CYP1A2 Puns

This is not a "kava fact", but a "kava theory".

Hello kava lovers! I submitted this question to r/askscience but it was removed, I assume because it didn't receive any answers in 9 hours.

So, check this out. Kava has been shown in vivo to inhibit the enzymatic pathway CYP 1A2. Russmann et al 2005 found with caffeine application during kava consumption that the clearance rate of caffeine was cut in half. After kava was stopped for 30 days caffeine metabolism increased 100% [1]. This evidence gives us strong indication that kava is a viable CYP1A2 inhibitor in the human body, not just in the lab or in petri dishes.

There are a limited number of drugs that use this pathway, and some endogenous chemicals produced internally by the body. Of these natural chemicals, I would like to focus on melatonin.

Melatonin was first isolated in the late 50s with reported mild sedative effects which plays a primary role in the timing of circadian rhythms, among other functions [2]. Melatonin is produced by the pineal gland during the night [3], and advances sleep onset in adults [4]. After melatonin is produced, and exerts its effect, it begins to be metabolized. Metabolization occurs through 3 separate pathways with the overwhelming majority being with CYP1A2 through the process of hydroxylation [5].

Now, we’ve already covered that kava shows a pretty strong inhibitory affinity for this pathway. My question is, if we manage to reduce the activity of CYP 1A2 would that, in turn, cause the reduction of metabolization of melatonin, and cause an increased or additional sedative effect? Some studies show melatonin levels sky-high in those with weakened expressions of this pathway, indicating that it does make a difference in how chemicals are processed through this enzyme [6]. We can also deduce this change by looking at tobacco consumption. Polycyclic hydrocarbons in tobacco smoke induce CYP1A2, as in it increases the activity, which has shown to cause lower levels of melatonin due to the increased activity of this enzyme [7].

Could this also speak a little towards why kava is routinely consumed after the sun has gone down? Could this speak to why some people find incredible insomnia relief in kava? Maybe, but this is a big maybe, and needs much more information to form fully. There is a paucity of research related to CYP inhibition, melatonin, and increased sedation.

[1] Russmann, Stefan, Bernhard H. Lauterburg, Yann Barguil, Erwan Choblet, Pierre Cabalio

I’ve come to realize that the reason melatonin, caffeine, and other compounds have no effect on me is because I metabolize them ridiculously quickly. I’ve begun to experiment with CYP1A2 inhibitors like Rhodiola Rosea and Bacoppa Monnieri to see if they’ll slow down the metabolism of these compounds but I haven’t noticed much yet.

Does anyone else here have this condition (or noticed something similar)? What has your experience with nootropics been like?

Hi! So if you don't know what these are, the SLC6A4 is the serotonin transporter gene. The short/long allele variant of this causes most antidepressants to not work. The CYP1A2 is a genotype for ultrarapid metabolism due to the enzyme activity so it makes many medications be ineffective. I have been thru so many antidepressants (10) and am now on Viibryd. The Viibryd is the first that actually does help some. It gets me to a point of not wanting to lay in bed all day and cry but not much more. As I have C-PTSD as well, I struggle with sleep. I can't say the last time I slept without waking up 10-20 times a night. I have tried Ambien, Restoril, Ativan, Xanax, and am now taking Lunesta. None have worked. My psyciatrist just had me try a low dose of Seroquel for sleep but just made me extremly groggy well into the next day (and no sleep improvement). I am just at a hopeless point of feeling like it will never get better. FYI, I am 36/M, and have actively been in therapy and seeing a psyciatrist for some time. Does anyone have any incite or reccomendations? I will try anything at this point just to enjoy my life again.

I have CYP1A2*11 , CYP1A2*16, CYP1A2*15 and CYP1A2*3 .

How would i metabolize according to this? Is 2 copies the more common variation or do all people have 4?

I am intermediate metabolizer of CYP2D6 as well.

https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0009279715002495 i stumbled about this article and thought its worth sharing, i wonder if other phenylpropenes do that too

(Icey, Public domain, via Wikimedia Commons)

Recently we covered CYP450 enzymes and how kava may inhibit the activity at some of these areas. Today we’re going to focus specifically on the enzyme CYP1A2, and how inhibiting it effects caffeine metabolism.

