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

zzz

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Moderator Note -- the first 29 posts of this thread have been split from this thread.

The best way to raise your nitric oxide levels is to take nitroglycerin or one of its relatives. Nitroglycerin is converted directly to nitric oxide by the body.

At the height of my worst episode of ME/CFS, I took a 10 mg tablet of isosorbide dinitrate (Isordil), which is essentially a longer acting form of nitroglycerin. I went from being bed bound to working full time in three days. Within three more weeks, I had achieved complete remission of all symptoms, and I remained that way for almost all of the next eight years. I didn't even need the Isordil during that time.

However, as you may have gathered, I had a major relapse eight years later, a day after some minor surgery. And tolerance to nitroglycerin or isosorbide dinitrate can develop quickly; it never worked the same for me. However, some people are able to derive great benefits from it for long periods of time.
 
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ebethc

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The best way to raise your nitric oxide levels is to take nitroglycerin or one of its relatives. Nitroglycerin is converted directly to nitric oxide by the body.

At the height of my worst episode of ME/CFS, I took a 10 mg tablet of isosorbide dinitrate (Isordil), which is essentially a longer acting form of nitroglycerin. I went from being bed bound to working full time in three days. Within three more weeks, I had achieved complete remission of all symptoms, and I remained that way for almost all of the next eight years. I didn't even need the Isordil during that time.

However, as you may have gathered, I had a major relapse eight years later, a day after some minor surgery. And tolerance to nitroglycerin or isosorbide dinitrate can develop quickly; it never worked the same for me. However, some people are able to derive great benefits from it for long periods of time.
@zzz - That's amazing - thanks for the suggestion! I'll email my doctor & ask her about it.. In addition to more energy, the best part of Arginine was the improved cognitive function... I had mental energy - motivation, better mental planning/organizational skills. Did you find that to be true? Do you know how nitric oxide manages to do that?? Do you think humidity makes your symptoms worse? I noticed that you live in Oregon. I live in the SF Bay Area, and I don't know if I could handle any more damp than I have now... I do love the moderate temps in the Bay Area, though, so there's no perfect place. I notice that I feel great at dry, high altitudes in the Summer... Ideally, I would move w the seasons, but it's hard to live like that.
 

zzz

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@zzz - I had mental energy - motivation, better mental planning/organizational skills. Did you find that to be true?
I had a complete remission of all symptoms - 100%. So although when I was sick, I often couldn't read and comprehend a single sentence in a book, during my remission I was working full time doing advanced software engineering. I felt no different than before my illness; I could work as hard as I wanted and really push myself, and never experience PEM. After a few years into my remission, I thought I had recovered for good. But it later became clear that my final relapse 16 years ago was indeed a relapse and not a second occurrence of ME/CFS when I understood certain events and test results that had happened during my remission that mystified me at the time but in retrospect, indicated that the illness was still present. (It's a long story.)
Do you know how nitric oxide manages to do that??
For a long time, I had no idea whatsoever. I had tried the Isordil because I was having all sorts of cardiac symptoms and dyspnea that were getting worse, but they seemed almost identical to the symptoms of a friend of mine who was visiting and who had chronic heart problems. I didn't think there was anything wrong with my heart, but I thought, hey, if this medicine works for her, maybe it will at least clear up these heart symptoms and breathing problems. So I took one of her pills. A few minutes later, the classic nitrate headache started coming on strong. (Don't take nitrates if you have migraines.) But at the same time the headache started coming on, all my ME/CFS symptoms started melting away, and I felt my old energy starting to return, literally minute by minute. This was completely unexpected. I was really sick, so it took three days to get to the point where I could work full time. On the second and third day, I also took a quarter tablet of Isordil, but it's not clear if that contributed to my recovery.

This was back in 1990, before the Web, and when almost no one knew much about ME/CFS. It was only a few years later that I read that other people sometimes found nitroglycerin useful. Finally, just a few months ago, I discovered the source of this knowledge. In 1996, Dr. Jay Goldstein published Betrayal by the Brain, in which he listed 23 medications that either singly or in combination could produce either partial or full remission of ME/CFS in most people, often in a matter of a day or two - just as I had experienced. Nitroglycerin was #2 on his list. In a section called "Limbic Regulation by Nitric Oxide," he spends eight pages answering your question about how nitric oxide works. That's a little much for me to type in here, but the first sentence is quite revealing: "Nitric oxide (NO) is the primary vasodilator in the brain."

This book plus its successor, Tuning the Brain, published in 2003, effectively form a single volume where the Goldstein protocol is defined. I finally figured out how to follow it a few months ago, and I've had excellent results so far.
Do you think humidity makes your symptoms worse?
No, it doesn't. And we certainly have plenty of humidity here. But this is one of those things that varies from person to person.
 

ebethc

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ISo I took one of her pills. A few minutes later, the classic nitrate headache started coming on strong. (Don't take nitrates if you have migraines.) But at the same time the headache started coming on, all my ME/CFS symptoms started melting away, and I felt my old energy starting to return, literally minute by minute.
@zzz - I do get migraines... actually, really bad sinus headaches; they're very localized and not any aura nor are they tension related. 2 sinus surgeries this year to make my sinuses bigger so that swelling doesn't completely close sinuses off & "strangle" my brain, reducing blood flow/oxygen.. Headaches are better since surgery. My sinuses, throat and lungs are constantly irritated & swollen. Hard to breathe & think... The tissue is stimulated by weather changes (esp low baro pressure), humidity and any kind of particulate matter irritates them (strangely, not allergies; my doc said it's the fact that pollen/dust/etc are particles, not an Ig reaction..). There's some relationship between N.O.-> baroreceptors (modulate the body's response to baro pressure) -> NMDA receptors -> release Norepinephrine (which stimulates attention).. Hence, the clearing of brain fog when I have N.O! At least, that's what I think is happening from what I've read tonight & before..

