INOSINE antinociceptive, antidepressant, anti neurogenic detrusor overactivity

[pattismith]

I remember I had a hard time interpreting that study because in discussion their conclusion was that dipyridamole potentiated the effect or inosine but their findings seem to imply the opposite.

To my recollection, Goldstein doesn't mention inosine anywhere but he did list dipyridamole as a drug he had good success with in his patient population.

It would be interesting to know why Goldstein was not interested in inosine, while many other CFS/ME doctors seem to use it a lot.

Inosine has different effects:

-binding to adenosine receptors outside the cell
-activities inside the cell
-catabolism inside the cell, leading to urate production via xanthine oxidase




Modulation of Inosine activity could be done
-either by adding a xanthine oxidase inhibitor (Allopurinol, or a more natural one for example Quercitin) in order to reduce the Urate production
-either by taking Dipirydamole in order to increase the effect on adenosine receptors and reduce the urate production.

Inosine is doing a great job for me (on pain and mood disorders) by binding to adenosine receptors, but I feel concerned that it may increase too much my blood urate, so I think about exploring these two possibilities.

Thank you for bringing it to me!

 

[Iritu1021]

It would be interesting to know why Goldstein was not interested in inosine, while many other CFS/ME doctors seem to use it a lot.

Inosine has different effects:

-binding to adenosine receptors outside the cell
-activities inside the cell
-catabolism inside the cell, leading to urate production via xanthine oxidase




Modulation of Inosine activity could be done
-either by adding a xanthine oxidase inhibitor (Allopurinol, or a more natural one for example Quercitin) in order to reduce the Urate production
-either by taking Dipirydamole in order to increase the effect on adenosine receptors and reduce the urate production.

Inosine is doing a great job for me (on pain and mood disorders) by binding to adenosine receptors, but I feel concerned that it may increase too much my blood urate, so I think about exploring these two possibilities.

Thank you for bringing it to me!

Good! I'm glad to hear its helping. You have to remember that Goldstein wrote his books a very long time ago. Most supplements were still pretty unknown back then.

I don't know if you have Goldstein's book or his algorithm. My copy is falling apart into separate pages now from being opened so many times over the years, I need to figure out where I can get it bound (this book holds a sentimental value for me).

His algorithm basically went in this order:


ALPHA 2 RECEPTORS (profiled with naphazoline eye drops, may be able to buy in the pharmacy)

Starting with alpha-2 receptors agonist or antagonist based on response to naphazoline eye drops.

BETTER: clonidine, gunfacine (Intuniv), midodrine, reboxetine

WORSE: Buspirone, mirtazapine (my note: I would add mianserin too; low doses of mianserine and mirtazapine are more sedating than high doses due to H1 effect)


TRH (this is hard to get; there is Abaris which is sublingual TRH but I don't know if it works the same way.

Response to TRH drops which IMO could be "estimated in reverse" by T3 causing TRH suppression. Some people use TSH suppression protocols for T3 but I actually feel really bad if my TSH is suppressed. If people were feeling worse with TRH spray, for Goldstein it was a predictor they would do well with adenosine.

You were able to tolerate T3 (TRH suppression) much better than I could so it makes sense that you respond to adenosine. I seem to need a decent level of TRH to function well and I think adenosine (based on my Cordyceps response) generally makes me worse.

BETTER WITH TRH: DHEA, Aricept, cycloserine, modafinil, Talwin, dopamine

WORSE WITH TRH: gotu kola, dipyridamole, baclofen, taurine, gabapentin and benzos.

