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If you’ve been following the mystery of long Covid since it emerged in 2020, you’ll recall interferons and serotonin have been clues from the start as combatants in the body’s prolonged battles against the virus. Theories about why symptoms persist long after the acute infection has cleared often point to two suspects: viral reservoirs where SARS-CoV-2 lingers and inflammation sparked by the infection that doesn’t subside.

New research published on Monday in Cell implicates both interferons and serotonin in long Covid in a way that brings together those hypotheses and could also explain “brain fog,” or the neurocognitive difficulties people endure. A team led by researchers from the University of Pennsylvania concludes that when long Covid depletes peripheral serotonin — the kind that circulates in our bodies and not just the brain — that deficit impairs memory and other brain functions. The authors hope further research will lead to testing potential treatments.


“These effects can explain a wide spectrum of symptoms that our patients with long Covid have. It certainly points us in a direction of the underlying root causes,” Benjamin Abramoff, director of Penn Medicine’s Post-COVID Assessment and Recovery Clinic and a study co-author, said in an interview.

The mechanisms are also linked to excessive blood clotting and autonomic dysfunction, in which the nervous system can’t control processes like heart rate or blood pressure. “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,” Abramoff said. “It seems to be a universal phenomenon.”

The research rests on an analysis of metabolites in the blood that compared people with long Covid to people who recovered completely, as well as animal models recreating infection and viral persistence. Serotonin levels were markedly lower in long Covid patients, likely driven by elevated interferon levels. Some long Covid patients still had some virus in stool samples, indicating reservoirs in their gastrointestinal tracts. That’s where interferons, proteins released by the immune system to fight the virus, set off inflammation that cuts down levels of a serotonin precursor, the amino acid tryptophan.


Low serotonin levels weaken vagus nerve signaling, the gut-brain connection that could explain neurocognitive problems that are one hallmark of long Covid. Serotonin signaling can also affect blood clotting, the GI tract, and the central nervous system, making it one of the most important neurotransmitters in the body, not just in the brain where it can be involved in anxiety and depression. The more long Covid symptoms patients had, the lower their peripheral serotonin levels, the study found.

“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,” Michelle Monje, professor of neurology and neurological sciences at Stanford University, said. She was not involved in the study. “These findings underscore the interconnectedness of brain function with the physiology of other organ systems.”

David Putrino, Nash Family Director of the Cohen Center for Recovery From Complex Chronic Illness at Icahn Mount Sinai, called it “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 in an interview about the paper. He was not involved in the research. “That is directly related to gut dysbiosis that has been seen in long Covid over and over again.”

Establishing serotonin depletion in animal models was helpful in explaining the mechanism but also in dispelling doubts about patients’ reports of brain fog, Putrino said. “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.”

Last month Putrino and a team that included Yale immunologist Akiko Iwasaki reported in Nature that they’d found distinct differences in blood samples from long Covid patients compared to other patients. Immune and hormonal dysfunction showed up for long Covid patients in abnormal T cell activity, reactivation of latent viruses such as herpesviruses and Epstein-Barr, and reduction of cortisol levels.

Putrino doesn’t recommend testing patients to diagnose long Covid based on his paper or on the new Cell work, but he suggests clinicians should add it to their checklists for understanding where dysfunction is coming 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.”

Wes Ely, a pulmonologist and critical care physician at Vanderbilt University Medical Center, said he has no doubt that viral persistence and inflammation combine in long Covid and praised the Cell paper for connecting them to reduced serotonin. Not involved in the study, he also sounded a note of caution.

“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.”

Penn’s Abramoff sees his team’s research, benefitting from a collaboration with University of California, San Francisco, and its biomarker collection, as a starting point.

“I don’t think there’s at this point any changes in terms of testing that needs to be done for the individual patient or treatments that are going to be effective for long Covid,” he said. “But I think there’s new promising insight into long Covid that will be pursued and can potentially lead to really beneficial therapeutics down the road.”

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