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.
