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Cytochrome P450 polymorphism and possible danger

Migrated topic.


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.

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.


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.



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It's an interesting question to be sure, and there's a lot to unpack, but the problem is, it's impossible to know what your CP450 make-up is like without either a very expensive (and painful) liver assay, or getting genotyped. Both of these are well beyond the capabilities of your average Nexian and so I would be hesitant to start making strong claims about anybodies make up.

Similarly, drug metabolism and processing is such a complex biochemical process that even if specific polymorphisms can be discovered, it would be a bit premature to start saying "Thing X leads to Experience Y."

I'm not sure, for example, a polymorphism might effect the DMT experience for you in that kind of way, since the drug so quickly penetrates the BBB and acts entirely on surface receptors, while (AFAIK) most CP450s are internal membrane proteins, on mitochondia and the ER. To be fair, my pharmacology class in college was a while ago so I may be remembering.

Polymorphisms can be spandrels. In the end, what we're talking about are slight genetic differences with consequences that aren't fully understood. The only way to truly see if a polymorphism is responsible for a certain variable is to do a comparative study with the polymorphism present and when it is removed by gene knockout.
I actually just started working in a lab that looks at CYPs and specifically differential expression of isoforms in ethnic groups. There seems to be a lot of environmental feedback too. We're actually looking at differential production of these two specific alternative splice variants in the presence of salt concentrations. Its interesting to think too, how the different metabolic CYP products of xenobiotics in turn can activate nuclear receptors (Aryl hydrocarbon, PXR, etc) (lots of splice variants of these too) that then go on to induce expression of different CYP enzymes. So in many ways our 'exposomes' are unique too, and potentially impact how our xenobiotic metabolism changes in the future.
I'm definitely not a CYP expert, I've just been studying them for a couple months in this new lab. But yes I think you're dead on with the fact that your expression profile dramatically alters the way you metabolize drugs, and I would be very careful scaling up your 5-meo dose as you're noting.
I had a breakthrough in understanding on these matters through a paper on melatonin and it's metabolism.

The point of it was to advise people to be careful in their dosing and the argument ran like this:

CYP1A2 breaks melatonin down after 4 or 6 hours in the liver. This way during waking hours the levels drop significantly so that when sleep is sought the levels can increase and a rhythm is induced, the sleep/wake cycle.

When someone lacks CYP1A2 in such a degree that during waking hours significant levels of residual melatonin are present (after taking it externally), the cycle is disrupted and production of endocrine melatonin fails.

So people tend to take more of it which in turn leads to early waking up and feeling groggy all day.

Also they mention that xanthines like caffeine are also done with this enzyme. So for me that was a big insight. The vicious cycle went like this: taking caffeine om the day and not having it removed from the bloodstream by the time I went to bed. So I took melatonin to sleep but in time I needed larger doses, woke up more early and got more sleep deprivation.

For a while I have done very small doses, like half a miligram. In a few days I started to sleep the full 8 hours without spending hours restless in bed halfway.

The other thing is that certain vegetables, medicines and other substances alter the expression of the CYP1A2.

@cave paintings: is that whay you mean by exposomes?

I can link you this piece but it is not in english so I don't think it's helpful. But on request I will ofcourse.

Anyway the melatonin story is quite innocent. Yes a little bit discomforting. But I'm glad to understand this dynamic (a little but enough) to see that having a go at 5-meo should be done with care. Like if others around take a large dose of something it means that I should let them but decide my own dose carefully.

So that's why this topic should deserve some attention. We don't know shit about this, but it seems to be variable which can be huge or maybe not so, it's good to find out...
This topic certainly has my attention! So many common herbs and spices interact with CYP enzymes that it's a technology in itself. Or even an art.
@ neurohack

Hey, sorry on long time to reply.

I suppose that is what I meant by exposome. It was really my first time employing the term, :d but yeah, just getting at this idea that our genome can reflect our xenobiotic/environmental exposure events over our lifetime, and obviously actively modulate our current experiences/drug interactions, in addition to how our pre-existing genetic dispositions due to variability, polymorphisms etc. modulates this.
Some of these ideas are still nascently forming for me. But as I study this field more, I am gaining a real appreciation for how involved this family is.