DOPAMINE (profiled with dopamine drops but might be able to interpolate from other agensts, like Ritalin):

BETTER: Forskolin, naltrexone, THC, testosterone, oxytocin, reboxetine, selegiline, ropinirole, oxytocin, hydergine, amantadine

WORSE: mestinon, nimotop, piracetam, risperidal, Ativan, verapamil

ADENOSINE DROPS

Better: adenosine, ascorbate, Buspar, EFAs, guafenesin, heparin, L-lysine, lidocaine, progesterone, Topamax, Nimotop, gabapentin, mecamylamine (note that he lists L-lysine and lysine separately)

Worse: cycloseine, DHEA, pregnenolone, taurine, testosterone, lamotrigine, piracetam, tramadol

At this point he tests ketamine, lidocaine, amantadine and gabapentin) and algorithm becomes somewhat useless as it basically jumps between the same two columns full of meds until he comes back with specific NDMA drugs:

NDMA RECEPTOR (judged by the response to guafenesin topical gel)

BETTER: diltiazem, Nimotop, Zofran
WORSE: cycloserine, high dose glycine/serine.

My only residual issue right now is sort of general lassitude (not the same as fatigue) and lack of motivation - which could be because I didn't address alpha2 adrenergic receptors and I don't have enough NE. Or it could be because my TRH is still too suppressed which again would result in low catecholamines. Or maybe I need to get my hands on some cycloserine to bump up my NDMA function (I couldn't find it but ordered some sarcosine yesterday which is used for the same purposes).

On the bright side, all my pain, dysautonomia and mood problems are pretty much resolved and I can tolerate most drugs and supplements without any problem.

 

[Iritu1021]

By the way he thought Lysine blocked NMDA in amygdala. This correlates with my experience when I was extremely overstimulated back in the early days of my illness and I took one pill of lysine and felt immediate calm which I haven't felt in months - it was a stronger effect than from benzos.

I'm pretty sure that back then I was having glutamate excitotoxicity and high intracellular calcium. Later on, I didn't have that effect anymore - so it's one of those things that only works when there is a serious excess.

I'm pretty much in the opposite side right now with all my settings compared to how I felt back then: never thought I'd say that but I feel too calm. But now it's just going to take patience and some minor tweaking and trying not to take any steps in the wrong direction but I feel like I'm 80% there. But at this point I feel certain that it is definitely possible to neurohack your way out of this!

 

[pattismith]

By the way he thought Lysine blocked NMDA in amygdala. This correlates with my experience when I was extremely overstimulated back in the early days of my illness and I took one pill of lysine and felt immediate calm which I haven't felt in months - it was a stronger effect than from benzos.

I'm pretty sure that back then I was having glutamate excitotoxicity and high intracellular calcium. Later on, I didn't have that effect anymore - so it's one of those things that only works when there is a serious excess.

I'm pretty much in the opposite side right now with all my settings compared to how I felt back then: never thought I'd say that but I feel too calm. But now it's just going to take patience and some minor tweaking and trying not to take any steps in the wrong direction but I feel like I'm 80% there. But at this point I feel certain that it is definitely possible to neurohack your way out of this!

I agree, I have so much improved during these last two years of experimentation.

I am still amazed that I can have some days where I feel 'normal". Thinking about it gives me strength to keep going when I am low and depressed.


Inosine is very potent, but has a bad side: by increasing blood urate level, it may induce gout arthritis.
this may be the reason why Goldstein prefers Dipyridamole, that increases blood adenosine and inosine, without increasing blood urate.

 

[Iritu1021]

I agree, I have so much improved during these last two years of experimentation.

I am still amazed that I can have some days where I feel 'normal". Thinking about it gives me strength to keep going when I am low and depressed.


Inosine is very potent, but has a bad side: by increasing blood urate level, it may induce gout arthritis.
this may be the reason why Goldstein prefers Dipyridamole, that increases blood adenosine and inosine, without increasing blood urate.

You're not going to found a drug that's entirely free of potential side effects but may be you can get away with less potency by using something more natural like C-4 strain of Cordyceps.

Caffeine is adenosine antagonist - do you feel like caffeine offsets the effect of inosine?

Did you get energy increase from inosine or just improvement in pain and better move?

 

[pattismith]

You're not going to found a drug that's entirely free of potential side effects but may be you can get away with less potency by using something more natural like C-4 strain of Cordyceps.

Caffeine is adenosine antagonist - do you feel like caffeine offsets the effect of inosine?

