Peripheral Serotonin Depletion

1 Wong et al. 2023 — Serotonin Reduction in Post-Acute Sequelae of Viral Infection

Full Citation:: Wong AC, Devason AS, Umana IC, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023;186(22):4851-4867.e20. (Wong et al. 2023) DOI:: 10.1016/j.cell.2023.09.013 PMID:: 37848036 Study Design:: Multi-mechanism translational study Sample Size:: Multiple cohorts; ~100+ Long COVID patients + controls + animal models Key Findings::

- Reduced serum serotonin in Long COVID via 3 converging mechanisms: (1) IFN-gamma-driven IDO activation diverting tryptophan from serotonin synthesis; (2) viral persistence reducing enteric serotonin absorption (impaired enterochromaffin cell function); (3) impaired platelet serotonin storage and release
- Serotonin reduction correlates with fatigue and cognitive impairment
- Mechanism extends to other post-viral fatigue states relevant to ME/CFS

Conclusion:: Peripheral serotonin depletion is a tractable mechanism in post-viral fatigue; proposed as biomarker and therapeutic target. Limitations:: Single group (Penn); platelet serotonin measurements need standardization (per Anderson 2024). Certainty:: 0.85

2 Mathé et al. 2025 — No Reduced Serum Serotonin in PASC (Null Result)

Full Citation:: Mathé P, Götz V, Stete K, et al. No reduced serum serotonin levels in patients with post-acute sequelae of COVID-19. Infection. 2025;53(1):463-466. (Mathé et al. 2025) DOI:: 10.1007/s15010-024-02397-5 PMID:: 39356444 Study Design:: Cross-sectional replication attempt Key Findings::

- No significant difference in serum serotonin between PASC and controls
- Contradicts Wong et al.\ 2023 Cell study
- Differences may relate to patient selection, timing, or sample handling

Conclusion:: Important negative finding; robustness of peripheral serotonin depletion requires clarification. Limitations:: Smaller sample; single center; unstandardized measurement. Certainty:: 0.60

3 Anderson et al. 2024 — Long COVID and Peripheral Serotonin: Commentary

Full Citation:: Anderson GM, Cook EH, Blakely RD, Sutcliffe JS, Veenstra-VanderWeele J. Long COVID-19 and peripheral serotonin: a commentary and reconsideration. Journal of Inflammation Research. 2024;17:2169-2172. (Anderson et al. 2024) DOI:: 10.2147/JIR.S456000 PMID:: 38628604 Study Design:: Methodological commentary Key Findings::

- Concerns: platelet-derived serotonin variability; platelet count/handling confounds; clinical significance unclear

Conclusion:: Calls for standardized measurement protocols and independent replication. Limitations:: Commentary; no primary data. Certainty:: 0.65

4 Thorpe et al. 2026 — Peripheral Serotonin in SARS-CoV-2 and Long COVID

Full Citation:: Thorpe DW, Jones LA, Martin AM, et al. The role of peripheral serotonin in SARS-CoV-2 infectivity, COVID-19 treatment and long COVID. Immunology and Cell Biology. 2026;104(4):368-376. (Thorpe et al. 2026) DOI:: 10.1111/imcb.70097 PMID:: 41795913 Study Design:: Narrative review Key Findings::

- Enterochromaffin cell serotonin modulates gut inflammation, immunity, platelet function
- SARS-CoV-2 infects enterochromaffin cells via ACE2, disrupting serotonin synthesis
- Depletion contributes to fatigue, cognitive impairment, autonomic dysfunction

Conclusion:: Peripheral serotonin as biomarker and therapeutic target. Certainty:: 0.70

5 Bai et al. 2024 — Serotonin Signaling as Therapeutic Target

Full Citation:: Bai L, Zhou F, Zhang L. Serotonin signaling: a new player and therapeutic target beyond long-haul coronavirus disease. MedComm. 2024;5(4):e523. (Bai, Zhou, and Zhang 2024) DOI:: 10.1002/mco2.523 PMID:: 38562420 Key Findings::

