A brief note before we start. Long COVID has generated a larger volume of research in a shorter time than almost any condition in modern medical history. Choosing three studies from this field requires difficult decisions about what “most important” means. The three below were selected for their methodological rigour, the novelty of their findings, the mechanistic insights they provide, their direct relevance to patients navigating this condition and ultimately, my opinion. Several honourable mentions appear at the end.

Study 1: The Immune Profiling Study That Found a Biological Fingerprint of Long COVID

Klein J, Wood J, Jaycox J, et al. Distinguishing features of long COVID identified through immune profiling. Nature. 2023;623(7985):139–148.

Published in September 2023 in Nature, this study enrolled 275 individuals with or without Long COVID in a cross-sectional design. The research was led by Jon Klein and colleagues at Yale School of Medicine, the Icahn School of Medicine at Mount Sinai, with multiple affiliated institutions. Senior authors include Dr Akiko Iwasaki, one of the leading immunologists in the Long COVID field, together with Dr David Putrino, whose wearable research we have decoded separately.

The study used multidimensional immune phenotyping alongside unbiased machine learning to identify biological features that distinguished Long COVID participants from those who had recovered fully. Rather than testing a specific hypothesis about what might be wrong, the researchers mapped the full immune landscape and let statistical models identify what was actually different.

The findings were substantial. Long COVID participants showed marked differences in circulating myeloid and lymphoid cell populations compared to matched controls who had recovered from COVID-19. Myeloid cells, which include monocytes and macrophages, were present in altered proportions and showed evidence of abnormal activation. Lymphoid populations, including T cell subsets, were similarly disrupted in ways that differed from what is seen in acute infection or normal recovery.

Participants with Long COVID showed evidence of exaggerated humoral immune responses directed against SARS-CoV-2, meaning they were still mounting high antibody responses to the virus months after infection. This is consistent with the viral persistence hypothesis: if residual viral antigen or viral fragments remain in the body, the immune system continues producing antibodies against them. Higher antibody responses directed against Epstein-Barr virus were also observed among Long COVID participants compared to controls. EBV reactivation during immune dysregulation is a recognised mechanism in other post-viral conditions.

The most striking individual finding was the role of cortisol. When the machine learning model integrated all the immune phenotyping data to identify what best distinguished Long COVID participants from controls, decreased cortisol levels were the single most significant individual predictor. Cortisol is the body’s primary stress hormone, involved in regulating inflammation, energy metabolism, sleep-wake cycles, immune response, blood pressure, together with a range of other physiological processes. Its depletion in Long COVID participants raises questions about hypothalamic-pituitary-adrenal axis dysfunction, a finding consistent with the fatigue, sleep disruption, along with the immune dysregulation that characterise the condition.

This study does not prove causality. It cannot tell us whether the immune abnormalities cause Long COVID symptoms, whether they are a consequence of something else, or whether they are a necessary feature of the condition in all patients. The cross-sectional design provides a snapshot rather than a longitudinal picture. Replication in independent cohorts is needed. What it does provide is the most comprehensive biological characterisation of Long COVID immune features published to date, using methods that are both rigorous, crucially, hypothesis-agnostic.

Study 2: The Study That Proved the Virus Persists in Body Tissues After Mild Infection

Zuo W, He D, Liang C, et al. The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China. Lancet Infectious Diseases. 2024;24(8):845–855.

The viral persistence hypothesis for Long COVID has been discussed since early in the pandemic: the idea that residual SARS-CoV-2, either intact virus or viral fragments, remains in body tissues after apparent recovery, continuing to drive immune activation, inflammation, along with symptoms. This study, published in the Lancet Infectious Diseases in 2024, provides the most direct and comprehensive evidence for that hypothesis to date.

Researchers collected 317 tissue samples from 225 patients who had recovered from mild COVID-19, meaning patients who had not been hospitalised. Samples were collected at one, two, and four months post-infection. The tissues sampled were diverse: liver, kidney, stomach, intestine, brain, blood vessel, lung, breast, skin, and thyroid. Blood samples were also collected at each timepoint.

Viral RNA was detected in 30% of solid tissue samples at one month, 27% at two months, 11% at four months. The persistence was not confined to one or two tissue types. Viral RNA was distributed across all ten types of solid tissue tested. Subgenomic RNA, a marker of active viral replication rather than residual non-replicating fragments, was detected in 43% of the solid tissue samples that tested positive for viral RNA, suggesting that in a meaningful proportion of cases the virus was not simply leaving traces but retaining the capacity for replication.

The statistical link between viral persistence and Long COVID symptoms was strong. Patients with detectable viral RNA in their tissues were 5.17 times more likely to have Long COVID symptoms (odds ratio 5.17, 95% CI 2.64–10.13, p<0.0001). Higher viral copy numbers were also associated with greater symptom burden.

The importance of this study extends beyond confirming what had been suspected. It provides a mechanistic target. If residual viral persistence drives Long COVID in a subset of patients, antiviral therapy that clears the reservoir becomes a rational treatment strategy. The RECOVER-VITAL trial testing extended course Paxlovid in Long COVID patients was designed precisely around this hypothesis. This study also helps explain why some Long COVID patients improve spontaneously over time: viral clearance may occur gradually in some individuals, allowing immune dysregulation to resolve.

Limitations are worth noting carefully. This was conducted in a single country with specific viral variants circulating at the time of infection. The patients had mild acute disease, which is appropriate for studying the most common Long COVID phenotype but may not reflect what happens after severe acute infection. The study could not establish definitively whether the viral RNA detected was causing symptoms, correlated with something else causing symptoms, or present coincidentally. The mechanism by which persistent viral RNA drives the specific symptom profile of Long COVID remains incompletely characterised.

Study 3: The Muscle Biopsy Study That Made Post-Exertional Malaise Impossible to Dismiss

Appelman B, Charlton BT, Goulding RP, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature Communications. 2024;15:17.

My personal favourite… We have decoded this study in detail in a previous piece, so the description here will be more concise. Published in January 2024 in Nature Communications, this study took skeletal muscle biopsies from 25 Long COVID patients with post-exertional malaise before exercise and one day after exercise triggered a crash, with the same protocol run in 21 healthy controls.

Before a single exercise bout, Long COVID muscle was already different from healthy muscle. Mitochondrial enzyme activity was reduced. The proportion of fast-twitch fibres that fatigue quickly was higher. These differences were present at baseline, without any exercise having occurred.

One day after exercise induced a crash, mitochondrial respiration dropped significantly in Long COVID patients while remaining stable in controls. Immune cells, specifically CD4+ T cells and mast cells, infiltrated the muscle tissue in ways not seen in controls. A key energy-generating enzyme called succinate dehydrogenase showed a significant interaction between group and time, falling in Long COVID patients after PEM while holding steady or rising in controls. Blood supply to the muscle was identical in both groups, ruling out the explanation that the damage was caused by reduced oxygen delivery, which is the hallmark of deconditioning.

The damage was visible under a microscope. It was measurable. It was specific to the crash window. The study provides the most direct evidence that post-exertional malaise involves objective cellular injury rather than subjective symptom amplification, reshaping how both researchers and clinicians think about exercise recommendations for this population.

A full decoded piece on this study including the subsequent debate in the published literature is available on Dysautonomia Decoded.

Honourable Mentions

The shared autonomic phenotype study by Novak and colleagues at Brigham and Women’s Hospital and Harvard Medical School (PLOS ONE, 2026) found that Long COVID and ME/CFS patients were essentially indistinguishable on detailed autonomic testing, with more than 90% of both groups showing reduced cerebral blood flow on standing. A full decoded piece is available on Dysautonomia Decoded.

The Walitt and Nath NIH deep phenotyping study (Nature Communications, 2024), which we decoded in the ME/CFS series yesterday, enrolled both post-infectious ME/CFS and Long COVID participants, documenting the autonomic, immune, along with sex-specific biological abnormalities across both groups simultaneously.

The microvascular retinal study by Wallraven and colleagues at the Technical University of Munich (BMC Medicine, 2026) found that post-COVID patients showed impaired retinal vessel dilation correlated directly with symptom severity, with ME/CFS patients showing nearly identical patterns. A full decoded piece is available on Dysautonomia Decoded.

The Bigger Picture

Three years of research have moved Long COVID from a disputed clinical entity to a condition with a growing biological evidence base. The immune system carries a measurable fingerprint in blood. The virus persists in body tissues in a substantial proportion of patients, linked statistically to symptoms with an odds ratio over five. Post-exertional malaise involves cellular damage visible under a microscope. These are not the findings of a functional or psychosomatic condition. They are specific, measurable, biologically coherent discoveries in peer-reviewed journals of the highest standing.

The research has not yet produced treatments that consistently work for most patients. That remains the most urgent gap. The mechanistic foundation being built by studies like these is what treatment development depends on.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Klein J, Wood J, Jaycox J, et al. Distinguishing features of long COVID identified through immune profiling. Nature. 2023;623(7985):139–148. https://doi.org/10.1038/s41586-023-06651-y

Zuo W, He D, Liang C, et al. The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China. Lancet Infectious Diseases. 2024;24(8):845–855. https://doi.org/10.1016/S1473-3099(24)00171-3

Appelman B, Charlton BT, Goulding RP, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature Communications. 2024;15:17. https://doi.org/10.1038/s41467-023-44432-3

Novak P, Systrom DM, et al. Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. PLOS ONE. 2026;21(1):e0341278. https://doi.org/10.1371/journal.pone.0341278

Walitt B, Nath A, et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nature Communications. 2024;15(1):907. https://doi.org/10.1038/s41467-024-45107-3

Wallraven T, Günthner R, et al. Microvascular remodeling and endothelial dysfunction across the post-COVID-19 spectrum. BMC Medicine. 2026;24(1):456. https://doi.org/10.1186/s12916-026-05144-9

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A note before we begin. ME/CFS has spent decades being systematically underfunded, dismissed and excluded from serious scientific inquiry. The three studies below represent a field that has begun to change that, not by proving a single cause, but by finding specific, measurable, biologically coherent abnormalities that accumulate into a picture that is very difficult to dismiss. That progress matters even when individual studies are small, preliminary, or surrounded by caveats.

Study 1: The Protein That Is Physically Dismantling the Mitochondria

Wang PY, Ma J, Kim YC, et al. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proceedings of the National Academy of Sciences. 2023;120(34):e2302738120.

The story of this study begins with a single patient, a 38-year-old woman with ME/CFS who took days to recover from any physical exertion, whose muscles were consistently failing to produce energy at a normal rate. Researchers at the National Heart, Lung and Blood Institute at the NIH began investigating her cells and found something specific: a protein called WASF3 was present at abnormally high levels in her skeletal muscle, and it was doing something measurable and damaging.

