Sam-E, Net Function, And More...

[Zap]

I've been up for a few hours now, and with all of the study information that has surfaced lately on NET function, I've been doing some in-depth reading. It is interesting to note that NET, in addition to its obvious effects on norepinephrine, also has effects on dopamine as well. Given its dependence on salt, this may at least partially explain why salt-loading has some positive effects.

One of the first things I came across that was of interest, is the fact that SAM-e (S-adenosyl-L-methionine) is a required co-factor in the synthesis of epinephrine from norepinephrine (one way it is metabolized via PNMT). SAM-e is also needed for biosynthesis of serotonin and dopamine.

I'm curious if anyone here has tried SAM-e and if it has had any effects, positive or negative. It isn't something I've ever tried, but there have been numerous studies done on it, and it seems to be at least as clinically effective as antidepressants, and is even a prescription drug in some countries.

Protein Kinase C (PKC), plays a role in NET as well. It may be of value to look into it further. Ruboxistaurin is an inhibitor, ingenol mebutate (from Milkweed) is an activator.

Rauwolfia is an herbal that is said to lower NE levels, though it also lowers serotonin levels as well. I'm not sure if it would be at all beneficial due to that fact, but for those with elevated NE it might be worth looking into further.

Reboxetine is a drug that is solely a NET inhibitor. Something I came across during my reading. I hadn't come across any drug that didn't also have a serotonin component before. Anyhow, the listed side effects are all things I experience on a regular basis!! (Insomnia, excessive sweating, vertigo/hypotension, dizziness, and limbs falling asleep.) It almost sounds like you could use this to produce the symptoms of dysautonomia in a healthy person.

MAO-A is one of the methods by which norepinephrine is degraded (as well as serotonin and dopamine). MAO-A is also involved in metabolism of tyramine. Functionality of this enzyme may explain the connections between tyramine rich foods and migraines.

It is also interesting to note that natural MAO-A inhibitors include Turmeric, Tobacco (Nicotine), Cat's Claw [(+)-catechin and (-)-epicatechin], Açai [(+)-catechin], and Kava (Desmethoxyyangonin, moderate affinity).

Well, I've exhausted my desire to read for now, but I've learned a number of interesting things.

[Chaos]

Interesting.

I've used Sam-E on and off for years. (Mostly "on"). Thought it was helpful. Recently my POTS doc has been weaning me off almost everything to see where I am at baseline as I've been put on so many different meds and supplements by so many different providers, so I stopped the Sam-E as well. Hard to say if I'm worse without it, because I've stopped so many things at once.

[Birdlady]

I took Sam-E at one time, but I was not doing very well at that time with various other issues, so I can't say either way what it did for me. I used it because I saw this study.

Effects of S-adenosyl-methionine on plasma norepinephrine, blood pressure, and heart rate in healthy volunteers.

http://www.ncbi.nlm..../pubmed/3961029

[issie]

Hmmmmm, recently added back tumeric and ginger and I am doing better.

Issie

[bellgirl]

Right now, I don't want to change a thing, but have always wondered about Sam-E, and took several supplements before being diagnosed. I'm still experimenting with frequency and combination of some of my supplements, but I am happy and a lot better, since I've added CoQ10, L-Carnitine, and lipoic acid to my regimen. I've also been on vitamin D, since the doctors found a deficiency at my request for blood work. I'm a firm believer in being our best advocate in all of this

[Zap]

Another late night of reading has given me a MUCH clearer picture than I had before. I think I should consider a career change, as this stuff is super fascinating to me. I'm starting to understand the different etiologies significantly more, as well as pharmacology in general, and why drugs, supplements, and herbs work so differently sometimes and similarly at others. I've really dug deep into NET function, both normal and abnormal, how this ties to genetics, and more.

The reason the same drugs work for subgroups of dysautonomia patients is that they do not closely modify the area in question causing the deficiency/excess. Instead they work much further down the chain to control the secondary symptoms, and so they are "effective" no matter what the root cause may be, as they express their function in a different set of chemical/enzymatic reactions or modulate the receptors directly, bypassing most/all of the underlying framework. However, THIS is exactly what causes side effects, because modulation (agonism/antagonism) of a said set of receptors, say 5-HT (serotonin), does not accomplish the same thing as the same effect on select receptors, say 5-HT1B, or even further down, on the metabolism of serotonin as a whole.

In short, COMT is fairly significant in NET function - it deactivates catecholamines (Dopamine, Norepinephrine) by giving them a methyl- group from SAM-e (and ties this function into the methyl cycle). Specifically, on the genetic side, one can have two types of COMT malfunction.

