“Mary Ann’s Transfusion”

by Dr. David Bell

This is the case history of a nurse who improved dramatically after a blood transfusion. It is excerpted from Dr. Bell’s book, Faces of CFS – Case Histories of Chronic Fatigue Syndrome, published in August, 2000. “Mary Ann’s Transfusion” illustrates one aspect of cases he has followed since the mid-1980’s. 

Reprinted with the kind permission of Prohealth.

***

Mary Ann was a bold and highly competent nurse in the intensive care unit of our local hospital, and I depended on her. Given that my specialty is pediatric medicine, I was always a little nervous treating adult patients who were in the midst of medical crises. I quickly learned I could count on the vivacious Mary Ann, who was then in her thirties, for the most up-to-date and reliable information about my patient’s status. Often, she suggested successful solutions to problems for which I had never been trained in medical school, like constipation. There should be a course on constipation in octogenarians who have suffered heart  attacks, but there isn’t.

In 1985, when the epidemic of CFS in Lyndonville began, eventually affecting more than two-hundred people in a town of 1,500 (or whatever), Mary Ann got sick, too, although some years passed before her diagnosis was readily apparent. The one constant, however, which began in 1985, was exhaustion. Mary Ann was weighted down with a panoply of other problems, as well: arthritis-like pains in her joints, sinus infections, allergies, migraine headaches, chest pain, shortness of breath. As the years wore on, these symptoms and many more resulted in her slide from being perhaps the finest ICU nurse I have ever known to little more than – in the eyes of the medical specialists she consulted – a hypochondriac. As a result, she was inhabiting a remorselessly bleak netherworld.

I tried to help Mary Ann, too, over the years. It was rapidly apparent to me, and eventually to her, that she had same disease from which so many of the patients she had met in the hospital in 1985 had suffered. I tried everything I could think of by way of drugs and other therapies to help her, but none of them worked to any appreciable degree. There was an aspect of her case that I found very interesting, perhaps because it seemed to me to be one of those elusive clues that might lead me to a more comprehensive understanding of the mechanism of the disease.

Mary Ann had a remarkable requirement for water. She rarely came into my clinic without a large container of ice water, from which she sipped continuously. I was pretty sure it was water, anyway; if it was vodka, I knew we were in for some big problems. It turned out not to be vodka, of course. Once, I asked Mary Ann to keep track of the amount of water she drank in one twenty-four hour period. Her consumption turned out to be four gallons a day. Persistent thirst is a sign of diabetes, and Mary Ann did indeed have diabetes, in addition to all her other problems. She had a rare kind, however, one called “diabetes insipidus,” which is not the “sugar diabetes” with which most people are familiar. In the primitive days of medicine, doctors would actually differentiate between the two forms of diabetes by tasting their patients’ urine. If the urine had a sweet taste, their diagnosis was sugar diabetes, known today more formally as “diabetes mellitus.” In the case of diabetes insipidus, the urine was tasteless, or “insipid.” Recalling this piece of medical history makes me wonder if I really want to return to the good old days of clinical medicine.

What struck me as most interesting about Mary Ann’s diabetes is the fact that it is caused by a deficiency of the brain hormone,  vasopressin, which, as I have noted, is a common finding in CFS sufferers. Among its many functions, vasopressin helps the kidneys absorb water and maintain the body’s fluid balance. When vasopressin is low, or missing entirely, water runs through the body without being absorbed, like a bucket with a hole in the bottom. Usually, diabetes insipidus signals damage to the pituitary gland in the brain, which manufactures vasopressin. Paradoxically, in spite of her gargantuan intake of water, lab tests suggested that Mary Ann was living in a state of perpetual dehydration.

I decided to measure the volume of blood circulating in Mary Ann’s body. In case anyone was wondering, it is not a good idea to measure someone’s circulating blood by taking it all out at once. Instead, a high-tech system deployed in a hospital radiology department requires only two small blood samples to determine the body’s entire circulating blood supply. A normal person has about five quarts of blood in their system. It turned out that Mary Anne had only 51 percent of the amount of circulating blood that would have been considered normal for a woman of her age and size.

