The ME Association ME/CFS (& Long Covid) Weekly Research Round-up

August 6, 2021

The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a FREE resource, available to anyone, and updated at the beginning of each month.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

ME/CFS Research Published 24 – 30 July 2021

Nine new research studies on ME/CFS have been published during this period and we have also included twelve studies on Long Covid. We highlight two on ME/CFS from the selection below:

The first study (1) examined the use of low dose of naltrexone (LDN) to help relieve symptoms of ME/CFS, which presumes the pathology of the disease is due to problems in the immune system. It was a small study and the researchers examined its effectiveness in vitro i.e., by studying cellular reactions in the lab.

A restoration of NK cell regulatory function was recorded, which might account for the claimed symptom improvements by people who take LDN.

It is hoped that this study – which builds on others with LDN – will lead to large randomised clinical trials which might reach positive conclusions about efficacy in ME/CFS. Until then, LDN use in ME/CFS remains speculative.

The sixth study (6) was a randomised, placebo-controlled trial of 207 people with ME/CFS. It looked at dietary supplementation using coenzyme Q10 and NADH (a reduced form of nicotinamide adenine dinucleotide).

It found that co-supplementation could improve perceived symptoms of ME/CFS – cognitive fatigue and sleep – and quality of life:

“These findings support the use of CoQ10 plus NADH supplementation as a potentially safe therapeutic option for reducing perceived cognitive fatigue and improving the health-related quality of life in ME/CFS patients.”

ME/CFS Research References and Abstracts

1. 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

Cabanas H, Muraki K, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S. Front Immunol. 2021 Jul 13;12:687806.


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic condition 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 benefit 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. TRPM3 ion channel activity was measured 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 using whole-cell patch-clamp technique.

We report that ME/CFS patients taking LDN have restored TRPM3-like ionic currents in NK cells. Small ionic currents with a typical TRPM3-like outward rectification were measured after application of PregS, a TRPM3-agonist, in NK cells from patients taking LDN.

Additionally, PregS-evoked ionic currents through TRPM3 were significantly modulated by ononetin, a TRPM3-antagonist, 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.

2. A paradigm for chronic fatigue syndrome: caught between idiopathic intracranial hypertension and spontaneous intracranial hypotension; caused by cranial venous outflow obstruction

J Nicholas P. Higgins & John D. Pickard (2021). Fatigue: Biomedicine, Health & Behavior.


Background:Clinical similarities between chronic fatigue syndrome and idiopathic intracranial hypertension, supported by measurements of intracranial pressure, invite suggestions that they may be connected, the first representing a mild version of the second.

Yet, if this is to be the basis for a structural explanation for chronic fatigue syndrome, it already seems incomplete, failing to explain cases where disability seems disproportionate. Is there some other confounding variable?

Purpose:To refine, in this theoretical paper, an earlier model connecting chronic fatigue syndrome with idiopathic intracranial hypertension to allow for a cerebrospinal fluid (CSF) leak.

Model:In this model, the primary structural problem is acquired obstruction to cranial venous outflow. This obstruction can take different forms, may be intermittent and subtle, and even be mistaken for normal venous anatomy, yet would be the driving force behind a tendency towards increased intracranial pressure.

This chronic elevation of intracranial pressure stresses the dural membrane maintaining the integrity of the subarachnoid space, which can rupture at a weak point, allowing CSF to leak away and intracranial pressure to fall. The clinical manifestation of this disorder is the product of the severity of cranial venous outflow compromise and of the competing forces on intracranial pressure.

In some instances, a CSF leak will mitigate the effects of venous compromise, in others it will compound it, producing a disease spectrum ranging through idiopathic intracranial hypertension, chronic fatigue syndrome, fibromyalgia, and spontaneous intracranial hypotension.

Conclusion:In chronic fatigue syndrome a normal intracranial pressure does not exclude significant physiological disturbance.

