This thread sparked me to do a bit of research on DXM, CPM and there possible interactions. I'm an organic chemist, not a pharmacologist however It doesn't take a lot of pharmacological understanding to get the feel of just how fucked up this combo is.
It's good that you're now moving on the side of caution. Your earlier assertion that CPM is pretty safe isn't something I agree with. Yes, by itself it may have massive LD50 and a wonderful therapeutic index. The endless anecdotes of acute and chronic side effects to CCC use bring this into question though. DXM only products simply don't have all these nasty reported side effects, implying that DXM ain't the problem. By itself, CPM may well be hella safe - when you mix it with DXM however the shit seems to really hit the fan, lets try and look at what could be going on. I'm confident that most of what's coming pretty scientifically sound, admittedly when I was reading about this stuff, especially CPM metabolism and the stereo selective nature of it, I got a bit overwhelmed - never paid enough attention in those oh so boring metabolism lectures last year :D
Looking at it step-by-step:-
- DXM and CPM are both metabolized by P450 enzymes.
- A massive amount of other drugs are to.
- The exact metabolic pathway of DXM is pretty complex, CYP2D6 is the main enzyme.
- CYP2D6 is also involved in the metabolism of CPM...
1) This is the first problem. The metabolic pathways of both drugs feature the same enzyme. In fact, CYP2D6 could well be the most common enzyme in drug metabolic pathways period. This raises lots of issues concerning the break down both drugs, for this reason alone their respective half lives will increase. If any of a vast multitude of other drugs, that are metabolized by CYP2D6, are present then this effect will be compounded further.
- Many people are genetically poor CYP2D6 metabolizers, for these people point 1) will be a lot worse.
- For normal CYP2D6 metabolizers, (with no other xenobiotic CYP2D6 subsrates administered) a study found the average elimination half life of CPM to be 18.0±2.0 h.
- For poor CYP2D6 metabolizers, the study found it to be 29.3±2.0 h.
- In addition to this huge genetic difference in cpm half life, there is a massive diversity between people who have normal CYP2D6 levels.
2) In other words, yes the time cpm stays in the system for varies massively between individuals, even those with normal CYP2D6 metabolism. Why? I don't know the full pathway of cpm metabolism but I wouldn't be surprised if additional P450 enzymes were involved. Cpm also has two enantiomers, (S) is responsible for most of racemic (as found in CCC) cpm's pharmacology. However (R) plays a complex indirect role which I'm not to sure I understand correctly. As far as I can tell, inhibition of CYP2D6 and/or low CYP2D6 levels cause the (R) enantiomer to become significant. Because of this (I think...), the actual receptor bindings differ between poor 2D6 mets and normal 2d6 mets and also anyone who has a CYP2D6 inhibitor in their system. So not only can peoples genetic vastly alter the time CPM is in the system for, but also it's actual pharmacology. Perhaps most important however is the role a 2D6 inhibitor could potentially play - obviously it will increase elimination half life, probably by a fair bit) but it could also actually alter the receptor affinities (in a way that's unknown to me..). Hold that bit in your mind, it will pop up again in a bit.
- This is where things start getting interesting, the actual pharmacology of CPM (and of course DXM).
- DXM has a relatively complex pharmacological profile:
* Antagonist of both NMDA and nicotinic receptors
* Agonist of sigma 1, 2 receptors
* 5-HT reuptake inhibitor
- The pharmacological profile of CPM is not fully understood, however it is a known:
* H-1 antagonist
* An SNRI
- The problem that underpins the CCC cocktail is that both drugs inhibit serotonin reuptake.
- The danger here is compounded by lack of research; no one seems to actually know just how potent an SNRI CPM actually is, it has however been suggested that It could be on the same level of serotonin reuptake potency as some of the weaker SNRI/SSRI antidepressants. I can't get access to the study that talks bout this though, I think in general no one really has a clue but it could well cause very significant reuptake inhibition.
3) It's pretty hard to get serotonin syndrome off of any single antidepressant, when there is only one reuptake inhibition going on a decent therapeutic index is observed. However when there are two it can very conceivably lead to very high levels of extracellular serotonin, this in turn can lead to serotonin syndrome the most extreme consequence of which is a rather unpleasant death.
- Unfortunately it gets even worse, CPM is an H-1 antagonist antihistamine, H-1 antagonists have a tendency to inhibit CYP2D6.
- Reflect back to problem 2, if CPM does inhibit CYP2D6 this way, it will be lengthening it's own half life, for some genetic makeups this half life will have already been lengthened substantially.
- Oh dear, It looks like a lot of antidepressants with serotonin reuptake mechanisms also inhibit CYP2D6. From this standpoint, it's not too far fetched that one or both of DXM and CPM could be doing so in this manner to.
4) As F&B pointed out on the first page, nicotinic antagonists and H-1 antagonists are a bad combination to have, at worst resulting in death.
5) Finally we have the problem of other xenobiotics. The horrible splurge of contraindicated modes of action and metabolic enzyme inhibition mean that a LOT of different recreational and medicinal drugs would make this combo far more dangerous than it already is. What's more, because of the numerous factors potentially messing with CYP2D6 and the possibility of massive genetic differences in natural CYP2D6 levels, the elimination half lifes of both DXM and CPM could be rather long, extended considerably when both are in the system at the same time, extended further by many different drugs and in general very hard to predict because of large deviations in half life between individuals - that's a bit convoluted but my point is that other xenobiotics would not necessarily have to be ingested at the same time as CCC, maybe not even on the same day, in order for further problems to arise.
Potential drugs that could make the combo even more nasty:-
- Pretty much any antidepressant or other drug for that matter that inhibits serotonin reuptake could be a very bad time with CCC, making SS far more likely.
- MAOI's are all potentially very bad. Inhibitors of MAO-A will increase the likelihood of SS, probably by a lot.
- Serotonin releasers; MDMA et. al. Again, will greatly increase SS risk. Some of these are actually MAOI's aswell /:
- Tramadol could lead to any number of horrible problems, greatly increased SS risk and increased rick of seizures being the most apparent. It's also an antagonist of several muscarinic and nicotinic acetylcholine receptors, so further risk there. It will also probably inhibit CYP2D6 further (as if the poor enzyme hasn't been inhibited enough) and has a long half life itself. Fun.
- Z-drugs. To a lesser extent any major CNS depressant, especially those that act on GABAa. Not as risky as the stuff above but still not fun.
- H-1 and H-2 antagonists
- Acetylcholine antagonists
- Cocaine, Methamphetamine
- Probably amphetamine to, while we're at it
Ok I give up, there are too many...
Basically CCC is horrible stuff that is harmful in a multitude of ways, could kill you directly in at least two ways - the likelihood shoots up with dose and with a whole range of other drugs - and is rather unpredictable in terms of half life. I'm very glad this stuff isn't available over here....
Hope that makes sense, I'm still feeling somewhat tweaked from a big speed session yesterday, which means I write far more than I ever normally would and use copious amounts of commas!
Peace