Did you get energy increase from inosine or just improvement in pain and better move?

inosine relieves almost all of my pains (100% of my neuropathic pains, 60% of my tendinitis pain and joints pain).
It releaves also my bad mood but I need to take the higher dosage three times a day to really notice it's effects.
It increases my energy up to a normal level and the action is rather quick (about an hour after intake)

It's interesting that caffeine is an adenosine receptor antagonist, because Caffeine works for me only if I take it with T3 and only if I don't take them every day....

I am currently investigating the relationship between thyroid and adenosine to understand the underlying process;

I received today my blood urate dosage: I am higher than the maximum level, so I am now doing a trial with Dipyridamole (maybe alone or associated to a lower dose of Inosine).

edit: it's also interesting to notice that since I started Inosine, I can now tolerate Doxycycline without any side effect, which seems increadible to me!)

 

[Iritu1021]

I lowered my T4 dose slightly and added forskolin and I got a nice burst of neurotransmitters from the upswing of TRH. This morning I felt great! I haven't felt this good in a very long time.

I think the root cause of our thyroid problem comes from PVN (paraventricular nucleus of hypothalamus) malfunction. It has adenosine receptors and 5HT and NE receptors and it also appears to be regulated (according to Goldstein).

Adenosine inhibits paraventricular pre-sympathetic neurons through ATP-dependent potassium channels.
https://www.ncbi.nlm.nih.gov/pubmed/20096091

So I think his algorithm is an attempt to restore hypothalamic settings of TRH/CRH back to normal. But I doubt he fully understood what he was doing, he was largely operating based on the impressive intuition that enabled him to distinguish certain recurrent patterns - but since he didn't have the subjective experience of the patient he probably didn't see the full picture.

Even if he understood what he was doing, he wasn't good in articulating it well neither in person nor in his book. He was able to achieve full recoveries in the office but since the patients didn't know what they were doing they probably would often lose the effect over time (like diabetics who got treated for diabetic coma in the hospital but got sent home without blood sugar training or glucometer).

Based on my current knowledge, I think his algorithm can be simplified and interpreted as such:

1) Modulate catecholamine levels to either boost or lower both CRH/TRH

2) Modulate GABA neurons in the hippocampus

3) Modulate dopamine receptors

4) Modulate adenosine receptors

5) Modulate NMDA receptors

6) Regulate sodium channels

7) Regulate calcium channels

8) Modulate glycine site on NMDA receptor

And according to his algorithm there is some sort of reciprocal response between GABA and NMDA that happens at the level of adenosine receptors.

p.s. I feel like I'm trying to interpret an old treasure map!

 

[pattismith]

p.s. I feel like I'm trying to interpret an old treasure map!

Exactely how I look at Goldstein. His experiments with patients are fascinating, but I am not able to understand it!

What product do you use for Forskohlin? I consider it to boost my adenyl cyclase.

 

[Iritu1021]

Exactely how I look at Goldstein. His experiments with patients are fascinating, but I am not able to understand it!

What product do you use for Forskohlin? I consider it to boost my adenyl cyclase.

I use Naturewise Forskolin + but I consider switching because it has chromium in it which compounds the effect on HPA. Forskolin is certainly one drug that comes up a lot in Goldstein's book. He recommended 10-20 mg of pure extract. If I take one pill of mine I get about 25 mg. However, I am pretty sure that with prolonged use forskolin can lower cAMP because the body tends to adopt in the direction opposite of where it will be pushed and in fact studies show that chronic forskolin use induces behavioral hypoactivity in animals.

So forskolin is something I will use for occasional boost but not regularly. Lithium on other hand is still the biggest game changer for me - but because I was able to weather the initial side effects from it and reset my homeostat in the right direction.

Lithium on other hand increases cAMP with prolonged use, however with acute use it lowers it. There are a lot of people who read it as "lithium making them hypo" and conclude that they should never take it again. In reality what they feel is a transient dip in cAMP levels. So combining lithium with forskolin for the first week or two is a potential option to ease the person into lithium if they can't handle the initial decrease in cAMP.

