Submitted:
01 September 2025
Posted:
03 September 2025
Read the latest preprint version here
Abstract
Keywords:
1. Setting the Stage
| COVID | Long COVID | |
|---|---|---|
| Date of First Paper | February 3, 2020 Nature – 19,000+ citations Lancet – 12,000+ citations |
November 3, 2020 JAMA – 446 citations |
| What is it? | A disease caused by a virus | The multiple, diverse consequences of a disease |
| Contagious | Yes, very | No |
| Test | Yes – PCR and rapid antigen | No |
| % of US afflicted population | ~90% | ~7% of those who had COVID |
| Length of illness | Typically, 5-10 days |
Months to years or perhaps permanent |
| Sex prevalence | Male | Female |
| Vaccination Impact | Significant reduction | No Long COVID vaccine and none is likely. However, pre-COVID vaccination helps. Post-COVID vaccination does not help. |
| Therapeutic objective | Avoid severe disease | Repair COVID damage |
| Therapeutic effectiveness tests | Biochemical tests based on the therapeutic type, i.e., antiviral, anti-inflammatory, oxygenation, and blood clots. |
Human trials and highly qualita—tive studies |
| Therapeutic placebo effect | Some | Can be significant |
| Disease / Virus | Common Long-Term Symptoms | Organs/Systems Affected | Duration | Percent Affected |
|---|---|---|---|---|
| COVID-19 | Fatigue, brain fog, postural orthostatic tachycardia syndrome, heart palpitations, gastrointestinal issues | Brain, nerves, lungs, heart, kidney, liver, pancreas, genitals, musculoskeletal, immune system | Months to years |
~5 –15% higher after severe cases |
| Epstein-Barr | Chronic fatigue, memory issues, muscle pain | Brain, immune system, liver | Months to years | ~10–15% chronic fatigue syndrome |
| Influenza | Fatigue, weakness, rare Guillain-Barré syndrome or encephalitis | Nervous system, lungs | Weeks to months | ~1–2% mostly severe cases |
| Coxsackievirus B | Myocarditis, fatigue, chronic inflammation | Heart, muscles | Weeks to lifelong | ~5–10% |
| Zika Virus | Guillain-Barré syndrome, neuropathy, fetal defects if pregnant | Nerves, brain (fetal/adult) | Weeks to lifelong |
<1% Guillain-Barré syndrome, neuropathy ~5–10% mild neurological symptoms |
| SARS / MERS | Lung damage, post-traumatic stress disorder, fatigue | Lungs, nervous system | Months to years | ~25–40% |
| RSV | Wheezing, asthma in kids, chronic cough | Lungs, airway | Months to years | ~30–50% of children with severe RSV |
| Measles | subacute sclerosing panencephalitis (very rare), immune suppression | Brain, immune system | Years later | Rare |
| Chickenpox | Shingles, nerve pain (post therpetic neuralgia) | Nerves, skin | Weeks to years |
20–30% get shingles; ~10–15% of those get postherpetic neuralgia |
2. Long COVID


3. Long COVID Prevalence



-
First, and most importantly, there is no diagnostic test for Long COVID. Thus, assessment techniques are qualitative. For example,
- There are self-assessments with different criteria, e.g., walk test or how are you feeling?
- Frequently there are not controls who also could have Long COVID symptoms, e.g., fatigue or depression.
- There are mail surveys, on-line forms, phone calls, all of which have low response rates. Someone who doesn’t feel well is more likely to respond than someone who feels great which bias results.
- There are different measures such as rate, risk ratios, and fully recovered.
- While there is a large symptom base, only a few symptoms are usually measured, usually fatigue or brain fog.

- 2.
- The pandemic changed behaviors, e.g., less exercise and sleep, which can result in one having “Long COVID” symptoms.
- 3.
-
Comorbidities affect the results. The comorbidities include:
- Pandemic medical impacts, e.g., depression which can overlap with and can exacerbate Long COVID symptoms.
- Age, sex, BMI, diseases, frailty, genetics
- Variants
- Therapeutics
- COVID Vaccination
- 4.
- There are different Long COVID definitions.
4. Long COVID Root Causes
- Inflammation: Inflammation is probably Long COVID’s major root cause. Inflammation includes recruiting white blood cells and the release of cytokines that initiate tissue swelling and injury.
- Persistent viral infection: viral antigens, RNA, and SARS-CoV-2 proteins remain present and active in the body’s tissues following acute infection and continue to damage it.
- Viral particle damage to organs. A COVID case results in 1-30 trillion viral particles in the body. Some proteins, particularly the spike, the nucleocapsid, and the nonstructural protein 1 (nsp1) directly damage organs.
