The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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3-Iodothyronamine ( T1AM ) administered to rodents induce a hypometabolic state

Discussion in 'Other Health News and Research' started by pattismith, Jan 22, 2018.

  1. pattismith

    pattismith Senior Member

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    Could T1AM induce peripheric thyroid resistance?

    Minireview: 3-Iodothyronamine (T1AM): a new player on the thyroid endocrine team?

    Scanlan TS1.
    2009
    Abstract

    3-Iodothyronamine (T(1)AM) is an endogenous compound with chemical features that are similar to thyroid hormone. T(1)AM has a carbon skeleton identical to that of T(4) and contains a single carbon-iodine bond. Theoretically, T(1)AM could be produced from T(4) by enzymatic decarboxylation and deiodination. Recent studies show that T(1)AM and higher iodinated thyronamines are subject to similar metabolic processing as iodothyronines such as T(4), suggesting a biological linkage between iodothyronines and iodothyronamines.

    In addition, single doses of T(1)AM administered to rodents induce a hypometabolic state that in certain ways resembles hibernation and is opposite to the effects of excess T(4).
    This review will discuss the latest developments on this recently discovered thyroid hormone derivative.

    Transport of thyroid hormones is selectively inhibited by 3-iodothyronamine

    2010
    Abstract
    Thyroid hormone transporters are responsible for the cellular uptake of thyroid hormones, which is a prerequisite for their subsequent metabolism and action at nuclear thyroid hormone receptors.

    A recently discovered thyroid hormone derivative, 3-iodothyronamine (T1AM), has distinct biological effects that are opposite those of thyroid hormone.
    Here we investigate the effects of T1AM on thyroid hormone transporters using COS-1 cells transfected with the multispecific organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 1C1, as well as the specific thyroid hormone transporters MCT8 and MCT10, and show that T1AM displays differential inhibition of T3 and T4 cellular uptake by these transporters.

    T1AM inhibits T3 and T4 transport by OATP1A2 with IC50 values of 0.27 and 2.1 µM, respectively.
    T4 transport by OATP1C1, which is thought to play a key role in thyroid hormone transport across the blood-brain barrier, is inhibited by T1AM with an IC50 of 4.8 µM.
    T1AM also inhibits both T3 and T4 uptake via MCT8, the most specific thyroid hormone transporter identified to date, with IC50 values of 95 and 31 µM, respectively. By contrast, T1AM has no effect on thyroid hormone transport by OATP1B3 and MCT10.
    Given that OATP1A2, OATP1C1, and MCT8 are all present in the brain, T1AM may play an important role in modulating thyroid hormone delivery and activity in specific target regions in the central nervous system.
     
    Last edited: Jan 22, 2018
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  2. pattismith

    pattismith Senior Member

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  3. pattismith

    pattismith Senior Member

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    Review ARTICLE (Only some extracts here)
    Front. Endocrinol., 31 May 2017
    Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut—From Gut to Brain?
    ...
    5. In Vitro Pharmacodynamics of T1AM

    ...
    With respect to the target profile of T1AM, α2 adrenoceptors are activated with a similar potency as noradrenaline. Neuronal membrane as well as vesicular transporters for dopamine and noradrenaline (45, 53) and all subtypes of muscarinic acetylcholine receptors (54) are functionally blocked in the micromolar or sub-micromolar range.

    Other role of Tironamines from a study quoted in the revue:
    Thyronamines inhibit plasma membrane and vesicular monoamine transport.
    Abstract
    Thyroid hormone has long been known to have important transcriptional regulatory activities. Recently, however, the presence of endogenous derivatives of thyroid hormone, thyronamines, has been reported in various mammalian tissues. These derivatives have potent in vitro activity with a class of orphan G-protein-coupled receptors, the trace amine-associated receptors, and profound in vivo effects when administered to mice.
    We report here a novel neuromodulatory role for thyronamines. In synaptosomal preparations and heterologous expression systems, thyronamines act as specific dopamine and norepinephrine reuptake inhibitors. Thyronamines also inhibit the transport of monoamines into synaptic vesicles. These observations expand the nontranscriptional role of thyroid hormone derivatives and may help to explain the pharmacological effects of thyronamines in vivo.