WASF3 is a protein that under normal circumstances has roles in cell migration and structure. When cells are under stress, specifically endoplasmic reticulum (ER) stress, the kind triggered by protein misfolding or metabolic disruption, WASF3 is produced in excess. In this patient, the excess WASF3 was travelling to the mitochondria and physically disrupting the assembly of respiratory supercomplexes.

Respiratory supercomplexes are the protein structures that mitochondria use to produce ATP, the cell’s energy currency. They need to be properly assembled to function. WASF3 was preventing that assembly, leading to reduced oxygen consumption and impaired energy production. The cell’s power plant was being actively sabotaged by one of its own proteins.

The researchers did not stop at a single patient. They obtained skeletal muscle biopsy samples from a broader cohort of ME/CFS patients and found increased WASF3 levels and aberrant ER stress activation across the group, not just in the index case. They then showed that blocking ER stress pharmacologically reduced WASF3 levels and restored mitochondrial function in the patient’s cells.

This is the most specific molecular mechanism identified in ME/CFS to date. It provides a plausible explanation for why ME/CFS patients experience profound exercise intolerance: their mitochondria are being actively disrupted by a stress-induced protein, not simply failing to produce enough energy in a general sense. It also, importantly, identifies a potential therapeutic target. If WASF3 can be reduced by addressing ER stress, and the preliminary cell data suggests it can, that is a tractable drug development direction.

The limitations are real. This was a small study. The cell work was done in vitro and in animal models. The jump from cells and mice to human clinical outcomes is significant. But the finding is specific, mechanistically coherent, and reproducible across multiple ME/CFS patient samples. Published in PNAS, one of the most prestigious multidisciplinary journals in the world, by NIH researchers, it represents the kind of institutional scientific validation ME/CFS has historically been denied.

Study 2: The Most Comprehensive Single Study of ME/CFS Mechanisms Ever Conducted

Walitt B, Nath A, et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nature Communications. 2024;15(1):907.

If the WASF3 study found one specific mechanism, this study tried to find all of them simultaneously. Published in Nature Communications in February 2024, it involved 75 investigators across 15 NIH institutes and centres, and at institutions across the US and internationally. Dr Avindra Nath, who led it, called it the most complex study he had ever been part of.

17 people with post-infectious ME/CFS and 21 healthy controls underwent one of the most comprehensive clinical and biological assessments ever applied to ME/CFS patients. Brain imaging. Immune profiling. Autonomic testing. Muscle function. Cardiorespiratory testing. Cognitive assessment. Metabolomics. The study was designed to capture the full biological phenotype rather than test a single hypothesis.

The autonomic findings were striking. ME/CFS participants had higher heart rates throughout the day. Their heart rate failed to drop normally overnight, the nocturnal dip that healthy people experience was blunted or absent. Heart and lung function showed reduced capacity to respond to exercise. These are objective, measurable, physiological differences, not symptom reports.

The immune findings were equally important. ME/CFS participants had higher levels of naive B cells and lower levels of switched memory B cells in the blood compared to healthy controls. This specific immune pattern suggests the immune system is failing to mount appropriate adaptive responses, the kind that help recognise and fight off pathogens the body has encountered before. The researchers proposed that the immune activation triggered by the initial infection is affecting the brain through downstream mechanisms, producing the motor, autonomic and cardiorespiratory dysfunction that characterises the condition.

One finding deserves particular attention: the data showed distinct differences between men and women with ME/CFS. The immune and clinical profiles diverged by sex in ways that suggest ME/CFS is not a single biological entity but a condition with sex-dependent pathophysiology. This has significant implications for both research design and treatment, and it is a finding that most small studies have been unable to detect.

The limitations are significant. 17 participants is a small number, and the study’s rigorous inclusion criteria meant that the most severely affected ME/CFS patients, those unable to attend the NIH Clinical Center for extended assessments, were excluded. The results reflect a specific, relatively early-stage, post-infectious phenotype. They may not represent all ME/CFS presentations. But the depth and rigour of what was done to those 17 people is without parallel in the ME/CFS literature, and the findings provide a foundation for larger, hypothesis-driven studies.

Study 3: The Largest Genetic Study of ME/CFS Ever Conducted

Ponting CP, et al. Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome. medRxiv preprint. August 2025.

I am a geneticist and I conduct GWAS studies as part of my own research. So I want to explain what was done here, why the scale matters, and what the findings actually mean, because genetics has a way of being either oversimplified or made incomprehensible in science communication, and this study deserves neither treatment.

A GWAS scans the entire genome across large numbers of cases and controls, looking for genetic variants that appear more frequently in those with the condition. The power of a GWAS is almost entirely determined by sample size. Rare variants, small effects, and heterogeneous conditions all require large numbers to detect signal above statistical noise. ME/CFS, being heterogeneous and historically underfunded, had never been subjected to a properly powered GWAS until this study.

DecodeME recruited 21,620 ME/CFS cases and 259,909 population controls with European genetic ancestry. This is a sample size that changes what is detectable. It is the difference between trying to spot a signal in static and having a clean frequency range. Funded with £3.2 million from the UK government and co-produced with patients and carers throughout, the study was published as a preprint in August 2025 and is currently undergoing peer review.

Eight genome-wide significant genetic loci were identified. Three of the most significant are located near genes involved in the response to viral and bacterial infection: BTN2A2, OLFM4 and RABGAP1L. This is not coincidental. ME/CFS is characterised by a post-infectious trigger in the majority of cases. Finding that genetic variants near infection-response genes are associated with increased risk of ME/CFS provides the first direct genetic evidence that the immune response to infection is not just a trigger but a biological vulnerability in people who go on to develop the condition.

Four of the eight loci were also associated specifically with cases where post-exertional malaise and fatigue were prominent features, which gives us confidence that the genetic signal is tracking the core features of ME/CFS rather than broader fatigue phenotypes.

The study found a broad global genetic correlation between ME/CFS and traits like insomnia, depression, and neuroticism. However, this requires careful interpretation: when looking at the specific causal risk genes discovered for ME/CFS, there was no direct overlap with depression. This genetic correlation maps vast shared biological networks, not a shared identity, meaning the findings likely point to common neurological and immune mechanisms rather than classifying ME/CFS as a psychological disorder.

The limitations are real and the authors are explicit about them. The sample was predominantly of European ancestry, limiting generalisability. The preprint has not yet completed peer review. As a GWAS of a heterogeneous condition, the eight loci identified likely represent the tip of a much larger genetic architecture. And GWAS identifies associations, not causes: the journey from a genome-wide significant locus to a therapeutic target is long and not guaranteed.

But this is the first time ME/CFS has been mapped genetically at a scale that gives the findings credibility. The signal is in the immune and infection-response biology. The condition is not a psychological phenomenon with a genetic component. It is a biological condition with genetic risk factors pointing toward its immune aetiology.

Honourable Mentions

Three other studies from this period have dedicated pieces on Dysautonomia Decoded. The Appelman biopsy study (Nature Communications, 2024) showed cellular damage, immune infiltration and mitochondrial decline in Long COVID muscle tissue one day after a crash, visible under a microscope (full article breakdown of this has been published, so give that a read!). The Singh brain microstructure study (Frontiers in Medicine, 2026) found microstructural differences in brain tissue in ME/CFS patients using advanced MRI. The Bergquist CSF proteomics study (Scientific Reports, 2026) found distinct protein signatures in spinal fluid linked to autonomic dysfunction and disease severity.

The Bigger Picture

A protein dismantling the mitochondria. A deep phenotyping study finding autonomic, immune and sex-specific abnormalities simultaneously. A genetic map pointing to infection-response biology. These are not the findings of a psychosomatic condition. They are specific, measurable, biologically coherent discoveries that converge on a picture of ME/CFS as a post-infectious, immune-mediated, neurologically expressed condition with a genetic substrate.

The research is moving faster than at any previous point in ME/CFS history. The treatments that this research will eventually generate are not yet here. But the scientific foundation for finding them is being built.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Wang PY, Ma J, Kim YC, et al. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proceedings of the National Academy of Sciences. 2023;120(34):e2302738120. https://doi.org/10.1073/pnas.2302738120

Walitt B, Nath A, et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nature Communications. 2024;15(1):907. https://doi.org/10.1038/s41467-024-45107-3

Ponting CP, et al. Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome. medRxiv preprint. 2025. https://doi.org/10.1101/2025.08.06.25333109

Appelman B, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature Communications. 2024;15:17. https://doi.org/10.1038/s41467-023-44432-3

Singh TB, et al. Microstructural alterations in brain tissue of ME/CFS and Long COVID. Frontiers in Medicine. 2026;13:1824498. https://doi.org/10.3389/fmed.2026.1824498

Bergquist J, Xiao W, et al. Proteomic signatures in cerebrospinal fluid in ME/CFS. Scientific Reports. 2026. https://doi.org/10.1038/s41598-026-46965-1

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The criteria were simple. The study had to be published between 2023 and 2026. It had to produce genuinely new knowledge rather than confirm what we already suspected.

Of course there are a lot of important research articles and all of the work is valuable as it aids advance our understanding… this is just my opinion!

Study 1: The First Genetic Map of PoTS

Qu H, Qu J, Chang X, et al. The genetic landscape of pediatric postural orthostatic tachycardia syndrome. Clinical Autonomic Research. 2025;35:431–451.

I am a geneticist and I conduct GWAS studies as part of my research. So when the first genome-wide association study of PoTS was published in February 2025, I read it differently to most people who cover this condition. And I want to explain exactly what was done, what was found, and why it is more significant than the headline numbers might suggest to someone without a genetics background.

A genome-wide association study, or GWAS, is a method for scanning the entire genome across large numbers of people with and without a condition, looking for genetic variants that appear more frequently in those with the condition. It is one of the most powerful tools in modern genetics, and it has transformed our understanding of conditions from schizophrenia to type 2 diabetes. But it has a fundamental requirement: a large, well-defined, homogeneous patient population. The bigger and cleaner the cohort, the more power the study has to detect signal above the statistical noise.

PoTS presents a specific challenge for GWAS that the authors address head-on. The condition is heterogeneous. Neuropathic PoTS, hyperadrenergic PoTS, hypovolemic PoTS, post-viral PoTS, they all meet the same diagnostic criteria but likely have different underlying mechanisms and therefore different genetic architectures. Running a GWAS on a mixed bag of subtypes is like trying to find the genetic signature of chest pain, the signal gets diluted by the heterogeneity before you can detect it. The authors acknowledge this directly and design their analysis accordingly.

