Brain, Behavior, and Immunity Available online 19 November 2025, 106185
Searching for blood biomarkers and treatment targets in Women with fibromyalgia – Protein interaction patterns and anti-satellite glia cell IgG antibodies as promising candidates
Author links open overlay panel Karolina af Ekenstam, Joana Menezes, Jenny E. Jakobsson, Helene Silverstein, Emerson Krock, Jeanette Tour, Katalin Sandor, Alexandra Kuliszkiewicz, Matthew Hunt, Kim Kultima, Macarena Tejos-Bravo, Camilla I. Svensson, Eva Kosek
https://doi.org/10.1016/j.bbi.2025.106185Get rights and content
Highlights
Anti-satellite glia cell IgG levels in fibromyalgia subjects (FMS) are associated with clusters of immunoregulatory proteins, aligning with the indications of autoimmune mechanisms in fibromyalgia.
The proteins that differentiate FMS from healthy controls exhibit characteristic interaction patterns, forming clusters aligned with different functional categories.
A better understanding of these mechanisms could lead to new objective diagnostic criteria identifying FMS likely to benefit from existing immunomodulatory treatments and pave the way for development of new treatment strategies for FM.
Abstract
Background
Recent studies suggest that autoreactive immunoglobulin G (IgG) antibodies binding to satellite glia cells (anti-SGC IgG) in the dorsal root ganglia influence pain intensity in a subgroup of fibromyalgia subjects (FMS), thus indicating altered immune activation. The main aim of this study was to identify proteins distinguishing female FMS from female healthy controls (HC) and within the FM group, proteins distinguishing FMS with high vs low levels of anti-SGC IgG. The secondary aim was to assess the associations between serum proteins and anti-SGC IgG, respectively, and FM symptoms.
Methods
Anti-SGC IgG was quantified using an immunofluorescence assay. Proteins in serum were assessed using Olink® Explore 384 Inflammation panel, regarding differences between FMS (n = 93) and HC (n = 40) and regarding differences between FMS with high (≥50 %) and low (<50 %) anti-SGC IgG, respectively. Proteins found to differ between groups (VIP ≥ 1.3) were further analyzed regarding protein-interactions using the software tool STRING (FM vs HC n = 56, high vs low anti-SGC IgG n = 55). Results from the FM group were also compared with two nociceptive pain conditions.
Results
In FMS, a cluster of immune system-related proteins was found among upregulated proteins, including CD40 and CD40L, with central roles in humoral immune response. CD40 levels were associated with more severe FM symptoms. In contrast, a cluster of tissue development-/regeneration-related proteins was found among downregulated proteins, this was not seen in nociceptive pain conditions. In FMS with high anti-SGC IgG, clusters dominated by immune system-related proteins were found among both upregulated and downregulated proteins. The cluster of upregulated proteins included CD79b, a protein necessary for B-cell receptor function, and CD4, a co receptor needed for T cell activation, thus with central role in activating various immune responses, including B-cell activation. Positive correlations were seen between some of these proteins and symptoms. On the contrary, several of the downregulated proteins correlated negatively to symptoms.
Conclusion
Our data support the involvement of the immune system in FM and indicate that further studies on autoimmune mechanisms, proteomics, and protein interaction analysis could lead to new objective diagnostic criteria identifying FMS likely to benefit from immunomodulatory treatments.
_______________________________________________________________________
Assessing the influence of lived-experience experts on healthcare providers in a virtual community of practice: a qualitative study
Author: Weaver SS, Carry M, Bertolli J, Godino J, Struminger B, Taren D, … Ramers CB (Laura Rodriguez Research Institute, USA)
Publication: Frontiers in Health Services (June 2025)
Link: https://www.frontiersin.org/journals/health- services/articles/10.3389/frhs.2025.1562651/full
This qualitative evaluation investigates how embedding lived-experience experts (LEEs) in a virtual community of practice shapes healthcare providers’ approach to complex, often misunderstood conditions such as long-COVID, ME/CFS and other post-acute infection syndromes (PAIS). By blending patients’ voices with professional discourse, the study aimed to illuminate whether this model could help reduce stigma, improve empathy, and change care practices.
Over an 18-month period, the project collected transcripts from regular webinar sessions (January 2022 – March 2024) in which LEEs - people living with Long-COVID, ME/CFS or PAIS, or caregivers - shared educational input to clinicians. In parallel, 22 patients receiving care from participating providers were interviewed using semi-structured methods to explore how they perceived those providers’ adoption of LEE-driven recommendations. Transcripts were thematically analysed via content analysis.
Key themes emerged around validating illness experience, shifting clinician beliefs about symptoms beyond psychological attribution, fostering empathetic communication, improving navigation of referrals, recognising fluctuating disability and encouraging patient self-management. Patients reported feeling heard, better understood and more confident in advocating for themselves. Many recounted that providers gradually incorporated LEE messages, especially around pacing and acknowledging disability, into interactions. Notably, participants described how integration of lived experience helped bridge the gap between biomedical uncertainty and human suffering in PAIS settings.
The authors argue that this model offers a promising way to reduce the “invisibility” of these syndromes. Involving LEEs as co-educators can shift provider attitudes, heighten validation of symptoms, and encourage more responsive care, especially in the context of long-COVID and ME/CFS. Future research should examine the longitudinal effects on clinician behaviour and explore how such models could scale across health systems to better address the needs of patients with PAIS.
_______________________________________________________________________
Pyridostigmine improves hand grip strength in patients with myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Schlömer E, Stein E, Kedor C, Rust R, Brock A, Wittke K, … Kim L (Charité-Universitätsmedizin Berlin, Germany)
Publication: Frontiers in Neuroscience (September 2025)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12441162/pdf/fnins-19-1637838.pdf
This paper explored whether low acetylcholine activity contributes to the reduced exercise capacity, muscle strength, and orthostatic intolerance seen in ME/CFS patients. The body requires acetylcholine for muscle activity, muscle activity control and cardiovascular adaptations such as standing up. Pyridostigmine (PS), also known as Mestinon, is a drug that inhibits the enzyme that breaks down acetylcholine. PS has been used off label for ME/CFS patients, specifically those with orthostatic intolerance to mitigate symptoms.
The study included 20 post-infection ME/CFS patients (7 men, 13 women) diagnosed using the Canadian Consensus Criteria. Muscle fatigue was assessed using hand grip strength (HGS) test with all patients recording values below the manufacturer’s cutoff.
During the first visit, baseline HGS values were obtained using a dynamometer. Participants held the dynamometer in their dominant hand and exerted maximum force for a 3 second period with 5-second rests. This was repeated 10 times, and the highest value over each 3 second period was recorded in kgs. This process was then repeated 60 minutes later and followed by a passive stand test that 7 participants declined. During the second visit, patients repeated the initial HGS protocol. After the first set of 10, 30 milligrams of PS was administered. HGS was retested after one hour, again followed by a passive stand test.
