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

[MeSci]

Clearly he doesn't mean literal innervation. I imagine he's talking about signalling originating in the brain towards lymph organs, reaching the lymphocytes via cytokine signalling as they pass through the organs.

Well, that would be plausible, but he did say "even individual lymphocytes are directly innervated by nerves from the hypothalamus." (My bolding)

 

[zzz]

@zzz, have you heard of AO+ Mist?

No, I have not.

I'd love to get your input on his ideas and how they might relate to Goldstein's work.

It's hard to get a good feeling for this product just from reading about it, but offhand, I don't see any direct connection to Goldstein's work.

I am puzzled by the claim that there can be innervation of individual lymphocytes. Lymphocytes are mobile and circulate in the blood.

Dr. Goldstein was very much aware of the mobile nature of lymphocytes. Reading his books makes that clear.

Lymphocytes have adrenergic receptors.

Exactly. They also have noradrenergic receptors. Since both epinephrine and norepinephrine are neurotransmitters, they can be used by the nervous system to innervate individual lymphocytes, exactly as Goldstein says. For further confirmation of this, @MeSci, Google "lymphocytes epinephrine" and also "lymphocytes norepinephrine".

Clearly he doesn't mean literal innervation.

Actually, he does.

I imagine he's talking about signalling originating in the brain towards lymph organs, reaching the lymphocytes via cytokine signalling as they pass through the organs.

This can also happen.

Well, that would be plausible, but he did say "even individual lymphocytes are directly innervated by nerves from the hypothalamus." (My bolding)

Again, a little work with Google will show how this mechanism has been observed by many. The hypothalamus is where the neural, immune, and endocrine systems all come together. In Goldstein's book Chronic Fatigue Syndromes: The Limbic Hypothesis, he discusses this extensively, providing voluminous references, as usual.

I too am puzzled by the reference to the therapeutic benefits of reducing NO, but NO is a puzzling and perverse compound with a range of properties, probably depending on where it is.

When there is an excess of NO, excessive peroxynitrite can be produced, and this can be very damaging, as peroxynitrite is a powerful oxidant. This is the centerpiece of Dr. Martin Pall's work, but the damaging effects of peroxynitrite are well known in general, and a little research can cover many of them.

As with most other things, some ME/CFS patients have an excess of NO, while others have a deficit. Either type of imbalance can cause problems.

And yes, it is possible for there to be too much NO in part of the brain and too little in another part. Dr. Goldstein found this to be true of many neurotransmitters. Again, much of these findings were based on published research.

I am wondering whether Dr G is/was better at clinical practice than theory.

I think that the simple way to answer that question is to read Dr. Goldstein's books. They are highly technical, but @MeSci, I believe you have the background to understand them. The relevant books are Chronic Fatigue Syndromes: The Limbic Hypothesis, Betrayal by the Brain, and Tuning the Brain, in that order. The first two are quite inexpensive when purchase used on Amazon.com. I have read all three of them, and I have to concur with others who say that these books, and Dr. Goldstein's theories in general, are the work of a genius. (See the quotes by professionals and professional journals at the beginning of these books to see an appreciation of his work by his peers.) In the quote that triggered this discussion, one researcher told Goldstein, "You're twenty years ahead of the times." Actually, it appears that he was much further ahead than that, as most of the ideas in his books have not been accepted by either mainstream medicine or the ME/CFS specialists, and no one has ever come near his success rate at treating ME/CFS patients. His books were published in 1993, 1996, and 2003, respectively.

So yes, Dr. Goldstein was excellent at clinical practice, but this was not by accident. Why has no one else been able to duplicate his treatment successes? The reason is simple and obvious: No one else is basing their treatments on the theoretical foundation developed by him.

@MeSci (and others), I am quite serious about my suggestion of reading Goldstein's books. There are almost 50 pages of references to sound experimental work in Tuning the Brain, with another 70 pages in Betrayal by the Brain; one of Goldstein's unique qualities was that he was able to bridge the gap between experimental neuroscience and clinical practice.

 

[JPV]

It's hard to get a good feeling for this product just from reading about it, but offhand, I don't see any direct connection to Goldstein's work.

It's an ammonia consuming probiotic spray that supposed to boost nitric oxide.

 

[halcyon]

Actually, he does.