I'll ask my doc...I definitely didn't get any headache or migraine w Arginine, so maybe that's a good sign for N.O. and me. I checked and Isordil comes in 5 mg pills, so maybe I could try a small dose. We'll see what my doc says...

thanks again.
 

Hip

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At the height of my worst episode of ME/CFS, I took a 10 mg tablet of isosorbide dinitrate (Isordil), which is essentially a longer acting form of nitroglycerin. I went from being bed bound to working full time in three days. Within three more weeks, I had achieved complete remission of all symptoms, and I remained that way for almost all of the next eight years. I didn't even need the Isordil during that time.

However, as you may have gathered, I had a major relapse eight years later, a day after some minor surgery.
@zzz, that is an extraordinary story! I read your above-quoted post, and then started reading several more of you forum posts (some of which I have quoted below) on your ME/CFS remission for 8 years after taking just one isosorbide dinitrate tablet. I am amazed. It seems that there could be much to learn here; your remission could shed a lot of light on the nature of ME/CFS.

May I ask, did any physical ME/CFS symptoms you may have had also go into remission after taking the single dose of isosorbide dinitrate? Physical symptoms such as cardiac problems, orthostatic intolerance, bowel symptoms, muscle weakness or pain, cold hands and feet, swollen lymph nodes, recurrent sore throat, blurred vision.


Dr. Jay Goldstein published Betrayal by the Brain, in which he listed 23 medications that either singly or in combination could produce either partial or full remission of ME/CFS
For anyone interested, Dr Goldstein's list of 23 best ME/CFS medications is to be found here. I will just copy this list below:
Dr Jay Goldstein's Top 23 Drugs For ME/CFS Treatment

Drug | Time to Onset of Action | Duration of Action

(1) Naphazoline HCL 0.1% eye drops | 2 - 3 seconds | 3 - 6 hours
(2) Nitroglycerin 0.04 mg sublingual | 2 - 3 minutes | 3 - 6 hours
(3) Nimodipine 30 mg oral | 20 - 40 minutes | 4 - 8 hours
(4) Gabapentin 100 to 800 mg oral | 30 minutes | 8 hours
(5) Baclofen 10 mg | 30 minutes | 8 hours
(6) Oxytocin 5 to 10 U intramuscular, or twice daily;
OR: Syntocinon 1 or 2 puffs three times a day | 15 minutes - 72 hrs | 12 - 24 hours
(7) Pyridostigmine 30 to 60 mg oral | 30 minutes | 4 - 6 hours
(8) Hydralazine 10 to 25 mg oral | 30 - 45 minutes | 6 - 12 hours
(9) Mexiletine 150 mg oral | 30 - 45 minutes | 6 - 8 hours
(10) Tacrine 10 mg | 30 minutes | 4 - 6 hours
(11) Risperidone 0.25 to 0.5 mg | 45 - 60 minutes | 8 - 12 hours
(12) Pindolol 5 mg twice a day | 15 minutes - 7 days | 12 hours
(13) Lamotrigine 25 to 50 mg four times a day | 30 - 45 minutes | 24 hours
(14) Sumatriptan 3 - 6 mg subcutaneous | 15 - 30 minutes | 16 hours
(15) Ranitidine 150 mg twice a day | 1 hour - 1 week | 12 - 24 hours
(16) Doxepin HCL elixir 2 - 20 mg at bedtime | 1 hour | variable
(17) Sertraline 25 to 50 mg every day before noon;
OR: Paroxetine 10 to 20 mg every day before noon | 1 hour - 8 weeks | 1 - 2 days
(18) Bupropion 100 mg three times a day | 30 minutes - 8 weeks | 8 - 24 hours
(19) Nefazodone 100 to 300 mg twice a day | 2 - 8 weeks | 24 hours
(20) Venlafaxine 37.5 to 75 mg twice a day | 1 - 4 weeks | 24 hours
(21) Glycine powder 0.4 grams per Kg of body weight daily in juice;
OR: Cycloserine 15 to 20 mg four times a day | 1 hour | 24 hours
(22) Felbamate 400 mg | 30 minutes | 6 - 8 hours
(23) Lidocaine 200 to 300 mg

I have just today ordered a copy of Betrayal by the Brain, which you can buy for around £5 second hand.

@zzz, is the book Tuning the Brain that you are reading more useful than the book Betrayal by the Brain, in terms of an ME/CFS patient trying to follow Goldstein's treatment protocol? Or are both books similar?

Is there anywhere in his books where Goldstein provides a flow diagram to follow, for systematically testing out the effects on a patient of the various drugs he recommends for ME/CFS?

Yet at the beginning of Tuning the Brain, which was written shortly before his retirement, he claimed he had reached the point where he could make 97% to 98% of his patients completely asymptomatic, usually in a matter of days or less.
Is it really true that Goldstein could make 97% to 98% of his ME/CFS patients completely asymptomatic? Surely if this were the case, we would have heard much more about Goldstein's protocols in the ME/CFS community.

