Piperine as codeine potentiator. CYP2E1 and paracetamol toxicity.

[>Marquis<]

APAP is metabolised by 2E1 and then conjugated with glutathione, right? So what happens to apap when 2E1 is inhibited? Supposedly this would eliminate/reduce the issue of toxicity due to glutathione depletion but would it create other problems, with a dose of say, 3 to 4g paracetamol, or would you just get a load of harmless apap-sulfate and apap-glucuronate?

I've been looking into piperine since I saw that loperamide post yesterday and it seems like it would be a great potentiator for the recreational user of OTC codeine;

--3a4 inhibition, which we want, but without any apparant inhibition of 2d6 (none I could find in my stroll through pubmed anyway).
--PGP inhibition has been shown to increase the amount of morphine crossing the BBB. Sounds good.
--2e1 inhibition would reduce any risks of toxicity associated with high-dose paracetamol, assuming that it doesn't end up being metabolised into some nasty bugger of a compound in some other manner.
--it's in black pepper so it's not going to cost you a bundle.

Possible negatives;

--piperine appears to inhibit some UDP-GDH/UGT. I haven't checked this out in depth(truth be told I've only just found out what "UGT" means), but UGT2B7 produces highly potent morphine-6-glucuronide whereas UGT1A3 gives the 3-glucuronide which is not active/possibly toxic. Inhibition of 2B7 would prolly produce some decrease in codeine effects or possibly complete negation of euphoria if the theory that codeine-6-glucuronide is responsible for codeine's activity is true. That would suck. If that's not the case and 1A3 is inhibited there could be a potency increase.

Update: This study found inhibition of UGT1A1 by piperine in rats and guinea pigs with no inhibition of UGT2B1. 1A1 is also involved in 3-glucoronidation. Kaloo kalay, no codeine 3-glucoronide for us to-day.

--I came across one study that mentioned MAO A and B inhibitory activity of piperine and apparantly mixing MAOI's and opiates is some bad juju if you want to stay alive.

Update: Codeine doesn't have any SRI properties and is OK to take with MAOI's.
--One other paper I glanced at referred to the neurotoxicity of piperine, but if it's being sold in health food shops and I sprinkle black pepper on my dinner every night I don't think it could be that bad.

Assuming the possible negatives turn out to be of no significance, this could be a pretty good tool in the recreational codeine user's hands. I'm too lazy right now to check about the MAO and UGT properties but hopefully one of you guys knows something about this?

 

[>Marquis<]

Well there you have it. it looks like piperine/black pepper is an effective potentiator for recreational codeine use. The only remaining issue of possible consequence is the effect of high dose (1-3g) paracetamol taken during pgp inhibition. I'll research that tomorrow although that only matters for CWE.

As to an effective dosage of black pepper for potentiation, I don't know. I'm going to try 1g(at ~5% piperine content) of freshly cracked pepper in water tomorrow before taking 1/3 of my normal (~350mg) codeine dose and I'll see how that works out.

I'd really appreciate some comments from you guys about this as there are educated people in this forum and I'm just a layman with access to pubmed. There could be something important that I'm missing.

 

[raybeez]

If you do an effective CWE and remove the APAP, then you don't need to waste any more brain power hypothesizing what would/wouldn't happen with its metabolism...

The abstract regarding MAO-A/B inhibition reports the IC50 values in micromolar required for inhibition. Do you know how that compares to IC50 values for 3A4/PGP inhibition?

 

[morphiquet]

piperine is also to some extent (which i don't know) decomposed by your gastric acid, so you should possibly put the black pepper into gastric acid-resistant capsules.

 

[fatality]

CAREFUL!!!! piperine has been shown to carcinogenic (ok well so is alot of stuff hey) but its been shown in tests with rats that it has a tumour promoting effect. see the link below about piperine..... or just google CRC handbook of alternative cash crops and look for pepper.

http://books.google.com.au/books?id...&oi=book_result&resnum=10&ct=result#PPA395,M1

i've been thinking of taking piperine to increase the effects of amphetamine but i dont know, for all the shit i snort/eat/plug whatev, i'm still shit scared of developing cancer....

 

[nuke]

The easiest way to potentiate amphetamine is to take it with a teaspoon or two of baking soda dissolved in water.

 

[Pomzazed]

^
,and DRINK A LOT of water too, you know excess sodium gives kidney problem in the same way as eating too much table salt a day.
well, I may be exaggerating, but drinking more water won't disturb you much anyway

 

[Tchort]

CYP2D6 Induction is a much more effective means of potentiating Codeine.

The Pgp/CYP3A4 Inhibition would be minimal from Piperine. While it will technically increase the potency of Morphine on paper, this does not always transfer to physiological benefits (i.e. increased warmth, euphoria, sedation, etc.). It's possible CYP3A4 Induction might increase the amount of Codeine converted to Norcodeine, which may or may not be beneficial in terms of potentiating the effects of Codeine.

The info you've posted is very interesting, though I doubt it would translate to concrete, noticeable potentiation.

CYP2D6 Induction via Glutethimide and Promethazine is very old and proven to work, both by increasing the percentage of Codeine converted into Morphine and by additive effects (increased sedation, nodding). Dexamethasone might make a good and fairly easily available Codeine potentiator, if the side effects are worth it.