    7. T1AM is Claimed to be an “Endogenous” Derivative of Thyroid Hormone—But Where and How is it Made?


    7.3. T1AM Is Not Derived from Circulating Thyroxine

    7.4. Ornithine Decarboxylase—The Missing Link
    ...A breakthrough in the mysterious biological pathway regarding the formation of T1AM was that in addition to deiodinases such as DIO1, ODC is involved....

    The entire enzymatic activity necessary to produce T1AM from T4 was shown to exist in intestinal tissue of mice (74). The tissue contained the enzyme ornithine decarboxylase (ODC) that is capable of decarboxylating T4 and its deiodinated intermediates.

    7.5. Gut Microbiota, Cecotrophy, Coprophagy
    In a recent review article (16), it is proposed that for T1AM formation, T4 must enter the gut and may not be formed enzymatically elsewhere. This could indeed explain the high levels observed by some researchers in the rat liver. But this may not be the end of the story, especially considering additional important players: the gut microbiota (75). It is long known that deiodination and degradation of T4 and T3 by gut microbiota occur in the intestine of rodents (76). Moreover, when one partially decontaminates rats by feeding ampicillin, the metabolism of T4 and T3 is drastically changed (77). The intestinal wall contains ODC, but rodent gut microbes in the cecum and colon are another excellent source as Klebsiella, Pseudomonas, and E. coli (78) feature abundant constitutive and inducible (i.e., biodegradative) ODC. These enzymes appear to differ in some respect from the mammalian counterparts as the potent irreversible blocker difluoromethylornithine, currently in clinical cancer trials (79), inhibits ODCs of Pseudomonas aeruginosa but not those of Klebsiella pneumoniae and E. coli (80). Furthermore, there are enzymes in the gut microbiota of humans, and perhaps rodents, that are capable of decarboxylating aromatic amines (81). It is suggested to analyze T1AM in germ-free rats or axenic mice to refute the hypothesis about the role of gut bacteria.
    ...
     
    Last edited: Feb 5, 2018
  4. Iritu1021

    Iritu1021 Breaking Through The Fog

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    I just found your post - wow! I have actually independently arrived at the same connection around the same time you did! I actually got there by exploring trace amines and TAAR receptors. When I saw I could really connect it to my own mixed experience with various different form of thyroid. I actually have been trying to develop it into a more comprehensive theory on my blog: www.chronicfatiguediagnosis.com.
    I also sent it to Robert Naviaux who described the "dauer state" in his metabolomics study and he replied that it was interesting and promised to "add it to their list of targeted molecules" but not sure how seriously he took it. I'm so glad that there is someone else out there who is seeing the connection here!
     
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  5. nanonug

    nanonug Senior Member

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    Very interesting stuff. This might explain why so many people with SEID feel better when they nuke the gut bacteria with Xifaxan, for example. It also lends credence to the old idea by some that SEID starts in the gut - the internist that diagnosed me with CFS at the time held that belief. In my case, my SEID started following an episode of acute food poisoning and subsequent IBS-D that never went away.
     
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  6. Iritu1021

    Iritu1021 Breaking Through The Fog

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    I think there are at least two ways to get to SEID based on T1AM theory. I focused my case around viral etiology because I had what my CFS specialist called "The highest EBV IgM titer she has seen in her 20+ years of practice" but I never had much gut issues except for when I had POTS (which were clearly histamine related) but certainly gut bacteria production could be an alternative route to get the same problem. It's still very unclear how and where T1AM gets produced, it's very possible that just like with T3 some of it is produced within the thyroid and the rest comes from peripheral conversion. Maybe the sickest people have a double whammy, e.g. an an impairment in both routes of production...
     
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  7. pattismith

    pattismith Senior Member

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    :lol: yes it seems we traced back the same prey!

    I have already found your PR blog while I was digging that hole, so we have already met there:


    I have let T1AM alone for some time, as I felt we are lacking scientific investigations on it, but I am thrilled to read your blog and I'm glad to meet you here! :)
     
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  8. Iritu1021

    Iritu1021 Breaking Through The Fog

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    Great to meet you too, pattismith! :)

    The reason I liked T1AM theory so much that I felt compelled to write about it, is because I feel it really integrates everything we know about this disease so far without contradicting any other existing theory. It just ties it all together.