- Viral persistence reduces enterochromaffin serotonin; IFN-gamma-IDO diverts tryptophan; platelet serotonin storage impaired
- Extends serotonin hypothesis to ME/CFS

Conclusion:: Serotonin signaling as tractable therapeutic target. Limitations:: Review; speculative therapeutic claims. Certainty:: 0.50

6 Taenzer et al. 2023 — Urine Metabolomics in Long COVID

Full Citation:: Taenzer M, Löffler-Ragg J, Schroll A, et al. Urine metabolite analysis to identify pathomechanisms of long COVID: a pilot study. International Journal of Tryptophan Research. 2023;16:11786469231220781. (Taenzer et al. 2023) PMID:: 38144169 Key Findings::

- Urine metabolomics shows tryptophan pathway shifts predicting reduced serotonin synthesis

Conclusion:: Systemic evidence of tryptophan diversion in post-COVID fatigue. Limitations:: Pilot; small sample. Certainty:: 0.45

7 Raij and Raij 2024 — Peripheral Serotonin in CFS and Hypothyroidism

Full Citation:: Raij T, Raij K. Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome. Frontiers in Endocrinology. 2024;15:1358404. (Raij and Raij 2024) PMID:: 38505756 Sample Size:: n=38 ME/CFS + hypothyroid + controls Key Findings::

- Lower serotonin associated with fatigue severity across both conditions
- L-carnitine correlated with serotonin levels (mitochondrial link)

Limitations:: Small cross-sectional; unreplicated. Certainty:: 0.55

8 Che et al. 2025 — Heightened Innate Immunity in ME/CFS (Lipkin Group)

Full Citation:: Che X, Ranjan A, Guo C, et al. Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS. NPJ Metabolic Health and Disease. 2025;3(1):34. (Che et al. 2025) PMID:: 40903540 Study Design:: Multi-omic analysis; multi-center collaborative Key Findings::

- Heightened innate immunity with tryptophan pathway alterations; inflammatory signatures linked to tryptophan diversion from serotonin

Limitations:: Tryptophan/serotonin not primary focus. Certainty:: 0.70

9 Wirth and Scheibenbogen 2026 — Neurotransmitter Imbalance in ME/CFS

Full Citation:: Wirth KJ, Scheibenbogen C. Imbalance of excitatory and inhibitory neurotransmitter systems in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2026;27(9):4041. (Wirth and Scheibenbogen 2026) PMID:: 42123618 Key Findings::

- Peripheral serotonin depletion co-occurs with altered central serotonergic signaling; part of global neurotransmitter network disruption

Certainty:: 0.65

10 Gunning et al. 2016 — POTS and Platelet Serotonin Deficiency

Full Citation:: Gunning WT 3rd, Karabin BL, Blomquist TM, Grubb BP. Postural orthostatic tachycardia syndrome is associated with platelet storage pool deficiency. Medicine (Baltimore). 2016;95(37):e4849. (Gunning et al. 2016) PMID:: 27631244 Sample Size:: n=181 POTS patients Key Findings::

- 81% of POTS patients had delta-granule storage pool deficiency; platelet serotonin significantly lower in POTS vs controls

Conclusion:: POTS is a low serotonin disorder. Limitations:: Retrospective; single center. Certainty:: 0.65

11 Raziq et al. 2021 — Serotonin in POTS and Vasovagal Syncope

Full Citation:: Raziq H, Fayyaz H, Azhar R, Hayyat A, Waqas S. Association of serotonin levels in patients of vasovagal syncope and postural tachycardia syndrome. J Pak Med Assoc. 2021;71(8):1963-1966. (Raziq et al. 2021) PMID:: 34418010 Key Findings::

