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The Blog


Thanks to John Bolecek for putting together this thought-provoking blog. A former Statewide Bicycle and Pedestrian Coordinator at the Virginia Department of Transportation, John was in great shape before he came down with long COVID and is now disabled. Check out John’s story “A life derailed by long COVID“.

This is a call for the NIH, FDA, Congress, and private donors interested in long-COVID clinical trials to come together, fund, and select a well-designed, meaningful slate of clinical trials.


The RECOVER Initiative’s low-risk, low-reward treatment trials have failed to impress. Here’s what it could be doing.

On February 13th of 2024, the National Institutes of Health (NIH) announced an additional $515 million for the RECOVER initiative to study long COVID. The NIH has largely fumbled the use of the money allocated so far, spending it mostly on observational studies that haven’t produced useful data yet, and failed to do even the most routine autonomic testing on all participants. (Only 20% of the cohort will undergo any autonomic testing.)

The slate of clinical trials the NIH has chosen is also weak and has been criticized previously. The NIH must use this new money wisely and expeditiously.

Many patients have been disabled over 4 years now. With limited time, money, and institutional capacity, trialing ineffective drugs will have a huge opportunity cost. Unfortunately, RECOVER funding is for one time use and, although desperately needed, there is no permanent program providing a yearly source of funds for long-COVID research.

The FY25 appropriations process is currently underway in Congress. Since NIH has moved so slowly and ineptly, Congress should consider naming specific drugs to trial and allocating additional funding for future trials to agencies other than the NIH, such as the Congressionally Directed Research Funds in the Department of Defense, the Advanced Research Projects Agency for Health (ARPA-H), or as Senator Marshall suggested during the Long COVID hearing in the Senate HELP Committee, the Biomedical Advanced Research and Development Authority (BARDA).


  • With the RECOVER Initiative’s initial funding ($1.15 billion) about to run out, the Initiative was handed a $500 million lifeline from the Biden administration. Whether RECOVER deserved such a lifeline is beyond the scope of this blog, but suffice it to say, the Initiative has impressed no one and its initial slate of clinical trials received much criticism.
  • With the tenuous funding state RECOVER is in, it behooves the Initiative to make the maximum use of its dollars. Thus far, it has spent the lion’s share of them on rudimentary observational studies that have failed to produce any insights, thus putting more pressure on RECOVER to deliver with its clinical trials.
  • RECOVER, however, continued its conservative bent by focusing mostly on low-risk, low-reward clinical trials. RECOVER was so behind the eight ball on its proposed exercise study that it was forced to postpone the study for a year and rejigger it. In its current iteration, people with post-exertional malaise will not be in the exercise portion of the study and people with PEM will instead engage in pacing. This 1,200-person may cost as much as $50 million.
  • In a similar vein, RECOVER is spending enormous amounts of money to study low-risk, low-reward treatments such as cognitive retraining, sleep hygiene, melatonin and light therapy for sleep that are well known and readily available. Its stimulant, transcranial magnetic stimulation, Ivabradine, Paxlovid and IVIG trials are more welcome, but all these treatments have been tried in ME/CFS and it is unlikely any will prove particularly helpful for more than a subset of patients.
  • RECOVER’s conservative, low-risk / low-reward approach to long COVID meant that it missed the chance to provide substantial help to long-COVID patients. By putting all its eggs in the big trials basket, RECOVER missed the chance to assess a wide variety of drugs in smaller trials that could have paved the way for real success. Check out the blog for a list of them.

The slate of trials put forth by NIH suggests the NIH thinks treating individual symptoms could be successful, and betrays a lack of understanding that long COVID is a systemic disease. It also assumes that patients have not tried even simple, accessible treatments. Instead of spending hundreds of millions of dollars attempting to address the low hanging fruit in these diseases, I assert the RECOVER Initiative should attempt to address the root causes and treat the most disabling aspects of the disease. Indeed, much of the critique of the trials has concerned RECOVER’s highly conservative approach to the treatment trials.

