Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in ME/CFS: A Randomized, Double-Blind,Placebo-Controlled Trial,2021,Castro-Marrero

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.

 

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.

 

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.

 

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.

 

Looking more closely at the conflicts of interests:

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]

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.

 

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.

 

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.

 

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.

 

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'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.

 

Whoops i somehow missed you were talking about deficiency, I agree with that obv

 

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.

 

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.