Codeine --> Morphine Conversion: Inducers/Inhibitors

[darkglobe]

THE BASICS OF CODEINE -> MORPHINE CONVERSION
CYP2D6 inducers theoretically potentiate codeine by stimulating its conversion to morphine. CYP3A4 inhibitors theoretically potentiate codeine by decreasing its conversion rate to norcodeine.

Reputation Comments on this post:

	good thread, very usefuk
	good info there! MB

[Handle]

Hey, darkglobe, great info to educate the curious! There are several important questions that arise from this, and it was felt that this may be a more appropriate place to ask than in the newbie intros. Searching slang phrases, one can see, "fours and dors" and "pncakes and syrup" mentioned re the use of codeine combined with glutethimide, which is said to boost the converion of codeine into morphine. Wait! Yes, it is known that glutethimide is used as a sleeping pill, and that structurally it bears some similarity to metharbital, but there are definitely stronger barbs out there that were available back in the time of 'Doriden' brand glutethimide [which makes up the dors part of the slang]. So the question must be asked, why would glutethimide be used in place of stronger depressants, if the only reason for taking it was to add a sleeping pill to an opiate. The reason must be that there were very strong beliefs that glutethimide actually boosted the conversion of codeine into morphine. Yes, it is now common knowledge that glutethimide is now basically never used, and that it was placed in a more restrictive schedule, but if people look at the online sources they will see many references to this combination. It would also explain why Doriden combos were mainly restricted to codeine, because if it was morphine or something like that, then there would be no need for the enzyme and therefore no need for the enzyme inducer. Finally, there are suggestions [from the well known online encyclo "-pedia"]
that dihydrocodeine is different from codeine in one significant way. There is the idea that codeine dosing must be spaced out, because a second dose within too short a period will meet with a deficient supply of conversion enzyme, and therefore be wasted because it cannot all be properly converted. Have others heard this? Like, within half an hour the second dose should not be administered, because it can't all get successfully converted? Well, that well known online source claims that dihydrocodeine has no such 'ceiling', now it is not known how this claim is made, on what basis, but it was there in the listing on dihydrocodeine, it said that unlike normal codeine it has an unlimited potential for conversion. Handle is not making this claim, and does not know where the idea comes from, but it was out there on that 'pedia' that everyone knows. Could this second point be addressed? The first one is of course an answer about glutethimide, does it really boost the enzymatic conversion of codeine, and then how was it made in the past [see handle's newbie intro]

Reputation Comments on this post:

Good questions, polite, solid knowledge, shows promising research potential!

[darkglobe]

I'm no expert on this, and I'd just like to point out that the above research was only compiled from other sources. I merely compile stuff that others have wrote (provided it hasn't been disproved), and I (as you seem to be) learning as I go.
But thank you for your comments, I post on DF to teach myself and others.

Also, I think it's fine to say Wikipedia on Drugs-Forum! Wikipedia is not a commercial site, and is a fantastic resource for anyone wishing to waste hours learning about stuff which is totally useless! (Guilty).

Anyhoo -

There is the idea that codeine dosing must be spaced out, because a second dose within too short a period will meet with a deficient supply of conversion enzyme, and therefore be wasted because it cannot all be properly converted. Have others heard this? Like, within half an hour the second dose should not be administered, because it can't all get successfully converted? Well, that well known online source claims that dihydrocodeine has no such 'ceiling',

Correctamundo, or at least for the Codeine part. Naturally, if the Codeine dosing is spaced out, the enzyme will be busy fiddling with the Codeine you've already given it, and the conversion rate will drop.
As for the "ceiling" you speak of, I actually think the dose ceiling for codeine (400mg if I remember correctly) exists not just out of a lack of enzyme, but for other reasons which I've forgotten, to be honest with you.

Now... the second point... I'm sorry about the longwinded reply but what I'm clumsily trying to say is.... well, I actually haven't the foggiest idea. I know very little about Dihydrocodeine, and I dont claim to. If I was to make a common sense guess, I would say that Dihydrocodeine probably does have a dose ceiling, but at what level the ceiling is and reasons for the ceiling existing, I don't know.

So yeah, apologies, but I'm not the one to ask in this case. Try Forthesevenlakes if he's still around. He knows his Opiates/Opioids.

[Tortoise]

Nice work Darkglobe. However, I think it's important to specify that regular antacids have no inhibitory effect on codeine to morphine conversion. In fact, they are quite useful to take before using codeine so that stomach acid doesn't degrade the codeine as much and causes slightly increased bioavailability of the drug.

