Metabolic Efficiency And Metabolic Rate - Doubt

[DaveFoster]

I had some first-hand experience with this during a high-dose caffeine period lasting about 3 months, along with occasional aspirin and supplements in DMSO. I think some other underlying issues may have contributed to bad feelings during this period, but the caffeine with a low intake of molybdenum and other methylation supporting supplements clearly had an effect. Adding in methylation support (300-600 micrograms molybdenum 3x/day, 5mg 2x/day lithium orotate, 1mg MTHF 3x/day, 16 mg Manganese/ 2x day) and magnesium has really stabilized mood. Lithium and manganese are taken at breakfast and dinner.

I also thinks its important to note that I never had any issues with caffeine previously. I have been restricting caffeine for the past several weeks but will gradually re-introduce it in the future. I suspect there will no longer be issues, but I will not be exceeding the amount of caffeine in a cup or coffee or two.

You ever wondered if it's just the lithium? Lithium is a mood-stabilizer, after all.

Also, maybe just avoiding sulfur-rich foods might be sufficient to attenuate the effects of DMSO, but I'm just surmising.

@haidut

I think you're right to support the studies showing serotonin inhibits lifespan due to another correlated piece:

Centenarians exhibit one universal trait: activity, particularly sociability.
SOURCE: U.S. centenarians have few regrets, stay active and social: poll

This appears again and again, and we constantly try to pin their lifespan on coffee, or nicotine, or alcohol, or a certain diet this way or another. At the end of the day, these people, such as the Ashkenazi Jews for example have close familial ties and communicate frequently within their family.

Nothing kills lifespan like social isolation/aggression. Queve every poet ever, most philosophers (looking at you, Nietzsche), and politicians.

 

[Peater Piper]

In any case, it just seems to work ..... and the side effects of even 30 gram a day doses are minor. The only hard thing to tolerate is the burn of having to stomach that much HCL, but again, side effects seem minimal, especially if doses are evenly spread out through the day.

That seems like a pretty big daily dose. Individual tablets are usually under a gram. Do you recommend getting a brand with or without Pepsin?

Is it worth getting a urine test for sulfites (or other labs that reveal methylation issues) or is it best to just experiment directly with Mo and Manganese for a few days to see if there's improvement? I have an appointment Tuesday and I'd like to get as much tested as I can that the doctor will agree to.

 

[tyw]

That seems like a pretty big daily dose. Individual tablets are usually under a gram. Do you recommend getting a brand with or without Pepsin?

Is it worth getting a urine test for sulfites (or other labs that reveal methylation issues) or is it best to just experiment directly with Mo and Manganese for a few days to see if there's improvement? I have an appointment Tuesday and I'd like to get as much tested as I can that the doctor will agree to.

Personally, I do not experience a difference between pepsin-containing or non-pepsin-containing Betaine HCL. 30 gram doses usually means just under 60 capsules a day of most over-the-counter supplements. This is the kind of dose that I've taken before to get rid of infections. At the longest, I've used such a dose for a month to clear up quite a serious infection (picked up during travel ).

IMO however, the active ingredient is the Betaine HCL, and addition of pepsin is not necessary, and is a potential risk factor is some individuals. eg: there are some potential contra-indications to esophageal damage with high dose Pepsin + NSAIDS (like aspirin) + pre-existing lower esophageal sphincter dysfunction.

I do not give recommendations for use of any of the compounds discussed.

----

@DaveFoster -- Lithium Orotate is probably the only form of lithium that is safely studied and effective in clinical practice. Again, appropriate dosing is important, and one will have to decide for themselves what is the appropriate amount.

Lithium is complementary to, but works on independent mechanisms to Molybdenum and Manganese. eg: Lithium has a direct role in brain dopamine homeostasis. Molybdenum and Manganese not as much. Lithium has lesser role in the hepatic methylation pathways, while molybdenum and manganese have a significant role.

.....