The researchers found that HGS fell after an hour without PS but doubled after PS administration. Heart rate rise whilst standing also dropped from 17 BPM to 13 BPM with PS. This indicates that PS could have significant benefits for ME/CFS patients with orthostatic intolerance, muscle weakness and impaired exercise capacity.
The authors acknowledge the limitations of the small sample size and the lack of a control group. They recommend further study of PS to validate these findings in a larger, controlled trial, and to better understand its effects on symptoms and function, as well as possible side effects.
_______________________________________________________________________
Biofabrication: . 2025 Aug 8;17(4). doi: 10.1088/1758-5090/adf66c.
Metabolic adaptation and fragility in healthy 3D in vitro skeletal muscle tissues exposed to chronic fatigue syndrome and Long COVID-19 sera
Sheeza Mughal 1 2, Félix Andújar-Sánchez 3 4 5, Maria Sabater-Arcis 1, Glória Garrabou 3 4 5, Joaquim Fernández-Solà 4, Jose Alegre-Martin 6 7, Ramon Sanmartin-Sentañes 6 7, Jesús Castro-Marrero 7, Anna Esteve-Codina 8 2, Eloi Casals 8 2, Juan M Fernández-Costa 1, Javier Ramón-Azcón 1 9
Affiliations Expand PMID: 40744071 DOI: 10.1088/1758-5090/adf66c
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid-19 (LC-19) are complex conditions with no diagnostic markers or consensus on disease progression. Despite extensive research, noin vitromodel exists to study skeletal muscle wasting, peripheral weakness, or potential therapies. We developed 3Din vitroskeletal muscle tissues to map muscle adaptations to patient sera over time. Short exposures (48 H) to patient sera led to a significant reduction in muscle contractile strength. Transcriptomic analysis revealed the upregulation of protein translation, glycolytic enzymes, disturbances in calcium homeostasis, hypertrophy, and mitochondrial hyperfusion. Structural analyses confirmed myotube hypertrophy and elevated mitochondrial oxygen consumption In ME/CFS. While muscles initially adapted by increasing glycolysis, prolonged exposure (96-144 H) caused muscle fragility and weakness, with mitochondria fragmenting into a toroidal conformation. We propose that skeletal muscle tissue in ME/CFS and LC-19 progresses through a hypermetabolic state, leading to severe muscular and mitochondrial deterioration. This is the first study to suggest such transient metabolic adaptation.
_______________________________________________________________________
BIOMARKER: SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis
Authors: Rostami-Afshari B, Elremaly W, Franco A, Elbakry M, Akoume MY, Boufaied I…, Moreau A (Université de Montréal, Canada)
Publication: Journal of Translational Medicine (July, 2025)
Link:https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06829-0
Sphingomyelin phosphodiesterase acid-like 3B (SMP-DL3B) is an essential immune-regulatory protein and is also involved in fat metabolism. The authors investigated its role in ME/CFS pathophysiology and its potential as a biomarker of disease severity.
The study included two independent cohorts. The Canadian cohort included 249 people with ME/CFS (Canadian Consensus Criteria) of which 208 were women, and 63 healthy controls (33 women) who were frequency-matched by age and sex. For replication, the authors used a Norwegian cohort of 141 people with ME/CFS (119 women), also diagnosed according to the Canadian Consensus Criteria. All participants from both cohorts were recruited before the COVID-19 pandemic, and blood samples were taken to analyse for SMPDL3B.
ME/CFS symptoms and severity were assessed with the 36-Item Short-Form Health Survey, Multidimensional Fatigue Inventory, and DePaul Symptom Questionnaire in the Canadian cohort. In the Norwegian cohort, a physician categorised disease severity from mild to severe ME/CFS (participants with very severe ME/CFS were excluded).
SMPDL3B levels in plasma were significantly higher in the Canadian ME/CFS cohort compared with controls. To evaluate the potential of SMPDL3B as a biomarker for disease severity, the authors used 30 ng/mL as a threshold to separate the Canadian ME/CFS cohort into low and high plasma SMPDL3B. Participants with SMPDL3B plasma levels above 30 ng/mL presented significantly greater symptoms and disease severity than those below 30 ng/mL. This finding was replicated in the Norwegian cohort.
The authors also found sex differences in the ME/CFS cohort: women had greater cognitive impairments, sleep problems, and post-exertional malaise, while men presented lower severity scores, but higher reduced motivation. The authors found that oestradiol modulated SMPDL3B levels in vitro, suggesting that oestradiol may contribute to the observed differences between men and women.
These findings suggest that SMPDL3B may be a biomarker of disease severity and a target for therapeutic interventions. However, further studies are needed to fully understand and validate its potential.
_______________________________________________________________________
Mol Cell Proteomics 2025 Dec;24(12):101467. doi: 10.1016/j.mcpro.2025.101467. Epub 2025 Nov 17.
Temporal Dynamics of the Plasma Proteomic Landscape Reveals Maladaptation in ME/CFS Following Exertion
Arnaud Germain 1, Katherine A Glass 1, Melissa A Eckert 1, Ludovic Giloteaux 1, Maureen R Hanson 2
PMID: 41237904 DOI: 10.1016/j.mcpro.2025.101467
Abstract
The overarching symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM), an exacerbation of symptoms following physical or mental exertion. To investigate the molecular underpinnings of PEM, we performed longitudinal plasma proteomics using the Somascan 7K aptamer-based assay to monitor 6361 unique plasma proteins in 132 individuals (96 females and 36 males) subjected to two maximal cardiopulmonary exercise tests separated by a 24-h recovery period. The cohort included 79 ME/CFS cases compared to 53 age- and BMI-matched sedentary controls, allowing us to distinguish disease-specific molecular alterations from those due to physical deconditioning. Longitudinal profiling revealed widespread proteomic changes following exertion, with the most pronounced alterations observed in ME/CFS participants during the recovery phase, coinciding with the onset of PEM. Compared to controls, patients with ME/CFS showed persistent dysregulation of immune, metabolic, and neuromuscular pathways. Key findings included suppression of T and B cell signaling, downregulation of IL-17 and cell-cell communication pathways, and upregulation of glycolysis/gluconeogenesis, suggestive of mitochondrial stress and impaired immune recovery from exercise. Proteomic associations with physiological performance (VO2max, anaerobic threshold) revealed disruptions between protein abundance and exercise capacity in ME/CFS versus controls. Correlations with symptom severity linked changes in immune-related proteins and ME/CFS symptoms, including muscle pain, recurrent sore throat, and lymph node tenderness. Sex-stratified analyses revealed distinct molecular responses between females and males, emphasizing the importance of considering sex as a biological variable in ME/CFS research. Finally, our analysis of sedentary controls contributes new data on molecular responses to acute exertion in a predominantly female sedentary cohort, a population historically underrepresented in exercise physiology studies. Together, these findings underscore the value of dynamic, proteomic profiling over time for characterizing maladaptive responses to exertion in ME/CFS and provide a foundation for deeper mechanistic investigation into PEM.