I am fascinated by your story of a complete remission from ME/CFS by one single tablet of isosorbide dinitrate, but I would guess that Goldstein did not obtain complete, long lasting remission for his ME/CFS patients all that often. The 98% figure seems very improbable: he has apparently treated 20,000 ME/CFS patients, so there must be thousands of these patients still in remission; but I don't see them posting their success stories on the ME/CFS forums. Of course, it could be that most are too busy living their lives to concern themselves with the ME/CFS community. However, you might expect at least to hear a few Goldstein success stories on the ME/CFS forums.

Or could it be that Goldstein's treatments often provided just temporary remissions from ME/CFS? You mentioned in one of your posts that it was not uncommon for many of Dr. Goldstein's treatments to lose their effects after a while, especially nitroglycerin.

By the way, your post here, in which you mention Goldstein's claim that for his mononucleosis patients, Zantac usually got rid of all the symptoms in a day or two; well, that claim does not seem to square with this double-blind, placebo-controlled study that found Zantac had little effect on mononucleosis. Any idea why that should be?
 
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Hip

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@zzz
Do you have any more info from Goldstein's books on how long the isosorbide dinitrate or nitroglycerin treatments for ME/CFS keep working, before they start to lose their effects?

I have an idea of what might be causing nitroglycerin to lose its effects — and possibly a way to reset the system so that nitroglycerin begins working again.
 

picante

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@zzz
Do you have any more info from Goldstein's books on how long the isosorbide dinitrate or nitroglycerin treatments for ME/CFS keep working, before they start to lose their effects?

I have an idea of what might be causing nitroglycerin to lose its effects — and possibly a way to reset the system so that nitroglycerin begins working again.
YES??? Don't leave us in suspense!
 

zzz

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@zzz, that is an extraordinary story! I read your above-quoted post, and then started reading several more of you forum posts (some of which I have quoted below) on your ME/CFS remission for 8 years after taking just one isosorbide dinitrate tablet. I am amazed. It seems that there could be much to learn here; your remission could shed a lot of light on the nature of ME/CFS.
I think so too. Since the onset of this illness can be very sudden (you can see my story here), wouldn't it be possible that a remission could be very sudden as well? Dr. Goldstein seems to have demonstrated this thousands of times.

I mentioned in that story that my last relapse 16 years ago took place in a period of about two seconds. In that time, I went from feeling completely healthy to feeling very sick all throughout my body. There's only one thing that travels that fast through the body, and that's nerve impulses. The basis of Dr. Goldstein's theory was that one or more neural networks in the brain were not working properly in this illness, and that these neural networks could be reset with the correct medications.

A while ago, I posted a version of my story on Cort Johnson's Health Rising site. Cort posted the following response; the quote in it was from my original post:
What an amazing story zzz– very compelling. How to explain the acute onset is a fascinating problem. I’m surprised more researchers aren’t interested…

Time will tell and it may be not be the entire picture but I think Goldstein was right

“Chronic Fatigue Syndrome is a disorder of the management of sensory input by the brain. Information from inside and outside the body is misperceived, resulting in inappropriate sensations. Touch can be painful, odors can cause illness, climbing a flight of stairs can be like climbing a mountain. If input is dysregulated, output will be also, because the brain will make regulatory decisions based on improper ‘data processing’”.

Thanks for the quote.

I could never make it through Goldstein’s books – they’re so complicated – but I think I should try again.
Everyone finds the books difficult to read, but I found them much easier on the second pass. @Hip, I've been meaning to contact you about these books, since this seems like this is right up your alley. Many of the subjects and medications you've addressed in various threads are also addressed directly by Dr. Goldstein.
May I ask, did any physical ME/CFS symptoms you may have had also go into remission after taking the single dose of isosorbide dinitrate? Physical symptoms such as cardiac problems, orthostatic intolerance, bowel symptoms, muscle weakness or pain, cold hands and feet, swollen lymph nodes, recurrent sore throat, blurred vision.
All my symptoms disappeared completely, except for the brief relapses that I mention in my story. The last five years of my remission I was symptom free with no relapses. I thought I was cured.

When I had my final relapse 16 years ago, some of the symptoms I had earlier never appeared with the intensity that they first had. These include cognitive dysfunction, memory problems, and TMJ syndrome (which never appeared again at all).
For anyone interested, Dr Goldstein's list of 23 medications is to be found here.
That was just as of his 1996 book, Betrayal by the Brain. By the time Tuning the Brain was published in 2003, Dr. Goldstein was using over 140 medications. That's how he was able to get his success rate up so high.
I have just today ordered a copy of Betrayal by the Brain, which you can buy for around £5 second hand.