Rather than trying to identify individual genome-wide significant loci, which would require sample sizes far beyond what was available for this rare condition, they took a gene-set analysis approach. Instead of asking which single genetic variant is associated with PoTS, they asked which biological pathways are enriched in PoTS patients. This is statistically appropriate and, in my view, the correct methodological choice for a phenotypically heterogeneous condition at this stage of genetic investigation.

The study recruited from the POTS Program at the Children’s Hospital of Philadelphia, one of the largest specialist paediatric PoTS programmes in the world. Two cohorts were used: a family cohort of 100 complete families and a case-control cohort of 207 unrelated cases compared with 4,063 ethnicity-matched controls. The whole exome sequencing component included 87 unrelated cases and 2,719 controls.

The common variant analysis identified 5,670 SNPs with nominal significance in both cohorts, pointing in the same direction. While none reached traditional genome-wide significance individually, 716 genes showed association at the gene level, far more than the 53 expected by chance. The over-representation analysis of those 716 genes pointed to gene sets involved in cell-cell junctions, synaptic membranes, transporter complexes, and early estrogen response as statistically enriched pathways in PoTS.

The estrogen response finding is particularly interesting. PoTS affects women at rates of up to 5 to 1 compared to men, and the connection with female sex hormones has been clinically observed but poorly understood at a molecular level. Finding early estrogen response genes overrepresented in a PoTS GWAS dataset provides a first molecular signal that the hormonal vulnerability of this condition may have a genetic basis.

The whole exome sequencing analysis was where the most striking findings emerged. By looking specifically at rare coding variants, the kind that have a larger individual effect on gene function but are too uncommon to detect by standard GWAS, the study identified 55 genes with genome-wide significance through burden analysis. These 55 genes tell a story that is coherent with what we know about PoTS clinically.

32 of the 55 genes are related to muscular function, specifically contractile fibre structure, extracellular matrix components, and cell-substrate junctions. This points toward skeletal muscle dysfunction, particularly in the calf muscle pump that drives venous return from the lower limbs, as a potential genetic contributor to PoTS. The calf muscle pump is one of the main mechanisms for pushing blood back toward the heart when standing. If its genetic architecture is subtly impaired in some PoTS patients, that would contribute directly to venous pooling on standing.

Multiple dynein axonemal heavy chain genes (DNAH1, DNAH2, DNAH3, DNAH10) appeared in the enriched gene sets, pointing toward microtubule dysfunction. Endothelial cell cilia, which depend on proper microtubule function, are increasingly recognised as sensors of blood flow. Dysfunction in endothelial cilia has been linked to vascular disorders including hypertension, and may contribute to the impaired vascular reactivity seen in PoTS.

43 of the 55 genes are associated with autism spectrum disorder in the GWAS catalog. This is a striking finding. Autonomic dysfunction is common in ASD, and there is increasing clinical recognition of co-occurrence between PoTS and neurodevelopmental conditions. The genetic overlap suggests a shared biological substrate that has implications both for understanding the aetiology of PoTS and for how we support patients who present with both conditions.

The limitations of this study are real and the authors are honest about them. The paediatric cohort from a single centre may not represent all PoTS presentations. The sample size limits the statistical power for individual variant detection. And the focus on European ancestry means findings may not generalise to other populations. Larger, multi-ancestry, multi-site GWAS studies in PoTS are urgently needed, and the findings here provide the gene-set hypotheses that future larger studies should explicitly test.

But this is the first genuinely systematic genetic investigation of PoTS, conducted with appropriate methodology for a heterogeneous condition, and its findings are biologically coherent with what we know. It is the starting point for the genetic understanding of this condition. A full dedicated piece decoding this study in even more detail is coming to Dysautonomia Decoded soon.

Study 2: The First Brain Scan Evidence That Brain Fog in PoTS Is Measurable

Seeley MC, et al. Novel brain SPECT imaging unravels abnormal cerebral perfusion in patients with postural orthostatic tachycardia syndrome and cognitive dysfunction. Scientific Reports. 2025;15:3487.

Brain fog is one of the most consistently reported and most consistently dismissed symptoms in PoTS. Researchers at the University of Adelaide used brain SPECT imaging in 56 PoTS patients who reported cognitive symptoms and found that 61% showed abnormal cerebral blood flow patterns. The regions most affected were the prefrontal cortex and sensorimotor cortex, the areas responsible for attention, decision-making and memory. Critically, abnormal perfusion was present even while patients were lying flat, not just on standing.

When the researchers modelled what was driving quality of life, the number of brain regions with abnormal blood flow accounted for 51% of the variance. Standing heart rate, the measure used to diagnose PoTS, accounted for none of that variance independently.

Brain fog is not a mood. It is measurable, visible on imaging, and directly linked to reduced cerebral perfusion. A full piece on this study is available on Dysautonomia Decoded.

Study 3: The Plasma Proteomics Study That Found 393 Differentially Expressed Proteins

Johansson M, et al. Plasma proteomics in postural orthostatic tachycardia syndrome reveals hypercoagulability, complement activation and increased adrenergic tone. Frontiers in Cardiovascular Medicine. 2023.

While study one addresses genetics and study two addresses brain imaging, this study went to the blood. Researchers from Lund University and the Karolinska Institute performed proteomics analysis on plasma samples from PoTS patients and matched healthy controls, identifying 393 differentially expressed proteins.

The PoTS samples showed evidence of a hypercoagulable state, complement activation, and increased adrenergic activity at the molecular level. This is not symptom data or imaging data. It is direct molecular evidence that PoTS is associated with measurable biological differences in the blood, spanning coagulation, immune activation, and autonomic signalling simultaneously.

The findings suggest that PoTS is not simply an autonomic condition with cardiovascular consequences. It involves broader systemic dysregulation that is detectable in the blood protein landscape. This also raises the genuine possibility that blood-based biomarkers could eventually be used for diagnosis or subtype stratification, though that work is at an early stage.

Honourable Mentions

Two other studies from this period have their own dedicated pieces on Dysautonomia Decoded.

The tilt table versus active stand comparison (Stiles, Raj et al., Autonomic Neuroscience, 2025) found that the same diagnostic threshold catches 98% of confirmed PoTS cases during a head-up tilt test but only 74% during an active stand test. Patients may receive very different results depending solely on which test they get.

The diagnostic bias study (Sediqi et al., JGIM, 2026) gave 1,027 physicians identical PoTS cases with only patient demographics changed. PoTS had the lowest diagnostic accuracy of all five conditions tested. Male physicians correctly diagnosed it in just 41.7% of cases.

The Bigger Picture

Three years ago the evidence base for PoTS was thin. The studies above represent a field genuinely moving in the right direction. Genetics is beginning to map inherited risk and biological pathways. Brain imaging is showing measurable neural abnormalities. Proteomics is identifying molecular signatures in the blood. And clinical research is documenting the systemic barriers that prevent patients from being diagnosed.

There is still no approved treatment for PoTS. The average diagnostic delay is still 7 years. But the science has never been more active, and the distance between where the research is and where clinical practice is has never been clearer.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Qu H, Qu J, Chang X, et al. The genetic landscape of pediatric postural orthostatic tachycardia syndrome. Clinical Autonomic Research. 2025;35:431–451. https://doi.org/10.1007/s10286-025-01110-2

Seeley MC, et al. Novel brain SPECT imaging unravels abnormal cerebral perfusion in POTS. Scientific Reports. 2025;15:3487. https://doi.org/10.1038/s41598-025-87748-4

Johansson M, et al. Plasma proteomics in postural orthostatic tachycardia syndrome. Frontiers in Cardiovascular Medicine. 2022. doi: 10.1038/s41598-022-24729-x

Stiles LE, Raj SR, et al. Physiological and clinical comparison of active stand and head-up tilt tests in POTS. Autonomic Neuroscience. 2025. https://doi.org/10.1016/j.autneu.2025.103281

Sediqi S, et al. Assessing the role of patient-physician sex concordance on diagnostic accuracy in primary care. Journal of General Internal Medicine. 2026. https://doi.org/10.1007/s11606-026-10670-6

Why the retina

The retina is the only place in the body where blood vessels can be observed non-invasively, in real time, without contrast agents or radiation. Retinal vessel analysis measures the diameter, function and response of these tiny vessels, and decades of cardiovascular research have established that retinal microvascular changes reliably predict systemic microvascular disease. Changes in retinal vessel diameter and function predict stroke risk, cardiovascular mortality and kidney disease with meaningful accuracy. The retina is essentially a window into the vascular health of the whole body, particularly the brain.

This is directly relevant to Long COVID and ME/CFS because persistent symptoms in both conditions, fatigue, brain fog, cognitive impairment, autonomic dysfunction, are increasingly linked to what is happening in the brain’s small blood vessels. If the brain is not getting enough blood, or if the blood vessels regulating its supply are not functioning properly, the symptoms that result look very much like the ones these patients experience.

What the All Eyes on PCS study actually did

The study, published in BMC Medicine in August 2026 by Wallraven, Günthner and colleagues at the Technical University of Munich and Charité Berlin, recruited 102 post-COVID syndrome patients and compared them with 204 age and sex matched healthy controls. This is a prospective, observational case-control design, which is a substantially stronger evidence base than the retrospective or self-report studies that dominate this space.

Participants underwent retinal vessel analysis measuring both static parameters (the diameter of arterioles and venules) and dynamic parameters (how vessels dilate in response to flickering light, a standardised stimulus called flicker light-induced retinal vasodilation). They also had blood tests for inflammatory and endothelial dysfunction markers including von Willebrand factor, soluble thrombomodulin and various cytokines. A subset of 20 patients with ME/CFS were also included for comparison.

What they found

Post-COVID patients showed significantly impaired retinal vessel dilation in response to flickering light compared to healthy controls. This is the dynamic functional measure, not just the structural diameter, and it reflects the ability of blood vessel walls to dilate appropriately in response to increased demand. Impaired retinal vessel dilation in this test is a marker of endothelial dysfunction, meaning the cells lining the inside of the blood vessels are not responding properly.

The severity of retinal microvascular changes correlated significantly with symptom severity. Patients with more severe post-COVID symptoms showed worse retinal vessel function than those with milder presentations. Neurocognitive symptoms including fatigue, impaired concentration and brain fog were specifically linked to worse retinal microvascular markers, consistent with the hypothesis that endothelial dysfunction contributes directly to the central nervous system manifestations of post-COVID syndrome.

