INOSINE antinociceptive, antidepressant, anti neurogenic detrusor overactivity

[Iritu1021]

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?

In my experience, every time you push through an uncomfortable zone, there is going to be some reset in receptors. If you push in the right direction, the reset is positive and if you push in the wrong direction the reset is negative. In fact most people never read Wilson's (as in "Wilson protocol") original book but if they did they would know that he said that the best kind of healing in his observation took place not when patients went on T3 but when they slowly tapered off it. He often would have patients start and stop T3 several times to "change the settings".

The problem with all those protocols is that once they go mainstream they often lose what made them successful in the first place. This is why I wrote in another thread that Blanchard protocol can't be just interpreted as T4/T3 ratio without accounting for the baseline hypothalamic state.

One other possible explanation for you @drob31 is that you have an autonomous production of T3 from your thyroid nodule, i.e. it doesn't respond well to TSH. Your high rT3 may be a sign of the cells trying to combat excess T3 levels. In that case you don't want to raise your TRH, just take some antidepressant or adaptogen that helps to balance HPA function (but not Ashwagandha). And in this case you can achieve the same effect with iodine as you do with T3. If your CRH was low than you would need T3 since iodine is not programmed to stimulate cortisol like T3 does.

You don't really seem to have "true CFS" in a sense most people with CFS do not go to gym every day and do martial arts but I think you went through CFS stage in the past due to combined HPA and HPT repression and maybe as a result your HPA and HPT axis have probably become somewhat "divorced" from each other.

I don't know which scenario is the right one, the first one (you have true central hypothyroidism) or the second one (you have TRH suppression due to autonomous thyroid hormone secretion) so the only way to figure out is to see how you respond. Either way, you probably don't have to come off thyroid completely in order to feel better.

 

[Iritu1021]

@drob31 , I just remembered you telling me that at one point your TSH went up and you felt better, is that right? If so, than I think central hypothyroidism is more likely. Can you think of what might have caused your TSH to go up at that time?

 

[pattismith]

Not only Inosine (and as well) activates adenosine receptors outside the cells, but it have activities inside.

One of this activity seems to produce catecholamine release from neurons:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC282417/pdf/pnas00300-0480.pdf

This activity is blocked by dipyridamole (blocking adenosine/inosine entry into cells), and so will be blocked by any adenosine reuptake inhibitors (Nimodipine as well).


So to find out if Inosine is active for you by binding to your Adenosine receptors or by intracellular activities,
taking Inosine + dipyridamole should give the answer.


I tried it once and wasn't happy with the result, but couldn't say if it was a side effect of Dipyridamole that was linked to it's adenosine/Inosine reuptake inhibition or not. Maybe I will do another trial.

Edit: I noticed altered memory since I started Inosine, and read several articles about the negative role of adenosine on memory.
Caffeine by blocking A2A adenosine receptor could improve stress induced memory alteration.

https://www.pnas.org/content/112/25/7833.short

 

[Iritu1021]

Here's what I was trying to point out earlier: CRH (or CRF) is not just a hormone that controls ACTH secretion; it has a direct effect on autonomic function separate from its effect on the pituitary.

 

[Iritu1021]

Not only Inosine (and as well) activates adenosine receptors outside the cells, but it have activities inside.

One of this activity seems to produce catecholamine release from neurons:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC282417/pdf/pnas00300-0480.pd


So to find out if Inosine is active for you by binding to your Adenosine receptors or by intracellular activities,
taking Inosine + dipyridamole should give the answer.

I did my Cordyceps experiment: I only feel an immediate effect from high dose of C.sinensis (high in adenosine) but no effect from C.militaris which is high in cordycepin but low in adenosine. So I'm pretty sure that adenosine is the ingredient that I respond to in Cordyceps and my current guess is that is has something to do with the stimulating effect on HPA.

 

[Iritu1021]

And here's my visualized thyroid "sweet spot" concept. This one would be for a case scenario where someone starts with a "dysautonomic gap" between their CRH and TRH. The dotted line is the optimal level for one's constitution.

Remember that CRH will determine sympathetic/ parasympathetic activity while TRH seems to determine glutamate/GABA balance. So we are not only talking about end hormones that they regulate but an overall neurotransmitter balance they will create in the brain and peripheral nerves.

If you have supersensitive receptors or abnormal ion channels than it is very difficult to tolerate large fluctuations of TRH and CRH.