@zzz, is the book Tuning the Brain that you are reading more useful than the book Betrayal by the Brain, in terms of an ME/CFS patient trying to follow Goldstein's treatment protocol? Or are both books similar?
The two books really form a single conceptual volume. Both are necessary to understand his work. Receptor profiling, which is what replaced the list of 23 medicines and what allowed him to know which of his 140 medicines were most likely to help a patient, is explained only in Tuning the Brain. This book is about twice the size of Betrayal by the Brain, and I find that I use it a lot more in my treatment based on this protocol, which I started in August.
Is there anywhere in his books where Goldstein provides a flow diagram to follow, for systematically testing out the effects on a patient of the various drugs he recommends for ME/CFS?
Yes; at the back of Tuning the Brain, Dr. Goldstein provides such a chart. It contains far fewer than the total of 140 drugs, but it does contain a few dozen of the most common ones. All the drugs he uses are listed in the pages after this chart. They're merely listed in alphabetical order, but after a while, you get a feel for how the whole process works, and the chart is not so important. Also, it's not 100% correct, as Dr. Goldstein acknowledges; the workings of the human brain are far too complex to be summarized in a simple chart.

Nevertheless, the chart is very helpful, especially when learning receptor profiling. Fortunately, @MNC posted a copy of the chart, along with a summary of how receptor profiling works, here. Although the chart looks a bit blurry, that's how it is in the book, too.
Is it really true that Goldstein could make 97% to 98% of his ME/CFS patients completely asymptomatic?
No; that figure includes patients who were significantly improved. In his terminology, these were people who could go back to work full time or mostly so, but still had some symptoms.
Surely if this were the case, we would have heard much more about Goldstein's protocols in the ME/CFS community.
Even with the qualification I added above, you would think so. The reasons why we haven't are complex; they're explained at the beginning of Betrayal by the Brain, and there's more detail given at the beginning of Tuning the Brain.

Nevertheless, for 20,000 patients to have come to see him (most from out of town), he had to be well known in his day. And indeed he was. In 2002, when it was clear that I was not going to get better on my own, I researched all the CFS specialists working at the time, and decided that Dr. Goldstein sounded like the best. I moved from Boston to Oregon in early 2003, with the intention of going down to California to see Dr. Goldstein once I got settled. By the time my move was complete in the spring of 2003, Dr. Goldstein had retired.

Still, there are influential people in the ME/CFS community who appreciate his work and have done their best to keep it alive. Dr. Goldstein's treatments are mentioned prominently both in Reviving the Broken Marionette and Chronic Fatigue Syndrome; a Treatment Guide (2nd Edition), which I think are the two best general treatment guides for ME/CFS available.. @Hip, I know that you got the list of Dr. Goldstein's medications from Erica Verrillo's Web site; she is the author of the second book. Here is an excerpt from an interview with her last year by Cort Johnson:
3) You’ve written two books on ME/CFS and you’ve had the disease for a long time. I noticed that you included Goldstein’s recommendations in this book. He was a very innovative physician with some really good ideas, but he was also a tough read and I think he’s being forgotten a bit. As someone who has kind of a historical overview of this disease do you see any other kind of gaps in knowledge that are appearing over time?

Jay Goldstein was way ahead of his time. His limbic hypothesis was an accurate account of how homeostasis is disrupted by CFS/ME. I still believe that damage to this very fragile part of our CNS is what produces the sympathetic dysregulation that characterizes this illness in both its acute and chronic stages. On a very basic level, CFS/ME manifests itself as a form of dysautonomia, and Jay Goldstein said it first. Unfortunately, his book is almost impossible to read, which is why the companion volume was written. That being said, researchers need to go back and re-read Goldstein’s book. Otherwise, they are just reinventing the wheel.
Returning to your post...
I am fascinated by your story of a complete remission from ME/CFS by one single tablet of isosorbide dinitrate, but I would guess that Goldstein did not obtain complete, long lasting remission for his ME/CFS patients all that often. The 98% figure seems very improbable: he has apparently treated 20,000 ME/CFS patients, so there must be thousands of these patients still in remission; but I don't see them posting their success stories on the ME/CFS forums. Of course, it could be that most are too busy living their lives to concern themselves with the ME/CFS community.
This is my impression.
However, you might expect at least to hear a few Goldstein success stories on the ME/CFS forums.
I think that that may have been more true at the time he was working than now. There are only a few people on this forum who have actually been patients of Dr. Goldstein's; as you might expect, they were in the group that he failed to help. Yet all the patients I've heard from seem to have a good deal of respect for Dr. Goldstein, whether or not they were helped. I haven't seen any former patients accusing him of being a fraud, for example.

You can see a fascinating description of a typical day at Dr. Goldstein's office (including one of his instant cures) in the last entry of Kelvin Lord's blog, Everything I Needed to Know About Managing My Health I Learned at Disneyland.
Or could it be that Goldstein's treatments often provided just temporary remissions from ME/CFS? You mentioned in one of your posts that it was not uncommon for many of Dr. Goldstein's treatments to lose their effects after a while, especially nitroglycerin.
When this would happen, Dr. Goldstein would look for a replacement therapy that would help the patient. Most of the time, he found one.
By the way, your post here, in which you mention Goldstein's claim that for his mononucleosis patients, Zantac usually got rid of all the symptoms in a day or two; well, that claim does not seem to square with this double-blind, placebo-controlled study that found Zantac had little effect on mononucleosis. Any idea why that should be?
I saw that study. Like most studies, it's hard to know exactly how it was done, how strict the methodology was, etc. But one thing I noticed is that they used twice the dose of Zantac that Dr. Goldstein used. This could be a confounding factor.

