Current Takeaway
Clinical management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID currently relies on the off-label repurposing of drugs and supplements targeting suspected pathological mechanisms. Key areas of investigation focus on resolving autonomic dysfunction (preload failure), restoring mitochondrial bioenergetics, correcting chronic neuroinflammation, and clearing persistent post-viral reservoirs. A growing body of clinical trial protocols, randomized pilot studies, and case reports tracks these interventions to identify promising signals that warrant larger-scale replication.
Recent clinical studies have evaluated several new interventions, including the acetylcholinesterase inhibitor donepezil for fatigue and depression in a subgroup of Post-Acute Sequelae of COVID-19 (PASC) patients with HHV-6B SITH-1-induced acetylcholine deficiency, telehealth-delivered cognitive rehabilitation for goal attainment, and physical/behavioral modalities like Tuina massage and mind-body retraining. A major safety signal emerged from the PoCoWiT randomized controlled trial, which tested high-dose oral methylprednisolone for post-COVID cognitive dysfunction; the trial was terminated early due to a cluster of serious adverse events—including pulmonary embolism, deep vein thrombosis, and serious infections—along with a complete lack of efficacy. Meanwhile, the PsyLoCo randomized waitlist-controlled trial (n=48) found that standardized psychotherapeutic group sessions did not significantly reduce somatic symptom burden, depression, or anxiety in Post-COVID-19 condition compared to treatment as usual, reinforcing that physical post-viral symptoms require biological rather than purely psychological management approaches.
Although these trials and mechanistic concepts offer biological rationales, the evidence base remains early and preliminary. Many studies are small, open-label, or lack randomized control groups, which limits statistical power and increases the risk of bias. Consequently, no pharmacological or behavioral intervention has achieved regulatory approval or demonstrated definitive, disease-modifying efficacy in large-scale, placebo-controlled settings, leaving substantial uncertainty regarding long-term safety, optimal dosing, and generalizability across heterogeneous patient cohorts.
Why This Matters
Finding safe and effective treatments for ME/CFS and Long COVID requires translating complex, multi-systemic pathomechanisms into targeted clinical interventions. Identified abnormalities—such as impaired vascular regulation (preload failure), neurovascular coupling deficits, mitochondrial respiration blockages, and hyperactive microglial signaling—directly align with the pharmacology of several existing medications. Repurposing these therapeutics provides an accelerated pathway to clinical applications compared to developing novel compounds from scratch.
Systematic research into these agents offers objective measures of efficacy to complement subjective patient-reported fatigue. For example, demonstrating that pyridostigmine improves peak oxygen consumption ( peak) and hand grip strength connects vascular autonomic regulation directly with muscular capacity. Similarly, evaluating oxaloacetate’s impact on objective cognitive tests (e.g., DANA Brain Vital) and metformin’s ability to prevent neurodegenerative protein aggregation in pre-clinical models grounds these interventions in measurable cellular pathways. These trials build a scientific foundation for stratifying patients into biologically defined subgroups who are most likely to benefit from specific metabolic, vascular, or immunomodulatory mechanisms.
State of Evidence
- Established:
- Metformin decreases the risk of developing post-COVID-19 condition (Long COVID) when administered during acute infection in overweight or obese adults.
- Pyridostigmine improves peak oxygen consumption ( peak) and right atrial pressure in patients with exertional intolerance and confirmed preload failure during invasive cardiopulmonary exercise testing.
- Oxaloacetate is safe and well-tolerated at daily doses up to 2,000 mg in clinical cohorts.
- High-dose oral methylprednisolone does not improve cognitive function in Post-COVID Syndrome and carries a high risk of serious adverse events (including deep vein thrombosis, pulmonary embolism, and serious infections), resulting in early trial termination.
- Plausible but early:
- Pyridostigmine enhances hand grip strength and decreases heart rate elevations upon standing.
- Oxaloacetate improves objective cognitive processing speed and reduces total symptom burden in Long COVID and ME/CFS.
- Metformin prevents cognitive deficits and synaptic damage in animal models by blocking the S1-spike-protein-induced hypoxia switch (HIF-1α) and downstream protein aggregation.
- Amifampridine increases functional scores and reduces excessive sleep requirements in patients with Post-COVID Syndrome.
- Low-dose ketamine infusions induce rapid, transient reductions in fatigue scores, peaking at 24 hours.
- Continuous sipping of high-dose cromolyn sodium improves symptoms of comorbid Mast Cell Activation Syndrome (MCAS) in post-viral patients.
- Sonlicromanol improves fatigue, pain, and physical function over long-term (52-week) open-label administration in mitochondrial disease models.
- Oral 5-ALA/SFC combined with ubiquinone resolves severe chronic fatigue in individuals with specific genetic mutations affecting mitochondrial function (e.g., ADCK1).
- Donepezil reduces fatigue and depressive symptoms in the subgroup of PASC patients seropositive for anti-SITH-1 antibodies.
- Telehealth-delivered cognitive rehabilitation improves daily goal attainment and resource management in Long COVID cognitive impairment.
- Tuina therapy (traditional Chinese manual massage) reduces overall and physical fatigue, anxiety, and sleep complaints in chronic fatigue syndrome.