I know I've said this before but I will keep on repeating this because it's so crucial: I am convinced that the main reason people aren't able to neurohack themselves out of their CFS or dysautonomia is because they judge their drugs by the immediate effects. I used to do that too and I couldn't get anywhere until I had a change in attitude about that.

Nobody in psychiatry would judge a drug by the immediate effect (unless the side effects are unbearable, then it will be discontinued). You're given a prescription, warned that it might make you feel worse at first and told to come back in 4 weeks for follow up - because that's how long it takes for chronic adaptation to take place. The same is probably also true for most adaptogenic herbs.

Psychiatrists who treat bipolar patients even have a saying: "if you prescribe a drug and the patient calls you next day and says they feel great already, discontinue the drug immediately". That's because they know that this is not the true effect and that the drug will only mess them up in the long run.

Prescribing drugs based on immediate reaction is the mistake that Goldstein was making and that's the mistake that most people on this forum are making over and over. Everybody eventually finds something that makes them feel great for a few days or weeks - and then they are back to where they were and they can't understand why this keeps happening. While it's good to have drugs for immediate relief, they do not lead to long-term improvement because receptors will adapt and tolerance will develop. The long-term solution is to find the drug that results in favorable adaptation with chronic use, not with acute use.

The drugs that provide immediate positive effects should only be used occasionally or short-term with breaks in between (known in nootropic circles as "cycling"). I'm taking forskolin right now because I need an extra boost in my TRH while I'm adjusting my thyroid dose but I will probably not use it for more than a week. Lithium orotate on other hand is something I plan on taking indefinitely.

 

[pattismith]

Nobody in psychiatry would judge a drug by the immediate effect (unless the side effects are unbearable, then it will be discontinued). You're given a prescription, warned that it might make you feel worse at first and told to come back in 4 weeks for follow up - because that's how long it takes for chronic adaptation to take place. The same is probably also true for most adaptogenic herbs.

I agree, even caffeine has different short term and long term effects, and I also noticed that the drugs that gives me a boost don't work if I take it every day (mostly cortisone, T3 + caffeine). Inosine seems more promising but acid uric is a limiting factor to it's use.


on the other hand, I need a very quick relief, because it's an acute problem for me to be able to keep my life on tracks, I don't have any other choice.

All the meds I was proposed put me in a state where I couldn't make it, so I had to give up.

Maybe Lithium is worth a try, i don't know... my HPT is still going down, I really don't know what to do to relieve the hypersensitivity of my HP to the T3 negative feedback...

 

[Iritu1021]

@pattismith

I have now come to realization that the way I react to T3 has nothing to do with T3 and everything to do with the suppression of TRH.

I think we have central hypothyroidism which may be a protective mechanism against glutamate (and/or serotonin) toxicity. TRH is a very potent neuromodulator that regulates practically every other neurotransmitter. So when we react immediately to T3 what we really react to is the change in one or more of the neurotransmitters that's regulated by TRH. The same for cortisol and CRH.

ACTH and TSH might not be accurate representations of CRH and TRH because they might have uncoupled or become desensitized to these hormones due to too much fluctuation. Maybe this is part of what Blanchard was doing with slow release micro T3 - helping to maintain TRH and CRH secretion in a steady state to prevent the T3 induced "up and down" phenomenon that he observed. He admits in the book that he did not really understand the science of what he was doing (he was an astute endocrinologist but not a neuroendocrinologist). He also observed that the right timing of T3 and T4 was important due to circadian rhythm (again likely related to CRH and TRH secretion).

Therefore, we need to change our thinking from end-organ hormonal effects to hypothalamic hormones and how they affect neurotransmitters.

When I went off T3 cold turkey I had "stiff person syndrome" (extremely painful) which has been linked to antibodies to GAD (glutamine decarboxylase which converts glutamine to GABA) and when I was on too much T3 I had myasthenia gravis symptoms similar to what Gingergirrl had and in her case it also seemed to be related to anti-GAD antibodies. I think these states in me where caused by severe glutamate/GABA imbalance due to rapid TRH fluctuation (while in autoimmune cases it might be a permanent activation or blockade based on the type of antibody). In my case, there seems to be bipolarity between the two states that's very much amplified by hormones.