Circulating markers of endothelial dysfunction and inflammation were elevated in post-COVID patients compared to healthy controls, and these markers correlated with both symptom severity and the retinal findings.

The ME/CFS subgroup showed similar retinal microvascular changes to post-COVID patients, suggesting shared underlying mechanisms. This is consistent with the Harvard comparison study published earlier in 2026, which found that Long COVID and ME/CFS patients were essentially indistinguishable on detailed autonomic testing.

The microclotting connection

These findings sit within a larger picture of microvascular dysfunction in post-COVID and ME/CFS that has been building in the research literature over the past four years. Professor Etheresia Pretorius at Stellenbosch University and colleagues have documented fibrin amyloid microclots in the blood of Long COVID patients, tiny, abnormally resistant clots that may impede blood flow through the smallest vessels. A 2024 analysis of ME/CFS plasma found dysregulated coagulation, endothelial dysfunction and downregulation of complement machinery. The Wallraven study adds retinal microvascular evidence to this picture, showing that the endothelial dysfunction is not just detectable in blood markers but visible in the functioning of real blood vessels in real patients.

Put together, the emerging picture is of a post-viral state in which the cells lining blood vessel walls throughout the body, and particularly in the brain’s microvasculature, are failing to function normally. Blood vessel dilation is impaired. Inflammatory markers are elevated. Coagulation is dysregulated. And these changes are detectable years after the initial infection in patients who had a relatively mild acute illness.

What this might mean for treatment

The authors note that endothelial function is a potential therapeutic target. Several interventions that improve endothelial function in other contexts, including exercise in those who can tolerate it, certain medications used in cardiovascular disease, and anti-inflammatory approaches, are already being studied in Long COVID and ME/CFS. The retinal vessel analysis framework could provide a non-invasive, accessible way of tracking whether those interventions are actually improving microvascular health, rather than relying solely on subjective symptom reports.

A separate 2024 study found that 41% of post-acute COVID syndrome patients had microvascular dysfunction detectable over two years after a mild initial infection, and that its presence was associated with increasing NT-proBNP levels over time, a marker of cardiovascular stress and potential cardiac remodeling. The scale and persistence of the vascular problem is becoming increasingly hard to dismiss.

The limitations worth naming

This is a single-centre study conducted in Munich, and the patient population attending a specialist post-COVID clinic may not be representative of all Long COVID presentations. The ME/CFS subgroup was small at 20 patients, limiting the conclusions that can be drawn from that comparison. The cross-sectional nature of the main analysis means it captures a snapshot rather than tracking how vascular function changes over time. And retinal vessel analysis, while validated, requires specialist equipment and trained operators that are not widely available in routine clinical settings.

The study also cannot yet tell us whether the endothelial dysfunction causes symptoms, is a consequence of other processes, or is one component of a multi-system dysfunction in which cause and effect are deeply entangled.

The take home message

Researchers looked into the eyes of Long COVID patients and found that the tiny blood vessels in their retinas are not functioning properly, in ways that correlate directly with the severity of their symptoms. The same findings appear in ME/CFS. The changes are detectable years after a mild infection. And they point toward the blood vessel lining itself as a potential site of disease and a potential target for treatment.

This is not in the mind. It is in the microvasculature.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Wallraven T, Günthner R, Lethen I, et al. Microvascular remodeling and endothelial dysfunction across the post-COVID-19 spectrum: a prospective observational case-control study. BMC Medicine. 2026;24(1):456. https://doi.org/10.1186/s12916-026-05144-9

Nunes M, Vlok M, Proal A, Kell DB, Pretorius E. Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery. Cardiovascular Diabetology. 2024;23:254. https://doi.org/10.1186/s12933-024-02315-x

Novak P, Systrom DM, et al. Shared autonomic phenotype of Long COVID and ME/CFS. PLOS ONE. 2026;21(1):e0341278.

American Journal of Medicine. Post-acute COVID-19 syndrome: prevalence of peripheral microvascular endothelial dysfunction and associations with NT-proBNP dynamics. 2024. https://doi.org/10.1016/j.amjmed.2024.09.022

Researchers at Stanford gave 1,027 primary care physicians across the United States identical clinical vignettes for five conditions: PoTS, Hashimoto’s thyroiditis, multiple sclerosis, syphilis and lupus. The only thing that changed between versions was the patient’s randomly assigned sex and race. Everything else, the symptoms, the test results, the history, was held completely constant. Then they asked the physicians to diagnose what was wrong.

PoTS had the lowest diagnostic accuracy of all five conditions. And the gap between male and female physicians was the largest for PoTS of any condition in the study.

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What beta blockers do

Beta blockers work by blocking beta-adrenergic receptors, the sites on the heart and blood vessels that respond to adrenaline and noradrenaline. When these receptors are blocked, the heart beats more slowly and with less force. The excessive heart rate on standing, the defining feature of PoTS, is reduced.

There are two main types worth knowing. Non-selective beta blockers, such as propranolol, block both beta-1 receptors (predominantly in the heart) and beta-2 receptors (in blood vessels, airways and elsewhere). Cardioselective beta blockers, such as bisoprolol and metoprolol, preferentially block beta-1 receptors. This distinction matters because blocking beta-2 receptors can cause peripheral vasoconstriction, bronchospasm in asthmatic patients, and metabolic effects that are absent with cardioselective agents.

In PoTS, propranolol is the most commonly prescribed and the most studied and bisoprolol is frequently used in the UK as an alternative.

What the evidence actually shows

Vanderbilt University, one of the leading autonomic research centres globally, conducted a placebo-controlled trial showing that low-dose propranolol (20mg) significantly reduced standing heart rate and improved symptoms in PoTS patients. Crucially, they found that low doses worked better than high doses. High-dose propranolol lowered heart rate effectively but did not improve symptoms and in some cases made exercise capacity worse. This is a finding that has not been widely communicated to prescribing clinicians.

A 2018 Korean randomised clinical trial compared propranolol, bisoprolol and pyridostigmine directly in 77 PoTS patients over three months. All three groups showed significant improvements in orthostatic intolerance scores, depression scores and quality of life. The beta blockers performed similarly to each other, though the trial was not designed to detect subtle between-drug differences.

A 2025 systematic review in Frontiers in Neurology pulled together 21 randomised trials covering approximately 750 patients across more than two decades of PoTS treatment research. Its conclusion was measured: propranolol, along with midodrine and ivabradine, has the strongest evidence base in PoTS, but the overall evidence is not yet strong enough to firmly establish which drugs should be used as first-line treatments. Large properly powered trials are still lacking.

A 2026 crossover trial compared propranolol, ivabradine and placebo directly in the same patients. Both active drugs reduced standing heart rate to a similar degree. Neither clearly outperformed the other on symptom measures, though ivabradine showed some advantages in quality of life scores. The question of which drug to reach for first remains genuinely open.

When beta blockers can make things worse

This is the part of the conversation that gets left out of most prescribing discussions.

Beta blockers can reduce plasma renin activity, which affects the kidney’s ability to retain fluid. In patients whose PoTS is primarily driven by low blood volume, this effect can reduce circulating volume further and worsen orthostatic intolerance rather than improve it. This connection is mechanistically sound but has not been directly studied in PoTS patients specifically. If a patient’s standing blood pressure is already low, adding a drug that further reduces cardiac output is unlikely to help and may genuinely harm.

Non-selective beta blockers including propranolol also block beta-2 receptors in peripheral blood vessels. In some patients this causes increased peripheral vascular resistance, which can make extremities feel cold and heavy and may contribute to worsening of the livedo-like discolouration some PoTS patients experience in their legs on standing.

Perhaps most clinically important is the hyperadrenergic PoTS picture. Hyperadrenergic PoTS is characterised by excessive sympathetic nervous system activity, elevated standing noradrenaline levels, a tendency for blood pressure to rise rather than fall on standing, and symptoms including tremor, anxiety-like sensations and sweating alongside the usual palpitations and dizziness. On the surface, this sounds like exactly the condition that beta blockers are designed for: block the adrenaline, calm the system, reduce the heart rate.

In practice, the picture is more complicated. The sympathetic overdrive in hyperadrenergic PoTS is often a compensatory response to an underlying problem, whether that is autoimmune autonomic dysfunction, mast cell activation, or central nervous system dysregulation. Blocking the adrenaline addresses the symptom without touching the underlying driver. In some patients this produces acceptable symptomatic relief. In others, particularly those where the sympathetic activation is serving as a compensation for poor venous return, blocking it removes a necessary adaptation and worsens overall function.

Vanderbilt specifically notes that beta blockers can aggravate orthostatic intolerance in patients with a low blood pressure phenotype. The contraindication is not universal but it is real, and it is frequently not considered at the point of prescription.

The dose question

The evidence consistently points toward low doses performing better than high doses in PoTS. Raj et al. at Vanderbilt found symptoms improved more with 10mg propranolol than with 20mg. Higher doses blunted the heart rate more effectively but did not improve how patients felt, and in some cases reduced exercise capacity.

This finding runs directly against the instinct to titrate upward when a treatment is not working. In PoTS, if a low dose of propranolol is not producing the desired effect, the answer may not be to increase the dose. It may be to reconsider whether propranolol is the right drug for this patient’s subtype.

The cardioselectivity question

For patients who have asthma, chronic obstructive pulmonary disease, or who experience significant peripheral side effects from propranolol, cardioselective alternatives such as bisoprolol and metoprolol are the appropriate next step. The head-to-head evidence in PoTS does not show a significant difference in efficacy between propranolol and bisoprolol. The difference lies in tolerability and side effect profile.

What this means practically

Beta blockers remain a reasonable first-line option for most PoTS presentations, particularly where the heart rate is elevated on standing without significant blood pressure changes. Low doses are better supported than high doses. If symptoms worsen, blood pressure drops, or the patient has features of low blood volume PoTS, beta blockers should be reconsidered rather than increased.

If you are on a beta blocker and feel worse than before, that is a valid and documented phenomenon, not an unusual reaction or a failure to tolerate a drug that should work. It is worth asking explicitly which PoTS subtype your clinician suspects you have and whether that subtype is supported by the evidence to benefit from beta blockade.

