E2 ModerateModerate confidencePEM not requiredCase-ControlPeer-reviewedReviewed
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No reduced serum serotonin levels in patients with post-acute sequelae of COVID-19.
Mathé, Philipp, Götz, Veronika, Stete, Katarina et al. · Infection · 2025 · DOI
Quick Summary
Researchers compared serotonin levels in the blood of 34 people with long COVID (PASC) and 14 healthy people. Serotonin is a chemical in the body that affects mood and fatigue. The study found no meaningful difference in serotonin levels between the two groups, suggesting that low serotonin is probably not the main cause of long COVID symptoms.
Why It Matters
This finding challenges the hypothesis that virally induced serotonin depletion drives PASC pathogenesis, which could redirect research toward alternative biological mechanisms. For patients, it suggests that low serotonin is unlikely a primary target, potentially preventing ineffective or unnecessary treatments and freeing resources for investigation of other ME/CFS-relevant pathways.
Observed Findings
Serum serotonin levels in PASC patients did not significantly differ from healthy controls.
Most subjects in both groups had normal serotonin levels with no subnormal readings observed.
No significant serotonin differences emerged when stratifying by predominant fatigue type.
No significant serotonin differences were found based on high overall fatigue scores.
No significant serotonin differences were observed according to depression severity.
Inferred Conclusions
Peripheral serotonin is not a reliable biomarker for PASC diagnosis or characterization.
Treatment of PASC with SSRIs or tryptophan supplementation should not be based solely on the assumption of lowered serotonin levels.
Virally induced peripheral serotonin depletion is unlikely a primary pathogenic mechanism in PASC.
Remaining Questions
Does serotonin dysfunction occur at the receptor, transporter, or synaptic level despite normal serum concentrations?
Are there serotonin abnormalities in cerebrospinal fluid or specific tissues that differ from peripheral blood?
What This Study Does Not Prove
This study does not rule out serotonin dysfunction occurring at the synaptic or receptor level, only peripheral serum concentrations. It does not exclude serotonin as relevant in specific PASC subpopulations or in tissues other than blood. The cross-sectional design cannot determine whether serotonin changes precede PASC onset or whether temporal fluctuations in serotonin occur during illness.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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