A++ CYP3A4 inhibitor and CYP2D6 inducer for codeine!?

[doubleheadedeagle]

This is mentioned many times before but no one asked if we can use dexamethasone as both CYP3A4 inhibitor and CYP2D6 inducer.

I was thinking if this combination might be right or might be dangerous. According to this page [https://liferaftgroup.org/long-list-of-inhibitors-and-inducers-of-cyp3a4-and-cyp2d6/] it says that dexamethasone is both an CYP3A4 inhibitor and a CYP2D6 inducer. We now for sure that it is a CYP2D6 inducer and not many things are known about its potentials as a CYP3A4 inhibitor, mostly it says that it is a CYP3A4 substrate.

I was thinking of adding to this combination Sodium Valproate and Ciprofloxacin if Dexamethasone wasn't enough of an inhibitor, what I know (might be wrong) is that the three of them are weak inhibitors so in combination it might be just right.

What do you guys think about this ?

 

[aced126]

Kinda risky don't you think? Just take more codeine if you want more codeine. You don't know how much these enzyme modulators will inhibit/induce and you may get way more or less than what you bargained for. Unless of course you have a genuine interest in this stuff, which in that case start with a really low dose of each inhibitor.

 

[belligerent drunk]

I agree that it is unwise to go balls to the wall right off the bat, start low and definitely don't combine many enzyme modifiers on your first time, start with just one. The idea is interesting though, but (without much reading) I see that dexamethasone is also a steroid, so... make sure you know what you're doing.

I have been wondering about this as well as I'm quite a fan of codeine. The only thing I've tried is eating grapefruit before ingesting the codeine, FYI it's a CYP3A4 inhibitor which means less codeine should be N-demethylated into the inactive norcodeine. I thought it worked at first, but after more definitive tests I really couldn't say that it did after all. I guess a 2D6 inducer would actually be quite useful, because with my tolerance 500 mg doesn't really get me where I like and I'd like to push the "ceiling" a little higher.

 

[doubleheadedeagle]

Yeah i was thinking of going very minimal in trying this. But I am a little bit confused about dexamethasone and its effects on CPY3A4 maybe because it is a substrate it is an inhibitor and an inducer at the same time, can this be true?

 

[dopamimetic]

One has to eat many grapefruits probably for it to exhibit significant effects, the people who use it with DXM are drinking >1 liter of juice ... but extracting the relevant compounds, I think it was bergamottin, could be interesting.

 

[sekio]

Dexamethasone is not something to be taking to mess with liver enzymes, it will mess with your horomones way more than the liver will... and going on valproate and cipro for enhancing codeine highs seems stupid.... let's develop antibiotic resistance for no good reason?

 

[doubleheadedeagle]

Dexamethasone is not something that dangerous in very low doses(>2mg or in my cases 0,5mg), it decreases cortisol levels.Cortisol in our time is a very bad hormone, it fights insuline, increasing blood sugar, cortisol decreases bone-formation favoring osteoporosis, and it also weakens the immune system. In the modern time cortisol is very high due to all the stressors that surround us.

Ciprofloxacin is an antibiotic that treats rare bacterial infection, it is most likely that most of us wont need it, but even if we develop tolerance to it there are many other alternatives.

And I use Sodium Valproate (Anti-convulsant) everyday, as prescribed by my doctor, so I wouldn't say it had any bad impact in me.

But unfortunately, for me, taking these inducers/inhibitors did not have any significant effect, as I thought in theory. I don't know why this would happen. Yesterday I had way better effects from them, in the same amount 225 mg. If anyone can explain why?
And by the way I heard a strange noise in my ears, mostly when I closed my eyes(I and many people can experience this while yawning) it is like facing the wind, but it
wouldn't stop, it was very annoying and I can say for sure that this interfered with the euphoria.

 

[belligerent drunk]

Ciprofloxacin is an antibiotic that treats rare bacterial infection, it is most likely that most of us wont need it, but even if we develop tolerance to it there are many other alternatives.

Antibiotic resistance is not something to be taken lightly, "there are many alternatives". Nowadays it's actually a big problem, so potentially making it worse just to get higher on codeine is... not very bright.

 

[Kittycat5]

And what rare bacteria are you talking about? Anthrax? Because Cipro treats some of the infections caused by some of the most common pathogenic bacteria, such as E. coli. Besides, ciprofloxacin primarily inhibits cyp1a2 so have no idea why you would need to do this when ingesting codeine. Cyp2d6 is also one of the least inducible isoenzymes. Dexamethasone and rifampin do seem to have some capability to do so, but they (especially dexamethasone) rarely lead to clinically important interactions.

 

[dopamimetic]

Antibiotic resistance is not something to be taken lightly, "there are many alternatives". Nowadays it's actually a big problem, so potentially making it worse just to get higher on codeine is... not very bright.