- Structured mind-body retraining (‘The Switch’) is associated with self-reported improvements in physical and emotional functioning in chronic fatigue and Long COVID.
- Not established:
- Definitive clinical efficacy or regulatory approval for any of these repurposed therapies in treating ME/CFS or Long COVID.
- The efficacy of metformin, ketamine, or amifampridine in large-scale, parallel-group, randomized, placebo-controlled trials specifically for ME/CFS.
- Long-term safety and tolerability of continuous high-dose protocols (e.g., cromolyn sodium or oxaloacetate) beyond several months.
- Definitive clinical efficacy of donepezil, Tuina therapy, or mind-body retraining in large-scale, pre-registered, placebo-controlled trials.
- Efficacy of psychotherapeutic group interventions (including psychoeducation, somatic symptom processing, and emotional regulation) for reducing core physical symptom burden in Post-COVID-19 condition; the PsyLoCo RCT found no significant superiority over treatment as usual.
- Clinical efficacy, safety, or validated dosing of computationally nominated repurposing candidates (e.g., pioglitazone, tideglusib, MHY1485) from transcriptomic signature screens in ME/CFS, which remain preclinical in silico and in vitro hypotheses without human trial evidence.
- Clinical efficacy of intermittent hypoxia-hyperoxia treatment (IHHT) in ME/CFS; published trial protocols (e.g., REenergizeME) record study methodology and investigational intent rather than clinical outcomes.
- Long-term safety, optimal dosing, and durability of donepezil, Tuina therapy, or cognitive rehabilitation programs.
- Key limitations:
- Small sample sizes in pilot studies (e.g., 20 patients for pyridostigmine hand grip, 10 patients for ketamine crossover, 5 patients for amifampridine and cromolyn series) limit statistical power and generalizability.
- High risk of placebo effects and response bias in open-label studies and retrospective case series.
- Crossover trial designs for drugs like ketamine are prone to carryover effects that confound efficacy comparisons against comparators like midazolam.
- Preclinical data (e.g., metformin’s protection of rat synapses, sonlicromanol’s primary mitochondrial disease trial) require human translational validation in ME/CFS before clinical conclusions can be drawn.
- Subgroup analyses (e.g., donepezil limited to SITH-1 seropositive patients) and lack of patient blinding in manual therapies (Tuina) or behavioral programs (The Switch, cognitive rehabilitation) limit the generalizability and control of placebo/expectation effects.
- Uncontrolled observational designs (The Switch cohort) cannot exclude spontaneous recovery or selection bias.
- The PsyLoCo trial’s small sample (n=48) and waitlist-controlled design in an outpatient psychosomatic setting limited statistical power to detect small effect sizes.
- Use of broad diagnostic criteria (e.g., 1994 CDC Fukuda criteria for Tuina) that do not require post-exertional malaise limits applicability to strict ME/CFS.
Timeline
2022-05-15 - Pyridostigmine trial identifies preload failure mechanism and acute exercise improvement
A randomized, placebo-controlled clinical trial of 39 female patients with ME/CFS showed that a single 60 mg dose of the acetylcholinesterase inhibitor pyridostigmine acutely increased peak oxygen consumption ( peak) and improved cardiac filling pressures during a second invasive cardiopulmonary exercise test (iCPET). This study provides physiological evidence that impaired vascular regulation (preload failure) is a key driver of exertional intolerance in ME/CFS, indicating that acetylcholinesterase inhibition can partially correct this deficit. Furthermore, the worsening of filling pressures in the placebo group during back-to-back testing offers an objective, physiological demonstration of post-exertional malaise. However, the study evaluated only the acute, immediate effects of a single dose, leaving it unproven whether daily oral use of pyridostigmine provides long-term functional improvement or safe symptom control. The findings also do not clarify if the drug’s benefits are restricted to patients with confirmed small fiber neuropathy.
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2023-06-08 - Metformin in COVID-OUT trial demonstrates prevention of Long COVID
The phase 3, randomized, quadruple-blind COVID-OUT trial involving 1,126 overweight or obese adults demonstrated that early outpatient treatment with metformin (initiated within seven days of acute SARS-CoV-2 symptom onset) reduced the incidence of a subsequent Long COVID diagnosis by 41% over a 10-month follow-up period. This trial establishes that a safe, inexpensive, and widely available metabolic medication can prevent the development of post-viral sequelae when taken during the acute phase. The preventive effect was most pronounced when metformin was started within three days of symptom onset, whereas ivermectin and fluvoxamine showed no efficacy. However, the trial was limited to adults aged 30–85 with overweight or obesity, meaning it does not prove whether metformin prevents Long COVID in individuals with normal body mass index or in younger cohorts. Additionally, the study was designed for prevention during acute infection and does not address whether metformin is effective as a treatment for individuals who have already developed chronic Long COVID.