- Autoantibodies: Infection with the SARS-CoV-2 virus can trigger autoimmune diseases.
-
Biological processes and organs are damaged.
- All our organs are damaged.
- Mitochondria, our energy workhorses, are greatly damaged by COVID. This results in fewer oxygen carrying molecules called ATP being generated for our bodies. This is a significant contributor to fatigue and brain fog.
- The proteins that are involved in healing are dysregulated.

5. Long COVID Biochemical Markers
- -
- Pain
- -
- Blood System
- -
- Vascular System
- -
- Retinal Microcirculation
- -
- Musculoskeletal Changes
- -
- Orthostatic Dysfunction
- -
- Cardiac Changes
- -
- Olfactory Bulb Changes
- -
- Lung
- -
- Diaphragm Weakness
- -
- Gut Permeability
- -
- Proteins
- -
- Metabolites
- -
- Bacteria Change
- -
- Brain Changes
- -
- Bacteria
- -
- Autonomic Disfunction
- -
- Connectivity
- -
- Microglial And Macrophage Activation
- -
- Brain Entropy
- -
- Kinesiophobia
- -
- Reaction Time
- -
- Chemosensory Impairment
- -
- Neurotransmitters
- -
- Serotonin
- -
- Protein Markers
- -
- Plasma Changes
- -
- Changes In Gene Expression
- -
- Viral Proteins
- -
- Spike Protein
- -
- N Protein Anti-Nucleocapsid Igg
- -
- Antibodies, Autoantibodies
- -
- Antibody Levels
- -
- Nasal
- -
- Autoantibodies
- -
- Coronavirus Imprinting
- -
- Immune System
- -
- Immune System Dysregulation
- -
- Previous Coronavirus Infection
- -
- Metabolic Changes
- -
- T Cells dysregulation
- -
- Monocytes
- -
- Tryptophan & Kynurenine
- -
- Myeloid Cells
- -
- Mitochondria, Oxidative Stress
- -
- Genetics
- -
- Genes
- -
- Epigenetic Changes
6. Reducing the Chances of Long COVID

6.1. Long COVID Treatments
| COVID Treatments |
Long COVID Treatments |
|
|---|---|---|
| FDA clinical treatment trials | 6,000 | 545 |
| PubMed published papersa | 198,000 | 17,000b |
| The Mouse the Roared papersa | 3,800c | 269d |
| Symptom | FDA Clinical Trial |
|---|---|
| Fatigue | 279 |
| Mental Health | 138 |
| Persistent Infection | 106 |
| Inflammation | 66 |
| Brain Fog | 63 |
| Antiviral | 51 |
| Gut Micro biodome | 16 |
| Microclotting | 14 |
| Cognitive Behavioral Therapy to Treat It | 12 |
| SSRI Antidepressants to Treat It | 12 |
| Auto Immune Diseases | 12 |
| Mitochondrial | 11 |
| Dementia | 10 |
| Year | Long COVID Trials Started |
|---|---|
| Pre 2020 | 2a |
| 2020 | 43 |
| 2021 | 120 |
| 2022 | 142 |
| 2023 | 155 |
| 2024 | 83 |
| 2025—through 8/31 | 57 |
- The scientific community is early in focusing on Long COVID, so clearly other treatments will be discovered.
- The huge, order of $2.3 billion, US Long COVID project called Recover Project is just gathering momentum. This will be a long term, well-funded project if for no other reason than the order of 20 million Americans suffer from Long COVID. This website lists its published papers Recover Project Published Papers.
- Though not as large as the US Recover Project, many countries have large Long COVID projects including, but not limited to the UK, Canada, Australia, China, Japan, South Korea, the European Union, and the Word Health Organization.
- That is, the number of Long COVID treatment papers in The Mouse That Roared dropped precipitously in July and august 2025.
6.2. Treatment Strategy
- I.
- Get the Right Set of Doctors
- II.
- Go to a Long COVID Clinic
- III.
- Consider Having Assessments for Root Causes
- Persistent Inflammation The main test for inflammation is for the IL-6 cytokine. Persistent Inflammation Test describes the test. Inflammation is probably the most important test as hyperinflammation is a leading cause of severe COVID which leads to the most severe cases of Long COVID.
- Mitochondrial Dysfunction This is probably the second most important test. Initial laboratory tests such as lactate, pyruvate, urine organic acids, and plasma amino acids can inform the clinician about possible mitochondrial dysfunction.
-
Persistent Infection The main tests are:
- Antibody Testing: Persistence of IgM or high IgG titers might indicate ongoing antigen exposure.
