The CYP2D6 mediated o-demethylation of codeine and the 'ceiling effect'

[TheJuner]

So as many of you are aware, codeine has a 'ceiling effect' which is reached at a dose of around 600mg. I believe that this ceiling effect can be attributed to the fact that codeine has to pass through the liver where it undergoes CYP2D6 enzyme mediated o-demethylation which converts the codeine into its active metabolite, morphine. So, my understanding of the ceiling effect codeine has is that the liver can only convert so much codeine into morphine at a given time. If this is the case, do super metabolizers have a higher ceiling dose? Furthermore, would a CYP2D6 enzyme inducer like glutethimide raise the ceiling dose of codeine?

 

[3DQSAR]

The ceiling dose can vary hugely based on genetics. Peoples of African descent are more likely to be super-metabolizers whereas quite a large proportion of peoples of South East Asian descent are poor metabolizers.

There a few other 'strong' CYP2D6 inducers but almost without exception, they are not medicines one would wish to take merely to increase the effects of codeine.

Glutethimide itself it chiral and as far as I have been able to work out, nobody has tested if one or both enantiomers are responsible for the enzyme induction or even if it's a metabolite that is responsible (since the two enantiomers are metabolised quite differently).

 

[TheJuner]

The ceiling dose can vary hugely based on genetics. Peoples of African descent are more likely to be super-metabolizers whereas quite a large proportion of peoples of South East Asian descent are poor metabolizers.

There a few other 'strong' CYP2D6 inducers but almost without exception, they are not medicines one would wish to take merely to increase the effects of codeine.

Glutethimide itself it chiral and as far as I have been able to work out, nobody has tested if one or both enantiomers are responsible for the enzyme induction or even if it's a metabolite that is responsible (since the two enantiomers are metabolised quite differently).

The fact that genetics determine whether or not codeine will work as an opioid-analgesic at all is something I remember reading about (specifically in the context of why codeine should stop being medically used). Wish more research was done on the respective isomers of Glutethimide, sadly it likely won’t happen given the fact that glutethimide has been discontinued virtually everywhere and illegal.

 

[MedicinalUser247]

Yeah, because if your mix Glutethimide with Codeine it converts more of the Codeine into Morphine. That and that Glutethimide has bad withdrawal effects.

 

[TheJuner]

Yeah, because if your mix Glutethimide with Codeine it converts more of the Codeine into Morphine. That and that Glutethimide has bad withdrawal effects.

Yep. The WDs from quitting a codeine and glutethimide habit would be absolutely miserable.

 

[3DQSAR]

I forgot to mention that codeine demonstrates the 'depot effect' which is to say that for most users (I suspect the super metabolisers are the exception), codeine itself will down-regulate enzyme production.

Put simply, if you take a given amount of codeine, there is no point in taking more for a further 4-6 hours as it will not undergo enzymatic O-demethylation.

I consider this to make codeine a more hazardous medicine than most people give it credit for as most people re-dosing will tend to repeat until the desired effects occur. All that happens is that ever larger amounts of codeine are being consumed. While death due to respiratory collapse can occur due to codeine abuse, I am lead to understand that seizures and other mechanisms are responsible for most fatalities.

I really have no idea if glutethimide will likewise O-demethylated semi-synthetic opioids such as dihydrocodeine, hydrocodone or oxycodone because none of them were in widespread use when '4s and Dors' was a popular 'cocktail'. Likewise tramadol MAY be more extensively converted to it's M1 metabolite (O-desmethyl tramadol). But I don't think anyone can say with any degree of certainty.

 

[TheJuner]

I forgot to mention that codeine demonstrates the 'depot effect' which is to say that for most users (I suspect the super metabolisers are the exception), codeine itself will down-regulate enzyme production.

Put simply, if you take a given amount of codeine, there is no point in taking more for a further 4-6 hours as it will not undergo enzymatic O-demethylation.

I consider this to make codeine a more hazardous medicine than most people give it credit for as most people re-dosing will tend to repeat until the desired effects occur. All that happens is that ever larger amounts of codeine are being consumed. While death due to respiratory collapse can occur due to codeine abuse, I am lead to understand that seizures and other mechanisms are responsible for most fatalities.

I really have no idea if glutethimide will likewise O-demethylated semi-synthetic opioids such as dihydrocodeine, hydrocodone or oxycodone because none of them were in widespread use when '4s and Dors' was a popular 'cocktail'.

