Saving money through potentiation of opiates

[Handle]

Hey, if that's a list for P450, do you have a comprehensive list like that [in english perhaps] for CYP2D6, for any other drugs apart from glutethimide that potentiate codeine by helping to quickly convert more of it to morphine?

[Paracelsus]

CYP2D6 is generally regarded as non-inducible. Rifampin AKA rifampicin (an antibiotic) is a nonselective CYP450 inducer, and dexamethasone (an antiinflammatory steroid) also induces CYP2D6, but this interaction is not considered clinically significant (source: google "flockhart cyp450 table")

Are you sure that gluthethimide potentiates codeine by inducing CYP2D6?

[Tortoise]

According to Wikipedia

"Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances[1]. It was originally a Schedule III drug in the United States under the Controlled Substances Act, but in 1991 it was upgraded to Schedule II, more than a decade after recreational abusers discovered that combining the drug with codeine produced a euphoria which closely resembles that obtained from heroin."

also

"Glutethimide is a CYP2D6 enzyme inducer. When taken with codeine, it enables the body to convert higher amounts of the codeine (higher than the average 5 - 10%) in to morphine.
The street name for a combination of Doriden and Codeine #4 is a "load" or "doors and fours" or "Pancakes" in Pancakes and Syrup (Glutethimide and codeine based cough syrup)."

Being wikipedia though, this could all be bullshit....

[Handle]

it's just that after reading some reference about this in Shulgin, I asked and read about two people who said that they did not combine glutethimide with morphine, methadone or heroin, they said it was pointless because then you were only adding the mild dumb down effect it has as a depressant. It was basically reserved for codeine because that was the only drug they felt it significantly enhanced.

[d1ce]

SWIM is a bit confused about all the information provided and is looking for some easy instrutions. From what SWIM has gathered, he should consume grapefruit juice AND tums some time before consuming hydro, oxy, ect. Is this correct? Also, how long should SWIM wait after consuming the tums+grapefruit juice before taking the meds and in what amounts?

[0utrider]

SWIM thinks the night before plus randomly before (if wanted) but most importantly 2 hours before..

[finriswolf]

Originally Posted by outriderx

SWIM thinks the night before plus randomly before (if wanted) but most importantly 2 hours before..

This is correct! 2-4 hours before dosing. The potentiation may last up to 24 hours (although the buzz wont).





Fin

[Handle]

I'll tell you the simple truth of what I saw in a methadone prescriber's handbook on this topic. It listed grapefruit juice as a substance that could inhibit breakdown of opioids by the liver, and could possibly raise serum methadone levels that way.
It then listed orange juice as actually something that could speed the renal excretion of opioids because it may lower serum ph, [and so I assume that the salts of opioids are amenable to kidney excretion more so than the free base, just a guess based on that listing.] It might also be that acidity has a slightly diuretic effect as well.

So that may be the key to why the delay is important, I mean, why you should take the GFJ a while before dosing. Because do opioids right on the heels of a big drink of GFJ, and the acid might actually help rinse it straight out of your system.
Meanwhile the liver effect is longer lasting [and maybe has a delayed action too] so that the [undesirable?] acidity of any sour juice can wear off first, leaving only the good and desirable inhibition of the P450.

I think that's why the delay is best and why tums type stuff may help [help against the bad rinsing effect of excess acidity]. Just a guess.

Reputation Comments on this post:

nice contribution!

[e-spacecadet]

SWIM appreciates O'potentiation, but forgot to take the GFJ beforehand and took it right after dosing - twice.

One can report one felt almost OD'd -twice!

[finriswolf]

Originally Posted by e-spacecadet

SWIM appreciates O'potentiation, but forgot to take the GFJ beforehand and took it right after dosing - twice.

One can report one felt almost OD'd -twice!

Space, when you say 'almost OD'd', what do you mean? Could you please give a few details regarding what SWYM may have used (opiate, dosage etc,.)? Thank you

Fin

[finriswolf]

"Because DHB is found in only certain parts of the grapefruit, the way grapefruit juice is
prepared can affect the degree of drug interaction. DHB is the main component
responsible for mediating the grapefruit effect in reconstituted frozen concentrate, the
most common form of juice consumption (10). An epoxide of DHB, found only in the
grapefruit peel, is also a potent inhibitor of CYP3A4. Frozen concentrates therefore have
a higher amount of active ingredient than freshly squeezed juice or the fruit itself,
because the pressure exerted to prepare the frozen concentrate squeezes the grapefruit
peel containing the DHB epoxide into the juice. Grapefruit and freshly squeezed juice do

not contain this epoxide, and thus have a lower amount of active ingredient" - Published Study

This is an important point. -Fresh juice is not as potent!- SWIM has been testing the GFJ theory and has had some interesting results. I will post some findings soon.