- T-cell Activation Profiles: Specialized tests can assess T-cell responses to SARS-CoV-2 antigens, indicating ongoing immune activity against the virus.
-
Autoantibodies Testing for autoantibodies triggered by COVID-19 involves specialized laboratory assays that detect the presence of antibodies targeting the body’s own tissues. They are several types.
-
Blood Tests to Detect Specific Autoantibodies
- Enzyme-Linked Immunosorbent Assay (ELISA): It is used to detect autoantibodies such as anti-nuclear antibodies (ANA), antiphospholipid antibodies, and others.
- Indirect Immunofluorescence: It is often used for detecting ANA or anti-neutrophil cytoplasmic antibodies (ANCA).
- Multiplex Autoantibody Panels: These are comprehensive tests that simultaneously evaluate multiple autoantibodies associated with autoimmune diseases.
-
Functional Assays
- Neutralization Assays: These check for autoantibodies interfering with normal immune pathways, such as those targeting type I interferons which is linked to severe COVID-19.
- Complement Activity Assays: These evaluate the activity of autoantibodies against the complement system.
-
Tissue-Specific Tests
- Thyroid Function Tests: If autoimmune thyroiditis is suspected, specific antibodies like TPOAb (thyroid peroxidase) can be tested.
- Liver Function-Related Autoantibodies: For autoimmune hepatitis, testing for anti-LKM1 or ANA might be necessary.
-
Specialized Tests for COVID-19-Triggered Autoimmunity
- Anti-Interferon Autoantibody Testing: This is relevant for severe COVID-19 cases as these autoantibodies may impair the immune response to the virus.
- Anti-Phospholipid Antibodies (aPL): Increased risk of blood clots in some COVID-19 cases can be linked to these autoantibodies.
- Cytokine Autoantibodies: These assess disruption in immune signaling pathways, especially in post-COVID syndromes.
-
- Gut microdome dysfunction—there are many tests.
- IV.
- Summarize Relevant Personal Medical Data
- Pre-existing health issues being sure to include any autoimmune disease and other COVID comorbidities such as diabetes, active cancer treatment, etc.
- COVID case data, including COVID dates, tests, severity, and therapeutics.
- COVID vaccination history.
- Long COVID history—start date, symptom trends, and treatments. The Cleveland Clinic’s table is an excellent way to summarize Long COVID symptom data.

- V.
- Discuss Candidate Treatments
- Most of the root cause papers address inflammation.
- The choice of assigning a paper to Broad Symptoms or Root Cause/Inflammation was a bit arbitrary and was often based on the way the paper’s data was presented.
- Notice how few organ-specific papers were written. This is not surprising as treating arrythmia, for example, induced by Long COVID is likely little different than treating non-COVID arrythmias.
- Only 70 papers reported total human trial sizes of 100 or more. This would be the minimum size for an FDA phase 2 trial which determines a treatment’s effectiveness. Only 27 papers reported studies of 300 or more humans in their trials.
- If one combines trials into the group that had the largest number of people in one trial, then exercise studies accounted for more than 10% of the papers.
- Corticosteroids—prednisone or dexamethasone
- Colchicine
- Low-Dose Naltrexone
- Antihistamines and Mast Cell Stabilizers
- Statins—atorvastatin, rosuvastatin
- Omega-3 fatty acids
- Palmitoylethanolamide
- Curcumin
- Resveratrol
- Q10
| Number of papers describing a treatment | Number of treatments |
| 6 | 1 |
| 5 | 1 |
| 4 | 1 |
| 3 | 6 |
| 2 | 18 |
| 1 | 107 |
- Reducing inflammation.
- Stimulating mitochondrial biogenesis and improve ATP production, which can reduce fatigue.
- Improving vascular tone, oxygen delivery, and tissue perfusion, potentially easing symptoms like brain fog or muscle aches.
- Rebalancing the autonomic nervous system through designed recumbent or supine exercise (e.g., rowing, swimming, recumbent cycling) which may help recondition the cardiovascular system and reduce orthostatic symptoms.
- Promoting neuroplasticity, potentially helping with cognitive symptoms (e.g., brain fog).
- Promoting lymphatic flow and helping clear cellular debris and immune complexes.
- Support fluid and waste clearance in the brain, helping with cognitive symptoms and sleep quality.
- Significantly increasing the amount of oxygen dissolved in the blood plasma, allowing more oxygen to reach tissues that may be oxygen-deprived or poorly cleared of fluids.
- Helping to reduce inflammation immune response.
- Promoting a more balanced immune function.
- Improving mitochondrial function, potentially increasing ATP production, reducing mitochondrial apoptosis signaling, and reducing oxidative stress. This leads to a boost in energy production and reduced fatigue.
