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Finally Found – A Natural Killer Cell Enhancer for ME/CFS?

For several years now, researchers at the National Centre for Neuroimmunology and Emerging Diseases (NCNED) at Griffith University in Australia have been leading the research on natural killer (NK) cells in chronic fatigue syndrome (ME/CFS). In fact, they recently published an overview on NK cells and ME/CFS.

natural killer cell failure ME/CFS

The natural killer cells in ME/CFS are pretty much a failure at killing infected cells.

NK cells play a critical role in the innate immune response which kicks in first to fight off an infection.  NK cells do just what their name implies: after alerting the immune system that trouble is ahead, they jump in and kill as many infected and damaged (cancer) cells as possible. The goal? To keep a pathogen in check long enough for big guns of the adaptive immune system (T and B cells) to rev up and ultimately destroy the invader.

For some time now, the Griffith group has focused on an unusual subject for ME/CFS –  ion channels – the very, very small channels in our neurons and cells – which play a big, big role in nerve and cell activation. Ion channels are getting a lot of interest in pain research but except for the Griffith team – not so much in ME/CFS.

The problem with NK cells in ME/CFS is that they’re just not killing very well. When given the chance to wipe out some infected cells, they pretty much poop out – not good news for anyone wanting to quickly knock down infections or remove cancerous cells.

NK cells, like many cells, require intracellular calcium to function properly, the levels of which are regulated, at least in part, by the ion channels the Griffith group is studying. These TRPM ion  channels are found in a wide variety of cells and tissues, and play a particularly important role in  sensory processing – a big concern in ME/CFS.

The ion channel that the Griffith group has been particularly interested in – TRPM member 3(TRPM3) – appears to be a jack of all trades. The fact that it can be activated by everything from temperature, natural chemicals, and toxins to synthetic compounds suggests it plays a fundamental role in the body, and, indeed, TRPM3 dysfunction has been implicated in inflammatory and neuropathic pain disorders.

Ion Channels and ME/CFS

The Griffith group’s findings in ME/CFS stretch back almost four years. In 2016, they showed that both TRPM3 and intracellular concentrations of calcium were reduced in the NK cells of ME/CFS patients. These findings suggested that in ME/CFS, the signal to kill  the pathogens wasn’t getting through to the NK cells.

That same year, Griffith introduced a potential explanation: the genes that governed TRP ion channel functioning – in particular, TRPM3 ion channel functioning – were loaded with mutations in ME/CFS. That same year, the group reported they’d found similar mutations in the B cells of ME/CFS patients.

ion channel issues

The ion channel / Ca mobilization issues in ME/CFS (From Impaired calcium mobilization in natural killer cells paper_

2017 brought another study validating the TRPM3 channel reductions. Further testing indicated something had gone wrong with the TRPM3 receptors themselves. When stimulation tests found a reduction in Ca2+ mobilization was occurring, the researchers proposed something startling: that TRPM3 channels across the body could be malfunctioning.

“As TRPM3 receptors are expressed throughout the human body, the current findings suggest that impaired TRPM3 function may play a significant role in the multisystemic pathomechanism of CFS/ME.”

Given how ubiquitous TRPM ion channels are, the loss of them body-wide could be responsible for many of the multitudinous symptoms associated with ME/CFS.

2018 and 2019 brought further validation of their previous findings (in small studies).  Just this month, the group published evidence that a related ion channel, TRPM2 – perhaps in a compensatory response – is over-expressed on ME/CFS patients’ NK cells. Despite its increased levels, it too was not functioning well.

Then in October of this year came a potential fix for the NK cell problem in ME/CFS.

Front. Immunol., 31 October 2019 Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients, Helene Cabanas1,2,3*Katsuhiko Muraki3,4,  Donald Staines1,2,3 and  Sonya Marshall-Gradisnik1,2, https://doi.org/10.3389/fimmu.2019.02545

Naltrexone hydrochloride (NTX) is best known in its low dose form in ME/CFS. It was referred to in this paper, though, simply as naltrexone. NTX in its normal dose functions as an opioid antagonist which reverses the effects of opioids. While it’s doing that, it also happens to activate the same TRPM3 channels that have been found inhibited in ME/CFS.