    My site is still work in progress, but the main reason I started it is because I believe that while the scientific evidence about T1AM is brand new, people have been actually unknowingly manipulating their T3/T1AM balance for a very long time but because it's such a fragile system (nanomolar concentrations make a huge difference) and because it requires faith into what you're doing, it's been hit and miss for most people, especially those with severe illness. There are people in various thyroid forums who without a doubt fit SEID picture - most of them with normal thyroid tests - and they have been able to fully recover just through using the right T3/T4 combinations, and others by using either lithium or iodine - and I believe that what is does is that is resets T1AM/T3 axis on genetic level that got thrown off. I'm pretty sure that this is how I got better.

    I've experimented with various thyroid hormones combinations relentlessly and I spent a fortune on out of pocket thyroid labs, to see how my symptoms and lab values correlated. If I could do it all over again I would certainly do it differently but I sort eventually "failed my way to success" and have been able to reset my deoidinases or some other metabolic process involved in this regulation. My baseline T3 level used to be 3.1 when I was ill, now it's set at 3.3 - and I gotta tell you, what a huge difference those two decimals make! (I'm actually now trying to reset it at 3.2). You can't get there through supplementation. I was taking huge doses of thyroid in the past, push my numbers through the roof, feel horrible, wake up in the morning, drag myself to the lab - and there it was, back at 3.1 again.

    If I could do it all over again, knowing what I know now, I would probably use tiny doses of T3 - like Kenneth Blanchard recommends and micro-doses of lithium orotate. It would be a much less painless way to get where I needed to get. But that was me, I think everyone is individual, some may need iodine instead of lithium, or for example sulfur to affect liver T4 metabolism, etc.

    That's what I'm trying to figure out right now and I will post on my blog when I have more insights.

    p.s. If anyone new to this thread wants to read please visit my blog at www.chronicfatiguediagnosis.com
     
  9. wastwater

    wastwater Senior Member

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    Dr Hyde mentions thyroid a lot
    I crudely used to think you can measure the severity of ME on the effect on the thyroid
    I’ve never had any POTS though but have hypothyroidism NOt otherwise specified on 75mcg levothyroxine
    It seems to get very slowly worse the hypothyroidism
    Interleukin 2 effects thyroid
     
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  10. Iritu1021

    Iritu1021 Breaking Through The Fog

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    T1AM opposes the action of the active thyroid within the cells. I used to think like most people that it was the T3 conversion that mattered but now I believe that it's actually the conversion or production of T1AM that these ratios were affecting by regulating my TSH levels and deoidinase enzymes. Hypothetically, if you presume that it's possible to have T1AM that's too low or too high, we have a number of possible states. Looking back retrospectively, I've experienced pretty much all of these states by changing T3/T4 ratios in my body or by indirectly altering my TSH synthesis through cortisol or norepinephrine.

    1. True T3 deficiency is compensated by the appropriate decrease in T1AM production = classical hypothyroidism

    2. True (T3) deficiency and low T1AM = presents as severe hypothyroidism but with more uncommon features of overstimulation, tachycardia and weight loss rather than depression and bradycardia, resembles the classic description of "adrenal fatigue" in hypothyroid patients

    3. Normal T3 levels and high T1AM = "functional hypothyroidism" (T3 is being over-opposed), typical ME/CFS with brain fog and fatigue

    4. Normal T3 and low T1AM = "functional hyperthyroidism", presents as hyperadrenergic POTS

    T1AM is converted to TA which regulates histamine production, and histamine via H3 receptors affects the level of all the other neurotransmitters in the brains. So once you add that to the equation, you end up with a whole plethora of other symptoms and variations.

    It's a whole big spectrum but with one underlying mechanism, and I also believe there must be some genetic predisposition that makes some people less capable of handling these swings.
     
  11. BadBadBear

    BadBadBear Senior Member

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    Wow, this thread is fascinating. I had needed 75 mcg T3 for the longest time, then starting treatment of EBV, have had to decrease my dose to approximately 50 mcg. I wonder if T1AM is causing this change? I had felt like some sort of cellular resistance was decreasing.