This person (which was my case in the early part of my illness) would start with hypoactive HPA and TSH that's in the upper end of normal due to hypothyroidism (however it's not as high as it needs to be due to HPA insufficiency). Therefore the person is both hypoadrenal and hypothyroid. They would not feel good on T4 alone because it doesn't provide adequate HPA stimulation but may initially feel really good, maybe briefly even great on T3 or NDT because it will stimulate both hormones but unless they use very precise physiologic doses (as in Blanchard's method) they will overshoot and find themselves in a different quadrant and fatigued just as bad but somewhat different than they were before.

If a person starts off with high CRH and/or TRH below optimal (central hypothyroidism) they will actually feel worse from T3 due to CRH going up too high. But too much T4 will end up with the same problem.

 

[Iritu1021]

also a word of caution regarding inosine for anyone with MCAS, it appears to stimulate mast cell degranulation:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508491/pdf/1002849.pdf

But CRH and TRH might really be the greatest offenders when it comes to endogenous histamine regulation in hypothalamic dysfunction - especially histamine levels within the brain.

Endocrinology. 1998 Jan;139(1):403-13.
Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects.


Brain Res. 2012 Dec 7;1488:72-80. doi: 10.1016/j.brainres.2012.10.010. Epub 2012 Oct 11.
Thyrotropin-releasing hormone-containing axons innervate histaminergic neurons in the tuberomammillary nucleus.

 

[drob31]

@drob31 , I just remembered you telling me that at one point your TSH went up and you felt better, is that right? If so, than I think central hypothyroidism is more likely. Can you think of what might have caused your TSH to go up at that time?

My TSH was higher before I crashed. So it was basically 3.5, and went down to 1.5-1.6 after my crash. So I felt way better before I crashed, although I've always had issues.

 

[drob31]

In my experience, every time you push through an uncomfortable zone, there is going to be some reset in receptors. If you push in the right direction, the reset is positive and if you push in the wrong direction the reset is negative. In fact most people never read Wilson's (as in "Wilson protocol") original book but if they did they would know that he said that the best kind of healing in his observation took place not when patients went on T3 but when they slowly tapered off it. He often would have patients start and stop T3 several times to "change the settings".

The problem with all those protocols is that once they go mainstream they often lose what made them successful in the first place. This is why I wrote in another thread that Blanchard protocol can't be just interpreted as T4/T3 ratio without accounting for the baseline hypothalamic state.

One other possible explanation for you @drob31 is that you have an autonomous production of T3 from your thyroid nodule, i.e. it doesn't respond well to TSH. Your high rT3 may be a sign of the cells trying to combat excess T3 levels. In that case you don't want to raise your TRH, just take some antidepressant or adaptogen that helps to balance HPA function (but not Ashwagandha). And in this case you can achieve the same effect with iodine as you do with T3. If your CRH was low than you would need T3 since iodine is not programmed to stimulate cortisol like T3 does.

You don't really seem to have "true CFS" in a sense most people with CFS do not go to gym every day and do martial arts but I think you went through CFS stage in the past due to combined HPA and HPT repression and maybe as a result your HPA and HPT axis have probably become somewhat "divorced" from each other.

I don't know which scenario is the right one, the first one (you have true central hypothyroidism) or the second one (you have TRH suppression due to autonomous thyroid hormone secretion) so the only way to figure out is to see how you respond. Either way, you probably don't have to come off thyroid completely in order to feel better.

The right side of my neck where my thyroid is always seems to get sore and inflammated during times of stress, etc. I'm not sure if this a red herring or not, since it's output is supressed right now anyway.

I'm considered dropping my t4 down and try to stabilize at a lower dose.

 

[drob31]

And here's my visualized thyroid "sweet spot" concept. This one would be for a case scenario where someone starts with a "dysautonomic gap" between their CRH and TRH. The dotted line is the optimal level for one's constitution.

Remember that CRH will determine sympathetic/ parasympathetic activity while TRH seems to determine glutamate/GABA balance. So we are not only talking about end hormones that they regulate but an overall neurotransmitter balance they will create in the brain and peripheral nerves.

If you have supersensitive receptors or abnormal ion channels than it is very difficult to tolerate large fluctuations of TRH and CRH.