Anecdotally, I've seen some people say that they get better results with Tagamet than with Zantac. The essential difference between the two drugs is that Tagamet crosses the blood brain barrier, whereas Zantac does not. This also means that Tagamet has a lot more side effects than Zantac, which is why Dr. Goldstein switched from Tagamet to Zantac when Zantac came out.
Do you have any more info from Goldstein's books on how long the isosorbide dinitrate or nitroglycerin treatments for ME/CFS keep working, before they start to lose their effects?
As with all his drugs, it varied completely by patient, and was unpredictable. Some people could use nitroglycerin patches indefinitely.
I have an idea of what might be causing nitroglycerin to lose its effects — and possibly a way to reset the system so that nitroglycerin begins working again.
I would certainly be very interested to hear about this.

Meanwhile, I should report that Dr. Goldstein's protocol has been working very well for me; I've gone from a 2 to a 4 in activity level since I started it in August. I am hampered by the fact that I have severe tinnitus reactions to drugs at this point, and the vast majority of drugs, including the ones Dr. Goldstein used, can cause tinnitus. Nevertheless, I am continuing to make progress.

@Hip (and others as well), I hope you find this helpful. I think you will find Dr. Goldstein's books fascinating.

[If people want to continue this discussion, it might be good either to continue it the Betrayal by the Brain thread, or to start a new thread, so as not to hijack the current thread. And please leave a link here to the new location as well. Thanks!]
 
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Hip

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@zzz
One observation: given that your ME/CFS went into full remission with dramatic speed after a single dose of isosorbide dinitrate, without requiring any further doses, it seems quite likely that your ME/CFS was being maintained by the brain getting locked into a disease state that was a self-perpetuating.

Taking the isosorbide dinitrate then knocked your brain out of this particular self-perpetuating state of equilibrium, when then allowed your brain to settle back into its normal healthy equilibrium state. Once this healthy equilibrium state was achieved from a single isosorbide dinitrate dose, you no longer needed any further doses, because you brain had now settled back into its self-maintaining state of normal health.

As an example of how this might work: the self-maintaining disease state of ME/CFS might conceivably be due to a vicious circle involving cerebral vasoconstriction and low blood circulation to the brain; this low blood flow might allow a build-up of reactive oxygen species in the brain, which then causes greater microglial activation, which in turn further increases the creation of reactive oxygen species (since activated microglia produce ROS), and this lead to a self-maintaining vicious circle, and a state of disease. Then once you took the isosorbide dinitrate which dilated all your cerebral blood vessels, the brain was knocked out of this self-maintaining disease state, and settled back into a healthy state.

I am not saying this ROS idea is necessarily what is happening in ME/CFS; it is just given as an example of how a self-perpetuating disease state might arise.



Since the onset of this illness can be very sudden (you can see my story here), wouldn't it be possible that a remission could be very sudden as well? Dr. Goldstein seems to have demonstrated this thousands of times.
That's an interesting point: perhaps the sudden onset variety of ME/CFS (ie, onset in a matter of days) may have a different metabolic etiology to gradual onset (one that manifests over months or a year). Mine was a gradual onset, after a viral infection which began as a bad sore throat. Did your ME/CFS involve any initial infection that you contracted, as far as you are aware?

I wonder if Goldstein published any data regarding the type of ME/CFS patients (sudden or gradual onset) that could sometimes be instantly placed into remission using nitroglycerin.



Dr. Goldstein's treatments are mentioned prominently both in Reviving the Broken Marionette and Chronic Fatigue Syndrome; a Treatment Guide (2nd Edition), which I think are the two best general treatment guides for ME/CFS available.
I have an ebook version of the second book (Erica Verrillo's), which I have started to look at. And I notice that in the free abridged eBook version of Maija Haavisto's book Reviving the Broken Marionette, there is also quite a lot of mention of Goldstein's treatments.
 
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Hip

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What Might Be Causing Isosorbide Dinitrate / Nitroglycerin To Lose Its Effect?

To begin with, note that the mechanism of action of nitroglycerin-induced vasodilation is still being debated, but it appears nitroglycerin may achieve vasodilation through inducing the enzyme endothelial nitric oxide synthase (eNOS), which generates the nitric oxide and this acts to dilate the blood vessels.

My hunch is that nitroglycerin may lose its effect if gene expression of eNOS gets down-regulated for some reason, such that there is then resistance to the vasodilating action of nitroglycerin.

How might eNOS expression get down-regulated? Nitric oxide (NO) biochemistry expert Dave Whitlock said that in hospital, when sodium nitroprusside is used to control blood pressure (it generates NO), the expression of eNOS thereafter gets down-regulated, due to all the excess NO from sodium nitroprusside. It can then be very difficult to get eNOS expression back to normal. So excess NO can lock eNOS into a down-regulated state.

Now another source of excess NO occurs via the enzyme iNOS, which is secreted by the immune system, and in particular, by microglia in the brain. Like eNOS, iNOS produces NO; but iNOS generates NO in far greater amounts than eNOS. The immune system uses this NO to fight pathgoens, since NO has potent anti-microbial properties. But if you have an ongoing infection or inflammation in the brain generating lots of NO through iNOS, then you might expect eNOS to get down-regulated. Dave Whitlock call this condition "low NO ratchet," and he explains it in his blog.


But what might be the mechanism of eNOS down-regulation? My idea is that an epigenetic mechanism may be involved.

One epigenetic mechanism that appears to be involved in eNOS expression is histone acetylation, as we will see below.

