Dr. Jay Goldstein's Rapid Remission ME/CFS Treatments.

geraldt52

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In what way do you think they are harmful?
My feeling is that our bodies have probably reset themselves in a manner that is the most efficient/effective, however much we don't like the result. Cancelling that reset with a drug/supplement, that essentially causes an equal and opposite effect, then requires our bodies to reset themselves, in self defense, in a less effective/efficient manner. I'm not sure that's a great idea when you're talking about the central nervous system, especially when it seems to seldom have long-lasting benefit.

To be clear, this is pure speculation on my part...and I certainly don't have any qualifications that would lend any weight to it.
 

Hip

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I think these temporary remissions or improvements actually have a good psychological and morale-boosting impact, as @Sidereal mentioned earlier. These brief remissions suggest that nothing in the brain is fundamentally damaged, and that beyond the cloud of this illness, there is still an intact you behind it all.

These rare remission periods, if you are lucky enough to have one, are also a nice "vacation" from ME/CFS! These vacations remind you what a normal human being is like!


I have to say, though, that some treatments I tried did lead to a significant improvement in ME/CFS symptoms, and these were not transient, but were maintained long term. Over the course of testing out hundreds of drugs and supplements, I found several medications which resulted in permanent improvements to my ME/CFS symptoms, as well as to my comorbid anxiety symptoms. Provided I keep taking these specific drugs and supplements, the improvements are maintained, and this has been the case over several years now.

In my case, the medications that have led to sustained improvements are: very low dose amisulpride, high dose selenium, N-acetyl-glucosamine, and perhaps some others. These all led to sustained improvements which have been maintained for years, and if I stop taking any of these medications, the symptoms they treat soon return.

So some treatments are permanent; others are temporary and transient.



Thinking about the possible metabolic mechanics behind these temporary and permanent improvements: perhaps when we take a drug to intervene with bodily processes, that intervention can occur on one of two levels:

• A level one intervention would occur within one of the body's homeostatic, feedback-regulated systems. This intervention may temporarily improve ME/CFS symptoms, but because the medication is working within a feedback-regulated system, the system soon re-adjusts itself back to its original state. Metabolism comprises thousands of feedback-regulated homeostatic processes, so it is not surprising to see such homeostasis involved in drug response.

An analogy would be trying to warm a centrally heated house by bringing in an electric fan heater. For a while, you may raise the temperature of the house, but soon the centrally heating thermostat detects this raised temperature, and adjusts and lowers the centrally heating output in order to keep the temperature at the level set on the thermostat.

• A level two intervention would actually act upon one of the body's homeostatic systems. In our analogy, this would be like raising the house temperature by altering the thermostat setting, which then changes the whole equilibrium set point of the feedback-regulated system.



However, the above "level one intervention" does not quite capture what often happens in the temporary ME/CFS remissions produced by drugs and supplements. If the transient nature of these remissions were just due to a feedback-regulated rebalancing process, then you would expect these drugs to work transiently every time you took them (provided you only took the drugs now and then).

But it seems that many ME/CFS patients find that a drug or supplement will significantly improve their symptoms temporarily (for a few hours, days or weeks), but then it stops working, and even if they take a long washout period of many months away from the drug, it never again provides the original symptomatic improvement. The drug become useless for them.

So homeostasis cannot really explain these transient, one-off remissions from drugs, which are often never to be seen again. Possibly this bodily adaptation to the drug may be an epigenetic one (ie, due to changes in gene expression regulation), and such epigenetic changes tend to be long-lasting.
 
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Hip

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Goldstein proposed an explanation along these lines and suggested high dose inositol as a possible solution.
That's very interesting. I just found a reference to inositol in this book about Dr Goldstein's treatments. Though it does not unfortunately specify the assumed mechanism of tolerance reversal.

I might try some inositol to see if I can get the two Goldstein drugs that did work for me (Wellbutrin and Lamictal) to start working again.

I have in the past often taken high doses of inositol powder (15 grams per day), as this is a known treatment for depression and anxiety, and it works reasonably well for me. I still have half a kilo of it lying around.
 

Violeta

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I think these temporary remissions or improvements actually have a good psychological and morale-boosting impact, as @Sidereal mentioned earlier. These brief remissions suggest that nothing in the brain is fundamentally damaged, and that beyond the cloud of this illness, there is still an intact you behind it all.
Except for possible genetic changes?
 

Lou

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@Gingergrrl Sorry, I have no answer for you, wish I did.