In those with the first form, there is reduced activity and so there is a surplus of methyl groups and dopamine. There are some benefits to this, but trade offs at the same time. Tyrosine rich foods and methyl donating supplements can be problematic in this type. (Turmeric, quercetin, tea, melatonin, SAM-e). Tryptophan rich foods are stressed instead.

The other type involves over-activity, and so there is a deficit of methyl groups and possibly dopamine as well. (Quercetin, tea, turmeric, ginkgo, SAM-e etc.) are beneficial as they provide more methyl groups to aid in the COMT process. Also, methylated B-12 (methylcobalamin)

Also pertinent in this process are the Vitamin D receptors. One (normal) state allows for higher dopamine levels and methyl donor availability. The abnormal state for Vit D results in Vit D NOT increasing dopamine production, so it will be low.

So there is a somewhat complex framework of webbing, that while not always the same, causes similar symptoms. Now if only I could actually find someone to work with that would be interested in helping to find and treat the root cause!

[issie]

Zap, we're looking into these functions and finding out which methylation process our bodies actually are and where the mutations are - with the genetic testing that we're doing through 23&me. You can convert some of your gene markers over and figure out which mutations you have in the pathways. I'm just learning about it and can't begin to explain it to you. But, there are others that do understand it and would be better at explaining.

One other person, whom I'm friends with, is also HyperPOTS - but, the two of us are soooo different in our genetics. I can use quercetin, turmeric and ginger and they make her sick. I'm supposed to get a certain type of b-12 or my body won't use it properly. l-arginine would give some energy and increase nitric oxide in some - but in me it converts into a free radical.

So, much to learn and I do believe delving into this - may give us some answers.

Issie

[Zap]

This is awesome! It sounds like you're probably looking for methylcobalamin, as those of us helped by turmeric/ginger, are likely overactive in the COMT pathway and deficient in methyl donors.

I'd love to get the genetic testing, but money is tight with my situation right now. That said, given some of the correlations out there, I think I can reverse engineer things until I can confirm them for sure. Then I can try similar therapies.

Given my success with turmeric/ginger, I believe that I have the overactive COMT pathway, which becomes deficient in methyl groups. Also given my recent doctor problems, I'm thinking that I might even be able to replace the bandaid meds currently being taken by supplements to aid in balancing the methyl cycle problems.

Let's take them set-by-set:

~~~~"Anti-Depressants"~~~~

Pamelor: Works as an inverse agonist or antagonist in multiple processes (decrease), including NET. If the migraines are triggered due to dopamine/NE problems, this slows the over-active COMT pathway, stopping depletion of methyl groups needed for other biological processes (including dopamine synthesis).

Escitalopram: SSRI. May be reducing pain/bowel issues somewhat. Moderate to no migraine effect. At best was helping curb the anxiety caused by chronic migraine and life instability.

----both replaced by:----

SAM-e: Works as a methyl donor in the COMT pathway, removing the bottleneck and allowing for dopamine synthesis, or other processes to continue unhindered, despite the over-active COMT process. May have as good or better migraine prophylaxis, as well as a balancing effect on neurotransmitters, which will also improve mood, well being, and possibly sleep.

~~~~Beta Blockade (presently trialing herbs, no doctor has actually tried meds yet)~~~~

Propranolol: Non-selective beta blocker, may be effective for migraine prophylaxis, reduction of sweating, balancing overactive adrenal response, and reversing the effects of PTSD.

----replaced by:----

Eucommia: Herbal non-selective beta blocker, from other reports has reduced side-effects possibly due to being more of a pure beta blocker, possibly not crossing the BBB. Will help with overactive adrenals, sweating, overall hyperadrenergic state and PTSD reversal.

~~~~MAO-I~~~~

May have other beneficial effects in the case of overactive COMT. Stop the rapid destruction of neurotransmitters like some anti-depressants, some also work as anxiolytics.

Turmeric/Ginger/Black Pepper - MAO inhibition

Passion Flower - MAO inhibition

Syrian Rue - affects both MAO pathways in larger doses, may also affect Nitric Oxide pathway

~~~~Other herbals, may be of use/benefit~~~~

Rhodiola rosea - anti-depressant like effects

Skullcap - Nitric Oxide inhibitor, inhibits histamine and leukotriene release

Wild-Lettuce - Anxiolytic

This just keeps getting more and more interesting!

[Birdlady]

I think I'm the person issie is referring to! haha I have 2 COMT mutations (V158M and H62H) and I also have a common synonmous MAOA mutation (R297R), but I thought Issie would have them too and she does not! All of this is so very complex where one thing cancels another thing out and then there's the concept of epigenetics too. There are many other COMT and MAOA mutations I do not have that are far more damaging to the function of those enzymes.

