Boosting Codeine conversion to Morphine

[jasoncrest]

I'm wondering about something, cause I'm getting tired of Bupe a bit, and OTC codeine-only tablets are OTC here, so I think I could switch to Codeine for a while and save the Bupes... Anyway:

Codeine is metabolized to Morphine with the CYP2D6 enzymes.

It has been shown that when taken in combination with a CYP2D6 inducer (Glutethimide, back in the 50s), it would produce a strong high, that would make a good heroin substitute.

Glutethimide is impossible to find these days.
However there are two OTC CYP2D6 inducers I can think of:
-St Johns Wort
-Glucocorticoids (Budesonide & Beclomethasone)

Now I have a few questions:

-If the average conversion rate from Codeine to Morphine is 10%, up to what level can you bring this conversion rate with inducers? 20% 50%??

-Would you have to take lots of St Johns Wort or Corticoids?

-These OTC inducers also induce other P450 enzymes, such as CYP3A4. So even if you get more Morphine, it will be eliminated quicker. Would taking a lot of CYP3A4 inhibitor work?
What would happen when the St Johns Wort/Corticoids induce CYP3A4 and Grapefruit Juice inhibit it?

 

[Ham-milton]

A sad thing about glutethimide, I know.

 

[haribo1]

para amino glutethimide is still in circulation to treat breast cancer (?). It would be possible to make glutethimide via the sandimayer reaction I guess...

 

[Ham-milton]

yeah, that's partially true. I think it's only used for cushings syndrome today

 

[5-HT2]

I wouldn't be taking glucocorticoids to enhance my high, if I were you. Glucocorticoids essentially induce a stress response, which is probably how they make people more susceptible to the rewarding effects of drugs. Moreover, chronically elevated glucocorticoid levels will make your body and brain more vulnerable to all kinds of insults.

 

[aj1976]

I'm wondering about something, cause I'm getting tired of Bupe a bit, and OTC codeine-only tablets are OTC here, so I think I could switch to Codeine for a while and save the Bupes... Anyway:

Codeine is metabolized to Morphine with the CYP2D6 enzymes.

It has been shown that when taken in combination with a CYP2D6 inducer (Glutethimide, back in the 50s), it would produce a strong high, that would make a good heroin substitute.

Glutethimide is impossible to find these days.
However there are two OTC CYP2D6 inducers I can think of:
-St Johns Wort
-Glucocorticoids (Budesonide & Beclomethasone)

Now I have a few questions:

-If the average conversion rate from Codeine to Morphine is 10%, up to what level can you bring this conversion rate with inducers? 20% 50%??

-Would you have to take lots of St Johns Wort or Corticoids?

-These OTC inducers also induce other P450 enzymes, such as CYP3A4. So even if you get more Morphine, it will be eliminated quicker. Would taking a lot of CYP3A4 inhibitor work?
What would happen when the St Johns Wort/Corticoids induce CYP3A4 and Grapefruit Juice inhibit it?

I think I'm in the same boat as you. I've found that St. John's Wort doesn't work with me. The only thing that did potentiate the codeine well enough, were low amounts of chlorpheniramine or promethazine or a benzo (but I doubt either class of drugs have anything to do with the amount of morphine produced. And the side-effects from the anti-histamines were bad although you get tolerant to them within 2-3days. Other problem is that the anti-histamines mentioned tend to worsen constipation. (I felt better after switching to Post's High Fibre cereal)

 

[haribo1]

Is dihydrocodeine OTC as well?

 

[jasoncrest]

Is dihydrocodeine OTC as well?

No....
I wish it was....
The only Opium alkaloids or Opioids that are OTC in France are:
-Codeine
-Ethylmorphine
-Noscapine/Narcotine
-Papaverine
-Loperamide
-Pholcodine (this one doesn't count I think; is it considered Opioid as it is Morpholino-Ethyl-Morphine?)

 

[haribo1]

Here is an interesting patent on the conversion of codeine to hydrocodone.
Palladium black? Well... Linky

 

[Acyl]

Apparently ginkgo biloba is a CYP2D6 inducer at high doses and an inhibitor at lowered doses..


from the same paper

"However, it has been shown that St. John’s
wort has an inhibiting effect on all three CYPs
in vitro
[12],
but this herb is also a potent inducer of CYP3A4

...


Gurley et al. have reported a modest increase in CYP2D6
activity in humans after an intake of St. John’s wort for 28
days [19], but argue that this can be attributed by other
factors. On the contrary, one report found no effect at all
in man of St. John’s wort on either CYP3A4 or CYP2D6
[20]."