- Lower serotonin in both POTS and VVS vs controls

Limitations:: Small; unreplicated. Certainty:: 0.40

12 Mar et al. 2014 — SSRI Hemodynamic Effects in POTS (RCT)

Full Citation:: Mar PL, Raj V, Black BK, et al. Acute hemodynamic effects of a selective serotonin reuptake inhibitor in postural tachycardia syndrome: a randomized, crossover trial. Journal of Psychopharmacology. 2014;28(2):155-161. (Mar et al. 2014) PMID:: 24227635 Sample Size:: n=20, randomized crossover Key Findings::

- SSRI increased standing HR and worsened symptoms in POTS; consistent with low serotonin hypothesis

Limitations:: Acute only; single dose. Certainty:: 0.75

13 Loçasso et al. 2024 — IL-6 and Serotonin in Fibromyalgia

Full Citation:: Loçasso FA, Filho HA, Alvarenga RMP, et al. Assessing the impact of IL-6 and serotonin on pain and symptomatology in fibromyalgia. J Pers Med. 2024;14(8):886. (Loçasso et al. 2024) PMID:: 39202077 Key Findings::

- Lower serotonin correlated with higher pain in FM; IL-6 inversely correlated with serotonin

Limitations:: Small (~40); unreplicated. Certainty:: 0.45

14 Paredes et al. 2019 — Serotonin, Pain Disorders, and Estrogen

Full Citation:: Paredes S, Cantillo S, Candido KD, Knezevic NN. An association of serotonin with pain disorders and its modulation by estrogens. Int J Mol Sci. 2019;20(22):5729. (Paredes et al. 2019) PMID:: 31731606 Key Findings::

- Serotonin modulates pain via 5-HT1A (inhibitory) and 5-HT2A/3 (excitatory); estrogen modulates serotonergic signaling; peripheral depletion may amplify pain

Certainty:: 0.60

15 Audhya et al. 2012 — Platelet Serotonin Correlates with CSF (r=0.97)

Full Citation:: Audhya T, Adams JB, Johansen L. Correlation of serotonin levels in CSF, platelets, plasma, and urine. Biochim Biophys Acta. 2012;1820(10):1496-1501. (Audhya, Adams, and Johansen 2012) PMID:: 22664303 Key Findings::

- Platelet serotonin correlates with CSF at r=0.97 in humans and rats using optimized siliconized-glassware HPLC/MS protocol
- Plasma (r=0.57-0.77) and urine (r=0.62-0.67) correlations weaker
- Validates platelet serotonin as minimally invasive CNS serotonin surrogate

ME/CFS Relevance:: Foundational for platelet serotonin index (PSI) as ME/CFS biomarker Certainty:: 0.80

16 Szeitz & Bandiera 2018 — Serotonin Analytical Methodology Review

Full Citation:: Szeitz A, Bandiera SM. Analysis and measurement of serotonin. Biomed Chromatogr. 2018;32(1):e4135. (Szeitz and Bandiera 2018) PMID:: 29135035 Key Findings::

- Comprehensive review of serotonin analytical methods: UV, fluorescence, HPLC, LC-MS/MS
- Covers pre-analytical variables, platelet-rich vs platelet-poor plasma, reference ranges

ME/CFS Relevance:: Essential reference for standardizing PSI assay protocols Certainty:: 0.85

17 de Jong et al. 2010 — Automated LC-MS/MS Serotonin Assay

Full Citation:: de Jong WHA, Wilkens MHL, de Vries EGE, Kema IP. Automated mass spectrometric analysis of urinary and plasma serotonin. Anal Bioanal Chem. 2010;396(7):2609-2616. (Jong et al. 2010) PMID:: 20140664 Key Findings::

- Validated on-line SPE-LC-MS/MS with 6-min run time and LOQ 0.9 nmol/L in plasma
- Established urinary reference interval (10-78 µmol/mol creatine, n=120)

ME/CFS Relevance:: Clinical-scale throughput suitable for PSI deployment Certainty:: 0.80