_______________________________________________________________________
Published: 12 December 2025
Long COVID involves activation of proinflammatory and immune exhaustion pathways
Malika Aid, Valentin Boero-Teyssier, Katherine McMahan, Rammy Dong, Michael Doyle, Nazim Belabbaci, Erica Borducchi, Ai-ris Y. Collier, Janet Mullington & Dan H. Barouch
Nature Immunology (2025)Cite this article
Abstract
Long COVID (LC) involves a spectrum of chronic symptoms after acute severe acute respiratory syndrome coronavirus 2 infection. Current hypotheses for the pathogenesis of LC include persistent virus, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction and complement activation.
Long COVID, like other post-acute infection syndromes, is thought to involve several mechanisms, including immune dysregulation, chronic inflammation and autonomic dysfunction. These authors propose a framework that integrates neuroimmune dysregulation, innate immune dysfunction and autoantibody-mediated mechanisms to explain the persistence and heterogeneity of long COVID.
SARS-CoV-2 infection triggers acute inflammation via viral entry through ACE2 receptors and the transmembrane protease TMPRSS2-mediated mechanisms, causing systemic immune activation and endothelial injury. In some individuals, especially older adults or those with metabolic or immunogenetic vulnerabilities, immune dysregulation persists, leading to chronic inflammation, microvascular dysfunction, and impaired immune resolution. This can lead to autoantibody production, T cell exhaustion, and neuroimmune imbalance.
Innate immune cells, particularly neutrophils and macrophages, are central to long COVID pathogenesis. Neutrophils release extracellular traps (NETs), which, if dysregulated, can drive tissue damage and autoimmunity. Macrophages contribute to chronic inflammation through cytokine production and antigen presentation, with aging-associated “inflammaging” amplifying these effects. Persistent activation of inflammasomes, complement dysregulation, and trained immunity further lead to sustained low-grade inflammation and breakdown of the body’s immune tolerance.
Autonomic nervous system (ANS) dysfunction is another feature and driver of long COVID. Sympathetic nervous system overactivation leads to neuroimmune dysregulation, promoting fatigue, orthostatic intolerance, and cognitive defects. Autoantibodies targeting ANS receptors may also enhance this. The complicated web of chronic inflammation, autoimmunity, and ANS imbalance makes long COVID a dyshomeostasis syndrome, with inflammaging acting as an amplifier, particularly in older adults and women.
The authors believe that biomarkers such as cytokine profiles, phenotyping immune cells, epigenetic clocks, and heart rate variability can aid early diagnosis, help sort people by their level of risk, and offer personalised interventions. They conclude that it can also provide insight into broader mechanisms of post-infectious and age-related chronic diseases.
_______________________________________________________________________
Publication: Journal of Clinical Medicine (September, 2025)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12428951/pdf/jcm-14-06269.pdf
Autonomic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Findings from the Multi-Site Clinical Assessment of ME/CFS (MCAM) Study in the USA
Anindita Issa 1,†, Jin-Mann S Lin 1,*,†, Yang Chen 1,†, Jacob Attell 1,2, Dana Brimmer 1, Jeanne Bertolli 1, Benjamin H Natelson 3, Charles W Lapp 4, Richard N Podell 5, Andreas M Kogelnik 6, Nancy G Klimas 7,8, Daniel L Peterson 9, Lucinda Bateman 10, Elizabeth R Unger, on behalf of the MCAM Study Group1,‡
Editor: Svetlana Blitshteyn PMCID: PMC12428951 PMID: 40944028
Abstract
Background/Objectives: Symptoms of autonomic dysfunction are common in infection-associated chronic conditions and illnesses (IACCIs), including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to evaluate autonomic symptoms and their impact on ME/CFS illness severity.
Methods: Data came from a multi-site study conducted in seven ME/CFS specialty clinics during 2012–2020. Autonomic dysfunction was assessed using the Composite Autonomic Symptom Scale 31 (COMPASS-31), medical history, and a lean test originally described by the National Aeronautics and Space Administration (NASA). Illness severity was assessed using Patient-Reported Outcomes Measurement Information System measures, the 36-item short-form, as well as the CDC Symptom Inventory. This analysis included 442 participants who completed the baseline COMPASS-31 assessment, comprising 301 individuals with ME/CFS and 141 healthy controls (HC).
Results: ME/CFS participants reported higher autonomic symptom burden than HC across three assessment tools (all p < 0.0001), including the COMPASS-31 total score (34.1 vs. 6.8) and medical history indicators [dizziness or vertigo (42.6% vs. 2.8%), cold extremities (38.6% vs. 5.7%), and orthostatic intolerance (OI, 33.9% vs. 0.7%)]. Among ME/CFS participants, 97% had at least one autonomic symptom. Those with symptoms in the OI, gastrointestinal, and pupillomotor domains had significantly higher illness severity than those without these symptoms.
Conclusions: ME/CFS patients exhibit a substantial autonomic symptom burden that correlates with greater illness severity. Individualized care strategies targeting dysautonomia assessment and intervention may offer meaningful improvements in symptom management and quality of life for those with ME/CFS and similar chronic conditions.
Keywords: dysautonomia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), infection-associated chronic conditions and illnesses (IACCIs), orthostatic intolerance (OI), postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), Composite Autonomic Symptoms Scale 31 (COMPASS-31), Patient Reported Outcome Measurement Information System (PROMIS), National Aeronautics and Space Administration (NASA) Lean Test
_______________________________________________________________________
Specialised care for severely affected ME/CFS patients
Authors: Saugstad OD, Sollie MG, Torp HA, Storla DG (Røysumtunet, Norway)
Publication: Fatigue: Biomedicine, Health & Behavior (October, 2025)
Link: https://doi.org/10.1080/21641846.2025.2565101
This study describes outcomes from a specialised Norwegian residential unit that began admitting people with severe or very severe ME/CFS in June 2021. The unit provides a low-stimulation environment and individually tailored care for individuals who often face major barriers in conventional healthcare. This study aimed to examine changes in illness severity in patients who attended the unit during its first three years of operation.
The authors conducted a retrospective review of medical records from adults diagnosed with ME/CFS (Canadian Consensus Criteria) and classified as severe or very severe based on NICE guidelines who had stayed at the unit for at least three months. The study included twenty-four patients aged 18–68. Most were women (83%), and nearly three-quarters were very severely affected upon admission. Care focused on sensory-adapted environments, assistance with daily activities, nutritional support, pacing strategies and (when clinically appropriate) adjunctive treatments including thiamine, vitamin B12, NADH, coenzyme Q10, low-dose naltrexone, or low-dose aripiprazole.
At the end of their stay, half of the patients experienced meaningful improvement: seven (29%) improved by at least one severity level, and five (21%) improved within their existing severity category. Younger age and shorter illness duration were associated with better outcomes: those who improved had a mean illness duration of 2.3 years, compared with 6.7 years in those without measurable improvement.