The antacid that does affect conversion is cimetidine (Tagamet), but this isn't a true antacid as such, rather a drug that inhibits proton pumps in the stomach. It just so happens to be a CYP2D6 inhibitor. Swim sometimes finds it useful to take a tagamet at the peak of a codeine high to prevent the morphine in his system from being killed. Any sooner than the peak and it prevents codeine conversion into morphine.

It's also worth noting that Swim regularly uses Diphenhydramine/Dimenhydrinate before codeine and he has never noticed a reduction in potency/euphoria. It really smooths out the ride for him and prevents itchiness, which he can't stand.

Thanks for the info brother!

[Paracelsus]

The original post is full of factual errors. I suggest it to be deleted. Seriously. It creates more confusion than it is informative. Tortoise's post is an example.

Originally Posted by darkglobe

Two of the more well-known P4502D6 inducers are shown below, including methods of action in as much detail as I can understand:

• Grapefruit Juice: This is a well-known but slightly ambivalent inhibitor or Cytochrome P4503A4. This method may not enhance the effects of Codeine, as it also inhibits Cytochrome P4502D6 (possibly resulting a net negative result).
• Antacids: Antacids are another substance rumoured to boost the metabolism of Codeine into Morphine, but again the answer is not certain. Antacids - like Grapefruit Juice - also inhibit Cytochrome P4502D6.

Neither grapefruit juice nor antacids induce CYP2D6. GFJ has NO effect on CYP2D6 (it is not an inhibitor) and SOME antacids (cimetidine) INHIBIT CYP2D6, along with other CYPs. Also look at my emphasis (underlined text).

Methadone: Technically, this synthetic Opiod seriously reduces the effects of Codeine. [3]

Practically, it would seriously increase the effects. Not the best example.

Basically, the information contained in this post could be reduced to the following: CYP2D6 inducers theoretically potentiate codeine by stimulating its conversion to morphine. CYP3A4 inhibitors theoretically potentiate codeine by decreasing its conversion rate to norcodeine. You don't need this huge bunch of 'research' to get that message across. I hate to say this, but the post really looks like the result of a manic episode.

[darkglobe]

Originally Posted by Paracelsus

You don't need this huge bunch of 'research' to get that message across.

Thank you for your corrections.

As I always have said - I do not research anything myself. I merely put together things I've read. If facts get lost in translation (and you've just proven they do), then my apologies.

Also lol @ GPJ/Antacids being inducers in one sentence and inhibitors the next. That is a ridiculous oversight on my part.

Originally Posted by Paracelsus

I hate to say this, but the post really looks like the result of a manic episode.

The post was indeed written during a time of slight mental unrest. I don't (and never have) liked your straight-to-the-point harshness, but you're correct, and life's too short for me to take offence, so: point noted, and thank you.

As for the future of the thread... the OP has been changed. I hope this is acceptable, Paracelsus. If not, feel free to change it.

[Handle]

Come on, is everyone basically just gonna make no comment at all on glutethimide? SWIM think's it's pretty relevant to the topic, because he strongly believes that it was not just combined with codeine because it was a depressant with a similar structure to metharbital, but because it was an enzyme inducer that helped change the codeine into morphine. Will nobody comment on this? If everyone's ignorant about how it's made, can they at least talk about personal memories of people who did this, what the doses were, and if they think it really did its job?

[Tortoise]

Perhaps I'll start a new thread on the topic...

[Handle]

Excellent!

[darkglobe]

.....

[Archangel]

Has been a long time ago for swim ,but he does remember thst glutetimide DID potentiate codeine.It gave a deeper feeling(the hursh feel of codeine was diminished) and it also potentiated the codeine ,so smaller dosages where required.From what swim can remember he would take 250-500mg of Glutetimide to 300-600mg codeine.Bear in mind though that swim had a well established tolerance at that time and could take 600mg-1.2g of codeine(on its own) per dosing and still do chores.Swim would sugest a 1:1-1:2 ratio (G/C)and keep the overal dosing on the low side,at least at first.

[Handle]

600mg of codeine, man, how does swim survive?

[samuraigecko]

ceiling point is like 400mg or 450mg isnt it? 600 would be a waste of time if that were the case.

[Paracelsus]

...and possibly dangerous, as excessive codeine (per se) tends to cause seizures, like most other *codeines and *codones do. That is also why codeine shouldn't be injected.

[samuraigecko]

Originally Posted by Paracelsus

...and possibly dangerous, as excessive codeine (per se) tends to cause seizures, like most other *codeines and *codones do. That is also why codeine shouldn't be injected.

appologies, one thought it was on topic because it was mentioned by the MOD that codeine should not be injected, and one was wondering why Oxycodone (when mentioned in the same type of group by ones self) do0es not have the same effect.

Sorry for taking it "off topic".

