Unraveling the Causes of Long COVID

Long COVD can be devastating for those it affects. Symptoms typically include fatigue, brain fog and memory problems that worsen after physical or mental exertion. Due to a poor understanding of the condition, no standard treatment exists and patients are often left in a lurch, exploring online forums and sharing mutual experiences in a quest for answers.

General hypotheses for the cause of long COVID include a persistent COVID infection, chronic inflammation, overactive blood clotting and a type of nervous system dysregulation involving the vagus nerve called “autonomic dysfunction.” Recent research from the University of Pennsylvania ties all of these mechanisms together with a potential unifying explanation (Wong 2023). Even more exciting is the fact that the research strongly suggests potential treatments for helping to reverse the core symptoms.

Long COVID and Reduced Serum Serotonin

Some of the initial research on long COVID focused on finding changes in the blood that differentiated long COVID patients from healthy controls. As the research progressed, consistent evidence began to emerge. The research found that some of the strongest correlations were blood levels of amino acids and amino acid metabolites, with low blood levels of serotonin having the strongest correlation with long COVID. Interestingly, cysteine, the precursor to the body’s antioxidant defenses, was also consistently low.

As the research progressed, correlational studies found that lower blood levels of serotonin also predicted the severity of long COVID symptoms, helping to confirm the relationship. Overall, the research showed that infection with COVID reduces serotonin in the bloodstream. Yet for those that recovered, serotonin levels returned to normal. Conversely, for those that developed long COVID, serotonin levels in the blood stayed depressed.

To understand the mechanism underlying the reduction in serotonin, the researchers used animal models of a chronic viral infection. The models demonstrated that continuing infection with COVID kept serotonin levels low. When the infection finally cleared, serotonin levels were restored. The model suggests that a persistent viral infection could contribute to depleted serotonin in the blood.

Inflammation from COVID Infection and Amino Acid Absorption

As the researchers continued teasing out the mechanisms, they next turned to why serotonin levels were depleted. Additional research found that blood levels of tryptophan, the amino acid precursor used by the body to manufacture serotonin, were lower in both acute and long COVID.

Initially, they suspected that tryptophan was being used in an alternate process for the production of a compound called kynurenine, a precursor to a number of brain-toxic compounds. And while levels of kynurenine are higher during acute COVID, levels return to normal in patients with long COVID, suggesting another mechanism must be the cause of the serotonin depletion.

Through a broad-based strategy, they explored intestinal cellular gene expression and discovered that the genes most strongly inhibited by viral infection and inflammation were those for nutrient absorption, particularly the genes necessary for the absorption of amino acids like tryptophan in the gut.

Based on the results, the researchers explored ways to circumvent the absorption problems. They found that they could avoid the absorption issues and increase circulating serotonin through supplementation with 5-hydroxytryptophan (5-HTP), a serotonin precursor that is absorbed through a different mechanism than tryptophan.

Inflammation, Blood Clotting and Serotonin

Another mechanism that appears to disrupt serotonin levels during COVID infection relates to reduced platelets throughout the bloodstream. Platelets are tiny cell fragments that are utilized in the production of blood clots. COVID is well known to cause problems with increased blood clotting. The excess clotting from COVID infections uses up platelets, often causing a marked decrease in their levels.

Notably, platelets aren’t just important for blood clotting. A side function of platelets involves the transport of serotonin, acting as a local storage site. While serotonin is carried freely in the bloodstream, enzymes rapidly degrade free serotonin. Storage levels in platelets therefore contribute significantly to the available levels of serotonin throughout the body. When platelets are in short supply, serotonin storage and transport becomes more limited, further depleting serotonin availability.

Memory Problems, Serotonin and the Vagus Nerve

The final piece of the puzzle related to the mechanism underlying memory problems found in patients struggling with long COVID. Animal studies exploring the effects of depleted blood levels of serotonin, either through reduced platelets or impaired amino acid absorption, both created memory problems. Interestingly, viral infections do not reduce serotonin levels in the brain, so the memory problems had to be caused by a mechanism somewhere else in the body.

The most likely connection between serotonin levels in the bloodstream and memory problems was the vagus nerve. The vagus nerve connects the brain and body and shows strong activation from levels of serotonin in the bloodstream. Further work suggested that reduced vagal stimulation from reductions in serotonin were likely disrupting memory formation.

In animal models, memory problems were effectively reversed through supplementation of the serotonin precursor 5-HTP or standard antidepressants that increase serotonin levels. Of interest, memory problems could also be reversed through the compound that gives chili peppers their hot kick, capsaicin. Capsaicin is known to stimulate nerves, and likely activates the vagus nerve in a way similar to serotonin, replacing the lost stimulation from low serotonin levels.

Conclusion

While the model is still hypothetical, the research into the underlying causes of long COVID is starting to suggest a number of possible mechanisms that explain the symptoms. Persistent COVID infection causes inflammation, disrupting tryptophan absorption and depleting platelet levels. Reduced tryptophan and platelets cause a drop in blood levels of serotonin. As serotonin decreases, stimulation of the vagus nerve is reduced, disrupting brain function causing memory problems.

The exciting thing is that the research suggests that by supporting serotonin levels, it may be possible to reverse the symptoms. I formulated SeroPlus, a supplement by Pure Encapsulations, for exactly this purpose: to increase serotonin production by a combination of 5-HTP and supplementary co-factors.

Additional benefits could also come from addressing the persistent infection and restoring normal antioxidant production in long COVID patients. Hopefully, as the research progresses, we can develop definitive treatments to reverse long COVID and end the suffering of patients struggling with this debilitating condition.

References

Wong AC, Devason AS, Umana IC, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023;186(22):4851-4867.e20. doi:10.1016/j.cell.2023.09.013