neurohack
Rising Star
It seems like a good move to open a topic on this. It comes down to the fact that different people can have different drug metabolism which may lead to adverse reactions in some cases. The role of the CYP enzymes in this is, in my opinion, not adequately brought to attention.
To put it simple let me give my experiences on these enzymes:
Kratom didn't work for me. Kava has little or no effect, Codeine had little or no effect. After iboga I immediately had cravings again for my addictions of that time, it almost got me into the hospital. I also nearly choked on iboga a second time. These drugs are known to be either prodrugs and metabolized by CYP2D6 in their active substance, or with iboga, the aftereffect is brought on by the metabolized product. Also, I can't use too much caffeine or I seriously don't sleep for the whole night. And if I use melatonin too much, the next day I feel it constantly, like it is still active in my system. So I need even more just to get a little sleep after that, and so it stacks. Both of these are removed by CYP1A2.
It is known that the expression of the genes responsible for these enzymes are polymorphic, meaning they differ from one ethnic group to the other. So some people naturally have more of these enzymes than others. Usually the people with the lowest levels are a small minority.
link
Some enzymes are variable and may be modulated by diet, others are not. When using melatonin I can only use very small doses, otherwise it crashes the next day. With iboga I'm not sure, it does work and when I prepare very meticulously it might work, but I don't expect any anti-addiction effects. As for kratom and other opiates, they don't interest me... I have adverse effects to smoalked DMT. Tried it multiple times and except the very low doses, it was a hellish ride. Like a bullet stuck in the barrel when shot... But oral DMT works fine for me, psilocybin as well, though I need to be careful not to take too much (I used to assume that a hellish ride on a large dose was the trip). However, more input is needed to verify that metabolism also plays a central role with these kinds of experiences. So... there's a batch of 5-meo on the shelf. If I just do what everyone else does, what will happen? I think that knowing what kind of metabolizer you are is very important to avoid bad trips at the very least.
For a good read up on the matter go here.
Please provide input to sort this matter further out.
Edit. Here follows a brief introduction based on information from the link given above:
'CYP' is a host of enzymes that use iron to oxidise things, often as part of the body's strategy to dispose of potentially harmful substances by making them more water-soluble. Bertz and Granneman (Clin Pharmacokinet 1997 32 210-58) found that 56% of 315 drugs were primarily cleared by CYP! Adding something like a hydroxyl group to a xenobiotic is just part of the body's strategy to get rid of the 'drug' - this is often followed by conjugugation to groups such as glucuronide to increase the solubility even further. To try and thoroughly confuse you, the initial P450-mediated oxidation is often referred to as "Phase I metabolism" and the subsequent conjugation (which has nothing to do with P450) as "Phase II".
CYP catalyses a variety of reactions including epoxidation, N-dealkylation, O-dealkylation, S-oxidation and hydroxylation. A typical cytochrome P450 catalysed reaction is:
NADPH + H+ + O2 + RH ==> NADP+ + H2O + R-OH
In different people and different populations, activity of CYP oxidases differs. Genetic variation in a population is termed 'polymorphism' when both gene variants exist with a frequency of at least one percent. Such differences in activity may have profound clinical consequences, especially when multiple drugs are given to a patient. There are profound racial differences in the distribution of various alleles - data on a drug that works in one way in one population group cannot necessarily be extrapolated to another group.
The explanations for the various polymorphisms are thought to be complex, but perhaps the most interesting is the high expression of CYP2D6 in many persons of Ethiopian and Saudi Arabian origin. 2D6 is not inducible, so these people have developed a different strategy to cope with the (presumed) high load of toxic alkaloids in their diet - multiple copies of the gene. These CYPs therefore chew up a variety of drugs, making them ineffective - many antidepressants and neuroleptics are an important example. Conversely, prodrugs will be extensively activated - codeine will be turned in vast amounts into morphine!
In contrast, many individuals lack functional 2D6. These subjects will be predisposed to drug toxicity caused by antidepressants or neuroleptics, but will find codeine (and indeed, tramadol) to be inefficacious due to lack of activation! Other drugs that have caused problems in those lacking 2D6 include dexfenfluramine, propafenone, mexiletine, and perhexiline. Perhexiline was in fact withdrawn from the market due to the neuropathy it caused in those 2D6 inactive patients unfortunate enough to be treated with it. Even beta-blocker removal may be impaired (for example, propranolol) in 2D6-deficient people.
Another potentially disastrous polymorphism is deficient activity of CYP2C9. This is because patients possessing this enzyme variant are ineffective in clearing (S)-warfarin - so much so that they may be fully anticoagulated on just 0.5mg of warfarin a day! As if this isn't enough, the same CYP is important in removal of phenytoin and tolbutamide, both potentially very toxic drugs in excess. The flip-side is that the prodrug losartan will be poorly activated and inefficacious with 2C9 deficiency. Azole antifungals, sulphinpyrazone, and even amiodarone may cause a similar effect by inhibiting the enzyme.
Occasionally one derives benefit from an unusual CYP phenotype. For example, cure rates for peptic ulcer treated with omeprazole are substantially greater in individuals with defective CYP2C19, owing to the sustained, high plasma levels achieved.
Variable expression of CYP has substantial clinical consequences, not only in different people and different race groups, but also in individuals as they progress from infancy to old age. For example: CYP1A2 is not expressed in neonates, making them particularly susceptible to toxicity from drugs such as caffeine.