[samuraigecko]

Very true about the codeine, although one wonders why people inject Oxycodone and do not generally get this effect. Could be that though chemically similar to codeine it is not actually made from codeine but rather Thebaine. Could be the case but would like to know others thoughts on it.

[Handle]

I honestly don't know if it's made from thebaine, my bet it yes it is made from thebaine, becaue I've seen synths on making oxy and they say it's quite direct from thebaine but a real pain to make out of codeine.

Anyway, oxycodone has a property that, although it is converted, and it does become stronger after conversion, the fact is that it still works in its original form.
So if someone injects it, even the unchanged oxycodone is a narcotic.
This is an advantage it has over other codeine related stuff.

So, if people are CYP2D6 deficient, well, it might not be as good for them, but it actually still works. There really are articles about this.

One also hears that of all things weak old dihydrocodeine [about 1-1.5 better than codeine] performed in some patients even though they were preloaded with cimetidine to block conversion. Sorry, not patients, I believe it was rats.
Anyway, one catch might be that just as you have to take GFJ a while before opiates to get a good sustained effect, I also believe that maybe blockers need a few hours head start, too. What I'm saying is, if you inject cimetidine and then two minutes later give them the dihydro, well maybe you will not get an accurate result. Maybe the cimet needed time to start working, who knows.

But anyway, oxycodone seems to have some unique advantages, at least compared to ordinary codeine, in that it can work when injected because it starts working before conversion, but it also keeps working after conversion.

[samuraigecko]

Oxy is made from Thebaine as are all of the "codone" drugs now. Hydrocodone used to be synthed from Thebaine and Codeine but is now synthed from Thebaine alone. As one can see from the chamical structures they are almost identical and have only a slight change in effect and duration. The reason for this is because things made from Thebaine are more readily accepted by humans. Example people take morphine in hospital, some can and some cant but a much higher percentage of people do not react to Codones at all and are easily taken by the masses with supposedly less side effects (immediate side effects anyway).

[Paracelsus]

Back on topic please.

[travelingman]

Who ever says that they have taken 1.2 grams of codeine is insane. SWIM took 4 100mg codeine suspended release, crushed them into fine powder and drank them down with water. After an hour SWIM turned beat red and felt like SWIMs eyes were going to burst out of the sockets.

SWIM also felt like SWIMS head was going to burst into 1 million little pieces. As far as banging codeine, please never never never try this. You will feel like battery acid is pumping through your veins and start praying that you had never even pondered doing so. Go the subcutaneous route if any.

Reputation Comments on this post:

Off topic and a bit offensive in the first sentence. Just -1 point though.

[Handle]

What if people take an antihistamine to prevent an allergic reaction?

Reputation Comments on this post:

off topic. -3 points

[darkglobe]

Not recommended, really, but then again neither is the recreational use of opiods!

@Travelingman: 4 x 100mg Codeine? Never heard of such a pill.... and suspended release preparations tend to be temperamental with most substances.

----------
Codeine is a pro-drug, hence the interest in its conversion into Morphine among users. Because Codeine is a pro drug, the side effects increase at dosage levels way past the efficacy ceiling of the drug... let's face it, human bodies can only do so much!

If SWITravelingMan had a bad Codeine experience, bad luck matey. It's possible you're one of the minority who lack the "magic" lol.

[Handle]

Alright well, I made my point, you've read it, so since this post is here now I might as well ask, why do we even have threads, seriously?
Look at the title. You could just write the title and then just write
Inducers: Glutethimide
Inhibitors: Cimetidine.
And then just have mods add to the list.
I don't think that would improve this site, surely these threads can bear a little discussion as well.
And this idea that every single minor side track needs its own thread would cause needless clutter.
But I mean, who has to clean it up? Who gets hurt? -I think people can sort out discussion without slavishly purging anything not mentioned specifically in the title.
I think getting away slightly from the title is harmless compared to diverging from the pretty good atmosphere with such behaviour.

Reputation Comments on this post:

you know who i am =D Nice one!

[Paracelsus]

LOL. Negative reputation is not a "punishment" but intended as constructive criticism. If I wanted to carry out personal fights with you, I could've made your reputation go well below zero in no time.

I do appreciate your openness, but I do not appreciate clogging this forum by going further and further from the initial topic (and ending up in bitching about bad reputation). The topic was the metabolism of codeine and not anything about related drugs. Remember that someone has to clean up your mess eventually. And I'm not just referring to you here. The opiates forum is a mess in general.

[Archangel]

Sr ,been caught up with other problems and this thread fell out of sight.
Yes 600mg is A LOT but a combination of practice and withdrawal from H in the presense of Codeine does tend to produce such results