Image description: picture shows a doctor conducting research into long Covid. The title reads-Low serotonin levels might explain some Long Covid symptoms, study proposes. Me Association logo bottom right

Research: Is Serotonin reduction a cause of Long Covid and can it be treated?

ME Association Comment

This is an interesting and quite complicated hypothesis about the possible cause of Long Covid – with many of the different components overlapping with what may be causing ME/CFS

The idea that a final factor in this sequence of events is a reduction in the level of an important brain chemical called serotonin is also relevant to ME/CFS where there is some research evidence to indicate that there are changes in the level of serotonin 

However, while there is some patient evidence in ME/CFS to indicate that treatment with drugs called selective serotonin reuptake inhibitors (SSRIs) can be of benefit we also know that many other people with ME/CFS are extremely sensitive to SSRIs – even at very low doses.This suggests that low serotonin is not a consistent causative factor in Long Covid

There has also been a large clinical trial of an SSRI medication (fluoxetine) in ME/CFS. This trial failed to demonstrate any benefit 

So while the low serotonin hypothesis requires further research in Long Covid, great care should be applied to using SSRI drugs in Long Covid until their safety and efficacy have been properly assessed in clinical trials.

Dr Charles Shepherd,
Trustee and
Hon. Medical Adviser
to the ME Association.
Member of the 2018-2021 NICE Guideline Committee.
Member of the 2002 Independent Working Group on ME/CFS.

Dr Charles Shepherd

Serotonin reduction in post-acute sequelae of viral infection, Levy, M, et al. | 16 October 2023


  • Long COVID is associated with reduced circulating serotonin levels
  • Serotonin depletion is driven by viral RNA-induced type I interferons (IFNs)
  • IFNs reduce serotonin through diminished tryptophan uptake and hypercoagulability
  • Peripheral serotonin deficiency impairs cognition via reduced vagal signaling


Post-acute sequelae of COVID-19 (PASC, “Long COVID”) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction.

Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory.

These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.

Low serotonin levels might explain some Long Covid symptoms, study proposes, by Catherine Offord

Viral infection appears to influence blood concentrations of the chemical messenger—but the connection to cognitive impairment remains murky.


Viral infection appears to influence blood concentrations of the chemical messenger—but the connection to cognitive impairment remains murky

Although theories abound, there is still no clear explanation for how infection with SARS-CoV-2 leads to lingering difficulty concentrating, problems with attention and memory, and other, often-debilitating symptoms associated with Long Covid.

Now, researchers studying people who reported these and other symptoms months postinfection propose a new possibility: That inflammation in response to SARS-CoV-2 causes a drop in serotonin—a chemical messenger involved in regulating mood and digestion, among myriad other functions—which in turn causes cognitive problems.

The current work, published today in Cell, began with an observation by researchers at Penn Medicine: People seeking treatment at a post–COVID-19 clinic there had lower levels of serotonin in their blood compared with people who had fully recovered from infection. Acute COVID-19 patients also showed reduced blood serotonin.

The researchers wondered whether viral infection might be driving down levels of the compound. (Some previous studies had already hinted at a link between serotonin levels and post–COVID-19 symptoms, but other research showed no such association.) To find out, the team infected mice with SARS-CoV-2 or injected them with a drug that stimulates a similar inflammatory response. Both treatments caused a drop in blood serotonin, says study co-author and University of Pennsylvania Perelman School of Medicine microbiologist Maayan Levy.

However, researchers found no differences between treated and untreated mice in brain serotonin levels—only serotonin in the blood. Study co-author Christoph Thaiss, also at the Perelman School of Medicine, says the team’s results suggest reductions in this “peripheral” serotonin circulating outside of the brain and spinal cord influences the hippocampus by reducing activity of the vagus nerve, a bundle of sensory fibers that sends information about the body to the brain.

Several findings from the study suggest the mouse results could be relevant to understanding Long Covid, the authors say. They found that patients with Long Covid at Penn Medicine and other institutions had reduced tryptophan levels in their blood. An analysis of stool samples also identified SARS-CoV-2 RNA in a handful of the Penn Medicine patients, which the scientists speculate could reflect the virus lingering in the digestive tract and impairing tryptophan absorption.

But other researchers caution there are gaps in this theory. “As the authors point out, peripheral serotonin is separate from brain serotonin,” says Jeffrey Meyer, a neuroscientist at the University of Toronto’s Centre for Addiction and Mental Health. He’s skeptical that reduced peripheral serotonin can explain patients’ symptoms. However, because brain levels of serotonin are influenced by tryptophan concentrations in the blood, the finding of reduced tryptophan “is interesting and might be relevant to Long Covid.”

It’s important to remember that Long Covid probably has multiple types, driven by different root causes, says Akiko Iwasaki, a Yale School of Medicine immunobiologist. Low serotonin may define one particular type, she says—though more work is needed to know how this might cause cognitive symptoms. In the meantime, she says, a clinical trial of SSRIs in people with lower-than-normal serotonin levels could “bring more insights.”

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