A physician talks to a patient while wearing a past.Share on Pinterest
New research suggests a link between long COVID brain fog, low serotonin, and gut inflammation. FG Trade/Getty Images
  • Long COVID is notoriously hard to diagnose and treat.
  • New research points to a link between lingering COVID-19 infection in the gut and diminished serotonin levels as a potential mechanism for long COVID-related brain fog.
  • Drugs that affect serotonin levels, such as SSRIs, could someday play a role in treatment.

Scientists may have unlocked a major piece of the mystery surrounding the mysterious cognitive issues associated with “long COVID,” and potential new treatment options.

Research published October 16 in the journal Cell investigates a comprehensive relationship between SARS-Cov-2, the virus that causes COVID-19, gut health, and serotonin, a neurotransmitter.

Specifically, researchers have discovered a link between brain fog associated with long COVID and diminished serotonin levels.

Using both human and animal studies, researchers found a link between low circulating serotonin levels in the blood and cognitive problems. The study is the first to combine different hypotheses about serotonin, the gut, and long COVID into a cohesive, unified theory.

“This is a beautiful and important study, Dr. Michelle Monje, PhD, a professor of neurology at Stanford University, told Healthline. Monje wasn’t affiliated with the research.

“The mechanism uncovered by this study highlights one of several ways that COVID and other inflammatory conditions can influence the brain and contribute to “brain fog” symptoms,” Monje added.

Prof. Damien Keating, PhD, director of the Flinders Health and Medical Research Institute at Flinders University in South Australia, whose previously published research explored the link between serotonin in the gut and COVID-19, called the study “groundbreaking.”

“[This study] brings together a number of aspects related to COVID-19 and long COVID, as all were shown to be linked to mechanisms associated with gut serotonin,” Keating, who wasn’t affiliated with the research, told Healthline.

At the center of the hypothesis is the neurotransmitter serotonin. Researchers have looked at the connection between serotonin and COVID-19 at various times, but the results have never been so compelling.

Although scientists worldwide have attempted to answer questions about the cognitive issues caused by long COVID with varying success, this new research may be the most complete hypothesis about these symptoms and their biological underpinnings.

The multi-pronged study began in the post-COVID clinic of the University of Pennsylvania, where researchers identified that patients with long COVID had low levels of serotonin in their bloodstream.

Serotonin isn’t just a “feel good” hormone but an important part of the body’s biochemistry that regulates bowel function, sleep, and the nervous system. Serotonin can also affect the brain and memory.

As researchers began piecing together the connection between long COVID, low serotonin levels, and cognitive problems in human patients, they also wanted to see if they could confirm their findings in an experimental study, they also wanted to confirm their findings in an experimental study with mice.

They observed that infected mice had similar issues related to low serotonin and cognitive impairment. When serotonin levels were restored using an SSRI, so did cognitive function.

The research investigates a long and complex series of biological mechanisms that begin in the gut and ultimately lead to cognitive symptoms in the brain.

Researchers have observed for some time that SARS-Cov-2, the virus that causes COVID-19, has been found to linger in the gut of people who’ve had COVID-19, even after symptoms have cleared.

These viral remnants can persist as a reservoir inside the gastrointestinal tract. This theory has consistently been supported by the presence of the SARS-Cov-2 virus in stool, even long after the virus has appeared to clear from the body.

“You have this pathway, this biochemical and biological pathway that is inhibited at its onset, and that has consequences, the end result of which is a reduction in serotonin,” said Dr. William Schaffner, a professor of infectious diseases at Vanderbilt University Medical School, told Healthline. Schaffner wasn’t affiliated with the research.

“These viral fragments continue to stimulate and provoke a chronic inflammatory response, which leads to a reduction in the absorption of tryptophan, which is a precursor to the chemical development of serotonin. Now it’s the circulating serotonin diminution, that may well relate to the brain fog and confusion kind of symptoms, ” he told Healthline.

Since the COVID-19 pandemic, the phrase “long COVID” has been hard to pin down.

Today, there is general acceptance within the medical community about what long COVID is.

Still, it is difficult to diagnose and treat the condition due to the myriad lingering, sometimes debilitating symptoms (over 200, according to the World Health Organization) in about 10–20% of people who develop COVID-19.

Now that a credible hypothesis has been formed that addresses the mechanism for at least some of those symptoms, what does that mean for treatment? In the short term, nothing.

However, the research has opened the door to investigate selective serotonin reuptake inhibitors (SSRIs), traditionally used in depression treatment, and similar drugs that affect serotonin levels in the body as a potential adjunct treatment for long COVID. However, rigorous clinical trials would have to occur before any such treatment option would be viable.

For now, treating long COVID is all about treating the specific symptoms, which can vary from person to person. And, while this new research is substantial, it only looks at a small number of the many symptoms reported by individuals dealing with the disease.

“The number one thing that I’m hearing from people with long COVID is that they have these symptoms that physicians are not understanding and not connecting the dots. The diagnosis of long COVID hasn’t been clearly defined because the symptoms are so vague,” said Dr. Adupa Rao, an associate professor of clinical medicine at the Keck School of Medicine at the University of Southern California.

Rao, who isn’t affiliated with the research, is one of the founder’s of USC’s Covid Recovery Clinic, and is currently overseeing a clinical trial to assess the effects of the ketogenic diet on gut inflammation associated with COVID-19.

“This research highlights how complex this long COVID diagnosis can be. It requires really thinking outside the box to establish a diagnosis and hopefully a treatment option in the near future,” he said.

New research suggests that diminished blood serotonin levels could cause cognitive impairment and “brain fog” in long COVID patients.

Serotonin levels appear to be diminished due to a series of downstream biological mechanisms caused by COVID-19-associated inflammation in the gut.

Focusing on drugs that affect serotonin levels could offer new treatment options for cognitive impairment caused by COVID-19, although none are currently on the horizon.