I meant in the sense that there aren't nerves growing into lymphocytes.

in·ner·vate
(ĭ-nûr′vāt′, ĭn′ər-)
tr.v. in·ner·vat·ed, in·ner·vat·ing, in·ner·vates
1. To supply (an organ or a body part) with nerves.
2. To stimulate (a nerve, muscle, or body part) to action.

Going with the second definition there, then yes, lymphocytes could of course be stimulated by the brain.

 

[zzz]

It's hard to get a good feeling for this product just from reading about it, but offhand, I don't see any direct connection to Goldstein's work.

It's an ammonia consuming probiotic spray that supposed to boost nitric oxide.

Nitric oxide has many different functions in the body, though. From the AO+ Mist Web site:

Thus, as a crucial first step to skin health, AOBiome aims to re-introduce Nitrosomonas to our skin’s ecosystem in order to restore natural NO levels on the skin.

Dr. Goldstein did not aim to restore natural NO levels on the skin; his use for nitric oxide was for increasing its levels in the brain, using it in its function as a neurotransmitter. That's why I don't see any connection.

 

[MeSci]

I meant in the sense that there aren't nerves growing into lymphocytes.

in·ner·vate
(ĭ-nûr′vāt′, ĭn′ər-)
tr.v. in·ner·vat·ed, in·ner·vat·ing, in·ner·vates
1. To supply (an organ or a body part) with nerves.
2. To stimulate (a nerve, muscle, or body part) to action.

Going with the second definition there, then yes, lymphocytes could of course be stimulated by the brain.

Note that your definition, and this page from Medical Dictionary, refer to organs, body parts, nerves, muscles, etc., not cells, neurons, myocytes, etc. I think all cells have receptors, don't they?

I guess it's just Goldstein using the term in an unconventional way.

I don't doubt Dr Goldstein's expertise generally; I am interested in his ideas and believe that they may indeed be effective, but unfortunately I don't have the time or the brainpower to read books. I have to work - paid and unpaid.

I don't use Google either, for ethical reasons - other search engines are fine and can be used to donate to charity!

EDIT - sorry if this is a bit garbled - masses of things to do as usual so am in a rush. I was addressing @zzz's points in the latter part of the message.

 

[JPV]

Dr. Goldstein did not aim to restore natural NO levels on the skin; his use for nitric oxide was for increasing its levels in the brain, using it in its function as a neurotransmitter. That's why I don't see any connection.

It's not just meant to be a topical treatment. They are currently promoting it that way, as a cosmetic product, until they get FDA approval to make medical claims. If you're interested, Whitlock explains it in more detail in an interview he did back in 2008...

An Engineering Perspective on CFS – by Dave Whitlock

Here are a few excerpts...

I am not a clinician, I am a researcher in NO (nitric oxide) with a chemical engineering background, so I tend to see physiology as a complicated chemical plant with exquisitely complex, precise, distributed and redundant control systems. We are mostly ignorant of the details of that control system, but that there is a control system and that it (usually) functions exquisitely well is beyond doubt. In CFS, much of that disruption results from low basal nitric oxide (my hypothesis).

I have a financial interest in the use of topical ammonia oxidizing bacteria to treat CFS and other things, but that is not yet ready to be available to the public. When the nitric oxide bacteria are available there will be a notice on that site. I have a blog where I discuss my research in NO and how low NO fits into many of the disorders of modern civilization.

The major symptom of CFS is exercise intolerance; that is fatigue brought upon by modest muscle activity. Muscle strength is not greatly decreased, but endurance is. Muscle is aerobic tissue, and to maintain metabolic output must generate ATP via oxidation which only occurs in mitochondria. CFS occurs due to an insufficient ATP production rate by the mitochondria in muscle. An insufficient ATP production rate in muscle comes from not enough mitochondria in those muscles. Chronic not enough mitochondria can only come from a chronic disruption of the regulation of mitochondria turnover and mitochondria biogenesis.

It turns out that NO is a major regulator of ATP level via the common action of ATP and NO on guanylyl cyclase (sGC). Low NO causes low ATP levels which turns off autophagy and which prevents recycling of mitochondria. Mitochondria biogenesis is also triggered by NO through sGC.