My thoughts on short term remissions(I've had three where it seemed I was good as cured) are not sophisticated at all, but in line with this thread believe all our symptoms spring from a single source, our inflamed brains.

Perhaps these brief remedies, medicines and others, when just the right metabolic circumstances exist, act much like aspirin for a headache, relieving temporarily the inflammation at root cause for the entirety of our symptoms.
 
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Hip

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In a post by @zzz earlier in this thread, the following excerpt from Goldstein's Betrayal by the Brain book was quoted, on the use of inositol to reverse drug tolerance in an ME/CFS patient:
A 16-year-old Caucasian female consulted me for symptoms of chronic fatigue syndrome experienced for two years, which resulted in her being homebound. She was too cognitively impaired to receive home schooling, although she had been an "A" student prior to her illness Her mother and a 14-year-old sister had milder forms of the illness. She initially had excellent responses to ranitidine [Zantac], naphazoline, nimodipine, oxytocin, and several antidepressants, but the benefit was always short-lived. After taking one gram of inositol she felt considerably better and was encouraged to resume agents to which she had developed tolerance. As long as she continued to take inositol 1 gm QID, these medications were again effective. She has returned to high school and will be graduating shortly.

From: page 127 of Goldstein's book: Betrayal by the Brain
So the inositol dose for reversing the loss-of-effect of drugs is 1 gram of inositol 4 times a day (possibly a single dose of 4 grams a day might also suffice).



I have just become aware that in his book Betrayal by the Brain, Dr Goldstein has a very interesting chapter called Receptor Desensitization and Drug Tolerance (where the above quote comes from). In this chapter he explains what he thinks may be mechanism for drug tolerance and drug loss-of-effect in ME/CFS patients.

You can read this chapter online in Google Books, see: Betrayal by the Brain (pages 123 to 127). I have also attached this very short chapter as a pdf file at the bottom of this post.

The chapter is only 5 pages long, but it is very dense with biochemical detail. I am having trouble penetrating it, but I shall try to summarize what I have understood (or at least what I think I have understood). So this is how Dr Goldstein explains the drug tolerance and drug loss-of-effect in ME/CFS patients:

• He starts the chapter by noting that there is a significant problem in treating ME/CFS patients, as they often become tolerant of the medications that are efficacious for them, and this tolerance can appear after just one dose of medication.

• Dr Goldstein then goes on to say that when a particular medication works for an ME/CFS patient, and they get a rapid positive response from it, he thinks that positive response is mediated by the alpha 1 adrenergic receptors in the brain.

Goldstein came to this conclusion because every time a drug he administered in his office had an immediate positive effect on an ME/CFS patient, the SPECT brain scans taken directly afterwards always showed significant hypoperfusion in the brain (ie, lowered blood flow), no matter which medication it was that cause the positive response; whereas if the medication did not have any effect on a patient, the brain perfusion remained unchanged.

So Goldstein observed that when any drug rapidly improved ME/CFS symptoms, this was always accompanied by brain hypoperfusion. Now it is activation of the alpha 1 adrenergic receptors that causes vasoconstriction and hypoperfusion, so this is why Goldstein implicated the alpha 1 adrenergic receptor in the dynamics of a positive response to a drug. See this post by zzz for more details of this positive response – hypoperfusion connection.

• Dr Goldstein then goes on to examine the process of adrenergic receptor desensitization, whereby the receptor starts to lose some of its response to agonists which would normally activate the receptor. From my understanding of what he wrote, I think Goldstein is proposing that drug tolerance and loss-of-effect is related to adrenergic receptor desensitization.

Goldstein describes the two routes of receptor desensitization: the down-regulation of receptor populations, and receptor uncoupling.

He focuses on the latter: receptor uncoupling, which is where the signal from an activated receptor is no longer sent into the cell, so the cell no longer responds to an activated receptor, and in this way the receptor becomes desensitized.

In the case of the adrenergic receptors, the signal from an activated receptor is sent into the cell via a messenger called G-protein. (The way G-protein carries the signal from the activated receptor into the cell is described in this video).

If I understand correctly, uncoupling an alpha 1 adrenergic receptor from the signal sent into the cell via G-protein involves the phosphorylation of the G-protein. So by phosphorylating the G-protein, you desensitize this receptor.

Goldstein says G-protein is phosphorylated by agents such as protein kinase A (PKA) and protein kinase C (PKC). This 2000 study indicates activation of PKC is involved in the desensitization of the α1 adrenergic receptor. So too much PKC or PKA may be behind the adrenergic receptor desensitization.