The authors note that patients with severe and very severe ME/CFS often have limited access to appropriate services, and specialised care environments may help stabilise symptoms and enhance quality of life. They conclude that structured, low-stimulation, individually tailored care shows promise for this patient group, and that further research is needed to clarify which components of care contribute most to improvement.
Autonomic dysfunction symptoms (dysautonomia) are common for many people with ME/CFS. This study investigated the impact of autonomic symptoms on ME/CFS severity.
Data that had been collected as part of the Multi-Site Clinical Assessment of ME/CFS (MCAM) study were analysed for this study. The study included 442 participants (301 with ME/CFS, 141 healthy controls (HCs)) aged 18-70 years, across seven ME/CFS clinics. Clinicians at each site determined participant eligibility.
Dysautonomia was assessed using three tools: medical history, the self-reported validated Composite Autonomic Symptom Scale 31 (COMPASS-31, covering six autonomic dysfunction domains), and the NASA Lean Test (assessing orthostatic intolerance). Illness severity was assessed using various tools, including the Centers for Disease Control and Prevention Symptom Inventory (CDC-SI), Patient-Reported Outcomes Measurement Information System (PROMIS) measures, Orthostatic Grading Scale (OGS), and the 36-item Short-Form Health Survey (SF-36v2).
Almost all participants with ME/CFS reported at least one autonomic symptom (ME/CFS 97%, HCs 38%). Compared to HCs, participants with ME/CFS had a statistically significantly higher autonomic symptom burden, functional impairment and illness severity, evident across all three dysautonomia assessment tools.
The findings suggest that for people with ME/CFS, autonomic dysregulation may contribute to the level of severity in fatigue, sleep disturbances, cognitive function, pain, post-exertional malaise (PEM), and functional impairment. Participants with symptoms in the OI, gastrointestinal, and/or pupillomotor domains had significantly higher illness severity, compared to those without these symptoms.
Compared to traditional autonomic dysautonomia screening tools (i.e., tilt table tests, cardiovascular autonomic reflex tests, or heart rate variability assessments), the COMPASS-31 and Lean Test are more accessible and affordable, enabling quicker diagnosis and treatment.
The authors suggest that treating dysautonomia symptoms in people with ME/CFS may reduce illness severity and improve functional capacity, and highlight this as an important area for future research. They also call for further research to assess innovations in autonomic testing technologies and protocols.
_______________________________________________________________________
2025 Mar 18:6:1527783.
doi: 10.3389/fpain.2025.1527783. eCollection 2025.
Preliminary safety and effectiveness of psilocybin-assisted therapy in adults with fibromyalgia: an open-label pilot clinical trial
Jacob S Aday 1 2, Jenna McAfee 1, Deirdre A Conroy 3, Avinash Hosanagar 3 4, Vijay Tarnal 1 2, Cody Weston 3, Katherine Scott 1, Dana Horowitz 4, Jamarie Geller 2 3, Steven E Harte 1 2 5, Niloufar Pouyan 1 2 5, Nicolas G Glynos 1 2, Anne K Baker 1 2, Jeffrey Guss 6, Alan K Davis 7 8 9, Helen J Burgess 3, George A Mashour 1 2 5, Daniel J Clauw 1, Kevin F Boehnke 1 2
Affiliations Expand: PMID: 40171515, DOI: 10.3389/fpain.2025.1527783
Abstract
Introduction: Fibromyalgia (FM) is the prototypical nociplastic pain condition, characterized by widespread pain and issues with cognition, mood, and sleep. Currently, there are limited treatment options available that effectively treat FM symptoms. Psilocybin-assisted therapy (PAT) is an emerging combined drug-therapy intervention, but no studies to-date have investigated PAT for FM.
Methods: Here, we report findings from an open-label, pilot clinical trial of PAT for FM (N = 5). In conjunction with psychotherapy (two preparatory, four integration sessions), participants received two doses of oral psilocybin (15 mg and 25 mg) delivered two weeks apart.
Results: Regarding safety (primary outcome), there were transient elevations of blood pressure or heart rate during dosing which normalized by the end of treatment, with no serious adverse events. Four of five participants reported transient headaches following dosing. Compared to baseline, participants reported clinically meaningful improvements in the following secondary outcomes one month following their second psilocybin dose (reported as Cohen's d): pain severity [d = -2.1, 95% CI(-3.7 to -0.49)], pain interference [d = -1.8, 95% CI (-3.27 to -0.24)], and sleep disturbance [d = -2.5, 95% CI (-4.21 to -0.75)]. Using the Patient Global Impression of Change, one participant reported their symptoms "very much improved," two reported "much improved," and two reported "minimally improved." We stopped recruitment early because of concerns about generalizability and changes in FDA guidance for psychedelic clinical trials that occurred data collection.
Discussion: This small open-label trial preliminarily supports that PAT is well-tolerated by people with FM, establishing a basis for larger randomized controlled trials.
Clinical trial registration: ClinicalTrials.gov, identifier, (NCT05128162).
Keywords: clinical trial; fibromyalgia; pilot; psilocybin; psilocybin-assisted therapy.
© 2025 Aday, McAfee, Conroy, Hosanagar, Tarnal, Weston, Scott, Horowitz, Geller, Harte, Pouyan, Glynos, Baker, Guss, Davis, Burgess, Mashour, Clauw and Boehnke.
PubMed Disclaimer
_______________________________________________________________________
Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid
Benjamin A. Krishna https://orcid.org/0000-0003-0919-2961, Eleanor Y. Lim https://orcid.org/0000-0002-4776-4820, Marina Metaxaki https://orcid.org/0000-0002-4552-1622, Sarah Jackson https://orcid.org/0000-0002-4230-9220, Lenette Mactavous https://orcid.org/0000-0001-7145-2934, NIHR BioResource, Paul A. Lyons https://orcid.org/0000-0001-7035-8997, Rainer Doffinger, John R. Bradley https://orcid.org/0000-0002-7774-8805, [...] , and Mark R. Wills https://orcid.org/0000-0001-8548-5729+5 authors
Science Advances 21 Feb 2024 Vol 10 Issue 8
DOI: 10.1126/sciadv.adi9379
Abstract
After acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a proportion of patients experience persistent symptoms beyond 12 weeks, termed Long Covid. Understanding the mechanisms that cause this debilitating disease and identifying biomarkers for diagnostic, therapeutic, and monitoring purposes are urgently required. We detected persistently high levels of interferon-γ (IFN-γ) from peripheral blood mononuclear cells of patients with Long Covid using highly sensitive FluoroSpot assays. This IFN-γ release was seen in the absence of ex vivo peptide stimulation and remains persistently elevated in patients with Long Covid, unlike the resolution seen in patients recovering from acute SARS-CoV-2 infection. The IFN-γ release was CD8+ T cell–mediated and dependent on antigen presentation by CD14+ cells. Longitudinal follow-up of our study cohort showed that symptom improvement and resolution correlated with a decrease in IFN-γ production to baseline levels. Our study highlights a potential mechanism underlying Long Covid, enabling the search for biomarkers and therapeutics in patients with Long Covid.
