Excessive daytime sleepiness (EDS), a condition afflicting roughly one-third of the American population, remains a perplexing and often overlooked health concern. Characterized by an overwhelming urge to fall asleep during waking hours, EDS significantly elevates the risk for severe medical conditions such as cardiovascular disease, obesity, and type 2 diabetes. Despite its prevalence and health implications, the biological underpinnings of EDS have not been fully elucidated. Now, a groundbreaking study spearheaded by researchers at Mass General Brigham and Beth Israel Deaconess Medical Center sheds new light on the molecular contributors to this condition, revealing complex interactions between diet, hormonal pathways, and metabolic processes.
In a detailed meta-analytical study published in Lancet eBioMedicine, investigators deployed cutting-edge metabolomic profiling to explore the biochemical landscape associated with EDS. Metabolites—small molecules generated through the body’s metabolic pathways—serve as crucial indicators of physiological states and dietary influences. By analyzing blood samples from a large and ethnically diverse cohort, the Hispanic Community Health Study/Study of Latinos, encompassing over 6,000 participants, the researchers identified seven blood-borne metabolites with strong associations to EDS. This meticulous cross-sectional analysis was further validated in independent cohorts including the Multi-Ethnic Study of Atherosclerosis (MESA) and studies conducted in the UK and Finland, underscoring the robustness and generalizability of the findings.
The study’s methodological rigor involved quantifying 877 metabolites using high-resolution blood metabolomics, a technique enabling precise detection of diverse biomolecules shaped by endogenous factors such as hormones and exogenous inputs like diet. Concurrently, participants’ sleepiness was assessed through a standardized questionnaire designed to capture the frequency of dozing episodes under various real-world scenarios, providing a phenotypic correlate to the biochemical data. This integrative approach allowed the researchers to bridge the gap between subjective symptomatology and objective molecular markers, a crucial advance for sleep medicine.
Among the key discoveries were metabolites linked to fatty acid metabolism, notably omega-3 and omega-6 fatty acids. These essential polyunsaturated fats, abundant in Mediterranean-style diets rich in nuts, fish, and olive oil, exhibited inverse relationships with EDS risk. This suggests a protective biochemical milieu fostered by diets promoting anti-inflammatory and neuroprotective effects. Omega fatty acids, known to influence membrane fluidity and signaling in neuronal tissues, may modulate wake-promoting neural circuits or reduce systemic inflammation that contributes to somnolence.
Intriguingly, the researchers also found that certain dietary metabolites such as tyramine—commonly elevated in fermented and overripe foods—were positively correlated with increased daytime sleepiness, particularly among males. Tyramine, a biogenic amine capable of influencing catecholamine release and vascular tone, may exert sex-specific effects on arousal systems. These findings point to a nuanced interaction between diet-derived metabolites and sex steroid-related pathways, indicating that biological sex modulates metabolic impacts on sleep regulation.
Further analysis illuminated the involvement of sex steroid metabolites, including progesterone, in sleep physiology. Progesterone metabolites are known to interact with neurotransmitter systems and influence melatonin biosynthesis, which regulates circadian rhythms. This hormone-associated metabolic signature reinforces the idea that endogenous steroid hormone biosynthesis intricately influences sleepiness, potentially altering susceptibility to EDS in hormone-dependent manners.
While the study established compelling associations, the authors acknowledge several limitations. The reliance on questionnaire-based sleepiness assessments, rather than polysomnographic studies in sleep laboratories, may introduce subjective bias or limit granularity in sleep architecture characterization. Additionally, the complexity of metabolite quantification and variability in absolute metabolite concentrations across individuals and populations presents challenges for clinical translation. Nevertheless, the study’s replication across multiple diverse cohorts addresses concerns about reproducibility and strengthens the biological relevance of the identified metabolites.
Looking forward, the identification of these metabolites opens exciting avenues for therapeutic intervention. Targeting metabolic pathways through diet modification or pharmacological agents could offer novel strategies to ameliorate EDS. In particular, the prospect of clinical trials investigating the efficacy of omega-3 and omega-6 fatty acid supplementation offers a tangible path to actionable treatment modalities. Such interventions could harness dietary components to modulate metabolite profiles, ultimately reducing daytime sleepiness and its associated health risks.
Moreover, the discovery of numerous unknown metabolites associated with EDS suggests that the metabolic landscape of sleepiness is far richer than currently understood. Ongoing research aims to characterize these novel molecules and unravel their functional roles in sleep–wake regulation. This metabolomic approach exemplifies the shift toward precision medicine in sleep disorders, emphasizing molecular profiling to tailor diagnostics and interventions.
Lead author Dr. Tariq Faquih emphasizes the transformative potential of elucidating the molecular etiology of EDS. “By integrating metabolic and genetic insights, we hope to illuminate the biological processes driving excessive sleepiness and identify early biomarkers,” Faquih explains. “This knowledge is critical for developing targeted therapies and helping patients regain alertness and improve quality of life.”
The study also highlights the intersectionality of genetic, hormonal, and environmental factors in governing sleep physiology. The sex-specific differences in metabolite associations underscore the necessity to consider biological sex in both research design and clinical management of EDS. Personalized approaches that incorporate metabolic profiling could revolutionize treatment paradigms for sleep disorders.
Beyond advancing scientific understanding, this research underscores the importance of diet as a modifiable factor influencing sleep health. With mounting evidence supporting dietary interventions for neurological and systemic diseases, the connection between Mediterranean-like dietary patterns, metabolite profiles, and reduced EDS risk adds a compelling dimension to nutritional guidance. This may catalyze public health initiatives promoting dietary strategies as a cornerstone of sleep wellness.
In summary, this large-scale metabolomic investigation elucidates pivotal molecular correlates of excessive daytime sleepiness, revealing the profound influence of steroid hormone biosynthesis and dietary metabolites. By bridging biochemical, genetic, and clinical perspectives, the study paves the way for innovative, targeted treatments addressing a major public health issue. As researchers proceed with clinical trials and deeper metabolite characterization, the prospect of mitigating EDS through metabolic modulation becomes an attainable goal.
The collaborative efforts of Mass General Brigham researchers, supported by funding from the National Institutes of Health and the JLH Foundation, exemplify the power of interdisciplinary science in unraveling complex health challenges. Their findings not only advance sleep medicine but also enrich our broader understanding of human metabolism, signaling a new era of metabolomics-driven precision health.
Subject of Research: People
Article Title: Steroid Hormone Biosynthesis and Dietary Related Metabolites Associated with Excessive Daytime Sleepiness
News Publication Date: 19-Aug-2025
Web References:
https://www.thelancet.com/journals/EBIOM/article/PIIS2352-3964(25)00325-1/fulltext
http://dx.doi.org/10.1016/j.ebiom.2025.105881
References:
Faquih, T. et al. “Steroid Hormone Biosynthesis and Dietary Related Metabolites Associated with Excessive Daytime Sleepiness.” Lancet eBioMedicine, DOI: 10.1016/j.ebiom.2025.105881
Keywords: Sleep disorders, Sleep deprivation, Sleep, Neurotransmitters, Hormones, Diets, Dietetics, Preventive medicine