I have now learned my lesson that the metabolic rate can only be as fast as your nervous system will permit. Both selenomethionine and lithium orotate stabilize glutamate (which affects intracellular calcium) and both of those supplements increased my T4 to T3 conversion. The same thing happened with atomoxetine which is NMDA antagonist. I definitely see a pattern there.

If your TRH (and glutamate/NMDA receptor activity) is too low right now then the reason you might be responding to adenosine could be due to this:

ADP is the strongest adenine nucleotide activator of glutaminase. Studies have also suggested ADP lowered the K(m) for glutamine and increased the V(max). They found that these effects were increased even more when ATP was present.

If you want my advice @pattismith I would say try to find a stabilizing drug that can lessen the fluctuations in your neurotransmitters. It might be lithium, or gabapentin, maybe lamotrigine. They might lower your glutamate too much initially (or create other temporary imbalance) but the receptors should adjust after a week or two on the right dose.

If you want to keep on using T3 than consider switching to slow release form and keep the level as steady as possible to avoid TRH fluctuations. Try to find your TRH comfort zone (which might have a very narrow therapeutic range). And be prepared to adjust the dose if you go on lithium. I'm not sure why lithium increases my thyroid production so much - it could be due to an autonomous nodule in my thyroid gland but most likely it's due to changing pituitary sensitivity to TRH.

I remember you mentioned a strong emotional response to pregabalin that scared you off - that might have been actually a positive response on neurotransmission but too much of a dose that "jolted" your limbic system out of sleep, so to speak. Gabapentin is a weaker drug than pregabalin that comes in much lower doses so you might want to give it a chance. I have noticed this in myself and heard from others who got better - it seems common to have a spike in CRH that results in melancholy depression right before things begin to improve (as there is also an increase in the risk of suicide in the first couple weeks when people with depression start taking antidepressants).

This is complicated stuff but we can figure it out, pattismith. I feel like I'm in the right ballpark right now on the general mechanism but I still need to figure out the best possible way to regulate this problem.

p.s. another thing I now realize is that contrary to what most people believe, an increase in GABA might actually have an activating rather than sedating response too by acting on interneurons which release DA and NE.

 

[Iritu1021]

Damn, I didn't realize I wrote a whole thesis here!

 

[S-VV]

@Iritu1021

A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS

Angus MackayWarren P Tate
First Published December 6, 2018
https://doi.org/10.1177/2058738418812342

You should really share your divination techniques!!

 

[Iritu1021]

Great article, thanks @S-VV! It's from New Zealand - looks like all the best CFS research is now coming from that part of the globe.

If people took Jay Goldstein more seriously we could be all much more ahead on this by now, he already knew it back in the 90s (which is pretty amazing).

This caught my attention as something pertinent to the original subject of this thread:

"Both microglia and astrocytes possess purinergic receptors that can bind ATP present in the interstitial fluid"

It is my understanding is that purinergic receptors can bind both ATP and adenosine.

I have also found this nice textbook article that explains how different drugs affect hypothalamic hormones.

https://books.google.com/books?id=9YzfDQAAQBAJ&pg=PA386&lpg=PA386&dq=methylphenidate effect on crh&source=bl&ots=iSxANl2rAJ&sig=To8qFYV9za2di4ze74wKiARRXMM&hl=en&sa=X&ved=2ahUKEwjJwPeQ95rfAhUOKKwKHWN_DjoQ6AEwFXoECAkQAQ#v=onepage&q=methylphenidate effect on crh&f=false

I believe that traditional ancient medicine (Ayurveda and Chinese) describes energetic states that are largely related to hypothalamic function. For example, Vata dosha in Ayurveda clearly implies HPA dysfunction to me while Pitta TRH dysfunction and Kapha likely refers to the rest of the hypothalamic hormones (that's just my own interpretation).

1) Decrease neuroinflammation and enhance neuroplasticity with a drug that has good CNS penetration and ideally an antiviral effect

2) Regulate TRH and CRH with drugs that stimulate/inhibit their release by matching the right drugs to the right points in circadian rhythm.