18 Chen et al. 2012 — Polyphenols Inhibit IDO-1 Enzymatic Activity

Full Citation:: Chen SS, Corteling R, Stevanato L, Sinden J. Polyphenols inhibit indoleamine 3,5-dioxygenase-1 enzymatic activity — a role of immunomodulation in chemoprevention. Discov Med. 2012;14(78):327-333. (S. S. Chen et al. 2012) PMID:: 23200064 Key Findings::

- IDO-1 inhibition potency: apigenin > wogonin > chrysin > baicalein > genistein > quercetin
- Curcumin potently inhibits IDO-1 but cytotoxic to neural stem cells
- IC50s in low µM range

ME/CFS Relevance:: Dietary polyphenols may suppress IDO activity and restore tryptophan for serotonin synthesis Certainty:: 0.65

19 Chen et al. 2012 — Natural IDO Inhibitors in Neural Stem Cells

Full Citation:: Chen S, Corteling R, Stevanato L, Sinden J. Natural inhibitors of indoleamine 3,5-dioxygenase induced by interferon-gamma in human neural stem cells. Biochem Biophys Res Commun. 2012;429(1-2):117-123. (S. Chen et al. 2012) PMID:: 23063682 Key Findings::

- Apigenin, baicalein, chrysin, wogonin inhibit IDO-1 with IC50s comparable to indomethacin
- Curcumin inhibits IDO-1 but shows cytotoxicity
- Inhibition post-translational (mRNA/protein unchanged); flavone backbone is IDO-1 pharmacophore

ME/CFS Relevance:: Identifies natural compounds for tryptophan-serotonin salvage strategies in inflammatory states Certainty:: 0.65

20 Jung et al. 2010 — Curcumin Suppresses IDO via COX-2/PGE2 Pathway

Full Citation:: Jung ID, Jeong YI, Lee CM, et al. COX-2 and PGE2 signaling is essential for the regulation of IDO expression by curcumin in murine bone marrow-derived dendritic cells. Int Immunopharmacol. 2010;10(7):760-768. (Jung et al. 2010) PMID:: 20399909 Key Findings::

- Curcumin suppresses IFN-γ-induced IDO expression via COX-2/PGE2 inhibition
- Acts upstream of IDO transcription, not on enzymatic activity directly

ME/CFS Relevance:: Anti-inflammatory IDO-suppression pathway relevant to restoring tryptophan→serotonin flux Certainty:: 0.60

21 Meyer et al. 2015 — 5-HTTLPR Genotype Predicts CFS Severity

Full Citation:: Meyer B, Nguyen CBT, Moen A, et al. Maintenance of chronic fatigue syndrome (CFS) in young CFS patients is associated with the 5-HTTLPR and SNP rs25531 A > G genotype. PLoS One. 2015;10(10):e0140883. (Meyer et al. 2015) PMID:: 26473596 Study Design:: Genotype-phenotype association study Sample Size:: 120 CFS patients (12-18 years) Key Findings::

- SS or SLG genotypes (low SERT expression) associated with fewer steps/day and higher disability at 30 weeks vs LA carriers
- SLC6A4 variation directly influences CFS maintenance and severity
- Replicates/extends Narita 2003 findings

Certainty:: 0.70

22 Bull et al. 2009 — SERT and IL-6 Polymorphisms in IFN-alpha-Induced Fatigue

Full Citation:: Bull SJ, Huezo-Diaz P, Binder EB, et al. Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Mol Psychiatry. 2009;14(12):1095-1104. (Bull et al. 2009) PMID:: 18458677 Study Design:: Prospective pharmacogenetic study Key Findings::

- SERT LL genotype (high-expression) associated with greater fatigue during IFN-alpha + ribavirin treatment
- IL-6 -174CC genotype independently associated with fatigue
- Gene-gene interaction between inflammatory signaling and SERT

ME/CFS Relevance:: Parallel model for cytokine-driven fatigue; demonstrates SERT genetics modulate fatigue susceptibility Certainty:: 0.65

References

Anderson, G. M., E. H. Cook, R. D. Blakely, J. S. Sutcliffe, and J. Veenstra-VanderWeele. 2024. “Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration.” Journal of Inflammation Research 17: 2169–72. https://doi.org/10.2147/JIR.S456000.

