Ribose: Why might it work for ME/CFS patients

[Pyrrhus]

Background:
Ribose is one of those supplements that have repeatedly been mentioned as helpful for ME patients. Some say it gives them slightly more energy than usual. Others say it works as a PEM-shielder, reducing the severity of PEM episodes. However, people who have problems regulating blood sugar report that Ribose, which is a type of sugar, can worsen problems with blood sugar.

Patient reports:
https://forums.phoenixrising.me/threads/d-ribose.52557/
(there are many more threads you can search for)

An old Phoenix Rising article about Ribose:
https://phoenixrising.me/treating-c...yalgia-the-cellular-energy-producers-d-ribose

An article about Ribose from patient journalist Adrienne Dellwo:
https://www.verywellhealth.com/d-ribose-for-fibromyalgia-715990


Mechanism of action:
So, why might Ribose supplementation increase someone's energy slightly? Why might it lessen PEM episodes? To answer these questions we can look into Ribose's mechanism of action.

In the literature, Ribose is generally known to boost resynthesis of ATP in depleted tissues. Since ATP is one of the main molecules that store energy in the cell, making more ATP available should provide the cell with more energy.

For example, a group at the University of Missouri used a rodent model of intense exercise to show that intense muscle contractions degrade ATP in the muscle. They then measured the rate at which the ATP was restored in the muscle. They found that when Ribose was added to the muscle right after the contractions, the rate that ATP was restored increased dramatically. [1]
From the paper:

(note that this study only looked at ATP synthesis via the purine salvage pathways)

Another example of Ribose boosting the resynthesis of ATP comes from a group in Denmark. This group used a random double-blind crossover design to measure the rate at which humans can recover ATP after exercise. Eight subjects performed one week of intense intermittent exercise. Immediately after this, half received Ribose for three days and the other half received placebo for three days. At the end of the three days, those who received Ribose had recovered their muscle ATP, but those who received placebo had not. [2]
From the paper:


These two experiments looked at muscle, but what about resynthesis of ATP in the brain? It is much harder to study ATP resynthesis in the brain, but there are a few reports that might shed some light.

An neuroscientist at the University of Warwick, who was working with post-mortem brain tissue, remarked that ATP levels were lower in dead brain tissue than they were in live tissue, but reported that the ATP levels in dead brain tissue could be restored to live levels of ATP with the addition of Ribose and adenine. They then proceeded to see if this could be applied to a model of brain injury. They used a rodent model of stroke and found that subjects who received Ribose and adenine directly after the stroke had the size of their brain lesions reduced by 38% over seven days, compared to subjects who just received saline after the stroke and saw their brain lesions reduced by only 18% over seven days. (Investigators were blinded as to which subjects received Ribose and which subjects received saline, but the study of 8 subjects was underpowered and could not therefore achieve statistical significance.) [3]
From the study:



Clinical application:
Now, what about clinical application of Ribose to patients with ME/CFS? The only clinical evidence comes from a 2006 open-label uncontrolled pilot study with 41 patients suffering from CFS and/or Fibromyalgia. This study provided patients with 5 grams of Ribose three times throughout the day, over 18 days. Patients filled out questionnaires covering energy, sleep, mental clarity, pain intensity, and well-being. The study found that Ribose was well-tolerated and resulted in significant improvement in approximately 66% of patients. [4]


So, what do you think?


References:
[1] https://pubmed.ncbi.nlm.nih.gov/11568162/
[2] https://pubmed.ncbi.nlm.nih.gov/14660478/
[3] https://pubmed.ncbi.nlm.nih.gov/28836168/
[4] https://pubmed.ncbi.nlm.nih.gov/17109576/

 

[Pyrrhus]

@Learner1 has provided some interesting feedback:

The first paper concludes:

"Ribose supplementation did not affect subsequent muscle force production after 60 min of recovery."

The second paper says:

[...]

"...Finally, the reduction in resting ATP observed after intense training does not appear to affect intense intermittent exercise performance."

This is an excellent point. Both those studies found that, despite increasing muscle ATP levels, there was no obvious increase in muscle strength. So maybe the benefit to ME/CFS patients may not come in the form of increased muscle strength, but as something else.

I would hypothesize that perhaps the increase in resynthesis of ATP means that the mitochondria work better and fewer H+ ions are released from the muscle. In this case, there would be less stimulation of the acid sensing ion channels (ASICs) on muscle nociceptors that appear to signal muscle soreness. If this is correct, it would mean that Ribose supplementation works partly by reducing muscle soreness, but not by increasing muscle strength. (Edit: updated hypothesis)

In the third paper, the key part of the experiment was done on rats, which makes it not as useful AND the author has a significant conflict of interest.

