Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Adster, Aug 15, 2012.
Celery inhibits P450?! Man, so many "healthy" foods with not-so-healthy properties.
try eating a low oxalate diet - lots of "healthy" foods are out or only can be eaten in small quantities because of their oxalate content
alice, I don't know.
Guaranteed sleep no supplementation :
Interesting link on the effect of grapefruit on CYP3A4 :
"it was noted that the intestinal content of CYP3A4 fell by more than 50% after consumption of even a single glass of grapefruit juice. "
http://www.cpronline.in/PDF1/CPR 1(2), 2011, 210-218. (21).pdf
Thank you. I am going to check it out.
I used to think that using supplements with BioPerine was a good thing because it increased the absorption of all my other supplements. Now that I learn what a P450 inhibitor actually I'm not so sure. There is a long list of foods, supplements, and prescription drugs that inhibit P450 enzymes. There's even BioPerine in DIM supplements which are supposed to increase P450 enzymes.
So does inhibiting P450 enzymes increase exitoxicity? I don't think I can stop my prescription drugs right now, but I'll look into food and supplements.
Yeah, when looking up information on various prescription drugs it often tells you not to consume grapefruit or grapefruit juice. I was compiling a list of P450 inhibitors, but I stopped because it's hard to know to what degree they work.
This is a good way of putting it. Even typing on the keyboard makes the tips of my fingers feel ultra sensitive. I need to wrap them into my hands every once and a while.
Sounds at first glance like either you are over-methylating or your glutamate / GABA balance is way out of whack.
Grapefruit juice affects first pass CYP metabolism primarily in the gut. And yes it can interfere with conversions of certain drugs from prodrugs like Allegra. But contrary to some of the conventional wisdom running around the forums it is not a significant hepatic inhibitor of CYPs unless you drink massive (and I mean massive amounts). Not like say fluconazole or something akin to that or even quercetin that is first and inhibitor in the short term and switches to an inducer long term. What grapefruit juice affects most is the oral bioavailability of a drug. If the bioavailability is already high as with say Medrol, then there is not much effect. But boy oh boy is the bioavailability is low, then yes it can increase significantly and watch out.
I found a ref on list of drug inhibitors and inducers on P450. What I have not been able to determine is which allele is responsible for the various reactions (poor metabolizers/ultrametaboizers).
Yeah, methylation effects can stack over time so it might take a few days before you notice you've gone too far which is why it's good to start slow and add only one supplement at a time. Methylation and B12 increase ATP so maybe that's part of the reason why the ATP supplements are causing problems (?) I agree with what Rich said about it not being a good idea to "push through" exitoxicity. I found another post of Rich's where he talks about excitoxicity and overdriving the methylation cycle. Although some people need to take methylcobalamin as he points out in the last paragraph of his post, he does have some words of caution about it:
"I actually prefer including both folinic acid and 5-MTHF. 5-MTHF is the form needed by methionine synthase, which is the enzyme with the partial block. Many people's cells are able to convert folinic acid to 5-MTHF well, but many others have inherited genetic polymorphisms that slow this conversion down considerably. The polymorphisms in the MTHFR enzyme are a good example, and these are very prevalent in the population.
Folinic acid is helpful for a couple of reasons. One is that it is very versatile, in that it can be converted to other forms of folate, which are needed to make DNA, RNA, and purines in general. Another factor is that folinic acid is polyglutamated when it is inside the cells, and this can help to lower the amount of free glutamate, which is an excitotoxin. Excitotoxicity is a problem in CFS, and it is often exacerbated when methylation cycle treatment is entered upon.
I prefer hydroxocobalamin for several reasons. One is that it allows the cells to control the amounts of the coenzyme forms of B12 (methylcobalamin and adenosylcobalamin) that they make, so that they can be matched to the need. Taking methylcobalamin in large dosages by injection or sublingually can overdrive the methylation cycle, as evidenced by a major rise in sarcosine, which I've seen in amino acids testing on some people who have been on this treatment for a while. I am not comfortable with overdriving the methylation cycle, both because I think it slows flow down the transsulfuration pathway and thus limits the normalization of the balance of the sulfur metabolism, including cysteine, glutathione, taurine and sulfate, and also because I am concerned about the possibility of overmethylation of DNA, which could have other deleterious effects.