We’ve seen quite a number of kava drinkers over the years remark about how their morning coffee began to be somewhat more of a stimulating experience. Some kava drinkers find this extra boost a side benefit of drinking kava. Other people experiencing this marked increase in stimulation may find it overpowering.

Caffeine metabolism occurs primarily in the liver, with a half-life of 5 hours, and requires about 8-10 hours to clear entirely. First pass metabolism accounts for 75-80% of caffeine’s metabolism in the body. The enzyme responsible for this is CYP1A2 [1].

Kava has been shown in its different forms to inhibit the enzyme CYP1A2 to varying degrees. In 2005 a study was carried out on kava drinking volunteers. They had the subjects stop drinking kava for 30 days, and measured the metabolic rate of caffeine both prior to and after the break. The caffeine metabolism ratio was shown to increase by 200% after 30 days. This indicated, when consuming kava on a regular basis, that some users can see what feels like DOUBLE the amount of caffeine they’ve ingested. This study also suggested these values return back to normal once kava drinking is stopped [2].

So, kava lovers, if you’ve been drinking your morning coffee and are seeing a definite increase in the stimulatory properties, this could be the culprit as to why.

[1] Institute of Medicine (US) Committee on Military Nutrition Research. Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington (DC): National Academies Press (US); 2001. 2, Pharmacology of Caffeine. Available from: https://www.ncbi.nlm.nih.gov/books/NBK223808/

[2] Cabalion, P., Barguil, Y., Duhet, D., Mandeau, A., Warter, S., Russmann, S., Tarbah, F., & Daldrup, T. (2005). Kava in modern therapeutic uses: To a better evaluation of the benefit/risk relation: researches in New Caledonia and in Futuna. Revista de Fitoterapia, 5(special issue), 53–70.

Kavaforums Discussion Thread: https://kavaforums.com/forum/threads/kava-caffeine-

We’ve seen in the past studies report that populations of countries which regularly drink kava experience a lower incidence of cancer in that population [1]. It is possible that some of this protection can be explained by the inhibition of certain drug-metabolizing enzymes in the liver.

What are cytochrome P450 enzymes?

We’ve covered this fact before in our series, however these enzymes are extensively involved in a variety of metabolic and biosynthetic processes. Currently there are over 1000 different P450 enzymes identified. These enzymes are primarily responsible for the clearance of xenobiotics. Xenobiotics are any chemical that comes into the body from the environment, and isn’t made endogenously, which are commonly known as “drugs”. These enzymes are thought to be present in every living species on earth [2]. Of the numerous enzymes, we will be focusing on one today, and that’s CYP1A2.

What is CYP1A2 and what does it do?

CYP1A2 is an enzyme found mainly in the liver. This pathway is involved with the metabolization of various drugs and environmental toxins. Specifically 1A2 is involved in the metabolization and activation of aromatic amines and polycyclic aromatic hydrocarbons.

CYP1A2 and Cancer

We now know that CYP1A2 is involved with the metabolism and activation of cancer causing molecules. Aromatic amines and polycyclic aromatic hydrocarbons are well known causative agents in elevated cancer risks [3,4,5]. Increases in CYP1A2 activity have been correlated with an increased risk of breast cancers [6].

CYP1A2 and Caffeine

Interestingly CYP1A2 is also the main pathway of metabolization of caffeine. Routinely caffeine is used to assay CYP1A2 activity [7]. When this enzyme is inhibited caffeine metabolism is reduced and caffeine exerts a longer/stronger effect [8].

CYP1A2 and Tobacco

Clozapine was used to investigate CYP1A2 activity in individuals who smoked tobacco products. It was found CYP1A2 was induced by smoking which caused clozapine to be cleared at a rate 2.5 times that of a non-smoker. It’s clear that smoking tobacco products causes an increase in the activity of this pathway [9,10].

CYP1A2 and Kava

Table 2

Table 1

Many s

Does that mean that mirtazapine inhibits other drugs that use CYP3A4 enzyme to be metabolised?

So that means if there is another drug that is metabolized by cy3pa4 it will produce less desired effects?