What I was also alluding to with my exposome ramble, was the fact that the CYP family's expression/induction (57 forms atleast in humans) is driven by the nuclear receptors: Aryl hydrocarbon, Pregnane X receptor, CAR, and PPAR. These nuclear receptors, in addition to serving their functions in development/physiological function, also can respond to a wide variety of exogenous ligands. Thus this activity/event of being agonized by plant compounds(plant polyphenolics, aromatic compounds etc.) or steroid-like synthetic chemicals for instance causes them to induce different CYP enzyme expression. Thus the potential for a lot of cross talk, enzyme interactions, drug interactions etc.

As, I said, I am still new to this area, and dont want to pretend to be an expert. There is really a lot to think about here though, and discuss.

I am wondering if the Ah Receptor, as it is agonized by tryptophan metabolites, binds DMT appreciably? I had a cursory search today, but was busy. Interesting to think about.

New thought,

I was speculating about DMT powerfully inducing CYP expression and thus this maybe being responsible for its hyper-sobering effect it can have on other drugs. This has happened for me atleast. My counter-thought to this is that appreciable increases in expression takes a lot longer than the DMT experience, and thus this is probably not the mechanism. But fun to speculate on what it could be inducing days after. Perhaps part of the 'detox' effect? This is given it did interact with a nuclear receptor like Ahr or others. Ahr has still to be married to an 'endogenous' ligand, but I guess most others presume its a steroid handler. Interesting to think about DMT's association with the sigma-1 receptor, which in turn interacts with mitochondria, where CYPs are also located.

Gotta be careful with speculating, but food for thought?
Hey, don't worry about speculating. This topic is mostly specalutive. But I have been thinking and maybe it's best to organize things a little, so we can work to get a solid foundation for this.

So first of all I thought about what to achieve. Obviously the main goal is to identify the relation between drug induced experience and metabolic mechanisms (CYP's). This in light of polymorphism and possibility of dangerous situations. For each psychedelic to find out how they interact and also if different ways of ingestion affect this process significantly.

Secondary: Also to provide a context so this matter becomes a bit more understandable. Why are there polymorphisms, what benefits does a specific type of metaboliser have compared to other types and how to use this to provide a basis for a pleasant experience? Some of these questions are more or less easy to answer, others require more information.

Third: how exposomes play a role and provide some details on foods for example in this regard.

The assumption here is that the quality of a psychedelic experience is largely determined by physical metabolism. Despite the layers of emotion, mentality and spirituality, the foundation for these are biochemical processes and if it doesn't go well at this level, how can the rest follow?

In literature on psychedelic (plants) this fact is often overlooked. I browsed through 'the Encyclopedia of Psychoactive Plants' by Christian Rätsch and found no mention at all of any CYP enzyme. On top of that it appeared to me he provides incorrect information at various entries. For example, he states that codeine passes through the body unchanged, while it is stated in other sources that this alkaloid is a prodrug for morphine. Also with regard to kratom he states it is nontoxic, while it may very well be that this is largely dependent on your CYP2D6 levels. The 5-meo entry lists nothing at all in regard to metabolism. Concluding that Rätsch has totally omitted this dimension.
Another piece is 'Garden of Eden' by Snu Voogelbreider. He mentions briefly on a lot of occasions that a particular alkaloid is metabolised by CYP2D6. Though a comprehensive explanation about what this is about is absent.

A friend of mine owns a book on iboga and here it is clearly stated that 10% of caucasians lack CYP2D6 and therefore don't get the levels of noribogaine needed for anti-addictive effects. This is stated as a warning, that for these people addiction is not cleared the way it is for most and therefore should be cautious. I will look this up and check the sources for this passage.

As a note, in the book 'Darkness Shining Wild' by Robert A Masters revolves around the experience of smoalking a high dose of 5-meo and ending up in the hospital through respiratory failure and subsequent years of intense psychological trauma. So the question I had was, is this due to a lack of CYP2D6? I think there are more accounts of these sorts.

One thing I would like to do as well is cast aside the unspoken taboo on the Nexus: having a bad trip on smoalked DMT. I heard some people say something about it, but I guess that most people who experience smoalking as a bad trip (no visuals or mindset, just physical agonizing discomfort like a bullet shot stuck in the barrel) just turn away so there aren't many here who can attest to that. To find out if this is due to metabolic inadequacy and possibly find & provide an alternative.

For now, the best I can do is rewrite my initial post with a sort of introduction to cytochrome P450. I provided a link at the bottom to a pretty good introduction, but I guess most people don't read it, so to quote it at length seems a good idea. Also try to answer some of the questions as to why this is polymorphic and put it in a evolutionary context.