Yes, the third paper was done on rodents because it would be entirely unethical to perform the same experiment on humans. This is a common problem when trying to study the human brain. I'm not sure what conflict of interest you might be referring to, as the author is not involved in the manufacture or sale of Ribose. There is a conflict-of-interest statement posted alongside the abstract, but that only concerns some laboratory techniques.

papers on high intensity athletes may not apply to PwME and that rat studies may not provide results that work in humans.

These are both points well taken.

Thank you so much for your thoughtful feedback.

 

[Hip]

In the literature, Ribose is generally known to boost resynthesis of ATP in depleted tissues. Since ATP is one of the main molecules that store energy in the cell, making more ATP available should provide the cell with more energy.

This ability of D-ribose to rebuild the stock of ATP molecules features in the Myhill, Booth and McLaren-Howard theory of PEM (detailed in this post).

Myhill et al hypothesize that PEM results when there is an emergency energy shortage in the cell during exertion, and ATP molecules are actually broken down and catabolized, in a desperate attempt to supply energy. This breaking down of ATP supplies the emergency energy needed, but afterwards you end up with a shortage of ATP.

This shortage has consequences, as the ATP molecule is the means to transport energy from the mitochondria into the cell (ATP is like an energy delivery van). So if you have a shortage of ATP, you cannot deliver enough energy to supply demand (too few delivery vans). This state of affairs is theorized to cause PEM.

According to the theory of Myhill and colleagues, you only get over PEM once your ATP molecules are re-synthesized. But this re-synthesis is a slow process, taking days.

And this is where D-ribose comes in, as the ATP molecule can be easily synthesized from D-ribose (de novo synthesis), so this supplement can speed up the replenishment of ATP, which means you get over PEM more quickly.


The Myhill, Booth and McLaren-Howard theory of PEM is only a hypothesis, it has not been proven, and there is no experimental evidence for it, to my knowledge. However, it does offer an interesting potential explanation of why D-ribose is observed to help PEM recovery in ME/CFS.

 

[bread.]

me/cfs is a secondary mitochondrial disease.

 

[Wishful]

me/cfs is a secondary mitochondrial disease.

We have to disagree on that, because I don't see my ME as having an obvious mitochondrial component. I see the common mito problem of ME as a downstream dysfunction.

 

[lenora]

Hello Everyone....I've know about Ribose for years, but have held off b/c of the blood sugar question. When that is truly proven, then I'll try it....until then it may cause more harm than help. Just not going to chance it. Yours, L.

 

[Learner1]

We have to disagree on that, because I don't see my ME as having an obvious mitochondrial component. I see the common mito problem of ME as a downstream dysfunction.

Mine does. And many other patients do too. And Prusty's work seems to indicate it does for those with herpes family viruses.

 

[Learner1]

This ability of D-ribose to rebuild the stock of ATP molecules features in the Myhill, Booth and McLaren-Howard theory of PEM (detailed in this post).

Myhill et al hypothesize that PEM results when there is an emergency energy shortage in the cell during exertion, and ATP molecules are actually broken down and catabolized, in a desperate attempt to supply energy. This breaking down of ATP supplies the emergency energy needed, but afterwards you end up with a shortage of ATP.

This shortage has consequences, as the ATP molecule is the means to transport energy from the mitochondria into the cell (ATP is like an energy delivery van). So if you have a shortage of ATP, you cannot deliver enough energy to supply demand (too few delivery vans). This state of affairs is theorized to cause PEM.

According to the theory of Myhill and colleagues, you only get over PEM once your ATP molecules are re-synthesized. But this re-synthesis is a slow process, taking days.

And this is where D-ribose comes in, as the ATP molecule can be easily synthesized from D-ribose (de novo synthesis), so this supplement can speed up the replenishment of ATP, which means you get over PEM more quickly.


The Myhill, Booth and McLaren-Howard theory of PEM is only a hypothesis, it has not been proven, and there is no experimental evidence for it, to my knowledge. However, it does offer an interesting potential explanation of why D-ribose is observed to help PEM recovery in ME/CFS.

@Hip The same pathways are used to create NAD+, NADH and then ATP. And d-ribose gas to go through multiple conversions to get there, which don't necessarily work in many of us.

 

[wigglethemouse]

It might also help for those patients who have an autosomal recessive AMPD1 gene variant causing adenosine monophosphate deaminase 1 deficiency .
https://rarediseases.info.nih.gov/diseases/547/adenosine-monophosphate-deaminase-1-deficiency

In many people, adenosine monophosphate deaminase 1 (AMPD1) deficiency does not cause any symptoms. The reasons for this are unclear. People who do have symptoms typically have muscle pain (myalgia) or weakness after exercise or prolonged physical activity. They often get tired more quickly and stay tired longer than others. Some people have more severe symptoms, but it is unclear whether these symptoms are due solely to AMPD1 deficiency, or additional factors.