So, this might be an on odd one, but my story is this: I have been physically dependent on caffeine for 25 years, and have come to recognize that, as I am hypersensitive to its negative effects, I must do my best to remove it from my life, or at least avoid physical dependence from here on out. I was also recently diagnosed with ADHD, whose symptoms are severely exacerbated by my caffeine intake.

Herein lies the rub: I’m roughly two weeks away from the end of a 6 month caffeine taper, and have finally reached a point in my life in which I am not concerned with the possibility of relapse. The problem, however, is that the production of chocolate confections is one of my greatest passions, and I do not want to give up something so important to me. I am willing to accept a middle ground in which I avoid consuming my work often enough to develop dependence, but would like to do anything I can to reduce the acute effects of caffeine and theobromine.

So the question is this: Is there a strong CYP1A2 inducer without notable psychoactive effects or dangerous side effects that I could take prior to the consumption of chocolate to at least increase the breakdown of caffeine enough to cause a significant reduction of effects? Is this line of questioning reasonable to begin with? I’d be extremely grateful for any insight!

Are their any Geneticists in this sub who are familiar with the relationship between Caffeine and the CYP1A2 gene variants? I have seen a lot of studies and news articles talking about how different people metabolize caffeine at a high and low rate depending on gene variants of CYP1A2, but typically I don't see a lot of actual quantitative analysis of how long caffeine can remain in the body.

I am interested in this because I seem to have a particularly slow metabolism of caffeine to the point where sometimes I have a coffee in the early morning, and still feel the effects by the time I go to bed. Is this just psychosomatic? Or can caffeine metabolism actually be that slow?

I'm super sensitive to caffeine and dark chocolate. Like if I have 1 cup of decaffeinated coffee in the morning it will affect my ability to sleep at night. Same goes with chocolate. It's super annoying as I can accidentally have something with coffee, tea or chocolate in it and it totally messes up my sleep cycle.

I read that the CYP1A2 enzyme can help the body break down the effects of caffeine. Has anyone tried taking this as a supplement to help with their sleep?

To put it another way, I'm hoping that taking this enzyme regularly could help with my body's ability to manage caffeine when I ingest it accidentally.

Question here guys, I'm wondering if my intake of curcumin could potentially increase estrogen as my E2 levels always seem to be on the high side. Nutrahacker tells me I am homozygous (AA) for CYP1A2, where A is the risk allele, meaning in this case perhaps less metabolism of estrogen.

CYP1A2 is a liver detox enzyme and among other things, oxidizes toxins, estrogen, melatonin, caffeine, and some drugs. Curcumin has been shown to inhibit CYP1A2 by multiple studies (Chen, 2010; Sasaki, 2017; Shamsi, 2017). So taking curcumin could mean less CYP1A2 activity, and therefore (potentially) less oxidation of things like in this case, estrogen, which could mean high E2.

Any thoughts? For what its worth, I don't have any E2 levels without curcumin, its just something I've taken for so many years now, but this got me thinking.

So I know this is the gene that influences the body’s ability to metabolize caffeine (the enzyme responsible for caffeine clearance is P450 and it is coded by CYP1A2). I have also read CYP1A2 has effects in metabolization of beta blockers. My question is what the effect is. In the case of caffeine, it remains in enhanced/prolonged effect in the body due to inability to clear it. Could it be said that if, due to a CYP1A2 deficiency, you lack the enzyme to properly metabolize caffeine, the same effect would be exerted on beta blockers? Thanks in advance.

So I had a genetic test done for my mental health medication and I just noticed that it says I have rare genetic variants that haven't been observed by the place that took my test so I was wondering if anyone had any information or anything because I'm honestly intrigued by it.

CYP1A2 125C>G, 5166G>A, 558C>A

Then CYP2C19*7

If anyone knows any information or even point me in right direction I would appreciate it so much. Thank you in advance.

For quite a few years I struggled to sleep after coffee consumption in the afternoons. I deduced that this was simply because I was sensitive to caffeine. I continued drinking black coffee in the mornings though.