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2023-06-22 - Vericiguat Phase 2 trial initiated for endothelial dysfunction in Post-COVID Syndrome
A randomized, double-blind, placebo-controlled Phase 2 clinical trial (NCT05697640) was initiated by Charité University in Berlin to investigate whether the soluble guanylate cyclase stimulator vericiguat improves physical function in patients with Post-COVID-19 Syndrome. The trial targets patients with confirmed endothelial dysfunction—a condition where impaired function of the inner lining of small blood vessels reduces local blood flow and tissue oxygenation. By evaluating a drug known to enhance nitric oxide signaling and promote vasodilation, the study aims to test if correcting endothelial impairment translates into improved physical capacity and reduced fatigue. However, the trial is ongoing with results yet to be published, and it remains to be proven whether vericiguat is safe and effective in this population. It also does not establish whether the drug’s mechanisms are applicable to post-viral patients who do not exhibit measurable signs of microvascular endothelial dysfunction.
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2024-01-25 - Amifampridine case series indicates reduction in neuromuscular fatigue and hypersomnia
A case series of five patients with Post-COVID Syndrome, including double-blind discontinuation trials in two participants, showed that the potassium channel blocker amifampridine led to a normalization of daily sleep duration and a significant increase in functional Bell scores (mean rising from 28 to 82). This observation suggests that amifampridine, which increases acetylcholine release at the neuromuscular junction, may target a shared neuromuscular pathway driving profound fatigue and excessive sleep requirements in post-viral syndromes. The recurrence of severe fatigue when active drug was replaced with a placebo during the discontinuation phase strengthens the likelihood of a direct pharmacological effect. However, the study’s extremely small sample size and descriptive nature limit the generalizability of the findings. It does not prove amifampridine’s efficacy or safety in a large, representative clinical trial, nor does it establish optimal dosing guidelines for the broader Long COVID or ME/CFS populations.
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2024-11-06 - Sonlicromanol Phase 2b program shows long-term improvement in mitochondrial symptoms
A Phase 2b trial program evaluating the mitochondrial-targeted drug sonlicromanol in adults with genetically confirmed m.3243A>G mitochondrial disease demonstrated significant long-term improvements in fatigue, pain, physical quality of life, and balance during a 52-week open-label extension. Although the initial 28-day randomized, placebo-controlled portion of the study failed to meet its primary cognitive endpoint, post-hoc analyses and the subsequent year-long extension showed clinical benefits, particularly in patients who were more severely affected at baseline. This trial provides supportive evidence that modulating cellular oxidative stress and inflammatory distress pathways can alleviate systemic symptoms associated with mitochondrial dysfunction, which is hypothesized to play a major role in ME/CFS. However, because the primary endpoint of the randomized portion was not met, the short-term efficacy of sonlicromanol remains unproven. Furthermore, the 52-week extension lacked a control group, and the drug has not yet been directly tested in patients diagnosed with ME/CFS or Long COVID.
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2024-12-26 - Genetic case study links ADCK1 mutation to ME/CFS and resolution via oral 5-ALA/SFC
A genetic case report of a 35-year-old woman with severe, long-standing ME/CFS identified a novel frameshift mutation in the ADCK1 gene, a gene critical for mitochondrial coenzyme Q10 synthesis, and documented significant clinical improvements following oral supplementation with 5-aminolevulinic acid with sodium ferrous citrate (5-ALA/SFC) and ubiquinone. This case provides a molecular link between a specific genetic mutation, mitochondrial energy failure, and severe chronic fatigue, illustrating the potential for gene-targeted metabolic therapies. The patient’s dose-dependent improvement in fatigue and daily activity levels suggests that addressing coenzyme Q10 and heme synthesis pathways can restore cellular energy production. However, this study describes only a single patient, which does not prove that the ADCK1 mutation is a common cause of ME/CFS or that 5-ALA/SFC is broadly effective for patients without this specific genetic variation. It also remains unverified whether the heterozygous ADCK1 mutation is sufficient on its own to cause ME/CFS pathobiology.
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2025-07-18 - REGAIN trial of Oxaloacetate in Long COVID reports cognitive gains but misses primary fatigue endpoint
The randomized, double-blind, placebo-controlled REGAIN trial of 69 adults with Long COVID showed that a daily dose of 2,000 mg of oral oxaloacetate (OAA) for 42 days did not produce a statistically significant difference in fatigue reduction compared to placebo on the primary Chalder Fatigue Questionnaire (CFQ). However, secondary measures revealed that the oxaloacetate group experienced significantly greater improvements in objective cognitive function (using the DANA Brain Vital battery) and a more rapid reduction in total symptom burden at day 21. These results suggest that targeting mitochondrial bioenergetics with oxaloacetate may selectively alleviate cognitive dysfunction (“brain fog”) and overall symptom severity, even when generalized fatigue scores remain unchanged. Nevertheless, because the trial failed to meet its primary efficacy endpoint for fatigue, the clinical utility of oxaloacetate as a general anti-fatigue agent remains unproven. The study’s single-center design, modest sample size, and short 42-day duration also limit the strength of the evidence.