The Australian researchers used something called a whole cell patch clamp technique to assess the functioning of NK cells from people with ME/CFS. This technique, which was developed in the 1970’s/80’s, enabled researchers to assess the functioning of single ion channels on cells for the first time. (It also won its creators the Nobel Prize.)

The study again found that low levels of TPRM3 channels were present in ME/CFS.  It showed that stimulating the NK cells from healthy controls worked – the NK cells sprang into action. The NK cells from the ME/CFS patients responded to the stimulation by remain dead as a door nail. That stimulation test suggested that whatever TPRM3 channels were present simply weren’t working.

ME/CFS patients, then, appeared to have two problems: they were losing TRPM3 ion channels and those that were still present were not working well.

Incubating the healthy controls’ NK cells in naltrexone had no effect on them, but the ME/CFS patients’ NK cells responded dramatically: they now appeared to be acting normally.

Besides presenting a possible treatment for the NK dysfunction in ME/CFS, the finding suggested the Griffith researchers’ original hypothesis could be correct: the mysterious NK cell dysfunction problem could derive from problems with the TPRM3 ions.

Sonya Marshall-Gradisnuk was enthusiastic about her team’s results

This was a laboratory study – a proof of concept study. It’s a long way from testing naltrexone in humans but it did hold out the potential of a treatment for the low NK functioning in ME/CFS.

Given that NK cells ferret out infected and cancerous cells and remove them, getting the NK cells functioning properly again in ME/CFS would be a big step forward.

The leader of the group, Sonya Marshall-Gradisnik, was clearly enthusiastic:

“This world-first discovery suggests new potential pharmaco-therapeutic interventions in ME/CFS.”  Professor Sonya Marshall-Gradisnik

Opioid Drugs and Immunosuppression

The study also raised the question of what effects opioid drugs could be having on the immune systems of people with ME/CFS. No studies have attempted to assess that issue, but this study and others suggests it could be negative.

Opioid drugs have been found to impair the functioning of macrophages, natural killer cells and T‐cells and weaken the gut barrier.  A 2013 review asserted that, given the prevalence of opioid use, “opioid-mediated immune suppression presents a serious concern in our society today”.

The effects of opioids are complex, however. Immune cells also secrete endogenous opioid peptides which relieve inflammatory and neuropathic pain.

Conclusion

 

breakthrough

A breakthrough for ME/CFS? Time will tell.

The studies have generally been small, but the results have been consistently positive. They suggest that poorly functioning TRPM3 and perhaps related ion channels could be causing the reduced NK cell cytotoxicity commonly found in ME/CFS. This study found that the opioid antagonist Naltrexone was able to reverse the TRPM3 and calcium mobilization problems in ME/CFS patients’ NK cells.

Reversing the poor NK cell cytotoxicity functioning to normal would be a major step forward. Further studies will be needed, however, to determine if the results seen in the laboratory apply to people with ME/CFS – which is often a perilous step. I couldn’t find any clue as to what the effective dose would be or whether the low dose form of naltrexone might help.

It bears mentioning that the Griffith group has evidence that another ion channel may not be working properly in ME/CFS, that these channels are widespread throughout the body, and a systemic dysfunction with them, if present, could cause many problems.

 

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43 Comments

  • Philip Brown

    December 19, 2019 at 2:01 pm - Reply

    Hi Cort,

    What does “…but it appears that its normal dose activity comes to bear here.” mean for potentially using LDN in ME/CFS?

  • Karin

    December 19, 2019 at 2:46 pm - Reply

    And for those of us already on LDN, how about slowly eeking up the dose? I’m tempted.

  • Cort Johnson

    December 19, 2019 at 6:34 pm - Reply

    Where is that from? Is that in the blog? I have no idea at all what dose of naltrexone would be effective. In the experiment, if I remember correctly, they incubated the NK cells in naltrexone for 24 hours and then tested them.