    I also have puzzled recently at why antihistamines like Benadryl seem to help so much with overstimulation (my Dr. thinks overstimulation is from thyroid changing). Even fractional doses make an impact.

    I feel like this theory might tie this all together, somehow.

    I know I have e,experienced cases 1, 2, 3, and 4 at times through this journey.
     
  12. pattismith

    pattismith Senior Member

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    Actually I started to dig into the T1AM when I received my Thyroid panel which is euthryroid:

    fT3 = 1.9 pg/ml (1.88 - 3.18) = 2.92 pmol/l (2.88 - 4.88)
    fT4 = 1.01 ng/dl (0.7 - 1.48 ) = 13 pmol/l (9.01 - 19.05)
    TSH = 0.97 µUI/ml (0.4 - 4)

    When I realised my T3 was so low, I tested rT3 which I received only a month later, it was very out of range high, with a very low fT3/rT3 ratio of 3.8!

    So I have the low T3 syndrome. I don't know if I already have this syndrome when my disease started 35 years ago, but it may be.

    And you are right about the T3 dose when you do a trial with it. I started a trial with it as soon as I received my panel and I found that only a tiny dose can help me. If I take 6.25 mcg in the morning, my symptoms are relieved one hour later and for 8 hours, then they are back.
    It doesn't work if I try to take another dose in the same day.
    it doesn't work if I increase the dose.(symptoms return)

    I don't get hyperthyroid symptoms when I increase T3, just a return to my usual symptoms..

    How would you say that lithium can modulate deiodinase?

    it seems that my D1 is underactive....

    Edit: from what I've read Lithium may impair D1, so it is really not what I need!

    http://www.psychiatrictimes.com/complex-interrelationship-lithium-and-thyroid

    "Lithium appears to impair the process of deiodination of T4 peripherally (deiodinase I) and within some cells (deiodinase III) (Terao et al., 1995). Eravci et al. (2000) found varying effects of lithium on different isoenzymes of deiodinase and noted that it appeared to enhance the activity of deiodinase II present in rat frontal lobes. This effect may contribute to alterations in cellular responsiveness to thyroxine."

    Edit-bis:

    in this article, it is hypothesized a potential "role of reverseTriiodothyronine (rT3) as an intermediate product of T1AM synthesis, as rT3 is the inactive deiodination product of T4 with no known physiological function"

    D1 is the deiodinase that recycle rT3, so in case D1 is involved in T1AM synthesis, it could explain why some patients are doing better with Lithium (which inhibits D1, so decrease T1AM).
     
    Last edited: Mar 7, 2018
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  13. Iritu1021

    Iritu1021 Breaking Through The Fog

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    @pattismith
    The effect of lithium on deiodinases appears to be dose-dependent: https://academic.oup.com/endo/article/141/3/1027/2988156

    We had a thread on lithium orotate here and it appears that taking standard (psychiatric doses) of lithium orotate had a different effect on people, either from "tired and wired" to "more calm", which probably had to do with their starting T3/T1AM balance point. At higher doses it lowers T4 to T3 conversion but at very low doses it may have a pure Dio2 enhancing effect. I don't yet really know what really low doses mean but based on my personal experience I would suggest starting <500 ug of lithium orotate or just adding a drop of liquid lithium to a glass of water and slowly increasing to tolerance. I suspect that a lot of people these days are lithium deficient because we lack lithium in our water. I think one day soon they will realize that it's an essential nutrient and will start adding it to water just like they started adding iodine to salt (https://www.nytimes.com/2014/09/14/opinion/sunday/should-we-all-take-a-bit-of-lithium.html). But when people with SEID go straight to 5 mg - which is the lowest dose you can buy - and what is essentially is "psychiatric dose" they get side effects and quit before they can achieve results on a genetic transcription level which takes at least a few weeks.