Searching for blood biomarkers and treatment targets in Women with fibromyalgia – Protein interaction patterns and anti-satellite glia cell IgG antibodies as promising candidates
Author links open overlay panel Karolina af Ekenstam, Joana Menezes, Jenny E. Jakobsson, Helene Silverstein, Emerson Krock, Jeanette Tour, Katalin Sandor, Alexandra Kuliszkiewicz, Matthew Hunt, Kim Kultima, Macarena Tejos-Bravo, Camilla I. Svensson, Eva Kosek
https://doi.org/10.1016/j.bbi.2025.106185Get rights and content
Highlights
Anti-satellite glia cell IgG levels in fibromyalgia subjects (FMS) are associated with clusters of immunoregulatory proteins, aligning with the indications of autoimmune mechanisms in fibromyalgia.
The proteins that differentiate FMS from healthy controls exhibit characteristic interaction patterns, forming clusters aligned with different functional categories.
A better understanding of these mechanisms could lead to new objective diagnostic criteria identifying FMS likely to benefit from existing immunomodulatory treatments and pave the way for development of new treatment strategies for FM.
Abstract
Background
Recent studies suggest that autoreactive immunoglobulin G (IgG) antibodies binding to satellite glia cells (anti-SGC IgG) in the dorsal root ganglia influence pain intensity in a subgroup of fibromyalgia subjects (FMS), thus indicating altered immune activation. The main aim of this study was to identify proteins distinguishing female FMS from female healthy controls (HC) and within the FM group, proteins distinguishing FMS with high vs low levels of anti-SGC IgG. The secondary aim was to assess the associations between serum proteins and anti-SGC IgG, respectively, and FM symptoms.
Methods
Anti-SGC IgG was quantified using an immunofluorescence assay. Proteins in serum were assessed using Olink® Explore 384 Inflammation panel, regarding differences between FMS (n = 93) and HC (n = 40) and regarding differences between FMS with high (≥50 %) and low (<50 %) anti-SGC IgG, respectively. Proteins found to differ between groups (VIP ≥ 1.3) were further analyzed regarding protein-interactions using the software tool STRING (FM vs HC n = 56, high vs low anti-SGC IgG n = 55). Results from the FM group were also compared with two nociceptive pain conditions.
Results
In FMS, a cluster of immune system-related proteins was found among upregulated proteins, including CD40 and CD40L, with central roles in humoral immune response. CD40 levels were associated with more severe FM symptoms. In contrast, a cluster of tissue development-/regeneration-related proteins was found among downregulated proteins, this was not seen in nociceptive pain conditions. In FMS with high anti-SGC IgG, clusters dominated by immune system-related proteins were found among both upregulated and downregulated proteins. The cluster of upregulated proteins included CD79b, a protein necessary for B-cell receptor function, and CD4, a co receptor needed for T cell activation, thus with central role in activating various immune responses, including B-cell activation. Positive correlations were seen between some of these proteins and symptoms. On the contrary, several of the downregulated proteins correlated negatively to symptoms.
Conclusion
Our data support the involvement of the immune system in FM and indicate that further studies on autoimmune mechanisms, proteomics, and protein interaction analysis could lead to new objective diagnostic criteria identifying FMS likely to benefit from immunomodulatory treatments.
_______________________________________________________________________
Assessing the influence of lived-experience experts on healthcare providers in a virtual community of practice: a qualitative study
Author: Weaver SS, Carry M, Bertolli J, Godino J, Struminger B, Taren D, … Ramers CB (Laura Rodriguez Research Institute, USA)
Publication: Frontiers in Health Services (June 2025)
Link: https://www.frontiersin.org/journals/health- services/articles/10.3389/frhs.2025.1562651/full
This qualitative evaluation investigates how embedding lived-experience experts (LEEs) in a virtual community of practice shapes healthcare providers’ approach to complex, often misunderstood conditions such as long-COVID, ME/CFS and other post-acute infection syndromes (PAIS). By blending patients’ voices with professional discourse, the study aimed to illuminate whether this model could help reduce stigma, improve empathy, and change care practices.
Over an 18-month period, the project collected transcripts from regular webinar sessions (January 2022 – March 2024) in which LEEs - people living with Long-COVID, ME/CFS or PAIS, or caregivers - shared educational input to clinicians. In parallel, 22 patients receiving care from participating providers were interviewed using semi-structured methods to explore how they perceived those providers’ adoption of LEE-driven recommendations. Transcripts were thematically analysed via content analysis.
Key themes emerged around validating illness experience, shifting clinician beliefs about symptoms beyond psychological attribution, fostering empathetic communication, improving navigation of referrals, recognising fluctuating disability and encouraging patient self-management. Patients reported feeling heard, better understood and more confident in advocating for themselves. Many recounted that providers gradually incorporated LEE messages, especially around pacing and acknowledging disability, into interactions. Notably, participants described how integration of lived experience helped bridge the gap between biomedical uncertainty and human suffering in PAIS settings.
The authors argue that this model offers a promising way to reduce the “invisibility” of these syndromes. Involving LEEs as co-educators can shift provider attitudes, heighten validation of symptoms, and encourage more responsive care, especially in the context of long-COVID and ME/CFS. Future research should examine the longitudinal effects on clinician behaviour and explore how such models could scale across health systems to better address the needs of patients with PAIS.
_______________________________________________________________________
Pyridostigmine improves hand grip strength in patients with myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Schlömer E, Stein E, Kedor C, Rust R, Brock A, Wittke K, … Kim L (Charité-Universitätsmedizin Berlin, Germany)
Publication: Frontiers in Neuroscience (September 2025)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12441162/pdf/fnins-19-1637838.pdf
This paper explored whether low acetylcholine activity contributes to the reduced exercise capacity, muscle strength, and orthostatic intolerance seen in ME/CFS patients. The body requires acetylcholine for muscle activity, muscle activity control and cardiovascular adaptations such as standing up. Pyridostigmine (PS), also known as Mestinon, is a drug that inhibits the enzyme that breaks down acetylcholine. PS has been used off label for ME/CFS patients, specifically those with orthostatic intolerance to mitigate symptoms.
The study included 20 post-infection ME/CFS patients (7 men, 13 women) diagnosed using the Canadian Consensus Criteria. Muscle fatigue was assessed using hand grip strength (HGS) test with all patients recording values below the manufacturer’s cutoff.
During the first visit, baseline HGS values were obtained using a dynamometer. Participants held the dynamometer in their dominant hand and exerted maximum force for a 3 second period with 5-second rests. This was repeated 10 times, and the highest value over each 3 second period was recorded in kgs. This process was then repeated 60 minutes later and followed by a passive stand test that 7 participants declined. During the second visit, patients repeated the initial HGS protocol. After the first set of 10, 30 milligrams of PS was administered. HGS was retested after one hour, again followed by a passive stand test.