The morning coffee started affecting my sleep and I started drinking other things that I really didn't enjoy like matcha and black tea etc. Eventually I stumbled across then caffeine consumption part of my 23and me results and realized that I didn't have the genetic markers that indicated I drank more caffeine.

A friend of mine that can drink coffee and go straight to sleep did have these markers. This all makes sense to me, I was curious if anybody else had correlated their results with how caffeine affects them.

Hi, recently got some genetic testing done and most of my enzymes came back relatively normal, except for CYP1A2, for which I have the ultrarapid metabolizer genotype (-3860G>A - G/A, -2467T>DELT - T/DELT, -163C>A - C/A).

Other than the fact that caffeine and other exogenous substrates will be cleared much quicker from my body, what does this mean for my health, and what kind of optimization can be done?

CYP1A2 is the primary liver enzyme for melatonin, and 90% of endogenous melatonin is metabolized in the liver. Does the pineal gland upregulate melatonin production to offset this? Should I be supplementing? I’ve had moderate insomnia my entire life. Some of it I can attribute to chronic pain and high stress levels, but with chronic sleep deprivation and chronic stress it really becomes a chicken or the egg situation.

I’ve done less research on this but CYP1A2 is also involved in steroid/androgen pathways and low T is not off the table for me, although I’ve never had it tested. Although my diet is high in protein and I am physically active, I have very low muscle mass and a high degree of laxity/hypermobility in my joints. The latter is at least partly hereditary, but I got it much, much worse than anyone in my family history.

Random bonus question: When G-protein coupled receptors exist in dimer form, do they share the G-protein? If so, would a heterodimer be able to activate the G-protein with either of the receptor’s ligands, meaning both ligands basically produce the same effect?

I had a gene test done and one of the things I saw was this: http://imgur.com/wJhe1PI

It talks about rapid metabolism - but is it in reference to only metabolizing specific things? I tried googling it but only got more confused.

...I'm just wondering how it interacts with Dexedrine-- is it synergistic, or should I avoid combining the two??

I don't want to step on anybody's toes here, but the amount of non-dad jokes here in this subreddit really annoys me. First of all, dad jokes CAN be NSFW, it clearly says so in the sub rules. Secondly, it doesn't automatically make it a dad joke if it's from a conversation between you and your child. Most importantly, the jokes that your CHILDREN tell YOU are not dad jokes. The point of a dad joke is that it's so cheesy only a dad who's trying to be funny would make such a joke. That's it. They are stupid plays on words, lame puns and so on. There has to be a clever pun or wordplay for it to be considered a dad joke.

Again, to all the fellow dads, I apologise if I'm sounding too harsh. But I just needed to get it off my chest.

I’ve read that MDMA metabolizes into MDA regardless of dose.

I’ve also read that taking high doses of MDMA it then converts to MDA.

Is it correct to believe that all MDMA converts to MDA in the body hence taking under 200mg is the safest route for harm reduction?

Does it work against them?

So I see a lot of posts and people talking about terp profiles affecting the high of cannabis, mainly in reference to Delta 9THC. And I've also heard that minor noids effect the high as well, which I could understand, like CBN for more relax and CBG for a little more upitty. So how do terps affect Delta 9THC, and can they also have similar, but maybe weaker, effects when used with Delta 8THC? And if not wth not, they're like one piece different molecularly, 9 and 8 THC.

Edit: if all anyone has to say is "DeLtA 8 dOeSn'T hAvE sTrAiNs" don't bother commenting, that's not what I'm asking, and my question is more indepth than that. I've just had too many of those stupid right-off comments and they piss me off. If you can't explain to me and that's all you have to say then please don't bother saying it. Nor am I really looking for a comparison of 8 and 9, cause I know they can be very different like green tea to cocaine for some strains.

Do your worst!

I'm surprised it hasn't decade.

For context I'm a Refuse Driver (Garbage man) & today I was on food waste. After I'd tipped I was checking the wagon for any defects when I spotted a lone pea balanced on the lifts.

I said "hey look, an escaPEA"

No one near me but it didn't half make me laugh for a good hour or so!

Edit: I can't believe how much this has blown up. Thank you everyone I've had a blast reading through the replies 😂

It really does, I swear!

They’re on standbi

Pilot on me!!