efficacy. At the ORL1 receptor, norBUP was a full agonist with low potency, while BUP was a potent partial agonist. In the writhing test, BUP and norBUP both suppressed writhing in an efficacious and dose-dependent manner, giving A50 values of 0.067 and 0.21 mg/kg, s.c., respectively. These results highlight the similarities and differences between BUP and norBUP, each of which may influence the unique pharmacological profile of BUP

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NorBUP exhibited high affinities for μ-, δ-, and κ-opioid receptors, withK i values in inhibiting [3H]diprenorphine binding in the subnanomolar and nanomolar range with a ratio of 1:45:13 for μ:δ:κ. In contrast, norBUP had a low affinity for the ORL1 receptor, with aK i value in inhibiting [3H]N/OFQ binding in the micromolar range. Similarly, BUP had high affinities for μ-, δ-, and κ-opioid receptors, with K i values in the subnanomolar range and had a low affinity for the ORL1 receptor, with aK i value in the micromolar range. (+)-BUP did not bind to μ-, δ-, or κ-opioid receptors or the ORL1 receptor.

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Both are partial agonists at μ- and κ-receptors, with norBUP having higher efficacy than BUP.

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NorBUP was a more efficacious but slightly less potent partial agonist than BUP at the μ-receptor, with an 81% maximal [35S]GTPγS binding response and an EC50 of 1.5 nM.

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i think less is more cuz some receptors are still open to let you feel the next dose, if you dose high every day your brain is just always full of bupe so you dont notice it.

d1nach said:

Ie 2 mg of will cause more activation at the mu opioid receptors than 16 mg of buprenorphine a mu opioid partial agonist due to higher doses interfering with the secondary metabolite norbuprenorphines bility to bind at the mu opioids as a full agonist.

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and back to this , that I know, BUT norbup doesn't have the ability to bind at small doses of bupe either, that's my point, I'm trying to figure how people are positive less is more because norbup, wen it doesn't even cross the BBB at a rate to bind and be effective.

I'm not applying ur saying ,ur just applying the logic that makes sense, I'm just saying that's what people always use as there general stance on why less is more, and it would make sense! but I don't know if there's any substance out there that would inihibit Norbup at a rate to cross the barrier and work as a full agonist..

and if it did let's say, is there knowledge out there that norbup would override the bup and not be blocked? ? I'm not saying there isn't facts that prove norbup would override everything on the receptor, I'm just asking everyone..

im really trying to get my finger around this subject and really understand, because the internet seems at lost as well lol

Thank you kleinerkiffer, about to read all that now and pull up the article, it seems to have more insight then I already have researched on the net

burn out said:

i think less is more cuz some receptors are still open to let you feel the next dose, if you dose high every day your brain is just always full of bupe so you dont notice it.

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Okay that makes more sense, then the fact that less is more because of norbup and that it would work as a full agonist. And stimulate and create dopamine hence euphoria.. but even though u leave more receptors, and leave more room for a re dose, it would still cause the same thing, no?

Because in the end all your doing is taking less for less to build, which make sense in the fact of ways not to get sick or not to grow a tolerance per say and be able to enjoy upcoming doses or whatever....but to me that makes that case more of, "less is more useful and productive" not really a less becomes more type of thing, if I'm making sense there with my words? Idk haha I hope

but it wouldn't technically speaking, make that "less" amount ur taking to be "more" then if u were to actually take more