The researchers found that HGS fell after an hour without PS but doubled after PS administration. Heart rate rise whilst standing also dropped from 17 BPM to 13 BPM with PS. This indicates that PS could have significant benefits for ME/CFS patients with orthostatic intolerance, muscle weakness and impaired exercise capacity.
The authors acknowledge the limitations of the small sample size and the lack of a control group. They recommend further study of PS to validate these findings in a larger, controlled trial, and to better understand its effects on symptoms and function, as well as possible side effects.
_______________________________________________________________________
Biofabrication: . 2025 Aug 8;17(4). doi: 10.1088/1758-5090/adf66c.
Metabolic adaptation and fragility in healthy 3D in vitro skeletal muscle tissues exposed to chronic fatigue syndrome and Long COVID-19 sera
Sheeza Mughal 1 2, Félix Andújar-Sánchez 3 4 5, Maria Sabater-Arcis 1, Glória Garrabou 3 4 5, Joaquim Fernández-Solà 4, Jose Alegre-Martin 6 7, Ramon Sanmartin-Sentañes 6 7, Jesús Castro-Marrero 7, Anna Esteve-Codina 8 2, Eloi Casals 8 2, Juan M Fernández-Costa 1, Javier Ramón-Azcón 1 9
Affiliations Expand PMID: 40744071 DOI: 10.1088/1758-5090/adf66c
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid-19 (LC-19) are complex conditions with no diagnostic markers or consensus on disease progression. Despite extensive research, noin vitromodel exists to study skeletal muscle wasting, peripheral weakness, or potential therapies. We developed 3Din vitroskeletal muscle tissues to map muscle adaptations to patient sera over time. Short exposures (48 H) to patient sera led to a significant reduction in muscle contractile strength. Transcriptomic analysis revealed the upregulation of protein translation, glycolytic enzymes, disturbances in calcium homeostasis, hypertrophy, and mitochondrial hyperfusion. Structural analyses confirmed myotube hypertrophy and elevated mitochondrial oxygen consumption In ME/CFS. While muscles initially adapted by increasing glycolysis, prolonged exposure (96-144 H) caused muscle fragility and weakness, with mitochondria fragmenting into a toroidal conformation. We propose that skeletal muscle tissue in ME/CFS and LC-19 progresses through a hypermetabolic state, leading to severe muscular and mitochondrial deterioration. This is the first study to suggest such transient metabolic adaptation.
_______________________________________________________________________
BIOMARKER: SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis
Authors: Rostami-Afshari B, Elremaly W, Franco A, Elbakry M, Akoume MY, Boufaied I…, Moreau A (Université de Montréal, Canada)
Publication: Journal of Translational Medicine (July, 2025)
Link:https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06829-0
Sphingomyelin phosphodiesterase acid-like 3B (SMP-DL3B) is an essential immune-regulatory protein and is also involved in fat metabolism. The authors investigated its role in ME/CFS pathophysiology and its potential as a biomarker of disease severity.
The study included two independent cohorts. The Canadian cohort included 249 people with ME/CFS (Canadian Consensus Criteria) of which 208 were women, and 63 healthy controls (33 women) who were frequency-matched by age and sex. For replication, the authors used a Norwegian cohort of 141 people with ME/CFS (119 women), also diagnosed according to the Canadian Consensus Criteria. All participants from both cohorts were recruited before the COVID-19 pandemic, and blood samples were taken to analyse for SMPDL3B.
ME/CFS symptoms and severity were assessed with the 36-Item Short-Form Health Survey, Multidimensional Fatigue Inventory, and DePaul Symptom Questionnaire in the Canadian cohort. In the Norwegian cohort, a physician categorised disease severity from mild to severe ME/CFS (participants with very severe ME/CFS were excluded).
SMPDL3B levels in plasma were significantly higher in the Canadian ME/CFS cohort compared with controls. To evaluate the potential of SMPDL3B as a biomarker for disease severity, the authors used 30 ng/mL as a threshold to separate the Canadian ME/CFS cohort into low and high plasma SMPDL3B. Participants with SMPDL3B plasma levels above 30 ng/mL presented significantly greater symptoms and disease severity than those below 30 ng/mL. This finding was replicated in the Norwegian cohort.
The authors also found sex differences in the ME/CFS cohort: women had greater cognitive impairments, sleep problems, and post-exertional malaise, while men presented lower severity scores, but higher reduced motivation. The authors found that oestradiol modulated SMPDL3B levels in vitro, suggesting that oestradiol may contribute to the observed differences between men and women.
These findings suggest that SMPDL3B may be a biomarker of disease severity and a target for therapeutic interventions. However, further studies are needed to fully understand and validate its potential.
_______________________________________________________________________
Mol Cell Proteomics 2025 Dec;24(12):101467. doi: 10.1016/j.mcpro.2025.101467. Epub 2025 Nov 17.
Temporal Dynamics of the Plasma Proteomic Landscape Reveals Maladaptation in ME/CFS Following Exertion
Arnaud Germain 1, Katherine A Glass 1, Melissa A Eckert 1, Ludovic Giloteaux 1, Maureen R Hanson 2
PMID: 41237904 DOI: 10.1016/j.mcpro.2025.101467
Abstract
The overarching symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM), an exacerbation of symptoms following physical or mental exertion. To investigate the molecular underpinnings of PEM, we performed longitudinal plasma proteomics using the Somascan 7K aptamer-based assay to monitor 6361 unique plasma proteins in 132 individuals (96 females and 36 males) subjected to two maximal cardiopulmonary exercise tests separated by a 24-h recovery period. The cohort included 79 ME/CFS cases compared to 53 age- and BMI-matched sedentary controls, allowing us to distinguish disease-specific molecular alterations from those due to physical deconditioning. Longitudinal profiling revealed widespread proteomic changes following exertion, with the most pronounced alterations observed in ME/CFS participants during the recovery phase, coinciding with the onset of PEM. Compared to controls, patients with ME/CFS showed persistent dysregulation of immune, metabolic, and neuromuscular pathways. Key findings included suppression of T and B cell signaling, downregulation of IL-17 and cell-cell communication pathways, and upregulation of glycolysis/gluconeogenesis, suggestive of mitochondrial stress and impaired immune recovery from exercise. Proteomic associations with physiological performance (VO2max, anaerobic threshold) revealed disruptions between protein abundance and exercise capacity in ME/CFS versus controls. Correlations with symptom severity linked changes in immune-related proteins and ME/CFS symptoms, including muscle pain, recurrent sore throat, and lymph node tenderness. Sex-stratified analyses revealed distinct molecular responses between females and males, emphasizing the importance of considering sex as a biological variable in ME/CFS research. Finally, our analysis of sedentary controls contributes new data on molecular responses to acute exertion in a predominantly female sedentary cohort, a population historically underrepresented in exercise physiology studies. Together, these findings underscore the value of dynamic, proteomic profiling over time for characterizing maladaptive responses to exertion in ME/CFS and provide a foundation for deeper mechanistic investigation into PEM.