Long COVID is a broad term describing any sequelae from a COVID-19 infection that persists for more than three months, including symptoms like persistent cough or loss of smell. The more serious, disabling versions of long COVID limit the amount of physical and cognitive activity patients can perform. Post-exertional malaise (PEM), the worsening of symptoms and capacity following even minor physical or mental exertion, limits many patients from functioning because they crash and can potentially decline after performing even basic activities of daily life.

The ability to increase cognitive and physical exertion without PEM should be the end point of a successful trial. Devices that track heart rate, sleep, daily steps, and heart rate variability (HRV) can provide a more complete picture of a patient’s recovery than patient-reported surveys and six-minute walk tests.

Ranked from worst to best; the reported RECOVER trials are listed below:

RECOVER has grouped their interventions into various categories. The first categories include RECOVER-VITAL, RECOVER-AUTONOMIC and RECOVER-NEURO which have details on the website. RECOVER-ENERGIZE and RECOVER-SLEEP were announced on May 8th, 2024 and now have ClinicalTrials.Gov pages. The list of drugs below may not be complete as it only reflects the current public disclosures from the NIH and the reporting in the STAT News article titled, “Underwhelming’: NIH trials fail to test meaningful Long COVID treatments — after 2.5 years and $1 billion”, from July 2023.


RECOVER confused

RECOVER announced its initial exercise trial before doing its homework, forcing it to backtrack for a year. In a turnaround, the 1,200-person trial will not trial exercise in people with post-exertional malaise. People with PEM will get pacing.

Exercise – Accessible and cheap – and recommended by most doctors – most long-COVID patients have undoubtedly already tried to exercise their way out – sometimes with the help of a physical therapist – of their illness.

Most long-COVID patients who are disabled, are so precisely because their ability to exert is limited by PEM. A recent study in the Netherlands showed that in long-COVID patients with PEM, exercise damages the muscles with increased amyloid-containing deposits and worsens their metabolism compared to controls. Graded exercise therapy has repeatedly shown to not work in those with PEM, yet RECOVER was adamant it was going to do an exercise trial.

How lost was RECOVER with regard to PEM, exercise and long COVID? RECOVER appeared to be caught off guard by the pushback from the ME/CFS and long-COVID communities when it announced the study over a year ago. STAT News reporting suggested that RECOVER, at least initially, wasn’t clear on or even interested in this strange post-exertional malaise (PEM) symptom.

The outcry caused RECOVER to retrench, and we’ve been in a holding pattern since then. RECOVER released the details of its long-awaited exercise trial a couple of days ago. Ultimately, it got the message – people with PEM will not take part in the exercise trial – but will participate in a pacing trial.

Trial funding is not available, but AI Copilot estimated that a 1,300-person clinical trial will typically cost about $50 million to try to increase activity in a group for whom exertion is not a problem and to assess a simple and well-known lifestyle change in patients for whom it is.

Brain training game software – This is akin to telling patients who can’t think clearly to play computer games to try to think better. Most importantly, it doesn’t address the most functionally limiting factor with regard to “brain fog” – the cognitive exertion problem that makes it impossible for many people with these diseases to work.

Goal management training (PASC-CoRE) – A series of virtual meetings where “trained study staff will help participants, plan and manage personal goals, learn mindfulness-based ways to work through distractions, learn skills to focus attention on goal-oriented tasks, and develop strategies to manage mental tiredness.” Goal management has nothing to do with treating an energy limiting, neuroinflammatory disease and it is hard to imagine a more insulting list of recommendations.


Sleep hygiene

RECOVER will determine if sleep hygiene – a well-known approach to sleep – helps.

Facing fierce criticism for its delay to producing trials in July of 2023, RECOVER provided information on five clinical trials. The sleep trial (474 participants) was slated to begin last fall, but only in the last week has RECOVER released the final protocols. The focus was going to be hypersomnia (too much sleep) which is found in ME/CFS, possibly in the earlier stages of the illness, but does not appear to be common.