Cause
Adenosine monophosphate deaminase 1 (AMPD1) deficiency is caused by changes (mutations) in the AMPD1 gene. This gene gives the body instructions to make an enzyme called AMP deaminase, which plays a role in producing energy in skeletal muscle cells. Mutations in the AMPD1 gene disrupt the function of AMP deaminase, which impairs the ability of muscle cells to make energy. This lack of energy can lead to the muscle problems associated with AMPD1 deficiency.

Treatment
Although there is no cure for AMP1 deficiency, there may be ways to manage symptoms. One possibility is the use of a sugar called D-ribose.This sugar is easily absorbed in digestive system and rapidly cleared by metabolic pathways. It may provide an additional source of energy for muscle' however, the helpful effects of D-ribose are short-term.

I could never find a good reason why it is suggested to take 5g of D-Ribose. It seems to be a rule of thumb and not optimal. I suspect much lower is just as useful if it works and may help with blood sugar problems.

 

[Pyrrhus]

It might also help for those patients who have an autosomal recessive AMPD1 gene variant causing adenosine monophosphate deaminase 1 deficiency .

That's very interesting, thanks for pointing that out.

I could never find a good reason why it is suggested to take 5g of D-Ribose. It seems to be a rule of thumb and not optimal. I suspect much lower is just as useful if it works and may help with blood sugar problems.

When reading papers trialling various supplements, I find that different trials of a given supplement often use the same dosages. Sometimes, the same dosages are used just to be able to compare results, not because someone has meticulously optimized the dosage. And when I go back to the original paper that chose that particular dosage, I sometimes find that they deliberately chose a large dose to increase their study's chance of finding an effect.

 

[Judee]

For me, d-ribose caused a strange heart response. My heart kept speeding up; slowing down even when I was just sitting. I felt very disoriented and started to experience chest pains. I ended up going to the ER because it was such an odd reaction and I thought I was having a heart attack.

It may be that I was taking too much (about 3 tsps per day) or not using it with other things it works better with like L-Carnitine, Coq10 or magnesium.

I've since used pinches of it mixed with those with no issues. However, neither way gives me any improvement in my ME/CFS energy levels whatsoever so I rarely ever use it now.

 

[Pyrrhus]

I would like to throw a little wrench in the works here. Feel free to skip over this post if you find it too technical.

When ATP is degraded during intense muscle contractions, the result is Inosine, which is then lost from the muscle.

When talking about resynthesis of ATP, there are actually three metabolic pathways that can be used:

1. the de novo pathway, which synthesizes ATP from Ribose
2. the HGPRT purine salvage pathway, which synthesizes ATP from hypoxanthine and Ribose
3. the APRT purine salvage pathway, which synthesizes ATP from Adenine and Ribose

For those interested, here are the details of the three pathways:


The de novo pathway:
Step 1 of the de novo pathway is to synthesize IMP from Ribose 5' Phosphate:

Step 2 of the de novo pathway is to convert IMP to ATP:

1. adenylosuccinate synthase converts IMP to adenylosuccinate
2. adenylosuccinate lyase converts adenylosuccinate into AMP
3. AMP is twice phosphorylated to ATP

The HGPRT purine salvage pathway:

1. Ribose-phosphate diphosphokinase converts Ribose to Phosphoribosyl pyrophosphate (PRPP)
2. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) converts PRPP and Hypoxanthine to IMP
3. adenylosuccinate synthase converts IMP to adenylosuccinate
4. adenylosuccinate lyase converts adenylosuccinate into AMP
5. AMP is twice phosphorylated to ATP

The APRT purine salvage pathway:

1. Ribose-phosphate diphosphokinase converts Ribose to Phosphoribosyl pyrophosphate (PRPP)
2. Adenine phosphoribosyltransferase (APRT) converts PRPP and Adenine to AMP
3. AMP is twice phosphorylated to ATP

 

[Learner1]

It might also help for those patients who have an autosomal recessive AMPD1 gene variant causing adenosine monophosphate deaminase 1 deficiency .
https://rarediseases.info.nih.gov/diseases/547/adenosine-monophosphate-deaminase-1-deficiency






I could never find a good reason why it is suggested to take 5g of D-Ribose. It seems to be a rule of thumb and not optimal. I suspect much lower is just as useful if it works and may help with blood sugar problems.

I have the AMPD1 SNP. D-ribose doesn't help at all, but the caffeine in coffee helps dissipate the excess adenosine.

 

[Martin aka paused||M.E.]

This ability of D-ribose to rebuild the stock of ATP molecules features in the Myhill, Booth and McLaren-Howard theory of PEM (detailed in this post).

Myhill et al hypothesize that PEM results when there is an emergency energy shortage in the cell during exertion, and ATP molecules are actually broken down and catabolized, in a desperate attempt to supply energy. This breaking down of ATP supplies the emergency energy needed, but afterwards you end up with a shortage of ATP.