_______________________________________________________________________
Published: 12 December 2025
Long COVID involves activation of proinflammatory and immune exhaustion pathways
Malika Aid, Valentin Boero-Teyssier, Katherine McMahan, Rammy Dong, Michael Doyle, Nazim Belabbaci, Erica Borducchi, Ai-ris Y. Collier, Janet Mullington & Dan H. Barouch
Nature Immunology (2025)Cite this article
Abstract
Long COVID (LC) involves a spectrum of chronic symptoms after acute severe acute respiratory syndrome coronavirus 2 infection. Current hypotheses for the pathogenesis of LC include persistent virus, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction and complement activation.
Long COVID, like other post-acute infection syndromes, is thought to involve several mechanisms, including immune dysregulation, chronic inflammation and autonomic dysfunction. These authors propose a framework that integrates neuroimmune dysregulation, innate immune dysfunction and autoantibody-mediated mechanisms to explain the persistence and heterogeneity of long COVID.
SARS-CoV-2 infection triggers acute inflammation via viral entry through ACE2 receptors and the transmembrane protease TMPRSS2-mediated mechanisms, causing systemic immune activation and endothelial injury. In some individuals, especially older adults or those with metabolic or immunogenetic vulnerabilities, immune dysregulation persists, leading to chronic inflammation, microvascular dysfunction, and impaired immune resolution. This can lead to autoantibody production, T cell exhaustion, and neuroimmune imbalance.
Innate immune cells, particularly neutrophils and macrophages, are central to long COVID pathogenesis. Neutrophils release extracellular traps (NETs), which, if dysregulated, can drive tissue damage and autoimmunity. Macrophages contribute to chronic inflammation through cytokine production and antigen presentation, with aging-associated “inflammaging” amplifying these effects. Persistent activation of inflammasomes, complement dysregulation, and trained immunity further lead to sustained low-grade inflammation and breakdown of the body’s immune tolerance.
Autonomic nervous system (ANS) dysfunction is another feature and driver of long COVID. Sympathetic nervous system overactivation leads to neuroimmune dysregulation, promoting fatigue, orthostatic intolerance, and cognitive defects. Autoantibodies targeting ANS receptors may also enhance this. The complicated web of chronic inflammation, autoimmunity, and ANS imbalance makes long COVID a dyshomeostasis syndrome, with inflammaging acting as an amplifier, particularly in older adults and women.
The authors believe that biomarkers such as cytokine profiles, phenotyping immune cells, epigenetic clocks, and heart rate variability can aid early diagnosis, help sort people by their level of risk, and offer personalised interventions. They conclude that it can also provide insight into broader mechanisms of post-infectious and age-related chronic diseases.
_______________________________________________________________________
Publication: Journal of Clinical Medicine (September, 2025)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12428951/pdf/jcm-14-06269.pdf
Autonomic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Findings from the Multi-Site Clinical Assessment of ME/CFS (MCAM) Study in the USA
Anindita Issa 1,†, Jin-Mann S Lin 1,*,†, Yang Chen 1,†, Jacob Attell 1,2, Dana Brimmer 1, Jeanne Bertolli 1, Benjamin H Natelson 3, Charles W Lapp 4, Richard N Podell 5, Andreas M Kogelnik 6, Nancy G Klimas 7,8, Daniel L Peterson 9, Lucinda Bateman 10, Elizabeth R Unger, on behalf of the MCAM Study Group1,‡
Editor: Svetlana Blitshteyn PMCID: PMC12428951 PMID: 40944028
Abstract
Background/Objectives: Symptoms of autonomic dysfunction are common in infection-associated chronic conditions and illnesses (IACCIs), including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to evaluate autonomic symptoms and their impact on ME/CFS illness severity.
Methods: Data came from a multi-site study conducted in seven ME/CFS specialty clinics during 2012–2020. Autonomic dysfunction was assessed using the Composite Autonomic Symptom Scale 31 (COMPASS-31), medical history, and a lean test originally described by the National Aeronautics and Space Administration (NASA). Illness severity was assessed using Patient-Reported Outcomes Measurement Information System measures, the 36-item short-form, as well as the CDC Symptom Inventory. This analysis included 442 participants who completed the baseline COMPASS-31 assessment, comprising 301 individuals with ME/CFS and 141 healthy controls (HC).
Results: ME/CFS participants reported higher autonomic symptom burden than HC across three assessment tools (all p < 0.0001), including the COMPASS-31 total score (34.1 vs. 6.8) and medical history indicators [dizziness or vertigo (42.6% vs. 2.8%), cold extremities (38.6% vs. 5.7%), and orthostatic intolerance (OI, 33.9% vs. 0.7%)]. Among ME/CFS participants, 97% had at least one autonomic symptom. Those with symptoms in the OI, gastrointestinal, and pupillomotor domains had significantly higher illness severity than those without these symptoms.
Conclusions: ME/CFS patients exhibit a substantial autonomic symptom burden that correlates with greater illness severity. Individualized care strategies targeting dysautonomia assessment and intervention may offer meaningful improvements in symptom management and quality of life for those with ME/CFS and similar chronic conditions.
Keywords: dysautonomia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), infection-associated chronic conditions and illnesses (IACCIs), orthostatic intolerance (OI), postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), Composite Autonomic Symptoms Scale 31 (COMPASS-31), Patient Reported Outcome Measurement Information System (PROMIS), National Aeronautics and Space Administration (NASA) Lean Test
_______________________________________________________________________
Specialised care for severely affected ME/CFS patients
Authors: Saugstad OD, Sollie MG, Torp HA, Storla DG (Røysumtunet, Norway)
Publication: Fatigue: Biomedicine, Health & Behavior (October, 2025)
Link: https://doi.org/10.1080/21641846.2025.2565101
This study describes outcomes from a specialised Norwegian residential unit that began admitting people with severe or very severe ME/CFS in June 2021. The unit provides a low-stimulation environment and individually tailored care for individuals who often face major barriers in conventional healthcare. This study aimed to examine changes in illness severity in patients who attended the unit during its first three years of operation.
The authors conducted a retrospective review of medical records from adults diagnosed with ME/CFS (Canadian Consensus Criteria) and classified as severe or very severe based on NICE guidelines who had stayed at the unit for at least three months. The study included twenty-four patients aged 18–68. Most were women (83%), and nearly three-quarters were very severely affected upon admission. Care focused on sensory-adapted environments, assistance with daily activities, nutritional support, pacing strategies and (when clinically appropriate) adjunctive treatments including thiamine, vitamin B12, NADH, coenzyme Q10, low-dose naltrexone, or low-dose aripiprazole.
At the end of their stay, half of the patients experienced meaningful improvement: seven (29%) improved by at least one severity level, and five (21%) improved within their existing severity category. Younger age and shorter illness duration were associated with better outcomes: those who improved had a mean illness duration of 2.3 years, compared with 6.7 years in those without measurable improvement.