  • Zena

    December 19, 2019 at 7:41 pm - Reply

    Anyone out there with M.E. who’s been prescribed high-dose naltrexone for non-M.E. reasons & can report on the experience?

  • Benjamin

    December 19, 2019 at 7:50 pm - Reply

    Cort – Thank you for publishing this very exciting research on the potential for a treatment of ME/CFS. As someone who has been suffering with this for nearly 2 years, I am so eager to find an effective treatment for the constant fatigue I’m experiencing. Are you aware of clinical trials for the use of Naltrexone as a treatment? It is possible to use it as a treatment today?

    I’m also interested to know if other ME/CFS patients are currently using Naltrexone as a treatment and what results have been experienced.

    My life has been so utterly changed by this insidious disease, and I so hope for some positive news and potential treatment based upon your research.

    Thank you for all your research work and to Dr. Sonya Marshall-Gradisnik and her entire research team…this means so much to those of us who are currently suffering with ME/CFS.

  • Rebecca Otis

    December 19, 2019 at 8:06 pm - Reply

    Yes, it’s in this paragraph in the blog: Naltrexone hydrochloride (NTX) is best known in its low dose form in ME/CFS, but it appears that its normal dose activity comes to bear here. NTX is an opioid antagonist which reverses the effects of opioids. While it’s doing that, it also happens to activate the same TRPM3 channels that have been found inhibited in ME/CFS.

    • Cort Johnson

      December 19, 2019 at 9:19 pm - Reply

      I’m going to take that out! It’s true that the authors referred to naltrexone throughout the paper not LDN. They did mention LDN because it obviously can be helpful in ME/CFS but when they referred to the substance used in the study they always stated naltrexone. i have no idea at all, however, how what they used in the laboratory relates to a dosage that might be helpful; i.e. I don’t have a clue which dosage might help NK cells in the body.

      Sorry about the confusion!

  • Leapy99

    December 19, 2019 at 8:41 pm - Reply

    Just watch you alcohol intake if you up the naltrexone dosage!!!

  • Liarne

    December 19, 2019 at 8:45 pm - Reply

    Hi
    Does this explain why some cfs patients can’t mount a response to viruses like the common cold. Ie they never get sick”

  • Nat

    December 19, 2019 at 8:55 pm - Reply

    I have been in LDN for at least 7 years I would love to have access to NK cell testing time see what’s happening with that

  • Lilpink

    December 19, 2019 at 8:59 pm - Reply

    There are more than a few good things associated with this work (and my ears were pricked from the first time I saw it presented to Invest Conference a few years ago) the least of which is the fact they used ICC to select patient sample cohort. I guess that’s why they’re getting such interesting results. It seems those who do use ICC, like Hanson and VanElzakker, are getting pretty curious results. Having the cleanest patient cohort possible (by using ICC) seems to be paying dividends. Now if the political shenanigans could just admit that the other criteria really aren’t anything like as selective and abandoned them and also decided to go the ICC route we might actually get somewhere. The TRPM3 findings *seem* to reflect the whole 50 years of my presentation of this disease. I hope other possible drug options could be suggested because whilst very low dose naltrexone isn’t the worst option for me it does throw up undesired side effects (thrush) which is problematical.

  • Tammie

    December 19, 2019 at 9:11 pm - Reply

    Cort, it’s in what you wrote in the article above (underneath a bunch of blue links), “Naltrexone hydrochloride (NTX) is best known in its low dose form in ME/CFS, but it appears that its normal dose activity comes to bear here. NTX is an opioid antagonist which reverses the effects of opioids. While it’s doing that, it also happens to activate the same TRPM3 channels that have been found inhibited in ME/CFS.”

    If I remember rt, the normal dose of naltrexone when used for addicts ranges from 50 – 100 mg (I could be wrong abotu this, though), but I do know that low dose is 4.5 mg or lower. Unfortunately, I couldn’t even tolerate .25 mg of LDN, so I’d be really scared to try a normal dose.

