Naltrexone is mostly used to help people addicted to opioid drugs safely withdraw from them, but LDN is used for a far different purpose. By temporarily blocking opioid receptors, LDN, in effect, unleashes them – causing a rebound effect and an increase in the production of the body’s endogenous opioids which reduces pain levels. LDN may also be able to inhibit microglial activity and thus reduce neuroinflammation.

LDN was pursued in FM because of its potential pain-relieving (those opioid receptors) properties but the fatigue, found in ME/CFS, however, is another matter. While this study did not assess LDN’s ability to reduce the fatigue and other symptoms in ME/CFS it explored LDN in a way that had never done before and it did it in ME/CFS to boot. That itself is quite unusual.

Siloed Fields

What’s taken years to get done in ME/CFS is getting done very quickly in long COVID – and that’s good news for both diseases.

The low dose naltrexone (LDN) saga in chronic fatigue syndrome (ME/CFS) is another example of how long it can take for findings in even a closely related disease to make it to the ME/CFS field. Despite the close biological connections between postural orthostatic tachycardia syndrome (POTS), dysautonomia, ME/CFS, and fibromyalgia (FM) researchers rarely collaborate, and rarely even seem to track findings in other diseases.

It took 8 years and dozens of small fiber polyneuropathy (SFPN) fibromyalgia studies, for instance, before David Systrom’s ME/CFS SFN study indicated, to no one’s surprise, that SFPN was commonly found in ME/CFS. Ditto with low-dose naltrexone (LDN). Despite LDN’s wide use in ME/CFS, it took 7 years from the date of the first FM trial for the first LDN ME/CFS study to show up. That study had moderately good results, but its methodology left much to be desired.

Things are already different in long COVID, though. Not much more than a year after long COVID was found, the first small fiber neuropathy has already been published, and the first low dose naltrexone study is already underway!

Aussies Take New Approach to LDN

ME/CFS may be lagging in the LDN field but Sonya Marshall-Gradisnik‘s Australian ME/CFS team at the National Centre for Neuroimmunology and Emerging Diseases (NCNED) undoubtedly shook the field up a bit with their new finding. Not only did they demonstrate a new property for LDN – its potential to improve natural killer cell functioning – but they linked LDN to their intriguing hypothesis that ion channels problems are causing ME/CFS

The NCNED study did not assess the impact LDN has on symptoms in ME/CFS. We’re still waiting on a good study to assess that.  Instead, they assessed the effects LDN may be having on the one really major immune consistently found in ME/FS – the inability of natural killer cells to do much killing.

Natural killer cells make up from 5-20% of the lymphocytes in the human body and man the first lines of our immune defense. Twenty years after the failure of NK cells in ME/CFS to kill pathogen-infected or otherwise damaged cells in ME/CFS, the cause remains unclear.

The study wasn’t just about NK cells, though. The NCNED group has been using natural killer (NK) cells to explore their idea that reduced calcium influx through the transient receptor potential (TRPM3) ion channels is causing natural killer dysfunction as well as ME/CFS.

Ion-Channel Receptor

Ion channels control the action in many cells. The NCNED believes problems with a specific channel called TRPM3 could be causing the symptoms of ME/CFS.

The Griffiths team has dug deeper into the NK issue than any other group, and a recent study suggested that reduced TRPM3 activity may be preventing NK cells from tricking pathogen-infected or otherwise damaged cells into committing cellular suicide (apoptosis). (Apoptosis is an orderly process that ensures that the pathogens infecting the cells are destroyed with it.) The study suggested that increasing TRPM3 activity could improve natural killer cell functioning.

The TRPM3 receptor problem, though, potentially goes far beyond NK cells. Since TRPM3 receptors affect a fundamental process – calcium and magnesium homeostasis – they play a role in many physiological processes. They’re particularly abundant in the dorsal root ganglia, a key sensory signal transmitting station that has been implicated in fibromyalgia. Problems with heat/cold sensations and pain hypersensitivity have been associated with them.

Wound up, Overheated and Tweaked: A Look at the Fibromyalgia Brain and Nervous System.

As signaling pathways associated with opioid receptors can inhibit TRPM3 receptor activity, they were of interest to the Griffiths group. These opioid signaling pathways don’t just alleviate pain: they also affect immune and central nervous system functioning.

The latest Griffiths study, “Potential Therapeutic Benefit of Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment“, found that NK cells of ME/CFS patients taking LDN had normal TRPM3 functioning. Since inhibited TRPM3 functioning has been linked to poor NK cell functioning, it’s possible that LDN was able to restore NK cell functioning.

To know if that’s true, we need placebo-controlled studies but the potential is there. The authors also believe that reduced endogenous opioid and beta-endorphin production in ME/CFS may be responsible for some of its symptoms.

Are All the “Feel-Good” Pathways Blocked in Fibromyalgia and Chronic Fatigue Syndrome?

While this study did not document that LDN reduces symptoms in ME/CFS, it does something potentially quite important: by demonstrating that LDN may be able to restore functioning in NK cells, it may help lay the groundwork for a large, effective study. Dr. Staines reported:

“This study serves to support the repurposing of marketed drugs and support prospective randomised clinical trials using Naltrexone in treating ME/CFS patients.’’

Is ME/CFS a TMPR3 Disease?

Natural killer cell dysfunction, while important, is a sideshow to the much bigger question – of whether wonky TMPR3 receptors in other cells could be causing ME/CFS?  Because TMPR3 is found on so many cells problems with it could conceivably cause all the symptoms in ME/CFS.

Five years ago, it appeared that NCNED was on the cusp of truly big things. in 2016, the Griffith News report, “Screening test for Chronic Fatigue Syndrome on its way“, stated the NCNED group had “identified new markers that can be used to screen patients and is now looking to partner with diagnostic companies to bring a test to market.” Dr. Marshall-Gradisnik expected the test “to become a laboratory standard to provide more certain, and cost-efficient, diagnosis for CFS.” 

