The Science of Sugar Substitutes — Why Erythritol Is Under Scrutiny
You switched to sugar-free.
You checked the label. Zero sugar. Zero calories. Keto-friendly.
The sweetener was erythritol — found in hundreds of "healthy" products, from protein bars to sugar-free ice cream to energy drinks.
The FDA approved it. It's been marketed as safe for decades.
Then researchers at the Cleveland Clinic studied 4,000 people across the U.S. and Europe.
And published the results in Nature Medicine.
The findings raised serious questions about what those labels really mean.
The shift toward sugar substitutes has introduced ingredients whose long-term effects are only now being thoroughly examined
Erythritol is found in hundreds of sugar-free, keto, and low-calorie products. Recent peer-reviewed research has raised questions about its cardiovascular safety. [Image: Created by Vella Team]
What You'll Learn
- What erythritol is — and why it became so popular
- What the 2023 Nature Medicine study of 4,000 people actually found
- What a 2025 brain cell study added to the picture
- What the critics say — and why it matters
- What you can actually do with this information
1. What Erythritol Is — And Why It's Everywhere
Erythritol is a sugar alcohol — a type of carbohydrate that occurs naturally in small amounts in some fruits and fermented foods. The erythritol used commercially is typically produced by fermenting corn, and it is approximately 70% as sweet as table sugar. It contains almost no calories, does not significantly raise blood glucose or insulin levels, and does not cause the digestive side effects associated with other sugar alcohols like xylitol or sorbitol at typical serving sizes.
The FDA granted erythritol "Generally Recognized As Safe" (GRAS) status in 2001. That designation — GRAS — means a substance is considered safe based on available evidence, but does not require long-term safety studies before approval. Since then, erythritol has become a standard ingredient in the low-sugar, keto, and diabetic-friendly product categories.
• Keto protein bars and snack foods
• Sugar-free ice cream and frozen desserts
• Stevia-blend sweeteners (erythritol is often the primary ingredient by volume)
• "Zero sugar" baked goods and chocolates
• Monk fruit sweetener blends
• Diabetic-friendly products and meal replacements
A single pint of sugar-free ice cream can contain up to around 30g of erythritol. A typical sugar-free beverage may contain a similar amount per serving, though this varies by product.
CU Boulder Today, July 2025 / Cleveland Clinic Newsroom, Feb. 2023
Because erythritol is produced naturally by the human body in small amounts — as a byproduct of normal metabolism — it was long assumed to be benign at dietary intake levels. That assumption is what the 2023 Cleveland Clinic study set out to examine more carefully.
The FDA's "Generally Recognized As Safe" classification does not require pre-market long-term safety studies. The Cleveland Clinic's lead researcher, Dr. Stanley Hazen, specifically noted this gap: "Cardiovascular disease builds over time, and heart disease is the leading cause of death globally. We need to make sure the foods we eat aren't hidden contributors." Cleveland Clinic Newsroom, Feb. 27, 2023 / FDA GRAS designation framework
2. What the 2023 Nature Medicine Study Actually Found
In February 2023, a team led by Dr. Stanley Hazen at the Cleveland Clinic published findings in Nature Medicine that drew significant attention from cardiologists and nutritional researchers worldwide.
The study examined blood samples from more than 4,000 people in the United States and Europe, tracking major adverse cardiovascular events — heart attack, stroke, and death — over a three-year period. It found that participants with higher circulating levels of erythritol in their blood were significantly more likely to experience one of these events.
• Tracking period: 3 years — measuring major adverse cardiovascular events (MACE): heart attack, stroke, death
• Finding: Participants with higher blood erythritol levels were significantly more likely to experience MACE
• Lab analysis: Erythritol caused platelets — blood clotting cells — to become easier to activate and form clots
• Clot risk: When erythritol was added to whole blood or isolated platelets, clot formation increased measurably
• Pre-clinical confirmation: Animal studies confirmed that clot formation increased under laboratory conditions after erythritol ingestion
• Important limitation noted by authors: This is an observational study — it demonstrates association, not causation
Witkowski M, Nemet I et al., Nature Medicine 29:710–718, 2023 / NIH Research Matters, 2023
The researchers also noted a complication in interpreting the data: erythritol is produced naturally by the human body, particularly under conditions of metabolic stress. People with existing cardiovascular risk factors — obesity, diabetes, metabolic syndrome — may already have elevated endogenous erythritol levels independent of dietary intake. This makes it difficult to determine from blood levels alone whether the erythritol came from food or from the body's own metabolism.
In 2025, researchers at the University of Colorado Boulder published a follow-up study in the Journal of Applied Physiology that took a different approach — rather than observing population-level associations, they tested erythritol directly on human brain cells in a laboratory setting.
They treated human cerebral microvascular endothelial cells — the cells that line the tiny blood vessels inside the brain — with an amount of erythritol equivalent to what a typical sugar-free beverage contains. Then they measured what happened.