This was a startling finding. If a person loses as much as 40 percent of their blood volume suddenly, they will usually die from shock. In science and in medicine, when one is trying to calculate what is “normal,” and what is “abnormal,” one will always encounter pitfalls. Mary Ann’s radically reduced blood volume caused me to think about what constitutes a true “normal” value for blood volume. Mary had gained weight in the course of her struggle with CFS, for instance, and I wondered if blood volume can be reduced in people who are overweight. I tried to come up with all sorts of explanations for Mary Ann’s radically low blood volume. In the end, I could draw only one conclusion: no matter what the mitigating circumstances of her case, Mary Ann’s blood volume was below normal.

The blood volume assay has been used for almost thirty years, and is considered to be highly reliable. The fact that Mary Ann – no matter how hard she tried – could not possibly fake the results of this particular test, seems especially significant to me given the vast array of medical experts who continue to insist that CFS is a psychosomatic condition. I will give my little finger to anyone who can successfully argue that this finding was psychosomatic.

I must confess that I am not the first doctor to discover that CFS patients have dramatically lowered blood volumes. Dr. David Streeten had been measuring the low blood volumes in CFS patients for some by the time I tested Mary Ann for the condition. Mary Ann just happened to be my first patient in whom I personally observed the phenomenon.

Dr. Streeten and I, being doctors, were excited by these findings and were enjoying our collaboration. Mary Ann, the patient, was enjoying very little about her life. In fact, she told me she was eager to experiment with therapies. I felt that her informed  consent was reliable, in part because of her nursing experience, which had left her well-versed in medical matters, and because she was, in my opinion, entirely rational. Thus, in December of 1997, I decided to attempt to raise Mary Ann’s blood volume level by giving her injections of vasopressin. I reasoned that, if she improved, I could reasonably suspect that low blood volume was at the root of  her symptoms and might also play an important role in CFS.

Unfortunately, complications with this therapy set in almost immediately. Mary Ann began suffering from “water intoxication,” the main risk of this treatment, since vasopressin causes the body to retain water. The newly expanded blood volume causes a dilution of the salt in the blood and Mary Ann’s blood sodium levels dropped markedly. Upon measuring her blood sodium, I halted the drug therapy immediately.

I was relieved when I determined that Mary Ann had suffered no physical difficulties because of the sharp drop in her blood sodium. In fact, curiously, two days after the therapy was stopped, she began feeling better than she had felt in years. However, the risks that accumulate with water “intoxication” and low blood sodium levels, in my mind, failed to justify the treatment, and we abandoned that particular effort.

I found myself unable to sleep at night thinking about why Mary Ann had felt so much better after her vasopressin infusion, even when it had caused complications. I was, and remain, perplexed by this seeming contradiction. Clearly, low blood volume levels are important and meaningful in some way to our understanding of the mechanisms of CFS, but, I am sorry to report, the puzzle remains unsolved at this date. And, soon enough, Mary Ann was just as ill as she had been prior to the vasopressin treatment.

Then, a wonderful thing happened: she developed a bleeding ulcer. I suspected the problem could be blamed on the large doses of ibuprofen Mary Ann routinely swallowed to control her muscle and joint pain. At any rate, the hemorrhage inside her abdomen caused her so much pain that Mary Ann rapidly found her way to the emergency room of our local hospital. The staff there determined that she was bleeding internally, and they followed standard protocol for such a condition: they gave her a blood transfusion. In fact, they gave her several pints until her stomach quit bleeding, at which point they sent her home. She began keeping a journal the day she came home and called it, “Diary of Lab Rat # 1.”

I always ask my CFS patients to fill out a questionnaire before each visit. I sometimes suspect that they believe these questionnaires, which force them to respond to a great many detailed inquiries about their symptoms and their level of activity, are a kind of punishment. Inevitably, these forms remind them of just how thoroughly rotten they feel. Nevertheless, I have found these questionnaires to be extremely helpful in monitoring their illness. It turns out, in case anyone was wondering, that the secret to interpreting fluctuating energy levels in CFS is in the fine details.

Mary Ann filled out one of these questionnaires the day after her transfusion and wrote that she was “whoogy and very tired.” I have never demanded of Mary Ann that she define “whoogy” for me, mostly because I can pretty well guess by the sound of it. The following day, however, Mary Ann was able to walk through the rooms of her house and even venture outside to her garden. She also discovered that, for the first time in her recent memory, she was not thirsty.