However, UGT2B7 also conjugates Norcodeine, Codeine and Morphine to their 3-/6- gluco. counterparts. Increased production of Codeine-6-Glucuronide (and Morphine-6-Glucuronide & Norcodeine-6-Glucuronide) may increase the subjective pleasurable effects of Codeine.

Hard to tell for sure without bioassay.

 

[jasoncrest]

I think you woudn't feel the potentiation.
Potentiation through enzymes inhibition/induction has never given any real noticeable potentiating effect on me...

CYP2D6 Induction via Glutethimide and Promethazine is very old and proven to work, both by increasing the percentage of Codeine converted into Morphine and by additive effects (increased sedation, nodding). Dexamethasone might make a good and fairly easily available Codeine potentiator, if the side effects are worth it.

Promethazine is a CYP2D6 inhibitor, not inducer. IMO people report "potentiation" when they use it with Codeine just because of the strong sedative effects of the promethazine, added to what's left of the effects of the Codeine (usually less euphoria due to the inhibition of the conversion to Morphine, but still itchiness, warmth, etc...)...

And I don't believe Dexamethasone would make a good potentiator, because it also induce CYP3A4, which then eliminates the Morphine quicker and make it weaker.
I experimented talking Codeine with a Dexamethasone analogue (Beclomethasone), with the same enzyme inducing properties. The result is that I would feel the same effects as usual from the Codeine, but then it would immediately wear off...

 

[>Marquis<]

Just thought I'd kill this thread with the final piece of the puzzle

http://www.ncbi.nlm.nih.gov/pubmed/16808005

That study found alkamides in black pepper to inhibit 2d6.

 

[Ne0]

Just thought I'd kill this thread with the final piece of the puzzle

http://www.ncbi.nlm.nih.gov/pubmed/16808005

That study found alkamides in black pepper to inhibit 2d6.

So what this means it dose not increase codeine potency?

So has anyone black pepper with codeine, did the effect last longer and were stronger? I need some effective easy to get potentation for codeine.

 

[Cartesia]

^ CYP2d6 is the enzyme that turns codeine into morphine... inhibiting it is the easiest way to ruin your codeine dose.. if we could find something to induce it to work more, we could make codeine much much more desirable!

3A4 is resoponsible for breakdown of opioids - if we could inhibit 3A4 - stop it from working so much, 1) more of the good stuff would build up in our system getting us higher, 2) we would stay higher for longer..

UGT2B7 - nobody is quite sure if it would be better to inhibit it or induce it.. or just leave it alone.. I know nothing of glucuronides and such

Sorry for bringing this one back up from the dead ... I really loved this idea it's sad to see that it died.

I swear I would pay someone a thousand dollars to find me a readily available 2d6 inducer (and a bonus thousand if the same thing inhibited 3A4)
...
Although I hear rumours within the public health system that codeine is going prescription only and/or having a linked database recording system in australia next year at the moment they just pretend to take down your details if they think you look dodgy.

 

[BodyHereMindGone]

I use a certain cluster headache pill to increase my codeine use... CYP3A4... Prescrition only.. Works like a charm tho (for me)

Forgot to add - The duration i feel is decreased while the overall "good feelings" are alot stronger which is what im usually after..

Perhaps a combo of this + something else? ...

 

[C_Tripper]

Glutethimide is a know 2D6 inducer from what I can remember. It was widely abused in the common "doors and fours" mixture: Doriden (glutethimide) and Tylenol 4 (codeine). It markedly increased the potency of codeine apparently.

 

[THE_REAL_OBLIVION]

Sorry to bump this (mildly) old thread, but here's my input about ingesting black pepper prior to codeine.

I've taken an empty (sigh) capsule of Hydromorph Contin, filled it with black pepper, and gulped it down. 20 mins later my CWE'd caffeine/codeine sludge was ready. And i did fall into one of those "pensive nods", most opi users will know what I mean. And to verify any of this wasn't placebo, i looked at my pupils and they are pinned, pinned like if i had 20mg of oxy or 40mg of oral morphine. It's not that great of a high (obviously), but it seems like the stuff works. It can't be placebo cos pinned pupils don't lie. I'm still feeling it, the only downside...which i'd call a minimal one, is that it seems to reduce the duration of the effects, but i dont mind, i wanted my comfy nod with full of constructive thoughts going through my mind while in a sort of trance, which I got %)

 

[Franklinparton]

Also Sorry to bump an old thread! But been reading about this a lot recently and thought I’d throw my 2 penny’s worth in.... I saw something recently on TV that new studies showed that Pepperine (just realised why OP said Pepperdine - stupid autocorrect) actually causes the [COLOR=rgba(0, 0, 0, 0.870588)]villi in the gut to grow larger, therefore increasing surface area, therefore increasing absorption. So it appears to be more about the absorption of the drug than potentiating, although it could do that too.

I started adding black pepper to most meals because the show I was watching said it massively increases absorption of nutrients. It occurred to me after it might help with codeine so a google search landed me here. I now take a shot of Apple cider vinegar with fresh ground black pepper 20-30 mins before I hit the codeine and I’d say it definitely hits harder. I’m pretty codeine tolerant and get that warm hit back after a good dose of pepper (and vinegar) I read on this forum elsewhere that codeine also absorbs better in more acidic contions - dunno whether it’s the vinegar or pepper, or both, but if you’re reading this wanting a more potent hit definitely give at a bash! [/COLOR]