In recent years, sugar substitutes have gained broad acceptance in public health circles, widely used in low-calorie diets and diabetes management. One compound in particular has become a mainstay of the growing market for “sugar-free” and “keto-friendly” products, appearing in everything from soft drinks to protein bars.
It offers the sweetness of sugar without the calories, spikes in blood glucose, or digestive discomfort associated with other sugar alcohols. Approved by major food safety agencies, it has become one of the most common artificial sweeteners on the global market.
Yet behind this nutritional convenience lies a set of biological questions that have not been fully resolved. A series of recent studies suggests that the compound may not be entirely passive in the body’s vascular system.
New research now adds detailed insight into how this sweetener may interact with the cells lining the blood vessels of the brain, raising further interest from the scientific community and health authorities.
Early Signs of Cellular Stress
A research team at the University of Colorado Boulder investigated the effects of erythritol, a low-calorie sugar alcohol, on human brain microvascular endothelial cells (hCMECs). These specialised cells form the inner lining of blood vessels in the brain and are essential for regulating blood flow, inflammation, and clotting.
The study, published in the Journal of Applied Physiology, exposed the cells to a level of erythritol equivalent to a single 30-gram serving, similar to what would be found in a standard artificially sweetened drink.
Within three hours, the cells exhibited a sharp increase in reactive oxygen species (ROS), a form of oxidative stress linked to cellular damage. The ROS level rose by 204 percent compared to untreated cells. To counter this, the cells elevated levels of superoxide dismutase-1 and catalase, enzymes that serve as antioxidant defences.
Despite this response, the oxidative stress remained high. The research team identified it as a possible trigger for subsequent changes in cell function, indicating that erythritol exposure could initiate biochemical strain even in the short term.
Vascular Signalling Imbalances
Beyond oxidative stress, the study observed changes in the cells’ ability to regulate nitric oxide (NO), a gas molecule that supports blood vessel dilation. Although the total amount of the enzyme endothelial nitric oxide synthase (eNOS) remained unchanged, its function was altered.
Phosphorylation of the enzyme at two regulatory sites was disrupted. This shift resulted in a 20 percent decrease in nitric oxide output, reducing the cells’ capacity to signal for vessel relaxation.
At the same time, production of endothelin-1 (ET-1), a peptide that prompts blood vessels to contract, increased by approximately 30 percent. Levels of Big ET-1, a precursor form of the molecule, were also elevated.
Taken together, the findings show that erythritol exposure changed the balance of vasodilation and vasoconstriction signals in the brain’s microvascular system. These effects may reduce the brain’s ability to maintain consistent blood flow, particularly in contexts where vascular stability is already compromised.
Altered Clot Response Under Lab Conditions
To test the sweetener’s effect on clot regulation, the researchers added thrombin, a clotting signal, to both treated and untreated cell cultures. In normal cells, this stimulus produced a 25 percent increase in tissue-type plasminogen activator (t-PA), a protein involved in dissolving clots.
In the erythritol-treated cells, however, there was no measurable increase in t-PA. The failure to release additional t-PA under stimulation suggested a blunted clot-dissolving response, a pattern associated with heightened risk of thrombotic events.
Though the study was conducted entirely in vitro, the results closely match vascular patterns often seen in the early stages of stroke and cerebrovascular dysfunction.
Supported by Population-Level Associations
These cellular-level findings align with earlier epidemiological work. A 2023 study involving more than 4,000 participants, published in Nature Medicine, found that individuals with elevated blood levels of erythritol were more likely to experience heart attacks and strokes over a three-year period. This association was independent of age, sex, and traditional cardiovascular risk factors.
The same study included a controlled intervention in which volunteers ingested erythritol. Subsequent blood testing showed increased platelet reactivity, a known precursor to clot formation. The results suggested a possible physiological pathway linking erythritol intake to cardiovascular risk.
In combination with the new cellular evidence, these population-based findings are fuelling further research into the vascular effects of non-nutritive sweeteners.
Regulation, Exposure, and Unanswered Questions
Erythritol is classified as “Generally Recognised as Safe” (GRAS) by the US Food and Drug Administration, and is authorised for use in food and drinks by the European Food Safety Authority. It occurs naturally in small quantities in fruits and fermented foods, but is typically consumed in much larger volumes as an additive.
The compound is known to cross the blood-brain barrier, making it capable of reaching the cells studied. Its metabolic profile also includes endogenous production, meaning the body can generate erythritol internally via glucose metabolism, especially in the liver and kidneys.
Because erythritol is found in a wide range of sugar-free products, many consumers may ingest multiple servings per day. No official intake thresholds are currently in place.
The researchers noted that their study did not investigate long-term or cumulative effects, nor did it assess health outcomes in living organisms. The data reflect immediate cellular responses to a single dose. Still, the biological mechanisms identified are consistent with processes involved in cerebrovascular disease.