Before her blood transfusion, Mary Ann typically experienced about an hour a day during which she could be upright. A week after the transfusion, however, Mary Ann’s life began to change radically. One morning, she wrote in her lab rat diary, “Did I get healthy blood–or what???” It seemed to her that virtually every symptom of illness had been muted – dramatically. One of the most exciting new developments was her newfound sense of mental clarity, something that CFS sufferers inevitably lose when they become sick. Before falling ill with CFS, Mary Ann had been a crossword puzzle whiz; now she began to work the crosswords again. She felt as if she was opening up all the dusty, long-shuttered cabinets in her memory, and was discovering that although they had been closed for a long time, the contents had remained in tact. She found she could keep her focus on the written page, too. She took up reading after a long hiatus. One evening, she set the newspaper down and realized with wonderment that, for the first time in years, she had read the journal from front to back.

She noted in her diary that she had pulled her grandchildren, all of them squeezed together in a red wagon, down the sidewalk. On the eleventh day after the transfusion, she wrote that she had played baseball with her older grandchildren for the first time. Soon afterward, she and her husband drove 200 miles looking for the perfect pair of bicycles – Mary Ann was anticipating long rides along the country roads. After all, she felt perfectly well. Mary Ann was even ready to do a TV commercial about her hair. One of the oddest symptoms of CFS is the complaint by many patients that they are losing their hair. Women in the most severe episodes of the disease often report they find clumps of hair in their brushes. My patients, women particularly, get annoyed with me over this particular issue, and not only because it’s hard for me to objectively assess this complaint. I rarely consider hair loss to be a pressing concern when there are so many more serious medical matters to face. I suggested to Mary Ann that blood transfusions were not currently the modality of choice to correct thinning hair.

Diary of Lab Rat # 1: “No nightmares like I used to have. I don’t feel ‘sick’ all the time. I’m praying that it will last, but if it doesn’t, I pray that I won’t get depressed. I know that God could heal me in a minute if He wanted, but He’s given me this illness, and now, feeling better, for a purpose. So I guess my job is to do His will and whatever He has in His plan.”

Whenever Mary Ann came to my clinic during her incredible respite from suffering, I was always reminded of the old Mary Ann who had worked in the ICU at the hospital. She was perky; she looked great. For the first time in years I was able to enjoy that wonderful, relaxed sense of comic timing that was her hallmark. It is incredible what CFS can do to a person.

The scientist in me was at war with the clinician in me over Mary Ann’s case. The scientist was insisting that Mary Ann’s metamorphosis could easily be ascribed to the placebo effect. Finally, I had to tell the scientist to stuff a sock in it. Mary Ann’s come-back-kid status had been precipitated by an event – a transfusion for an abdominal hemorrhage – that was virtually an accident. Still, I asked myself again and again: what was the secret of the blood transfusion? What was it telling me about CFS?

I began thinking about other blood-related clues I had observed over the years. People with CFS typically report they feel much worse after lab technicians draw multiple vials of blood from them for diagnostic tests. In addition, I had observed that by administering IV fluids to people with CFS, I could often generate a temporary improvement in their symptoms. Most significantly, I realized, the constellation of symptoms that make up the entity we know as CFS, particularly weakness, dizziness, and difficulty concentrating resemble the symptoms of shock due to blood loss.

Nevertheless, from my experience with Mary Ann, I had learned that simply expanding a patient’s blood volume wasn’t the answer. I have since speculated – but it is only speculation – that the answer might lie in the red blood cells themselves or the blood vessels carrying them. Scientists in Australia and England have suggested that red blood cells of CFS patients are misshapen, and appear to be damaged. They have advanced the hypothesis that the capability of red blood cells to carry oxygen around the body is impaired in CFS sufferers. Maybe the infusion of new red blood cells into Mary Ann’s body was what made the difference. Maybe this really was, as my patient had called it, “healthy blood.” In other words, normal, undamaged red blood cells, coupled with an increase in general blood volume, might explain Mary Ann’s rebound. Mary Ann’s deterioration began six weeks later.

“Day 46,” she wrote in her diary. “Starting to spiral down.” She had to put her crossword puzzles away; her mind was growing foggy and confused. “Fingers keep latching up and dropping and breaking stuff,” she wrote a few days later. On another day, she wrote, “Dizzy if I stand up and I have to hold on to something.” The following day: “It’s been worth it…but if it’s over I have to keep from falling apart.” And finally, “Quietly starting to panic.” She was unable to pull her grandchildren in their wagon.

