Tchort
Bluelight Crew
- Joined
- Mar 25, 2008
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- 2,392
Since Valentine4's thread was closed, I wanted to create a thread to continue one of the discussions.
Popular junkie lore and media sensationalism have pushed certain ideas of Methadone potentiation. The feds are concerned about people taking herbal supplements, acid reflux medication and anti-depressants with Methadone to increase the high, the media jumps all over reports of Methadone clinic patients and recreational drug users stealing Prilosec to boost their Methadone, and the death of Anna Nicole Smith's son from a combination of anti-Depressants and Methadone.
So, according to numerous sources, Methadone is metabolised by the Cytochrome P450 group of enzymes.
So we know for certain that three Cytochrome P450 enzymes are involved in the metabolism of Methadone, with the possibility of more being involved (Note: Previously CYP2C9 and 2C19 were thought to be involved, but this has not been confirmed (Crettol et al. 2005).").
CYP3A4 is listed in many places as the 'most important' enzyme involved in the metabolism of Methadone.
Also
And
So, while CYP3A4 is very important in the metabolism of Methadone, it is found in very high numbers compared to other CYP450 enzymes, which means that the maximum potentiation of subjective physiological effects from inhibiting CYP3A4 will be less than that of a less prevalent enzyme.
The other important enzyme in the metabolism of Methadone is CYP2B6. This enzyme is much less prevalent than CYP3A4. In fact,
"CYP2D6 is entirely absent in a significant portion of the population (1 out of 15 persons), resulting in
increased sensitivity to methadone’s effects; conversely, some persons have high activity of this
enzyme and are rapid metabolizers of methadone (Eap et al. 2002)."
The impact and importance of this enzyme in Methadone metabolism is a recent discovery, and there are not many known inducers and inhibitors of CYP2B6 (compared to other known enzymes). Interestingly, there is one particular known strong inhibitor of CYP2B6, which is my main focus in creating this thread: Orphenadrine.
Orphenadrine (Brand name Norflex) is an anti-cholinergic/anti-muscarinic of the ethanolamine antihistamine class that is related to Diphenhydramine. It has a number of clinical uses, and on its own has many interesting attributes.
The note specifically on combining Orphenadrine with Hydromorphone is very interesting, as it gives a good indication of what can be expected from a combination of Opioids and Orphenadrine in general.
As a strong CYP2B6 Inhibitor, Orphenadrine should potentiate the subjective physiological effects of Methadone more than a CYP3A4 Inhibitor and/or CYP2D6 Inhibitor (Cimetidine, GFJ, Goldenseal, Cat's Claw, Ranitidine, etc) or a competing substrate (Omeprazole [Prilosec]).
But, since strong CYP2B6 Inhibition is not the only mechanism that Orphenadrine effects the subjective effects of Methadone, it is not a stretch to assume the combined impact of Orphenadrine on the metabolism and subjective effects of Methadone would be one of potentiation.
Note: I do not endorse anyone consume any of the substances mentioned in this post. Specifically, taking a CYP2B6 Inhibitor with Methadone could very likely lead to coma or death, as the respiritory depression of Methadone would be greatly enhanced, which could likely cause a non-lethal dose of Methadone to become a highly lethal dose of Methadone. Since enzyme levels are so variable, and 1 in 15 people is estimated to not have any CYP2B6 enzyme at all, it would be very dangerous to put this into practice. Oversedation and respitory depression kills thousands of people every year- almost always this is the result of combining substances with a strong Opioid, and Methadone is notorious for causing death in people who recklessly consume it in high or regular doses, and especially when combined with other substances to enhance it.
So, do not under any circumstances try anything in this post. This is for educational and debate purposes only!
Popular junkie lore and media sensationalism have pushed certain ideas of Methadone potentiation. The feds are concerned about people taking herbal supplements, acid reflux medication and anti-depressants with Methadone to increase the high, the media jumps all over reports of Methadone clinic patients and recreational drug users stealing Prilosec to boost their Methadone, and the death of Anna Nicole Smith's son from a combination of anti-Depressants and Methadone.
So, according to numerous sources, Methadone is metabolised by the Cytochrome P450 group of enzymes.
CYP450 Enzymes Metabolizing Methadone
CYP3A4: Important methadone metabolizer (can also be induced by methadone during the early start-up phase of MMT).
CYP2B6: Relatively recently discovered as an important methadone metabolizer.
CYP2D6: Secondary role (methadone can inhibit this enzyme in same cases and this enzyme is particularly involved in the metabolism of active R-methadone).
CYP1A2: Possibly involved (clinical significance still under investigation).
So we know for certain that three Cytochrome P450 enzymes are involved in the metabolism of Methadone, with the possibility of more being involved (Note: Previously CYP2C9 and 2C19 were thought to be involved, but this has not been confirmed (Crettol et al. 2005).").
CYP3A4 is listed in many places as the 'most important' enzyme involved in the metabolism of Methadone.
Cytochrome P450 3A4 (abbreviated CYP3A4), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. CYP3A4 is also, correspondingly, present in the largest quantity of all the CYPs in the liver.