Three years ago, Science Alert reported thatStaines and his team have been working to figure out the best markers that can be used to test for these faulty receptors, so they can begin to create a CFS/ME test”, and were “looking for medications” that act on these receptors. They were also looking for medications that act on these specific calcium ion channels in the hopes of finding potential treatments for the disease.

Recently, Marshall-Gradisnik said in no uncertain terms that she believes an ion channel dysfunction is causing ME/CFS.

“We now further understand that the pathophysiology of ME/CFS is due to ion channel dysfunction and the interaction of the opioid receptor that causes impaired Ca2+ signalling and Ca2+-mediated cell functions, including immune function,”

The Gist

  • Low-dose naltrexone or LDN is a compounded drug often used in fibromyalgia, ME/CFS, and other diseases to reduce pain. It appears to do this by temporarily shutting down the opioid receptors – causing them to kind of explode with a burst of endogenous opioids that reduce pain. The fact that LDN often works in FM suggests that the endogenous opioid system is not working well. LDN may also be inhibiting the activity of microglial cells in the central nervous system.
  • Since the first LDN trial in fibromyalgia seven years ago it wasn’t until last year that the first retrospective LDN study was done in ME/CFS. Similarly, it took almost 10 years after small fiber neuropathy was documented in FM for the first ME/CFS SFN study to appear. Long COVID seems to be breaking this trend – both LDN and SFN studies have already been completed or are underway in long COVID.
  • Building on a recent finding which suggested that TRPM3 ion channels were dysfunctional in the natural killer (NK) cells in ME/CFS, the Australian team assessed TRPM3 ion channel functioning in ME/CFS patients taking LDN and found that the channels were functioning fine (!). That suggested, but does not prove – as no controls were involved in this study – that besides helping with pain, that LDN may be helping to improve immune functioning as well. The Australian group believes that a dysfunction in these ubiquitous ion channels is causing ME/CFS.

Five years ago, it seemed that the group was on the cusp of producing a diagnostic test for ME/CFS. Three years ago the search for medications to affect the TRPM3 ion channel was underway. I’m attempting to find out how those efforts are going.

Several small studies have found that LDN produces positive benefits in FM or ME/CFS but both diseases lack the large placebo-controlled, double-blinded studies needed to validate those findings. Given that drug companies have no interest in easily compounded drugs, one might think that the National Institutes of Health – with the urgent need to develop better pain drugs – might be willing to pick up the tab but it’s refused to fund LDN studies. Thankfully, two large and rigorous studies are, however, underway in Denmark and Spain.

LDN Studies Needed

While several small FM or ME/CFS LDN studies have shown efficacy, the picture is incomplete. We still lack the large double-blinded, placebo-controlled studies that are needed to truly validate those results. The same pattern has played out in chronic pain as well. While LDN is often prescribed for chronic pain and has shown promising results, two 2018 and 2020 systematic reviews of LDN use in chronic pain conditions concluded that more randomized control studies are needed.

Since LDN is compounded it doesn’t lend itself to large, drug-company-funded trials. In the U.S. that would leave LDN study in the hands of philanthropists or the National Institutes of Health (NIH). One might think that NIH would take a special interest in a potentially helpful drug in a field (pain) that it acknowledges desperately needs better drugs.

Unfortunately, that’s not so. Jarred Younger was unable, despite numerous attempts, to get NIH funding for a large LDN ME/CFS trial.  The NIH also refused to fund a clinical trial of dextro-naltrexone, which Younger believes has the potential to blow the pants off LDN in terms of effectiveness. Younger reported that he was able to find the materials needed to manufacture the drug and even had the infrastructure in place for production and testing, but the NIH wouldn’t fund it. Younger concluded that the NIH will not fund LDN trials.

Thankfully, Denmark and Spain will.  While there’s still no determinate LDN ME/CFS trial in sight, a100-person randomized double-blind, placebo-controlled LDN FM Study began this year in Denmark and should wrap up in early 2023. A large, double-blinded Spanish LDN fibromyalgia trial is due to begin soon as well.

Long COVID is again demonstrating that what hasn’t happened in almost ten years in ME/CFS can happen very quickly in long COVID. A double-blinded, placebo-controlled Long COVID LDN plus NAD+ trial is underway in Michigan.  Recruitment still appears to be open. Find out more about it here.

It’s remarkable how far behind the US, easily the biggest driver of medical research in the world, and a major funder of clinical trials is with regard to clinical trials for ME/CFS. The few major clinical trials underway for ME/CFS are taking place outside of the U.S.

(The NIH is funding one good trial in ME/CFS – an N-acetylcysteine trial – which will be covered soon.)

Meanwhile, the scientific literature supporting the use of LDN is slowly growing. A recent study indicated that, as Jarred Younger believes, LDN has the potential to shift microglial cells from producing pro-inflammatory to anti-inflammatory cytokines. Another double-blinded, placebo-controlled study found that LDN was as effective as amytriptyline and produced much fewer side effects in people with painful cases of diabetes.  Last year a study found that intranasal LDN performed well in reduced opioid side-effects in animal studies, and another which showed that LDN re-oriented macrophages away from pro-inflammatory to anti-inflammatory cytokine production might have real implications for the “aggressive monocytes” found in COVID-19.

Health Rising’s Low Dose Naltrexone Resource Page

HR’S LDN Resource page spells out treatment options, where to get LDN, etc, and provides links to the many Health Rising blogs on LDN

Low Dose Naltrexone (LDN) Fibromyalgia and Chronic Fatigue Syndrome Resource Center













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