Sleep is a period of high NO level. When nitric oxide synthase is inhibited, so is sleep. Disruption of sleep is another major symptom of CFS. Sweating during sleep is another. It is my hypothesis that sweating during sleep occurs to provide ammonia to the bacteria I am working with so that they generate NO/NOx on the skin, some of which is absorbed and that this is an important aspect of normal regulation of NO/NOx physiology.

Martin Pall has presented a hypothesis that CFS results from peroxynitrite damage to mitochondria and other components of cells, and that this peroxynitrite damage is due to too much NO. This is incorrect. Peroxynitrite is a normal and absolutely necessary signaling molecule. Peroxynitrite only occurs in vitro when near equimolar fluxes of superoxide and NO are produced. When there is an excess of either NO or superoxide then peroxynitrite and damage due to peroxynitrite is not observed. In CFS it is observed that there is an increased accumulation of peroxynitrite damaged proteins. At steady state, production minus repair equal accumulation. The accumulation of damaged proteins can occur either from an increased rate of production (at constant repair) (Pall’s hypothesis) or from reduced repair (at constant or even reduced production rate) (my hypothesis).

He also mentions some of the same NO treatments that Goldstein employed and offers explanations as to why they might not be so effective...

Nitroglycerine has been called an NO donor, it is not. It does have some NO/NOx effects, but the precise mechanisms are not well understood. It likely has to do with generation of NO/NOx species in mitochondria, but at the expense of mitochondria aldehyde dehydrogenase (which is destroyed). This is thought to be the mechanism behind what is called “nitrate resistance” where people lose the ability to respond therapeutically to nitroglycerine. Nitroglycerine does cause migraines, and does cause oxidative stress. It may be exerting more of a long term “anti-NO” effect following a short term “NO effect” because of compensatory rebound.

Sildenafil (Viagra). This is not an NO donor, it can potentiate some effects of NO. A major pathway for NO is the activation of soluble guanylyl cyclase and the formation of cGMP. This cGMP relaxes smooth muscle and by doing so sets the vascular tone, and also activates the mechanism that causes erections. When sGC is activated an enzyme (PDE5) is produced that destroys cGMP and so regulates its concentration. Viagra inhibits that enzyme and so increases the amount and lifetime of the cGMP produced by sGC. Only some effects of NO are mediated through cGMP. There is a feedback circuit that down regulates the NO produced when the level of cGMP goes up. With PDE5 inhibited, there is still enough cGMP to produce effects mediated through cGMP. However there is less NO produced, so there are less of the other effects of NO mediated through non-cGMP effects. There was a trial where a single dose of Viagra exacerbated obstructive sleep apnea. There are rare reports of non-arteritic anterior ischemic optic neuropathy associated with use of PDE5 inhibitors. Viagra also causes migraines. I suspect that these side effects are due to feedback inhibition of NO production.

If Viagra did “cure” CFS, that would be readily apparent. It hasn’t been reported, and there isn’t anything in the physiology behind how Viagra works to suggest (to me) that it might. It does interfere with NO physiology in ways that are not completely understood. I suggest that its use be kept to a minimum, that is only for its prescribed indications and then at the minimum dose that is effective while being vigilant for neurological or other side effects. People with CFS may be more susceptible to those side effects due to compromised NO and mitochondria status.

 

[MeSci]

An Engineering Perspective on CFS – by Dave Whitlock

Muscle is aerobic tissue, and to maintain metabolic output must generate ATP via oxidation which only occurs in mitochondria.

I wonder if there are some important gaps in Whitlock's knowledge. I went to the above page and can find no reference to anaerobic ATP production/glycolosis/lactic acid/lactate. Muscle is not 'aerobic tissue' - muscle mitochondria can also produce ATP anaerobically, which causes a rise in lactate levels, especially in ME/SEID. Avoiding that can prevent PEM.

 

[JPV]

I wonder if there are some important gaps in Whitlock's knowledge. I went to the above page and can find no reference to anaerobic ATP production/glycolosis/lactic acid/lactate. Muscle is not 'aerobic tissue' - muscle mitochondria can also produce ATP anaerobically, which causes a rise in lactate levels, especially in ME/SEID. Avoiding that can prevent PEM.

I don't know, I'm not that knowledgable about these things. I'm posting this info in order to encourage more discussion as I find the subject quite compelling.

There's been some discussion of Whitlock's theories on this thread but I'd love to hear more opinions.

