That it could result in a particular stressful situation? In order to succesfully be able to process the body resorts to adrenal activation, ie stresshormones to keep the person awake and increase heartrate and such, all in order to bump up metabolism. I have this speculation that a 'good' experience depends on the body giving a sort of green light signal once the situation has been 'assessed' and the subconscious intelligence has determined that the removal of the agent can be done in a safe time frame without toxic side effects. If that green light can't be given due to excessive concentrations and multiple agents it will resort to others means to get the process going, hence steering into a 'bad' experience...

I think that was what happened when this shaman once gave me way too much in a bad place with too much people. The brew was very rich and contained lots of additives, I could tell. But it wouldn't pass over and I spent more than 10 hours in a state of more or less sheer terror. But at the same time very rationally aware and selfcontrolled just couldn't really move or talk. The content of the trip wasn't personal, it was just deep subconscious terror infused by the bad state of affairs externally. That was also my only shaman experience. He told afterward he felt the need to give me a particular large dose. The guy was ignorant if you ask me. Just a high horse shaman of 'impeccable lineage'...

Anyway, I don't really know how to steer this topic right now. For me the conclusion is that poor metaboliser isn't that bad. But, that it needs to be accounted for to avoid experiences such as I just described. These can have long lasting influences. Leading to a sort of vicious cycle. For not only xenobiotics and proceseed through CYP's. Endobiotics as well, such a adrenal hormones. And if you have for example some form of PTSS then being a poor metaboliser can hold you into this for extended periods.

I have done some consulting and testing and found out about constant high stress levels and lack of deep sleep for extended periods now. Even without those tests I already knew that. I am pretty sure this has deteriorated the poor metaboliser condition to the level of having to refrain from alkaloids in general. They bring out the condition and point it out very clearly but also worsen it. So taking drugs whether psychedelics or some form of medicine lead invariably to a bad trip or toxicity.

However not all. Cannabis still works, has no toxicity and relieves the condition. Also I tolerate huge amounts of alcohol. Though keep away from that. Instead I use it to dissolve stuff like ashwagandha extract. For I found that taking it tinctured doesn't lead to toxic side effects. Using dried extract would not have effect and give nausea.

A side note. I opened a topic on lucid dreaming elsewhere on the forum. Have been doing that very often recently. That's due to this unnatural state of constant stress level and lack of deep sleep. It's like the one fun side effect of this overall not so fun condition. But it's symptom of something disturbed and having to lack deep sleep is a bitch.

All in all I'm glad to got to this level. For I see now why taking medications would have been a worse thing to do in such a situation. I remember how it went with kratom. Back in the day I wanted to get off weed, for I have used it as a medicine for insomnia for years. The amounts of kratom I had to take to get sufficient effect quickly made me terribly sick for days and I also got withdrawal during that. Man I can't tell how much it sucks to have both at the same time.

Just sticking to the path of self exploration to eventually be able to manage things with such precision that I can work around it.

I do want to find out if a poor metaboliser is a evolutionary adaptation or it is degenerative condition (due to lack of proper nutrition over generations?). I mean is this group going to be removed from the gene pool for it is a bad adaptation to current living standards?

Cannabinoids do inhibit CYPs..

Yes I read that paper...

Things took a more personal turn even more. Right now I am going to test my CYP450 levels, especially CYP2D6. I want to know for sure whether or not my intuition that I am a poor metabolizer is correct. It also seems a good idea to screen for other related metabolic defects, like MTHFR.

It seems that my whole interest in this topic has been a way to become aware of the fact that my body has serious detox problems. It could be that I'm genetically predisposed to this. And that it has been brought out through a period of intense stress, could be traumatic experience. From this I do not seem to recovering, though I have completely removed the situation from life. This I reason from the symptoms I encounter daily, my body seems to be doing a frantic effort to detox through all means. That on top of the metabolism are mounted more psychological processes and these also do not resolve despite all effort and the fact the cause has been removed.

So to keep it on topic. In order to have a healthy relation with psychedelics, it's important to have the metabolic system be able to cope with it. People who have the mutations that cause low levels of CYP and possibly other factors have a hard time processing. They will have smaller margins and need to be aware of these limitations. If not properly accounted for, it's possible to sink into situations that resolve either very slowly or maybe not at all. At this point I can't be sure how dire this can get, but my experience suggest that if you're having similar experiences it's a good advice to be very careful and also screen to know without a doubt.