    My hunch right now is that D2/D3 imbalance is more likely to be the culprit. For some people the iodine might be the trick, which could be the reason why Dr. Brownstein and his mega-doses of iodine are so popular. Clearly, they exceed daily needs of our bodies but some people swear by the method. I would never risk trying that high of a dose personally. I can definitely feel jump in my thyroid production just from rubbing a drop of Lugol's iodine solution on my wrist.

    It is very hard to regulate T3 by taking supraphysiological doses (which is essentially what you are doing right now) because you get feedback TSH inhibition. I've been there and I sort of felt like I was "chasing my own tail" the whole time. You should read Kenneth Blanchard's book. He didn't know about T1AM method but he just stumbled on realized that people did much better when they were using T4 and tiny doses of compounded slow release T3 (as low as 0.1 mcg and maximum 1.5 mcg). When you take low doses like this with slow release you avoid getting "highs" that lower your own T3 production. The alternative is Wilson's method where you just keep raising doses until you completely take TSH out of equation by suppressing it and fully depend on exogenous T3 - however it is very "cowboyish" and requires being religious about the timing of the doses. Nevertheless, it definitely works for some people, and Wilson claims that after a few of those titration rounds most of his patients were able to eventually get off thyroid completely and still feel fine.
     
  14. Iritu1021

    Iritu1021 Breaking Through The Fog

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    @BadBadBear. Anti-histamines that cross blood brain barrier definitely work for anxiety/overstimulation for me when my brain histamine is high. Lately I've been taking tiny doses of beta-histine which is H3 receptor antagonist. I already wrote about it on my blog in this post (http://www.chronicfatiguediagnosis.com/2018/02/26/t1am-and-histamine-connection/) and also in "Histamine: The Song of Ice and Fire".

    I'm not going to repeat all of that here, but to make the long story short I think that in order to survive all the rollercoaster of T1AM imbalance, our brain auto-inhibitory pre-synaptic H3 receptors undergo major adaptation. The bad thing about H3 receptors is that they are constitutive receptors, e.g. they are constantly activated, even when nothing is acting on them.

    There are some people out there writing about "histamine intolerance" but I think that it is very easy to confuse "histamine intolerance" with "histamine sensitivity". The first one is true enzymatic deficiency in histamine metabolism which is probably pretty rare. The second is the price you pay every time you histamine levels spike (from food, allergen, stress, etc) after your body had to adopt to abnormal baseline levels of histamine.

    We need to keep in mind how nervous system regulates itself. If you have severe baseline deficiency of neurotransmitter, your cells will respond by increasing or decreasing the number of receptors. This by the way the same principle as to why SSRIs initially make people worse for the first week - the serotonin level has to drop before it rises.

    Lately, I've been experimenting with tiny doses of betahistine which is H3 antagonist and H1 agonist. With the very first dose I took, I could feel powerful change taking place in my brain perfusion. However, it also has too much stimulating effect on me, probably due to H1 agonist part of it and my receptors are so sensitive right now.

    There are also H2 receptors which appear to play a major role in brain function but are still poorly understood as they have yet to come up with something that can cross blood brain barrier and bind them. Overall, I still have a lot to learn on the brain histamine subject but it's very intriguing and promising.

    It's funny how doctors never believe us and miss on the opportunity. They'd rather fit us into their established worldview than believe us and try to connect the dose. It's also a hard disease to understand from the outside. There are so many different inner subtypes of "fatigue" or "anxiety" but they are hard to communicate to someone. To quote David Foster Wallace: "I'd tell you all you want and more, if the sounds I made could be what you hear..."
     
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  15. Learner1

    Learner1 Forum Support Assistant

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    Fascinating discussion! I have a few questions since you're building the "grand theory of everything";):

    1) How does MCAS play into this scenario?

    2) How does this interplay with the adrenergic and muscarinic antibodies many of us have, which may be behind at least some cases of POTS?

    3) What would a patient do who takes tiny doses of iodine, and who'd reduced high rT3 on T3 only for a couple years, added T4 back to highish, but equivalent doses of T3/T4 (50/137) and still has suppressed TSH and feels somewhat sluggish but can't go any higher with T3/T4 without hyper symptoms, but fT3/fT4 are mid range with this dosing? Where does one start with thisT1AM theory?

    Thank you for any answers here...
     