Fin

[bineon]

Jeeze I wish I would have read this earlier!
I just took a Demerol prescribed for this tooth-ache I have... Anticipating upset stomach, I also took a Pepto Bismol =[

I sure hope my state of consciousness isn't altered. How do I counter the effects?!?!?!?

[e-spacecadet]

Originally Posted by finriswolf
Space, when you say 'almost OD'd', what do you mean? Could you please give a few details regarding what SWYM may have used (opiate, dosage etc,.)? Thank you

Fin

Sorry for the vagueness. SWIM uses roughly the same amount of heroin ea day - between 1/2 & 2/3gm. Two different days, swim used a typical dose and immediately ate a few spoonfuls of frozen GFJ concentrate. After maybe an hour or more, not sure, one felt increasingly, annoyingly, too high. One felt as one feels when she uses too much h and it's no longer nice. It felt how when (stupidly) a 2nd dose is used, mistakenly thinking the 1st wasn't enough. For SWIM, both feelings are head pressure, 'zoned out', eyes super-pinned, not sure if breathing will continue if sleep happens, and generally uncomfortable. SWIM purposefully kept busy and looked forward to getting beyond it. Now maybe this is ideal for some, but SWIM likes to feel GOOD and a nice friendly euphoria.
Actually, SWIM can't say it's really that euphoric anymore, using it daily. But one normally feels an uplifting, anxiety eliminating, calming (fuzzy blanky) energy. The "almost OD" is a nerve-racking, "been here before, don't like it - scary, did my heart just stop?" feeling.
So maybe SWIM should try a little less of each - but it's hard for a habits to be changed... Will have to remind SWIself to try again.

[finriswolf]

Originally Posted by e-spacecadet

Sorry for the vagueness. SWIM uses roughly the same amount of heroin ea day - between 1/2 & 2/3gm. Two different days, swim used a typical dose and immediately ate a few spoonfuls of frozen GFJ concentrate. After maybe an hour or more, not sure, one felt increasingly, annoyingly, too high. One felt as one feels when she uses too much h and it's no longer nice. It felt how when (stupidly) a 2nd dose is used, mistakenly thinking the 1st wasn't enough. For SWIM, both feelings are head pressure, 'zoned out', eyes super-pinned, not sure if breathing will continue if sleep happens, and generally uncomfortable. SWIM purposefully kept busy and looked forward to getting beyond it. Now maybe this is ideal for some, but SWIM likes to feel GOOD and a nice friendly euphoria.
Actually, SWIM can't say it's really that euphoric anymore, using it daily. But one normally feels an uplifting, anxiety eliminating, calming (fuzzy blanky) energy. The "almost OD" is a nerve-racking, "been here before, don't like it - scary, did my heart just stop?" feeling.
So maybe SWIM should try a little less of each - but it's hard for a habits to be changed... Will have to remind SWIself to try again.

Thank you so much for the detail! SWYM 'ate' several spoonfulls?! Oh my, this throws a twist into SWIMs current studies.....

Thanks again!

Fin

[e-spacecadet]

Can one share any of these current studies?

[The_Tortured_Soul]

Juices come in handy very much so. I love these neat little tricks.

[0utrider]

*GLUTHETHIMIDE A combination of codeine and gluthethimide (a sleeping agent) has been used in some places as a heroin substitute. Gluthethimide is an enzyme-inducer, and it allows the body to convert more than 10% of codeine into morphine. Note that this combination increases the addiction potential of codeine.]

found this.. any info on that?

[Handle]

Hehe, this is my old obsession. Glutethimide is called an "enzyme inducer" and is the only supposed inducer for CYP2D6, and it was used with codeine, they did not use it with other opiates. This is all the proof I need that they were not using it for its hypnotic effects, because if they were, then they would have been happy to use it with other things like morphine and methadone as well. But since use was almost entirely restricted to combo's with codeine, I see that as the proof that it was used specifically as an enzymatic inducer for the opiate that needed it [codeine], and therefore was not just being used as a general downer. So, like grapefruit juice to restrict p450,
glutethimide was a very specific potentiator of codeine.