For me this means I have to get these tests, also to prove me wrong if so. Also be patient, it may be that psychedelics have to be left alone for a long time now or maybe even never again.

I will get back to this once I have results and know without a doubt whether I'm right or wrong.

It might take a while to get a proper test for this. So meanwhile just trying to be as accurate as possible. It doesn't hurt to be on the safe side. I've said more than enough, CYP450 can be a bitch.

I'm a bit critical about the terminology. Poor metaboliser, what kind of designation is that? Like you're a genetic loser, bad luck you just got unlucky... Also the way it's described as a lacking. Why on earth would a significant group of the population be lacking some critical enzymes? For living especially these days, you really need a good detox path for all those pesiticides, antibiotics and growth hormones that are present in food. Not to mention other pollution that comes through water and air...

Anyway. I started to look at this from a little different vantage point. It maybe a genetic cause but all in all, the information coding for let's say CYP2D6 is present. Maybe it's a modified gene, rendered inactive or even epigenetically turned off. Who knows, but in the end there is no clear lack of something. It's just that the mindset views it as a lack and a poor condition.

I'm not sure what this all amounts to, but the mindset that you lack something and are poor in a certain respect is just shortsighted and doesn't contribute. There are other ways and maybe distorted genetics can be made up by conscious effort.

So for a start let's look at CYP2D6 inducers.

The Induction of CYP1A2, CYP2D6 and CYP3A4 by Six Trade Herbal Products in Cultured Primary Human Hepatocytes



There may be others. Another thing to look into in more depth is the interaction of MAO enzymes and specifically CYP2D6 through harmalas & tryptamines. It might be that a PM is better off combining these 2 than just tryptamines, or the other way round.

What is also needed is contributions from someone on the other side of the spectrum. A ultra-rapid metabolizer. My guess is that if you're on this side, you probably need a bigger dose of tryptamines than most other people (way more), it wears out very quickly and you sober-up very quickly. The risk is that in the case of a prodrug you can easily overdose. Another risk is that you'll be inclined to take more cause it will be generally pleasant...

This in contrast to the PM by the way. You take a little and have a very uncomfortable coming-up. The plateau will be okay but afterward the coming-down takes very long and probably days on end you'll be not quite sober yet. If take or combine too much it will backfire on you and instead on effect you'll have a halfeffect and mostly side-effect which are best described as a toxic feel. Some effects will be more pronounced in the days after for it will circulate in the bloodstream for quite a while.

Now this keeps on my mind all the time. Why on earth do middle-easterners have a high rate of ultra-rapid metabolizers in contrast to the rest of us? Has this to do with civilization? It's known that the ME has the oldest civilizations in the world. With that comes trade and ofcourse psychoactive herbs or goods. Is it evolution through civilization that sparked this prominence of the URM group in these regions? So in contrast, the PM's are likely to have originated in high lattitudes were neither abundant trade or plantlife with alkaloids occurs. My guess is that's it either an adaptation to cold or poor nutrition. But then again this group also is found in tropical regions so it is probably not the right guess...

So is the PM a dialing down of the more common types? Or did it originate totally on it's own? It's known that to be a URM you need multiple copies of a working CYP2D6 gene, to become a PM it just needs to be either modified or possibly epigenetically turned off. But why? How come that in modern times this group still exists? We've been using medications for quite some while now, it would be obvious that this group starts to extinguish as there are no obvious benefits to it...

Yeah its complicated.

To touch on a few of your thoughts regarding the evolution and distribution of CYP variants though, I'd note a couple things.
I've heard a few people theorize that at least with regard to CYP3A4 metabolism, some of the polymorphisms may have been selected for in response to colder, cloudier regions like you say, but its hypothesized this could be due to the need to regulate vitamin d metabolism. As a number of cyps are involved in synthesis and degradation of vitamin d, one would want to select for low expression/activity of CYP-degrading enzymes in colder places. And important to note that CYPs are involved in mineralcorticoid hormone synthesis as well, and these regulate things like salt retention, blood pressure etc. Thinking about salt-limiting regions might put some of these things in context too.
Also, with regard to variants clustering in regions, there's a lot of work being done on glaucoma and cyp1b1 variants in highly consanguineous populations like some of these pakistani and roma groups.
Not sure if I mentioned that in a past conversation.