Zap I see from your signature you are researching this aspect, so feel free to get a hold of me. I'm fascinated by it too.

[ramakentesh]

I've been up for a few hours now, and with all of the study information that has surfaced lately on NET function, I've been doing some in-depth reading. It is interesting to note that NET, in addition to its obvious effects on norepinephrine, also has effects on dopamine as well. Given its dependence on salt, this may at least partially explain why salt-loading has some positive effects.

Very true, perhaps peripheral dopamine can account for the blood volume problems via activation of d1 kidney receptors and increased salt extraction. Cvertainly possible. Kidney Dopamine is being investigated.

In NET deficiency or inhibition you can have peripheral increases in NE effects but NE in the brain where alpha 2 receptors dominate results in decreases in sympathetic outflow - that is NE In the brain activates alpha 2 receptors and reduces sympathetic outflow while also causing peripheral vasoconstriction and tachycardia. Complex...

Several herbal remedies have recently been found to activate NET activity but whether they work in circumstances where there is either a mutation or a epigenetic mechanism that supresses the protein via gene supression seems unlikely.

Some level NE is required to maintain blood pressure. problem is in NET inhition its impaired and you can have BOTH increased and reduced effects in a confusing result. if you up NE it might help with dizziness, but could worsen it via activation of alpha 2 central receptors if its a centrally acting medication, etc. Conversely reducing sympathetic activity peripherally might help less than centrally maybe?

[issie]

Hey Dana, yup, you're the one. Zap, Dana is a wiz when it comes to this stuff and maybe the two of you will be able to put your heads together and come up with some ideas. But, I hope you do it publicly, so we can all benefit.

Just a word of caution on the Sam'e. There are warnings for any who are bipolar or may tend to have manic swings. It can make that worse. So, Sam'e will not be something for everyone.

You mentioned Passion Flower. It is too strong for me. But, I've found Lemon Balm to be of benefit - it is milder and seems to work the same. Some of us are so sensitive to things.

And to throw another monkeywrench into things. I need to up my nitric oxide, not decrease it. As Rama, mentioned - some of us are too vasoconstricted and NO dilates us. But, there is a fine line between how much to dilate and how much to constrict. Too much dilation increases pooling and causes edema.

And as for meds. Clonidine really helps to suppress sympathetic expression - but, is a vasodilator - and did contribute to more edema. I was also more dizzy with it. (But, it sure was nice to have the wild swings - leveled out. It also made my blood pressure more normal without drastic swings in it.) I'm off of it at the moment - trying to get the edema down.

Yes, this subject is ONE of the things I'm concentrating on at the moment. Very interesting. Keep those brain storms coming.

Issie

[Zap]

Well, just thought I'd update this thread. I took 200mg SAM-e last night (enteric coated by Jarrow). After a while, I definitely felt different, more balanced than anything else has done in a while. Got a bit melancholy later on in the evening (after taking my PM dose of Escitalopram). Not sure if there is a cross-reaction or if it was just situational with last night.

I'll be continuing the SAM-e for a few days to better characterize its effects, but I think it has the potential to be something that eventually is part of and/or replaces other parts of my treatment.

I've been off the Eucommia for a bit, and will eventually add it back after I can characterize the SAM-e separate from it. Regardless, I'm hopeful that it may be a new answer. I'm also planning to reduce to one D3 per day, as I've been supplementing for a while to boost the low levels. If I don't notice any side effects from dropping to one per day, I'll stick with it.

[ramakentesh]

Interesting read.

[Angela]

so i saw my neuro and once again declined clono. starting wellbutrine low dose and we will see how it fares. one thing I am positive about is the dopamine factor, but i am a little sketch with on the serotonin part.

[Chaos]

After being off Sam-E for awhile, I tried going back on it but definitely noticed a big increase in "excess sympathetic drive" type symptoms. Will be curious to see how your trial goes Zap.

[Zap]

Well, that was a while back now - I was never able to tolerate the SAM-e, but that was when I was on a whole slew of meds compared to where I am now. I have considered giving it another go now that there aren't tons of neurotransmitter altering things floating about in the bloodstream. I know I feel much more myself, but given the need for dopamine and methyl donors, I would think SAM-e would be the ticket.

Still could be wrong, though.... but I now have genetic information available to me that I didn't before too, and I have fast acting enzymatic action that breaks down neurotransmitters, so having more building blocks should theoretically be a good thing.

Considering that I'm having sympathetic fallout lately (OH, dizziness, etc.) maybe it would balance me.

I wanted to give Wellbutrin a go, just for the fact that it doesn't modulate serotonin. Some of the theories I've been reading lately state that there may be excessive amounts, rather than deficiencies, of the neurotransmitters at work.