Viral Persistence and Serotonin Reduction Can Cause Long COVID Symptoms, Research Finds

Patients with long COVID can exhibit a reduction in circulating levels of the neurotransmitter serotonin, according to a new research.

The mechanisms that cause long COVID have not been studied in depth, and treatments that are widely effective in reducing these long-term symptoms have not yet been developed.

“Many aspects of the basic biology underlying long COVID have remained unclear. As a result, we are lacking effective tools for the diagnosis and treatment of the disease,” said senior author, Maayan Levy, PhD, an assistant professor of Microbiology at Penn Medicine. “Our findings may not only help to untangle some of the mechanisms that contribute to long COVID, but also provide us with biomarkers that can help clinicians diagnose patients and objectively measure their response to individual treatments.”

Researchers evaluated the effects of long COVID in blood and stool samples from various clinical studies and in small animal models.

The researchers determined that a subset of patients with long COVID had traces of the SARS-CoV-2 virus in their stool samples even months after acute COVID-19 infection, which suggests that components of the virus remain in the gut of some patients long after infection. They found that this remaining virus, called a viral reservoir, triggers the immune system to release proteins that fight the virus, called interferons. These interferons cause inflammation that reduces the absorption of the amino acid tryptophan in the gastrointestinal (GI) tract.

Tryptophan is a building block for several neurotransmitters, including serotonin, which is primarily produced in the GI tract and carries messages between nerve cells in the brain and throughout the body.  

The researchers found that when tryptophan absorption is reduced by persistent viral inflammation, serotonin is depleted, leading to disrupted vagus nerve signaling, which in turn can cause several of the symptoms associated with long COVID, such as memory loss.

Now, our research shows that there are biomarkers we may be able to use to match patients to treatments or clinical trials that address the specific causes of their long COVID symptoms, and more effectively assess their progress,” said co-senior author, Sara Cherry, PhD, a professor of Pathology and Laboratory Medicine.

The authors took this insight one step further, to identify if replenishing tryptophan or serotonin in patients who exhibit deficiencies could treat long COVID symptoms. They demonstrated that serotonin levels could be restored, and memory impairment reversed, in small animal models through treatment with serotonin precursors or selective serotonin reuptake inhibitors (SSRIs).

“Our study provides a unique opportunity for further research to determine how many individuals with long COVID are affected by the pathway linking viral persistence, serotonin deficiency, and dysfunction of the vagus nerve and to uncover additional targets for treatments across the different symptoms patients experience.”  said co-senior author, Christoph Thaiss, PhD


Andrea C. Wong, Ashwarya S. Devason, Iboro C. Umana, Timothy O. Cox, Lenka Dohnalová, Lev Litichevskiy, Jonathan Perla, Patrick Lundgren, Zienab Etwebi, Luke T. Izzo, Jihee Kim, Monika Tetlak, Hélène C. Descamps, Simone L. Park, Stephen Wisser, Aaron D. McKnight, Ryan D. Pardy, Junwon Kim, Niklas Blank, Shaan Patel, Katharina Thum, Sydney Mason, Jean-Christophe Beltra, Michaël F. Michieletto, Shin Foong Ngiow, Brittany M. Miller, Megan J. Liou, Bhoomi Madhu, Oxana Dmitrieva-Posocco, Alex S. Huber, Peter Hewins, Christopher Petucci, Candice P. Chu, Gwen Baraniecki-Zwil, Leila B. Giron, Amy E. Baxter, Allison R. Greenplate, Charlotte Kearns, Kathleen Montone, Leslie A. Litzky, Michael Feldman, Jorge Henao-Mejia, Boris Striepen, Holly Ramage, Kellie A. Jurado, Kathryn E. Wellen, Una O’Doherty, Mohamed Abdel-Mohsen, Alan L. Landay, Ali Keshavarzian, Timothy J. Henrich, Steven G. Deeks, Michael J. Peluso, Nuala J. Meyer, E. John Wherry, Benjamin A. Abramoff, Sara Cherry, Christoph A. Thaiss, Maayan Levy. Serotonin reduction in post-acute sequelae of viral infection. Cell, 2023; DOI: 10.1016/j.cell.2023.09.013

University of Pennsylvania School of Medicine. “Viral persistence and serotonin reduction can cause long COVID symptoms, research finds.” ScienceDaily. ScienceDaily, 16 October 2023. <>.

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