Also, the origination and extent of cooking food is also worth thinking about. Burnt food = polycyclic aromatic hydrocarbons (char) - these compounds activate the AhR which would then go turn on CYP genes. Some CYPs then act on these combustion byproducts and can activate them to procarcinogenic or benign forms (bioactivation vs detoxification). This may have been a selection pressure in early evolution too. If one is expressing variants that perform more procarcinogenic metabolic transformations - it is less likely to be passed on if these people died quicker.

Food for thoughts. Hope things are going well with you.

That is not necessarily the case as death may occur after reproduction has occurred. To what extent would PAH's cause heritable genetic damage? And where is the line between genetic damage, mutation and evolution?

It's fascinating how metabolic responses to xenobiotics can cause long term switching of gene expression, some of it heritable.

Yes that's true, I suppose I was being more speculative and obtuse in my observations there, thanks for reigning me in.
I didn't mean to say PAH's would cause heritable genetic damage (though I guess its not out of the question).
And I don't know if there is a delineating point between genetic damage, mutation and evolution either. I guess I was just trying to point to broad evolutionary strokes, that if there did exist some really damaging CYP variants that had a higher propensity for genetic damage due to their metabolic transformations of environmental components (particularly PAHs), we might see this being selected against in the 'long run' evolutionarily. Obviously this is not totally true, as its well documented that our currently expressed CYPs turn lots of common PAHs (cigarette smoke, etc) into carcinogenic compounds, and these haven't been selected out of our genomes.

As you mention at the end, it is interesting to speculate on the heritable aspects of xenobiotic exposure, and I have often mused about the introduction of fire and these DNA damaging compounds as a diversification point in the CYP repertoire (in addition to being able to consume more plants/phytochemicals after certain components have been heat-inactivated).
The CYP family is already extremely diverse however, and hardly needs the introduction of fire to account for this diversity. I believe plants have the largest repertoire.
I had a mentor compare CYP evolution to immune cells, in the sense that they have to recognize or be ready to encounter a wide array of endogenous and exogenous compounds and respond (metabolize) to them in the most biologically 'appropriate' way, recognizing 'self' from 'nonself' molecules similar to the immune system. And the nuclear receptors that regulate them are often promiscuous in their ligands as well.

That's an interesting comparison, CYP and co. being to chemical intruders as lymphocytes are to biological intruders. And there's sure to be some overlap, perhaps through the interplay of antibody cofactors with the metabolic system. After all, once microorganisms have been neutralised we still need to deal with the products of their apoptosis or whatever. (This, as you can probably tell, is a vague outline off the top of my head. I'm putting these ideas together for the first time here. I'd love to study this kind of stuff formally some day.)

Hey guys, is there some good book that explains the intricacies from a first year college level upward?

In particular some kind of comprehensive view that not only discusses the factual CYP business, but also how it relates to other systems in the human body.

Like the endocrine system. I can't tell this idea came from a textbook, but it has been on my mind for a while now. Consider the activity of endocrine glands with it's various alkaloids and hormonal secretions. These compounds will end up being processed by CYP enzymes, that's what they're for.

So it seems to me that there is a very intimate relation between both systems. Like if you secrete a lot of neurotransmitters, there also needs to be a considerable amount of enzymes to break them down. If not, then things would get stuck. Feelings, emotions and states all come and go.

But if you don't make enough enzymes then secretions have to be held back too. It can get stuck in a vicious cycle as well. Secretions caused by stress create more stress by circulating for too long.



Nice you mention CYP3A4. I've started a topic on oral cannabis metabolism. That THC is converted exclusively through 3A4 activity into 11-OH-THC. which does not occur in the plantmaterial, and which is far more potent that THC.