Edit2: Found this youtube vid that covers the basics pretty well, though it might a little oversimplified.
[youtube]
To put it simple let me give my experiences on these enzymes:
Kratom didn't work for me. Kava has little or no effect, Codeine had little or no effect. After iboga I immediately had cravings again for my addictions of that time, it almost got me into the hospital. I also nearly choked on iboga a second time. These drugs are known to be either prodrugs and metabolized by CYP2D6 in their active substance, or with iboga, the aftereffect is brought on by the metabolized product. Also, I can't use too much caffeine or I seriously don't sleep for the whole night. And if I use melatonin too much, the next day I feel it constantly, like it is still active in my system. So I need even more just to get a little sleep after that, and so it stacks. Both of these are removed by CYP1A2.
It is known that the expression of the genes responsible for these enzymes are polymorphic, meaning they differ from one ethnic group to the other. So some people naturally have more of these enzymes than others. Usually the people with the lowest levels are a small minority.
The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers.
link
Some enzymes are variable and may be modulated by diet, others are not. When using melatonin I can only use very small doses, otherwise it crashes the next day. With iboga I'm not sure, it does work and when I prepare very meticulously it might work, but I don't expect any anti-addiction effects. As for kratom and other opiates, they don't interest me... I have adverse effects to smoalked DMT. Tried it multiple times and except the very low doses, it was a hellish ride. Like a bullet stuck in the barrel when shot... But oral DMT works fine for me, psilocybin as well, though I need to be careful not to take too much (I used to assume that a hellish ride on a large dose was the trip). However, more input is needed to verify that metabolism also plays a central role with these kinds of experiences. So... there's a batch of 5-meo on the shelf. If I just do what everyone else does, what will happen? I think that knowing what kind of metabolizer you are is very important to avoid bad trips at the very least.
For a good read up on the matter go here.
Please provide input to sort this matter further out.
Edit. Here follows a brief introduction based on information from the link given above:
'CYP' is a host of enzymes that use iron to oxidise things, often as part of the body's strategy to dispose of potentially harmful substances by making them more water-soluble. Bertz and Granneman (Clin Pharmacokinet 1997 32 210-58) found that 56% of 315 drugs were primarily cleared by CYP! Adding something like a hydroxyl group to a xenobiotic is just part of the body's strategy to get rid of the 'drug' - this is often followed by conjugugation to groups such as glucuronide to increase the solubility even further. To try and thoroughly confuse you, the initial P450-mediated oxidation is often referred to as "Phase I metabolism" and the subsequent conjugation (which has nothing to do with P450) as "Phase II".
CYP catalyses a variety of reactions including epoxidation, N-dealkylation, O-dealkylation, S-oxidation and hydroxylation. A typical cytochrome P450 catalysed reaction is:
NADPH + H+ + O2 + RH ==> NADP+ + H2O + R-OH
In different people and different populations, activity of CYP oxidases differs. Genetic variation in a population is termed 'polymorphism' when both gene variants exist with a frequency of at least one percent. Such differences in activity may have profound clinical consequences, especially when multiple drugs are given to a patient. There are profound racial differences in the distribution of various alleles - data on a drug that works in one way in one population group cannot necessarily be extrapolated to another group.
The explanations for the various polymorphisms are thought to be complex, but perhaps the most interesting is the high expression of CYP2D6 in many persons of Ethiopian and Saudi Arabian origin. 2D6 is not inducible, so these people have developed a different strategy to cope with the (presumed) high load of toxic alkaloids in their diet - multiple copies of the gene. These CYPs therefore chew up a variety of drugs, making them ineffective - many antidepressants and neuroleptics are an important example. Conversely, prodrugs will be extensively activated - codeine will be turned in vast amounts into morphine!
In contrast, many individuals lack functional 2D6. These subjects will be predisposed to drug toxicity caused by antidepressants or neuroleptics, but will find codeine (and indeed, tramadol) to be inefficacious due to lack of activation! Other drugs that have caused problems in those lacking 2D6 include dexfenfluramine, propafenone, mexiletine, and perhexiline. Perhexiline was in fact withdrawn from the market due to the neuropathy it caused in those 2D6 inactive patients unfortunate enough to be treated with it. Even beta-blocker removal may be impaired (for example, propranolol) in 2D6-deficient people.
Another potentially disastrous polymorphism is deficient activity of CYP2C9. This is because patients possessing this enzyme variant are ineffective in clearing (S)-warfarin - so much so that they may be fully anticoagulated on just 0.5mg of warfarin a day! As if this isn't enough, the same CYP is important in removal of phenytoin and tolbutamide, both potentially very toxic drugs in excess. The flip-side is that the prodrug losartan will be poorly activated and inefficacious with 2C9 deficiency. Azole antifungals, sulphinpyrazone, and even amiodarone may cause a similar effect by inhibiting the enzyme.
Occasionally one derives benefit from an unusual CYP phenotype. For example, cure rates for peptic ulcer treated with omeprazole are substantially greater in individuals with defective CYP2C19, owing to the sustained, high plasma levels achieved.
Variable expression of CYP has substantial clinical consequences, not only in different people and different race groups, but also in individuals as they progress from infancy to old age. For example: CYP1A2 is not expressed in neonates, making them particularly susceptible to toxicity from drugs such as caffeine.
Edit2: Found this youtube vid that covers the basics pretty well, though it might a little oversimplified.
[youtube]