  • Cort Johnson

    December 19, 2019 at 9:25 pm - Reply

    No clinical trials of regular dose Naltrexone are underway so far as I know. (I think I would know, though :))

  • Cort Johnson

    December 19, 2019 at 9:27 pm - Reply

    I’m afraid that no clinical trials of regular dose Naltrexone are underway so far as I know. (I think I would know.) I imagine that some doctors will be trying this but I don’t know how they will come up with a dose. I’m pretty ignorant in those matters, however. They would know better than I.

  • Barbara

    December 19, 2019 at 10:00 pm - Reply

    Does anyone know about the side effects of regular dose Naltrexone? I see Lilpink notes Thrush is a side effect. Obviously some people take the full dose for non-Me purposes..

  • Barbara Berk

    December 19, 2019 at 10:20 pm - Reply

    Hi Cort, Thanks for all your hard work and reporting of findings. I am so grateful to you.

    Low dose naltrexone did nothing for me, but I would have no idea if higher dosages would be helpful. It would be great if some studies were done to determine the effectiveness of higher doses of naltrexone.

    Thanks again.

  • Benjamin

    December 19, 2019 at 10:40 pm - Reply

    Nat and Lilpink – You both mention that you are on LDN…is this to treat ME/CFS and if so has it been effective for you? Many thanks.

  • Andrea K. Frankel

    December 19, 2019 at 11:10 pm - Reply

    http://Www.lef.org has a product called NK Cell Activator, made from a proprietary enzymatic modified rice brand. Any idea how this factors in?

  • debsw

    December 20, 2019 at 12:12 am - Reply

    I personally think it is probably risky to deviate away from the use of naltrexone in its low dose form until clinical trials establish an optimal dose because in its low dose form LDN boosts endorphins and in its high dose form it reduces endorphins. The immune and neurological benefits appear to be greatest when endorphins are boosted. In terms of efficacy, there is little hard science but Jarod Younger has been investigating this drug for some time and carried out a trial for Fibromyalgia patients where I recall that approximately half of patients had a very good outcome with pain relief. From memory, few had adverse effects. Anecdotal evidence suggests that some ME/CFS patients find this drug very helpful but I don’t think it is a cure on its own. Like the cholinergic drugs, beta blockers, calcium ion channel blockers and drugs like neurontin / gabapentin, LDN appears to exert some influence on nitric oxide, which may go some way to explaining the ion channel influence? I am hoping to try this drug in the new year given its benefits to multiple systems and the seemingly low risk of adverse effects. Meditation also boosts endorphins.
    https://selfhacked.com/blog/top-22-scientific-health-benefits-low-dose-naltrexone/

  • Billie

    December 20, 2019 at 12:32 am - Reply

    Who on earth with CFS/ME can tolerate alcohol?

  • Kathy Bungard

    December 20, 2019 at 1:10 am - Reply

    I would very much like to know how taking a calcium channel blocker such as Verapamil might influence this topic? I’ve taken it for more than 20 years as a migraine prophylactic.

  • Jayne Barnard

    December 20, 2019 at 2:08 am - Reply

    For those asking for personal experience with LDN, I’ve been on for 2.5 years now, a very gradual progression upward from 0.15 to 2 mg daily. It is a necessary but not sufficient part of my management plan. It’s not a cure.

    it has helped me move closer to normal functioning, the first prescription medication that has ever done that in nearly 30 years (the next medication to do that is Mestinon). Overall my improvements are consistent from <30% functional to consistently 50% with appropriate pacing but I can only intermittently perform at/above 60% of my previous activity level. Higher dose has triggered side effects such as (re)interrupted sleep rather than further improvements

    How it seems to work for me:

    a) raised my body's ability to fight off random germs more quickly (instead of taking weeks of spiking temperature to subdue whatever germs I might pick up from a grocery cart or someone sneezing, I now recover temperature stability after an outing in about 48 hours),

    b) calmed my brain wiring so I don't stay in hyper-arousal (tired but wired) as often or for as long,

    c) improved my concentration when awake and prolonged the duration of my sleep (chicken/egg )

    d) lowered my overall muscle and joint pain.

    Again, not a cure for everything wrong in my body. But a significant improvement in my body's feeling of ease under normal (for me) operations.