 

[haidut]

xanthine oxidase is something that I see a lot of. Lots of times people complain that they can't handle coffee or chocolate. Give them molybdenum and manganese, and suddenly all issues go away

Man, it's deja-vu all over again. Not sure if you know the forum user @gbolduev but he would give you a hug if he heard you say this. He is a big proponent of manganese, molybdenum, zinc, etc supplementation to balance the system and claimed the same thing - caffeine can deplete these minerals and make things worse, and the problem could be fixed easily with supplementing these. Search the forum for his posts. I always thought your reasoning reminded me of somebody here, and now I realize it is him. Not that there is anything wrong with two people saying the same thing :)
Btw, xanthine oxidase is overexpressed in stressful situations and contributes to iron toxicity in the liver. So, maybe not a bad thing if caffeine suppresses it.
Caffeine: A vitamin-like nutrient, or adaptogen. Questions about tea and coffee, cancer and other degenerative diseases, and the hormones.
"...Caffeine stops production of free radicals by inhibiting xanthine oxidase, an important factor in tissue stress. "

"...One of the ways in which uric acid functions as an “antioxidant” is by modifying the activity of the enzyme xanthine oxidase, which in stress can become a dangerous source of free radicals. Caffeine also restrains this enzyme. There are several other ways in which uric acid and caffeine (and a variety of intermediate xanthines) protect against oxidative damage. Coffee drinkers, for example, have been found to have lower levels of cadmium in their kidneys than people who don’t use coffee, and coffee is known to inhibit the absorption of iron by the intestine, helping to prevent iron overload."

 

[tyw]

@haidut, that comment from Peat does not make sense .....

Caffeine is a Methyl Xanthine . How is a xanthine itself going to "inhibit" an enzyme that is designed specifically to breakdown xanthines.

That's a circular argument -- Caffeine is xanthine => Xanthine oxidase causes stress => A xanthine like caffeine "keeps xanthine oxidase busy" => stress reduced??!!

Uric acid is produced by the action of xanthine oxidase on xanthines. If you want uric acid, then you need high xanthine oxidase activity.

And the claim that "xanthine oxidase causes stress" is too simplistic. Xanthine oxidase produces reactive oxygen species, and potentially reactive nitrogen species. But to do so, it must have a Xanthine to start with .... no xanthine (eg: caffeine), no xanthine oxidase activity, no resultant ROS.

It is clear that we have a feedback system here, wherein xanthine oxidase is a regulator of a system determining how much Xanthine is "allowed to be active" at any one time.

Are we going to say that Caffeine is "bad"? No. Context matters. Just like context matters in ROS production, which should be seen as a feedback signal to do something, and not as an inevitable stressor.

Sidenote: we see this sort of feedback everywhere in the body -- from ROS being required for release and conversion of Thyroid hormones, to ROS stopping excessive energy into cells, to ROS mediating a robust immune response in neutrophils. ROS is a signal that packs a punch, it should be regulated by the body according to what balance seems best.​

Now, unlike gbolduev, I do not view xanthine oxidase as a "depletor" of supporting transition metals and co-factors (if that is actually what they think). I thus do not see a point in supplementing more of these transition metals than is necessary to maintain balance.

More importantly, I am concerned with why an imbalance is present in the first place.

More Molydenum / manganese / etc .... is not a good thing. A balanced amount of such compounds that is needed to deal with incoming xanthines (and other methylation related pathways) is required, no more, and no less.

Of course, "balance" is a ridiculously difficult concept to pin down. Look at this one system (xanthine oxidase) alone, and you also have to touch the amazingly complicated Cytochrome P450 system, which is in turn regulated by and used for so many things that we cannot even begin to count .... PUFA handling, circadian clock priming, chelation of excess minerals, etc, etc ....

The only thing we have is practical experiment -- eg: Coffee and caffeine makes some people very jittery, have heart palpitations, feel cold, etc ... Caffeine is not a universal "metabolism booster", and requires a lot of upstream pre-processing steps to become effective.

If coffee works without these side effects in one person, then that's good.

If it doesn't work despite all the liver and metabolism support and what not, then there may be an issue handling caffeine, and if that issue is related to methylation, a simple experiment is to add said methylation support compounds, and see if the issue resolves itself.