Yeah.. and it's not just all about you, but these immune bacteria spread around and make the antibiotics worthless for anyone.

To come back to the topic, are there any potent CYP inhibitors known besides the usual chinidine, some SSRIs, bupropion (stronger than thought by personal experience)? Especially targeting the 2D6 but also 3A4, in attempt to replicate that Nuedexta - making DXM more potent, longer lasting and avoiding the DXO metabolite to form, making it a potential powerful antidepressant.

Using (very) low dose chinidine doesn't seem to be that dangerous as it's just 1/10 of what usually is used, but something that does not have any cardiac effects at all would feel safer and even better if it was from a plant source, so that it could be obtained without a prescription.

Bergamottin might be interesting, but that only inhibits 3A4 when it's the 2D6 that is more important (probably).

 

[Kittycat5]

I dont think there is any one agent that is classified currently as a potent 3A4 and 2D6 inhibitor. There are plenty of strong inhibitors for the various enzymes though.

Here is what the FDA uses.

http://www.fda.gov/Drugs/Developmen...rugInteractionsLabeling/ucm093664.htm#potency

 

[doubleheadedeagle]

I agree with all of you that antibiotic resistance "might" be a problem. But we can't prevent it, it is a part of natural selection. All we can do is develop new types of treatment and they are being developed almost everyday. And if IIRC antibiotic resistance doesn't happen if you just take one pill, it mostly happens when doctors prescribe antibiotics to infection that can resolve in it's own, so antibiotic resistance occurs when taking a certain type of antibiotic over a certain period of time (as therapy) when not needed.

 

[dopamimetic]

Hmm.. isn't it the other way round? That antibiotics have to be used exactly as prescribed and dosing them wrong (too little, too short) will lead to resistances, because the bacteria won't get killed all over and some of them learn how to live with the antibiotic ...

 

[doubleheadedeagle]

Yes in the case when antibiotics are needed, but in case when they are not needed(ie as enzyme inducer/inhibitor), if they are used for the time they are supposed to use then that bacteria that "would have healed" by itself, develops defense mechanisms.

 

[belligerent drunk]

No, we can prevent antibiotic resistance to a certain extent and that's why doctors have become cautious prescribing antibiotics for everything. The less we use them, the less chance there is that certain bacteria will develop resistance. THAT is a part of natural selection, it doesn't work though if there's no antibiotic to begin with. Also, I'm not an expert on antibiotics, but AFAIK it's already quite a big problem that is taking millions of lives each year and developing new classes of antibiotics is not as trivial as you may think.

 

[doubleheadedeagle]

I absolutely agree that antibiotics shouldn't be used for everything, but don't forget that mutations can happen for millions of reasons.
And by the way I love this discussion and this forum in general, it really serves as harm reduction and as a good way to share knowledge.

Peace and love to everyone

 

[aced126]

Any time bacteria is exposed to an antibiotic, it has a chance of developing resistance. What I mean by this is the antibiotic (acting as a selection pressure) will kill off any normal bacteria and will not affect the bacteria with an advantageous mutated gene/allele (e.g they might have a mutatant gene coding for a peptidase with very good activity against penicillins and the like: B-lactamase). Thus the antibiotic will allow the mutant bacteria to reproduce while eliminating the normal bacteria. This would not be the case if the bacteria had not been exposed at all (the normal bacteria, which is in excess population, would've put competed the mutant bacteria).

 

[belligerent drunk]

It is true that bacteria mutate and change in overall pretty quickly, and that's a problem in and of itself, my point is that there is really no need to add any more to that problem unless absolutely necessary.

So I'll say it again that I'm a fan of codeine, but I haven't come across a reasonable/sensible way to potentiate it by modifying enzyme activity. After all, if you're not that opioid-tolerant, you can get off pretty nicely on codeine, especially if you add some other drugs into the mix - many people like antihistamines and/or GABAergics.

 

[doubleheadedeagle]

I totally agree with all of you, but I was trying to broaden the perspective. And anyway ciprol didn't show to be a good inhibitor. And from now on I will take the matter of antibiotic resistance more serious, I live in a country that the general public isn't much informed about this stuff.

Yes it is true that I don't have developed a big tolerance to codeine but it seems that I have an enzyme deficit, because i have done it less than 20 times, and it didn't have any effects on small doses 90mg or 120mg, at 150mg I started to feel it and 225mg is a moderate dose for me. I have just come off 360mg it was nice, but my sister was very high on 90mg.

 

[belligerent drunk]

Hey, no harm in a friendly discussion! Asking questions (even if they may not be very bright at first) is really the way to broaden your knowledge. Only fools don't want to ask questions.