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2025-08-07 - Review proposes multi-systemic metformin protocols for ME/CFS metabolic dysfunction
A comprehensive literature review proposed a strong biological rationale for repurposing metformin to address the metabolic, inflammatory, and gut dysbiosis pathways characteristic of ME/CFS and Long COVID. The authors consolidated evidence showing that metformin inhibits mitochondrial complexes I and IV, reduces reactive oxygen species, modulates mTOR signaling to improve energy regulation, and exerts anti-inflammatory and mast-cell-stabilizing effects. This perspective highlights metformin as a multi-action agent that could serve as a core component of a multi-faceted treatment strategy targeting metabolic stress. However, the review is a synthesis of previous in vitro, animal, and clinical data, which does not prove that metformin is clinically effective or safe for patients already suffering from chronic ME/CFS. Additionally, the drug’s significant gastrointestinal side effects represent a major clinical challenge that may limit its usability in patients with pre-existing gut dysbiosis or irritable bowel syndrome.
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2025-08-19 - ANKTIVA Phase 2 trial initiated to target viral reservoirs in Long COVID
A Phase 2, exploratory, single-arm clinical trial (NCT07123727) was initiated to evaluate the safety and immunological effects of the IL-15 superagonist ANKTIVA (nogapendekin alfa inbakicept-pmln) in up to 40 adults with Long COVID. The trial targets persistent viral reservoirs and immune dysregulation by using immunotherapy to boost the count and activity of Natural Killer (NK) cells and CD8+ T cells, which are often depleted or dysfunctional in chronic post-viral states. If successful, this immune-enhancing approach could help clear lingering viral proteins and restore healthy immune surveillance. However, the trial is currently recruiting, and no clinical efficacy or safety data have been published yet. The single-arm, open-label design of the trial also means that future results will lack a placebo control group, making it difficult to separate the drug’s therapeutic effects from spontaneous recovery.
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2025-09-03 - Pyridostigmine trial demonstrates short-term improvement in hand grip strength and orthostatic tolerance
A within-subject clinical study of 20 patients with post-infectious ME/CFS showed that a single 30 mg dose of pyridostigmine significantly improved hand grip strength recovery (by a median of 2.6 kg) and reduced heart rate elevations during a standing test (from a median of 17 bpm to 13 bpm) after one hour. These findings suggest that pyridostigmine can provide rapid, temporary relief for muscle fatiguability and orthostatic intolerance by increasing acetylcholine availability at the neuromuscular junction and enhancing parasympathetic activity. The objective improvement in muscle strength recovery directly addresses the neuromuscular weakness reported by patients. However, the study’s non-randomized, non-controlled design and very small cohort size introduce a high risk of bias. It does not prove the efficacy of pyridostigmine in a controlled setting, nor does it determine whether these acute benefits persist with chronic dosing.
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2025-09-16 - Solriamfetol trial reports reduction in fatigue severity and improved executive function in ME/CFS
An 8-week, double-blind, randomized, placebo-controlled Phase 4 trial involving 38 adults with ME/CFS showed that the dual norepinephrine-dopamine reuptake inhibitor solriamfetol significantly reduced self-reported fatigue severity and improved overall executive function, particularly metacognitive skills like planning and memory. This trial indicates that targeting central monoamine pathways can alleviate cognitive and fatigue symptoms, offering a wakefulness-promoting therapeutic option. However, the trial was small and conducted at a single site, which limits the generalizability of the findings. The study did not find a significant improvement in the interference of fatigue on daily life activities, and the rapid dose titration caused side effects such as anxiety and sleep loss in several participants, leaving optimal dosing and long-term tolerability unproven.
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2025-09-23 - Oxaloacetate ME/CFS trial demonstrates cognitive improvement and fatigue-cognition coupling
A 90-day, randomized, double-blind, placebo-controlled trial of 82 adults with ME/CFS demonstrated that a daily dose of 2,000 mg of oral oxaloacetate significantly improved objective cognitive performance (using DANA Brain Vital) at the 60-day mark compared to a placebo control. The study identified a strong “fatigue–cognition coupling” effect only in the oxaloacetate-treated group, where higher baseline fatigue was strongly associated with reduced cognitive gains, suggesting the drug acts on a biological pathway that links these two core symptoms. Upright activity time (UP Time) also showed a modest increase at the 30-day mark. However, the study did not find statistically significant differences in overall responder rates or general fatigue scores between the treatment and placebo groups. It remains unproven whether oxaloacetate can reliably reduce generalized fatigue or if it is only effective in a specific sub-phenotype of patients with coupled cognitive and metabolic dysfunction.
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2025-11-07 - Metformin shown to protect brain synapses and prevent protein clumping in SARS-CoV-2 spike model
A preclinical molecular study using human neuronal cell lines and a rat model demonstrated that intranasal exposure to the SARS-CoV-2 S1 spike protein caused cognitive impairment, synaptic dysfunction, and aggregation of toxic phosphorylated tau and alpha-synuclein, all of which were prevented by treatment with metformin. The study maps a direct pathway where the viral spike protein stabilizes the hypoxia switch HIF-1α, turning off genes essential for healthy brain connections, which is blocked by metformin’s metabolic action. This provides a clear molecular mechanism explaining metformin’s protective role against “brain fog” and neurodegenerative markers during post-viral syndromes. However, these findings are based on human cell lines and a six-week rodent model, which does not prove that metformin will reverse established cognitive impairment or stop neurodegenerative-like protein clumping in chronic human patients. It also does not clarify if vaccination-induced spike protein exposure behaves similarly to the viral models used in the study.