Seems like it went unnoticed:

Oral cannabis CYP450 metabolism

This is the stuff I do most these days. In between the weeks I do it once, not regularly. Sometimes I notice the effect doesn't come. Yes I get a stoned little high buzz, but not the definite psychedelic character. When it does come, it's very defined and nice as well. It's like tripping on cannabis with all the characteristics of it but also the more trippy qualities normally found with tryptamines.

And my skin color, well sometimes I'm ashamed cause I don't get tanned unless I really really spend lots of time in the sun, but usually I burn before that. The margin is very small and the yield low. Usually there's nobody more white than me on the beach. Just a little more tan than albino. Which is strange cause my brother, father and his family are all tanned, coal black hair and brown eyes. On my mothers side it's mixed but only me and my mother have this very white tan.

Anyway I come to see that this highly variable types of metabolisers could differ for various CYP's. It could be that someone is poor with regards to CYP2D6 but intermediate for 3A4. I've read nowhere that this is actually the case. But with my current understanding it seems unlikely that someone is purely poor metaboliser over the whole spectrum. It would be more logical to look at individual enzymes this way.

Think this topic is about to reach some kind of conclusion. I regret that it is very difficult if not impossible at this point to describe a clear research based indication of the various types of metabolisers and the (classic) psychedelics. Much of what has been said in this topic is derived from research on other but related fields of research. So there is a good chance that there have been made reasonable suggestions which can prove helpful for any psychedelic explorer. But any firm statements cannot be made at this point. Reading a topic like this should provide some clues with which anyone can familiarize him/herself with this material in order to be able to judge for themselves how this applies to them.

Last but not least. I'm looking into spices and herbs now. Especially spices, really the tasty ones like pepper, curcuma, nutmeg, cloves. It kinda dawned on me that the really sharp ones might be worth investigating. At least now it looks like a mixed picture, some inhibit certain CYP's while expressing others. My current hypothesis on this is that sharp food is detrimental to enzyme production so it's good to cut sharp spices if you want to trip with low levels of CYP's. Based on the idea that low CYP levels are beneficial to those living in cold climates and that traditionally sharp spices weren't available to people in those regions.

Again the data is mixed so it isn't a clear line to draw as to the just stated hypothesis. A lot of it makes (common) sense but in detail there are many intricacies and therefore I do regret not having a formal education in this field. Anyway here's a nice summary of various herbs and spices I've been reading:

Pharmacokinetic Interactions of Herbs with Cytochrome P450 and P-Glycoprotein

I'm really open to any suggestions or comments at this point. If not then I may just try to summarize the most profound points discussed in this topic and leave it at that.

Alright last post.

There is a little suggestion or kind of method for insuring that levels of P450 enzymes remain high as possible. This simple but long eluding idea has to do with food and diet. The idea is that just as with MAO there is a possible diet for insuring that they're optimally expressed. It came from reading Terence McKenna actually. He didn't say anything about P450, but in his book Food of the Gods talks about how spices and herbs revolutionized Europe. That prior to importing spices, coffee, cacao and other, the diet was very poor in terms of these. So in a flash it became a revolution, people started to consume great deals of them.

Anyway, what I then realized is that a very simple diet or adjustment may improve levels:

* reduce exotic spices to the bare minimum
* avoid exotic fruits for they modulate the system profoundly
* keep superfoods to a minimum (raw cacao, noni juice, goji berries etc)
* avoid artificial flavourings, convervatives, pesticides, herbicides and growth hormones etc
* avoid charring/ burning foods

the list goes on, but these are the main point. The idea is that after a few weeks of this kind of diet the CYP450 levels will adjust and probably the system will be less taxed. Some of the spices, like curcumin, black pepper etc do have good effects on the system. But it may be advisable to keep the dose low.

I just didn't understand that a lot of (super)foods are very complex and for some people the side effects will be stronger than the benefits because of P450 levels.

Another influence is this page I found:

Detoxificatie en de detoxratio

This page is in Belgian, or Dutch - there is no difference. It goes in depth on both phase I & II. It was an eye opener, much detail and references. The main idea proposed is that poor metaboliser = poor detoxer. Phase I is the main pathway of detoxification and if this is overtaxed it fails and due to more toxicity and spirals into disfunction. Phase II is taken in detail as well. The need for both to be adjusted to each other, some products of Phase I may be more toxic than the initial compounds and cause trouble if Phase II is not fast enough to cope with it.