Audhya, Tapan, James B Adams, and Leah Johansen. 2012. “Correlation of Serotonin Levels in CSF, Platelets, Plasma, and Urine.” Biochimica Et Biophysica Acta (BBA) — General Subjects 1820 (10): 1496–1501. https://doi.org/10.1016/j.bbagen.2012.05.012.

Bai, L., F. Zhou, and L. Zhang. 2024. “Serotonin Signaling: A New Player and Therapeutic Target Beyond Long-Haul Coronavirus Disease.” MedComm 5 (4): e523. https://doi.org/10.1002/mco2.523.

Bull, S J, P Huezo-Diaz, E B Binder, J F Cubells, G Ranjith, C Maddock, C Miyazaki, et al. 2009. “Functional Polymorphisms in the Interleukin-6 and Serotonin Transporter Genes, and Depression and Fatigue Induced by Interferon-Alpha and Ribavirin Treatment.” Molecular Psychiatry 14 (12): 1095–1104. https://doi.org/10.1038/mp.2008.48.

Che, X., A. Ranjan, C. Guo, K. Zhang, R. Goldsmith, S. Levine, K. J. Moneghetti, et al. 2025. “Heightened Innate Immunity May Trigger Chronic Inflammation, Fatigue and Post-Exertional Malaise in ME/CFS.” NPJ Metabolic Health and Disease 3 (1): 34. https://doi.org/10.1038/s44324-025-00079-w.

Chen, S, R Corteling, L Stevanato, and J Sinden. 2012. “Natural Inhibitors of Indoleamine 3,5-Dioxygenase Induced by Interferon-Gamma in Human Neural Stem Cells.” Biochemical and Biophysical Research Communications 429 (1-2): 117–23. https://doi.org/10.1016/j.bbrc.2012.10.009.

Chen, Sophie S, Randolph Corteling, Lara Stevanato, and John Sinden. 2012. “Polyphenols Inhibit Indoleamine 3,5-Dioxygenase-1 Enzymatic Activity — a Role of Immunomodulation in Chemoprevention.” Discovery Medicine 14 (78): 327–33.

Gunning, W. T., B. L. Karabin, T. M. Blomquist, and B. P. Grubb. 2016. “Postural Orthostatic Tachycardia Syndrome Is Associated with Platelet Storage Pool Deficiency.” Medicine (Baltimore) 95 (37): e4849. https://doi.org/10.1097/MD.0000000000004849.

Jong, Wilhelmina HA de, Marianne HL Wilkens, Elisabeth GE de Vries, and Ido P Kema. 2010. “Automated Mass Spectrometric Analysis of Urinary and Plasma Serotonin.” Analytical and Bioanalytical Chemistry 396 (7): 2609–16. https://doi.org/10.1007/s00216-010-3466-5.

Jung, I D, Y I Jeong, C M Lee, K T Noh, S K Jeong, S H Chun, O H Choi, et al. 2010. “COX-2 and PGE2 Signaling Is Essential for the Regulation of IDO Expression by Curcumin in Murine Bone Marrow-Derived Dendritic Cells.” International Immunopharmacology 10 (7): 760–68. https://doi.org/10.1016/j.intimp.2010.04.006.

Loçasso, F. A., H. A. Filho, R. M. P. Alvarenga, S. L. Schimidt, F. K. Fiorelli, P. D. S. Ramos, S. C. L. Leidersnaider, et al. 2024. “Assessing the Impact of IL-6 and Serotonin on Pain and Symptomatology in Fibromyalgia: An Exploratory Clinical Study.” Journal of Personalized Medicine 14 (8): 886. https://doi.org/10.3390/jpm14080886.