- Stimulating the growth of new neurons and improved neuroplasticity thereby potentially improving cognitive function.
- Reducing chronic stress which increases inflammatory cytokines which are already elevated in Long COVID.
- Improving mood and symptom perception which may help people feel better, even if the underlying pathology remains.
- Improving sleep quality which can significantly reduce daily symptom burden and improve mitochondrial function.
- Regulating the autonomic nervous system which is linked to fatigue, and breathlessness.
- Improving cognitive function which can help cope with brain fog and develop compensatory strategies, even if they don’t reverse the cause.
| Procedures | |||
|---|---|---|---|
| Trial Size | Treatment | Improvement | |
| 50-99 | Fecal Transplant146 Enhanced External Counter Pulsation147 Spinal Cord Transcutaneous Stimulation & Respiratory Training148 Digital Cognitive Training149 Unified Phycological Protocol150 Wearable Brain Activity Sensing Device151 Trained With Orange, Lavender, Clove And Peppermint Oils152-3 Contracting And Relaxing Pneumatic Cuffs 0n The Calves, Thighs, And Lower Hip154 |
Sleep Broad Lung Fatigue And Concentration Broad Broad Broad Impact Broad Impact |
|
| 25-49 | Immunoadsorption155 Vagus Nerve Stimulation156-158 Transcutaneous Electrical Nerve Stimulation159-161 Tragus Nerve Stimulation162-163 Matt Pilates164 Photobiomodulation165-166 Stellate Ganglion Block167-171 Ropinirole172 Acupuncture173 Expectation Management174 |
Broad Broad Neurological Pain And Fatigue Broad Fatigue Pain And Fatigue Smell And Broad Restless Leg Syndrome Well Tolerated, No Measures On Outcomes Minor Broad |
|
| 10-24 | Dance175 Aripiprazole176 Continuous Positive Airway Pressure177 Olfactory Training With Vitamin A178 Functional Septorhinoplasty179 Virtual Reality Training180 Neuromodulation181 |
Broad Reduced sleep duration Cognition No Impact Smell No Impact No Apparent Impact |
|
| 1-9 | Oronasal Drainage182 Plasmapheresis183-184 Light To Restore Circadian Rhythm185 Neural Feedback186 Plasma Exchange Therapy187 |
Broad Cognition Sleep More Alert No Impact |
|
| Drugs | |||
| Trial Size | Treatment | Improvement | |
| 50-99 | Leronlimab188 Sea Urchin Eggs189 Co-UltraPEALut190 Naltrexone191-193 Antihistamines194-195 Amantadine196 Propranolol197 Lithium198 Metoprolol199 Rintatolimod200 Gabapentin201 |
Inflammation Pain Memory & Fatigue Broad & Tremors Broad But Uneven Fatigue Orthostatic Hypotension No Improvement Cardiovascular No Impact No Impact |
|
| 25-49 | Valtrex + Celecoxib202 AXA1125203 Plasma204-205 Treamid206 Palmitoylethanolamide Co-Ultramicronized With Luteolin207-208 Phosphatidylcholine209 Aripiprazole210 Hochuekkito211 |
Broad Fatigue Smell Improved Lung Capacity Improved Smell Improved Inconclusive Reduced Sleep Needs Reduced Fatigue |
|
| 10-24 | Creatine212 | Fatigue | |
| 1-9 | Casirivimab/Imdevimab213 Nicotine Patch214 Bupropion215 Methylphenidate216 Guanfacine217 Intravascular Immunoglobulin Therapy218 Ivabradine219 Minocycline220 Epipharyngeal Abrasive Therapy221 |
Complete Remission Broad And Major Broad Broad Cognition Orthostatic Hypotension Orthostatic Hypotension Orthostatic Hypotension Cleared Viral RNA |
|
| Nutrients | |||
| Trial Size | Treatment | Improvement | |
| 50-99 | Nutritional Supplements Plus Exercise222 Ayurveda System Of Medicine223 Astragalus Root Extract224 Marine Oils225 Endocalyx226 Glycocalyx Dietary Supplement227 |
Broad Diarrhea And Broad Fatigue Fatigue Cardiovascular Cardiovascular |
|
| 25-49 | Beet Juice228-229 Probiotics230-231 Maraviroc And Pravastatin232 |
Fatigue And Sleep Inflammation Broad |
|
| 10-24 | Salmon Oil233 Tinospora Cordifolia234 |
Inflammation Inflammation |
|
| Procedures | ||
| Infrared light235 | Cell cultures | Two ten minute exposures led to 80% IL-6 reduction in gene assay. |
| Hyperthermia236 | Review/ hypothosis | Modulates necroinflammation. |
| Drugs | ||
