“Patients taking fluvoxamine reported steadily improving fatigue and quality-of-life scores over 60 to 90 days, with fewer side effects than those on placebo, they said.

The findings were published on March 30,2026 in Annals of Internal Medicine.

The investigators enrolled 399 adults with fatigue persisting 90 or more days following a confirmed SARS-CoV-2 infection.

The trial was conducted in 22 outpatient medical sites in Brazil between October 2023 and February 2025.

The subjects were randomized to 60-day treatment with fluvoxamine (100 mg twice daily), metformin (750 mg twice daily) or matching placebo.

The study excluded people with diabetes, stroke, Lyme disease or other COVID-19 complications. It also excluded people identified as substance abusers, those with uncontrolled psychiatric conditions and those already being treated with fluvoxamine or metformin.

The primary outcome was the change between baseline and 60-day scores on the Fatigue Severity Scale (FSS), a 9-item self-reported measure of fatigue severity, with higher scores indicating worse fatigue.

The investigators reported that, at day 60, fluvoxamine subjects had achieved a significant reduction in fatigue compared with placebo subjects. And the effect was sustained at day 90.

Fluvoxamine treatment also improved quality-of-life scores, while metformin treatment showed no such benefit.

They reported that adverse events were less frequent with fluvoxamine (20.0%) than with metformin (28.8%) or placebo (29.7%).

The authors concluded, “This study supports the potential benefit of fluvoxamine in people with long COVID and fatigue lasting at least 90 days after acute COVID-19.”

This effect is called psychological cessation fatigue, and its influence on ex-smokers is not affected by how long you’ve been an ex-smoker or whether you vape to reduce cravings.  Even after years of not smoking, after withdrawal symptoms and conditioned responses are no longer strong, and even with regular hits of nicotine from vaping, the cumulative mental and emotional cost of sustaining not smoking can become so high that it overwhelms your coping skills and motivation to stay quit.

This study followed almost 2,000 adult ex-smokers in Australia, Canada, England, and the United States.  Most participants had quit smoking years before the study began.  At the start of the study, each participant expressed 1) how tired he or she was with trying to stay quit, 2) how strong the urge to smoke was in the past 24 hours, and 3) how confident he or she was in remaining an ex-smoker.

Two years later, 9.2% of the ex-smokers had begun smoking again.  The odds of relapse among ex-smokers with high fatigue were 1.64 times higher than those with low fatigue.  In other words, the ex-smokers who were most tired of trying to sustain not smoking had a 64% higher likelihood of relapse than ex-smokers who expressed no cessation fatigue.

High urge to smoke and low confidence with remaining an ex-smoker also predicted smoking relapse, but the predictive strength of cessation fatigue was both stronger and at least partly independent of these other two measures.

Lead author Dr Hua Yong, of Deakin University in Australia, says “Smoking is notoriously hard to quit.  About 95% of unassisted attempts to quit ultimately end in relapse, and even when evidence-based treatments like nicotine patches are used, relapse rates are still high.  Our research suggests that ‘tiredness with efforts to remain not smoking’ can be a useful screening tool to catch ex-smokers who are at higher risk of relapse and give them support when they need it.  We could incorporate assessment of cessation fatigue in routine health checks and be ready to provide relapse prevention interventions where needed. Ex-smokers might also be advised to seek more help when they begin to experience fatigue.”

“It was surprising to me that the prevalence was that high,” says Torri Metz, MD, vice chair of research of obstetrics and gynecology at University of Utah Health, who co-led the nationwide study. “This is something that does continue to affect otherwise reasonably healthy and young populations.”

Intersecting risks

Prior research had shown that COVID affects pregnant people in uniquely risky ways. A COVID infection during pregnancy is more likely to lead to hospitalization or death, compared to an infection outside of pregnancy. COVID also increases the risk of pregnancy-related complications such as preterm birth or stillbirth. But until this study, the risk to pregnant people of developing long COVID was unknown.

The researchers enrolled more than 1500 people nationwide who had been sick with COVID for the first time while pregnant, and assessed self-reported long COVID symptoms at least six months after infection. As part of the National Institutes of Health RECOVER project, a massive nationwide collaboration to understand and treat long COVID, the large size of the study established solid associations and provided a picture of risk that was accurate for pregnant people across demographic groups.

The researchers found that 9.3% of people who contracted COVID during pregnancy went on to experience long-term symptoms. Some of the most common long COVID symptoms participants experienced were fatigue, gastrointestinal issues, and feeling drained or exhausted by routine activities.