Next to acquire more information, for this is thoroughly technical and I have no medical background. In light of this, I asked myself what specialist would need to know about this? So it seemed obvious that an anaesthesiologist would be the ideal candidate. A psychiatrist would be second, but I don't like these people and don't really trust that this is common knowledge among these people. Anyway, trying to find some medical contact for help on this...

@cave paintings. Sorry I can't answer your speculations right now. Been busy reading up on the deeper layers of this but I do understand what you're trying to say. Have not yet found enough insight to provide a decent response, so it has to wait for now. I am excited about your position as researcher in this field, that's just so good to have around - hope you like getting along with this and who knows if it's possible to make a real contribution by sorting this out.
Guys Fellow Nexians of this thread, I'm EXCEEDINGLY interested in following up key concepts raised in this thread. CYP modulation is paramount when it comes to the understanding of psychoactivity (or lack thereof) in nutmeg (my pet subject, in case you hadn't noticed!)

It seems nutmeg synergises very positively with psilocybin at least. Perhaps it could do the same with DMT. Of course, it could just make matters worse, or have no effect at all. In fact, if you've defective CYP expression it might be a completely stupid idea. It would depend on your exact enzyme profile. It must be emphasised here, this will not involve choking down tablespoonfuls of turpentine-flavoured powder. Rather one needs to make a 1:3 tincture with 80% alcohol and then use the absolute minimum amount needed for mild mood elevation and sensory enhancement. Because of the variations of CYP expression encountered between different people this amount needs to be personally calibrated. Safety first!

Here is a quick summary of what can be found elsewhere on the Nexus:


"Proper enzyme inhibition means that CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C9, CYP2E1, and CYP3A4 are inhibited while CYP2D6 is not.

CYP2D6 should not be inhibited. Common things that inhibit CYP2D6 include grapefruit, black pepper, and the ever popular MDMA.

Myristicin is primarily inactivated by P450 enzymes CYP1A2 and CYP3A4. The P450 enzyme CYP2D6 might be critical to getting good effects.

Elemicin is probably metabolized into an active psychedelic by CYP3A4, and metabolized into a melatonin-like drug by CYP1A2. Or possibly the melatonin effect is caused by it NOT being metabolized at all. It’s highly likely that CYP1A1, CYP1B1, CYP1A2, CYP2A6, CYP2C9, and CYP2E1 can all cause 1-hydroxy-elemicin to form. CYP2D6 might be needed for psychedelic activity.

CYP2A6, CYP2C9, and CYP2E1 primarily inactivate safrole by conversion to 1-hydroxy-safrole. CYP2D6 might be needed for psychedelic/empathogenic activity.

CYP1A2 and CYP2A6 cause the inactive 1-hydroxy-estragole to form. It’s possible that CYP2D6 is needed for psychedelic activity.

Estragole and myristicin seem to be much easier to activate than elemicin or safrole.

Cinnamon bark oil takes care of CYP2A6 and CYP2E1 nicely, I don’t know if it can knock out CYP2C9. That’s where clove leaf comes in because it knocks out CYP2C9 very well along with CYP3A4, CYP1A1, and CYP1B1. Also German chamomile oil knocks out CYP1A2. By having CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C9, CYP2E1, and CYP3A4 inhibited while leaving CYP2D6 alone, you help ensure that these allylbenzenes are not inactivated orally.

To help activate these oils once they get past the P450 enzymes, a few tricks have been posted on various forums. One method some use is excessive exercise. Another is to take them with phenylalanine. Yet another reported method is to take the oils with phenethylamine.

By playing with CYP3A4 and CYP1A2 inhibitors the “melatonin effect” can be caused or eliminated. CYP3A4 inhibitors seem to cause it, and CYP1A2 inhibitors seem to reduce it. A combination of both CYP3A4 and CYP1A2 inhibitors causes it for several hours but then produces a delayed trip on top of the “melatonin effect”.


Coffee seems to always enhance and help activate these oils if taken 30-60 minutes beforehand. How this works is unknown. BUT Caffeine is a CYP1A2 inhibitor.

Cayenne pepper, at 800 mg in a capsule, boosts the effects of these oils if taken AFTER the oils are taken. How this works is unknown.

2 tablespoons licorice root seems to boost the effects making it more like mescaline.

Saint John’s Wort is a good CYP3A4 inducer."
(Based on work by, and quoting, 69ron.)


"The Oilahuasca Diet"

Piperidine (from black pepper cold water extract or supplement with lysine), cinnamon/vanilla, soya beans (contain PEA???).