View attachment 30548

This person (which was my case in the early part of my illness) would start with hypoactive HPA and TSH that's in the upper end of normal due to hypothyroidism (however it's not as high as it needs to be due to HPA insufficiency). Therefore the person is both hypoadrenal and hypothyroid. They would not feel good on T4 alone because it doesn't provide adequate HPA stimulation but may initially feel really good, maybe briefly even great on T3 or NDT because it will stimulate both hormones but unless they use very precise physiologic doses (as in Blanchard's method) they will overshoot and find themselves in a different quadrant and fatigued just as bad but somewhat different than they were before.

If a person starts off with high CRH and/or TRH below optimal (central hypothyroidism) they will actually feel worse from T3 due to CRH going up too high. But too much T4 will end up with the same problem.

If CRH was high, wouldn't that mean cortisol would go high as well? I feel like my CRH and or cortisol is lower with higher doses of t4. Although I could be way off here.

 

[Iritu1021]

If CRH was high, wouldn't that mean cortisol would go high as well? I feel like my CRH and or cortisol is lower with higher doses of t4. Although I could be way off here.

My curve was an example of someone who uses T3 to boost their HPA function. For T4 it would be different since you actually decrease natural production of T3 by the thyroid gland which would lower CRH.

On another hand, what you what you are feeling now could also be due to the decrease in excitatory neurotransmitters from low TRH. Cortisol in itself is not a psychological "stress hormone" while CRH is.

A skewed T4/T3 ratio in the early morning might also affect the circadian rhythm of cortisol production.

I never thought about it this way but now I see that symptomatic subclinical hypothyroidism (elevated TSH with normal thyroid hormones) might not actually be due to mild deficiency of thyroid hormone but an inability of the CNS to handle the increase in TRH - which in turn could be due to supersensitive receptors. But the same issue of supersensitivity may apply if you overshoot TRH in the other direction.

The average dose in subclinical hypothyroidism seems to be 0.5 mg/kg or less. Which for me is still more than the 50 mcgs I'm taking now. I used to think I need 1.7 mcg/kg which is a full replacement dose but in retrospect, it was a mistake because for me there are a lot of downsides that came with low TRH (apathy, a decrease in motivation and, worst of all, neuroinflammation).

 

[BadBadBear]

The average dose in subclinical hypothyroidism seems to be 0.5 mg/kg or less. Which for me is still more than the 50 mcgs I'm taking now. I used to think I need 1.7 mcg/kg which is a full replacement dose but in retrospect, it was a mistake because for me there are a lot of downsides that came with low TRH (apathy, a decrease in motivation and, worst of all, neuroinflammation).

What do you think is the best way to move from a full replacement T4 dose to the lowest needed dose? I have been thinking about making my annual attempt at lowering my thyroid meds. Currently on 1/2 grain Armour plus 125 of T4.

I would for sure like to test whether I still need any T3 or not. I did bloodwork earlier today before changing anything.

Curious if inositol has moved anything in my thyroid labs.

 

[Iritu1021]

What do you think is the best way to move from a full replacement T4 dose to the lowest needed dose? I have been thinking about making my annual attempt at lowering my thyroid meds. Currently on 1/2 grain Armour plus 125 of T4.

I would for sure like to test whether I still need any T3 or not. I did bloodwork earlier today before changing anything.

Curious if inositol has moved anything in my thyroid labs.

If your TSH is suppressed you probably won't be able to convert your own T4 efficiently unless TSH comes up more or less in the normal range.

TSH often gets "stuck" with prolonged T3 use and may not come up unless you completely stop taking T3 which usually requires enduring a period of drug withdrawal and hypothyroidism. If you want it to be as painless of a process as possible, you can do it very slowly and gradually, decreasing both T4 and T4 by no more than 10% every week. But even with this gentle approach, you should be prepared that it might not be fully painless. Every time I lower thyroid, it does a hit job on my mood and energy until all the receptors re-adjust to the new settings.

Stopping T3 seems to be especially hard for people with hypothalamic dysfunction. Not only TRH is more sluggish to bounce back but the bigger problem with T3 is the change it induces in HPA settings. You will be initially hypoadrenal when you lower T3. However, in my experience, 1 mcg or less of slow release T3 or less is enough to prevent this from happening and it can do so without suppressing TSH.

