Castro-Marrero, Jesús, Zaragozá, Maria-Cleofé, López-Vílchez, Irene et al. · Antioxidants (Basel, Switzerland) · 2021 · DOI
This study tested whether taking melatonin (1 mg) and zinc (10 mg) together could help reduce fatigue in ME/CFS patients. Over 16 weeks, people taking the supplement reported feeling less physically tired compared to those taking placebo, and they also reported better overall quality of life. The supplements appeared to be safe with no serious side effects reported.
ME/CFS patients have few evidence-based treatment options and frequently experience severe fatigue that limits daily functioning. This study provides preliminary evidence that a safe, inexpensive, accessible combination supplement may meaningfully reduce fatigue perception and improve quality of life, offering potential hope for symptomatic relief while research into underlying causes continues.
This study does not prove that melatonin and zinc treat the underlying biological causes of ME/CFS—it only shows perceived fatigue reduction in a small sample. The findings are correlational and may reflect placebo effects or natural symptom fluctuation; larger, longer-term studies with objective functional measures are needed before recommending this as standard treatment. The lack of significant zinc biomarker changes raises questions about whether zinc contributed meaningfully to the observed effects.
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 →
The first block is for the primary paper and is the citation you should use in research work. The atlas-snapshot line only applies if you are specifically referring to this atlas’s reading of the paper on the date shown.
Primary citation
Castro-Marrero, Jesús, Zaragozá, Maria-Cleofé, López-Vílchez, Irene, Galmés, José Luis, Cordobilla, Begoña, Maurel, Sara, et al. (2021). Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.. Antioxidants (Basel, Switzerland). https://doi.org/10.3390/antiox10071010
BibTeX
@article{mecfsatlas-castro-marrero-2021-effect-melatonin,
author = {Castro-Marrero, Jesús and Zaragozá, Maria-Cleofé and López-Vílchez, Irene and Galmés, José Luis and Cordobilla, Begoña and Maurel, Sara and Domingo, Joan Carles and Alegre-Martín, José},
title = {Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.},
journal = {Antioxidants (Basel, Switzerland)},
year = {2021},
doi = {10.3390/antiox10071010},
note = {PubMed: 34201806},
url = {https://www.mecfsatlas.com/evidence/castro-marrero-2021-effect-melatonin},
}Atlas snapshot reference
ME/CFS Atlas. Generator v1 / Scanner v1.4 / policy v0.1. Accessed 2026-05-26. https://www.mecfsatlas.com/evidence/castro-marrero-2021-effect-melatonin
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