“This is a critical study as pregnancy and the post-partum period are one of the most vulnerable times in an individual’s life,” said David Goff, M.D., Ph.D., division director for the Division of Cardiovascular Sciences at the NIH’s National Heart, Lung, and Blood Institute. “By better understanding how individual characteristics interact with SARS-CoV-2 infection during pregnancy and lead to an increased risk of long COVID, this study yields important insights to potentially develop targeted interventions for this population.”

Because the symptoms of long COVID can overlap with the symptoms of pregnancy itself, Metz says that it’s especially important for obstetricians to be vigilant for them. “I doubt most obstetric clinicians are as aware of long COVID as perhaps we should be,” Metz says. “But people are having these symptoms, and we need to make sure that we’re not forgetting that these could be long-term manifestations of their SARS-CoV-2 infection.”

To ensure that the reported long COVID symptoms weren’t symptoms of pregnancy, the researchers did a secondary analysis that was restricted to people who reported symptoms more than 12 weeks after giving birth. The estimated risk of long COVID remained similar, confirming the initial findings.

Metz says that while the rate of long COVID observed was surprisingly high, it could underestimate the actual risk of long COVID for pregnant people. On average, people reported whether or not they had symptoms of long COVID 10 months after their initial infection, which means that the study could have missed people whose symptoms resolved earlier.

Several factors were associated with an increased risk of long COVID. People with anxiety or depression prior to their infection, as well as people with obesity, were more likely to experience lasting symptoms. Self-reported financial hardship was also associated with higher rates of long COVID, although the study could not determine whether financial difficulties were a cause or a consequence of extended symptoms.

“Our results highlight that people who were pregnant when they got COVID may have significant long-term symptoms after pregnancy, like fatigue even after simple activities that they did before the infection,” says senior author Vanessa Jacoby, MD, MAS, director of the Clinical and Translational Science Institute at UCSF, and a professor of obstetrics, gynecology, and reproductive sciences as well as Associate Vice Chancellor for Clinical Research. “We encourage people to speak with their healthcare provider about persistent symptoms to connect with appropriate support and care,” she says.

A continued concern

Previous estimates of long COVID rates following infection in the general population range from 10% to over 20%, putting the researchers’ results on the lower end of the risk spectrum. Metz says that this could be because pregnant people’s immune systems tend to react less strongly to infection. This puts pregnant people at higher risk of severe symptoms during the infection, but may put them at lower risk of long-term organ damage that can lead to persistent symptoms. Pregnant people tend to be overall younger and healthier than other populations, which could also contribute to the difference.

But the high prevalence of long COVID, including in pregnant populations, emphasizes that health practitioners should keep an eye out for its symptoms, Metz says. “We need to have this on our radar as we’re seeing patients. It’s something we really don’t want to miss. And we want to get people referred to appropriate specialists who treat long COVID.”

U of U Health’s Long COVID Clinic specializes in caring for patients with prolonged symptoms of COVID-19. Learn more about the clinic here.

About RECOVER: The National Institutes of Health Researching COVID to Enhance Recovery (NIH RECOVER) Initiative brings together clinicians, scientists, caregivers, patients, and community members to understand, diagnose, and treat long COVID. RECOVER has created one of the largest and most diverse groups of Long COVID study participants in the world. In addition, RECOVER clinical trials are testing potential interventions across five symptom focus areas. For more information, please visit recoverCOVID.org.

This research was published as “Post–Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) After Infection During Pregnancy” in Obstetrics and Gynecology.

The study was funded by the National Institutes of Health (NIH) Agreements OTA OT2HL161847, OT2HL161841 and OT2HL156812 as part of the Researching COVID to Enhance Recovery (RECOVER) Research Initiative.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

In the trial, 12 people with post-COVID-19 fatigue syndrome were randomized to take a placebo or 4 grams of creatine monohydrate per day for 6 months. Creatine intake caused a significant increase in creatine levels in leg muscles and across the brain at both 3-month and 6-month follow-ups. Creatine supplementation also led to a significant reduction in general fatigue after 3 months of intake, and it significantly improved scores for several post-COVID-19 fatigue syndrome–related symptoms—including loss of taste, breathing difficulties, body aches, headaches, and difficulties concentrating—at the 6-month follow up.

“Endorsing creatine might be of great importance in tackling this prevalent condition, but additional studies are warranted to confirm our findings in various post-COVID-19 cohorts,” said corresponding author Sergej M. Ostojic, MD, PhD, of the University of Novi Sad, in Serbia.

URL upon publication: https://onlinelibrary.wiley.com/doi/10.1002/fsn3.3597

The study – published in Physiological Reports – examined top-flight soccer players for the first time and explored the impact of long Covid on elite athletes.

It found 77 per cent of those studied fought general fatigue for 37 days and 54 per cent battled muscle fatigue for 38 days after testing negative.