This shortage has consequences, as the ATP molecule is the means to transport energy from the mitochondria into the cell (ATP is like an energy delivery van). So if you have a shortage of ATP, you cannot deliver enough energy to supply demand (too few delivery vans). This state of affairs is theorized to cause PEM.

According to the theory of Myhill and colleagues, you only get over PEM once your ATP molecules are re-synthesized. But this re-synthesis is a slow process, taking days.

And this is where D-ribose comes in, as the ATP molecule can be easily synthesized from D-ribose (de novo synthesis), so this supplement can speed up the replenishment of ATP, which means you get over PEM more quickly.


The Myhill, Booth and McLaren-Howard theory of PEM is only a hypothesis, it has not been proven, and there is no experimental evidence for it, to my knowledge. However, it does offer an interesting potential explanation of why D-ribose is observed to help PEM recovery in ME/CFS.

My ATP levels are normal, even under stress test. But I do get PEM easily!

 

[Hip]

My ATP levels are normal, even under stress test.

Do you know how the test you took measures ATP levels?

 

[Martin aka paused||M.E.]

No honestly not. But it were three tests at three different labs and three different cell types... so I think it’s very clear that my ATP output is normal... via Instagram I found more ppl who sent me their Tests and some of them also came back normal. Just shared my findings with Stanford... let’s see if that’s new to them!

 

[Hip]

three tests at three different labs and three different cell types... so I think it’s very clear that my ATP output is normal

It could be normal, but measuring ATP levels is not an established science, so I would not entirely trust these lab results.


ME/CFS studies have obtained conflicting results regarding how much ATP is present in the cells of ME/CFS patients, with some studies like the Myhill papers finding low amounts of ATP in many (but not all) patients, and other studies like the Lawson paper finding higher than normal ATP in ME/CFS.

Dr John McLaren-Howard (one of the Myhill authors) wrote this excellent explanation for why his team found ME/CFS are generally low in cellular ATP, but Lawson found higher amounts of ATP in ME/CFS. Basically, his explanation revolves around the mitochondrial blocking factor that several researchers have now found present in ME/CFS patients' blood (the so-called "something in the serum" in ME/CFS patients).

In Lawson's setup, this blocking factor was excluded from the cells he tested (because he used lab cultured cells), so the cells likely just started behaving as normal healthy cells. But Myhill's group used cells freshly taken directly from ME/CFS patients' blood, which thus would have still included the blocking factor.


So you can see that if ATP production in ME/CFS is thwarted by "something in the serum" — a blocking factor in the blood which throws a spanner into the workings of the mitochondria, any test for cellular ATP levels would have to be very careful not to wash that blocking factor out from the cells before testing.

 

[Martin aka paused||M.E.]

It could be normal, but measuring ATP levels is not an established science, so I would not entirely trust these lab results.


ME/CFS studies have obtained conflicting results regarding how much ATP is present in the cells of ME/CFS patients, with some studies like the Myhill papers finding low amounts of ATP in many (but not all) patients, and other studies like the Lawson paper finding higher than normal ATP in ME/CFS.

Dr John McLaren-Howard (one of the Myhill authors) wrote this excellent explanation for why his team found ME/CFS are generally low in cellular ATP, but Lawson found higher amounts of ATP in ME/CFS. Basically, his explanation revolves around the mitochondrial blocking factor that several researchers have now found present in ME/CFS patients' blood (the so-called "something in the serum" in ME/CFS patients).

In Lawson's setup, this blocking factor was excluded from the cells he tested (because he used lab cultured cells), so the cells likely just started behaving as normal healthy cells. But Myhill's group used cells freshly taken directly from ME/CFS patients' blood, which thus would have still included the blocking factor.


So you can see that if ATP production in ME/CFS is thwarted by "something in the serum" — a blocking factor in the blood which throws a spanner into the workings of the mitochondria, any test for cellular ATP levels would have to be very careful not to wash that blocking factor out from the cells before testing.

Thank you very much for your explanation! That makes a lot of sense to me!

 

[Learner1]

My ATP levels are normal, even under stress test. But I do get PEM easily!

Or your PEM could be caused by something else, like a hormone or nutrient deficiency, like lack of thyroid hormone, testosterone, B12, glutathione and)or other antioxidants, or certain amino acids.

 

[Martin aka paused||M.E.]

Or your PEM could be caused by something else, like a hormone or nutrient deficiency, like lack of thyroid hormone, testosterone, B12, glutathione and)or other antioxidants, or certain amino acids.

My contact in Stanford said "there’s no one theory fits em all"... there seem to be subgroups even with PEM. Hormones and nutrients are in check, but amino acids and immune system not