The second step is hopefully temporary assuming that eventually, PVN will be able to repair itself if provided with the right conditions.

My current hypothesis is that there are four main quadrants and people can shift between them depending on which drugs or hormones they take (or when their own hormones change due to stress or menopause).

a) both CRH and TRH are too high (sensory sensitivity, fibromyalgic symptoms, "brain on fire", losing weight; extreme stress intolerance; depression, high cortisol, TSH >1.5)

b) both CRH and TRH are low (extreme fatigue that temporarily improves with stress; low normal TSH, low normal ACTH)

c) CRH is high, TRH is low ("wired but tired", high flow or hyperadrenergic POTS, high ACTH, high DHEA, TSH <1.5)

d) CRH is low, TRH is high (low ACTH, TSH > 1.5, "tired but wired", adrenal fatigue, will initially respond to T3 but then may flop to B or C)

 

[S-VV]

Fantastic theory @Iritu1021 !!!

Please don't stop thinking about it, your perspective and approach is invaluable.

Right now I'm focusing on O2/Co2 hypoxia &TCA cycle after my microbiome intervention (FMT included) yielded no significant results.

If that doesn't work either I'm definitely going to start focusing on TRH, CRH and 5HTP receptors. So time to dust off that Goldstein

 

[drob31]

Good! I'm glad to hear its helping. You have to remember that Goldstein wrote his books a very long time ago. Most supplements were still pretty unknown back then.

I don't know if you have Goldstein's book or his algorithm. My copy is falling apart into separate pages now from being opened so many times over the years, I need to figure out where I can get it bound (this book holds a sentimental value for me).

His algorithm basically went in this order:


ALPHA 2 RECEPTORS (profiled with naphazoline eye drops, may be able to buy in the pharmacy)

Starting with alpha-2 receptors agonist or antagonist based on response to naphazoline eye drops.

BETTER: clonidine, gunfacine (Intuniv), midodrine, reboxetine

WORSE: Buspirone, mirtazapine (my note: I would add mianserin too; low doses of mianserine and mirtazapine are more sedating than high doses due to H1 effect)


TRH (this is hard to get; there is Abaris which is sublingual TRH but I don't know if it works the same way.

Response to TRH drops which IMO could be "estimated in reverse" by T3 causing TRH suppression. Some people use TSH suppression protocols for T3 but I actually feel really bad if my TSH is suppressed. If people were feeling worse with TRH spray, for Goldstein it was a predictor they would do well with adenosine.

You were able to tolerate T3 (TRH suppression) much better than I could so it makes sense that you respond to adenosine. I seem to need a decent level of TRH to function well and I think adenosine (based on my Cordyceps response) generally makes me worse.

BETTER WITH TRH: DHEA, Aricept, cycloserine, modafinil, Talwin, dopamine

WORSE WITH TRH: gotu kola, dipyridamole, baclofen, taurine, gabapentin and benzos.

DOPAMINE (profiled with dopamine drops but might be able to interpolate from other agensts, like Ritalin):

BETTER: Forskolin, naltrexone, THC, testosterone, oxytocin, reboxetine, selegiline, ropinirole, oxytocin, hydergine, amantadine

WORSE: mestinon, nimotop, piracetam, risperidal, Ativan, verapamil

ADENOSINE DROPS

Better: adenosine, ascorbate, Buspar, EFAs, guafenesin, heparin, L-lysine, lidocaine, progesterone, Topamax, Nimotop, gabapentin, mecamylamine (note that he lists L-lysine and lysine separately)

Worse: cycloseine, DHEA, pregnenolone, taurine, testosterone, lamotrigine, piracetam, tramadol

At this point he tests ketamine, lidocaine, amantadine and gabapentin) and algorithm becomes somewhat useless as it basically jumps between the same two columns full of meds until he comes back with specific NDMA drugs:

NDMA RECEPTOR (judged by the response to guafenesin topical gel)

BETTER: diltiazem, Nimotop, Zofran
WORSE: cycloserine, high dose glycine/serine.

