Dr. Natalie Eaton-Fitch talks with us about low-dose naltrexone (LDN) and the search for a drug to treat myalgic encephalomyelitis. Image courtesy of Dr. Natalie Eaton-Fitch.
In the world we live in people are suffering from all kinds of illnesses, which require a variety of different medications to treat them.
Often, the road to finding a novel medication for a particular illness can take many years, as the money for medical trials usually comes from drug companies who have to spend large amounts of money on research and then conduct the different stages of medical trials to ascertain efficacy and safety.
In the myalgic encephalomyelitis (ME) community, we have faced decades of neglect from the medical establishment, who have not put the requisite sums into research. Sadly, it would appear that none of the big drug companies have taken any interest into conducting research into medications to treat ME.
This gap in research has been filled by small groups of researchers at various universities. Rather than wait for years in the hope of some new medication, some scientists have turned to cheap, safe, repurposed drugs as potential treatments for ME.
One such scientist is Dr. Natalie Eaton-Fitch.
Dr. Eaton-Fitch is a research fellow at the National Centre for Neuroimmunology and Emerging Diseases (NCNED) located at Griffith University in Australia. Her research interests include the pathophysiology of ME, Long COVID and natural killer (NK) cells. Dr. Eaton-Fitch’s work is aiming to develop a diagnostic test for ME and to repurpose drugs for the treatment of the illness.
How did you get involved in the field of ME research?
There are a number of reasons — the most significant being that I’ve lived my life watching a family member battle with ME, and have done so for the past 30 years. The other is my interest and enthusiasm in immune biology.
I reached out to Professor Marshall-Gradisnik at the National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffith University after I completed my undergraduate degree. I pursued postgraduate studies with Professor Marshall-Gradisnik as my mentor, and I have since been awarded my PhD. I continue working with the team at the NCNED as a research fellow.
Naltrexone was originally developed to help people with alcohol and drug addictions. However, in the last 10 years, a small number of doctors have started using low-dose naltrexone (LDN) to treat people with ME. Can you explain how LDN came to be used as a repurposed drug to treat people with ME?
The use of repurposed LDN started in the later 1980s after the positive effects of LDN were reported. LDN has multiple biological functions, including the release of endorphins and immunomodulation.
Subsequently, LDN was reported to significantly reduce pain, cognitive, and fatigue symptoms in different patient cohorts — for example in multiple sclerosis and fibromyalgia. Indeed, as these are some of the hallmark symptoms of ME, LDN held promise as a pharmacotherapeutic option.
A few months ago I listened to a medical lecture by Dr. Keith Berkowitz and Dr. Mobeen Syed, who were talking about the use of LDN to treat patients with Long COVID.
During their presentation, they proposed that the mechanism of action for LDN was to suppress inflammation in the body — which would help to reduce the severity of Long COVID symptoms in many patients.
Can you explain how LDN works to help some people with ME?
Immune system dysfunction is reported in both Long COVID and ME. Naltrexone, while an opioid receptor inhibitor at high doses, acts as an immunomodulator at low doses. LDN increases the release of beta-endorphins, which are a substance involved in many biological functions — including, but not limited to, pain management.
As an example, endorphins are related to the hypothalamic-pituitary-adrenal (HPA) axis, which is dysfunctional in ME patients and is associated with some metabolic and immune responses.
Furthermore, immune dysfunction is observed through reduced natural killer (NK) cell cytotoxic activity. (Natural killer cells are innate immune cells that eliminate tumour cells and virus-infected cells. NK cell cytotoxicity refers to their ability to eliminate these target cells).
NK cells are part of the innate immune system responsible for elimination of viral-infected and malignant cells. LDN is believed to increase NK cell cytotoxic function through the release of beta-endorphins and through restoration of a calcium channel known as transient receptor potential melastatin 3 (TRPM3).
TRPM3 is a member of a family of transient receptor potential (TRP) ion channels with a vital role in calcium signaling in cells. Calcium is required for a number of biological functions, one of which is immune function.
Dysfunction of TRPM3 means the passage of calcium into cells is reduced and this impairs cell function and is associated with the symptoms of ME. The restoration of TRPM3 is hypothesised to restore cell function across body systems.