3. Radiation exposure and mitochondrial insufficiency in Chronic Fatigue and Immune Dysfunction Syndrome

Andrej Rusin, Megan Li, Alan Cocchetto, Colin Seymour, Carmel Mothersill. Medical Hypotheses, 2021, 110647.


Chronic fatigue and Immune Dysfunction Syndrome (CFIDS) is a heterogeneous disease that may be promoted by various environmental stressors, including viral infection, toxin uptake, and ionizing radiation exposure.

Previous studies have identified mitochondrial dysfunction in CFIDS patients, including modulation of mitochondrial respiratory chain activity, deletions in the mitochondrial genome, and upregulation of reactive oxygen species (ROS).

This paper focuses on radiation effects and hypothesizes that CFIDS is primarily caused by stressor-induced mitochondrial metabolic insufficiency, which results in decreased energy production and anabolic metabolites required for normal cellular metabolism.

Furthermore, tissues neighbouring or distant from directly perturbed tissues compensate for this dysfunction, which causes symptoms associated with CFIDS. This hypothesis is justified by reviewing the links between radiation exposure and CFIDS, cancer, immune dysfunction, and induction of oxidative stress.

Moreover, the relevance of mitochondria in cellular responses to radiation and metabolism are discussed and putative mitochondrial biomarkers for CFIDS are introduced. Implications for diagnosis are then described, including a potential urine assay and PCR test for mitochondrial genome mutations.

Finally, future research needs are offered with an emphasis on where rapid progress may be made to assist the afflicted.

4. Improving awareness of myalgic encephalomyelitis among healthcare professionals

Ruth Richardson. British Journal of Healthcare Management 0 0:0, 1-3.


Myalgic encephalomyelitis, or chronic fatigue syndrome, represents a significant human and economic health burden. Ruth Richardson of UK charity Action for ME discusses the need to increase awareness of this condition among healthcare professionals and shares resources to help with this.

5. Benefits of micronutrient supplementation on nutritional status, energy metabolism, and subjective wellbeing

Maggini S, Óvári V, Ferreres Giménez I, Pueyo Alamán MG. Nutr Hosp. 2021 Jul 28. English. Epub ahead of print.


The human body, particularly the brain, requires energy, stored in the form of adenosine triphosphate. Energy metabolism during cellular respiration is dependent on the presence of multiple micronutrients, which act as essential components, coenzymes, or precursors at every stage.

An adequate supply of multiple micronutrients is vital for efficient energy production. However, micronutrient intakes below the recommended dietary allowance are common, even in industrialized countries.

Intakes of vitamins A, D, E, folate, iron, zinc, and selenium are suboptimal across all age groups. Suboptimal micronutrient levels have been shown to contribute to low energy levels, physical and mental fatigue, and impaired cognitive performance and wellbeing – symptoms frequently present in the general population.

When supplemented in combination in well-conducted trials, multiple micronutrients ± coenzyme Q10 reduced oxidative stress in chronic fatigue syndrome; in healthy people they increased cerebral blood-flow hemodynamic response, energy expenditure, and fat oxidation; reduced mental and physical fatigue; improved the speed and accuracy of cognitive function during demanding tasks; and reduced stress.

The results from these clinical trials suggest that even in industrialized countries, where adults might be assumed to have a healthy, balanced diet, there is a rationale to supplement with multiple micronutrients, including coenzyme Q10, to improve nutritional status, support energy metabolism, and improve subjective wellbeing.

6. Effect of Dietary Coenzyme Q10 Plus NADH Supplementation on Fatigue Perception and Health-Related Quality of Life in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

Castro-Marrero, J.; Segundo, M.J.; Lacasa, M.; Martinez-Martinez, A.; Sentañes, R.S.; Alegre-Martin, J. Nutrients 2021, 13, 2658.


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating neuroimmune disease, probably of post-viral multifactorial etiology. Unfortunately, no accurate diagnostic or laboratory tests have been established, nor are any universally effective approved drugs currently available for its treatment.