The most common reason beta blockers fail in PoTS is not that the drug does not work. It is that the drug is being used for a subtype it was not designed to address.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Raj SR, et al. Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more. Circulation. 2009;120(9):725-734. https://doi.org/10.1161/CIRCULATIONAHA.108.846501

Moon J, Kim DY, Lee WJ, et al. Efficacy of propranolol, bisoprolol, and pyridostigmine for postural tachycardia syndrome: a randomized clinical trial. Neurotherapeutics. 2018;15(3):785-795. https://doi.org/10.1007/s13311-018-0612-9

Pierson BC, et al. Oral medications for the treatment of postural orthostatic tachycardia syndrome: a systematic review. Frontiers in Neurology. 2025;15:1515486. https://doi.org/10.3389/fneur.2024.1515486

Raj SR, et al. Canadian Cardiovascular Society position statement on postural orthostatic tachycardia syndrome and related disorders of chronic orthostatic intolerance. Canadian Journal of Cardiology. 2020;36(3):357-372. https://doi.org/10.1016/j.cjca.2019.12.024

JACC: Advances. A randomized crossover trial of ivabradine, propranolol, and placebo in postural orthostatic tachycardia syndrome. 2026. https://doi.org/10.1016/j.jacadv.2026.102795

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What the study did

The research team, led by Dr David Putrino at Mount Sinai School of Medicine and including Dr Akiko Iwasaki at Yale and Dr Amy Proal at PolyBio Research Foundation, analysed data from 4,244 participants with Long COVID, ME/CFS and other complex chronic conditions who had used the Visible app. This is the largest dataset of its kind by a significant margin.

Each morning, participants recorded three biometric measures using the Visible wristband: heart rate, heart rate variability (HRV), and breathing rate. Each evening they reported the severity of three core symptoms: brain fog, crashes, and fatigue.

The researchers then asked a specific question: can morning biometric data predict how someone feels that evening, beyond what their previous day’s symptoms would already tell you?

What they found

HRV data could predict crashes in individuals with quite good accuracy, though your data was good at predicting your own patterns of crashing rather than other people’s crash patterns. This distinction matters enormously. The model is personalised, not population-level.

Within-person increases in heart rate and decreases in HRV in the morning were associated with worsening symptom reports in the evening. In plain terms: if your HRV drops and your resting heart rate rises in the morning, that morning signal predicts a harder evening, before the evening has happened.

The models that combined morning biometrics with the previous evening’s symptom reports performed significantly better than models using either type of data alone. The most predictive window was morning biometrics, which outperformed biometrics measured throughout the day. There appears to be something specifically meaningful about the morning physiological state as a predictor of how the day will unfold.

Why HRV specifically

Heart rate variability is the variation in time between consecutive heartbeats. It is not the same as heart rate. High HRV generally indicates a well-regulated nervous system with good parasympathetic activity. Low HRV suggests sympathetic dominance, reduced autonomic flexibility, and often correlates with poor recovery, stress, or illness.

In ME/CFS and Long COVID, HRV is consistently reduced compared to healthy controls. The autonomic nervous system in these conditions is operating with less flexibility and less capacity to adapt to demands. What this study shows is that on days when HRV drops further than a person’s own baseline, something measurable is happening that predicts worsening symptoms later that day. The body is giving a signal before the crash arrives.

Why the personalised aspect matters so much

One of the most important findings is that the predictions were individualised. Your HRV pattern predicting your crashes is not the same as a population-level average predicting everyone’s crashes. This fits with everything we know about ME/CFS and Long COVID: the conditions are heterogeneous, individual thresholds vary enormously, and what constitutes a warning signal for one person may be meaningless for another.

This has direct implications for how wearable data should be used in clinical and self-management contexts. A blanket threshold, “HRV below 50 means you’ll crash,” is not what this study supports. What it supports is that your own morning data, tracked consistently over time, can become a meaningful personalised predictor of your own symptom trajectory. That is a meaningful step forward from the current situation where most people are flying blind.

The connection to pacing

This study connects directly to the pacing principle we have discussed in previous pieces. Pacing in ME/CFS and Long COVID means staying within your individual energy envelope to avoid triggering post-exertional malaise. The problem has always been that identifying the envelope is difficult, subjective, and usually only apparent in retrospect, after the crash has already happened.

If morning biometric data can reliably predict worsening symptoms before they occur, even with modest accuracy, that has real potential as a pacing tool. Not perfect, not universal, but a data-driven signal that could help people make more informed decisions about activity before they have already overcommitted.

What this study cannot yet tell us

The study is observational. It can identify correlations between morning HRV and evening symptoms but cannot tell us why the relationship exists or whether intervening on the signal would change the outcome. Knowing a crash is likely and being able to prevent it are different things, and this study addresses the first but not the second.

The data comes from Visible app users, a self-selected population who have already sought out wearable technology for their condition management. This group may differ from people with ME/CFS and Long COVID who are not using wearables, potentially being more engaged with self-monitoring or having different symptom profiles.

The findings also vary in how well they predict across individuals. For some participants the morning signal was highly predictive. For others the relationship was weaker. The study cannot yet tell us which characteristics predict who will benefit most from this kind of monitoring.

What it means practically

If you are using a wearable and tracking symptoms, the morning HRV reading may be more informative than you realise. A lower-than-usual HRV in the morning, particularly combined with a higher-than-usual resting heart rate, appears to be a signal worth paying attention to before planning activity for the day.

This does not mean you need the Visible app specifically. Any wearable that measures HRV, and most modern smartwatches do, combined with consistent daily symptom tracking, gives you the raw data to start noticing your own patterns. The key word throughout this research is within-person. The comparison point is your own baseline, not a population average.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Aitken A, Sawyer A, Iwasaki A, et al. Digital physiological biomarkers predict within-person symptom changes in complex chronic illness. npj Digital Medicine. 2026;9:257. https://doi.org/10.1038/s41746-026-02543-3

Sawyer A, Preston R, Leeming H, et al. Wearable technology in the management of complex chronic illness: preliminary survey results on self-reported outcomes. Frontiers in Digital Health. 2025;7:1662255. https://doi.org/10.3389/fdgth.2025.1662255

Appelman B, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature Communications. 2024;15:17. https://doi.org/10.1038/s41467-023-44432-3

A 2024 study published in Healthcare by van Campen, Rowe, Verheugt and Visser, with co-authorship from Johns Hopkins University, looked directly at what happens to brain blood flow and cardiac output during tilt testing in ME/CFS and PoTS patients whose heart rate and blood pressure responses appear completely normal. What they found dismantles a core assumption in how these conditions are currently tested and diagnosed.

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What is cerebrospinal fluid and why does it matter

Cerebrospinal fluid, or CSF, is produced continuously by the brain, circulates around the brain and spinal cord, and drains back into the bloodstream. It carries nutrients, removes waste products, and provides a window into what is happening in the central nervous system in a way that blood tests simply cannot. Changes in CSF protein levels are used to diagnose conditions like multiple sclerosis, meningitis, Alzheimer’s disease, and Guillain-Barré syndrome.

ME/CFS strongly involves the central nervous system. Cognitive impairment, autonomic dysfunction, neuroinflammation and brain inflammation are core features of the condition. The question this study asked was: if we look directly into the fluid surrounding the brain and spinal cord of people with ME/CFS, what do we actually find?

What the study did

Researchers led by Dr Jonas Bergquist at Uppsala University in Sweden, in collaboration with Dr Wenzhong Xiao at Harvard Medical School, analysed CSF samples from 31 people diagnosed with ME/CFS. They identified and quantified 902 proteins in the fluid and then looked for patterns associated with two things: disease severity (mild, moderate, severe) and whether patients also had PoTS.

This is a genuinely sophisticated piece of work. Rather than looking for one or two specific proteins, they mapped the full protein landscape of the CSF and then asked which biological pathways were being activated or suppressed depending on how sick someone was and whether their autonomic nervous system was also involved.

What they found in PoTS patients

In ME/CFS patients who also had PoTS, two pathways were significantly enriched compared to those without PoTS: neutrophil degranulation and platelet activation.

Neutrophils are the most abundant white blood cells in the body, the first responders of the immune system. When they degranulate, they release a burst of inflammatory chemicals designed to destroy pathogens. Finding enriched neutrophil degranulation pathways in the CSF suggests an active inflammatory response happening in or around the central nervous system specifically in the subgroup of ME/CFS patients who also have autonomic dysfunction.

Platelet activation is part of the blood clotting cascade. Activated platelets aggregate and promote clot formation. In the CSF context, enriched platelet activation pathways suggest a prothrombotic, or clot-promoting, environment in the fluid surrounding the brain. This fits with the emerging microclotting hypothesis in Long COVID and ME/CFS, where tiny clots in the microvasculature are thought to impede blood flow and nutrient delivery to tissues including brain tissue.

What they found in severe cases

In patients with the most severe ME/CFS, several additional pathways were enriched that are worth unpacking carefully because some of the language here is alarming and deserves context.

The complement cascade was enriched in severe cases. The complement system is part of the innate immune system that enhances the ability of antibodies and phagocytic cells to clear pathogens. When it is activated chronically in the wrong context it can cause significant tissue damage. Complement dysregulation has been found in Long COVID, Alzheimer’s disease, and several autoimmune conditions.

Coagulation-related pathways were also enriched, specifically the formation of fibrin clot pathways. This again points toward a prothrombotic environment in the CSF of the most severely affected patients.

Then there is the Alzheimer’s related finding. The study found enrichment of Alzheimer’s disease related neuronal degeneration markers in severe ME/CFS CSF. This needs to be stated with precision: this does not mean ME/CFS patients are developing or will develop Alzheimer’s disease. What it means is that proteins associated with the neurodegenerative processes seen in Alzheimer’s disease, proteins involved in neuronal damage, protein misfolding, and inflammatory neurodegeneration, appear to be elevated in the spinal fluid of people with the most severe ME/CFS presentations.

This is a finding that demands replication and much more investigation before any clinical conclusions can be drawn.

Why this is significant for the broader picture

Previous work by Bergquist’s group found that approximately 8 in 10 ME/CFS patients have abnormalities in craniocervical structures, the junction between the skull and the top of the spine. These abnormalities can increase CSF pressure and impair its flow, potentially concentrating inflammatory proteins in the fluid rather than allowing them to drain normally. This study’s findings fit into that framework: if CSF flow is impaired and inflammatory processes are active, proteins associated with immune activation, coagulation and neurodegeneration would accumulate.

The fact that different protein signatures are associated with PoTS status versus severity also supports the idea that ME/CFS is not one condition but a cluster of overlapping pathophysiological processes, exactly the kind of mechanistic heterogeneity that makes both diagnosis and treatment so difficult.

What this study cannot tell us

Thirty-one patients is a very small sample. The findings are hypothesis-generating rather than definitive. There is no healthy control group in this study, which means we cannot confirm that these protein patterns are absent in healthy people or present only in ME/CFS rather than in other neurological conditions. The cross-sectional design means we do not know whether these protein changes cause symptoms or are a consequence of them. And CSF sampling via lumbar puncture is invasive, which makes large-scale replication studies difficult to run.

