Long COVID: Progressing Toward an Effective Treatment

"The underlying pathophysiology of long COVID remains poorly understood, and evidence-based, disease modifying treatments for it have not been identified."

Nassem Bazargan, MPH, Editorial Director, MedLitera

"Our hope is that it won't take as long with long COVID because of what we learned from HIV, but these things don't just happen instantly, it takes a lot of work."

Igho Ofotokun, MD, Emory University School of Medicine

Post-Acute Sequelae of SARS-CoV2 infection, Post-COVID-19 Syndrome and long-haul COVID-19 are various names for the perplexing illness Long COVID—a name coined by patients. Governments have designated significant funds to research this disabling condition and find a treatment for it.

Through its National Institutes of Health (NIH), the U.S. government has appropriated close to $1.8 billion for Long COVID research via its Researching COVID to Enhance Recovery (RECOVER) program. And recently, the German government announced that it had committed half a billion Euros (approximately $582 million U.S.) in research funding for a “National Decade against Post-Infectious diseases” from 2026-2036. (Marshall, M., “Long-COVID research just got a big funding boost: will it find new treatments?,” Nature, December 8, 2025).

There still is no treatment for this illness. Nonetheless, progress is being made. In this post, I provide an update on what researchers have accomplished.

Long COVID (a recap). The NIH defines Long COVID as "ongoing health problems lasting 3 months or longer after initial SARS-CoV-2 infection, encompassing diverse symptoms like fatigue, brain fog, shortness of breath, often appearing in relapsing/remitting patterns." An estimated 6% of people who become infected with SARS-CoV-2 develop Long COVID. It affects up to 400 million people worldwide. Finding a treatment that will restore the health of these patients is a top research priority.

Understanding the pathogenesis is key to finding a treatment. To find an effective treatment for a disease requires knowing the etiology (the cause) of the disease and understanding the mechanisms that underlie it, that is the pathogenesis. (To put it simply, etiology is what starts the disease and pathogenesis explains its journey and effects on the body.) In the case of Long COVID, the etiologic agent (SARS-CoV-2) was already known in the spring of 2020 when the first cases of Long COVID were seen. But the pathogenesis of the disease is still not fully understood.

Early on, researchers hypothesized that Long COVID is due to persistence of SARS-CoV-2. Researchers at Stanford University and elsewhere tested this theory by treating Long COVID patients with Paxlovid, an antiviral drug. They found that Paxlovid was ineffective in relieving the symptoms of Long COVID.

The finding that Paxlovid didn't work for Long COVID didn't rule out, however, the possibility that viral persistence is involved in the pathogenesis. In fact, one of the leading ideas about pathogenesis is the so-called persistent antigen hypothesis first put forward by my University of Minnesota colleagues, Professors Apostolos Georgopoulos and Lisa James. What antigen (viral protein) is involved is unknown, but the SARS-CoV-2 spike protein is one contender.

Several other hypotheses regarding the pathogenesis of Long COVID are, in my opinion, also highly tenable. One is the idea that Long COVID is a neurological disease. (Sutherland, S., "Long COVID Now Looks Like a Neurological Disease, Helping Doctors to Focus Treatments," Neuroscience, March, 2025). Another is that Long COVID is an inflammatory/immune disorder. (Aid, M., et al., "Long COVID involves activation of proinflammatory and immune exhaustion pathways," Nature Immunology, December 12, 2025).

Two key hypotheses. From my reading of the scientific literature on Long COVID, two highly tenable hypotheses have emerged that, in my view, deserve special emphasis. These hypotheses are not mutually exclusive; indeed, they may well reinforce one another.

First, Long COVID may represent a form of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in which the etiology—that is, the cause—is known. ME/CFS is a puzzling and disabling disease similar to Long COVID. In fact, the parallels between these two conditions are striking.

Both are characterized by profound fatigue, post-exertional malaise, unrefreshing sleep, and cognitive difficulties ("brain fog"). Both can be triggered by an infectious agent. The critical difference is that while the precise trigger for most ME/CFS cases remains elusive, in Long COVID we know the culprit: SARS-CoV-2.

A landmark study published in early 2025 found that 4.5% of post-COVID-19 participants met ME/CFS diagnostic criteria, compared with only 0.6% of participants who had not been infected. (Vernon, S.D., et al., “Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study,” Journal of General Internal Medicine, April 2025). This finding supports the hypothesis that SARS-CoV-2 infection triggers a post-infectious syndrome essentially identical to ME/CFS. Therefore, understanding Long COVID may provide a paradigm-shifting opportunity to finally crack the code of ME/CFS itself—a perplexing problem that has frustrated researchers (including me) for decades.