This study aimed to examine whether oral coenzyme Q10 and NADH (reduced form of nicotinamide adenine dinucleotide) co-supplementation could improve perceived fatigue, unrefreshing sleep, and health-related quality of life in ME/CFS patients.

A 12-week prospective, randomized, double-blind, placebo-controlled trial was conducted in 207 patients with ME/CFS, who were randomly allocated to one of two groups to receive either 200 mg of CoQ10 and 20 mg of NADH (n = 104) or matching placebo (n = 103) once daily.

Endpoints were simultaneously evaluated at baseline, and then reassessed at 4- and 8-week treatment visits and four weeks after treatment cessation, using validated patient-reported outcome measures.

A significant reduction in cognitive fatigue perception and overall FIS-40 score (p < 0.001 and p = 0.022, respectively) and an improvement in HRQoL (health-related quality of life (SF-36)) (p < 0.05) from baseline were observed within the experimental group over time.

Statistically significant differences were also shown for sleep duration at 4 weeks and habitual sleep efficiency at 8 weeks in follow-up visits from baseline within the experimental group (p = 0.018 and p = 0.038, respectively).

Overall, these findings support the use of CoQ10 plus NADH supplementation as a potentially safe therapeutic option for reducing perceived cognitive fatigue and improving the health-related quality of life in ME/CFS patients.

Future interventions are needed to corroborate these clinical benefits and also explore the underlying pathomechanisms of CoQ10 and NADH administration in ME/CFS.

7. Chronic fatigue syndrome and long covid: individualisation, not compartmentalisation

Russell S Malcolm. BMJ 2021;374:n1863.

No abstract available

8. The reification of the clinical diagnosis of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) as an immune and oxidative stress disorder: construction of a data-driven nomothethic network and exposure of ME/CFS subgroups

Maes M, Kubera M, Stoyanova K, Leunis JC. Curr Top Med Chem. 2021 Jul 27. [Epub ahead of print].


The approach towards myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010,8,35).

The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO).

Using PLS, we trained, tested, and validated this knowledge – and data-driven causal ME/CFS model, which showed adequate convergence, construct, and replicability validity. This bottom-up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome.

We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.

9. The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a meta-analysis of public DNA methylation and gene expression data

Malato J, Sotzny F, Bauer S, Freitag H, Fonseca A, Grabowska AD, Graça L, Cordeiro C, Nacul L, Lacerda EM, Castro-Marrero J, Scheibenbogen C, Westermeier F, Sepúlveda N. Heliyon. 2021 Jul 29;7(8):e07665.  [Online ahead of print].


People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course.

Since this reporting is in line with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed to explore whether the expression of the human angiotensin-converting enzyme-2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in this neglected clinical population.

In particular, a low expression of ACE2 is usually indicative of a high risk of developing COVID-19. We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets.

We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients with ME/CFS when compared to healthy controls. Accordingly, in newly collected data, we found evidence for a higher proportion of samples with an ACE2 expression below the limit of detection in patients with ME/CFS than in healthy controls.

Altogether, patients with ME/CFS could be at a higher COVID-19 risk when infected by SARS-CoV-2. To further support this conclusion, similar research should be conducted for other human cell entry receptors and other cell types, namely, those mainly targeted by the virus.

Long-COVID Research References

  1. Post-COVID-19 acute sarcopenia: physiopathology and management
  2. Post-infection cognitive impairments in a cohort of elderly patients with COVID-19
  3. Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning
  4. Long COVID
  5. Long covid—mechanisms, risk factors, and management
  6. Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID
  7. Mild COVID-19 and Impaired Cell-Endothelial Crosstalk: Considering Long-Term Antithrombotics and Vascular Protection?
  8. Long covid: reshaping conversations about medically unexplained symptoms
  9. The road to addressing Long Covid
  10. Long-term COVID-19 control requires high vaccination and intermittent control measures
  11. Long COVID and mental health
  12. Post-acute Sequelae of SARS-CoV-2 Infection and Subjective Memory Problems

Katrina Pears, Research Correspondent, ME Association

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