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  16. pattismith

    pattismith Senior Member

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    Low T3 syndrome is always stated in papers as a down regulation of D1, and I have two heterozygous polymorphism on the DIO1 gene that can lower my D1 activity.

    However, I do not exclude to have an upregulation of D3, as I found that organophosphates can do that, and I was exposed years ago.

    I also found here that "Diverse signals are able to regulate D3 expression in vitro and in vivo: retinoic acid, serum growth factors, estrogens and progesterone, TGFβ, Wnt-βcatenin, and Shh/Gli2 increase D3 levels, whereas glucocorticoid and growth hormone reduce D3 levels"

    I tryed lower level of T3, but couldn't see any effect under 6.25 mcg, however, I can only take one dose a day, with an effect 1h00 later and lasting for 8 hours, which is unexpected for this drug, so it may be caused by non nuclear TH receptors. My current view is that it could quickly modulate my ion channels and rescue my muscle and brain dysfuntion...
     
  17. Iritu1021

    Iritu1021 Breaking Through The Fog

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    How low did you try though? It sounds like you have both true hypothyroidism and T1AM dysfunction since you said you first developed CFS and years later hypothyroidism. In that case, low dose T3 would not be enough for you, you would need the appropriate dose of T4 topped off with a little T3 for T1AM balance (Blanchars's method). Did you start at low doses from scratch or back pedal from higher ones, did you use sustained release and were you taking T4 at the same time? And how low did you go? In my experience, once you are over 1 mcg, you are already entering the TSH suppression loop, so after that it doesn't really matter whether it's 3.25 or 6.25. I doubt that any doctor except for Blanchard out there (who is probably no longer practicing) would prescribe a dose of T3 under 1 mcg to you.

    My pharmakinetics with T3 were similar to yours - peak at 1 hr, start wearing off about 6 hrs later, and then I felt like crap. And when I tried to dose more frequently the come downs would get even worse. The timing of the dose seems to play a role too since TSH has a circadian rhythm.

    What I do know from my personal experience is that I was taking high doses of T3 and still feeling hypo. Then once I added lithium orotate, I had to immediately stop taking T3 because I felt like my thyroid levels suddenly shot through the roof. It happened very fast but then I used high doses - which is why I'm trying to warn people who are already on T3 to be careful when adding lithium. And you should make sure you don't have iodine deficiency before you do that.

    Taking high doses of lithium definitely made me feel hypothyroid while I was taking it but it seemed to have induced some genetic adaptive mechanisms to kick in and "over-wrote" my cellular settings. For years my TSH used to be around 1.2 -1.5, my T4 was 1.1-1.2, my T3 was set around 3.0-3.1 (not that all the values within the normal range). These days my TSH is 4.0 which technically meets criteria for subclinical hypothyroidism but I feel way LESS hypothyroid than I did when it was low. It started climbing up when I was on very low doses of slow release T3 (1 mcg or less) and then went up even more from lithium orotate - but so did my T4 and T3 levels! This is why when I read Blanchard's book I knew right away what he meant by the phenomenon of "TSH release" which as he writes in his book he observed in over 1000 of his patients.

    I think the current doses of lithium were invented for stabilizing neuronal membranes and rapidly suppressing T3 levels through Dio1 inhibition to treat acute mania. My issues, on other hand, were probably caused by lithium deficiency (I had very low lithium on my hair metal test). I believe what I needed was simply to restore my lithium levels back to normal. In psychiatry, they usually start manic patients on high dose lithium which helps with mania makes them very depressed and than they fix the depression by adding high dose T3.

    I agree with your quote that estrogen, progesterone, cortisol and retinoic acid big players in this regulation process. I definitely can relate my symptom fluctuation to my monthly cycle and therefore estrogen levels. Estrogen seems to make it worse. (I am actually kinda looking forward to menopause now!) Retinoic acid seems to play a big part too - but not beta-carotene, only active Vitamin A. Cortisol is a whole other thing... I know I had some link on that one but I can't remember it now, it will come back to me.

    As I mentioned earlier, I used to check my thyroid labs all the time and I kept track of my detailed symptoms on the day when I was get my blood drawn. I think that's what really helped me make sense of it all.