Glutethimide’s CYP2D6 enzyme inducing effects will potentiate any opioid that is metabolized by CYP2D6 mediated o-demethylation. Glutethimide if combined with say, dihydrocodeine, would result in the effects of the dihydrocodeine being massively potentiated because the CYP2D6 enzyme inducing effects of glutethimide would increase the amount of DHC’s active metabolite, which is dihydromorphine (a substance that is significantly stronger than morphine both by weight and also in terms of its binding affinity for the MOR).

 

[3DQSAR]

Is dihydromorphine significantly more potent? The only nation I know of that uses it widely is Japan. They also use DHC rather than codeine which makes sense since DHC is active in it's own right...

Maybe it's as simple as with DHM in use, DHC

 

[3DQSAR]

BTW what I mean is that almost all codeine is made from morphine rather than extracted from plants, so if one has a factory converting morphine to DHM, DHC then makes sense... and SE Asians being poor metabolizers making DHC the logical option.

 

[TheJuner]

Is dihydromorphine significantly more potent? The only nation I know of that uses it widely is Japan. They also use DHC rather than codeine which makes sense since DHC is active in it's own right...

Maybe it's as simple as with DHM in use, DHC

Dihydromorphine is 1.2-1.8x the potency of morphine iirc, and has a higher binding affinity at the mu opioid receptor than morphine does. Also while dihydrocodeine is active on its own, which makes it a better analgesic compared to codeine, which basically just works as a prodrug for morphine, dihydromorphine is one of dihydrocodeine’s major active metabolites which is yielded from CYP2D6 mediated o-demethylation.

Given that dihydrocodeine is stronger than codeine, active on its own, and its major active metabolite yielded through CYP2D6 enzyme mediated o-demethylation is stronger than morphine, using dihydrocodeine with a CYP2D6 enzyme inducer like glutethimide would be an amazing combo. If codeine and glutethimide is extolled for being an incredibly euphoric drug combination, imagine dihydrocodeine and glutethimide instead…one must also remember that glutethimide isn’t just a CYP2D6 enzyme inducer but is also a potent sedative hypnotic in its own right. While it isn’t a barbiturate it is pharmacologically similar to barbiturates and its effects were most comparable to pentobarbital.

 

[MedicinalUser247]

I'll give you a hint... Oxymorphone. Otherwise when it comes to my own personal agenda I refuse to design power opiates.

 

[TheJuner]

Is dihydromorphine significantly more potent? The only nation I know of that uses it widely is Japan. They also use DHC rather than codeine which makes sense since DHC is active in it's own right...

Maybe it's as simple as with DHM in use, DHC

I'll give you a hint... Oxymorphone. Otherwise when it comes to my own personal agenda I refuse to design power opiates.

Mmm oxymorphone…

 

[chippermonk]

Glutethimide’s CYP2D6 enzyme inducing effects will potentiate any opioid that is metabolized by CYP2D6 mediated o-demethylation. Glutethimide if combined with say, dihydrocodeine, would result in the effects of the dihydrocodeine being massively potentiated because the CYP2D6 enzyme inducing effects of glutethimide would increase the amount of DHC’s active metabolite, which is dihydromorphine (a substance that is significantly stronger than morphine both by weight and also in terms of its binding affinity for the MOR).

As it so happens, I have 2 ancient doridens that I got from from grandmother's medicine cabinet long, long ago. I can never figure an optimal and safe way to use them. I don't have any significant opiate tolerance and I would never IV them. It sounds like it converts codeine to morphine, and in my limited experience, I disliked morphine ( though a lot of other opiates are nice, if not something I feel compelled to do regularly). Furthermore, I really dislike sedatives like seconal and quaaludes and wouldn't want that feeling to interfere with a nice mellow opiate buzz.
Yet here I am, a curious guy with them in my possession. Maybe I'll just cut one up in fourths and try it with a small dose of codeine or oxy and see how it goes. In any case, I just don't feel safe trying to get a full on dors-and-fours experience.
Any advice?