Enzyme inhibition:
German chamomile CYP1A2
Cinnamon/vanilla CYP2A6, CYP2E1
Cloves CYP2C9, CYP3A4, CYP1A1, CYP1B1

Anise CYP2C9

Sweet basil (methylchavicol =estragole)
Elemi (elemicin)
- in coffee or on skin

Mucuna pruriens, Griffonia, Black cohosh, Oxytocin
Hey I haven't forgot about this thread friends!

Just been busy, and need to organize my thoughts before posting something substantial.

I'm attaching a paper on cannabis and CYP inhibition that I found in cosmic spore's mj research thread.
I'm wondering if the CYP1b1 inhibition may have a role in glaucoma relief, as CYP1b1 mutations are known to occur in a few congenital glaucomas, and perhaps cannabinoids are kicking off a substrate that is aberrantly metabolized. Speculations, speculations.

I'm secretly hoping we summon corpus_callosum.. He/she knows a lot about CYP interactions I believe, because you have to know a lot about drug interactions for doctor stuff 😁 , and corpus could maybe bring some of my speculations back to earth :lol:

Anyhow, I'll be back on here, and want to help organize and answer some of the questions formulated


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Thanks for the thought-provoking pdf's!

The detail about genetics in the second paper throws a certain degree of light on the notion of exposomes (was that your own coinage, btw?)

I'm visualising biomolecular epigenetic cellular mechanics that doesn't at present lend itself terribly well to verbal description 😁

Eagerly awaiting your posting of 'something substantial'!
Yo been off for a while - glad to see this topic is still alive! Added some content to the first post & attached a paper that serves as further introduction material.

Since you both seem to know awful lot about cellular biology, can I ask some questions?

1) CYP2D6 is considered a high affinity ⁄ low capacity enzyme, which implies that CYP2D6 will preferentially metabolize drugs at lower concentrations. (see pdf first post). What does high affinity/ low capacity exactly mean?

2) what is general mechanism for CYP's to be induced due to xenobiotics. I thought about this and am stuck with this: When psilocybin enters the bloodstream a messenger (hormone?) is triggered that induces the formation of CYP enzymes in the liver. They are produced on demand and when sufficient are present the concentration psilocybin steadily declines for it is made water soluble. This is phase I, as I understand it. Is this simplified model correct and what does phase II entail exactly, is it also founded upon CYP's or are other enzymes resposible?

3) is there a relationship between MAO enzymes and CYP's?

4) am I correct in stating that the whole CYP science is in it's infancy and we got a bunch of confusing terms and lack of overall insight?
neurohack said:
Yo been off for a while - glad to see this topic is still alive! Added some content to the first post & attached a paper that serves as further introduction material.

Since you both seem to know awful lot about cellular biology, can I ask some questions?

1) CYP2D6 is considered a high affinity ⁄ low capacity enzyme, which implies that CYP2D6 will preferentially metabolize drugs at lower concentrations. (see pdf first post). What does high affinity/ low capacity exactly mean?

2) what is general mechanism for CYP's to be induced due to xenobiotics. I thought about this and am stuck with this: When psilocybin enters the bloodstream a messenger (hormone?) is triggered that induces the formation of CYP enzymes in the liver. They are produced on demand and when sufficient are present the concentration psilocybin steadily declines for it is made water soluble. This is phase I, as I understand it. Is this simplified model correct and what does phase II entail exactly, is it also founded upon CYP's or are other enzymes resposible?

3) is there a relationship between MAO enzymes and CYP's?

4) am I correct in stating that the whole CYP science is in it's infancy and we got a bunch of confusing terms and lack of overall insight?

Yes, still alive! I need to give some feedback on earlier posts as well.
But with regard to your listed questions here.

1) I read through the pdf you posted a bit, and saw where they referenced cyp2d6 as high affinity/low capacity. I think the implication here is that, as you mentioned, cyp2d6 is a high affinity enzyme for at least its endogenous substrates, and thus will bind them at low concentrations. The low capacity I assume is referring to the substrate turnover rate, or how quickly it can modify its ligands. Thus it is easily saturated at higher concentrations, and other CYPs or oxidases may begin metabolizing the excess substrate. If someone else has more profound insight on this, please feel free to chime in!