    I should also mention that I've been a "naturally skinny" person my whole life, then when I got sick I lost a lot of weight and muscle mass. But when I went on high doses of Armour, I paradoxically gained 20 lbs. Perhaps that could be because T1AM shifts metabolism from fat breakdown to fat storage. I normally have high byproducts of fatty acid metabolism on my functional medicine testing but when I was taking NDT or T3 they would go down. T1AM also affects glucose metabolism and protein breakdown. One of the things that I observed depending on thyroid hormone levels is the alteration in fat, carbs and protein cravings.
     
  18. Iritu1021

    Iritu1021 Breaking Through The Fog

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    The other thing that just came to my mind right now about histamine: I remember Teitelbaum writing in his book that tiny doses of doxepin (which is a tricyclic antidepressant) seem to be very helpful in many of his CFS patients. And at very low doses doxepin appears to be a pure H1 antagonist, not much different from Benedryl but probably with better access to CNS.
     
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  19. Iritu1021

    Iritu1021 Breaking Through The Fog

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    @Learner1 - all excellent questions!
    T1AM is converted to TA which has been shown to stimulate histamine production from mast cells that line neurons, which in turn seems to alter everything else. This is an excellent summary of how histamine affects and is affected by other neurotransmitters: https://www.ncbi.nlm.nih.gov/books/NBK27927/table/A1021/?report=objectonly.

    I also made an attempt to simplify and visually summarize this article on my website: http://www.chronicfatiguediagnosis.com/2018/02/28/histamine-regulation-by-various-neurotransmitters/

    Norepinephrine is now believed to function as a cofactor to T3 hormone. So when T1AM is off, T3 is off, which means NE is off, which means Ach must follow. Over time, everything is knocked out of balance.

    My T1AM theory is still very much "work in progress", I'm operating in the dark here based on observation and intuitive conclusions - which is why it would be nice to have more data points from people other than myself to create and test some kind of "operation manual"... It's too early for me to offer any specific advice, I can only provide general guidance based on my personal experience and correlations I made - but you could try looking into lithium as I explained above. Perhaps rT3 may is an indirect reflection of T1AM synthesis (especially given the fact that the theory about it blocking thyroid receptors seems to have been disproven). It's what we don't test for that matters here.

    Without knowing and accounting for T1AM levels, T3 and T4 values are pretty much meaningless when taken by themselves. There is probably no such thing as the right ratio, only the ratio that's right for you. So much of this is trial and error and learning self-titration, just like diabetics learn to regulate their insulin - but of course you can't properly titrate unless you know what you're titrating, and this knew knowledge about T1AM is bound to be a big game changer in how we approach this "thyroid game".

    On second thought, have you tried stopping iodine to see what happens (iodine can have suppressive effect on TSH if you have too much of it). In general, it seems like lithium and iodine have sort of an opposite effect on deiodinases.

    What I do now is that I have no desire to wait 10-15 years for the pharma industry to catch up to this and come up with some synthetic ligand that will probably end up being pulled off the market later on...
     
    Last edited: Mar 8, 2018
  20. pattismith

    pattismith Senior Member

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    Well, I never say such a thing, I always have been euthyroid with thyroid panels in the normal ranges.
    This is why it took me so much years to realize I had a peripheric TH conversion dysfunction, which I had confirmation when testing my rT3.

    Low T3 syndrome is actually an euthyroid sick syndrome, not a true classic hypothyroidism, and I think concepts mustn't be confused.
    I suppose this syndrome was present from the begining I was sick with CFS, which in my case was a progressive worsening illness that started at teenage.
    It seems to me it started with sexual hormons rising, which is consistent with D3 activation by Progesterone and Estrogene.

    Low T3 syndrome is linked to low T1AM in the study I read, however a low T1AM may be sufficient to block T3 in that case, because T3 is already very low.

    Knowing that T1AM has the ability to block T3, I think the fT3/T1AM ratio would be a better parameter to study.

    The lowest T3 dose I tryed was 3 mcg.

    (I tryed a little bit of T4 but couldn't tolerate it, either alone or with T3)
     
    Last edited: Mar 8, 2018

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