 

[jasoncrest]

Apparently ginkgo biloba is a CYP2D6 inducer at high doses and an inhibitor at lowered doses..

That's interesting. Ginko, even in high doses has only beneficial effects I think.

Since the 3 OTC/legal CYP2D6 inducers all have side-effects (Ethanol, Glucocorticoids and St Johns Wort), a good way to strongly induce CYP2D6 would be to take moderate doses of many different CYP2D6 inducers....

Take all that with a strong CYP3A4 inhibitor to potentiate the converted Morphine and make it last longer, and Codeine could really become quite strong...

-

My main question remain unanswered:
# With lots of different CYP2D6 inducers, up to which rate can we bring Codeines conversion to Morphine?
(average rate is 10% of the Codeine converted to Morphine; can we raise this rate to, say, 50%?? That would be amazing!)

 

[QuasiStoned]

I find this all rather interesting because I think I am CYP2D6 deficient and I wonder what some drugs would be like with a normal conversion, such as DXM and Codeine.

You know, I read a study one time that morphine may not cause the primary effects of codeine because it is eliminated so quickly. I'm going from memory though but I thought they speculated there may have been another metabolite or something.

 

[johanneschimpo]

My main question remain unanswered:
# With lots of different CYP2D6 inducers, up to which rate can we bring Codeines conversion to Morphine?
(average rate is 10% of the Codeine converted to Morphine; can we raise this rate to, say, 50%?? That would be amazing!)

That appears to be a hard question to answer specifically.

Personally, and with no experience, I think inducing an enzyme(s) to do twice the work (so 20% instead of 10% ) would be a hard enough task. I wouldn't expect 10% conversion from codeine to the active molecule to rise anywhere near 50%, maybe it could double at most with perfect enzyme inducing (induction? I don't know).

 

[johnm214]

Glutethimide is impossible to find these days.
However there are two OTC CYP2D6 inducers I can think of:
-St Johns Wort
-Glucocorticoids (Budesonide & Beclomethasone)

Do you have a citation for the premise that st. john's wort induces cyp2d6 activity? I wasn't aware that this was known to be the case.

If not, what is the basis for your belief it does so?

 

[Slay]

oh man, jason and one of his interesting codeine threads on ADD again :D i like your style dude

 

[jasoncrest]

oh man, jason and one of his interesting codeine threads on ADD again :D i like your style dude

Yeah I'm completely fascinated by Codeine, how it works, how is it possible to increase the effects, the pharmacology, etc... eventhough there's no reason for that, as I'm on Bupe and fine with that....

 

[monstanoodle]

i'll add that i took some DHC with some grapefruit juice and it didn't seem to potentiate it at all, though i took some codeine later with some GFJ and it almost made me have a nod on.

conclusion: GFJ doesn't seem to work very well with DHC for some unknown reason

 

[johnm214]

Apparently ginkgo biloba is a CYP2D6 inducer at high doses and an inhibitor at lowered doses..


from the same paper

"However, it has been shown that St. John’s
wort has an inhibiting effect on all three CYPs
in vitro
[12],
but this herb is also a potent inducer of CYP3A4

...


Gurley et al. have reported a modest increase in CYP2D6
activity in humans after an intake of St. John’s wort for 28
days [19], but argue that this can be attributed by other
factors. On the contrary, one report found no effect at all
in man of St. John’s wort on either CYP3A4 or CYP2D6
[20]."

Regarding the cyp2d6, I hadn't seen Acyl's whole post, but yeah, I really don't think St John's Wort is any good at potentiating cyp2d6. This isoenzyme is just about impossible to effectivly induce and you can probably forget about it baring new discoveries or access to a the two drugs that are somewhat useful (from memory, not sure)

But really if your not born w/ it it doesn't seem like you'll get it.


One other question from reading these boards, why are you drinking grapefruit juice w/ codeine? Is there any evidence this is effective? I thought the actions were pretty much inconsequential, I'll look for some papers later though.

I believe it dealkalkalates the nitrogen in opiates, but I don't recall this being a signifigant pathway as far as analgesia is concerned.

 

[Reminisant B]

I have started a similar thread on nordihydrocodeine but I wonder whether it is possible to rather than inducing CYP2D6/7 enzymes(which is hard to do effectively) - it might be possible to induce CYP3A4 to produce more norcodeine.

There is little info on what enzymes are involved in norcodeine->normorphine but even if they are less potent the conversion might occur in greater amounts than 10%. (?) It's also possible glucoronidation rate might be different and increase the relative potency due to the amount converted rather than potency of nor-compounds in vivo.