If the issues resolve itself, it tells the person that their methylation systems are out of whack. This doesn't say anything about whether caffeine is good or bad, but it does say that caffeine is causing an even worse imbalance in that system. The consequence of this are going to depend on context, but we cannot put the blame on xanthine oxidase -- it is the entire system that is out of whack.

.....

 

[DaveFoster]

Personally, I do not experience a difference between pepsin-containing or non-pepsin-containing Betaine HCL. 30 gram doses usually means just under 60 capsules a day of most over-the-counter supplements. This is the kind of dose that I've taken before to get rid of infections. At the longest, I've used such a dose for a month to clear up quite a serious infection (picked up during travel ).

IMO however, the active ingredient is the Betaine HCL, and addition of pepsin is not necessary, and is a potential risk factor is some individuals. eg: there are some potential contra-indications to esophageal damage with high dose Pepsin + NSAIDS (like aspirin) + pre-existing lower esophageal sphincter dysfunction.

I do not give recommendations for use of any of the compounds discussed.

----

@DaveFoster -- Lithium Orotate is probably the only form of lithium that is safely studied and effective in clinical practice. Again, appropriate dosing is important, and one will have to decide for themselves what is the appropriate amount.

Lithium is complementary to, but works on independent mechanisms to Molybdenum and Manganese. eg: Lithium has a direct role in brain dopamine homeostasis. Molybdenum and Manganese not as much. Lithium has lesser role in the hepatic methylation pathways, while molybdenum and manganese have a significant role.

.....

Interesting; thanks for laying that out.

 

[haidut]

You ever wondered if it's just the lithium? Lithium is a mood-stabilizer, after all.

Also, maybe just avoiding sulfur-rich foods might be sufficient to attenuate the effects of DMSO, but I'm just surmising.

@haidut

I think you're right to support the studies showing serotonin inhibits lifespan due to another correlated piece:

Centenarians exhibit one universal trait: activity, particularly sociability.
SOURCE: U.S. centenarians have few regrets, stay active and social: poll

This appears again and again, and we constantly try to pin their lifespan on coffee, or nicotine, or alcohol, or a certain diet this way or another. At the end of the day, these people, such as the Ashkenazi Jews for example have close familial ties and communicate frequently within their family.

Nothing kills lifespan like social isolation/aggression. Queve every poet ever, most philosophers (looking at you, Nietzsche), and politicians.

Nice study, thanks. Do you know what is one biomarker of social isolation / stress - decreased levels of allopregnanolone in the brain. Lower levels of pregnenolone too, but that part does not seem as consistent. So, social isolation inhibits the steroid synthesis at the very top - the side cleavage enzyme. It is too early to tell if pregnenolone / progesterone / allopregnanolone administration can reverse the pathology caused by isolation or even replace the social ties. I am hoping that it can reverse effects of isolation but cannot replace the social ties. Otherwise, Big Pharma will start marketing "friend & family" pills soon...

 

[haidut]

@haidut, that comment from Peat does not make sense .....

Caffeine is a Methyl Xanthine . How is a xanthine itself going to "inhibit" an enzyme that is designed specifically to breakdown xanthines.

That's a circular argument -- Caffeine is xanthine => Xanthine oxidase causes stress => A xanthine like caffeine "keeps xanthine oxidase busy" => stress reduced??!!

Uric acid is produced by the action of xanthine oxidase on xanthines. If you want uric acid, then you need high xanthine oxidase activity.

And the claim that "xanthine oxidase causes stress" is too simplistic. Xanthine oxidase produces reactive oxygen species, and potentially reactive nitrogen species. But to do so, it must have a Xanthine to start with .... no xanthine (eg: caffeine), no xanthine oxidase activity, no resultant ROS.

View attachment 4001

It is clear that we have a feedback system here, wherein xanthine oxidase is a regulator of a system determining how much Xanthine is "allowed to be active" at any one time.

Are we going to say that Caffeine is "bad"? No. Context matters. Just like context matters in ROS production, which should be seen as a feedback signal to do something, and not as an inevitable stressor.

