That a disease itself causes loss of function does not mean it is not made additionally worse by being malnourished on top of the disease.
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Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in ME/CFS: A Randomized, Double-Blind,Placebo-Controlled Trial,2021,Castro-Marrero
rvallee
Senior Member (Voting Rights)
One problem is with the many interpretations of fatigue. It's wildly inconsistent, varying between specialties and people.
I got a particular lesson on that when I had an appointment at a sleep clinic, where it was basically impossible to reconcile the fact that fatigue does not in any way mean sleepiness/somnolence, which frankly I had (and still do have) too little of. Which it obviously does in a sleep clinic, even though this is not the fatigue I ever meant.
I had a different meaning. My GP had a different interpretation. The sleep clinicians have a different interpretation. It's all ambiguous because no one agrees on what it means, like warm to someone living in a tropical climate vs. polar temperatures, as opposed to everyone agreeing on what 15C means.
There's simply too much interpretation as to what it means. There is even a good kind of fatigue, similar to a runners'/gym high. So what do the questionnaires mean by fatigue? What do the patients? The researchers? The reviewers? The clinicians? They basically all have different interpretations, it's impossible to have consistency of meaning given failure of basic vocabulary.
This is from a Spanish team
Jesús Castro-Marrero 1,*
Maria-Cleofé Zaragozá 2,
Irene López-Vílchez 3,
José Luis Galmés 4,
Joan Carles Domingo 5
Sara Maurel 6
José Alegre-Martín 7
1. Division of Rheumatology, ME/CFS Unit, Vall d'Hebron Hospital Research Institute, 08035, Barcelona, Spain; jesus.castro@vhir.org
2, 3, 4. Clinical Research Department, Laboratorios Viñas, 08012, Barcelona, Spain;
5 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028
6 Department of Neurosciences, University of the Basque Country, 48940 Leioa, Bizkaia, Spain
7 Division of Rheumatology, ME/CFS Unit, Vall d'Hebron University Hospital Research Institute, 08035, Barcelona, Spain
Given two of the authors are from something called an 'ME/CFS Unit', the paper shows a disappointing awareness of the illness and existing treatments.
The reference for the finding that CBT and GET are ME/CFS treatments based on scientific evidence was also written by the lead author of this study.
Castro-Marrero, J; Sáez-Francàs, N.; Santillo, D.; Alegre, J. Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome. Br J Pharmacol 2017, 174, 345-369. doi: 10.1111/bph.13702
They suggest they have done a 'detailed review of the literature' to come up with a whole list of 'marginal nutritional deficiencies which may be of etiological significance' in ME/CFS. I know that the deficiency claims for at least some of the things listed don't hold when you look carefully at the studies.
So, even if I was ignoring all of the good points made already in this thread, I'm three paragraphs in to the introduction and I've already lost faith in this study and the authors. The ME/CFS Unit is probably treating their patients with GET and CBT and various supplements, and blaming the patients if they don't improve - because 'it's all evidence based'.
Jesús Castro-Marrero 1,*
Maria-Cleofé Zaragozá 2,
Irene López-Vílchez 3,
José Luis Galmés 4,
Joan Carles Domingo 5
Sara Maurel 6
José Alegre-Martín 7
1. Division of Rheumatology, ME/CFS Unit, Vall d'Hebron Hospital Research Institute, 08035, Barcelona, Spain; jesus.castro@vhir.org
2, 3, 4. Clinical Research Department, Laboratorios Viñas, 08012, Barcelona, Spain;
5 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028
6 Department of Neurosciences, University of the Basque Country, 48940 Leioa, Bizkaia, Spain
7 Division of Rheumatology, ME/CFS Unit, Vall d'Hebron University Hospital Research Institute, 08035, Barcelona, Spain
Given two of the authors are from something called an 'ME/CFS Unit', the paper shows a disappointing awareness of the illness and existing treatments.
The reference for the finding that CBT and GET are ME/CFS treatments based on scientific evidence was also written by the lead author of this study.
Castro-Marrero, J; Sáez-Francàs, N.; Santillo, D.; Alegre, J. Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome. Br J Pharmacol 2017, 174, 345-369. doi: 10.1111/bph.13702
They suggest they have done a 'detailed review of the literature' to come up with a whole list of 'marginal nutritional deficiencies which may be of etiological significance' in ME/CFS. I know that the deficiency claims for at least some of the things listed don't hold when you look carefully at the studies.
