Daytime Sleepiness Biomarkers: Seven Molecules That Revealed the Problem

A multicenter study published in Lancet eBioMedicine found seven molecules in the blood that were statistically associated with excessive daytime sleepiness (EDS). The clues point in two directions: steroid hormone production and dietary metabolites. Some ω-3/ω-6 fatty acids were associated with a lower risk of sleepiness, while tyramine (a biogenic amine characteristic of fermented/overripe foods) was associated with a higher risk, especially in men. The authors replicated the results in independent cohorts, which increases the credibility of the findings.

Background of the study

Excessive daytime sleepiness (EDS) is a common and under-recognized problem: up to a third of adults in the US are estimated to experience it, and the associated risks include cardiovascular and metabolic complications, decreased performance, and decreased quality of life. At the same time, EDS is often “masked” as the consequences of sleep deprivation or apnea, and the biological mechanisms remain unclear. Against this background, metabolomics – a “snapshot” of thousands of small molecules in the blood – seems a logical tool to link a subjective symptom with objective metabolic pathways.

In recent years, the field has moved toward large, multiethnic analyses. Previously, atlases of associations between nocturnal sleep phenotypes and hundreds of metabolites in large cohorts (e.g., HCHS/SOL) were constructed, providing a basis for searching for signatures of daytime sleepiness specifically and replicating them in independent samples. This strategy increases the chance that the associations found are not “local artifacts” but reproducible biological signals.

A new paper in Lancet eBioMedicine highlights two lines of evidence: steroid hormonogenesis and dietary signatures. The researchers identified seven metabolites associated with EDS, some of which fall within the steroid synthesis pathway and some of which reflect diet: higher levels of omega-3/omega-6 fatty acids were associated with less sleepiness, while the biogenic amine tyramine (typical of fermented/overripe foods) was associated with more, especially in men. This is consistent with the idea that both hormonal regulation of wakefulness and dietary composition may tweak daytime alertness.

It is important to remember that we are talking about associations, not proven causality. The authors directly call for intervention studies - to check whether dietary adjustments (including omega-3) or targeted effects on steroid pathways reduce the severity of EDS and whether they change the "signature" of metabolites in the blood. If these links are confirmed in RCTs, clinicians will have a path to personalized recommendations that take into account the patient's gender, background sleep disorders, and metabolic profile.

How was this tested?

The baseline was the multi-ethnic HCHS/SOL cohort (≈6,000 participants), where researchers measured 877 metabolites in the blood and compared them with standardized daytime sleepiness questionnaires. Then, key links were confirmed in independent samples - MESA and in studies from the UK and Finland, which reduces the risk of a "local" effect. This design helps to link the subjective symptom (daytime sleepiness) with objective biochemistry and assess the contribution of diet, hormonal levels and gender.

What exactly did they find?

The main "pattern" was in the steroid hormone pathways and adjacent lipid sub-satellites (including sphingomyelins and long-chain fatty acids). In the main model, seven metabolites were associated with EDS; three more markers were added in the male subgroup. Associations with ω-3/ω-6 looked protective (less sleepiness), and with tyramine - unfavorable (more sleepiness), and male gender modified the effect. These results are consistent with biology: lipids affect membrane fluidity and neurosignaling, and steroid metabolites affect circadian and wakefulness circuits.

Why is this important?

EDS is a common but underestimated problem associated with cardiovascular, metabolic risks and decreased quality of life. The new work provides for the first time specific molecular “anchors” that can potentially be monitored, and some of them can be modified by diet. This brings sleep medicine closer to personalized strategies: assess biomarkers, take into account gender, lifestyle and choose interventions - from nutrition to targeted pharma approaches.

How it might work (mechanical hypotheses)

The researchers identify two “axial” lines. The first is steroid hormones: metabolites of progesterone and related pathways are capable of changing the excitability of neural networks, indirectly influencing the tendency to “nod off” during the day. The second is dietary traces: the ω-3/ω-6 fatty acid profile reflects the anti-inflammatory nature of the diet, and tyramine (fermented cheeses, sausages, sauces, marinades, overripe fruits) can theoretically increase drowsiness through its effect on catecholamines and vascular tone; the effect, judging by the data, is stronger in men. These are associations for now, but they are biologically plausible and reproducible in independent samples.

What does this mean "in practice" now?

• Diet as a lever. Maintaining a diet rich in ω-3/ω-6 (fish, nuts, seeds, vegetable oils) is smart not only for your heart, but also, perhaps, for daytime alertness.
• Be careful with tyramine if you have severe daytime sleepiness (especially in men): pay attention to the proportion of fermented and “overripe” foods; this is not a ban, but a reason for an experiment with exclusion/replacement and self-observation.
• We look for the root causes. If EDS is persistent, it is important to rule out sleep apnea, sleep deficit, depression, hypothyroidism, side effects of medications - diet here is a supplement, not a replacement for diagnosis. (Self-diagnosis by questionnaire is only the first step.)

Important limitations

These are observational data: causality has not been proven. Sleepiness was assessed by questionnaire, not polysomnography; metabolomics is sensitive to methods and interpersonal/interlaboratory variability. Even with replication, there are potential confounding factors (sleep patterns, medications, chronic diseases). Therefore, it is premature to talk about an "omega-3 treatment for sleepiness" - randomized trials are needed.

What will science do next?

The authors directly name the following steps:

• Interventional RCTs: To test whether ω-3/ω-6 (from diet or supplements) reduces EDS severity and changes metabolite signature.
• Targeted validation of steroid pathways: finding out which links in hormonogenesis really “move the needle.”
• Gender awareness: unpacking male/female differences from analytics to the clinic.
• Decoding “unknown metabolites” and integrating with genetics/transcriptomics for a complete sleep multiomics.

Source (study): Faquih T. et al. Steroid Hormone Biosynthesis and Dietary Related Metabolites Associated with Excessive Daytime Sleepiness. Lancet eBioMedicine, 2025. DOI: 10.1016/j.ebiom.2025.105881.