GPS data from 10 games after they returned to play uncovered a four per cent decline in match performance – despite no drop in lung capacity.

The study was led by Dr Michele Girardi who worked in collaboration with the University’s School of Sport, Rehabilitation, and Exercise Sciences.

He hopes the research will help improve the return-to-play protocols for sports stars recovering from the virus.

Dr Girardi said: “This is among the first studies that looked at the impact of COVID-19 on professional footballers.

“One original aspect is that we studied players’ metabolic power during official matches following the infection.

“We were surprised to see such an impact on players’ capacity to exercise at high intensities.

“The study findings suggest that fatigue symptoms should carefully be considered for a safe and effective return-to-sport after COVID.

“We were limited on who we could study but the findings are a cause for concern and show more must be done to help players as they return to sport.

“This research also has wider implications as football players were in a unique position during the ongoing pandemic and were almost canaries in the coalmine.

“The world of football was very unusual as when we all had to self-isolate from everyone they continued to train, meet in groups and play.

“A lot is still being learnt about the impact of COVID-19 and we’re hopeful this research will help support clubs as they guide players back to play and help inform public health policy on long COVID.”

Dr Girardi worked with colleagues in Italy to study players in the Italian Serie C league for the paper entitled ‘COVID-19 disease in professional football players: symptoms and impact on pulmonary function and metabolic power during matches’.

One anonymous club opened its doors to a team of researchers, which also included academics from the University of Padua, University of Rome “Foro Italico”, University of Verona and University College London.

Data of 13 players who were infected with COVID was studied over the course of roughly six months.

They had an average age of 24, were just under 6ft and weighed around just over 12 stone.

It is now hoped the study will be expanded with more teams taking part to understand the impact of coronavirus.

Dr Girardi added: “Although this is a relatively small sample size this is vital data which shows more needs to be done to understand the impact of COVID on young healthy people.

“The virus has not gone away and sports teams are high-risk environments which can act as real vectors for infection.”

And researchers are discovering why. The SARS-CoV-2 virus, like many viruses before it, is bad news for the brain. In a study published Dec.16 in Nature Neuroscience, researchers found that the spike protein, often depicted as the red arms of the virus, can cross the blood-brain barrier in mice.

This strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain.

The spike protein, often called the S1 protein, dictates which cells the virus can enter. Usually, the virus does the same thing as its binding protein, said lead author William A. Banks, a professor  of medicine at the University of Washington School of Medicine and a  Puget Sound Veterans Affairs Healthcare System physician and researcher. Banks said binding proteins like S1 usually by themselves cause damage as they detach from the virus and cause inflammation.

“The S1 protein likely causes the brain to release cytokines and inflammatory products,” he said.

In science circles, the intense inflammation caused by the COVID-19 infection is called a cytokine storm. The immune system, upon seeing the virus and its proteins, overreacts in its attempt to kill the invading virus. The infected person is left with brain fog, fatigue and other cognitive issues.

Banks and his team saw this reaction with the HIV virus and wanted to see if the same was happening with SARS CoV-2.

Banks said the S1 protein in SARS-CoV2 and the gp 120 protein in HIV-1 function similarly. They are glycoproteins – proteins that have a lot of sugars on them, hallmarks of proteins that bind to other receptors. Both these proteins function as the arms and hand for their viruses by grabbing onto other receptors.  Both cross the blood-brain barrier and S1, like gp120, is likely toxic to brain tissues.

“It was like déjà vu,” said Banks, who has done extensive work on HIV-1, gp120, and the blood-brain barrier.

The Banks’ lab studies the blood-brain barrier in Alzheimer’s, obesity, diabetes, and HIV. But they put their work on hold and all 15 people in the lab started their experiments on the S1 protein in April. They enlisted long-time collaborator Jacob Raber, a professor in the departments of Behavioral Neuroscience, Neurology, and Radiation Medicine, and his teams at Oregon Health & Science University.

The study could explain many of the complications from COVID-19.

“We know that when you have the COVID infection you have trouble breathing and that’s because there’s infection in your lung, but an additional explanation is that the virus enters the respiratory centers of the brain and causes problems there as well,” said Banks.

Raber said in their experiments transport of S1 was faster in the olfactory bulb and kidney of males than females. This observation might relate to the increased susceptibility of men to more severe COVID-19 outcomes.

As for people taking the virus lightly, Banks has a message:

“You do not want to mess with this virus,” he said. “Many of the effects that the COVID virus has could be accentuated or perpetuated or even caused by virus getting in the brain and those effects could last for a very long time.”

This study was partially supported by a National Institute on Aging-funded COVID-19 supplement to a shared RF1 grant of Banks and Raber.​

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