So, even if I was ignoring all of the good points made already in this thread, I'm three paragraphs in to the introduction and I've already lost faith in this study and the authors. The ME/CFS Unit is probably treating their patients with GET and CBT and various supplements, and blaming the patients if they don't improve - because 'it's all evidence based'.
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I guess at least the team did do a blinded, placebo controlled study, even if prompted by the manufacturer of the supplements. Plenty of ME/CFS clinicians have been prescribing melatonin and zinc for a long time.
I note that the participants are heavily medicated. The first column of numbers is the placebo group, the second is the treatment group. Around 80% of them are on anti-depressants, 20% on anxiolytics and 40% on opioids (almost the same number as those taking NSAIDS), 60% on anticonvulsants. This seems abnormally high. Another reason to feel concerned about what is happening in the clinic.
I have to wonder what possible reason the authors had for collecting and reporting marital status of the participants in this study. Again, the left column is the placebo group, the right column is the treatment group. The marital status figures for the treatment group add up to 23 participants, but there were 24 participants in that group. This suggests that maybe other figures don't quite add up either.
The melatonin/zinc combination had no effect on sleep:
A professor familiar with the use of melatonin supplements in production animals to alter reproductive characteristics was concerned enough at the idea of dosing young people with melatonin to write a paper and to appear in the media. Melatonin is a hormone - I don't think we know what the long term effects of giving it to children and adolescents are. When I last looked, melatonin supplements for sleep issues were only approved in Australia for people over 55 (or thereabouts). I've written before about how the Royal Children's Hospital in Melbourne prescribed my son both ritalin and melatonin for no reason other than he had ME/CFS.
I really hope the null result of this study puts an end to the prescribing of melatonin and zinc as treatments for ME/CFS. Unfortunately, I suspect it will be used as 'evidence' to do exactly the opposite.
The inevitable conclusions of these types of supplement studies are made - 'let's try again with bigger doses, longer interventions and different sorts of people...'
this paper said:
The safety of melatonin is one of my hobby horses. This study does not say what efforts were made to record adverse events. We know one patient withdrew from the treatment arm due to a rash from ibuprofen. How can it be known that the rash was not at least partly a consequence of the treatment? How can it be known that the pain that the ibuprofen was taken for was not a consequence of the treatment? Unlikely I know, but clearly there were some judgements made about what adverse events were 'relevant'. It's even possible that the claimed worsening upon withdrawal of the supplement (touted as evidence of the utility of the supplement)was actually just the body taking time to recalibrate and make its own melatonin hormone.this paper said:
A professor familiar with the use of melatonin supplements in production animals to alter reproductive characteristics was concerned enough at the idea of dosing young people with melatonin to write a paper and to appear in the media. Melatonin is a hormone - I don't think we know what the long term effects of giving it to children and adolescents are. When I last looked, melatonin supplements for sleep issues were only approved in Australia for people over 55 (or thereabouts). I've written before about how the Royal Children's Hospital in Melbourne prescribed my son both ritalin and melatonin for no reason other than he had ME/CFS.
I really hope the null result of this study puts an end to the prescribing of melatonin and zinc as treatments for ME/CFS. Unfortunately, I suspect it will be used as 'evidence' to do exactly the opposite.
Ah, that was this group. That study is discussed in the forum, I'll add the link. They got a tiny tiny improvement, the smallest possible without being a null result. The study was supported by the supplement manufacturer. It really could not be seen as evidence of the combination doing anything.this paper said:
I've clipped that out of the paper, but trust me, it makes even less sense in context. The fact that two completely different dietary supplements are said to be safe and well-tolerated tells us nothing about whether two other dietary supplements are safe or well tolerated.this paper said:
So, no evidence of zinc deficiency in people with ME/CFS.this paper said:
The inevitable conclusions of these types of supplement studies are made - 'let's try again with bigger doses, longer interventions and different sorts of people...'
What are the funders and peer reviewers doing? There has to be better quality control processes to stop this.the conclusion said:
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spinoza577
Senior Member (Voting Rights)
It might induce a change which would not be achieved by normal levels (which are themselves induced by the body working as usual).
In case that triggers for MR/CFS might have done such changes, it looks even reasonable. It may be complex though, cf. combinatorics.
With vitamins/minerals that are part of many enzymes and/or reactions it would indeed be complex to figure out. I'd still expect to see some evidence of deficiency though, as in people with functional B12 deficiency - normal B12 levels (although commonly in the lower end of the reference range) but increased methylmalonic acid as it needs B12 to be metabolized.