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2026-01-22 - High-dose continuous oral cromolyn sodium improves comorbid MCAS symptoms
A retrospective case series of five patients with ME/CFS or Long COVID and comorbid Mast Cell Activation Syndrome (MCAS) showed that a continuous sipping regimen of high-dose oral cromolyn sodium (1,600 to 2,400 mg daily) significantly improved fatigue, cognitive function, and heart rate control. By spreading the total dose throughout the day in a water bottle rather than using discrete bolus doses, the protocol aims to maintain stable plasma concentrations of the drug and improve patient tolerance. This provides a practical dosing strategy for patients who fail standard low-dose regimens. However, the retrospective case series design lacks a control group, and the very small number of patients (five) means the efficacy and safety of this high-dose protocol are not proven. Systematic prospective trials are required to validate these findings and to monitor for potential adverse effects of long-term high-dose cromolyn exposure.
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2026-01-22 - Ketamine crossover trial reports rapid but transient reductions in chronic fatigue
A randomized, double-blind, crossover trial involving ten participants with chronic fatigue (including ME/CFS and fibromyalgia) showed that a single low-dose ketamine infusion reduced fatigue scores by 21% at three days and by nearly 39% at 24 hours. The study demonstrates that low-dose ketamine, an NMDA receptor antagonist, can induce rapid, clinically relevant reductions in severe chronic fatigue. However, due to the small sample size and a strong placebo response in the active control (midazolam) group, the difference in fatigue reduction between the groups did not reach statistical significance. The crossover design also introduced significant carryover effects, where the fatigue-reducing effects of the first infusion influenced the baseline of the second period. These limitations mean that the efficacy of ketamine over active controls remains unproven, and parallel-design trials are needed to confirm the drug’s therapeutic value.
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2026-03-04 - Molecular hydrogen review consolidates early evidence for oxidative stress reduction
A narrative mini-review of clinical and mechanistic evidence concluded that consuming hydrogen-rich water is a promising, low-risk adjunctive therapy that may improve fatigue and physical function in patients with ME/CFS and Long COVID. The review highlights molecular hydrogen’s selective antioxidant properties, which allow it to reduce cellular oxidative stress and support mitochondrial health without disrupting essential cellular signaling. Results from three early-stage, developmental clinical trials suggest the treatment is feasible and well-tolerated. However, the current clinical evidence is restricted to small, open-label or pilot studies relying heavily on self-reported outcomes. These early findings do not prove the clinical efficacy of molecular hydrogen, and larger, placebo-controlled trials incorporating objective biometrics and biomarkers are needed to confirm the therapeutic benefits.
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2026-06-03 - Trial protocol published to evaluate acupuncture for cognitive function in post-COVID ME/CFS
A randomized controlled trial protocol published in Frontiers in Neurology by Luo et al. outlines the design of a prospective, three-armed trial (NCT07357688) evaluating the efficacy and neural mechanisms of acupuncture in 129 patients with post-COVID ME/CFS and 30 healthy controls. Participants are randomized to verum acupuncture, sham acupuncture (non-penetrating), or waitlist control for 8 weeks (3 sessions/week). The primary outcome is change in information processing speed (Symbol Digit Modalities Test [SDMT]), with secondary outcomes including cognitive batteries and brain metabolites/connectivity measured via fMRI. As a trial protocol, this publication outlines study methodology only and does not report clinical efficacy or safety data.
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2026-06-08 - Preclinical study of sodium deoxyribonucleate in post-viral chronic fatigue syndrome model
In an animal study published in the Medical academic journal, Filatenkova et al. evaluated the nucleotide-based drug sodium deoxyribonucleate in a Poly I:C Wistar rat model of post-viral chronic fatigue syndrome. A single administration of the drug on day 1 post-induction improved exploratory activity, reduced anxiety-like behaviors, normalized splenic lymphocyte activities, and normalized post-exercise plasma lactate levels, although muscle weakness was not resolved. Hypothalamic cytokine gene expression was also restored. As a preclinical study in a rodent model, these findings demonstrate early biological pathways and do not represent evidence of clinical efficacy or safety in humans. Furthermore, the drug was administered immediately after induction, representing acute protection/prevention rather than treatment of long-standing chronic illness.
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2026-06-08 - FDA approves Tonmya (sublingual cyclobenzaprine) for fibromyalgia, discussed for off-label ME/CFS relevance
On June 8, 2026, the FDA approved Tonmya (sublingual cyclobenzaprine, though captions rendered the brand name variably as Tonmya or Tomaya) for the treatment of fibromyalgia. In a Younger Lab commentary, Dr. Jarred Younger discussed the drug’s pharmacokinetic rationale, explaining that sublingual delivery bypasses first-pass hepatic and gut metabolism, avoiding the rapid conversion to norcyclobenzaprine and reducing next-day grogginess compared to oral generic Flexeril. While published clinical trials demonstrated a clear separation between Tonmya and placebo in improving fibromyalgia severity, sleep, and fatigue, there are no head-to-head trials comparing it to cheap oral generics. Given that ME/CFS, Long COVID, and Gulf War Illness have zero FDA-approved treatments, Dr. Younger framed Tonmya as potentially useful off-label for these conditions due to their overlapping symptom profiles, though he noted that no ME/CFS-specific efficacy data exist. Practical limitations include a high out-of-pocket cost of approximately 15 for generic oral formulations, mucosal irritation or chemical burn risk if the tablet does not dissolve before sleep, and the necessity of a 2-month trial to properly judge efficacy.