What is histone acetylation? Well the following precis extract from this article explains the how epigenetic mechanism of histone acetylation works:
When an acetyl group is attached to a histone, the DNA becomes less tightly bound, so that its genes can be more easily expressed. Conversely, removing acetyl groups from a histone inhibits access to the genes, effectively silencing the genes. A histone deacetylase (HDAC) is an enzyme that removes acetyl groups, so it is a mechanism for silencing groups of genes. About 11 HDACs are known.

Now this study found a very interesting connection between histone deacetylase 1 (HDAC1) and eNOS gene repression:
Induction of eNOS expression by histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate was observed in all four different types of non-endothelial cells examined.

Our data suggest that HDAC1 plays a critical role in eNOS repression.
So this suggests that HDAC inhibitor sodium butyrate, which is available as a supplement, might help make epigenetic changes that then stops the repression of eNOS expression, allowing eNOS to do its job of dilating blood vessels; and in addition, it's conceivable that sodium butyrate will help nitroglycerin to regain its effect.

This Wikipedia article lists some HDAC inhibitors that may also be beneficial for this purpose; but I think you may need to specifically employ HDAC1 inhibitors. Some HDAC1 inhibitors is listed here.


It's interesting that coxsackievirus B3 acetylatizes histones during viral replication, and that the HDAC inhibitor trichostatin A protects against CVB3-induced myocardial injury.

Note though that all the above speculation about the involvement of histone acetylation in the development of nitroglycerin tolerance is just mine. But there has been research into the reason why nitroglycerin tolerance develops: this study looking at the mechanism of nitroglycerin tolerance suggested superoxide involvement; and this study suggested that nitroglycerin tolerance is multifactorial.



Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction

This study found that folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction; the authors hypothesis that tetrahydrobiopterin (BH4) is involved. And this study demonstrates that folic acid reverses the endothelial dysfunction induced by BH4 depletion.

So folic acid and BH4 supplementation may help nitroglycerin regain its vasodilating effect. You can buy BH4 in 2.5 mg capsules at these places: 1, 2, 3, 4. But 2.5 mg is quite low compared to the 100 mg found in the prescription BH4 medication called Kuvan. This paper says sauna may help raise BH4. I understand that BH4 is sensitive to degradation by free radicals, so you would be advised to take antioxidants when you take BH4.

More info on BH4 as an essential cofactor for the activation of nitric oxide synthase is found in this article. It mentions that methylfolate (L-5-MTHF) may help substitute for BH4 when BH4 is deficient.
 
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zzz

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One observation: given that your ME/CFS went into full remission with dramatic speed after a single dose of isosorbide dinitrate / nitroglycerin, without requiring any further doses, it seems quite likely that your ME/CFS was being maintained by the brain getting locked into a disease state that was a self-perpetuating.

Taking the isosorbide dinitrate then knocked your brain out of this particular self-perpetuating state of equilibrium, when then allowed your brain to settle back into its normal healthy equilibrium state. Once this healthy equilibrium state was achieved from a single isosorbide dinitrate dose, you no longer needed any further doses, because you brain had now settled back into its self-maintaining state of normal health.
That's exactly what I think happened, and it seems completely consistent with Dr. Goldstein's theories. It has long been noted that the longer you have ME/CFS, the more difficult it is to recover. I can see that this can be explained by understanding that the longer the affected neural networks are in their diseased state, the more long term potentiation occurs in that state, and the more difficult it is to move them out of that state. Based on Dr. Goldstein's results, it is always possible, though, at least in theory, although multiple doses and possibly a maintenance dose may be required to keep them out of the diseased state.
As an example of how this might work: the self-maintaining disease state of ME/CFS might conceivably be due to a vicious circle involving cerebral vasoconstriction and low blood circulation to the brain; this low blood flow might allow a build-up of reactive oxygen species in the brain, which then causes greater microglial activation, which in turn further increases the creation of reactive oxygen species (since activated microglia produce ROS), and this lead to a self-maintaining vicious circle, and a state of disease. Then once you took the isosorbide dinitrate which dilated all your cerebral blood vessels, the brain was knocked out of this self-maintaining disease state, and settled back into a healthy state.
Initially, Dr. Goldstein would do SPECT scans of his patients before and after treatments. What he found extremely surprising (I believe he says he was "shocked") was that for those medications that had an immediate effect, the SPECT scans directly afterwards show dramatic hypoperfusion in the brain. If the medication did not have an effect, perfusion was normal. This hypoperfusion occurred regardless of which medication caused the improvement. Betrayal by the Brain has some interesting color pictures of these SPECT scans.

The instantaneous reactions were not limited to nitroglycerin, although for standard oral drugs they could take up to 30 to 60 minutes. One of Dr. Goldstein's favorite medications was naphazoline eye drops 0.1% (prescription strength) because when they worked, they worked in two or three seconds. Very often when they worked (which was about 20% of the time), they would relieve all symptoms. He would formulate some of his medications for nasal use when he could, since the olfactory nerves go straight to the brain. He describes how this worked with patients:
Even though my nurse tells new patients what to possibly expect ("Don't feel surprised if you feel better in thirty seconds." "Yeah, right, after I've seen over twenty-five doctors and spent my life savings"), they are understandably flabbergasted when his prediction comes true.
He has some interesting descriptions of the looks on patients' faces when symptoms that they've had for decades disappear in seconds.
That's an interesting point: perhaps the sudden onset variety of ME/CFS (ie, onset in a matter of days) may have a different metabolic etiology to gradual onset (one that manifests over months or a year). Mine was a gradual onset, after a viral infection which began as a bad sore throat. Did your ME/CFS involve any initial infection that you contracted, as far as you are aware?
On May 31st, 1990, I felt a little feverish for a bit, but then it passed. The next couple of days, I started getting unusual prostate symptoms. By the end of the second day of this, I was getting GI symptoms as well, and starting to develop a low-grade fever. It was looking more and more like the flu, and although I felt sick, I went into work for the next week and a half and managed to struggle through the day. The "flu" remained more or less at constant intensity.