Deficiency symptoms for zinc are vague and can have many causes. It can also take a while for a deficiency to show up in bloodwork, so a good dietary assessment is helpful to see if intake is adequate over time. RDA values differ somewhat between countries (in Norway 7mg for women/9mg for men, while in the US 8mg for women/11mg for men), so there's not an agreement on how much we should consume (I don't remember how old the rda in the US are, the Norwegian ones will be updated soon and may or may not change). On the whole taking a 10mg supplement if the diet is sufficient and bloodwork is fine, with no telltale signs of zinc deficiency, does not sit right with me.
High doses of other supplements, such as antioxidants, are also associated with increased risk of cancer. It's not without risk to take supplements.
cassava7
Senior Member (Voting Rights)
I am baffled that the ME/CFS unit at Vall-d'Hebron would treat people with GET:
- In November 2020, Castro-Marrero and Alegre-Martin (director of the unit) signed Millions Missing France's open letter against GET for long Covid and ME/CFS
- Their 2017 review of treatments for ME/CFS seemed to recommend "adaptative pacing" while at least mentioning that GET is controversial
- In 2020, Castro-Marrero visited Dr Hanson's team at the Cornell Center for Enervating Neuroimmune Disease, which is taking part in a clinical trial on PEM with 2-day CPET
I agree that these numbers seem high, though the clinic is a tertiary care center so it is likely skewed towards more severely affected patients: 36 out of 46 (78%) patients who completed the final assessment at 4-week post-treatment have been ill for longer than 10 years. Comorbid depression is not surprising in such a population. It is also possible that some anti-depressants (e.g. tricyclic) are (also) being prescribed for neuropathic pain or migraine.
The authors do not say how many patients suffered from comorbid fibromyalgia, which could explain the high prevalence of opioids. Similarly to some European countries, CFS and fibromyalgia are strongly associated illnesses in Spain, so the clinic may really be treating both populations without distinction.
This is a pre-print, but it should certainly not pass peer review without major modifications, the first of which should be to switch the positive result to a null one.
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Mm.
We have high levels of serum B12 ( minimal supplement in a multi vit powder) and high MMA on organic acid test.
Something is out of whack.
I tend to think pwME are outliers on blood tests . Bodies are incorporating all the feedback loops they can to function. Looking outwith serum may give bigger clues
Whilst hair testing has limits we have done it around once a year and results are far from normal ranges .
It has changed over time but electrolyte and metals are generally seriously out of whack.
Here's the link to the 2017 paper reviewing treatments of ME/CFS.
Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome, 2017, Castro-Marrero et al.
Yes, @cassava7, I'm left not quite sure what treatments are promoted. The attitude is not 'GET for all', it is a bit more nuanced. I'll copy some quotes from the 2017 paper over on that thread.
cassava7
Senior Member (Voting Rights)
Looking more closely at the conflicts of interests:
So it seems that Laboratorios Viñas and the clinical leads at the ME/CFS unit have been collaborating closely for a number of years, with funding involved. I'm afraid supplements from the lab might quite effectively be recommended or sold to patients at the clinic...
[1] Cambras T, Castro-Marrero J, Zaragoza MC, Díez-Noguera A, Alegre J. Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PLoS One. 2018 Jun 6;13(6):e0198106. doi: 10.1371/journal.pone.0198106. PMID: 29874259; PMCID: PMC5991397.
Author Contributions: J.C.-M., J.A.-M., S.M. and J.L.G.; formal analysis (...) J.C.-M, S.M., M.L., J.L.G. and J.A.M.; data curation, J.C.-M, M.C.Z, and I.L.V.; writing—original draft preparation, J.C.-M., and J.A.M.; writing—review and editing (...) J.C.-M.; supervision
Acknowledgments: The authors are grateful to (...) Prof. Trinitat Cambras (Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona,Barcelona, Spain) for reviewing of the manuscript and for providing critical feedback on the updated draft.
Conflicts of Interest: M.C.-Z., I.L.-V., and J.L.G. are employees of Laboratorios Viñas, S.A. As stated in the author contributions, the funders declare that they had no role in the analysis, interpretation and presentation of data. JC-M received financial support from Laboratorios Viñas, S.A. to conduct this study.