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2026-06-25 - MYOFLAME-19 trial of losartan and prednisone for post-COVID cardiac inflammation presents results at International ME/CFS Conference 2026
Prof. Dr. Valentina Puntmann presented findings from the MYOFLAME-19 trial, a 16-week randomized, placebo-controlled trial evaluating the angiotensin receptor blocker losartan (with or without the corticosteroid prednisone) in 279 patients with post-COVID fatigue syndrome showing subclinical cardiac inflammation on MRI. While the study did not meet its primary confirmatory endpoint of improving left ventricular ejection fraction (LVEF) using a conservative unpaired t-test, an ANCOVA analysis adjusting for baseline LVEF showed a statistically significant treatment effect. The trial showed directional proof of concept with improvements in cardiac volume, reduced tissue and systemic inflammation (CRP, D-dimer, lymphocytes), and reduced fatigue. However, the study suffered from a high attrition rate (11.8%), and LVEF may not be the optimal endpoint for post-infectious endothelial dysfunction.
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2026-06-25 - Conference presentation reports early safety termination and lack of efficacy in PoCoWiT methylprednisolone RCT
At the Internationale ME/CFS-Konferenz 2026, Lucas Adam presented preliminary results from the PoCoWiT trial, a double-blind randomized controlled trial (RCT) evaluating high-dose oral methylprednisolone (1 mg/kg/day for 4 weeks followed by tapering) for cognitive dysfunction in Post-COVID Syndrome (PCS). The trial was terminated early by the Data and Safety Monitoring Board (DSMB) after enrolling 96 of 180 planned patients due to a cluster of five serious adverse events occurring exclusively in the active treatment group and a clear lack of efficacy. These severe events included deep vein thrombosis (DVT), pulmonary embolism (PE), atypical pneumonia, pyelonephritis, and severe headache requiring hospitalization. Efficacy analyses revealed no statistically significant difference in cognitive recovery between the methylprednisolone and placebo groups, with both showing only a minor, identical 3-point improvement on the Memory Quality Questionnaire (MMQ) at the 8-week follow-up. This early termination establishes a prominent safety warning against using high-dose oral corticosteroids for post-COVID cognitive impairment, though the study was underpowered due to its early cessation and limited to a narrow cognitive phenotype.
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2026-06-28 - Preclinical metabolomics study indicates Ginseng stem-leaf saponins modulate brain-gut pathways in chronic fatigue syndrome mice
A preclinical animal study published in the Journal of Pharmaceutical and Biomedical Analysis by Wu et al. evaluated the effects of Ginseng stem-leaf saponins (GSLS) in a chronic fatigue mouse model induced by a long-term forced-swimming protocol. Using untargeted metabolomics, the authors analyzed brain tissue and fecal samples, identifying 17 differential metabolites in the brain and 17 in feces. GSLS supplementation partially normalized metabolic abnormalities mapping to lipid-derived mediators, membrane-lipid remodeling, and energy/redox cofactor pathways. As a preclinical study in a mouse model, these findings represent early exploratory biology and do not demonstrate therapeutic efficacy or clinical safety in human patients.
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2026-06-28 - Preclinical study finds Sijunzi decoction modulates gut microbiota and metabolic profiles in chronic fatigue syndrome rats
A study published in the Journal of Chromatography B by Shan et al. evaluated the traditional herbal formulation Sijunzi Decoction (SJZD) in a multi-factor stress-induced rat model of chronic fatigue syndrome. Daily administration of SJZD for 30 days improved body weight, gastrointestinal motility, exhaustive swimming time, and skeletal muscle ATPase content, while regulating 25 serum and 7 fecal metabolites and enhancing intestinal microbiota diversity. As a preclinical study in a rodent model, these findings demonstrate biological pathways in animals and do not represent clinical efficacy or safety in humans, and the specific bioactive components of the multi-herb formulation were not isolated.
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2026-06-28 - Randomized controlled trial preprint evaluates specialized pro-resolving mediators and telerehabilitation in Post-COVID Condition
The ARACOV-02 double-blind randomized controlled trial (n=144), published as a preprint, evaluated the combination of a specialized pro-resolving mediator (SPM)-enriched marine oil supplement and a 12-week telerehabilitation program in individuals with Post-COVID-19 Condition. Although no statistically significant between-group differences were observed after 12 weeks, both the treatment and placebo groups showed significant within-group improvements in quality of life, fatigue, and functional capacity (partly due to the active rehabilitation program in both arms). The SPM group demonstrated significant improvements in dyspnea that were absent in the placebo group, and high supplement compliance was associated with broader clinical improvements. As a preprint, this work has not yet undergone formal peer review to validate the findings.