Then, on the morning of June 12th, when I woke up, it felt like I had been run over by the proverbial truck during the night. This was not the same disease I'd had the last week and a half. This wasn't any disease I'd ever had. The only thing I could think it might be was CFS, which I had read about a year previously in Time Magazine. (Time's coverage of the disease in 1989 was a lot more accurate than what you still see in many places today. Sigh.) CFS was my working hypothesis, and nothing ever caused me to change it.

Now just to make things complicated, a few months before I had returned from living in Nepal for two years, where I had gotten giardia multiple times. Not only is giardia a known trigger for ME/CFS (and a very high risk factor), but it is the only pathogen known to have caused ME/CFS outbreaks. (See Osler's Web.) On top of that, my giardia was always treated (successfully) by Bactrim, another risk factor for ME/CFS. About a month before I came down with my "flu", I was treated with Cipro for an infection - as a fluoroquinolone, it's yet another risk factor for ME/CFS. I hallucinated after the first dose and stopped it immediately. Finally, a few days before I came down with my "flu", I finished a ten-day retreat in the New York Berkshires - the heart of Lyme disease country. Lyme was so widespread there that we were given a special talk on watching out for the ticks and what to do if you found one on you. I did eventually rule out Lyme disease, however.
I wonder if Goldstein published any data regarding the type of ME/CFS patients (sudden or gradual onset) that could sometimes be instantly placed into remission using nitroglycerin.
I'm rather sure he did not. Again, in his practice, nitroglycerin was just one of many drugs that could put people into instant remission. Whether or not they experienced such a remission seemed to have nothing to do with their illness history, as Goldstein's case reports illustrate.

I also wanted to revisit one question you raised in your initial post on this subject:
By the way, your post here, in which you mention Goldstein's claim that for his mononucleosis patients, Zantac usually got rid of all the symptoms in a day or two; well, that claim does not seem to square with this double-blind, placebo-controlled study that found Zantac had little effect on mononucleosis. Any idea why that should be?
I don't have any further answers to that specific question, but wanted to add that Dr. Goldstein also used Zantac for treatment of CFS. He started this when CFS was known as "Chronic Epstein-Barr Virus", and found that it helped about 20% of his patients. So once it became clear that EBV was not the causative agent behind CFS, he still continued using Zantac, since it worked for some people. There is even a thread here on PR started by someone who says of Tagamet, "I've been taking it for about a month, and I am 90% recovered after a very long, painful relapse." The first link cited by the poster refers to Dr. Goldstein's findings. The thread went for 12 pages, and then people apparently forgot about this. The original poster, faith.hope.love, has not been seen on PR since her final post in the thread, presumably due to her recovery.
 
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Hip

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Initially, Dr. Goldstein would do SPECT scans of his patients before and after treatments. What he found extremely surprising (I believe he says he was "shocked") was that for those medications that had an immediate effect, the SPECT scans directly afterwards show dramatic hypoperfusion in the brain. If the medication did not have an effect, perfusion was normal. This hypoperfusion occurred regardless of which medication caused the improvement. Betrayal by the Brain has some interesting color pictures of these SPECT scans.
Very interesting indeed. I take it you meant to write that the brain showed hyperperfusion after a successful treatment, rather than hypoperfusion. That is to say, the treatment led to increased blood flow to the brain.

This makes me think that vasoconstriction in the brain could be a key disease-maintaining factor in ME/CFS. And as I speculated in my above post, it could be that endothelial nitric oxide synthase (eNOS), which generates the nitric oxide that dilates the blood vessels, is down-regulated in ME/CFS, leading to chronic hypoperfusion in the brain.


I had gotten giardia multiple times. Not only is giardia a known trigger for ME/CFS (and a very high risk factor), but it is the only pathogen known to have caused ME/CFS outbreaks. (See Osler's Web.) On top of that, my giardia was always treated (successfully) by Bactrim, another risk factor for ME/CFS. About a month before I came down with my "flu", I was treated with Cipro for an infection - as a fluoroquinolone, it's yet another risk factor for ME/CFS.
I have not come across Bactrim or fluoroquinolones being risk factors for ME/CFS. I actually take Bactrim now and then if I have a flare up of my recurrent urinary tract infection.

By the way, a single dose of tinidazole or ornidazole has been shown to be curative in 90% of Giardia cases.


There is even a thread here on PR started by someone who says of Tagamet, "I've been taking it for about a month, and I am 90% recovered after a very long, painful relapse." The first link cited by the poster refers to Dr. Goldstein's findings. The thread went for 12 pages, and then people apparently forgot about this.
Very interesting thread indeed. A 90% recovery in ME/CFS just from taking the H2 receptor antagonist Tagamet (cimetidine) for a month is very impressive. Though I note though in this post of the thread, made 3 years later, @faith.hope.love had a relapse. But nevertheless very thought-provoking.