Months passed. My heart broke whenever Mary Ann came to the office. Searching for a therapy that might help, or at least do no harm, I decided to give her weekly intravenous infusions of a liter, or about a quart, of saline water, the salty, purified water that is titrated to mimic the salt content of our bodies. I offered the therapy to her on the grounds that we might be able to raise her blood volume simply by administering extra fluid to her blood stream. Mary Ann felt a bit better after this treatment, though its good effects lasted just two days. I continue to provide Mary Ann with this treatment on a weekly basis, because it offers her some relief, which happens to be more than any other therapy can offer.

One might ask: why not give Mary Ann with another blood transfusion? The question goes to the heart of clinical medicine. As doctors, we must err on the side of caution. In fact, my profession and the federal government each has a responsibility to protect us all from medical charlatans. Before the government can approve a new treatment for a disease, for instance, scientists must apply for grant money, submit protocols for their experimental therapy to review boards, and those protocols must be approved by these boards. After all this, the therapy must be thoroughly tested on significant numbers of patients, and the results submitted to the government for further review. It’s a good system, and without it, great harm might be done.

Doctors who work each day in the trenches of clinical medicine cannot undertake this kind of research. We would require sizable grants from the government to begin the work, an enormous amount of free time, and a veritable hoard of interns and residents to carry out the study using real patients. Clearly, a small town doc like me, living near the end of the world, cannot test in an appropriately scientific fashion the effect of blood transfusions in CFS. And it’s hard to imagine any medical journal would publish Mary Ann’s case history, because it is merely speculative, even if highly provocative. Sometimes, I feel the only solution for me is to develop multiple personalities or else go mad.

When I am wearing my “scientist” hat, I remain skeptical. When I am in my office, talking to Mary Ann, I sometimes think I’m going to go ballistic over the scientific establishment’s onerous demands for expensive, lengthy, double blind studies. Yet, giving Mary Ann another transfusion cannot be done now, as there is no established protocol for
this treatment in CFS. I’m not just worried about going to jail. It is possible that another transfusion might cause Mary Ann harm. I just don’t know.

In the old days, patients rarely learned very much about whatever disease had laid them low. There were no support groups, no newsletters, no conferences, and no unscientific books like this one. As a result, patients were rarely frustrated about scientific progress in their particular disease. For the most part, they remained blissfully ignorant about new ideas and new developments that could directly impact their destinies. Most especially, patients did not read about crackpot ideas like blood transfusions as a treatment for CFS.

I remain convinced that CFS is a treatable disease. Perhaps it will be impossible to fully reverse CFS once it has a foothold in a patient, but I believe many of the symptoms will be alleviated, once we learn how. It saddens me profoundly to see Mary Ann as she is today. Only our shared faith that CFS may someday be amenable to treatment allows me to shield her from that sadness.

Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review

Abstract:

Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic multisystem disorders characterized by persistent fatigue, pain, cognitive dysfunction, sleep disturbances, and reduced quality of life. Increasing evidence implicates mitochondrial dysfunction, oxidative and nitrosative stress, immune dysregulation, and altered redox and nicotinamide adenine dinucleotide (NAD+) metabolism as interconnected mechanisms contributing to fatigue, although the strength of evidence varies across these pathways. Micronutrients are essential components of mitochondrial bioenergetics, antioxidant defense, and immune-metabolic regulation.

This narrative review critically examines the mechanistic and clinical evidence supporting mitochondrial-oriented micronutritional interventions in fibromyalgia and ME/CFS, including NAD+ precursors, B-complex vitamins, magnesium, coenzyme Q10, alpha-lipoic acid, GlyNAC, L-carnitine, pyrroloquinoline quinone, taurine, and creatine. Mechanistic plausibility is distinguished from clinical efficacy, as disease-specific randomized controlled evidence remains limited for several interventions. We further discuss biomarkers, metabolic phenotyping, and precision nutrition within a systems-based micronutrition framework.

Finally, we present the rationale for a future randomized, double-blind, placebo-controlled trial in fibromyalgia patients with clinically significant fatigue, which is planned for 2027, subject to ethics approval and prospective registration, as a strategy for future clinical validation.

