Study details

For the study, researchers performed an analysis of metabolites in the blood of patients with long COVID and compared them to patients who completely recovered from COVID-19. The researchers also used animal models, recreating infection and viral persistence.

They found that interferons can cause inflammation, which can reduce the body's ability to absorb the amino acid tryptophan, which helps produce serotonin in the gut. Blood clots that form after a COVID-19 infection can also hurt the body's ability to circulate serotonin.

Lower levels of serotonin can then disrupt the vagus nerve system, which is the connection between the gut and brain. Serotonin plays a role in short-term memory, and the researchers suggested that lower levels of serotonin could lead to "brain fog," memory problems, and other neurocognitive issues.

The researchers found that the more symptoms of long COVID a patient had, the lower their peripheral levels of serotonin.

"We found that it's really across the board that these decreases of serotonin are noted, so it's not only in those with neurocognitive effects, but also with pulmonary effects and cardiovascular dysfunction," said Benjamin Abramoff, director of Penn Medicine's Post-COVID Assessment and Recovery Clinic and a co-author on the study.

"These effects can explain a wide spectrum of symptoms that our patients with long COVID have," Abramoff added. "It certainly points us in a direction of the underlying root causes."

Discussion

David Putrino, Nash Family Director of the Cohen Center for Recovery From Complex Chronic Illness at Ichahn Mount Sinai, said the study is a "beautiful work."

"This serotonin finding really makes sense in the context that they placed it, this idea that we could be having reduced intestinal absorption in long Covid of certain chemicals like tryptophan," he said. "That is directly related to gut dysbiosis that has been seen in long COVID over and over again."

Putrino added that establishing serotonin depletion in animal models also helped explain the mechanisms of the disease while preventing any doubts of reports of brain fog from patients.

"When you have such a potent group of folks looking to minimize long COVID, being able to very directly show it in an animal model really does show you that we're not dealing with some sort of psychosomatic disorder," he said.

Putrino said he doesn't recommend doctors test patients to diagnose long COVID but recommends clinicians add it to the list of understanding where dysfunction may come from in their long COVID patients.

"Not everyone's going to have low serotonin. Not everyone's going to have low morning cortisol. Not everyone's going to have T cell exhaustion," he said. "But these are the places we should be looking."

"This is an elegant and important paper that provides new mechanistic insights into the myriad ways immune challenges outside of the brain can influence cognitive functions," said Michelle Monje, professor of neurology and neurological sciences at Stanford University. "These findings underscore the interconnectedness of brain function with the physiology of other organ systems."

"This is an excellent study that identifies lower levels of circulating serotonin as a mechanism for long COVID," said Akiko Iwasaki, an immunologist at Yale University. She added that the researchers "showed that one-two-three punch to the serotonin pathway then leads to vagal nerve dysfunction and memory impairment."

Wes Ely, a pulmonologist and critical care physician at Vanderbilt University Medical Center, said he is certain viral persistence and inflammation combine in long COVID patients and praised the study for connecting them to serotonin levels.

"It's encouraging to read these data. What we have to do is put our patient's cap on because we've got a long way to go to really understand the biology of this disorder, long COVID, and other post-infectious syndromes," he said. "This is what's so hopeful. What we're doing here is we're building hypotheses that should be tested to understand and treat long COVID better and then have those same discoveries applied to future pandemics and future post-infectious syndromes." (Cooney, STAT, 10/16; Belluck, New York Times, 10/16)

According to an  analysis  published in JAMA Internal Medicine, six factors could significantly increase your risk of developing long COVID — and one factor could protect you.