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2026-06-29 - Clinical trial subgroup study links donepezil efficacy to SITH-1-induced acetylcholine deficiency
A randomized clinical trial subgroup analysis published in Frontiers in Pharmacology showed that the acetylcholinesterase inhibitor donepezil significantly improved fatigue and depressive symptoms in Post-Acute Sequelae of COVID-19 (PASC) patients positive for anti-SITH-1 antibodies. The researchers demonstrated that latent HHV-6B reactivation in the brain and olfactory bulb can express the SITH-1 protein, which subsequently drives a reduction in brain acetylcholine levels. In the study’s cohort of 156 PASC patients, approximately 63% were seropositive for anti-SITH-1 antibodies and presented with more severe baseline symptoms. Within this seropositive subgroup, donepezil treatment led to statistically significant improvements on the Chalder Fatigue Scale and HADS depression scores compared to placebo, suggesting anti-SITH-1 testing could serve as a companion diagnostic. However, the study does not establish donepezil’s efficacy in the broader, seronegative PASC cohort, and the relatively short trial duration means long-term safety and tolerability in this population remain unproven.
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2026-07-01 - Randomized clinical trial evaluates telehealth-delivered cognitive rehabilitation for Long COVID
A randomized clinical trial published in JAMA Network Open demonstrated that a 10-week, individualized, telehealth-delivered cognitive rehabilitation program significantly improved functional outcomes in 78 adults with Long COVID cognitive impairment. At the 3-month mark, 84% of the rehabilitation group reported a clinically meaningful improvement in achieving personal goals in daily life, work, and hobbies, compared to 53% of the usual care control group, with improvements sustained at 6 months. Rather than curing the underlying pathology or increasing baseline cognitive capacity (as shown by only minor improvements in standardized cognitive test scores), the program primarily helped patients develop compensation strategies and manage cognitive resources more efficiently. These results indicate that structured cognitive pacing and rehabilitation are highly effective for functional management, although the resource-intensive nature of one-on-one telehealth delivery may limit scalability. Additionally, the trial’s reliance on unblinded, self-reported functional outcomes introduces a potential reporting bias, and the program must be carefully paced to avoid triggering post-exertional malaise.
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2026-07-04 - Transcriptomic signature screen nominates four metabolism-targeting compounds for ME/CFS
A bioinformatics and in vitro drug-repurposing study published as a preprint on Research Square by Dehlia et al. re-analyzed two independent public transcriptomic datasets (GSE14577 and GSE227375) to identify therapeutic candidates targeting metabolic dysfunction in ME/CFS cohorts. By extracting a consensus 46-gene expression signature reflecting disruptions in cytokine signaling, immune pathways, lipid and nucleotide metabolism, and cellular redox balance, the authors queried the Connectivity Map (CMap) L1000 database to prioritize perturbagens predicted to reverse the ME/CFS gene expression profile. This computational screen nominated four repurposed compounds: the PPAR-gamma agonists pioglitazone and rosiglitazone, the GSK-3beta inhibitor tideglusib, and the mTOR pathway activator MHY1485. In vitro validation in mouse C2C12 skeletal muscle myoblasts demonstrated that pioglitazone, tideglusib, and MHY1485 significantly increased mitochondrial membrane potential in TMRM and JC-1 assays, providing preclinical support for their capacity to counteract cellular metabolic suppression. However, as an unreviewed preprint, the findings are based solely on in silico re-analysis and mouse muscle cell-line assays rather than patient-derived primary cells or validated animal models of ME/CFS. The underlying transcriptomic cohorts did not report severe or bedbound patient representation, and these potent pharmacological agents have no human clinical trial evidence, validated dosing, or established safety profiles in ME/CFS, precluding off-label use.
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2026-07-05 - Feasibility study evaluates telehealth-delivered ketogenic metabolic therapy for post-viral illness
A cross-sectional survey evaluating a fully remote telehealth program that combined ketogenic metabolic therapy, thiamine supplementation, circadian entrainment, and mindfulness coaching in 41 international patients with post-viral illness (including Long COVID) reported high acceptability and perceived benefits. Upon program completion, 96% of participants reported the multicomponent intervention was helpful, and 75% felt ‘a lot better’. However, the evidence level is limited, as the study relied entirely on a small, self-reported survey design without a control or placebo group. Furthermore, the multicomponent nature of the program prevents isolating the therapeutic efficacy of ketogenic therapy or thiamine from lifestyle changes, mindfulness, or natural recovery.
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2026-07-10 - Randomized controlled trial reports efficacy of Tuina therapy for chronic fatigue syndrome
An assessor-blinded, single-center randomized controlled trial (RCT) involving 110 adults with chronic fatigue syndrome demonstrated that Tuina therapy (traditional Chinese manual massage) combined with usual care significantly reduced fatigue severity compared to usual care alone. Over a 4-week protocol consisting of 12 sessions, the Tuina group showed significant reductions in fatigue scores (adjusted mean difference -2.90) and sleep complaints, with a higher proportion achieving a minimal clinically important difference (89.1% vs 69.1%). The therapy demonstrated a more pronounced effect on physical fatigue (effect size 0.70) than on mental fatigue (effect size 0.41), while also significantly reducing anxiety. These findings suggest that gentle, tailored manual therapies are safe and helpful adjunctive options for managing somatic symptoms and sleep issues in chronic fatigue. However, because patients could not be blinded, the results are susceptible to expectations and placebo effects, and the use of the 1994 CDC Fukuda diagnostic criteria limits generalizability to patients with strict, post-exertional malaise-defined ME/CFS.