Goldstein points out that PKC or PKA receptor desensitization is not receptor-type specific, it hits other receptors too (this is known as heterologous desensitization). In other words, if this PKC or PKA pathway is activated, it would desensitize other types of receptor too (this I guess paints a picture of ME/CFS involving multiple brain receptor types being desensitized).

Goldstein says he has covered the possible role of PKC or PKA in ME/CFS in his previous books.

Goldstein says that the supplement acetyl-L-carnitine is a PKC activator (so might potentially make things worse, I guess).


At this point, I am starting to have more difficulty in following the biochemical pathways that Goldstein is referring to. Plus it's past my bedtime, so my brain and concentration are wilting.

Goldstein seems to say that inositol trisphosphate (IP3) is involved in the alpha 1 adrenergic receptor desensitization, and Goldstein is suggesting that IP3 might be stimulated by high doses of the supplement inositol (though I have often taken high dose inositol at up to 15 grams daily, and notice no improvement in ME/CFS).




The following paper also makes some interesting remarks on the subject of alpha 1 adrenergic receptor desensitization:

Mechanisms Involved in a1B-Adrenoceptor Desensitization

The paper says that:
Many hormones and neurotransmitters are capable of inducing a1B-adrenergic receptor phosphorylation and desensitization; among them: adrenaline and noradrenaline, phorbol esters, endothelin-I, bradykinin, lysophosphatidic acid, insulin, EGF, PDGF, IGF-I, TGF-β, and estrogens.
It's worth noting that TGF-β levels are significantly higher in ME/CFS,1 so this may be affecting alpha 1 adrenergic receptor desensitization.



In summary:

• Observations from Goldstein suggest that desensitization of the alpha 1 adrenergic receptors may be behind ME/CFS.

This conclusion arises because every drug Goldstein found to work for ME/CFS was seen to induce an apparent re-sensitization of this adrenergic receptor (as evidenced by the vasoconstriction and hypoperfusion).

• Goldstein examined the possible receptor desensitization mechanisms, and focused on the receptor uncoupling mechanism (where the signal from an activated receptor is no longer transmitted into the cell, thus effectively deactivating the receptor).

• Goldstein explains that receptor uncoupling occurs when the G-protein in the receptor is phosphorylated. So I believe Goldstein may have thought ME/CFS is in part caused by too much phosphorylation of the G-protein of these α1 adrenergic receptors.

• If over-phosphorylation of the G-protein is playing a major role in ME/CFS, then we need to look at what might be causing this. Possible factors include elevated PKA and PKC, and perhaps the chronically elevated TGF-β found in ME/CFS.
 

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Gingergrrl

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@Hip or @zzz, I haven't read all of the above post but is inositol (per Goldstein) only for meds that worked but you built a tolerance to or also for meds that you never tolerated due to side effects (in the hope of tolerating these meds?)

Also, have we found out more if he did indeed pass away or is still alive?
 

Gingergrrl

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@Gingergrrl Sorry, I have no answer for you, wish I did.

My thoughts on short term remissions(I've had three where it seemed I was good as cured) are not sophisticated at all, but in line with this thread believe all our symptoms spring from a single source, our inflamed brains.

Perhaps these brief remedies, medicines and others, when just the right metabolic circumstances exist, act much like aspirin for a headache, relieving temporarily the inflammation at root cause for the entirety of our symptoms.
No worries @Lou and I think you may be right although in my case, I have not experienced any remissions yet. But I keep hoping...
 

Hip

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@Hip or @zzz, I haven't read all of the above post but is inositol (per Goldstein) only for meds that worked but you built a tolerance to or also for meds that you never tolerated due to side effects (in the hope of tolerating these meds?)
I think it is only the former. The word "tolerance" seems to have two distinct meanings: one is where a person builds up an immunity to a drug as they continue to take it, and this is what Goldstein is analyzing and trying to address; and a second meaning refers to the level of side effects that someone experiences when taking a drug.
 

Hip

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@Hip, that's how I read it too.
I am glad to hear that, as I am unsure if I have understood it correctly.



G-Protein Coupled Receptor Problems in ME/CFS?

I am just wondering if Goldstein's biochemical explanation of the very rapid drug tolerance that occurs in ME/CFS might have wider significance. I am wondering if this rapid desensitization to drugs phenomenon goes further, and might explain some of the pathological features of ME/CFS.