The combo was slang termed "pancakes and syrup" and "fours and dors" [the syrup of the first phrase is codeine cough syrup, and the dors of the second phrase refers to doriden, an old brand name for glutethimide]

[0utrider]

oh well... too bad, so SWIMs guess ıs tıme & money would be smarter to ınvest ınto more codeıne and grapefruıt juıce, rıght?

(btw ın the pm ı meant the CWE FAQ ın my sıgnature, whre ı also posted thıs quote)

[Handle]

Hey also in response to Allyourbase and others, there is an idea out there that antacids would be succesful only if combined with oral use of opiates. Well, there is a chance that actually the applications are wider, I don't know the mechanics exactly of how antacids help, but I do know that all this about first pass is not the only significant exposure to the stomach and liver.

Did you all know that with severe opiate OD hospitalisations, many hospitals will still do gastric lavage, even when the opiate was injected!

Why?

Because the body accumulates the toxic opiates in the stomach, it is a biological process that occurs even with parenteral use. I think it is to force stuff through the liver, no matter where it came from, to break them down.

So don't dismiss these tricks just because you are not swallowing a dose, swims.
I am just saying, people should at least research this theory, because I'm telling you its surprising how things end up in the gut even when "you" didn't put them there, and when they do end up there,you can be ready for them. At least try it out and report back, I mean if you're already using opiates for whatever reason, legit or otherwise, a few tums wouldn't hurt as a little experiment.

Could someone please tell me, is there a definitive plan of action, with doses and timing schedules set out in this forum, for potentiation? If you have a CWE FAQ, some brainy ones should set out a definitive FAQ for potentiation, and separate the categories into codeine based potentiation [where you want to slow down the P450 without disrupting the CYP2D6], and also non codeine potentiation [where it's only P450 that matters] and give specific tips for specific routes of administration.

Reputation Comments on this post:

very good post, why not start a potentiators FAQ ! ;)

[Paracelsus]

Because the body accumulates the toxic opiates in the stomach, it is a biological process that occurs even with parenteral use. I think it is to force stuff through the liver, no matter where it came from, to break them down.

I highly doubt that. There is no mechanism that I know of by which substances in the blood go to the stomach (except bleeding into the stomach), and the liver metabolizes substances in the bloodstream anyway. But I may be wrong, so please provide references beyond the gastric lavage hunch.

[Handle]

I'll have to find something to back it up. Give me time. Meanwhile, are there any potentiators that everyone agrees on for injected opiates [by potentiators, I'm strictly talking stuff that stops the breakdown]

I'm too lazy to search through the whole thread, can someone just tell me, has this all been strictly about oral use? Is there anything that works with injection?

I wish there was an FAQ for this, if we can have one for CWE, why not for potentiation? Something definitive.


OK, Paracelsus, here is the evidence that you're after. The first one seems unrelated, as it is about snake venom being tested in rodents, but the article proves that venom can accumulate in the stomach even after subcutaneous injection. Without gastric bleeding.

www.doaj.org/doaj?func=abstract&id=24326&openurl=1



But it doesn't make clear if it's in the cavity of the stomach or the tissues of the stomach, nor can I leap to say it must be true for opiates as well. So now here are references to Oxford Journals cached text of British Journal of Anaesthesia articles on the same subject [but you would need an institutional portal to access the full text, or register with Oxford Journals]






EFFECT OF ANTACIDS ON THE PLASMA CONCENTRATION OF PHENOPERIDINE

Br. J. Anaesxh., 51, 741. Trudnowski, R. J., and Gessner, T. (1975). Gastric sequestration. of meperidine following intravenous administration. Abstracts ...
bja.oxfordjournals.org/cgi/reprint/55/6/535.pdf
ADVERSE EFFECTS OF OPIOID ANALGESIC DRUGS

dogs, gastric sequestration of fentanyl has been demonstrated, but a small fraction only of the ...... following conservative doses of intravenous naloxone. ...
bja.oxfordjournals.org/cgi/reprint/59/1/61.pdf
Pharmacokinetics and clinical anaesthesia

10 Trudnowski RJ, GessnerT. Gastric sequestration of. meperidine following intravenous administration. Abstracts, ASA meeting, Chicago. 1975: 327. ...
www.cja-jca.org/cgi/reprint/32/S3/S12.pdf



As you can see, they all seem to refer to Trudnowski and Gessner, 1975, and here is another excerpt that gives a simple explanation of this property

Pharmacokinetics
and clinical anaesthesia C.J. Hull MB BS FFARCS


Even worse, some drugs (such as opioids) are sequestrated in low-pH zones, and may re-enter the systemic circulation after variable periods.10" This phenomenon
may cause gross irregularities in the plasma decline curve, so that model identification may become impossible.