Educational coaching for sleep – Sleep hygiene information is free and accessible, a Google search away. RECOVER underestimates the number of treatments the average patient has tried to get better sleep. Trying sleep hygiene is a logical first step that any sleep doctor or PCP will suggest.

Melatonin – Accessible and cheap, many patients have already tried melatonin. While it may help some fall asleep, it often does not help patients stay asleep nor does it treat unrefreshing sleep.

Light therapy – If something so accessible and cheap worked, we would know about it. Unfortunately, some patients are so severe, they are sensitive to both light and sound.



Pacing is already a well-known approach in both the ME/CFS and long-COVID communities.

Pacing – Presumably added to RECOVER-ENERGIZE due to criticism of the exercise trial, this trial is geared towards those with PEM. They will undergo structured pacing to see if it helps their symptoms.

Patients with PEM have learned to pace in their own way, but unavoidable exertions due to work, childcare and other activities of daily living make serious pacing a privilege for most. A management strategy is not exciting for patients, who are looking to regain as much of their lives as possible, but may help further the scientific evidence around pacing.

Transcranial direct current stimulation (tDCS) – NIH claims this is a noninvasive form of brain stimulation. Participants will wear a headset that delivers a mild electrical current to specific parts of the brain to increase activity.

Modafinil and Solriamfetol – Modafinil is a central nervous system stimulant used to combat narcolepsy which results in people falling asleep in the middle of the day, and is also used in attention deficit hyperactivity disorder which may be common in ME/CFS and fibromyalgia (FM).

Modafinil’s stimulation of the sympathetic nervous system seems iffy given the sympathetic nervous system upregulation found in long COVID (and ME/CFS). Modafinil also, though, promotes dopamine production which may be low in long COVID and ME/CFS.

Some ME/CFS studies have shown that stimulants can be helpful and modafinil is on the ME/CFS Clinician Coalition’s list of potential drugs to use (with caution) in ME/CFS. Modafinil may help around the edges, and given the functional issues with long COVID, is arguably worth trying. It will not, however, get at the cause of long COVID.


Paxlovid – COVID antiviral targeting viral persistence. There are already several other Paxlovid trials being run. A trial at Stanford ended early, presumably because of a lack of efficacy. Another at Yale will readout later this spring.


Intravenous immunoglobulin (IVIG) – A pooled antibody used in autoimmune diseases, extremely expensive and inaccessible to patients. The trial is proposing to use a high dose for a long period and has thorough endpoints. Unfortunately, there is a forced exercise component of this trial, no open extension for placebo patients, and an intense regimen of in-person visits that will exclude more severe patients.

The Case for IVIG Treatment in Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, Small Fiber Neuropathy, and POTS : IVIG#3

Ivabradine – Currently used off-label for autonomic dysfunction. This drug lowers heart rate without lowering blood pressure, an advantage over beta blockers for those with low blood pressure. This drug is still on patent and extremely expensive, with many US patients sourcing from Canadian pharmacies. Getting this drug on label would make it more easily covered by insurance. Uniformed Services University of the Health Sciences (USUHS), a federal hospital in NIH’s backyard in Bethesda, Maryland has already launched and started recruiting for an Ivabradine trial.

Ivabradine – Could a “Wonder Drug” For POTS Work in ME/CFS?


What NIH should trial


Instead of spending hundreds of millions of dollars on low reward treatments, RECOVER could be trialing drugs that have a chance at getting at the core of long COVID.

Various papers and groups have suggested lists of drugs to trial for long COVID. Unfortunately, few drug trials are underway. An editorial in the Lancet Infectious Diseases titled, “Where are the Long COVID trials”, published in August 2023 stated, “ClinicalTrials.gov currently lists 386 trials under the search term Long COVID.

However, only 94 of those studies are classed as interventional and are currently recruiting, and even more disturbing, only 12 trials are testing pharmacological interventions. The rest comprise follow-up of trials in acute infection, rehabilitation, food supplements, telehealth, psychological support, physiotherapy, acupuncture, light therapy, Chinese herbal medicine etc.”