2) So you are somewhat correct, but off on a few points. When we talk about inducibility of CYPs, this is mediated by nuclear receptors. Nuclear receptors are proteins that act both as transcription factors AND are able to bind ligands (endogenous or xenobiotic). A transcription factor is a protein that directly interacts with DNA, and has the ability to turn a gene's expression on or off (in conjunction with other transcription factors). So when we say a CYP is induced by an exogenous ligand, such as say - the pesticide TCDD which interacts with the Aryl-hydrocarbon nuclear (AhR) receptor, the pesticide binds to AhR, inducing the receptor to go turn on CYP1 genes.
Other nuclear receptors turn on CYP2/3/4 families. And there are other interactions/caveats/nuances that we won't get into.
Another clarification with your example, is that the nuclear receptors typically aren't taking transcription of a gene from 0 or none to ON or 100%. There are normal or basal amounts of these enzymes that are always turned on, but adding exogenous compounds can potentially induce increased transcription. So they aren't totally produced on-demand. Transcription of appreciable amounts is not instantaneous, and can take hours to days.

You're pretty much right on with your Phase I description, except for what I noted, that its not really an on-demand process of expression, as much as we have these CYPs ready to roll and expressed already to help metabolize xenobiotics. The link between Phase I and Phase II is that PI serves to make compounds more water soluble, but also to add on nice functional groups (hydroxyls etc) where 'neutralizing' conjugate compounds (glucuronic acid, sulfates, glutathione) can be attached that serve to decrease the biological activity of the drug, make it even more water soluble, and make it accessible for our transporters to move the compound out of our body.

Phase II relies on CYPs and other oxidases (such as MAOs) to make the compound conjugatable, but employs different enzymes. (glutathione S-transferase is the most well known I think).

Psilocybin may or may not induce CYPs through nuclear receptors, but it is certainly metabolized by them, with CYP2d6 being the most prominent right? If psilocybin were to induce nuclear receptor activity, I would speculate it might be the Aryl hydrocarbon receptor, as we know this is responsive to tryptophan metabolites.

3) Evolutionarily, probably, but I'm not sure. Not an expert here. They're both mixed function oxidases that catalyze similar reactions which can be seen as Phase I. I'm not sure what transcription factors regulate MAO expression.

4) Actually the CYP field has been pretty damn extensively studied. That's definitely not to say there aren't a lot of questions remaining though. They're a reaaally old family of enzymes. And one of the oldest conserved genes across all kingdoms from what I understand. The number of possible drug interactions multiplied by inter-individual variability really creates a huge matrix of complications and uncertainties. The number of polymorphisms and splice variants, as well as splice variants in the nuclear receptors that regulate them really is a headache haha, but fascinating.

You're somewhat correct on the confusing nomenclature. The name of the CYP does not tell you about its inherent function. The nomenclature is based off of amino acid similarity in the protein.
For example: CYP1A1*1 - CYP1 indicates >40% amino acid identity, 'A' indicates the subfamily (>55% amino acid identity), '1' indicates the specific enzyme, '*1A' indicates the specific variant (due to a polymorphism or splice pattern).

Hope I've helped answer some of your questions and hope I haven't befuddled you more.

Here is a dense, but excellent review on nuclear receptors and CYPs.


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The ayahuasca health guide:

Medications metabolized by cytochrome isoform (CYP2D6) such as antidepressants, tricyclic
antidepressants, serotonin reuptake inhibitors, perphenazine, neuroleptics, beta-blockers, and
antiarrhythmics may also prove dangerous in combination with ayahuasca, as CYP2D6 blocks the
metabolic pathway needed to rid the body of serotonin. It has also been found that some populations
have a genetically-linked weakened CYP2D6 pathway, making those persons more susceptible to
serotonin toxicity (Brierley & Davidson 2012; Brown 2010). African-Americans and white populations
have been found to have weaker CYP2D6 pathways, while Asian, Middle Eastern and North African
populations tend to have stronger CYP2D6 pathways.

Brierly, D. I., & Davidson, C. (2012). Developments in harmine pharmacology-implications for ayahuasca use and drug-dependence treatment. Progess in Neuro-Psychopharmacology & Biological Psychiatry, 39, 263-272.

Brown, C. H. (2010). Drug-induced serotonin syndrome. Medscape.

The first paper doesn't mention CYP2D6. Can't open the second paper without account. And I have doubts about the quote. Seems that they want to say: some medications block the cyp2d6 pathway and therefore serotonin syndrome may occur...

Callaway, JC (2011). Fast and slow metabolizers of Hoasca.