Sidenote: we see this sort of feedback everywhere in the body -- from ROS being required for release and conversion of Thyroid hormones, to ROS stopping excessive energy into cells, to ROS mediating a robust immune response in neutrophils. ROS is a signal that packs a punch, it should be regulated by the body according to what balance seems best.​

Now, unlike gbolduev, I do not view xanthine oxidase as a "depletor" of supporting transition metals and co-factors (if that is actually what they think). I thus do not see a point in supplementing more of these transition metals than is necessary to maintain balance.

More importantly, I am concerned with why an imbalance is present in the first place.

More Molydenum / manganese / etc .... is not a good thing. A balanced amount of such compounds that is needed to deal with incoming xanthines (and other methylation related pathways) is required, no more, and no less.

Of course, "balance" is a ridiculously difficult concept to pin down. Look at this one system (xanthine oxidase) alone, and you also have to touch the amazingly complicated Cytochrome P450 system, which is in turn regulated by and used for so many things that we cannot even begin to count .... PUFA handling, circadian clock priming, chelation of excess minerals, etc, etc ....

The only thing we have is practical experiment -- eg: Coffee and caffeine makes some people very jittery, have heart palpitations, feel cold, etc ... Caffeine is not a universal "metabolism booster", and requires a lot of upstream pre-processing steps to become effective.

If coffee works without these side effects in one person, then that's good.

If it doesn't work despite all the liver and metabolism support and what not, then there may be an issue handling caffeine, and if that issue is related to methylation, a simple experiment is to add said methylation support compounds, and see if the issue resolves itself.

If the issues resolve itself, it tells the person that their methylation systems are out of whack. This doesn't say anything about whether caffeine is good or bad, but it does say that caffeine is causing an even worse imbalance in that system. The consequence of this are going to depend on context, but we cannot put the blame on xanthine oxidase -- it is the entire system that is out of whack.

.....

See these links. It looks like caffeine is an inhibitor of XOD but relatively weak (uM or even mM concentrations).
Inhibition of Partially Purified Xanthine Oxidase Activity From Sera of Patients With Gout
Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxida... - PubMed - NCBI

"...Although caffeine is a weak inhibitor of XOD compared to allopurinol and especially sodium tungstate, it might affect the re-use of purines in myeloid cells (this system is quite robust in leukocytes and is not affected by allopurinol or tungastates, which are specific XOD inhibitors only – especially tungstates, where tungsten replaces molybdenum in the catalytic site of the enzyme causing its irreversible inhibition). Caffeine is known to inhibit HGPRT, however, in myeloid cells its inhibitory effects are more striking since it is not metabolised in these cells [25]. This means that, upon inhibition of XOD by caffeine, levels of hypoxanthine are increased. However, hypoxanthine can't be converted into IMP and further down to AMP [21] (for more details, see Supplementary Figure S2). This lack of increase in AMP levels prevents the activation of AMP kinase and subsequent phosphorylation of mTOR at T2446."

 

[AJC]

Standard dose would probably be, Molydenum 300-500mcg x 4 a day, and Manganese 10-20mg x 2 a day, both spread out as evenly as possible, and/or timed with intake of substances that will potentially increase demand for methylation pathways.

Pharmacokinetics are pretty fast with these compounds, which means that effects are seen quickly, and effects are lost quick. Acute dosing will usually demonstrate significant effects, to which one can use as a basis to see if these pathways are indeed compromised in a particular individual. I cannot make recommendations for chronic dosing.

Methyl xanthines are just one of the components that require these transition metals for handling. Some of the material that Koveras posted is useful in determining what else may benefit from this. Generally, any handling of sulfates tends to require such pathways, and this will generalise to foods like certain leafy greens, pork, shellfish, and anything that contains a lot of sulfur-containing amino acids.

.....

Sweetness, thanks.

 

[raypeatclips]

For regular consumption, potatoes apparently have up to 600 mcg molybdenum per 100g and mussels have up to 6.8mg manganese per 100g, according to various websites.