To conclude this, my interest comes from here: For years I've been harassed by quite extraordinairy forms of bad situations after another. After I found a way to end this, I got terribly fatigued, was sick for a long time and generally wouldn't even recover from a superficial skin puncture. Till this day... Like my entire system is unable to get past this, that my metabolism has somehow changed. Due to other experiences as well, like nearly getting killed by not having anti-addiction effects of a large dose Iboga, I began to search and later research what led me to Phase I detoxification and P450 enzymes. Now I know that actually I may have not been such a poor metaboliser after all, but due to years of extensive strain (physical, emotional, mental and in a sense spiritual) something just collapsed and Phase I detoxification may actually be a big player in this. This profoundly affected psychedelic experiences and the pure frustration of having to cope with lack of support for not only this, but also being dumped like a failure through a long stroke of bad luck made me adamant to figure it out myself.

Thank you for reading and good luck!

Does this enzyme group in question have anything to do with tolorance?

Also does initial saturation of substrate, say psilocybin, have any effect on dose response curve in the event that another dose is taken afterwards?

I imagine the answers to the above are 'probly not', am also wondering if anyone knows a DNA test that will tell us what is the state of our P450 group enzymes or is it to a large extent a more epiginetic question of what we're expressing and what is ideal to induce. I don't know I guess my body takes care of it all ok, the mind likes to know though! Great Nexian Biology class right here.

I do not know for sure. Maybe the question is which mechanism can possibly be responsible for tolerance? So if you check all possibilities, what is left? To my current knowledge phase 1 is left. It's the first line in drug metabolism. As far I know there's no other mechanism that can prevent additional doses from reaching the same effect as the first.

So yes, to my knowledge this group has certainly to do with this. But incomplete knowledge can lead to errors, nor do I know the details. Please correct me if I'm wrong.



The question is not understood properly here. But CYP enzymes work on low levels. If the levels are very high, suddenly, then toxicity of the concentration destroys enzymes so it takes longer and more enzymes need to be produced. Afterward the mitochondria might have less capacity for producing a new batch for another dose.

By the way the mitochondria replicate very often and prolonged toxicity damages them, thus preventing proper replication, DNA damage etc leading to less of them and enzymes over time.



As far I know DNA testing is the way of determining the inherent information to produce enzymes. Epigenetics are probably not testable. This is more in the line of food choices long term and ancestor diet.

Question is do you want to check this out? It's like a lottery and most enzyme defects are connected to increased risks on this or that disease. If you're in bad luck and have multiple phase 1 enzymes missing or poorly available - and miss a lot of the phase 2 modifications like methylation, sulfation, acetylation etc. Then the verdict is going to be 'high risk factor'. This is the kind of information you don't want your insurance company to know...

sad that this is the direction it's going.

Good news is that after testing my 'diet' for enzyme promotion I'm happy to announce that it seems to improve conditions. Generally after a few weeks there seems to be an improved basic well being. Dips just don't go as deep as they used to do and ups are more likely to occur. Remarkable is the improvement of sleep, it's easier to get into, lasts longer without interruptions and leads to degree of being rested at waking. Some of these things I've never experienced before.

Thorough testing in putting back and removing various items on the list is in progress. I will post the full list, including things I already was on due to other (but probably related issues). So here's the full list:

- no refined sugar
- no additives
- no glutes
- avoid charred foods
- avoid non-organic foods if possible
- very moderate lactose (like once a week)
- avoid exotic fruits like mango or papaya
- keep exotic spices to a minimum (curcuma, pepper, nutmeg, cinnamon etc)
- moderate superfoods except algea (take a minimum)
- eat a lot of raw vegetables (avoid vegetables like spinach or others that cause nausea)
- eat a lot of raw (food) mushrooms

and for me I add MSM and drink chaga tea now. All this combined gives a good result. I shows me that diet is paramount to wellbeing in a nutshell.

Again, please correct if there's false or incorrect information. I'm not educated on this and only in this through circumstances.