Source: Abanades S, Fernández I, Capdevila N, Cardona F. Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review. Nutrients. 2026 Aug 19;18(16):2702. doi: 10.3390/nu18162702. PMID: 42654282. https://www.mdpi.com/2072-6643/18/16/2702 (Full text)

Targeting Bioenergetic, Redox and Prostaglandin Pathways in Long COVID-Associated Post-Exertional Malaise and Brain Fog: A Nutraceutical Translational Hypothesis

Abstract:

Post-exertional malaise (PEM) and cognitive dysfunction (hereafter “cognitive dysfunction”, including the patient-reported syndrome often described as “brain fog”) are among the most disabling features of Long COVID; yet, approved disease-modifying treatments remain lacking. Emerging evidence implicates interacting disturbances in mitochondrial bioenergetics, redox regulation and neurovascular inflammation, although much of the supporting evidence remains indirect and derives from acute COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), primary mitochondrial disease, inflammatory biology and mechanistic pharmacology rather than from direct Long COVID intervention trials.

This hypothesis-generating narrative review develops a mechanism-based translational framework: that a pathway-targeted nutraceutical programme may modulate selected elements of these three axes, subject to prior demonstration of formulation quality, pharmacokinetic feasibility, target engagement and safety. Candidate modules comprise coenzyme Q10 and alpha-lipoic acid for bioenergetic/redox support; selenium, sulforaphane and resveratrol for Nrf2-thioredoxin-related redox regulation; and Boswellia serrata, luteolin and eicosapentaenoic acid for putative prostaglandin/resolution-pathway modulation. Sonlicromanol provides a conceptual mechanistic precedent for combined redox and prostaglandin-directed pharmacology, but it is not considered pharmacologically equivalent to an eight-agent nutraceutical combination.

We summarise the mechanistic rationale, distinguish direct from indirect evidence, define qualitative evidence-grading criteria, outline safety and interaction considerations, and propose a staged translational research programme. This framework is intended to generate falsifiable hypotheses for future Long COVID studies, not to imply established clinical efficacy.

Source: Praet SFE. Targeting Bioenergetic, Redox and Prostaglandin Pathways in Long COVID-Associated Post-Exertional Malaise and Brain Fog: A Nutraceutical Translational Hypothesis. Nutrients. 2026 Aug 13;18(16):2650. doi: 10.3390/nu18162650. PMID: 42654231. https://www.mdpi.com/2072-6643/18/16/2650 (Full text)

REenergizeME: intermittent hypoxia-hyperoxia treatment for myalgic encephalomyelitis/chronic fatigue syndrome-protocol for a randomised, placebo-controlled trial

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling condition characterised by post-exertional malaise (PEM), autonomic dysfunction and markedly reduced quality of life. Its prevalence has increased following the COVID-19 pandemic, yet no effective disease-modifying treatments are available and underlying mechanisms remain unclear. Evidence implicates immune-metabolic dysregulation, impaired energy metabolism, vascular dysfunction and altered oxygen handling. Intermittent hypoxia-hyperoxia treatment (IHHT) is a non-pharmacological intervention proposed to induce adaptive physiological and cellular responses via hypoxia- and redox-sensitive pathways. This trial evaluates the clinical efficacy of IHHT in ME/CFS and explores associated mechanisms.

Methods and analysis: This randomised, placebo-controlled, participant- and assessor-blinded clinical trial will enrol 104 female patients aged 20-59 years who meet the International Consensus Criteria for ME/CFS along with a healthy control group for mechanistic comparisons. Participants will be randomised 1:1 to IHHT or placebo following baseline assessments. The intervention will be delivered over 8 weeks. The primary endpoint is change in quality of life measured by the vitality domain of the Short Form-36 Health Survey. Secondary endpoints include PEM severity, fatigue severity, cognitive severity, functional capacity and autonomic symptoms assessed using validated patient-reported outcome measures and objective tests. Exploratory endpoints include pain phenotyping, autonomic, sudomotor and neurophysiological assessments, tissue oxygenation by near-infrared spectroscopy, peripheral small-fibre nerve assessments using corneal confocal microscopy and skin biopsy and immune-metabolic and oxidative stress biomarkers. Assessments will be conducted at baseline; post-treatment; and at 3, 6 and 12 months follow-up.

Ethics and dissemination: The trial is conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation – Good Clinical Practice guidelines and was approved by the Danish Scientific Ethical Committees (De Videnskabsetiske Medicinske Komitéer, VMK; approval no. 2500959). Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publications and scientific conferences.

Trial registration number: ClinicalTrials.gov Identifier: NCT07317401.