| Tocilizumab237 | Trial underway | Reduce inflammation |
| Baricitinib238 | Trial underway | Reduce inflammation |
| Peptide LTI-2355239 | Cell cultures | Mitigated inflammation in the respiratory tract. |
| CB2R agonists240 | Hypothosis | Reduce inflammation |
| Ginkgolide B-loaded lubosomes And vesicular LNPS241 | Human cell cultures | May protect against cell death |
| SPIKENET, SPK242 | Mice | Reversed the development of severe inflammation, oxidative stress, tissue edema, and animal death. Recall, vaccines in humans didn’t help. |
| Fermentable fiber243 | Hypothesis | Reduce autoantibodies |
| Polyphenols244 | Hypothesis | Reduce autoantibodies |
| Resveratrol245 | Hypothesis | Reduce gut microdome dysfunction |
| Boost nicotinamide adenine dinucleotide (NAD+)246 | Hypothesis | Reduce gut microdome dysfunction |
| Gamunex-C247 | Proposed trial | Broad relief |
| Paracetamol and Dexketoprofen Trometamol248 | Analytic technique | Broad relief when administered with rivaroxaban |
| Modafinil249 | Literature search | Broad relief |
| Kyungok-go250 | Proposed trial | Broad relief |
| Cyclobenzapring Hydochloride251 |
Company annoucement | Reduce pain and improved sleep |
| Ivabradine and midodrine252 | Review of 32 studies | Reduced brain fog |
| Omega-3 fatty acids252 | Review | Improve mental health |
| Aspartate or Asparagine253-254 | Hypothosis | Improve vision |
| Macitentan255 | Hamsters | Restored bone loss |
| Tanshinone IIA256 | Chemical evaluation | Inflammation |
| Epigallocatechin-3-gallate-palmitate257 |
Cell culture |
Neurological |
| Tuning Organelle Balance In Human Mesenchymal Stem Cell258 | Cell Study | Major mitochondrial production |
| L-carnitine259 | Theory | Fatigue |
| Niclosamide260 | Review | Broad |
| Larazotide261 | Proposed trial | Broad |
| Ecstasy262 | FDA Vote | Too risky |
| Sodium Pyruvate Nasal Spray263 | Proposed trial of drug useful in flu | Broad |
| Nutrients | ||
| Korean Herbs264 | Mice cell cultures | Decreased nitrous oxide levels in some cell types. |
| Melatonin265-268 | Hypothesis -3, Literature search | Reduce inflammation |
| Flavonoids Nobiletin & Eriodictyol269 | Human cells | Reduced pathogen-stimulated release of inflammatory mediators. |
| Herbs270 | Safety test | Broad improvements |
| Vitamin B12271 | Hypothesis | Improve vision |
7. What Should I Consider If I Don’t Want to or Can’t Go to a Long COVID Clinic?
- I believe I have Long COVID.
- I have the typical broad symptoms such as brain fog and fatigue.
- I have a fine GP who is not expert in Long COVID.
- I can’t get root cause diagnostic tests.
- Exercise—I would get a script to get physical therapy or use the Pace Me application
- Oxygenation—I would try to get to a hyperbaric chamber but if I couldn’t, I would do home oxygenation.
- Improve Mental Health—I would get Cognitive Behavioral therapy
- Spa & Hot Spring Bathing—Sure, why not! Fun and relaxing
- Mediterranean Diet—It has been shown to be good for one’s health, so why not?
- Fasting diet, no sugar—I would try it as it would be good for my general health
- Weight Loss—If I was overweight, definitely as it is good for one’s health
- Yoga—if I am healthy, I would pursue as part of my exercise program
- Contracting and Relaxing Pneumatic Cuffs on The Calves, Thighs, and Lower Hip—I would consider it even though it was a small trial
- SSRI Inhibitors
- Traditional Chinese Medicine
- SIM01—Gut Microbiota-Derived Formula
- Transcutaneous Nicotine
- P2Y12 Inhibitor
- Prospekta
- Cyclobenzaprine Hydrochloride
- Vortioxetine
- Donepezil
- Bufei Huoxue
- Apportal
- L-carnitine—mitochondrial dysfunction though not reported in the papers discussed here.
- Q10—though the trials were uneven, it has been shown to be good for mitochondrial dysfunction.
8. Conclusions
Acknowledgments
Appendix A. Summary of Long COVID Treatment Papers, Including Trial Sizes


Appendix B. Summary of Long COVID Treatments and Control Groups



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