Here’s another potential mechanism for LDN: (there are quite a few)
LDN has also been shown to block toll-like receptor 4 (TLR4), a recognition receptor found on immune cells such as microglia. Microglia are immune cells of the central nervous system that are involved in neuroinflammatory responses such as pain, cognitive dysfunction, fatigue, sleep disturbances and mood disorders.
As neuroinflammation is documented in ME, LDN might regulate TLR4/microglia activity, reducing neuroinflammation, which may relieve the above mentioned symptoms.
A small number of medical trials have been conducted into the use of LDN as a potential treatment for ME. Based on the results of these trials how successful has LDN been in helping people with ME?
Current research suggests that LDN is a safe and effective pharmacotherapeutic option for alleviating the symptoms of ME with minimal adverse effects.
Some people who take LDN say it has really helped with their fatigue. Others (I include myself in this camp) say LDN has helped with pain issues but not with fatigue issues. How would you explain that?
LDN predominantly has anti-inflammatory and anti-pain mechanisms through the following pathways:
(i) opioid receptor inhibition;
(ii) increased endorphin release and activity;
(iii) TRPM3/immune regulation; and
(iv) microglia/TLR4 regulation.
Also, as you’re aware, the presentation and trajectory of ME as an illness varies widely among patients. As this variation may be due to different genetic and functional changes, the response to LDN may also vary. This is why the NCNED also aims to investigate other, but similar, potential pharmacotherapeutic targets.
What further research is needed into low-dose naltrexone, in order to prove its efficacy as a treatment for people with ME?
Rigorous placebo-controlled randomised clinical trials are required to further identify the efficacy of LDN in ME.
You mention the need for randomised placebo-controlled trials for LDN. On what scale would these trials need to be? Across how many countries? In different subsets of people with ME?
Clinical trials go through a series of phases to test the safety and effectiveness of drug candidates. These phases start with small cohorts before moving into larger cohorts.
Small-scale trials are currently demonstrating that LDN is safe and effective in improving symptoms of ME. Large-scale clinical trials involving several hundred, then subsequently several thousand participants (meeting more recent diagnostic criteria such as CCC or ICC) will be needed to approve LDN for the treatment of ME.
Do you know of any other repurposed medications that are being used by researchers as possible treatments for people with ME?
There are numerous medications used off-label for targeting specific symptoms of ME. However, there is little evidence regarding efficacy.
The off-label use of Aripiprazole, used to manage symptoms of mood in mental health disorders, has gained interest recently as a potential pharmacotherapeutic option for ME. At low levels, Aripiprazole stimulates dopamine production, affecting cognition, sleep, mood, inflammation, energy production and movement.
Can you tell us about your own research into low-dose naltrexone as a potential treatment for ME?
At the NCNED we aim to identify a diagnostic/screening test for ME patients and to discover pharmacotherapeutic treatments to improve symptoms and quality of life.
We previously reported on impaired TRPM3 ion channel function and associated signaling pathways in ME patients. Thus, TRPM3 ion channels provide a pharmacotherapeutic target.
TRPM3 ion channels are calcium channels located on various cells throughout the body. When activated, these channels open to allow calcium to flow into the cell, where calcium acts as a secondary messenger to help stimulate cell function — for example to stimulate NK cell cytotoxicity.
TRPM3 ion channels also respond to various threats/stressors such as infection, allergens, chemicals, surgery, changes to temperature and are involved in inflammatory and pain responses (nociception). Genetic, expression, and functional changes in TRPM3 have been reported in NK cells of ME patients.
We demonstrated that naltrexone treatment of isolated NK cells from ME patients restored the TRPM3 ion channel function, and subsequently confirmed the efficacy of LDN by demonstrating benefit in the pathophysiology of ME.
Therefore, our future research aims to complete a clinical trial into the therapeutic efficacy of LDN in ME. Research at the NCNED will focus not only on TRPM3 ion channel pathology, but also on changes to brain MRI in response to LDN.
Bronc is a former historian who is active in his local ME support group. He enjoys interviewing scientists involved in ME research to help himself and others better understand their illness.
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