Furthermore, public money is needed to target drugs without a profit motive. Additionally, without a single biomarker, patients are potentially suffering from different underlying causes. With the current slate of fiscally constrained, small trials, it is difficult to identify subsets of patients. Public funding would enable otherwise private trials to be larger, and more testing could be done to identify subsets.

NIH should also convene an international group of researchers experienced in treating dysautonomia and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and should solicit ideas from these groups. Some long-COVID patients are lucky enough to respond to similar treatment approaches. This group should include Mark Davis, Derya Unutmaz, Ian Lipkin, Amy Proal, Peter Rowe, Carmen Scheibenbogen, Øystein Fluge, Olav Mella, John Chia, Liisa Selin, Maureen Hanson, David Systrom, Lucinda Bateman, Ron Davis, and Avi Nath, among others.

In no particular order, the following is a list of drugs that should be trialed, grouped by hypothesis.

Viral persistence and reactivation:

These drugs should be trialed alone and in combination.

Ensitrelvir / Leritrelvir  A COVID antiviral, approved in Japan and China respectively, they are 3CL protease inhibitors similar to Paxlovid but with fewer drug interactions, and potentially safer to take for longer periods because they does not contain Ritonavir.

Remdesivir / VV116 – Remdesivir is an broad antiviral drug that is administered intravenously, requiring daily trips to an infusion center, making it difficult to trial. VV116, also known as “Oral Remdesivir”, would make administration of a trial much cheaper and more practical for patients.

Rintatolimod – Trademarked ‘Ampligen’, a drug that targets the TLR3 Pathway to increase innate immune function. A poorly run phase 2 trial that failed to screen patients for post-exertional malaise or use immune function as an entrance criterion did not show statistically significant results; howeve,r several long-COVID and ME/CFS patients report reductions in PEM and the ability to increase activity while they remain on the drug.

Anti-SARS-CoV-2 monoclonal antibodies (mAbs) – May help clear persistent virus. In contrast to oral antivirals, which can only stop viral replication, mAbs could bind to virus particles, replicating or not, and alert T-cells to clear the debris. A small trial testing the mAb AER002 is being conducted at the University of California San Francisco.

Immune checkpoint inhibitors – Checkpoint inhibitors like PD-1 inhibitors, combat T cell exhaustion. There is a potentially risky safety profile for those who may have autoimmunity. Recently mentioned in the NIH ME/CFS intramural study, and by Liisa Selin, and Maureen Hanson at the 2023 Invest in ME conference.

2-thiouridine – A broad-spectrum antiviral drug candidate that targets positive-strand RNA viruses like SARS-COV-2.


Anti CD-19, Anti CD-20, Mycophenolate, Tacrolimus, Jak/STAT inhibitors, IL-1 Blockers, IL-6 Antagonist, and TNF-Alpha Inhibitors – Drugs floated by Avi Nath, Clinical Director at Senior Investigator and Clinical Director at National Institute of Neurological Disorders and Stroke at NIH. He has suggested these immunomodulating drugs be tested in ME/CFS and long COVID in a platform trial.

Baricitinib (Olumiant) is a JAK1/JAK2 inhibitor with antiviral properties. Wes Ely MD is in the midst of a large baricitinib long COVID trial that does not need more funding but Ely’s trial is listed here as an example of the kind of creative approach to long COVID that the RECOVER Initiative did not pursue.

From Skeptic to Advocate: Wes Ely, Long COVID, ME/CFS and his Big Baricitinib Trial

Bacille Calmette-Guerin (BCG) vaccineUsed as an immunotherapy for cancer. Case reports and a paper have outlined a hypothesis on how it might work for long COVID. One person with ME/CFS recovered using the vaccine.

Adam’s BCG Vaccination Chronic Fatigue Syndrome (ME/CFS) Recovery Story


BC007 – An oligonucleotide aptamer that neutralizes G protein-coupled receptor autoantibodies. Originally developed to treat heart failure in dilated cardiomyopathy by removing functional autoantibodies. A case series in Germany showed significant improvements in four long-COVID patients. A phase 2 trial is underway in Europe.