My other concern is that methylcobalamin is known to be chemically able to methylate inorganic mercury. Many PWCs have significant body burdens of inorganic mercury as a result of having amalgam fillings in their teeth during an extended period while glutathione has been low, so that they have not been able to detox mercury at normal rates. Methylmercury can cross the blood-brain barrier readily. Mercury is a potent neurotoxin if it gets into the brain. This problem has been observed in guinea pigs. I don't have solid evidence for it in humans, but have heard from perhaps three people who may have had this problem, based on what they have reported. So I prefer to be cautious.
This having been said, some people have had good experience with methylcobalamin. It can be especially helpful if a person has a shortage of methyl groups, though that can also be helped by taking some additional trimethylglycine (some of which is in the multi that is part of the simplified treatment). or some SAMe. It's used a lot subcutaneously by the DAN! doctors in autism treatment, and as you probably know, freddd on this forum advocates its use as well. In his case, because of a mutation in the intracellular B12 processing enzymes, his body is not able to utilized hydroxocobalamin readily. But I believe that this is a rare situation, based on the published literature. freddd does not agree that it is rare, based on his experience."
Something else about this topic from dbkita who I trust as much as Rich on methylation issues. There does seem to be some disagreement between them about B12, but I'm hoping this person will explain their position further. For myself at least, methylcobalamin did cause me problems and I wasn't taking any folate except that from my food.
"Overmethylation is a very,very real thing. It is basic biochemistry. People focus on methylation via the cycle, but in fact methylation via SAMe (mostly) is a huge regulator of gene expression, even silencing certain genes. Too much methylation can have HUGE effects on the body. Period. Anything to the contrary is just ... wrong.
That being said overmethylation is NOT generally the province of b12 generally since even the methyl b12 variant has a very short half-life. Some people on these forums take massive doses to force it to high overpowering concentrations in the CNS to help them with fundamental neurological issues.
On the other hand taking too much SAMe directly, too much TMG and for sure too much 5mthf or even folinic acid for many (or even folic acid for like 40% of the population) can overmethylate you. For those who lack the C677T SNP, riboflavin can also really spark methylation. Those with A1298C mutations are susceptible to overmethylation since the SAMe negative feedback mechanism on MTHFR via allosteric binding is inhibited (which can be really bad). P5p is also a contributor and can spark those with trans-sulfuration problems. B12 has much less impact on overmethylation (though mb12 will reduce melatonin and can cause some insomnia regardless of 'startup' effects).
Personally I overmethylated myself for two years taking too much methylfolate, TMG, r5p, p5p and even some SAMe (the last of which made me understand clinically that I was hammering myself wrongly). And no it was no detox or start-up effects. That tune gets real old real fast for some of us. And it wasn't low potassium either since I got 10 grams per day in diet and supplements. It was simply over-methylation."
Another possible cause of excito-toxicity could be excess methyl donors.
There are studies about this that are not fully conclusive, but I've felt toxic from taking high amounts of them.
Some methyl donors are easy to find, because they contain the word, methyl, in them. But others are harder to find.
If someone finds that they are sensitive to methyl groups, then I would suggest they not 'push through' with them, but reduce them.
Pushing through can be scary, and I don't think its necessary. I agree with others -- keep tapering down the dosage to a point where you aren't feeling really sick from the start-up (plus taking enough potassium that you don't experience muscle cramps and spasms). It's going to take longer at smaller dosages, but my experience is that you will still get to the same place.
That's true. I was surprised how many supplements I was taking that turned out to be methyl donors. Thanks to greenshots for this list. I've also heard choline mentioned as a methyl donor.
methyl THF, Methyl B 12
Some types of carnitine (Not fumarate version)
TMG & DMG
Melatonin (but its actually calming in those not COMT +|+
Phosphatidylserine isn't techically a methyl donor but can act as one
drugs like Ritalin, Adderall, & other ADHD drugs (thats why they work so well)
And there are probably others but this is all I can think of right now.