 

[moriwatzi]

Oral Molybdenum doses are effective at around 300-500 mcg. Personally, I would go with the higher range.

Interesting to note that the "symptoms of sulfite toxicity" quite closely resemble those of copper-toxicity. Molybdenum is used to reduce levels of copper in liver and kidneys via faecal excretion, opposed to Penicillamine which drives copper excretion via urine. The "reddening of the skin / hives" is a typical reaction to Molybdenum especially in the beginning of supplementation, I think it is caused by mobilisation of copper from storage. When using Mb urine ph should be monitored closely. It makes it highly acidic.

 

[papaya]

Best diet is that which causes you the least stress. Seeking a good diet is about "stress reduction", not "energy optimisation".

I do not care for optimising macronutrient ratios unless it is for specific athletic performance purposes.

In my experience, disease is almost always caused by some factor other than nutrition (with the exception of over- and under-nutrition).



Never touched any thyroid medications before. Never really did well with natural thyroid as well.

Supplements vary according to needs, though usually it is restricted to methylation support (Mo, Mn, Li, 5-MHTF), and then Pregnenolone and DHEA (oral). Only taken when needed, determined through my wooowooo TCM methodologies.

Occasional herbal remedies as needed in response to pathogens ... too many varieties to list here. As a generic anti-pathogen though, I always carry a lot of Betaine HCL in case of major infection.

.....

do you ever use iodine? what are your thoughts on nicotine gum/lozenges for add?

 

[tyw]

For regular consumption, potatoes apparently have up to 600 mcg molybdenum per 100g and mussels have up to 6.8mg manganese per 100g, according to various websites.

You will need to provide sources on that claim of Molybdenum in potatoes. All the sources I see never list potatoes as a significant source of molybdenum. Also, if potatoes did contain that much molybdenum, people would be dying of molybdenum overdose ....

USDA food database claims 3.4mg Manganese for 100g of Mussels -- Mollusks, mussel, blue, raw Nutrition Facts & Calories , either way, that's insufficient for therapeutic use.

do you ever use iodine? what are your thoughts on nicotine gum/lozenges for add?

Lugol's solution around only for water purification in case of contamination. But honestly, I never use it, and never need to use it.

I assume 'add' is a acronym for Attention Deficit Disorder. If so, then this is too complicated to answer. You can search this forum for my previous posts on nicotine to look at some of the mechanics, but any brain related disorder cannot be isolated to simple neurotransmitter analysis.

It is probably a good idea to avoid nicotine if possible, and if used, only in acute low doses (search around for what is the recommended dose).

Speaking of methylation, nicotine is so dependent on methylation and de-methylation pathways working well (those interested can lookup P450 mechanics), and then has so many downstream effects on local and global methylation .... It must be respected as a powerful substance that can imbalance the body, and experimentation must be handled with caution.

.....

 

[papaya]

You will need to provide sources on that claim of Molybdenum in potatoes. All the sources I see never list potatoes as a significant source of molybdenum. Also, if potatoes did contain that much molybdenum, people would be dying of molybdenum overdose ....

USDA food database claims 3.4mg Manganese for 100g of Mussels -- Mollusks, mussel, blue, raw Nutrition Facts & Calories , either way, that's insufficient for therapeutic use.



Lugol's solution around only for water purification in case of contamination. But honestly, I never use it, and never need to use it.

I assume 'add' is a acronym for Attention Deficit Disorder. If so, then this is too complicated to answer. You can search this forum for my previous posts on nicotine to look at some of the mechanics, but any brain related disorder cannot be isolated to simple neurotransmitter analysis.

The recommendation is however to avoid nicotine if possible, and if used, only in acute low doses (search around for what is the recommended dose).

Speaking of methylation, nicotine is so dependent on methylation and de-methylation pathways working well (those interested can lookup P450 mechanics), and then has so many downstream effects on local and global methylation .... It must be respected as a powerful substance that can imbalance the body, and experimentation must be handled with caution.
Ok, thanks, I def won't be trying nicotine. Does taking thyroid meds/ndt cause imbalances? I'm in the process of getting myself off them. Do you think that's a good or bad idea? Also, would u suggest I go to a tcm practitioner? I've always been interested in tcm. I always heard that a lot of Chinese herbs are filthy and have lots of pathogens tho.
.....