I actually tried H2 receptor antagonist famotidine (Pepcid) 60 mg daily, but stopped after two days as it made me extremely vague and very unaware (in a different way to normal brain fog). A thread detailing my famotidine experience is here. Though note that famotidine is associated with mental confusion in elderly patients, so perhaps I would have been better off trying Tagamet or Zantac.
 

Hip

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In terms of improving brain vasodilation and brain blow flow in ME/CFS, one experiment I performed a few years ago was breathing carbon dioxide gas, which is a potent cerebral vasodilator.

The method and results of my carbon dioxide breathing experiments are detailed in the first post of this thread (archived on the Wayback Machine). In the light of Dr Goldstein's amazing treatments for ME/CFS using the vasodilator nitroglycerin, and your experience with isosorbide dinitrate, I might try my carbon dioxide breathing treatment again soon.

Though I am not sure if CO2 breathing is safe. There might be serious risks involved in breathing carbon dioxide, especially at high concentrations, so I don't recommend that anyone try this. I know my blood oxygen level (as measured by a pulse oximeter) goes down from around 99% to around 92% for about 30 seconds as I breath in the CO2. But I don't hold the CO2 in my lungs for more than around 10 seconds (mainly because I very rapidly get very light headed as I breath in the CO2, and feel as though I may pass out if I don't quickly expel the CO2 again from my lungs).
 
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zzz

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Very interesting indeed. I take it you meant to write that the brain showed hyperperfusion after a successful treatment, rather than hypoperfusion. That is to say, the treatment led to increased blood flow to the brain.
@zzz, was it hypo or hyper in those scans?
It was hypoperfusion - decreased blood flow to the brain. That's why Dr. Goldstein was shocked - it's completely counterintuitive. But you can see it quite clearly in the pictures in his book; it's a fairly significant reduction. And he always found this after a successful treatment, regardless of the medicine.. He also discusses this phenomenon in a number of places.
 
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Hip

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It was hypoperfusion - decreased blood flow to the brain. That's why Dr. Goldstein was shocked - it's completely counterintuitive. But you can see it quite clearly in the pictures in his book; it's a fairly significant reduction. And he always found this after a successful treatment, regardless of the medicine.. He also discusses this phenomenon in a number of places.
Hmmm, I am very confused about this. Studies have shown that ME/CFS patients already have cerebral hypoperfusion, especially in the brainstem, in comparison to healthy controls; yet Goldstein found that after a successful treatment for ME/CFS, this hypoperfusion actually increased?!

Could it be that the pattern of hypoperfusion after one of Dr Goldstein's successful ME/CFS treatments was different to the pattern of hypoperfusion before treatment? In other words, might it be not so much in the degree of hypoperfusion that counts in ME/CFS etiology, but rather where in the brain the hypoperfusion occurs? Did the SPECT scans Goldstein had taken show where in the brain the increases in hypoperfusion occurred as a result of succesful treatment?
 
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zzz

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Hmmm, I am very confused about this.
You can imagine how Dr. Goldstein felt when he first saw it.
Studies have shown that ME/CFS patients already have cerebral hypoperfusion, especially in the brainstem, in comparison to healthy controls; yet Goldstein found that after a successful treatment for ME/CFS, this hypoperfusion actually increased?!
Yes, that's exactly what he found. Here is the caption under the first two sets of pictures of SPECT scans:
A typical pre- and post-exercise or pre- and post-treatment Xenon Brain SPECT in a CFS patient, demonstrating frontotemporal hypoperfusion at baseline, and increased global hypoperfusion after the intervention. Hypoperfusion after exercise may be related to endothelin, and after treatment to norepinephrine and neuropeptide Y.
So he found that hypoperfusion after a successful treatment looked remarkably similar to hypoperfusion after exercise. (You'll see the pictures yourself.) It's the theorized mechanisms of action that differ. NE and NPY are both vasoconstrictors, so that fits. And Goldstein had postulated deficiencies of NE and NPY in CFS patients; he goes into detail about these and other neurotransmitters on pages 54 and 55.

In the color plates, he also shows global hypoperfusion for patients who have reacted positively to naphazoline, nitroglycerin, nimodipine, and Diamox. He also has a sequence with the caption:
Some patients do not fatigue with exercise, but feel exhausted after intellectual exertion. This patient (a) could run marathons (b), but had to drop out of Cambridge after becoming ill because doing calculations made him feel much worse (c).
The pictures (a) and (b) look almost identical, while (c) shows obvious hypoperfusion. Here's evidence, @Hip, that your symptoms manifest in the brain the same way that those of PWME who are exhausted from physical exercise do.
Could it be that the pattern of hypoperfusion after one of Dr Goldstein's successful ME/CFS treatments was different to the pattern of hypoperfusion before treatment? In other words, might it be not so much in the degree of hypoperfusion that counts in ME/CFS etiology, but rather where in the brain the hypoperfusion occurs. Did the SPECT scans Goldstein had taken show where in the brain the increases in hypoperfusion occurred as a result of succesful treatment?
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.

It's interesting, though, that no one has followed up on this, isn't it? And this book was published 18 years ago...
 
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