    Side note: it has not, at this dose, changed my thyroid picture (still need meds) but has mitigated autoimmune blood markers and symptoms from Sjogrens & Scleroderma.

  • Nancy Madlin

    December 20, 2019 at 4:27 am - Reply

    All this study says, from what I can see, is that Naltrexone has a positive effect in NK cells in the lab.

    People who are taking LDN now may be experiencing increased health of their killer cells, I think. Do you agree??

    From what I understand there is a dosage range that has generally worked better for CFS — this is from HealthRising:

    “Most people probably start with 1.5 mgs and then increase over a couple of weeks or a month. (According to Dr. De Meirleir, an ME/CFS specialist, starting doses in ME/CFS can be as low as 0.5 mg. and end up being 5 mg. or more.) In general he finds that 1.5 mg. isn’t enough and 6 mg. is too much and that most people end up taking from 3-4.5 mgs. a day.. He suggests that patients decrease and then increase their dose every few months to check that their requirements for the drug haven’t changed.”

    https://www.healthrising.org/treating-chronic-fatigue-syndrome/drugs/low-dose-naltrexone-ldn-fibromyalgia-chronic-fatigue-syndrom/

    Note: it can take months to see results. I think many have tried it and given up too soon, or not experimented sufficiently with the dose.

    I’ve been taking 2.5 mg and it definitely helps reduce PEM symptom spikes. I think it also positively influences my mood, which is greatly appreciated as I find my CFS affects my brain via vicious negativity, always pushed towards survival mode. I would take more but cost is a concern. I take many supplements and have to test regularly and prioritize for cost.

    I haven’t looked up citation yet but it is my impression that regular dose Naltrexone has not had good results with CFS. That is why low dose is suggested and popular.

    I love HealthRising. Power to the CFS hackers!!!!

  • Beca

    December 20, 2019 at 5:18 am - Reply

    Regarding calcium channel damages and the origins of these: Dr. Martin Pall asserts in his research that bombardment with EMFs and wifi, 5G, etc. are greatly responsible for these and increasing symptoms of ill health in recent years. (EMF/electromagnetic energy is different from universally abundant scalar/qi/prana energy, which cannot produce profit for stockholders, and research on this has been suppressed.)

    Have been taking LDN 4.5 for about 15 years and think this eliminated fibro pain to the point where it would be hard to state if I still have it. Would not dream of stopping it. Relapses occur from overdoing and get fixed with magnesium malate, nootropics, adaptogens, acupuncture, scalar energy devices and yoga type techniques in combination.

  • Elsie

    December 20, 2019 at 5:45 am - Reply

    Thanks for this write-up. Could you be more specific about the other ion channel they are looking at? I seem to have missed this in reading the research papers.

    “It bears mentioning that the Griffith group has evidence that another ion channel may not be working properly in ME/CFS, that these channels are widespread throughout the body, and a systemic dysfunction with them, if present, could cause many problems.”

    • Cort Johnson

      December 20, 2019 at 2:43 pm - Reply

      They found evidence that TRPM2 was dysregulated as well.

  • Elizabeth Edwards

    December 20, 2019 at 6:33 am - Reply

    Benjamin – You might find this ME-Pedia article helpful as a primer on LDN, with references for further reading/ videos. Also Cort’s own Health Rising blog. That and the Science for ME forum are great sources of news and information on the evolving science and many patient forums provide good places for personal discussion of treatments tried, etc.
    There are no quick/guaranteed fixes, but hope this helps! Also, remember different things seem to help different people; as yet there’s no wonder cure or even symptom alleviation that works for everyone.. so until then, the art is in matching up what seems like it might have the best chance of helping in your own particular case. Then finding a doctor to prescribe it, if it’s a prescription only medicine/treatment. Local forums/support groups may be the best sources of information for this.
    Do the research and be very careful what you decide to spend your money on. since it’s easy to waste many 1000s on useless and even downright dangerous/ harmful treatments, not to mention the energy and emotional investment…
    Good luck!