Hey great response neurohack, thank you

My two cents on some of these topics regarding CYPs/tolerance and things:

There are other mechanisms that give rise to individual tolerances and sensitivities, along with acquired tolerance from repeat dosing. One's individual CYP polymorphisms and variants affect both their activites and the levels of their expression. So hypothetically Bob who has X nucleotide change in the gene coding for his CYP3A4 enzyme could be more sensitive to alcohol because it either produces a slower functioning enzyme than sally's cyp3a4, or Bob could have the same cyp3a4 variant as sally but express (produce) it at lower levels. These are two reasons why people can be differentially sensitive.
Tolerance from repeat dosing (as mentioned with psilocybin, above) can happen from upregulating enzymes like CYPs which breakdown the drug, but it can also occur by quite a few other mechanisms. One off the top of my head is the downregulation of receptors for the drug from the membrane surface so that less signal is sent 'down'. Another option is a cell could upregulate drug-efflux pumps to export drugs from the cell. Another could be the saturation of downstream effectors in signaling cascades. Another could be the depletion of neurotransmitters necessary to transmit a signals.

Hey, nice explaining. The tolerance issue does seem much more complex than imagined. Thank you for broadening the scope.

One question, or two maybe ?

How about the actual gene coding itself. In all possible mutations does the basic information remain in tact? Say it says 'produce this enzyme by these parts in this sequence'. Then the mutated version says 'do not produce enyzme by these parts in this sequence', or 'produce this enzyme by not these parts and not this sequence'. Simplified a negation, but practically a nucleotide change that depending on the place either simply negates or produces a less potent version?

Another where do the genes for phase 1 lie? Are they mitochondrial DNA altogether or nuclear DNA? (please forgive my lack of adequate terms here). And how about phase 2 in this regard?

Last a quick update. Maybe most of you don't care, no problem. But integrating this knowledge through diet into a practice with tangible results has become a ripe fruit so to say. What I can say is that time and time again coming back to the diet I came up with does time and time again bring back a sort of 'normal situation': Where before fatigue, depression and overall a total non-enjoyment of both waking and sleeping states was 24/7, now when attending the dietary rules this dissipates. Life becomes more or less effortless, if seen from where I was before. On top of that it seems that this diet is not it, it can be dropped after a while. Things stay good for a while, but do fall back into the previous condition. So I observed this connection to what seems to be epigenetic factors: seeing my family brings me in contact with their (our) unresolved issues to do with traumatic family past. Whenever I spent a time with them, the issues with that start to occupy my mind and this coincides with the deterioration of the accumulated progress. Learning how to disidentify with these things has helped a lot. But it does not cover it all, so diet stays the cornerstone here. Anyway, what I'm wondering is how deep this goes. Could it be that by clearing all connections that allows this past to become 'my' present time and time again, the epigenetic factor diminishes in such a degree, the diet won't be neccessary anymore? I haven't tripped thusfar, the ground is still to shaky but hopes are still solid this will come again.

Ah well some story here. Someone needs to knock through the ice first. Banging the head is never a pretty sight, so please bear my ignorance.

Hey, so with regard to the things I can give closer to 'black and white' answers about, rather than the things you mention below which I feel less informed about to make a judgement.

The gene coding for the enzyme itself absolutely can carry mutations that dramatically modify the enzyme's function. Other times however, a mutation may result in no dramatic effect (a 'silent' mutation). The cytochrome 450 family is also known to undergo quite a lot of alternative splicing. This is a cutting and pasting of various parts of the gene when it is being translated to protein, and people can produce dramatically different splice variants.
As for your second question.. the genetic material for the great majority of proteins produced in a cell derive from the nucleus. Though you are correct that mitochondria do have a genome that encodes a number of extremely physiologically relevant genes. The cytochrome p450s are produced from the nuclear genome, but the proteins are transported to the mitochondria and endoplasmic reticulum where they sit in the outer membranes. Phase 1 metabolism, for simplicity can be reduced to thinking about the CYPs. Phase 2 enzymes are also produced from the nuclear genome as far as I know. Phase II enzymes also have roles in protecting against oxidative stress and reactive oxygen species, along with their 'detoxification' axis.

Hope this helped, don't know if I convolute matters further sometimes.
It is perhaps more relevant to think about what the gene product (protein) does, rather than where it is produced.