 

[chippermonk]

As far as potentiating tramadol through CYPD26, by whatever means, I assume you would likewise run a greater risk of seizures, since that is a risk with high doses of tramadol

 

[TheJuner]

As it so happens, I have 2 ancient doridens that I got from from grandmother's medicine cabinet long, long ago. I can never figure an optimal and safe way to use them. I don't have any significant opiate tolerance and I would never IV them. It sounds like it converts codeine to morphine, and in my limited experience, I disliked morphine ( though a lot of other opiates are nice, if not something I feel compelled to do regularly). Furthermore, I really dislike sedatives like seconal and quaaludes and wouldn't want that feeling to interfere with a nice mellow opiate buzz.
Yet here I am, a curious guy with them in my possession. Maybe I'll just cut one up in fourths and try it with a small dose of codeine or oxy and see how it goes. In any case, I just don't feel safe trying to get a full on dors-and-fours experience.
Any advice?

Im so fucking jealous of you goddamn.

 

[TheJuner]

As it so happens, I have 2 ancient doridens that I got from from grandmother's medicine cabinet long, long ago. I can never figure an optimal and safe way to use them. I don't have any significant opiate tolerance and I would never IV them. It sounds like it converts codeine to morphine, and in my limited experience, I disliked morphine ( though a lot of other opiates are nice, if not something I feel compelled to do regularly). Furthermore, I really dislike sedatives like seconal and quaaludes and wouldn't want that feeling to interfere with a nice mellow opiate buzz.
Yet here I am, a curious guy with them in my possession. Maybe I'll just cut one up in fourths and try it with a small dose of codeine or oxy and see how it goes. In any case, I just don't feel safe trying to get a full on dors-and-fours experience.
Any advice?

Yeah use like 125mg glutethimide and a small dose of codeine (maybe 30mg or something like that) to start out if you plan on trying tje combination.

 

[TheJuner]

As far as potentiating tramadol through CYPD26, by whatever means, I assume you would likewise run a greater risk of seizures, since that is a risk with high doses of tramadol

I’m not actually sure if tramadol+glutethimide would further reduce your seizure threshold tbh. But the seizure risk is both dose dependent and increases proportional to dose and also glutethimide has anticonvulsant effects by virtue of its GABAA agonist activity so you shouldn’t worry about a seizure from combining the two. You are justified in considering this though because the glutethimide’s CYP2D6 enzyme inducing properties will increase the amount of O-DSMT you’re getting from the tramadol.

 

[chippermonk]

So, it sounds like glutethimide increases amounts of different metabolites, depending upon the specific opioid it is acting on. So codeine converts to more morphine than normal. I guess there are some opioids which result in metabolites that are more euphoric than morphine would be, like say with oxy or hydro?

 

[TheJuner]

So, it sounds like glutethimide increases amounts of different metabolites, depending upon the specific opioid it is acting on. So codeine converts to more morphine than normal. I guess there are some opioids which result in metabolites that are more euphoric than morphine would be, like say with oxy or hydro?

Yes you're exactly right. Oxycodone is metabolized by CYP2D6 enzyme mediated o-demethylation and gets converted into oxymorphone. Hydrocodone is an interesting one because in addition to hydrocodone's analgesia being partially due to the fact that it gets metabolized into the stronger opioid hydromorphone, hydrocodone has several other active metabolites that directly contribute to its ability to induce its analgesic and opioid effects. In addition to your body converting hydrocodone into hydromorphone, the same enzymatic pathway will convert hydrocodone into other active metabolites like dihydromorphine and dihydrocodeine.

 

[TheJuner]

Yes you're exactly right. Oxycodone is metabolized by CYP2D6 enzyme mediated o-demethylation and gets converted into oxymorphone. Hydrocodone is an interesting one because in addition to hydrocodone's analgesia being partially due to the fact that it gets metabolized into the stronger opioid hydromorphone, hydrocodone has several other active metabolites that directly contribute to its ability to induce its analgesic and opioid effects. In addition to your body converting hydrocodone into hydromorphone, the same enzymatic pathway will convert hydrocodone into other active metabolites like dihydromorphine and dihydrocodeine.

Both oxycodone and hydrocodone combined with glutethimide sound amazing and I'd have trouble choosing between choosing lol. I think I'd probably choose oxycodone for my opioid to be combined with glutethimide because I've just found it to be consistently way more euphoric than hydrocodone, and combined with glutethimide you'd be getting a way more intense opioid high than you normally would from just oxycodone alone because the CYP2D6 enzyme inducing properties are enabling your body to convert a higher portion of the dose into oxymorphone.