Also
A substrate is any drug metabolized by one or more CYP enzymes, and more than half of all
medications that undergo metabolism are CYP3A4 substrates (Piscitelli and Rodvold, 2001).
And
CYP3A4, the most abundant metabolic enzyme in the body, can vary 30-fold between individuals
in terms of its presence and activity in the liver (Eap et al. 2002; Leavitt et al. 2000). This enzyme also
is found in the gastrointestinal tract, so methadone metabolism actually can begin before the drug
enters the circulatory system (Hardman et al. 1996). The amount of this enzyme in the intestine can
vary up to 11-fold, partially accounting for some individual differences in the breakdown and
absorption of methadone (Levy et al. 2000).
So, while CYP3A4 is very important in the metabolism of Methadone, it is found in very high numbers compared to other CYP450 enzymes, which means that the maximum potentiation of subjective physiological effects from inhibiting CYP3A4 will be less than that of a less prevalent enzyme.
The other important enzyme in the metabolism of Methadone is CYP2B6. This enzyme is much less prevalent than CYP3A4. In fact,
"CYP2D6 is entirely absent in a significant portion of the population (1 out of 15 persons), resulting in
increased sensitivity to methadone’s effects; conversely, some persons have high activity of this
enzyme and are rapid metabolizers of methadone (Eap et al. 2002)."
The impact and importance of this enzyme in Methadone metabolism is a recent discovery, and there are not many known inducers and inhibitors of CYP2B6 (compared to other known enzymes). Interestingly, there is one particular known strong inhibitor of CYP2B6, which is my main focus in creating this thread: Orphenadrine.
Orphenadrine (Brand name Norflex) is an anti-cholinergic/anti-muscarinic of the ethanolamine antihistamine class that is related to Diphenhydramine. It has a number of clinical uses, and on its own has many interesting attributes.
Euphoria is an effect reported by many patients and orphenadrine has been investigated for use against depression, as first reported in June 1958 in the American Journal of Psychiatry (Am J Psychiatry 114:1113–1115, June 1958)
. . .
Orphenadrine exerts its effects both peripherally and in the central nervous system (CNS). In this latter respect, is similar to the chemically-unrelated drug nefopam as being a centrally-acting but non-opioid analgesic. Rather than binding to receptors as do opioids, benzodiazepines, seritonergic stimulants and the like, the central effect is the result of a change in the dopamine:acetylcholine ratio in the CNS because like other anticholinergics, it modifies dopamine and acetylcholine levels. Orphenadrine can also have a more comprehensive effect in both acute and chronic pain -- i.e. working against suffering -- in that the same effect also produce slight to moderate euphoria that lasts many hours and which is, for the above-given reasons, not the potential basis of addiction and abuse. Another reason for this drug's lack of habituation potential would be that the result of repeated supertherapeutic doses and/or significantly shortened dosage intervals is unpleasant, producing side effects much like those of atropine.
. . .
Patients given hydromorphone and orphenadrine simultaneously report increased efficacy and duration of action of both agents, reduction of nausea, insomnia, and boosted euphoria to a level greater than the sum of its parts. The itching notable with codeine, dihydrocodeine, morphine and the like are also lessened or eliminated.
. . .
Last but not least, orphenadrine may have yet another effect with respect to opioids: a clonidine-like effect on withdrawal symptoms useful for abrupt "cold turkey" cessation or accelerated tapers. Other NMDA receptor antagonists have been demonstrated to have weakened opioid withdrawal syndromes.[2] Clonidine is another drug that has these effects, although usually much stronger that orphenadrine.
The note specifically on combining Orphenadrine with Hydromorphone is very interesting, as it gives a good indication of what can be expected from a combination of Opioids and Orphenadrine in general.
As a strong CYP2B6 Inhibitor, Orphenadrine should potentiate the subjective physiological effects of Methadone more than a CYP3A4 Inhibitor and/or CYP2D6 Inhibitor (Cimetidine, GFJ, Goldenseal, Cat's Claw, Ranitidine, etc) or a competing substrate (Omeprazole [Prilosec]).
But, since strong CYP2B6 Inhibition is not the only mechanism that Orphenadrine effects the subjective effects of Methadone, it is not a stretch to assume the combined impact of Orphenadrine on the metabolism and subjective effects of Methadone would be one of potentiation.
Note: I do not endorse anyone consume any of the substances mentioned in this post. Specifically, taking a CYP2B6 Inhibitor with Methadone could very likely lead to coma or death, as the respiritory depression of Methadone would be greatly enhanced, which could likely cause a non-lethal dose of Methadone to become a highly lethal dose of Methadone. Since enzyme levels are so variable, and 1 in 15 people is estimated to not have any CYP2B6 enzyme at all, it would be very dangerous to put this into practice. Oversedation and respitory depression kills thousands of people every year- almost always this is the result of combining substances with a strong Opioid, and Methadone is notorious for causing death in people who recklessly consume it in high or regular doses, and especially when combined with other substances to enhance it.
So, do not under any circumstances try anything in this post. This is for educational and debate purposes only!