Mar, P. L., V. Raj, B. K. Black, I. Biaggioni, C. A. Shibao, S. Y. Paranjape, W. D. Dupont, D. Robertson, and S. R. Raj. 2014. “Acute Hemodynamic Effects of a Selective Serotonin Reuptake Inhibitor in Postural Tachycardia Syndrome: A Randomized, Crossover Trial.” Journal of Psychopharmacology 28 (2): 155–61. https://doi.org/10.1177/0269881113512911.

Mathé, P., V. Götz, K. Stete, D. Walzer, H. Hilger, S. Pfau, M. Hofmann, S. Rieg, and W. V. Kern. 2025. “No Reduced Serum Serotonin Levels in Patients with Post-Acute Sequelae of COVID-19.” Infection 53 (1): 463–66. https://doi.org/10.1007/s15010-024-02397-5.

Meyer, Benedicte, Chinh Bkrong Thuy Nguyen, Aurora Moen, Even Fagermoen, Dag Sulheim, Hilde Nilsen, Vegard Bruun Wyller, and Johannes Gjerstad. 2015. “Maintenance of Chronic Fatigue Syndrome (CFS) in Young CFS Patients Is Associated with the 5-HTTLPR and SNP rs25531 A > G Genotype.” PLoS One 10 (10): e0140883. https://doi.org/10.1371/journal.pone.0140883.

Paredes, S., S. Cantillo, K. D. Candido, and N. N. Knezevic. 2019. “An Association of Serotonin with Pain Disorders and Its Modulation by Estrogens.” International Journal of Molecular Sciences 20 (22): 5729. https://doi.org/10.3390/ijms20225729.

Raij, T., and K. Raij. 2024. “Association Between Fatigue, Peripheral Serotonin, and L-Carnitine in Hypothyroidism and in Chronic Fatigue Syndrome.” Frontiers in Endocrinology 15: 1358404. https://doi.org/10.3389/fendo.2024.1358404.

Raziq, H., H. Fayyaz, R. Azhar, A. Hayyat, and S. Waqas. 2021. “Association of Serotonin Levels in Patients of Vasovagal Syncope and Postural Tachycardia Syndrome.” Journal of the Pakistan Medical Association 71 (8): 1963–66. https://doi.org/10.47391/JPMA.053.

Szeitz, András, and Stelvio M Bandiera. 2018. “Analysis and Measurement of Serotonin.” Biomedical Chromatography 32 (1): e4135. https://doi.org/10.1002/bmc.4135.

Taenzer, M., J. Löffler-Ragg, A. Schroll, P. Monfort-Lanzas, S. Engl, G. Weiss, N. Brigo, and K. Kurz. 2023. “Urine Metabolite Analysis to Identify Pathomechanisms of Long COVID: A Pilot Study.” International Journal of Tryptophan Research 16: 11786469231220781. https://doi.org/10.1177/11786469231220781.

Thorpe, D. W., L. A. Jones, A. M. Martin, R. A. Coleman, C. Allman, R. A. Peterson, and D. J. Keating. 2026. “The Role of Peripheral Serotonin in SARS-CoV-2 Infectivity, COVID-19 Treatment and Long COVID.” Immunology and Cell Biology 104 (4): 368–76. https://doi.org/10.1111/imcb.70097.

Wirth, K. J., and C. Scheibenbogen. 2026. “Imbalance of Excitatory and Inhibitory Neurotransmitter Systems in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” International Journal of Molecular Sciences 27 (9): 4041. https://doi.org/10.3390/ijms27094041.

Wong, A. C., A. S. Devason, I. C. Umana, et al. 2023. “Serotonin Reduction in Post-Acute Sequelae of Viral Infection.” Cell 186 (22): 4851–4867.e20. https://doi.org/10.1016/j.cell.2023.09.013.