  • Elizabeth Edwards

    December 20, 2019 at 6:35 am - Reply

    Whoops – left out the link…
    https://me-pedia.org/wiki/Low_dose_naltrexone

  • Billie

    December 20, 2019 at 7:06 am - Reply

    In reply to Leapy……. Do you really think for one minute, anyone with CFS/ME could
    tolerate drinking alcohol?

  • Michelle Fielding

    December 20, 2019 at 1:19 pm - Reply

    They are talking about Low Dose Naltrexone but have shortened it to Naltrexone…. don’t confuse the two

    • Cort Johnson

      December 20, 2019 at 2:41 pm - Reply

      Are you sure? Researchers are usually very precise in their terminology and they referred to the drug as Naltrexone throughout. They referred to LDN when they noted that LDN does work for some people. Do you have a link or something to document that?

  • fabio

    December 20, 2019 at 3:45 pm - Reply

    I’d be VERY CAREFUL about this “new finding” . A lot of ME/CFS patients, including me, have been using LDN. In my case, it didn’t work and gave me depresson and blurred vision also with very very little dosage. In others, the improvement has been from light to mid, but didn’t last more than one year. So, it’s not that simple.

  • Michelle

    December 20, 2019 at 3:55 pm - Reply

    I wonder if you gave LDN long enough, it gets better and better with time…. blurred vision may be cause dosage was too high or accelerated too quick…. generally eyes improve on LDN

  • Michelle

    December 20, 2019 at 3:57 pm - Reply

    Naltrexone hydrochloride (NTX) is best known in its low dose form in ME/CFS. It was referred to in this paper, though, simply as naltrexone. …. in the above article

  • Verena

    December 20, 2019 at 6:12 pm - Reply

    I might refer people to the original studies using Naltrexone. At high dose it was used for addictions. Accidentally prescribing a low-dose to someone, cured a tumour. Further applications of low dose Naltrexone help autoimmune issues and with cancer. I would suggest that the low dose has been proven and people using high-dose do not get the same benefit. However I have seen people with autoimmune issues going up to 12 mg with success. I cannot get past 1.5 mg at this time but I have seen Improvement in my energy and cognitive functioning.

  • Grace

    December 21, 2019 at 5:26 pm - Reply

    If the NK cells find and kill cancerous cells; and these NK cells aren’t functioning properly in ME patients- would that mean there is a higher incidence of cancers in ME patients?

  • Cort Johnson

    December 22, 2019 at 1:45 am - Reply

    One might think but the evidence of increased cancer risk in ME is thankfully very spotty. Just possibly one very rare cancer – the increased incidence of which would still leave it very rare.

  • Sally

    December 23, 2019 at 10:33 pm - Reply

    My brain doesn’t function that well anymore. How does this immune system issue fit in with low IGG levels? The body is a wondrous, complex thing but I am trying to understand how the process works for those of us born with deficient immunity. Any explanation for a layman would be appreciated. Thanks.

  • RivkaC

    December 25, 2019 at 5:30 am - Reply

    I’ve thought about trying LDN but have found enough improvement with K PAX Immune Support that I’m not ready to jump to another med yet.

    • Cort Johnson

      January 1, 2020 at 4:05 pm - Reply

      Nice- Congratulations – and thanks for passing that on.

  • Sandra

    January 13, 2020 at 6:17 pm - Reply

    My (private) endocrinologist (UK) is going to try me on LDN if T3 or cortisol treatment doesn’t help (T3 isn’t helping yet – after about four weeks)

  • Janet MacLennan

    February 7, 2020 at 1:25 pm - Reply

    Hello, I believe Jarred Younger is in the process of studying the effects of LDN on people with ME, following a successful trial with people with Fibro. Details here: https://www.meassociation.org.uk/wp-content/uploads/MEA-Summary-Review-Low-Dose-Naltrexone-LDN-in-MECFS-02.11.19.pdf. The LDN research trust suggest a dose of 4.5 mg (this has to be gradually titrated up from a tiny dose)- Younger suggests experimenting with raising/ lowering your dose (up to, I think, 6mg). I’ve been on it for 9 months, and it has made a huge difference- in fact, my NHS GP is attempting to prescribe it for me (I buy it privately atm)