Source: Nochi M, Kristensen SK, Mehrani N, Guerreiro I, Nørholm IMD, Chandra S, Olufsen M, Gudbergsen LR, Brinth LS, Stokholm R, Karlsson P, Tankisi H, Mehlsen J, Foldager CB, Olsen RKJ. REenergizeME: intermittent hypoxia-hyperoxia treatment for myalgic encephalomyelitis/chronic fatigue syndrome-protocol for a randomised, placebo-controlled trial. BMJ Open. 2026 Aug 14;16(8):e117729. doi: 10.1136/bmjopen-2026-117729. PMID: 42601095. https://bmjopen.bmj.com/content/16/8/e117729 (Full text)

Hyperbaric oxygen therapy improves clinical symptoms and functional capacity and modulates thalamic connectivity in ME/CFS: a prospective cohort study

Abstract:

Background: Hyperbaric oxygen therapy (HBOT) has been proposed as a treatment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but evidence remains limited. This study evaluated its clinical effectiveness and feasibility, as well as associated functional brain changes.

Methods: Thirty patients with ME/CFS (mean age 42.3 ± 11.7 years; 7 males, 23 females) received 40 HBOT sessions. Clinical outcomes were assessed at baseline, during treatment, and four weeks post-treatment. The primary outcome was change in the physical functioning subscale of the Short Form-36 Health Survey (SF-36 PF). Secondary outcomes included severity of core symptoms assessed via questionnaires, exercise capacity, handgrip strength, cognitive performance, orthostatic intolerance, and brain magnetic resonance imaging (MRI; volumetry and functional connectivity [FC]). Thirty age- and sex-matched healthy controls (mean age 42.3 ± 11.3 years; 7 males, 23 females) were included for MRI comparison.

Results: SF-36 PF significantly improved during HBOT compared with baseline (g = 0.71, p = 0.006). SF-36 pain (p = 0.002, g = 0.79) and Chalder Fatigue Scale also showed clinically meaningful reductions (p < 0.001, g = -0.87). Exercise capacity (g = 0.66), muscle strength (g = 0.40), and information processing speed (g = 0.52) improved significantly after treatment (all p < 0.05). Treatment adherence was high and tolerability was favorable, with no major adverse events reported. Functional MRI analyses revealed increased thalamic FC in ME/CFS patients compared to healthy controls in bilateral sensorimotor (p < 0.001, t = 5.65, FDR-corrected) and visuo-occipital regions (p < 0.001, t = 5.40, FDR-corrected) at baseline. Following HBOT, thalamic hyperconnectivity shifted toward patterns observed in healthy controls. Responders, defined as a ≥ 10 points increase in SF-36 PF, showed greater reductions in thalamic hyperconnectivity than non-responders (p < 0.001, t = -4.34 to -5.18, FDR-corrected).

Conclusions: HBOT was well tolerated and associated with significant improvements in physical functioning, fatigue, pain, and cognitive performance in ME/CFS. The post-treatment shift in thalamocortical connectivity toward healthy control patterns and its association with clinical response support the hypothesis that functional thalamic dysregulation contributes to ME/CFS pathophysiology and may be modulated by HBOT. This provides a network-level rationale for controlled trials to confirm therapeutic efficacy.

Trial registration: ClinicalTrials.gov NCT06118138. Registered 01 November 2023 – Retrospectively registered, https://clinicaltrials.gov/study/NCT06118138?cond=ME%2FCFSamp;term=HBOTamp;rank=1.

Source: Kim L, Cammà G, Peters CK, Mantwill M, Müller O, Leprêtre N, Heindrich C, Rust R, Krill M, Hartung TJ, Reeß LG, Krohn S, Heymann CV, Wittke K, Finke C, Scheibenbogen C. Hyperbaric oxygen therapy improves clinical symptoms and functional capacity and modulates thalamic connectivity in ME/CFS: a prospective cohort study. J Transl Med. 2026 Jun 5. doi: 10.1186/s12967-026-08324-6. Epub ahead of print. PMID: 42249466. https://link.springer.com/article/10.1186/s12967-026-08324-6 (Full study available as PDF file)

Low-Dose Naltrexone: What is the Evidence? A Narrative Review

Abstract:

Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026.

Title and abstract searches for “low dose naltrexone” identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology.

Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg.