My only residual issue right now is sort of general lassitude (not the same as fatigue) and lack of motivation - which could be because I didn't address alpha2 adrenergic receptors and I don't have enough NE. Or it could be because my TRH is still too suppressed which again would result in low catecholamines. Or maybe I need to get my hands on some cycloserine to bump up my NDMA function (I couldn't find it but ordered some sarcosine yesterday which is used for the same purposes).

On the bright side, all my pain, dysautonomia and mood problems are pretty much resolved and I can tolerate most drugs and supplements without any problem.

I keep reading the word adenosine. I know caffeine blocks adenosine receptors. I wonder what the connection is here?

 

[Iritu1021]

Yes, @drob31 did you fully read my replies in this thread? You need to read through to understand what I'm about to say now. And the study that S-VV linked confirms my suspicion that I told you about earlier - that it's not the thyroid itself that makes you feel better but the effect of thyroid on HPT axis. And if you don't approach it from the perspective of hypothalamus it's very easy to miss "the sweet spot" - which as you know from your experience does exist.

My theory is adenosine receptors in the hypothalamus affect CRH secretion. But literally, every NT will affect hypothalamus to some degree, which is why people with CFS and dysautonomia tend to have such strong reactions to literally everything they take. Or more rarely they feel great on something but lose the effect as soon as the receptors adapt.

Since I know you wouldn't mind, I will review your case here since other people are getting interested in this theory and hopefully they can benefit from your experience (I've been following @drob31 closely for almost a year). If my memory fails me somewhere then please correct me.

I suspect your baseline state before you went in T4 was high CRH + normal TRH (although you've been in different quadrants before we met, especially since your TSH used to be much higher). You probably had some degree of central hypothyroidism because your TSH was not high enough for you. You weren't hypothyroid to a significant degree because you had pretty high GD on SPINA (conversion) to compensate for low GT and the excess T3 stimulated your HPA axis (T3 would make you overstimulated). If I recall correctly when we first met you felt "wired but tired" (i.e. you had to go to the gym even when you knew you shouldn't, had more anxiety). At this stage caffeine probably would make you feel overstimulated (a hyper-excitatory state with excess glutamate and catecholamine/adrenergic activity). Exercise probably helped you to lower your CRH/cortisol but given hypothalamic over-sensitivity would sometimes send you to low TRH/CRH state which I think manifest as fatigue and as apathy or atypical depression.

Remember that most of the T4 conversion takes place within the cells. Thyroid normally produces a minuscule amount of T3 in the proportion that Blanchard estimated - and I believe he even suggested or implied that the main purpose of the T3 released by the thyroid into bloodstream along with a much larger dose of T4 is a way for HPT and HPA axis to stay in close communication for each other.)

Then you went on T4 so you TRH came down and your CRH came down with it. You felt really a lot better for a while but contrary to what I told you (or what Blanchard would tell you), you rushed to increase the dose rather than wait and see what happens on the lower dose (not placing any blame here you since I've made the same mistake myself). As a result, you've ended up with a really suppressed TRH and your CRH also began to decline to match it. During this stage, your reaction to caffeine has changed because you were now in hypo-excitatory state, especially in the mornings when natural production of TRH is the lowest.

When you tried to lower your thyroid dose you developed melancholy type depression due to TRH rebound causing CRH rebound. Rather than tolerating this, you upped your T4 dose even more and drove yourself further down into low TRH/ low CRH quadrant.

When baseline CRH stays low for a while, adrenal receptors will become overly sensitive. So it's a state of overall apathy and lassitude but with stress intolerance due to any release of CRH (from emotional stress, overexertion or illness) leading to high bursts of cortisol, which in turn lowers peripheral thyroid conversion - something that becomes much higher to counteract when you have permanently suppressed TRH.

So if you ever decide to try lowering your T4 dose again, maybe you can help offset the initial discomfort by using an adaptogen that lowers CRH and boosts TRH production. I think Ashwagandha (Sensoril extract) might be a good one for you to try.

 

[Iritu1021]

Fantastic theory @Iritu1021 !!!

Please don't stop thinking about it, your perspective and approach is invaluable.