 

[raypeatclips]

You will need to provide sources on that claim of Molybdenum in potatoes. All the sources I see never list potatoes as a significant source of molybdenum. Also, if potatoes did contain that much molybdenum, people would be dying of molybdenum overdose ....

USDA food database claims 3.4mg Manganese for 100g of Mussels -- Mollusks, mussel, blue, raw Nutrition Facts & Calories , either way, that's insufficient for therapeutic use.

Cooked mussels on the same website list the amount I mentioned Mollusks, mussel, blue, cooked, moist heat Nutrition Facts & Calories

Yeah the potatoes amount was way off, I first saw it on this website: Food Data Chart - Molybdenum

 

[jaa]

...Molybdenum ...Manganese...

Which supplements do you use for these? I've been searching online and none look too appealing.

Anyone else find a good supplement source?

 

[haidut]

@charlie please delete this comment.

Not a bad idea. Let me see how many people will ask about bringing it back. If there is sufficient demand I'll put it back online. Obviously I'd prefer for it to be used rather then throw away a decent amount of high purity steroid, but we'll see how it goes.

 

[papaya]

Oh my, there is tons of research and some clinical trials as well. Big Pharma is currently trialing a few TPH inhibitors (and as such anti-serotonin) drugs for IBS and quickly found out that these people were also losing weight and getting "remission" from their diabetes. So, one of the TPH inhibitors is now in clinical trials for both obesity and diabetes. The research is not really new and was known even since cyproheptadine and ketanserin were synthesized that they can help diabetes. Look at the ketanserin Wiki page, it says it at the very top. Here are some other recent studies.
Serotonin as a New Therapeutic Target for Diabetes Mellitus and Obesity
Peripheral Serotonin: a New Player in Systemic Energy Homeostasis
Improved oral glucose tolerance following antiserotonin treatment in patients with chemical diabetes. - PubMed - NCBI
Improved oral glucose tolerance following antiserotonin treatment in patients with chemical diabetes

As far as I know, the TPH inhibitor trialed for obesity and diabetes is LX-1031 but cypro, ketanserin, lisuride, bromocriptine, metergoline, etc should all help and it is not a coincidence that bromocriptine is officially approved for diabetes II by the FDA - when used in lower doses it is primarily dopaminergic and anti-serotonergic.
Bromocriptine - Wikipedia

wow! so a person that has type 2 diabetes & is suspected of having parkinsons disease should definitely be using bromocriptine instead of metformin??? do you think that taking low dose bromocriptine would be a good idea if diabetes & parkinsons disease runs in your family?

 

[haidut]

wow! so a person that has type 2 diabetes & is suspected of having parkinsons disease should definitely be using bromocriptine instead of metformin??? do you think that taking low dose bromocriptine would be a good idea if diabetes & parkinsons disease runs in your family?

Well, I am not a doctor but bromocriptine certainly does not have potentially lethal lactic acidosis as a side effect (which metformin does). Also, the way metformin lowers blood sugar is not good, it prevents gluconeogenesis in the liver and simulates stress/starvation. Bromocriptine lowers FFA and imprpoves the actual oxidation of glucose, which is what you'd expect to see in a healthy person. Metformin is much like the statins - it tries to lower the "evil" glucose by any means necessary, which of course ends up backfiring really bad.

 

[papaya]

Well, I am not a doctor but bromocriptine certainly does not have potentially lethal lactic acidosis as a side effect (which metformin does). Also, the way metformin lowers blood sugar is not good, it prevents gluconeogenesis in the liver and simulates stress/starvation. Bromocriptine lowers FFA and imprpoves the actual oxidation of glucose, which is what you'd expect to see in a healthy person. Metformin is much like the statins - it tries to lower the "evil" glucose by any means necessary, which of course ends up backfiring really bad.

you may not be a dr, but you're a brilliant man! as always, thank you so much for the information!