 

[Iritu1021]

Goldstein's opinion on HPT dysfunction.

http://www.ncf-net.org/forum/99gold.htm

My own experience with thyroid correlates with his observation about it playing a role in trigeminal nerve function because when my TRH was both too high and too low I have pain in the face and neck (or throat) in the distribution of trigeminal nerve. When TRH was too high it felt more like a pressure/tightness sensation and when it was too low it felt like neuroinflammation. @drob31, the pain in your neck that you mentioned might also related to trigeminal nerve.

TRH regulates serotonin, norepinephrine, GABA, glutamate and dopamine. CRH stimulates norepinephrine secretion via locus ceruleus and sensitizes mast cells to histamine. So if both CRH and TRH are dysregulated you can end up in complete chaos when it comes to neurotransmitters. NE is the one with the potential to be the most severely affected if both are too high or too low (hyperadrenergic or hypoadrenergic POTS).

 

[Judee]

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

Ditto!

I'm trying to follow your "nucleotide investigations" but you members are brain-iacs.

I did wonder one thing about the inosine and blood urate. Something that I've heard from my nutritional books is that cherries and cherry juice help with high levels of uric acid and gout. Would that work or does it need a stronger medicine?

 

[hapl808]

In my experience, every time you push through an uncomfortable zone, there is going to be some reset in receptors. If you push in the right direction, the reset is positive and if you push in the wrong direction the reset is negative. In fact most people never read Wilson's (as in "Wilson protocol") original book but if they did they would know that he said that the best kind of healing in his observation took place not when patients went on T3 but when they slowly tapered off it. He often would have patients start and stop T3 several times to "change the settings".

Not sure if you're still active, but what you wrote in this thread about receptors and Goldstein and such is interesting. That approach always 'rang true' to me, but I've never been able to figure out how to implement it beyond random shooting in the dark.

I have a lot of muscular issues (somewhere between MS and stiff person symptoms - not diagnosed with either). Lost the ability to walk unassisted years ago, so I usually use crutches around the house.

But the cognitive things are what I notice because they fluctuate a bit. My baseline is mild headaches and bad brain fog. If I overdo it by talking on the phone for an hour, the following day I get acid reflux, then the day after I usually get a migraine. This is very repeatable.

I have a whole host of stuff, but I think the whole 'pushing in the wrong direction' has been tough. I tried guanfacine recently, and it just made me feel bad and didn't seem to improve my heart rate or anything (always tachycardic).

Lithium orotate interests me, but I've only tried a small bit of it and couldn't really judge.

Something like LDN I tried for longer, but it just didn't seem to do much other than make my dreams weird.

Very curious if you have any good strategies for testing out methodically, or deciding which substances are likely to affect homeostasis in a way that might reset receptors. So many options - inosine, caffeine, benfotiamine, cordyceps, passion flower, hawthorn, lithium, licorice, theanine, melatonin, ketotifen, gabapentin, LDA, etc.

 

[hapl808]

I've been thinking more about this idea of trying to reset receptors by pushing in the 'wrong' direction so the body responds. It's basically the opposite of the effect we experience where we improve for a brief period after starting something new, then the benefit goes away.

 

[ilivewithcfs]

Hi!
Since I have reasons to believe, that my CFS is viral in nature, I want to try Inosine pranobex. I have a question about the dosage.
I've done my research, and I was only been able to find dosage recommendations for imunovir and not inosine. I've also read, that imunovir and inosine are not the same. Does anybody knows recommended dosage regimen for inosine? If you do, please share. Imunovir is not available in my country.
Thanks.

 

[Judee]

the dosage.
I've done my research, and I was only been able to find dosage recommendations for imunovir and not inosine. I've also read, that imunovir and inosine are not the same. Does anybody knows recommended dosage regimen for inosune? If you do, please share. Imunovir is not available n my country.
Thanks.

Not sure this will help but Sue Jackson talks about Imunovir and Inosine on her blog: https://livewithcfs.blogspot.com/2014/04/imunovir-update-and-inosine.html

Also there are some reviews on Webmd for Inosine that mention a slightly different rotational dosing than I think Sue's doctor gave her.

Can't read much right now so hope that will at least answer some of your questions @ilivewithcfs.

Edit: And I did try Inosine at one point. Initially it seemed to help some but then I started to get my "heart tiredness" and had to stop it. I think because it raises uric acid levels which may be why I asked earlier in this thread about cherries and cherry juice lowering uric acid levels though I cannot recall now if that was why I asked that.

 

[ilivewithcfs]

Thanks! That's really helpful