None of this diminishes the importance of the findings. It contextualises them.

The take home message

Something measurable, specific, and biologically meaningful is happening in the cerebrospinal fluid of ME/CFS patients. The protein signatures differ depending on severity and on whether autonomic dysfunction is also present. The pathways implicated, immune activation, coagulation, neurodegeneration, are not the pathways of a psychosomatic condition. They are the pathways of a biological disease affecting the central nervous system.

For a condition that has spent decades being dismissed as psychological, each study that finds objective, measurable, central nervous system involvement is not just scientifically interesting. It is politically and clinically necessary.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Bergquist J, Xiao W, et al. Proteomic signatures in cerebrospinal fluid and their clinical associations in patients with ME/CFS. Scientific Reports. 2026. https://doi.org/10.1038/s41598-026-46965-1

Tronstad K, et al. Widespread differences in circulating blood proteins in ME/CFS. University of Bergen. 2026.

Cervia-Hasler C, et al. Persistent complement dysregulation with signs of thromboinflammation in active Long COVID. Science. 2024;383:eadg7942.

Today let’s decode a study published just two weeks ago in Frontiers in Medicine that did something quietly significant. It took patients with ME/CFS and patients with Long COVID, gave them an MRI and used two different advanced imaging techniques to look at the microscopic structure of their brain tissue. Not function, not blood flow, not activation patterns, but the actual physical integrity of the tissue itself.

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1. REGN7544 (Regeneron monoclonal antibody)

Stage: Phase 2 trial, currently recruiting

What it is: REGN7544 is a monoclonal antibody developed by Regeneron that targets NPR1, a receptor involved in regulating blood volume and cardiovascular function. When NPR1 is blocked, the body retains more fluid, which directly addresses the hypovolemic component of PoTS.

The evidence: Phase 1 results showed REGN7544 durably increased blood pressure by 5 to 10mmHg and produced biomarker changes consistent with increased plasma volume. No major safety signals were identified. The Phase 2 trial (NCT06593600) is now recruiting adults with confirmed PoTS across US and Canadian sites.

Pros: This is one of the first pharmaceutical company-led trials designed specifically for PoTS rather than repurposing an existing drug. The mechanism is targeted and biologically coherent. Phase 1 safety data is reassuring.

Cons: Results are not expected until at least 2027. The trial requires participants to stop most existing PoTS medications, which is a significant barrier for those who are managing. And targeting only the hypovolemic mechanism means it may not help patients whose PoTS is primarily neuropathic or hyperadrenergic.

2. IVIG (intravenous immunoglobulin)

Stage: Phase 2 trial completed (iSTAND), results pending

What it is: IVIG is a pooled immunoglobulin preparation derived from thousands of healthy donors. It modulates the immune system, which is relevant to PoTS given the growing evidence for autoimmune mechanisms in a subset of patients. It has been used in autoimmune neurological conditions for decades.

The evidence: A retrospective analysis of 38 patients with refractory autoimmune dysautonomias found that 84.5% improved with IVIG treatment. The iSTAND trial (NCT03919773), the first double-blind randomised controlled trial of IVIG specifically in PoTS, completed in 2023 at UT Southwestern. Results are pending publication. Multiple case series describe significant symptom reduction, with some patients able to reduce or discontinue oral medications.

Pros: Long established safety profile in other conditions. Targets the autoimmune mechanism rather than just managing symptoms. Some patients report transformative improvement.

Cons: Extremely expensive, often in the range of thousands of pounds per infusion, and rarely funded by NHS or insurance without a confirmed autoimmune diagnosis. Infusion-related side effects including headache, nausea and fatigue are common. Supply is limited as it is derived from human donors. And we do not yet know which PoTS patients are most likely to respond, likely those with confirmed autoimmune features, but this is not routinely tested for.

3. Subcutaneous immunoglobulin (SCIG)

Stage: Case series, no RCT yet

What it is: SCIG delivers the same immunoglobulin therapy as IVIG but via self-administered subcutaneous injections at home rather than hospital infusions. This is a significant practical advantage for patients who struggle to attend hospital appointments.

The evidence: A 2022 case series published in Neurology followed seven patients with severe, treatment-refractory PoTS treated with either SCIG or therapeutic plasma exchange. All seven improved, with an average 50% reduction in COMPASS-31 autonomic symptom scores and a 217% improvement in functional ability scores. Six of seven were able to reduce or stop oral medications. Five returned to work or school.

Pros: Home administration, better tolerability than IVIG in some patients, same mechanism. The functional improvement data from this case series is striking.

Cons: Seven patients. This is a very small case series and the results, however dramatic, cannot be generalised without proper controlled trials. No RCT exists. Access is extremely limited and the autoimmune evidence base for PoTS remains in development.

4. Therapeutic plasma exchange (TPE/plasmapheresis)

Stage: Case series and retrospective studies, no RCT

What it is: TPE physically removes plasma from the blood and replaces it with donor plasma or albumin solution. The idea is to remove circulating autoantibodies that may be driving autonomic dysfunction in a subset of patients.

The evidence: A 2025 paper in Cureus reviewed the evidence for TPE in PoTS and found consistent signals of benefit in patients with severe, refractory disease and suspected autoimmune involvement. The same case series cited above found significant improvements in two patients treated with plasmapheresis specifically.

Pros: Can produce rapid improvement in patients where autoantibodies are a primary driver. For severe, refractory cases it offers a mechanism that oral medications simply cannot address.

Cons: Invasive, requiring repeated sessions via central line access. Expensive. Effects may be temporary as autoantibodies regenerate, requiring ongoing treatment. Almost never available on the NHS for PoTS. Evidence remains at the case series level only.

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5. Low dose naltrexone (LDN)

Stage: Pilot RCT at University of Calgary, recruiting 2026, results expected 2030

What it is: At doses of 1 to 4.5mg (a fraction of the standard opioid antagonist dose), naltrexone appears to reduce neuroinflammation via TLR4 receptor antagonism and upregulate endogenous opioid production. We decoded this in detail in a previous piece.

The evidence: A 2023 Cleveland Clinic case series showed meaningful improvement in autonomic symptom burden. A 2025 Cureus review of 29 dysautonomia patients found reduced pain and autonomic symptom scores. A 2025 systematic review in Long COVID found consistent signals for fatigue, PEM and brain fog.

Pros: Inexpensive (compared to other options), widely available off-label, well tolerated, anti-inflammatory mechanism is plausible and increasingly supported.

Cons: No RCT specifically in PoTS yet. The Calgary trial results are not expected until 2030. We do not know which patients are most likely to respond and there are patients for whom it does not work or causes sleep disturbance.

6. Semaglutide (GLP-1 receptor agonist)

Stage: Single case report showing benefit (2026), no trial

What it is: Originally a diabetes and weight management drug, semaglutide crosses the blood-brain barrier and appears to have neuroprotective and anti-inflammatory effects via GLP-1 receptors in the autonomic nervous system. We decoded this in our most recent piece.

The evidence: A 2026 case report in Clinical Autonomic Research described significant improvement in PoTS symptoms following semaglutide. The proposed mechanism involves reduction of neuroinflammation in autonomic brain regions. Contrast with tirzepatide (dual GLP-1/GIP agonist) which worsened symptoms in another patient via vasodilatory GIP receptor effects.

Pros: Already widely prescribed, relatively accessible, plausible anti-inflammatory mechanism, may benefit patients with neuroinflammatory PoTS.

Cons: Single case report. This is the weakest evidence level of anything on this list. Should not be used as a PoTS treatment without significant further research. And it may actively harm some patients depending on subtype.

7. Vagus nerve stimulation (transcutaneous auricular)

Stage: Small RCT published 2024, larger trial underway

What it is: A clip attached to the ear delivers gentle electrical stimulation to the vagus nerve via the tragus, boosting parasympathetic activity and reducing sympathetic overdrive. We decoded the ear clip trials in detail previously.

The evidence: A 2024 RCT of 57 post-COVID PoTS patients found significant reductions in postural tachycardia at one month, maintained at one year follow-up. A larger trial combining vagus nerve stimulation with slow-paced breathing is underway.

Pros: Non-invasive, drug-free, home-administered, durable effects in the published trial. The physiological rationale is well understood and directly addresses the sympathetic-parasympathetic imbalance at the core of PoTS.

Cons: 57 patients, single centre. The device used (Parasym) is commercially available but expensive and not NHS-funded for PoTS. The one-year durability finding is encouraging but needs replication in larger samples.

8. Creatine supplementation

Stage: Feasibility study 2024, small RCTs in Long COVID 2024 to 2025

What it is: Creatine replenishes phosphocreatine stores, supporting cellular energy production at the mitochondrial level. Relevant to PoTS given the evidence for mitochondrial dysfunction in post-viral dysautonomia and ME/CFS.

The evidence: A 2024 MRS brain imaging study showed measurable increases in brain creatine after 16g daily supplementation in ME/CFS patients, alongside self-reported improvements in fatigue and cognition. A 2025 trial in Long COVID found 4 weeks of 6g daily creatine significantly reduced fatigue and increased grip strength.

Pros: Inexpensive, widely available, excellent long-term safety record, directly addresses a documented mechanism.

Cons: No RCT in PoTS specifically. The evidence is in ME/CFS and Long COVID populations. The right dose, timing and duration for PoTS is unknown. Some patients report initial worsening, possibly due to metabolic shifts in an already dysregulated system.

9. Time restricted eating (TRE)

Stage: Open-label pilot study published 2025, larger trials needed

What it is: Limiting food intake to an 8 to 10 hour window daily without changing what is eaten. The proposed mechanism involves reduced inflammation, improved mitochondrial function, and better autonomic regulation via circadian rhythm entrainment.

The evidence: A 2025 Scientific Reports pilot study of 20 PoTS patients found an average 11 bpm reduction in standing heart rate, significant improvements in fatigue, GI symptoms, insomnia and exhaustion, and measurable increases in mitochondrial ATP production. The effect on heart rate was comparable in magnitude to some pharmacological interventions.

Pros: Free, low risk, no prescription required, addresses multiple mechanisms simultaneously.

Cons: 20 patients, no control group, improvements not sustained long term in other populations, and individual tolerance varies significantly particularly in patients with GI symptoms or disordered eating history.

10. Antihistamines (particularly H1 and H2 combined)

Stage: RCT published July 2026 (Lancet), earlier case reports

What it is: H1 blockers (cetirizine, loratadine, fexofenadine) and H2 blockers (famotidine) reduce histamine-mediated vasodilation and mast cell-driven inflammation. Particularly relevant in patients with MCAS overlap.