• ↑ Oxidative stress: Reactive oxygen species (ROS) production increased significantly — a marker of cellular stress
• ↓ Nitric oxide production: Cells produced less nitric oxide — a molecule that relaxes and widens blood vessels
• ↑ Endothelin-1: Cells produced more of this protein, which constricts blood vessels
• ↓ Clot-busting ability: When challenged with a clot-forming compound, the cells' ability to produce the natural clot-dissolving compound t-PA was markedly reduced
Senior author Prof. Christopher DeSouza: "Big picture, if your vessels are more constricted and your ability to break down blood clots is lowered, your risk of stroke may increase."
Berry A, DeSouza C et al., Journal of Applied Physiology, 2025 / CU Boulder Today, July 2025
The researchers were careful to note the limitations of a cell study: results observed in isolated cells in a laboratory do not automatically translate to what happens in a living human body at the same doses. Larger human studies are needed to confirm whether these cellular effects occur at the scale that would produce clinically meaningful changes in stroke risk.
The CU Boulder cell study used an erythritol concentration equivalent to approximately 30g — roughly the amount in a typical sugar-free beverage or a pint of sugar-free ice cream. This is a standard single serving for many products on the market. The researchers noted that for consumers who use multiple erythritol-containing products per day, cumulative exposure could be substantially higher. CU Boulder Today, July 2025 / Journal of Applied Physiology, 2025
4. What the Critics Say — And Why It Matters
The erythritol research has not gone unchallenged. The Calorie Control Council — an industry association representing manufacturers of low-calorie sweeteners — stated that the findings are "contrary to decades of scientific research showing reduced-calorie sweeteners like erythritol are safe, as evidenced by global regulatory permissions for their use in foods and beverages."
Independent researchers have also raised methodological concerns worth understanding.
• The endogenous production issue: The human body naturally produces erythritol, especially under metabolic stress. People with diabetes or obesity — already at higher cardiovascular risk — may have elevated erythritol independent of diet, making the association difficult to interpret
• The cell study limitation: Laboratory results on isolated cells don't always translate to effects in living humans at equivalent doses
• What researchers agree on: More long-term human studies are needed. The current evidence raises questions that warrant investigation — but does not establish erythritol as definitively harmful at typical dietary intake levels
Frontiers in Nutrition, "Plasma erythritol and cardiovascular risk," 2023 / CNN, Feb. 2023
What the scientific community broadly agrees on: the existing safety approval for erythritol was granted without long-term cardiovascular studies, and the recent findings are significant enough to warrant further investigation. That is a different conclusion from "erythritol is dangerous" — but it is also a different conclusion from "erythritol is safe."
The researchers who published these studies were consistent in one message: they are not recommending that everyone eliminate erythritol immediately. They are recommending awareness, moderation, and follow-up research.
That said, the practical guidance emerging from the science is clear enough to act on.
• If you are at elevated cardiovascular risk — consider limiting intake. Dr. Andrew Freeman, director of cardiovascular prevention at National Jewish Health, stated: "In an abundance of caution, it might make sense to limit erythritol in your diet for now" — particularly for those with existing heart disease, diabetes, or stroke risk factors.
• Avoid assuming "zero sugar" means zero risk. Sugar-free labeling reflects glucose and fructose content. Sugar alcohols including erythritol are not always disclosed on front-of-pack labels.
• Consider whole food alternatives where possible. Naturally sweet foods — fruit, small amounts of honey or maple syrup — carry their own considerations but have longer safety records at typical intake levels.
• Consult a registered dietitian or physician for personalized guidance, particularly if you use erythritol-containing products regularly as part of a diabetes or weight management plan.
The Cleveland Clinic's Dr. Hazen made the point that is perhaps most important to carry away: the regulatory framework that approved erythritol as safe was not designed to catch long-term cardiovascular signals. The GRAS designation requires that a substance be generally recognized as safe — not that it has been demonstrated safe over decades of high-frequency use in the modern quantities now found in the food supply.
Both research teams — Cleveland Clinic (2023) and CU Boulder (2025) — recommend the same next step: larger, longer-term human studies to confirm whether dietary erythritol intake at current population levels is associated with measurable cardiovascular outcomes. Until those studies are completed, the researchers encourage consumers to be conscious of how much erythritol they are consuming daily, and to read ingredient labels carefully. Cleveland Clinic Newsroom, 2023 / CU Boulder Today, July 2025 / American Physiological Society, April 2025
📊 What You Now Know
- Erythritol is one of the most widely used sugar substitutes — found in keto, sugar-free, and diabetic-friendly products — and has held FDA GRAS status since 2001, without requirement for long-term cardiovascular safety studies
- A 2023 study in Nature Medicine (Witkowski, Nemet et al., Cleveland Clinic) examined 4,000+ people and found that higher blood erythritol levels were significantly associated with heart attack, stroke, and death over a 3-year period
- The same research team found that erythritol caused platelets to become more reactive and clot more easily — a potential mechanism for the observed cardiovascular association
- A 2025 cell study (Berry, DeSouza et al., CU Boulder / Journal of Applied Physiology) found that erythritol reduced nitric oxide production and clot-dissolving capacity in human brain blood vessel cells at a single-serving dose
- The scientific debate is legitimate: the 2023 study is observational, causation has not been established, and the body produces erythritol naturally — making interpretation complex
- Both research teams recommend the same practical step: be aware of how much erythritol you consume daily, read labels carefully, and consult a physician if you are at elevated cardiovascular risk
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