Although these features contribute to its appeal, current evidence does not support routine clinical use. LDN may have a pragmatic role in treatment-resistant cases where standard therapies have failed, provided its experimental status and uncertain efficacy are clearly explained. Larger, well-designed RCTs with objective endpoints, along with N-of-1 approaches to identify potential responders, are needed to clarify its true clinical value.

Source: Gouda AHK, Aitcheson NEC, Steadman KJ. Low-Dose Naltrexone: What is the Evidence? A Narrative Review. Adv Ther. 2026 Apr 30. doi: 10.1007/s12325-026-03612-5. Epub ahead of print. PMID: 42060160. https://link.springer.com/article/10.1007/s12325-026-03612-5 (Full text)

Human Endogenous Retroviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Emerging Roles in Pathogenesis, Immunity, Biomarkers and Therapeutics

Abstract:

Human endogenous retroviruses (HERVs) are potential driving forces of the pathophysiology of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), linking post-infectious immune dysfunction to chronic inflammation and immune and neurocognitive dysfunction that are hallmark features of ME/CFS.

Accumulating evidence from related autoimmune diseases and cancers has shown that reactivated HERVs can contribute to disease pathogenesis by amplifying immune activation through viral protein-mediated innate sensing, long terminal repeat (LTR)-driven transcription, and disrupting epigenetic silencing. HERV signatures are therefore promising biomarkers for diagnosis, patient stratification for drug-repurposing trials, and therapy monitoring.

Accumulating evidence suggests a possible correlation between HERV expression and ME/CFS symptom severity, alterations in immune phenotypes, function and inflammatory gene networks. Importantly, locus-specific HERV profiling is a promising approach for distinguishing ME/CFS from overlapping or co-morbid conditions and healthy controls. Furthermore, HERV-targeted antibodies, immune modulators, epigenetic and antiviral interventions offer promise as concomitant therapeutic strategies for ME/CFS.

Additional research incorporating viromics and other-omics validation, functional assays, and HERV-stratified clinical trials is now needed to realise this potential and to transform ME/CFS from a symptom-based syndrome into a mechanism-driven, treatable condition.

Source: Perera KD, Oltra E, Carding SR. Human Endogenous Retroviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Emerging Roles in Pathogenesis, Immunity, Biomarkers and Therapeutics. Int J Mol Sci. 2026 May 12;27(10):4309. doi: 10.3390/ijms27104309. PMID: 42196290; PMCID: PMC13207908. https://pmc.ncbi.nlm.nih.gov/articles/PMC13207908/ (Full text)

Underuse of Pharmacologic Therapies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Before Specialist Evaluation

Abstract:

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem neurologic disease characterized by profound fatigue and decreased functional capacity, postexertional malaise, and unrefreshing sleep, along with cognitive impairment and/or orthostatic intolerance. Its prevalence has risen exponentially with the COVID-19 pandemic. Pharmacologic therapies have been used successfully by ME/CFS specialists but may be underused by the general medical field.

Methods: To assess this potential practice gap, we retrospectively analyzed the records of 571 patients with an ME/CFS diagnosis referred to our ME/CFS specialty clinic in Minnesota during 2018-2022. We ascertained medications that had already been tried at the time of consultation and also ascertained supplement use.

Results: With the exception of medications primarily used for pain and anxiety, use of pharmacotherapy for ME/CFS symptom management as proposed by specialists was limited. Overall, 68.3% of patients had had at least 1 medication potentially prescribed for ME/CFS; the most common were serotonin-norepinephrine reuptake inhibitors, gabapentin, and tricyclic antidepressants. A slightly larger share of patients, 72.2%, reported having taken at least 1 dietary supplement; the most common were vitamin D, vitamin B12 and B complex, and fish oil.

Conclusion: Our findings suggest that potentially helpful medications for ME/CFS are being underprescribed in the general medical field and that patients may resort to supplements to manage symptoms. Better education of clinicians about available treatment options and treatment guides may improve management of this debilitating disease.