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2026-07-10 - Observational cohort study evaluates ‘The Switch’ mind-body retraining program
An observational feasibility and efficacy study of “The Switch” mind-body retraining program in 104 participants (75 with chronic fatigue syndrome and 29 with Long COVID) reported significant self-reported improvements in physical role limitations and emotional functioning. These benefits were observed at 2 months and remained stable at 12 months, with no significant differences in clinical outcomes between telehealth (Zoom) and face-to-face delivery formats. The comparable efficacy of online delivery suggests that virtual programs may offer a viable option that reduces the orthostatic and energetic travel burdens on patients. However, the study’s lack of a randomized control group or active comparator makes it impossible to rule out placebo effects, selection bias, or spontaneous recovery. Furthermore, the findings are limited by their complete reliance on unvalidated, self-reported diagnoses and subjective health questionnaires without objective functional or physiological confirmation, and patients must remain within their physiological pacing limits to avoid triggering severe crashes.
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2026-07-28 - PsyLoCo RCT finds no efficacy of psychotherapeutic group intervention for Post-COVID-19 condition
The PsyLoCo randomized waitlist-controlled trial (n=48, pre-registered DRKS00040598/OSF osf.io/tdn38) evaluated 10 bi-weekly manual-guided group psychotherapeutic sessions—combining psychoeducation, somatic symptom processing, and emotional regulation training—against treatment as usual (TAU) in an outpatient psychosomatic setting for patients with Post-COVID-19 condition. The primary outcome (somatic symptom burden, SSS-8; p=0.091) and secondary outcomes (depression PHQ-9, p=0.251; anxiety GAD-7, p=0.588) showed no statistically significant superiority of the group psychotherapy intervention over TAU. The trial’s small sample size (n=48) limited statistical power to detect small effects, and the waitlist-controlled design cannot fully account for non-specific therapeutic contact effects. These null findings are consistent with a growing body of evidence indicating that core physical post-viral symptom burden does not respond to psychotherapeutic interventions alone, though supportive psychological care may still address coping and quality of life. The study was conducted in a Post-COVID-19 condition cohort and does not directly assess efficacy in classic ME/CFS populations meeting post-exertional malaise criteria.
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2026-08-14 - REenergizeME protocol published for a sham-controlled trial of intermittent hypoxia-hyperoxia treatment
A clinical trial protocol published in BMJ Open by Nochi et al. outlines the design of the REenergizeME study, a prospective, randomized, double-blind, sham-controlled trial (NCT07317401) evaluating intermittent hypoxia-hyperoxia treatment (IHHT) in ME/CFS. The trial investigates whether 8 weeks of IHHT—which repeatedly cycles brief intervals of normobaric hypoxia (10–14% O2) and hyperoxia (30–36% O2) to activate hypoxia-inducible factor (HIF) and cellular redox adaptations—can improve mitochondrial bioenergetics and microvascular oxygen extraction. The protocol plans to enroll 104 female participants aged 20–59 meeting the 2011 International Consensus Criteria (ICC), randomizing patients to active IHHT or sham gas and comparing them with a separate, non-randomized healthy-control group. The primary outcome is health-related quality of life measured by the SF-36 vitality subscale, alongside multi-system secondary assessments including near-infrared spectroscopy (NIRS) tissue oxygenation, skin biopsy intraepidermal nerve fiber density, corneal confocal microscopy, and autonomic testing over 12 months of follow-up. As a trial protocol, this publication outlines study methodology and mechanistic rationale only and does not report clinical efficacy, tolerability, or safety results. Severely affected and bedbound individuals are explicitly excluded due to the requirement for frequent in-clinic visits over eight weeks, and hypoxic gas challenges carry a theoretical risk of provoking post-exertional malaise in susceptible patients while posing practical challenges for maintaining effective sham blinding.
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Open Questions
- What are the optimal patient stratification criteria? Given the heterogeneity of ME/CFS and Long COVID, identifying specific clinical phenotypes (such as preload failure, mitochondrial dysfunction, or MCAS) is crucial to match patients with the most appropriate pharmacotherapeutic mechanism.
- Do acute signals translate to long-term clinical efficacy? Pilot trials demonstrating short-term or single-dose improvements (e.g., pyridostigmine for exercise capacity or ketamine for fatigue) must be followed by long-term tolerability and safety studies.
- Can combination therapies target multiple pathways simultaneously? Because these conditions are multi-systemic, research is needed to determine if combining low-risk metabolic, autonomic, and immunomodulatory interventions yields synergistic clinical benefits.
- What role remains for psychotherapeutic support? Given that the PsyLoCo RCT found no effect on physical symptom burden, further work is needed to clarify whether psychological interventions have utility for secondary outcomes like coping, quality of life, or functional adaptation rather than core disease modification.