Paxlovid, Vitamin Supplements Show Promise With Long COVID

Paxlovid, an antiviral approved last year to treat acute infections of COVID-19, is showing great potential as a new treatment for long COVID and may be the most promising experimental therapy now being studied for treating the condition.

New research offers strong evidence that Paxlovid provides significant benefits for COVID-19 patients who are at high risk for severe or prolonged disease, particularly older adults and those who are immunocompromised, said Lisa Sanders, MD, medical director of Yale’s Long COVID Multidisciplinary Care Center, New Haven, Connecticut. 

“We all know that long COVID is a disease smorgasbord of illnesses that have been somehow triggered by COVID. So, the question is, are there some types of these disorders that can respond to Paxlovid?” Sanders said. 

Some patients have also benefitted from supplements such as N-acetyl cysteine (NAC), as well as vitamins B, C, D and alpha lipoic acid, in which the risks are low and there are potential benefits, Sanders said.

As researchers continue to study new treatments for long COVID, for which there are no standard approved therapies, Sanders suggested doctors might turn to Paxlovid and other promising therapeutics that have shown benefits in preliminary study findings.

A study published last year by JAMA Internal Medicine reviewed the charts of nearly 300,000 veterans with severe acute COVID infections. The study found that Paxlovid treatment reduced the likelihood of developing long COVID. But a more recent study at Stanford University, Palo Alto, California — the STOP-PASC trial— did not find Paxlovid improved symptoms when given to 155 patients who had already recovered from acute infection. Participants with long COVID symptoms — and who had on average recovered from acute infection around 16 months earlier — were given a 15-day course of Paxlovid. Common symptoms like fog, fatigue, and cardiovascular or gastrointestinal symptoms did not improve.

However, long COVID likely has multiple drivers. Viral persistence may still be at play for a subset of patients. This means that despite the fact that patients recover from acute infection, hidden reservoirs of SARS-CoV-2 are still present in the body, possibly bringing on long COVID symptoms. Which means Paxlovid may help some long COVID patients but not others, Sanders explained. That’s why research needs to continue to identify the best cases for Paxlovid’s use and to identify other treatments for those who do not benefit from Paxlovid.

The PAX LC trial at Yale suggests there may not be a one-size-fits-all treatment for the condition, but a range of factors that may determine the best therapy for individual patients. Led by Yale School of Medicine’s Harlan Krumholz, MD, and Akiko Iwasaki, PhD, the study tested the effects of Paxlovid overall and was designed to determine who is most likely to benefit from antiviral treatment and gain further understanding of the immune response in Iong COVID. Results should be reported soon. 

“This acknowledges one line of thinking that long COVID is caused by viral persistence,” Sanders said. “Do these people have hidden reservoirs of the virus? The question is, are there people who seem to respond (to Paxlovid)? And if so, what characterizes these people?”

Low-Risk, High-Reward Supplements

Some of Sanders’s colleagues at Yale are focusing on long COVID’s neurological symptoms and neuropathogenesis. There’s evidence showing these symptoms — notably brain fog — can be treated with supplements. 

In 2022, a Yale study by Arman Fesharaki-Zadeh, MD, PhD, found promise in treating brain fog through a combination supplement of NAC and guanfacine — the latter developed by Yale neuroscientist, Amy Arnsten, PhD. 

The two published their study in Neuroimmunology Reports in November 2023. NAC is available over the counter and patients can get a prescription for guanfacine off-label from their physician. Guanfacine is approved to treat high blood pressure by decreasing heart rate and relaxing blood vessels. But it’s also been shown to treat attention-deficit/hyperactivity disorder (ADHD) and other cognitive issues. 

Though NAC can treat respiratory problems, it’s also commonly used to treat postconcussion symptoms. Fesharaki-Zadeh found that it helps treat brain fog, increases energy, and improves memory. When paired with guanfacine, substantial benefits were reported, such as better multitasking abilities and markedly improved organizational skills. 

Sanders is now using NAC and guanfacine for patients in her clinic. 

‘Mitochondrial Enhancement’ Through Vitamins

Sanders has also used a combination of alpha lipoic acid and vitamin C, and a combo of B vitamins that make up what’s called a “mitochondrial enhancement regimen.”

To treat a very common symptom like fatigue, Sanders prefers supplement combinations over other drugs like Modafinil or Adderall. 

Modafinil is a central nervous system stimulant used to reduce extreme sleepiness due to narcolepsy or other sleep disorders. Adderall is an amphetamine also used to treat narcolepsy as well as ADHD. Both work on your sleep and alertness, but long COVID affects the whole body, causing a physical fatigue similar to postexertional malaise (PEM) that isn’t remedied by those kinds of drugs, as studies suggest what’s involved in PEM is mitochondria, Sanders said. 

PEM is a worsening of symptoms that occurs after minimal physical or mental exertion. These are activities that should be well tolerated, but PEM causes extreme fatigue and flu-like symptoms. It’s become a hallmark symptom of long COVID after having already been a key diagnostic factor in myalgic encephalomyelitis/chronic fatigue syndrome.

As Sanders noted in her long COVID blog, which tracks the latest research and treatment options for doctors who treat long COVID patients, previous studies have shown low vitamin D levels may not only increase the risk for severe COVID-19 but delay recovery from long COVID. Those without long COVID had higher levels of vitamin D compared with long COVID patients. Vitamin D is known to boost the immune system.

Sanders found that those with vitamin D deficiencies are most likely to benefit from this approach. For people who don’t have sufficient sun exposure, which prompts the production of vitamin D, she says supplementation with 1000 IUs of vitamin D3 daily is enough for most adults.

Research is also currently being underway on the use of the diabetes drug metformin in people with acute COVID infections to determine if it may reduce the likelihood of developing long COVID. In a recent long COVID clinical trial, early outpatient COVID-19 treatment with metformin decreased the subsequent risk for long COVID by 41.3% during 10-month follow-up. 

Other New Treatments Under Study

Sanders believes the foundation for many of long COVID’s symptoms could be neurological. 

“I think that long Covid is probably a neurologic disorder,” Sanders said. 

Lindsey McAlpine, MD, director of the Yale Medicine NeuroCovid Clinic, is focusing on neuropsychiatric long COVID and the causes of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC). Symptoms of neuro-PASC include cognitive impairment, headaches, and dizziness.

“Lindsey is trying to see which parts of the brain are involved and see if there are phenotypes of brain abnormalities that match up with clinical abnormalities,” Sanders said.

The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”

Utilizing advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurological issues post covid.

Many of McAlpine’s patients with cognitive symptoms have responded well to NAC and guanfacine. 

Still, the hope is that her brain-imaging studies will bear fruit that leads to a better understanding of long COVID and new treatment methods.