If there is a general problem in ME/CFS that is causing receptors to become desensitized far too quickly with use, this might explain some of the mental PEM effects. G-protein coupled receptors are a class of receptor that naturally desensitize to a degree when they go through a period of high activation, and this slight and temporary desensitization with use occurs in everyone, even healthy people.

Both the adrenergic and dopaminergic receptors are G-protein coupled receptors, ie, they rely on G-protein to relay their activation signal into the cell.

This natural desensitization of receptors with use, if it were abnormally exaggerated in ME/CFS, could well explain mental PEM effects like brain fog after mental exertion. If in ME/CFS, G-protein coupled receptors are becoming too rapidly desensitized with normal use of the brain, this desensitization would make these receptors non-functional or under-functional for a while afterwards, which could explain the state of brain fog and the difficulties in information processing that can appear after mental exertion.


Note that arousal is a physiological response in the brain regulating consciousness, attention, and information processing, and involves noradrenaline and dopamine, among other neurotransmitters.

I have observed myself, that whenever my brain becomes excited and aroused for several hours (such as during excitable socializing with friends), then the next day or two, I find this leads to PEM involving high levels of brain fog and increased fatigue, and major problems in thinking and processing information. I pay for my few hours of heightened arousal during socializing with increased brain fog during the subsequent days.

Could it be that this mental PEM brain fog phenomenon is explained by an abnormal, far too rapid desensitization of our G-protein coupled receptors (the noradrenaline and dopamine receptors) which quickly renders these receptors under-functional for a few days?



Certainly the evidence from Goldstein's drug testing indicates that there may be abnormally rapid desensitization of G-protein coupled receptors in ME/CFS.

The significantly higher levels of TGF-β found in ME/CFS could be one factor that explains this abnormally rapid desensitization: as mention above, TGF-β increases the desensitization of G-protein coupled receptors.

The ARB drug losartan reduces TGF-β activation in the brain, so possibly this might be helpful in combating this too rapid desensitization. 1 Possibly losartan might help reverse the drug tolerance problem too.


But there could be other factors present in ME/CFS that are also causing abnormally rapid desensitization, through elevated phosphorylation of the G-protein. It would be interesting to try to identify these.
 
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Sidereal

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Very interesting ideas, @Hip. Interestingly, back before he was so focused on the brain, Goldstein speculated about TGF-β being the crucial immunological piece of the puzzle driving the show (in his 1990 book, I think, talk about being ahead of the times).

A few weeks ago a systematic review was published (authored by P D White's group, no less!) showing TGF-β to be the most consistent abnormality in ME/CFS immune studies.

@nandixon, did you ever end up trying the ARB?
 

Sidereal

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I wonder if this thread would get wider attention/readership it deserves if its title were less bombastic and off-putting to long-term ME/CFS patients many of whom are understandably jaded and skeptical about any claims of "instant remission"?
 

Gingergrrl

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I wonder if this thread would get wider attention/readership it deserves if its title were less bombastic and off-putting to long-term ME/CFS patients many of whom are understandably jaded and skeptical about any claims of "instant remission"?
I didn't even realize what the title was b/c I have been following this thread for so long and get the alerts but I agree with you.
 

JES

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I read this thread through, it's for sure one of the most interesting ones on this board. I haven't read the book, but some of the claims here (especially this "instanst remission" part and the "98% of patients asymptomatic") for me go to category "too good to be true".

I got the impression that Dr Goldstein only got to see many of his patients once or a couple of times. With such short follow-up, it's quite bold to state those patients become asymptomatic. I'm not saying it's a lie and that those treatments wouldn't work, but the duration of the effect is the critical bit. The problem is, I and many other CFS patients, particularly those who are not severely ill and react to supplements, can temporarily improve a lot on some dietary supplements and OTC drugs. The problem is, the effect doesn't last and for most, never returns, which is what @Hip has explained well in earlier posts.

So the question for me is, is it worth testing these drugs, some of which are unproven or even dangerous when administered wrong, if the effect we get is the same as from much safer supplements, i.e. the effect wears off. At least I would like to hear some more long-term success stories of said drug before trialing it. We should look at this issue critically.
 

Sushi

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I wonder if this thread would get wider attention/readership it deserves if its title were less bombastic and off-putting to long-term ME/CFS patients many of whom are understandably jaded and skeptical about any claims of "instant remission"?
@zzz let us know how you feel about the title of the thread. It can be changed it you wish.