Abstract-Harmine, a major alkaloid in ayahuasca (hoasca), is a selective and reversible inhibitor
of the enzyme monoamine oxidase-A (MAO-A). It is also a selective inhibitor of the human
cytochrome P450 isozyme 2D6 (CYP 2D6), which metabolizes harmine to a more hydrophilic
derivative for eventual excretion. CYP 2D6 exhibits a wide range of polymorphisms in human
populations, and variations in this enzymatic activity could account for differences in effects between
individuals who use hoasca. This report broadly describes two subgroups of CYP 2D6 phenotypes—
i.e., fast and slow metabolizers of harmine—in 14 experienced male members of the União do Vegetal
(UDV) who received a standardized dosage of hoasca. To compensate for metabolic variations in
their normal religious practice, the administered dose of hoasca is always determined by the presiding
mestre, who is responsible for deciding the actual amount for each individual. This age-old method
compensates for metabolic variations between individuals and variations in both the alkaloid profile
and strength of the hoasca.

Selective serotonin reuptake inhibitors (SSRIs) are
antidepressants that have high affinity for CYP 2D6
(Bourin, Chue & Guillon 2001), in addition to the seroto-
nin reuptake site. Many antipsychotic medications are also
metabolized to a significant extent by CYP 2D6, and pre-
scription recommendations have already been made with
this in mind (Oscarson 2003; Dahl 2002). Thus, harmine’s
metabolism by CYP 2D6 provides another good reason to
avoid the combination of SSRIs and other monoaminergic
medications with hoasca (Callaway & Grob 1998). More
common drug substances, such as tobacco smoke, are also
known to affect CYP 2D6 metabolism (Tiihonen et al.
2000), although the use of tobacco is common among in-
digenous users of B. caapi infusions, both smoked and as
an admixture to the decoction, where it is claimed to modu-
late the effect (Wilbert 1991).

The purpose of this article has been to describe a natu-
ral variation in the metabolism of harmine by healthy men,
which was already observed empirically by those who use
hoasca and related beverages on a regular basis. It is per-
haps more important to keep in mind that the mestre, shaman
or padrinho is responsible for knowing both the strength of
the tea and the general constitution of the individual re-
ceiving it. As with other pharmacologic substances, this is
simply a matter of adjusting the administered dose after
careful consideration. In any case, it is hard to imagine a
lethal overdose when the effective dose is so near the point
of emesis, unless other medications are involved.

I found this paper interesting. At first I thought it was bad science. Since I mistaken that they let a mestre decide who was poor or rapid metabolizer. But they just measured the bloodplasmalevels over time and gave everyone the same standardized dose.

Considerable variations were observed for the metabo-
lism of harmine in healthy men after ingesting a standard
dose of hoasca. From the current available information, it
seems that this difference in effect can be explained by
individual differences in CYP 2D6 enzymatic activity. The
metabolism of DMT by MAO is blocked by harmine, al-
though DMT is probably still metabolized by kynureninase,
while THH may be metabolized by other enzymatic ac-
Hi cave,

Forgot to get to this. But I think what 'high affinity/ low capacity' means in the context of CYP2D6: It can metabolize a broad range of compounds but only in small quantities. Let me know if this is correct.
This CYP2D6 variance would explain ayahuasca effects that persisted for twice the time of other participants. My enzyme output was (more than!) saturated by the second cup... It's not common knowledge that ayahuasca is not merely down to the MAO inhibition. There is a non-linearity in dose/response effects for reasons such as this.

Interesting links, although it's a shame they are - in places - couched in terms such as "recreational beverage Ayahuasca" and "5-MeO-DMT belongs to a group of abused tryptamine derivatives". Does this reflect a necessity to satisfy certain funding criteria, perhaps?
Another consideration to think about in addition to what has already been discussed is the kinetics of enzyme action. This consideration is a general concept for many substances and I assume also plays a role when "titrating" your use of an entheogen such as ayahuasca. As already stated, you only have so many enzymes and at a large enough concentration, all the enzyme active sites become saturated.

Prior to saturation, increasing the concentration of a substance leads to increased metabolism as more of the substance is available to interact with enzyme active sites. This can often be graphed and can be described by a function that is exponential. This is also known as first order kinetics.

However, at a certain concentration, the enzymes become saturated and increasing the concentration will not result in increased metabolism. This is known as saturation or zero order kinetics. Once this occurs, metabolism will chug along at an essentially constant rate. I would assume that titrting your dose of an agent beyond saturation could result in a change in the person's emotional/psychosocial/subjective experience as the entheogen metabolism and ultimately, elimination may markedly change.

The above is pure speculation based on a generic application of enzyme kinetics, but inducing or inhibiting enzymes will likely alter kinetics.
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