Right now I'm focusing on O2/Co2 hypoxia &TCA cycle after my microbiome intervention (FMT included) yielded no significant results.

If that doesn't work either I'm definitely going to start focusing on TRH, CRH and 5HTP receptors. So time to dust off that Goldstein

Sounds good. Hope it works out for you but if not, maybe by then my theory and the method to go with it will be more fully hatched...

 

[drob31]

Yes, @drob31 did you fully read my replies in this thread? You need to read through to understand what I'm about to say now. And the study that S-VV linked confirms my suspicion that I told you about earlier - that it's not the thyroid itself that makes you feel better but the effect of thyroid on HPT axis. And if you don't approach it from the perspective of hypothalamus it's very easy to miss "the sweet spot" - which as you know from your experience does exist.

My theory is adenosine receptors in the hypothalamus affect CRH secretion. But literally, every NT will affect hypothalamus to some degree, which is why people with CFS and dysautonomia tend to have such strong reactions to literally everything they take. Or more rarely they feel great on something but lose the effect as soon as the receptors adapt.

Since I know you wouldn't mind, I will review your case here since other people are getting interested in this theory and hopefully they can benefit from your experience (I've been following @drob31 closely for almost a year). If my memory fails me somewhere then please correct me.

I suspect your baseline state before you went in T4 was high CRH + normal TRH (although you've been in different quadrants before we met, especially since your TSH used to be much higher). You probably had some degree of central hypothyroidism because your TSH was not high enough for you. You weren't hypothyroid to a significant degree because you had pretty high GD on SPINA (conversion) to compensate for low GT and the excess T3 stimulated your HPA axis (T3 would make you overstimulated). If I recall correctly when we first met you felt "wired but tired" (i.e. you had to go to the gym even when you knew you shouldn't, had more anxiety). At this stage caffeine probably would make you feel overstimulated (a hyper-excitatory state with excess glutamate and catecholamine/adrenergic activity). Exercise probably helped you to lower your CRH/cortisol but given hypothalamic over-sensitivity would sometimes send you to low TRH/CRH state which I think manifest as fatigue and as apathy or atypical depression.

Remember that most of the T4 conversion takes place within the cells. Thyroid normally produces a minuscule amount of T3 in the proportion that Blanchard estimated - and I believe he even suggested or implied that the main purpose of the T3 released by the thyroid into bloodstream along with a much larger dose of T4 is a way for HPT and HPA axis to stay in close communication for each other.)

Then you went on T4 so you TRH came down and your CRH came down with it. You felt really a lot better for a while but contrary to what I told you (or what Blanchard would tell you), you rushed to increase the dose rather than wait and see what happens on the lower dose (not placing any blame here you since I've made the same mistake myself). As a result, you've ended up with a really suppressed TRH and your CRH also began to decline to match it. During this stage, your reaction to caffeine has changed because you were now in hypo-excitatory state, especially in the mornings when natural production of TRH is the lowest.

When you tried to lower your thyroid dose you developed melancholy type depression due to TRH rebound causing CRH rebound. Rather than tolerating this, you upped your T4 dose even more and drove yourself further down into low TRH/ low CRH quadrant.

When baseline CRH stays low for a while, adrenal receptors will become overly sensitive. So it's a state of overall apathy and lassitude but with stress intolerance due to any release of CRH (from emotional stress, overexertion or illness) leading to high bursts of cortisol, which in turn lowers peripheral thyroid conversion - something that becomes much higher to counteract when you have permanently suppressed TRH.

So if you ever decide to try lowering your T4 dose again, maybe you can help offset the initial discomfort by using an adaptogen that lowers CRH and boosts TRH production. I think Ashwagandha (Sensoril extract) might be a good one for you to try.

Thanks for the breakdown and analysis. Do you still think having some t4 is nessasary to allow increase in TRH/CRH? So even if I tapered down, i may need 25 or 50 mcg?

 

[drob31]

Another thought.... would we hypothetically reset the PVN back to normal if we tapered off in such a way to leave us with normal TRH/CRH?