Reduced Serotonin Levels in Long COVID Patients Impair Cognition

A recent study published in Cell hypothesizes the potential pathophysiology of long COVID, also called post-acute sequelae of COVID-19 (PASC), noting that some cognitive symptoms may be linked to serotonin depletion.

The metabolomic investigation looked at human cohort studies, animal models of viral infections, and organoid cultures.

Using data from a cohort of patients with long COVID at Penn Medicine, the researchers compared the metabolite profile of patients with long COVID, patients with acute COVID, and patients with symptom-free recovery. They found significant metabolite differences and molecule depletions in patients with long and acute COVID-19. However, the most considerable depletion was serotonin.

Beyond that, the researchers noted that serotonin levels could predict the probability of full recovery and long COVID.

According to the Cleveland Clinic, low serotonin levels are linked to depression, mood disorders, anxiety, sleep disturbances, digestive issues, suicidal behavior, obsessive–compulsive disorder, post-traumatic stress disorder, panic disorders, schizophrenia, and phobias.

Although long COVID is not marked by all of the symptoms of low serotonin, there is some overlap. For example, the CDC notes that symptoms like fatigue, brain fog, headaches, sleep disturbances, depression, anxiety, diarrhea, and stomach pain can characterize long COVID.

After establishing the link between serotonin and long COVID, the researchers used transgenic mouse models to narrow down the mechanism. According to the publication, the presence of viral RNA and type I interferon-driven inflammation can contribute to three methods of serotonin depletion.

First, these compounds can reduce the intestinal absorption of tryptophan, a serotonin precursor. Next, they can cause platelet hyperactivation and thrombocytopenia, which prevent the body from effectively storing serotonin. Finally, it can increase monoamine oxidase (MAO), which degrades serotonin.

Furthermore, the researchers determined that “Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory.”

Although further research is needed, the connections made in this study may explain the neurocognitive symptoms of long COVID. Future studies may evaluate how strategies to modulate serotonin levels, such as taking selective serotonin reuptake inhibitors (SSRIs), eating more food with tryptophan, getting sunlight, and exercising, may impact long COVID symptoms.