The evidence: A July 2026 Lancet Infectious Diseases RCT of nearly 800 Long COVID patients found a small but real additional benefit from famotidine-loratadine combination at 12 weeks compared to specialist care alone, though this was not sustained at 24 weeks. Earlier case reports described near-complete symptom resolution in some Long COVID patients following antihistamines, and the mechanism is coherent for patients with MCAS features.

Pros: Cheap, over the counter, excellent safety profile, immediately accessible, worth trying under clinical supervision particularly if symptoms fluctuate with food, alcohol, heat or menstrual cycle.

Cons: The Lancet benefit was modest and not sustained. Effect likely limited to patients with a histamine or mast cell component. Not a standalone treatment.

The honest summary

The PoTS treatment pipeline is more active than it has ever been, driven largely by the surge in post-COVID cases that has finally forced this condition into properly funded research. But none of the 10 treatments above has yet crossed the threshold of large-scale, properly controlled, replicated evidence specifically in PoTS. The strongest candidates are those that target the autoimmune mechanism (IVIG, SCIG, TPE) for a specific subset of patients, and those that are safe, accessible, and mechanistically coherent enough to try under clinical supervision while the larger trials complete (LDN, creatine, antihistamines, TRE).

The treatments furthest away are those in early phase trials (REGN7544). The treatments most likely to reach clinical practice first are those already used off-label with a growing evidence base.

If any of the above are relevant to your situation, the right move is always to raise them explicitly with your clinician rather than self-initiating, particularly for immunotherapies, which carry real risks and require careful patient selection.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

REGN7544 Phase 2 trial for POTS (PINNACLE). NCT06593600. ClinicalTrials.gov. Frontiers

Schofield JR, Chemali KR. Intravenous immunoglobulin therapy in refractory autoimmune dysautonomias: a retrospective analysis of 38 patients. American Journal of Therapeutics. 2019;26(5):e570-582.

Nelson C, Kesterson S, Schofield J, Blitshteyn S. Immunotherapy with subcutaneous immunoglobulin or plasmapheresis in patients with postural orthostatic tachycardia syndrome. Neurology. 2022.

Baykara et al. Therapeutic plasma exchange in postural tachycardia syndrome. Cureus. 2025;17(9):e91804.

Blitshteyn S, Suresh S, Lorenzi LM. Significant improvement of postural orthostatic tachycardia syndrome with semaglutide: a case report. Clinical Autonomic Research. 2026;36:315-317.

Stavrakis S, et al. Noninvasive vagus nerve stimulation in postural tachycardia syndrome. JACC: Clinical Electrophysiology. 2024;10(2):346-355.

Holwerda AM, et al. Six-week creatine supplementation in ME/CFS: a magnetic resonance spectroscopy feasibility study. Nutrients. 2024;16(19):3308.

Dzotsi M, et al. Time-restricted eating improves quality of life, heart rate, and mitochondrial function in POTS. Scientific Reports. 2025;15:34345.

Morin L, et al. Efficacy of famotidine-loratadine with specialist supportive care for fatigue in post-COVID condition. The Lancet Infectious Diseases. 2026.

iSTAND Trial. IVIG treatment study for POTS subjects. NCT03919773. ClinicalTrials.gov.

What GLP-1 receptor agonists actually do

GLP-1 stands for glucagon-like peptide-1, a hormone produced in the gut after eating that stimulates insulin release, suppresses glucagon, slows gastric emptying and reduces appetite. GLP-1 receptor agonists mimic this hormone and have proven remarkably effective for blood sugar control and weight loss.

What is less well known outside specialist circles is that GLP-1 receptors are not confined to the pancreas and gut. They are found throughout the brain, in the autonomic nervous system, in the vagus nerve and in regions involved in cardiovascular regulation. This means GLP-1 agonists are not purely metabolic drugs, they have neurological and autonomic effects and in people with already dysregulated autonomic systems, those effects matter.

The case that suggests benefit

A 2026 case report (case report = one interesting case of one/ small collection of people, not a trial) published in Clinical Autonomic Research describes a patient with confirmed PoTS who was started on semaglutide (Ozempic/Wegovy) for weight management. Over the following months, their PoTS symptoms improved significantly, to a degree that surprised their treating clinician enough to write it up.

The proposed mechanism is genuinely interesting. GLP-1 receptors in the brain are involved in regulating inflammation and protecting neurons. Semaglutide, which crosses the blood-brain barrier, appears to have neuroprotective and anti-inflammatory effects in the central nervous system. Given that neuroinflammation is increasingly implicated in PoTS and Long COVID dysautonomia, this is a plausible and exciting mechanism rather than just a happy coincidence.

The same research group has previously published work on neuroinflammation at the dorsolateral inferior medulla as a possible central nervous system localisation for PoTS and Long COVID. The dots are starting to connect.

The case that suggests harm

However, a 2025 case report tells a very different story. A patient with PoTS was started on tirzepatide (Mounjaro), and their symptoms worsened dramatically. Marked tachycardia and orthostatic intolerance both increased significantly after starting the drug.

The key difference between semaglutide and tirzepatide is that tirzepatide is a dual agonist. It activates both GLP-1 receptors and GIP receptors (glucose-dependent insulinotropic polypeptide). GIP receptors are found in blood vessel walls and appear to promote vasodilation. For most people this is not a significant problem. For someone with PoTS, where blood is already pooling in the lower limbs due to inadequate vasoconstriction on standing, adding a drug that promotes vasodilation could substantially worsen orthostatic intolerance. That appears to be exactly what happened here.

The adverse event data

A 2024 analysis presented at the American College of Cardiology searched the FDA’s adverse event reporting database for cases of cardiac dysautonomia symptoms, specifically tachycardia, palpitations, dizziness and PoTS, associated with semaglutide and liraglutide. Of 35,307 total adverse event reports, 307 met criteria for cardiac dysautonomia or related symptoms. The authors concluded that both drugs have a small incidence of cardiac dysautonomia as an adverse event, the majority of which was classified as non-serious, but called for more studies.

It is important to note that adverse event databases capture reports of symptoms occurring in people taking a drug, not proof that the drug caused them. People with PoTS who are prescribed GLP-1 agonists may experience PoTS symptoms that would have occurred regardless. The signal is worth watching but should not be over-interpreted.

What this means in practice

The picture emerging is nuanced. Semaglutide, which acts only on GLP-1 receptors, may actually have beneficial effects on autonomic function in some PoTS patients through anti-inflammatory and neuroprotective mechanisms. Tirzepatide, with its additional GIP receptor activity and vasodilatory effects, may worsen orthostatic intolerance in the same population.

None of this is yet at the level of clinical guidance. Both drugs are prescribed off-label for many things, but neither is approved or recommended for PoTS specifically. If you have PoTS and are being considered for a GLP-1 agonist for weight management or diabetes, it is worth raising your autonomic history explicitly with your prescribing clinician and discussing which specific drug within this class is being proposed, because they are not interchangeable for this patient population.

If you are already on a GLP-1 agonist and notice your PoTS symptoms worsening, this research provides a plausible biological explanation and is worth discussing with your team rather than dismissing as coincidence.

The bigger picture

GLP-1 receptor agonists are increasingly being studied beyond their original metabolic indications, for neurological conditions, cardiovascular disease, addiction, and now autonomic disorders. The biology is genuinely interesting and the potential therapeutic applications are wide. For the PoTS and Long COVID community, this is an area worth watching closely, not because there is enough evidence to recommend these drugs for autonomic symptoms, but because the mechanism is plausible, the early signals are mixed in ways that are informative, and the research is moving quickly.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Blitshteyn S, Suresh S, Lorenzi LM. Significant improvement of postural orthostatic tachycardia syndrome (POTS) with semaglutide: a case report. Clinical Autonomic Research. 2026;36:315–317. https://doi.org/10.1007/s10286-026-01197-1

Katapadi A, et al. Can GLP-1 agonist for weight loss cause cardiac dysautonomia? A study of the FAERS database. JACC. 2024;83(13 Supplement):27. https://doi.org/10.1016/S0735-1097(24)02017-5

Sheth K, Kim S, Porterfield L, et al. The expanding scope of GLP-1 receptor agonists: six uses beyond diabetes. Current Atherosclerosis Reports. 2025;27:76. https://doi.org/10.1007/s11883-025-01319-6

Blitshteyn S. Neuroinflammation at the dorsolateral inferior medulla: a possible central nervous system localization for POTS and long COVID. Clinical Autonomic Research. 2025.

I should say upfront that I go to the gym (though mainly to walk on the treadmill and write these articles). My partner, who has PoTS, does not currently go to the gym in the way I do. The irony of creatine being the supplement most associated with people who want to lift heavy things, turning out to be potentially relevant to people who crash after lifting a cup of tea, is not lost on me.

Why creatine matters at a cellular level

Creatine’s job in the body is to help maintain energy supply during periods of high demand. It does this by replenishing phosphocreatine, a rapidly available energy reserve that the cell uses to regenerate ATP, the molecule that powers essentially everything the body does. When you exercise, phosphocreatine stores get depleted. In healthy people, they replenish relatively quickly. Supplementing with creatine increases the pool of phosphocreatine available, which is why it became a staple of sports nutrition.

In ME/CFS and Long COVID, something goes wrong with this energy system at a much more fundamental level. Studies consistently show that patients have lower creatine and phosphocreatine levels in both skeletal muscle and the brain compared to healthy controls. The mitochondria, which are supposed to produce ATP efficiently through oxidative phosphorylation, are not functioning properly. The body falls back on less efficient anaerobic pathways, which deplete energy faster and produce lactic acid as a byproduct. This is part of why even minor exertion triggers the cascade we decoded in our PEM piece: the system is running on empty before the activity even starts, and the crash afterwards reflects a body that has genuinely run out of the cellular currency it needs to function.

If the problem is partly a depleted phosphocreatine pool and impaired energy metabolism, supplementing with creatine is at least a biologically plausible intervention. It’s not a cure. It’s not addressing the underlying immune dysregulation or mitochondrial damage. But it might help the cell cope better with the energy crisis that exertion triggers.

What the studies actually show

A 2024 feasibility study published in Nutrients gave 14 ME/CFS patients 16g of creatine monohydrate daily for six weeks and used brain MRI spectroscopy to measure creatine levels in two regions of the brain before and after supplementation. Creatine levels in the brain increased measurably. Participants also reported improvements in fatigue, cognitive function and grip strength, though this was a small study without a placebo control, which limits how much we can conclude from the symptom data.