Source: Grach SL, Seltzer J, Mueller MR, Aakre CA, Natividad LT, Lawson DK, Ganesh R, Hurt RT. Underuse of Pharmacologic Therapies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Before Specialist Evaluation. Ann Fam Med. 2026 Apr 29:250266. doi: 10.1370/afm.250266. Epub ahead of print. PMID: 42055743. https://www.annfammed.org/content/early/2026/04/24/afm.250266-0 (Full text available as PDF file)

Regulatory Cycles of Orexin and Glucagon-Like Peptide-1 in Post-Viral Syndromes

Abstract:

Post-viral syndromes are heterogeneous multisystem diseases without a uniform etiology that occur as a result of acute viral infections. During the COVID-19 pandemic, the number of patients increased dramatically due to infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is known as post-acute sequelae of COVID-19 (PASC), with many cases also meeting the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the most severe form of a post-viral disease, characterized by severe fatigue, post-exertional malaise (PEM), unrefreshing sleep, neurocognitive impairment, and autonomic and immune dysregulation.

Orexin (OX) neuropeptides, which regulate arousal, metabolism, and neuroendocrine functions, may serve as a central link between stress, immune activation, and metabolic changes in these syndromes. Notable phenotypic similarities between OX system dysfunction and core features of PASC and ME/CFS, including fatigue, sleep issues, impaired glucose metabolism, and neuropsychiatric symptoms, support a mechanistic model in which impaired OX signaling contributes to post-viral endocrine and metabolic dysfunction.

This review examines the role of OX in regulating glucose metabolism, HPA axis activity, and systemic homeostasis, with a specific focus on sexually dimorphic expression and function in relation to post-viral syndromes. We also highlight the effect of glucagon-like peptide-1 (GLP-1), another key player in metabolism, which also has neuroprotective, anti-inflammatory, vasoprotective, and immunomodulatory effects. We further emphasize emerging therapeutic strategies, such as GLP-1 receptor agonists (GLP-1RAs) and drugs targeting the OX system.

Together, these insights provide an integrated framework for understanding and targeting the neuroendocrine-metabolic underpinnings of PASC, ME/CFS, and other post-viral syndromes.

Source: Ruhrländer J, Schieffer E, Schieffer B. Regulatory Cycles of Orexin and Glucagon-Like Peptide-1 in Post-Viral Syndromes. Endocr Rev. 2026 Apr 27:bnag009. doi: 10.1210/endrev/bnag009. Epub ahead of print. PMID: 42037238. https://pubmed.ncbi.nlm.nih.gov/42037238/

Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID

Abstract:

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are complex multisystem conditions with significant functional disability. Many patients experience symptoms of orthostatic intolerance, which can be captured in some cases as Orthostatic Hypotension (OH) or Postural orthostatic Tachycardia Syndrome (PoTS) on objective testing. Conservative treatments are recommended for first-line symptom management, but there is a lack of efficacy evidence. This study aims to assess the feasibility of an 8-week clinically supervised, personalised Dysautonomia Management Protocol (DMP) in a cohort of ME/CFS and LC patients with subjective and objective evidence of orthostatic intolerance (dysautonomia).

Methods: ME/CFS and LC patients with objective dysautonomia on the 10 min active Lean Test (LT) were recruited to an 8-week DMP, with interventions introduced cumulatively every two weeks. Interventions included increasing daily fluid intake to 3 litres and salt intake to 10 g, pacing to avoid crashes and calf activation. Baseline and weekly data collection included the LT, Composite Autonomic Symptom Score questionnaire (COMPASS-31) and Yorkshire Rehabilitation Scale (YRS).

Results: Sixteen participants completed the 8-week program, five discontinued during the program, and one was withdrawn following a severe crash. The COMPASS-31 improved by 7.7 points from week 1 to week 8 (p = 0.045), with a medium Cohen’s d effect size of 0.55. For the same period, there was a non-significant (p = 0.16) improvement in the YRS symptom severity score by 2 points. Comparing the final two weeks of the program with the first two weeks, mean heart rate during the LT decreased by 4.8 beats per minute (p = 0.032), with a medium Cohen’s d effect size of 0.44. Adherence to the interventions was highly variable, with none of the patients able to fully employ all four recommendations.

Conclusions: The results suggest that targeted conservative interventions could influence autonomic function and symptom reduction. However, the magnitude of change was limited, and statistical significance might not necessarily relate to a clinically significant improvement in symptoms.

Source: Barr J, Marsden L, Dassanayake T, Almutairi N, McKeever V, Gaber T, Tarrant R, Godfrey B, Witton S, Sivan M. Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID. J Clin Med. 2026 Mar 25;15(7):2510. doi: 10.3390/jcm15072510. PMID: 41976810. https://www.mdpi.com/2077-0383/15/7/2510 (Full text)