The funders did not analyze or interpret the data, but Castro-Marrero (JCM), who received funding from the lab, did so, along with most things from supervising the study to writing the manuscript with Alegre (JAM). Cambras, who reviewed the manuscript, has authored a study on ME/CFS with them and Zaragoza (MCZ), who is an employee of the lab. [1]Acknowledgments: The authors are grateful to (...) Prof. Trinitat Cambras (Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona,Barcelona, Spain) for reviewing of the manuscript and for providing critical feedback on the updated draft.
Conflicts of Interest: M.C.-Z., I.L.-V., and J.L.G. are employees of Laboratorios Viñas, S.A. As stated in the author contributions, the funders declare that they had no role in the analysis, interpretation and presentation of data. JC-M received financial support from Laboratorios Viñas, S.A. to conduct this study.
So it seems that Laboratorios Viñas and the clinical leads at the ME/CFS unit have been collaborating closely for a number of years, with funding involved. I'm afraid supplements from the lab might quite effectively be recommended or sold to patients at the clinic...
[1] Cambras T, Castro-Marrero J, Zaragoza MC, Díez-Noguera A, Alegre J. Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PLoS One. 2018 Jun 6;13(6):e0198106. doi: 10.1371/journal.pone.0198106. PMID: 29874259; PMCID: PMC5991397.
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Invisible Woman
Senior Member (Voting Rights)
I believe that is currently the case in the UK too.
Interestingly, I was in the chemist one day and overheard another patient having a chat with the pharmacist. He was clearly younger than me by up to a decade and he had an NHS prescription for Circadin.
It would appear he was being weaned off an antidepressant being used at least in part as a sleep aid and was given Circadin instead.
Kids get melatonin via prescription in UK.
Invisible Woman
Senior Member (Voting Rights)
This is something I spent a lot of time and money pursuing with a very experienced consultant dietician. We did all sorts of tests, exclusion diets, we tried things and dropped things.
It was enormously helpful in some ways & I got IBS under control (yeast & sugar free diet) but nothing made a difference to the ME. Even when we sorted clear underlying problems like low zinc, chromium, manganese etc. I didn't actually feel much better for it because the symptoms of ME probably mask whatever the symptoms of the deficiencies were.
Invisible Woman
Senior Member (Voting Rights)
It can be given but I got the impression it's not that common.
When I asked my own GP about it when I was first prescribed it privately they were happy to do it but the practise wouldn't allow them because I was under 55.
Even though I had tried the z drugs and the old style antihistamines and all the other things they recommended.
Peter T
Senior Member (Voting Rights)
One problem evaluating supplementation is distinguishing between correcting imbalance and maintenance doses.
I regularly go into B12 deficiency, and when in deficiency notice an improvement in my overall ME symptoms following a B12 injection, however subsequent injections have no subjectively noticeable impact, though I assume they are preventing me to returning to a deficit, which is what usually happens when injections are stopped, usually because of practical issues around getting to my GP and lack of domiciliary provision.
I regularly go into B12 deficiency, and when in deficiency notice an improvement in my overall ME symptoms following a B12 injection, however subsequent injections have no subjectively noticeable impact, though I assume they are preventing me to returning to a deficit, which is what usually happens when injections are stopped, usually because of practical issues around getting to my GP and lack of domiciliary provision.
I'm wondering if this could be concerning i.e. "the difference between fatigue and the perception of fatigue". Is this the line those focused on psychological interventions take? You're not really unwell you just think you are.
Don't get me wrong I'm not opposed to psychology but I think studies should have objective measures/outcomes - the use of questionnaires, to measure outcomes, concerns me.
Marky
Senior Member (Voting Rights)
Whoops i somehow missed you were talking about deficiency, I agree with that obv
Blueskytoo
Senior Member (Voting Rights)
Another n=1 here - I take 10mg slow release melatonin, which is a big dose but smaller ones don’t work for me. I also have severe ME. Melatonin helps me *get* to sleep, although it doesn’t help me *stay* asleep, and I take zinc as part of my daily multi-vitamin/mineral (my attitude to this is very much along the lines of “it’s not going to fix anything but it can’t hurt”).
Neither have made the slightest difference to my ME symptoms apart from the fact that I find it easier to fall asleep. I still wake up feeling tired and unrefreshed, I still have the same levels of fatiguability, I still have severe ME. I just don’t now lie awake for hours at night most of the time.
Invisible Woman
Senior Member (Voting Rights)
I find how I take it makes a big difference too. The effect is very subtle & can easily be overridden if I do anything too stimulating between that and sleep.