 

[JPV]

Since no one else seemed interested, I went ahead and ordered a month's supply of AO+ Mist, which just arrived today. I'll keep everyone posted, if it seems like a promising intervention.

Anyway, here's another interesting NO connection that I just became aware of...

Candida albicans suppresses nitric oxide (NO) production by interferon-gamma (IFN-γ) and lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages (NCBI)

Transcriptional Response of Candida albicans to Nitric Oxide and the Role of the YHB1 Gene in Nitrosative Stress and Virulence (NCBI)

 

[RustyJ]

The hypoperfusion due to ME/CFS was regional, whereas the hypoperfusion due to a successful treatment was global. Exactly how the successful treatment produced the hypoperfusion and what its significance was was apparently something that Dr. Goldstein was unable to determine.

I haven't read the whole thread, so I apologize in advance if this has already been mentioned. I am disturbed that hypoperfusion is increased after nitroglycerin treatment. Could it be simply the imbalance of perfusion which causes symptoms, rather than where in the brain? Then introducing equilibrium globally provides the relief.

So this would not be a cure but more of a hack.

If this is the case, would it not be also possible to argue that a treatment which increases perfusion globally may achieve the same result?

Perhaps Whitlock Pall was leaning in the right direction when he suggested that too much NO may be the cause.

 

[JPV]

Perhaps Whitlock was leaning in the right direction when he suggested that too much NO may be the cause.

I think that it's Pall that maintains that too much NO is an issue. Whitlock seems to think that the problem is not enough NO.

 

[RustyJ]

I think that it's Pall that maintains that too much NO is an issue. Whitlock seems to think that the problem is not enough NO.

Yeh, sorry. Thanks for correcting that.

 

[heapsreal]

I think those with a tendency for high bp would probably get improvements in hypoperfusion with nitrates and those with a tendency for low bp would have a negative effect??

@RustyJ

 

[zzz]

I haven't read the whole thread, so I apologize in advance if this has already been mentioned. I am disturbed that hypoperfusion is increased after nitroglycerin treatment. Could it be simply the imbalance of perfusion which causes symptoms, rather than where in the brain? Then introducing equilibrium globally provides the relief.

The short answer is "No". For the complete explanation why, you need to read Goldstein; there's really no easy way to sum it up. It's a very complex system; much of Goldstein's brilliance lay in his ability to understand and explain its complexity. But you can't make it simple, any more than you can make quantum mechanics simple.

I think those with a tendency for high bp would probably get improvements in hypoperfusion with nitrates and those with a tendency for low bp would have a negative effect??

There's actually no correlation there at all. For example, see @Gingergrrl's thread I took Nitroglycerin tonight and it helped! What does this mean? She relates how nitroglycerin helped her in traditional Goldstein style, even though she has very low BP. Nitroglycerin dropped her BP, but made her symptoms better.

The neurological benefits of nitric oxide found by Goldstein are completely independent of its vasodilatory effects.

 

[Sidereal]

So this would not be a cure but more of a hack.

Definitely a hack and not a cure. But I'd rather have reduced symptoms in the meantime while we wait for a cure that may never come.

 

[heapsreal]

@zzz
i was generalizing with blood pressures as a general rule bp below 100/syst in many health circles its contraindicated as it can drop blood pressure dangerously low, cause fainting etc. Even blood pressures above 100/syst in some it can drop bp too low in those sensitive to it.

 

[Thomas]

I tried calling Goldstein the other day but there was no answer.
But I have a question: I've done 2 IV ascorbate sessions as per the Goldstein protocol and it has either done nothing or made me feel worse (is that even possible?). 20grams of vit c but the naturopath also forgot to tell me that he put b vitamins in there as well.

I felt good the during the day/night after the infusion but since the next day and today I feel very flu like and toxic since receiving the second one two days ago. Thoughts?

I'm also wondering whether I should cancel the third one for next week or try it again minus the b complex. Either way I'lol be pretty useless for the next little while.

 

[Sidereal]

Vitamin C definitely makes me worse. It was liposomal not IV but the same applies.

 

[Thomas]

Thanks @Sidereal i don't know much about methylation and that realm of the ME therapies but do my symptoms I described above sound consistent with what an adverse reaction to B vitamins and/or vitamin c would be?