But anytime you get the mitochondria/Kreb cycle moving you can usually expect more start up, too. Maybe it won't be bad or anything but you'll probably notice something.
I believe the theories about methylation and other biochemistry cycle start up that goes something like this "if you're not feeling anything, its probably not doing much for you but when you feel a bit lousy, you know its working.". The key part of this phrase being "a bit" rather than feeling God awful and just trying to push through it.
There's also a thread talking about methyl donors.
Some things don't need to be a methyl donor to cause overmethylation such as B6/P5P and B2/R5P. This from dbkita:
P5P is not a methyl donor, But it is crucial to making methylfolate (by making the methylene intermediate, riboflavin-5-p controls the final step), to making methionine with the methionine synthase enzyme, to making dopamine and serotonin. to making gaba, to breaking down glycogen, and to regulating the trans-sulfuration pathway.
P5p will stimulate the body's own production of methylfolate and will also stimulate the methylation cycle and the conversion of homocysteine to cystathione via the CBS enzyme. Not to mention it affects a ton of other reactions in the body.
But these are chemical reactions at chemical equilbrium to one another. So you may find that doubling your P5p will have far less impact on the methylation cycle than say increasing methyfolate even slightly. But someone with the CBS mutations upregulating the trans-sulfuration pathway may find both changes intolerable. On the other hand someone who is low in dopamine and serotonin who is deficient in P5p may find it a remarkable thing.
In other words, if P5p is not the rate limiting step then adding more will not exacerbate the problems but could impact other reactions. Btw what most people miss on these forums is R5p (riboflavin 5 phosphate) is often the rate limiting step to making your own methylfolate from the methylene intermediate. Ironically everyone focuses on P5p due to its role in methionine synthase and emphasize supplementing 5mthf. But if your MTHFR gene is not defective with a C667 mutation then r5p is probably the rate limiting step and too much could flood your methylation cycle if you can process your folates from vegetables well enough.
Thanks for the list, Lotus, and greenshots. Methionine is a predominant methyl donor too. In an animal test, the researchers induced hypermethylation with large doses of methionine. Hypermethylation occurrs in cancer tumors.
Lately, I've felt like I just can't solve my own puzzle; so many things I take to reduce inflammation, seem to increase it.
( It's particularly frustrating when the research concludes that a substance is anti-inflammatory.)
At least I'm finding some more things that don't help. Some things will be reduced, some will need to be avoided.
Methione also increases SAMe levels. TMG and Betaine HCL (which functions the same as TMG which is sometimes called anhydrous betaine) also raise SAMe. Betaine HCL is used as a digestive enzyme so anyone taking those might want to check the ingredients in their digestive enzymes. As Rich said, TMG and SAMe can be useful for those with a shortage of methyl groups, but it seems for others there can be too much of a good thing.
Something about SAMe that I was wondering is that some people say that SAMe increases homocysteine, but my understanding is that it can also reduce it (?) TMG and methione are said to reduce homocysteine... I hope someone will weigh in on this subject because I have not seen this issue resolved in other threads discussing it.
Which supplements does she take? Is it all methylation type stuff or something else? This is great that it's helping so much.
Hi Lotus, Good ol' Dr. Weil thinks that SAMe probably won't increase homocysteine. At least, he thought this in '08.
Adb12, Mb12, Methylfolate, Multi B, and L-Carnitine Fumurate.
At one time she was taking A,D,E,C,K, Calcium, Mag, Zinc, Omega 3 and a few other things, but she mainly takes those 5 above now. If she "crashes" from skipping vitamins. I add in some of those basics for extra insurance on a quick recovery.
Basically Freddd's protocol gave her an amazing recovery in a few months time. She ran a triathalon in May 2011 after starting the protocol in Oct 2010. And she was bad off it 2010, depression, anxiety, fibromyalgia, flu 3 times a year, constant sinusitis and upper respiratory infections, year round zpac and steroids for infections, pnuemonia, sleep problems, TMJ, IBS, you name it. All of that was gone in a few months time. You can read through all of my early posts and get a pretty good idea of what "pushing through" was like.
I think I could titrate her to effect, and monitor potassium better knowing what I know now. But we are learning more and more all the time.
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