The authors note that patients with severe and very severe ME/CFS often have limited access to appropriate services, and specialised care environments may help stabilise symptoms and enhance quality of life. They conclude that structured, low-stimulation, individually tailored care shows promise for this patient group, and that further research is needed to clarify which components of care contribute most to improvement.
Autonomic dysfunction symptoms (dysautonomia) are common for many people with ME/CFS. This study investigated the impact of autonomic symptoms on ME/CFS severity.
Data that had been collected as part of the Multi-Site Clinical Assessment of ME/CFS (MCAM) study were analysed for this study. The study included 442 participants (301 with ME/CFS, 141 healthy controls (HCs)) aged 18-70 years, across seven ME/CFS clinics. Clinicians at each site determined participant eligibility.
Dysautonomia was assessed using three tools: medical history, the self-reported validated Composite Autonomic Symptom Scale 31 (COMPASS-31, covering six autonomic dysfunction domains), and the NASA Lean Test (assessing orthostatic intolerance). Illness severity was assessed using various tools, including the Centers for Disease Control and Prevention Symptom Inventory (CDC-SI), Patient-Reported Outcomes Measurement Information System (PROMIS) measures, Orthostatic Grading Scale (OGS), and the 36-item Short-Form Health Survey (SF-36v2).
Almost all participants with ME/CFS reported at least one autonomic symptom (ME/CFS 97%, HCs 38%). Compared to HCs, participants with ME/CFS had a statistically significantly higher autonomic symptom burden, functional impairment and illness severity, evident across all three dysautonomia assessment tools.
The findings suggest that for people with ME/CFS, autonomic dysregulation may contribute to the level of severity in fatigue, sleep disturbances, cognitive function, pain, post-exertional malaise (PEM), and functional impairment. Participants with symptoms in the OI, gastrointestinal, and/or pupillomotor domains had significantly higher illness severity, compared to those without these symptoms.
Compared to traditional autonomic dysautonomia screening tools (i.e., tilt table tests, cardiovascular autonomic reflex tests, or heart rate variability assessments), the COMPASS-31 and Lean Test are more accessible and affordable, enabling quicker diagnosis and treatment.
The authors suggest that treating dysautonomia symptoms in people with ME/CFS may reduce illness severity and improve functional capacity, and highlight this as an important area for future research. They also call for further research to assess innovations in autonomic testing technologies and protocols.
_______________________________________________________________________
2025 Mar 18:6:1527783.
doi: 10.3389/fpain.2025.1527783. eCollection 2025.
Preliminary safety and effectiveness of psilocybin-assisted therapy in adults with fibromyalgia: an open-label pilot clinical trial
Jacob S Aday 1 2, Jenna McAfee 1, Deirdre A Conroy 3, Avinash Hosanagar 3 4, Vijay Tarnal 1 2, Cody Weston 3, Katherine Scott 1, Dana Horowitz 4, Jamarie Geller 2 3, Steven E Harte 1 2 5, Niloufar Pouyan 1 2 5, Nicolas G Glynos 1 2, Anne K Baker 1 2, Jeffrey Guss 6, Alan K Davis 7 8 9, Helen J Burgess 3, George A Mashour 1 2 5, Daniel J Clauw 1, Kevin F Boehnke 1 2
Affiliations Expand: PMID: 40171515, DOI: 10.3389/fpain.2025.1527783
Abstract
Introduction: Fibromyalgia (FM) is the prototypical nociplastic pain condition, characterized by widespread pain and issues with cognition, mood, and sleep. Currently, there are limited treatment options available that effectively treat FM symptoms. Psilocybin-assisted therapy (PAT) is an emerging combined drug-therapy intervention, but no studies to-date have investigated PAT for FM.
Methods: Here, we report findings from an open-label, pilot clinical trial of PAT for FM (N = 5). In conjunction with psychotherapy (two preparatory, four integration sessions), participants received two doses of oral psilocybin (15 mg and 25 mg) delivered two weeks apart.
Results: Regarding safety (primary outcome), there were transient elevations of blood pressure or heart rate during dosing which normalized by the end of treatment, with no serious adverse events. Four of five participants reported transient headaches following dosing. Compared to baseline, participants reported clinically meaningful improvements in the following secondary outcomes one month following their second psilocybin dose (reported as Cohen's d): pain severity [d = -2.1, 95% CI(-3.7 to -0.49)], pain interference [d = -1.8, 95% CI (-3.27 to -0.24)], and sleep disturbance [d = -2.5, 95% CI (-4.21 to -0.75)]. Using the Patient Global Impression of Change, one participant reported their symptoms "very much improved," two reported "much improved," and two reported "minimally improved." We stopped recruitment early because of concerns about generalizability and changes in FDA guidance for psychedelic clinical trials that occurred data collection.
Discussion: This small open-label trial preliminarily supports that PAT is well-tolerated by people with FM, establishing a basis for larger randomized controlled trials.
Clinical trial registration: ClinicalTrials.gov, identifier, (NCT05128162).
Keywords: clinical trial; fibromyalgia; pilot; psilocybin; psilocybin-assisted therapy.
© 2025 Aday, McAfee, Conroy, Hosanagar, Tarnal, Weston, Scott, Horowitz, Geller, Harte, Pouyan, Glynos, Baker, Guss, Davis, Burgess, Mashour, Clauw and Boehnke.
PubMed Disclaimer
_______________________________________________________________________
Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid
Benjamin A. Krishna https://orcid.org/0000-0003-0919-2961, Eleanor Y. Lim https://orcid.org/0000-0002-4776-4820, Marina Metaxaki https://orcid.org/0000-0002-4552-1622, Sarah Jackson https://orcid.org/0000-0002-4230-9220, Lenette Mactavous https://orcid.org/0000-0001-7145-2934, NIHR BioResource, Paul A. Lyons https://orcid.org/0000-0001-7035-8997, Rainer Doffinger, John R. Bradley https://orcid.org/0000-0002-7774-8805, [...] , and Mark R. Wills https://orcid.org/0000-0001-8548-5729+5 authors
Science Advances 21 Feb 2024 Vol 10 Issue 8
DOI: 10.1126/sciadv.adi9379
Abstract
After acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a proportion of patients experience persistent symptoms beyond 12 weeks, termed Long Covid. Understanding the mechanisms that cause this debilitating disease and identifying biomarkers for diagnostic, therapeutic, and monitoring purposes are urgently required. We detected persistently high levels of interferon-γ (IFN-γ) from peripheral blood mononuclear cells of patients with Long Covid using highly sensitive FluoroSpot assays. This IFN-γ release was seen in the absence of ex vivo peptide stimulation and remains persistently elevated in patients with Long Covid, unlike the resolution seen in patients recovering from acute SARS-CoV-2 infection. The IFN-γ release was CD8+ T cell–mediated and dependent on antigen presentation by CD14+ cells. Longitudinal follow-up of our study cohort showed that symptom improvement and resolution correlated with a decrease in IFN-γ production to baseline levels. Our study highlights a potential mechanism underlying Long Covid, enabling the search for biomarkers and therapeutics in patients with Long Covid.
RSS Feed