Blood Cleanser: Apheresis in Long COVID and ME/CFS – Does it Work?

Rituximab, Cyclophosphamide, and Daratumumab – Drugs used in cancer. Øystein Fluge, a Norwegian doctor and researcher in the Department of Oncology and Medical Physics at the University of Bergen who splits his time between cancer and ME/CFS patients, has run trials and observed improvements with these drugs in subsets.

Anti-FcRn drugs and IgG degraders – Drugs that work by preventing the recycling of IgG antibodies back into the blood. Efgartigimod, a medication approved to treat myasthenia gravis, currently in a Phase 2 trial to treat post-COVID POTS, does not need another trial; however, other candidates for trial include Rozanolixizumab, Batoclimab, and Nipocalimab.

Autonomic Dysfunction:

Pyridostigmine, Midodrine, Fludrocortisone, and Desmopressin: FDA approved drugs currently used off label for POTS. The private sector has no incentive to trial these drugs, and therefore, a public effort is needed to get these drugs ‘on label’ which would increase access for patients by ensuring they are included in medical school curriculums, more easily covered by insurance, and that primary care physicians know about them. Pyridostigmine is being trialed with ME/CFS in an Open Medicine Foundation-funded trial and was able to promote energy production during an exercise test.

Lifting ME/CFS: The OMF’s Unique Two-Drug Clinical Trial to Begin Soon


ASHA-091 – A drug that works as a mitochondrial fragmentation inhibitor. Asha Therapeutics may run a long-COVID trial.

Omalizumab – Trademarked ‘Xolair’, some long-COVID patients have Mast Cell Activation Syndrome (MCAS). A trial should be run to see if those patients with high urine or serum tryptase benefit from this expensive monoclonal antibody. Formerly approved for allergic asthma, this drug was recently FDA approved to also treat food allergies.

AMX0035 – A combination of sodium phenylbutyrate and taurursodiol. Targets both the endoplasmic reticulum and mitochondria. In the fall of 2023. NIH published a paper that found high levels WASF3 in those with ME vs controls. A clinical trial for ME/CFS has been floated but not started. Long-COVID patients should also be tested for this protein and included in trials if they also have elevated levels. This drug is approved for ALS, but the drug was pulled based on poor results from a phase 3 trial.

Glymphatic flow stimulation – Some studies suggest COVID can impact glymphatic flow. No one has deeply studied the role of glymphatic flow in long-COVID sleep. Can drugs or other techniques that increase gymphatic flow treat unrefreshing sleep?

Dextro Naltrexone – A stronger form of low-dose naltrexone which temporarily blocks pain receptors, encouraging the body to produce more endorphins. Some patients experience a mild or moderate amount of relief from low dose naltrexone. While low dose naltrexone is not a cure, and although not effective for some patients, a trial should be run to understand the pathway and why this drug works for some subsets. Dextro naltrexone is not an available drug and patients do not currently have access to try it. Jarred Younger believes he will be able to get a trial underway in the near future.

Jarred Younger III : Treatments – A Better LDN and the Hunt for Microglia Inhibitors

Low-dose Aripiprazole – An antipsychotic and putative anti-neuroinflammatory at low doses, Dr. Bonilla at Stanford published a retrospective study in 2021 of its use in 101 patients at the Stanford University ME/CFS clinical practice.

Abilify Shows Promise in Retrospective Chronic Fatigue Syndrome (ME/CFS) Study

Vagus Nerve StimulationA recent study from the University of Oklahoma shows that vagus nerve stimulation improved autonomic function in a group with POTS. While not a cure, a large trial should be run to see if this can provide some relief to patients.

Vagus Nerve Stimulation in ME/CFS, FM, POTS and Long COVID – Is its Promise Being Fulfilled?

Thanks to Stephen Smith of @postviraltrials for providing input on trial suggestions



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