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Potential therapeutic benefit of Low Dose Naltrexone in [ME/CFS]: Role of Transient Receptor Potential Melastatin 3 ion channels, 2021, Cabanas et al

Discussion in 'ME/CFS research' started by Andy, Jul 13, 2021.

  1. Andy

    Andy Committee Member

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    Full title: Potential therapeutic benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 ion channels in pathophysiology and treatment

    Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic illness of unknown aetiology classified as an immune dysfunction syndrome and neurological disorder. The discovery of the widely expressed Transient Receptor Potential Melastatin 3 (TRPM3) as a nociceptor channel substantially targeted by certain opioid receptors, and its implication in calcium (Ca2+)-dependent Natural Killer (NK) cell immune functions has raised the possibility that TRPM3 may be pharmacologically targeted to treat characteristic symptoms of ME/CFS. Naltrexone hydrochloride (NTX) acts as an antagonist to the mu (μ)-opioid receptor thus negating its inhibitory function on TRPM3. Based on the benefits reported by patients on their symptoms, low dose NTX (LDN, 3.0–5.0 mg/day) treatment seems to offer some potential suggesting that its effect may be targeted towards the pathomechanism of ME/CFS.

    As there is no literature confirming the efficacy of LDN for ME/CFS patients in vitro, this study investigates the potential therapeutic effect of LDN in ME/CFS patients. Whole-cell patch-clamp technique was used to measure TRPM3 ion channel activity after modulation with Pregnenolone sulfate (PregS) and ononetin in NK cells on 9 ME/CFS patients taking LDN and 9 age- and sex-matched healthy controls.

    We report that ME/CFS patients taking LDN have restored TRPM3-like ionic currents in NK cells. Application of PregS enabled the measurement of small ionic currents with a typical TRPM3-like outward rectification in NK cells from patients taking LDN. Additionally, PregS-evoked ionic currents through TRPM3 were significantly modulated by ononetin in NK cells from ME/CFS patients taking LDN. These data support the hypothesis that LDN may have potential as a treatment for ME/CFS by characterising the underlying regulatory mechanisms of LDN treatment involving TRPM3 and opioid receptors in NK cells. Finally, this study may serve for the repurpose of marketed drugs, as well as support the approval of prospective randomized clinical studies on the role and dose of NTX in treating ME/CFS patients.

    ETA: Full paper now available at https://www.frontiersin.org/articles/10.3389/fimmu.2021.687806/full
     
    Last edited: Jul 13, 2021
    hinterland, jamari, Barry and 16 others like this.
  2. Andy

    Andy Committee Member

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    NCNED hype train intensifies...

    Code:
    https://www.facebook.com/NCNED/posts/334745418156819
     
  3. Andy

    Andy Committee Member

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    Full paper now available, original post amended to include direct link to it.

    From the paper,

    This to me seems an odd thing to do,
    They are relying on patient self-report "before" and "after" taking LDN as evidence that the LDN helped patients. (I'll leave the claimed changes in biological processes to people who might understand it). I'll need to be convinced that this is a "significant and key step forward for ME/CFS patients.".

    ETA:
    The self-reported changes can be seen here, https://www.frontiersin.org/files/A...-687806-HTML/image_m/fimmu-12-687806-t003.jpg

    There obviously is improvement reported but out of 12 different symptom categories;
    1 person reported their muscle pain resolving;
    1 person their sore throat resolved;
    2 people their 'tender lymph nods';
    1 person their 'other immune disturbances';
    and 3 people their 'urinary disturbances'.
     
    Last edited: Jul 13, 2021
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  4. MeSci

    MeSci Senior Member (Voting Rights)

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    Sorry but I can't read the whole paper, but could someone tell me the length of time for which the patients were followed? I ask because I have found a few things quite effective for a couple of years, and then no more.
     
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  5. Andy

    Andy Committee Member

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    As far as I can see they don't tell us that.
     
  6. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Which is weak evidence... Also, I'm not sure what the relevance of calcium channel function in NK Cells is to ME anyway. What occurs in leukocytes in circulation is not the same as what happens in other tissues...

    That said, it would be nice to have a proper double blinded LDN study, even if it ends up just revealing that it doesn't work.
     
  7. Andy

    Andy Committee Member

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    jamari, Simon M, Hutan and 1 other person like this.
  8. Simone

    Simone Senior Member (Voting Rights)

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    They’re really relying on the changes in TRPM3 activity, when they apply the agonist and antagonist, compared to healthy controls (and compared with previous studies), to demonstrate potential therapeutic benefit. In this study, the TRPM3 channels of patients taking LDN seem to respond more like those of healthy controls, than they do in patients (in previous studies) not taking LDN.

    But, of course, we don’t see whether these patients had faulty TRPM3 channels before they took LDN, and the LDN modified them, or if their TRPM3 channels were working better in these patients to start with. And we don’t know how much benefit these patients were getting from LDN.

    But their assumption is that improving TRPM3 function will help patients because TRPM3 dysfunction is the cause of ME/CFS.

    If they do get funding for a clinical trial, I hope that they do it properly and dig down into subgroups, rather than just use it to support their TRPM3 hypothesis. We know anecdotally that LDN doesn’t help everyone, and we really need to know which patients it does and doesn’t help. At the very least, I’d like them to use their TRPM3 model to examine this.

    But to me, their LDN studies just further undermine their claim that TRPM3 dysfunction is the cause of ME/CFS. If it was the cause, and LDN improves TRPM3 function, then LDN should help everyone, and be almost curative for some. Speaking as someone who’s had good benefit from it, I don’t think anyone would claim it was curative. Don Staines tried to address this in a recent media article, but it sounded a lot like tap dancing to me.

    https://www.smh.com.au/national/que...ion-to-a-complex-disease-20210714-p589nv.html
     
  9. James Morris-Lent

    James Morris-Lent Senior Member (Voting Rights)

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    "efficacy of LDN for ME/CFS patients in vitro"

    Totally meaningless. We don't have any biomarkers - much less any such known to be clinically significant - so the idea of in vitro efficacy means nothing.
     
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  10. Sbag

    Sbag Senior Member (Voting Rights)

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    Louie41 likes this.
  11. Frenetik19

    Frenetik19 Established Member

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    I tried LDN a couple of decades ago, only small amount, went into town, and started hallucinating/having visions, etc, people turning into monsters, grotesques, etc. I have never had similar before or since,. i really couldn't in good faith carry on using it. only my experience though.
     
  12. Marky

    Marky Senior Member (Voting Rights)

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    maybe it was halloween
     

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