If you deal with waves of drowsiness during the day, you might be among the estimated 33% of the population who suffer from excessive daytime sleepiness (EDS), a common but often unrecognized condition that's linked to a host of increased health risks including cardiovascular disease and diabetes. Now, researchers have identified the biological markers of it, bringing targeted treatment within reach.
Not surprisingly, EDS is often present in people with nighttime sleep disorders and other biological clock disturbances, as well as it being a potential indicator of other conditions such as Alzheimer's disease. But there's increasing evidence that it has its own standalone set of biomarkers. Researchers at Mass General Brigham set out to identify these biological and metabolic markers, investigating whether there were specific metabolites and pathways that might help explain or predict EDS beyond existing sleep disorders.
The team started with the health data of 6,071 individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and 877 different metabolites – the molecules made or used when the body breaks down food, drugs, chemicals or tissue (for example, fat) – which play a critical role in regulating metabolism. They also drew data from a questionnaire that gauged how often these 6,071 people experienced drowsiness during the day, covering various scenarios.
From this, adjusting for age, sex, BMI, background, smoking, alcohol, and physical activity, the researchers identified seven key metabolites that were significantly associated with daytime sleepiness. Two were steroidal (pregnenediol sulphate, tetrahydrocortisol glucuronide), three were related to and influenced by diet (dihomo-linoleate, docosadienoate, sphingomyelin) and two were unannotated metabolites, or not fully identified and understood, though likely also linked to steroid hormones such as testosterone or progesterone (X-11470, X-11444).
Each of the seven was found to have some influence on sleep, either due to low or high levels circulating in the bloodstream of the participants who reported symptoms of EDS.
The researchers then performed a replication study, looking at several other, diverse cohorts – the US Multi-Ethnic Study of Atherosclerosis dataset, the UK Biobank and Finland's Health2000 – to see if these metabolites were also present in these populations that reported daytime sleepiness.
While several of the target metabolites featured, not all were detected. That’s not because the results were wrong; instead, the other studies used different lab tools, and not every tool can see the same molecules. Still, some related chemicals did show up in the secondary studies and followed the same patterns, suggesting the biological links between diet, hormones, and sleepiness are real.
“Our study suggests diet and genetics may play an important role in EDS,” said lead author Tariq Faquih, a postdoctoral fellow in the Division of Sleep and Circadian Disorders at Brigham and Women’s Hospital. “As we learn what’s happening biologically, we are beginning to understand how and why EDS occurs, the early signs that someone might have it, and what we can do to help patients.”
The good news is that several of the metabolites identified were directly influenced by diet, suggesting that upping intake of certain foods could have a significant impact on EDS. People with higher levels of dihomo-linoleate, an omega-6 fatty acid used to build hormones and regulate inflammation, felt less sleepy during the day. Dihomo-linoleate levels be boosted by eating more nuts and whole grains, and by using vegetable oils like sunflower or safflower.
Another standout was docosadienoate (22:2n6), a lesser-known but equally important omega-6 fatty acid. Like dihomo-linoleate, higher levels of docosadienoate were linked to better alertness, and this metabolite is thought to support brain function and may play a role in regulating melatonin, the hormone that helps you fall asleep. To increase levels of this metabolite in the bloodstream, it can help to eat more fatty fish (salmon or sardines), chia seeds, flaxseeds and seaweed like nori and wakame.
The study also identified sphingomyelin, a fat found in brain and nerve cell membranes. Higher sphingomyelin levels were associated with better sleep efficiency and less sleepiness during the day. While our bodies can make sphingomyelin, levels are influenced by diet and overall metabolic health. Foods rich in choline, such as eggs, soy, dairy and lean meats can help maintain and supplement sphingomyelin levels in the blood.
While diet plays a role in EDS, the study also identified several hormone-related metabolites that were just as influential. Unlike diet-related metabolites, these molecules are made in the body, especially in the adrenal glands, and they reflect how well our internal systems are regulating things like stress, sleep, and energy.
One of the strongest signals came from pregnenediol sulphate, a metabolite formed from pregnenolone – a precursor to hormones like progesterone and testosterone. Pregnenolone acts as a neurosteroid – chemicals that help regulate brain function. They’re known to interact with GABA receptors, which are the same calming pathways targeted by sleeping pills and anti-anxiety drugs. In the study, people with higher levels of pregnenediol sulphate felt less sleepy during the day, suggesting that this hormone may play a role in brain alertness. While we can’t boost this one directly through diet, lifestyle changes like better stress management and physical activity could help.
Another important hormone byproduct was tetrahydrocortisol glucuronide, a metabolite of cortisol, the body’s primary stress hormone. Essentially, high levels of this metabolite is an indication that the body is responding to stress effectively, and people with more of it were less likely to report daytime sleepiness. While cortisol is ultimately controlled by your internal clock and stress response, maintaining a regular sleep schedule, managing stress and getting morning light exposure can all help support good levels of this metabolite.
Finally, the study identified two unannotated metabolites – X-11470 and X-11444 – that haven’t yet been chemically identified but showed strong links to reduced sleepiness. Based on genetic and chemical analyses, these compounds are likely related to hormone metabolism, and play a role in regulating the body's sleep-wake cycle.
Interestingly, four metabolites that seemed to influence sleepiness were sex-related. These male-specific ties suggest that sex hormones, fat metabolism or gut-related processes might interact differently with sleep regulation in men. Higher levels of 1-stearoyl-2-arachidonoyl-GPC – a fat molecule involved in building cell membranes and hormone signaling – were linked to less sleepiness, possibly by maintaining brain alertness. And this one can be boosted through choline-rich foods like eggs, fatty fish and dairy fat. Another related metabolite, 1-palmitoyl-2-arachidonoyl-GPC, appeared to have a similar impact. While diet doesn't have a direct influence on this one, foods rich in choline and healthy fats can support it.
Meanwhile, high levels of two male-specific metabolites – tyramine O-sulphate and phenylacetylcarnitine – were linked to increased daytime sleepiness in men. Tyramine is a compound that forms in fermented or aged foods, such as old cheeses, cured meats and some wines, and while these foods aren’t harmful for most people, they might influence fatigue in some people. Meanwhile, phenylacetylcarnitine is produced when gut bacteria break down protein and it's believed to play a role in energy output – and high levels in the blood, for men at least, were tied to more drowsiness during the day. Still, this pathway is not well understood.
The researchers caution that their research has its limitations – such as daytime sleepiness data being gathered through a survey rather than clinical studies, and precise levels of the metabolites linked to EDS weren't calculated – however, the findings pave the way for further studies, including human trials, to develop dietary or therapeutic interventions for the condition.
“Conducting a clinical trial would be a big next step and could help us understand if omega-3s and omega-6s obtained from diet could help lower risk of EDS,” added Faquih.
The study was published in the journal eBioMedicine.
Source: Mass General Brigham