Second, accumulating evidence suggests that Long COVID is fundamentally a neurological disease—in common parlance, a “brain disease.” Brain imaging studies using MRI have revealed structural changes in the brains of Long COVID patients, including reductions in gray matter volume and changes in regions associated with memory and cognition. A seminal study using magnetic resonance spectroscopy found that Long COVID patients have elevated levels of glutamate in the posterior cingulate cortex—a finding remarkably similar to what researchers have found in ME/CFS patients. (Thapaliya, K., et al., “Imbalanced Brain Neurochemicals in Long COVID and ME/CFS: A Preliminary Study Using MRI,” American Medical Journal, March 2025).

In a 2025 review, researchers proposed that neuroinflammation may be central to Long COVID's pathogenesis. (Komaroff, A., Lipkin, I., Dantzer, R., “Causes and symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome,” Cell Reports Medicine, August 19, 2025). They suggest that persistent inflammation stimulates neural circuits responsible for generating "sickness behavior"—the constellation of fatigue, malaise, and cognitive slowing that characterizes both acute infection and Long COVID. This neuroinflammatory hypothesis helps explain why so many Long COVID symptoms—brain fog, fatigue, sleep disturbance, autonomic dysfunction—appear to originate in the central nervous system. If Long COVID is indeed primarily a brain disease, then therapeutic strategies targeting neuroinflammation and neural repair mechanisms may offer the most promising path forward.

Where treatments stand today. Scientists have made substantial progress in understanding the pathogenesis of Long COVID. Despite these advances, the U.S. Food and Drug Administration has yet to approve any medications specifically for its treatment. Fortunately, the therapeutic landscape is evolving rapidly. A few years ago, only a dozen or so clinical drug trials for Long COVID were underway. Now, there are more than 50.

The NIH's RECOVER-Treating Long COVID initiative has announced four agents entering clinical trials: low-dose naltrexone, an immunomodulatory opioid receptor antagonist; baricitinib, a JAK-STAT inhibitor already approved for rheumatoid arthritis; GLP-1 receptor agonists, which have anti-inflammatory and anti-thrombotic properties; and stellate ganglion block, a procedure targeting autonomic dysfunction. The Schmidt Initiative for Long COVID, a nonprofit founded by philanthropists Eric and Wendy Schmidt, is funding multiple clinical trials including tests of monoclonal antibodies and repurposed medications. In addition, private funders like the PolyBio Research Foundation have stepped up to support trials of IVIG, immunomodulators, and other therapies.

What patients can do now. While awaiting more definitive treatments, Long COVID patients have options. Many healthcare systems now offer post-recovery clinics featuring interdisciplinary teams to help patients manage their symptoms. Cognitive rehabilitation programs have shown promise in clearing the brain fog that troubles many Long COVID patients. Structured pacing—a program designed to help patients regulate their daily activities to avoid triggering post-exertional malaise—is the subject of active clinical trials and can be implemented with a trained coach.

Prevention, however, remains paramount. The only sure way to prevent Long COVID is to avoid getting COVID-19 in the first place. Multiple studies have demonstrated that COVID-19 vaccination reduces not only the risk of severe acute disease but also the risk of developing Long COVID. If you haven't yet received the most recent COVID-19 vaccine, I encourage you to get vaccinated—but as always, consult with your primary healthcare provider first.

The physician's essential role: Care and hope. At this point, I want to emphasize something that often gets lost in discussions of pathogenesis and therapeutics: the critically important role of the physician in providing not just medical care, but hope.

Hope is not wishful thinking or false promises. Rather, it is the well-founded confidence that science is advancing, that researchers are working tirelessly to understand and treat this illness, and that the patient is not alone in their struggle.

The Long COVID research trajectory gives genuine grounds for optimism. In the past year alone, scientists have published important work on blood clotting abnormalities, the impacts of exercise, evidence of viral persistence in the spinal cord, and reduced blood flow to the brain. As those involved in Long COVID research emphasize, there is reason for hope—even if progress has not come nearly fast enough for the millions suffering from this condition.

Long COVID represents one of the most significant public health challenges of our time. Nonetheless, as someone who has devoted much of my career to studying post-infectious syndromes, I remain optimistic.

We now understand more about Long COVID's pathogenesis than we ever understood about ME/CFS at the same point in its history. We have identified multiple promising therapeutic targets. And we have a global community of researchers, clinicians, and patient advocates working together toward effective treatments. We are making progress.

But Long COVID patients face an especially challenging situation. Many have been told their symptoms are "all in their head" or have been dismissed by healthcare providers unfamiliar with the condition. I am physician who has witnessed the devastating impact of ME/CFS on patients' lives. Therefore along with the best symptom management that can be offered, I believe communicating hope is one of the most important things a physician can do for a patient suffering from Long COVID.