Trudnowski RJ, GessnerT. Gastric sequestration of
meperidine following intravenous administration.
Abstracts, ASA meeting, Chicago. 1975: 327.



So there you are, you might think, it is a simple matter of alkaloids getting sucked into high acidity regions. Not so. Due to the H1 and H2 response elicited by opiates in particular, you know, the itching, all that,well, it also happens to include acid secretion by the stomach! So that gives you a clear and direct mechanism by which gastric sequestration of opiate alkaloids present in the body, is actually mediated by the response those very opiates elicit in the first place.



What I'm saying is, acidity sucks in alkaloids [notably opiates as CJ Hull points out], and opiates in particular cause a histamine response that increases stomach acidity. I think fentanyl has lower gastric sequestration because it causes less of a histamine response, but that might just be because of the lower doses needed.




So the body automatically responds to opiates with the result that they are drawn into the stomach, and this is a particular effect and consequence seen with opiates. No gastric bleeding necessary, and I think the whole issue of pH makes clear that we are actually talking about inside the stomach,

not the tissue of the stomach, also because of the word "sequestration" I think it's pretty clear.



But Paracelsus, your last comment is sort of cryptic, when you say "the liver metabolises substances in the bloodstream anyway" you make me think that there is a chance that injected opiates could be prolonged by grapefruit juice. What I think you're saying is, you could still derive some benefit by slowing down bloodstream exposure to the liver, "second pass" in a sense. I mean, just because you can skip the liver the first time, I still don't think that say, injected heroin is suddenly immune from breakdown by the liver.


Is that what you're saying? That there might still be benefits for IV users if they drink GFJ? That is what interests me.

[0utrider]

I'd also agree that this would be a great idea, a managed potentiators faq, just need someone for doing that/starting it and going through this thread and adding up all the info and managing he thread

back to the topic, afaik there is no potentiators for injection since you just pass the liver, but i know that, for example, chlorpheniramine and other anti-histamines make the opiate effects stronger (but also have their own little terrible effects, so dont play witht that), i guess that would also go for injection, and if that would work there would be surely more possibilities out there..

[Paracelsus]

But Paracelsus, your last comment is sort of cryptic, when you say "the liver metabolises substances in the bloodstream anyway" you make me think that there is a chance that injected opiates could be prolonged by grapefruit juice. What I think you're saying is, you could still derive some benefit by slowing down bloodstream exposure to the liver, "second pass" in a sense. I mean, just because you can skip the liver the first time, I still don't think that say, injected heroin is suddenly immune from breakdown by the liver.

Is that what you're saying? That there might still be benefits for IV users if they drink GFJ? That is what interests me.

Basically correct, at least theoretically. If you take a look at this paper you will see that typical amounts of grapefruit juice (1-2 glasses) selectively inhibit intestinal CYP3A4 (and therefore only bypass some of the first-pass metabolism of the respective opioid). Large amounts also inhibit liver CYP3A4, which would possibly prolong the action of snorted, smoked, or injected opioids. This has not been extensively tested, though.

[Handle]

Well then, if you were prepared and had the time for a significant "lead in" period, the paper seems to suggest that 3 days in advance can actually build up and still have an increased effect over same day GFJ.

Shame for some people, low on money and on opioid maintenance buprenorphine, trying to maximise a once in a while hit, if they took GFJ on previous days all the buprenorphine would foul up the hammer.

So, what is ideal, what dose, and howl long before drug use is appropriate?
I looked at the graph in the paper, amazing, the blood levels of drug were almost double the non GFJ levels, but they had double strength.

The one reason I worry that 2xSS is not equal to 1xDS, is because DS has less water. So I worry, the more you drink of SS, maybe you create a diuretic effect not obsoived with DS, because DS is less dilute, has less water.

If there is a risk of flushing the drugs right out, then it doesn't matter if you keep the drug in active form safe from the liver, because it will be safely speeding away from the liver down a urinal!

I'm just appealing to anyone who feels they should, please do an FAQ for this.