A separate 2024 randomised controlled trial took a more targeted approach, combining 8g creatine with 3g of glucose, the rationale being that glucose helps transport creatine into cells more efficiently. The creatine-glucose combination produced large effect sizes for reducing difficulties concentrating and body aches in Long COVID patients, with an effect size of 0.80 for concentration and 1.33 for body aches, which are genuinely substantial numbers. Adding glucose outperformed creatine alone for elevating brain creatine levels, which is an interesting finding given that brain fog is one of the most consistent and debilitating features of these conditions.

Most recently, a 2025 trial found that just four weeks of 6g per day creatine supplementation significantly reduced fatigue scores and increased peripheral grip strength in Long COVID patients. A June 2025 review specifically on creatine and post-viral fatigue syndrome concluded that impaired creatine metabolism is a key contributor to the bioenergetic disruption seen in these conditions, and that supplementation shows genuine promise.

What we still do not know

The ME Association reviewed the 2024 MRS study and made a fair point: it was a small study without a placebo control, which means we cannot rule out placebo effect for the symptom improvements, even if the brain creatine changes were objectively measured. No large, properly powered, double-blind randomised controlled trial of creatine in ME/CFS has yet been conducted. The optimal dose, duration, and whether combining with glucose is necessary are all open questions. And crucially, we do not know whether creatine helps with PEM specifically, or whether it simply reduces baseline fatigue without affecting how the body responds to exertion.

There is also a practical concern specific to this patient population: some people with ME/CFS and Long COVID report that high doses of creatine initially worsen symptoms, possibly because any intervention that shifts cellular metabolism can be destabilising in an already dysregulated system. Starting low and increasing slowly, under clinical supervision, seems to be the sensible approach if anyone is considering it.

What this means practically

Creatine monohydrate is one of the most studied and safest supplements available. It is inexpensive, widely accessible, and has a well established safety profile across decades of sports science research. The emerging evidence for its role in ME/CFS and Long COVID is genuinely interesting and mechanistically coherent. It is not yet at the level of a clinical recommendation, but it is at the level of something worth discussing with your clinician, particularly if fatigue and brain fog are prominent features of your presentation.

The cell does not know whether its phosphocreatine stores are depleted because you did deadlifts or because you had a conversation that lasted too long. In both cases, it needs the same thing to recover. The question the research is still answering is whether supplementation actually helps bridge that gap when the underlying energy system is as compromised as it is in these conditions.

The answer so far is: possibly yes, in some people, at the right dose. Which in a field with very few treatment options is not nothing.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Holwerda AM, et al. Six-week supplementation with creatine in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a magnetic resonance spectroscopy feasibility study at 3 Tesla. Nutrients. 2024;16(19):3308. https://doi.org/10.3390/nu16193308

Kakagia D, et al. Eight-week creatine-glucose supplementation alleviates clinical features of long COVID. Journal of Nutritional Science and Vitaminology. 2024;70(2):174–178. https://doi.org/10.3177/jnsv.70.174

Twomey R, et al. Creatine and post-viral fatigue syndrome: an update. Journal of the International Society of Sports Nutrition. 2025. https://doi.org/10.1080/15502783.2025.2517278

Santos et al. Creatine supplementation reduces fatigue and increases grip strength in Long COVID patients. 2025.

If you have Long COVID, PoTS or any post viral condition, you have probably had a quiet worry cross your mind at some point. Something like… all this inflammation, all this immune chaos, is it doing something to my cells long term. Could it raise my cancer risk?

A new review in Cancer Reports (Orue, Cornejo and Rangel, 2026) takes that question seriously and goes looking for the biology. It is a dense one, so I have decoded it for you. Short version first, then the detail, because you deserve to know what the evidence actually supports and where it runs out.

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For a long time the honest answer was that we don’t really know. Thankfully, that answer is slowly changing.

What PEM actually is

PEM is not tiredness after exercise, let’s get this straight. It is a pathological worsening of symptoms following physical or cognitive exertion that would not normally cause a response. The key features are that it is delayed and can often peak 12 - 48 hours after the ‘triggering activity’. This is disproportionate to the effort involved and importantly not relieved by rest in the way normal fatigue or tiredness is.

PEM is the hallmark feature of ME/CFS and has emerged as a significant feature of Long COVID. A 2026 systematic review published in Frontiers in Immunology analysed the existing evidence and proposed an important point…PEM is not caused by a single broken system, but it is the result of multiple systems failing to communicate properly with each other. This includes a lack of coordination of multiple systems, specifically the metabolic, immune and nervous systems interacting in a way that amplifies and sustains the response to exertion rather than resolving it.

How common is it in Long COVID

Unfortunately, a lot more common than many clinicians realise. A study published in April 2026 followed 220 patients with post-COVID syndrome and found that 26.4% met criteria for PEM. That’s more than one in four!!! The same study found PEM to be significantly more common in those who had their initial COVID infection earlier in the pandemic (before vaccines), which raises interesting questions about whether viral variants and immune response timing play a role in who develops it. I would like to understand more about this.

Another study from 2025 comparing Long COVID patients with ME/CFS patients and healthy volunteers found something nuanced - PEM descriptions in Long COVID were generally less severe than in ME/CFS on validated questionnaires, but objectively, when patients were put through a standardised exercise test, the responses were real and measurable. In other words, the subjective reporting may actually underestimate what is happening physiologically.

The three systems involved

The 2026 Frontiers in Immunology review is the most comprehensive mapping of PEM mechanisms published to date. Here is the picture it draws.

The first is metabolic dysfunction. The mitochondria, the parts of the cell responsible for producing energy, are not functioning normally in PEM patients. Research including the Appelman muscle biopsy study we decoded last week shows that cellular energy production drops measurably after exertion triggers a crash. The cell’s ability to switch between different energy sources is impaired, and a key enzyme involved in this process drops in Long COVID patients while remaining stable in healthy controls after the same exercise. The body is not just tired. It is losing its ability to produce energy efficiently at a cellular level.

The second is immune dysregulation. After exertion, PEM patients show elevated inflammatory markers and evidence of immune activation that persists well beyond what would be expected from normal exercise. Mast cell activation, cytokine release, and NK cell dysfunction have all been implicated. The immune system, rather than helping the body recover, appears to amplify the damage. This may partly explain why the crash arrives hours after the triggering activity rather than immediately: the immune cascade takes time to build.

The third is nervous system injury. Autonomic dysfunction, small fibre neuropathy, and neuroinflammation all appear in the picture. The nervous system’s ability to regulate the body’s response to physical stress is compromised. For people with PoTS or dysautonomia specifically, this third mechanism is particularly relevant because the autonomic nervous system is already under strain before any exertion is introduced.

What makes PEM particularly difficult to treat is that these three systems do not operate independently. They feed back into each other. Metabolic dysfunction drives immune activation. Immune activation worsens autonomic function. Autonomic dysfunction impairs the very regulation processes that would normally help the cell recover. You are not dealing with one problem. You are dealing with a loop. Figure 1 shows this cascade visually.

Why this matters for how PEM is managed

The current evidence does not support pushing through PEM. The Appelman study showed structural cellular damage that was visible under a microscope and worsened with exertion. The 2025 Frontiers study showed that exercise testing reliably induced measurable symptom worsening in Long COVID patients. The 2026 mechanistic review identified no intervention that breaks the loop cleanly, though it highlighted pacing as the only strategy consistently supported by the available evidence for preventing further damage.

This is worth saying plainly: pacing is not giving up. It is protecting a biological system that, based on everything the current evidence shows, is being measurably damaged by crossing the exertion threshold.

What we still do not know

The 2026 review is honest about the limits of what it can conclude. Most of the mechanistic evidence comes from ME/CFS research, and whether the same mechanisms operate identically in Long COVID PEM is not yet confirmed. The studies that do exist in Long COVID are small. Measurement of PEM itself is inconsistent across studies, with some relying on self-report and others using objective exercise testing, which makes comparison difficult. And crucially, we do not yet have good tools to predict who will develop PEM after exertion, which means the current clinical advice is essentially conservative across the board rather than personalised.

Larger, properly designed trials measuring PEM objectively across both Long COVID and ME/CFS populations are urgently needed. The mechanism is starting to come into focus. The treatment evidence has not kept pace.

The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.

References

Liu Z, et al. Pathophysiological mechanisms of post-exertional malaise: an integrative analysis based on the metabolism-immune-neuro interaction model. Frontiers in Immunology. 2026;17. https://doi.org/10.3389/fimmu.2026.1774310

Bonilla P, et al. Post-exertional malaise in post-COVID-19 syndrome: a shift in the frequency across pandemic phases. Journal of Clinical Medicine. 2026;15(8):2948. https://doi.org/10.3390/jcm15082948

Stussman B, et al. Post-exertional malaise in Long COVID: subjective reporting versus objective assessment. Frontiers in Neurology. 2025. https://doi.org/10.3389/fneur.2025.1534352

Appelman B, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature Communications. 2024;15:17. https://doi.org/10.1038/s41467-023-44432-3

What are antihistamines and why might they matter ?

Histamine is a chemical produced by your immune system (particularly by mast cells, the cells that trigger allergic responses). Most people (me included) encounter antihistamines at some stage, such as hay fever tablets, drugs that block histamine receptors and reduce the sneezing and itching that accompany allergic reactions.

Though histamine does far more than trigger allergies… It regulates blood vessel dilation, influences heart rate, controls gastric acid and acts as a neurotransmitter in the brain - playing a central role in immune activation and inflammation. In conditions where mast cells are overactive, such as in mast cell activation syndrome (MCAS) or where histamine clearance is impaired (perhaps the case in a subset of Long COVID, ME/CFS and PoTS patients), histamine can drive a wide range of symptoms that look nothing like a classic allergic reaction: brain fog, fatigue, orthostatic intolerance, gastrointestinal problems and cardiovascular symptoms.

This is why antihistamines have been appearing on the radar of researchers and clinicians working in these conditions. It is not that histamine is the root cause. It is that for some patients, it appears to be a significant amplifier of symptoms through a mechanism that antihistamines can partially address.

The new Lancet trial

Published in The Lancet Infectious Diseases on 8th July 2026 and funded by the NIHR, this is the largest trial of antihistamines in Long COVID to date. Led by UCL and UCLH, it recruited around 800 adults in England with Long COVID. Patients were randomly assigned to one of four groups: 1) specialist care alone, 2) specialist care plus a combination of famotidine (40mg; usually used for acid reflux) and loratadine (10mg), 3) specialist care plus colchicine (an anti-inflammatory used to treat gout) or 4) specialist care plus rivaroxaban (a blood thinner).

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