Friday Favorites: Does the Sweetener Allulose Have Side Effects? Is It a Healthy Sweetener?

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

First, there was sugar and high fructose corn syrup, the original industrial sweeteners. They were cheap, but had lots of empty calories, and contributed to diseases such as obesity, type 2 diabetes, cavities, and metabolic syndrome. So, then came the second-generation sweeteners, the artificial sweeteners, the colored pastel packets: Nutrasweet, Splenda, and Sweet & Low. Practically zero calories, but adverse effects have been described; cautions have been raised. For example, artificial sweeteners were found to induce glucose intolerance by altering the gut microbiome, thereby producing the counterintuitive effect of inducing metabolic derangements. They also taste kind of funny. Enter the third-generation sweeteners: sugar alcohols, such as sorbitol, xylitol, and erythritol. Low-calorie sweeteners, however, their laxative effects can create difficulties, which brings us to rare sugars like allulose, which are natural sweeteners with low or zero calories and a sugar-like taste.

For those of you who haven’t heard of allulose, it’s been through a bit of a rebranding. Just like rapeseed oil morphed into canola, forcing municipalities to update their town slogans, allulose used to be called psicose, a sugar you may not want to eat in the shower.

The name “psicose” is derived from the antibiotic from which it was isolated. That’s a strange origin story for a sweetener. In the Frontiers of Bioengineering and Biotechnology, emphasis is placed on the fact that allulose is a real and natural sugar rather than artificial. But ironically, if you look at the reference they cite, it talks about how allulose is made, via functionalized polyhydroxyalkanoate nano-beads decorated with D-tagatose 3-epimerase (DTE) produced in recombinant endotoxin-free branded bacteria.

Now, technically allulose is a natural sugar, a so-called rare sugar, which have been defined by the International Society of Rare Sugars as sugars that are present in limited quantities in nature. But recent technological advances, such as enzymatic engineering using genetically modified microorganisms, now allow manufacturers to produce otherwise rare sugars like allulose in substantial quantities. But small amounts have pre-existed in the food supply; so, the FDA granted it generally-recognized-as-safe status. But it’s been like really small amounts, like a few dozen milligrams, or a quarter of a quarter of a quarter of a teaspoon.

See, allulose is generated when fructose is heated. That’s why this poor guy kept breaking out in hives eating such a strange variety of foods, because he happened to be allergic to allulose, and allulose is created incidentally in the process by which high fructose corn syrup is made. So, basing the safety of allulose on the fact that it’s already been present in our food supply isn’t very convincing. You don’t know if it’s safe until you put it to the test.

Unlike table sugar, allulose is safe for the teeth—isn’t apparently metabolized by cavity-causing bacteria to make acid…and build up plaque. It doesn’t raise blood sugars, even in diabetics. It can be labeled as having zero calories, though technically it may have like one and a half calories per teaspoon, similar to what you see with erythritol. Also like erythritol, it’s only about 70 percent as sweet as table sugar but has almost the same taste, performance, and texture as regular sugar. Are there any toxicities?

Allulose is considered a relatively nontoxic sugar. What does that mean? Well, in pets, we know a sweetener called xylitol can be extremely dangerous in dogs. As little as a half teaspoon in a 30-pound dog can be life-threatening, whereas a similar dose of allulose apparently wouldn’t be a problem––though like over a half cup at a time could make them sick. This was a single dose study, though. The long-term safety of allulose was tested over a period of a few months, and didn’t seem to cause any harmful effects at a dose of about one and a half teaspoons a day for healthy 30-pound dogs. In fact, their cholesterol actually went down, leading the investigators to suggest clinical studies to see if it’s something vets should start prescribing for overweight pooches.

What about in people? When the dose of allulose was gradually increased to identify the maximum single dose for occasional ingestion, no cases of severe gastrointestinal symptoms were noted until a dose of 0.4 g/kg of bodyweight was reached, which could be about seven teaspoons, with severe symptoms of diarrhea noted once you get up around nine teaspoons. And, you say, who could eat that much sugar at a time anyway? A single can of Coke has 10 teaspoons, and a bottle of Mountain Dew has nearly twice that. So, allulose is clearly not suitable as a standalone sweetener for sugary beverages.

In terms of a daily upper limit given in smaller doses throughout the day, once you hit around 17 teaspoons a day, depending on your weight, people start getting severe nausea, abdominal pain, headache, diarrhea. So, people should probably stay under single doses of about seven teaspoons, and not to exceed about 15 for the whole day. The average American may be getting 17 teaspoons of added sugars a day. So, it’s certainly not something the food industry can completely switch over to.

In this way, allulose is close to xylitol in terms of maximal single dose, whereas the average-weight man in the U.S. could get away with 14 teaspoons of erythritol at a time, and the average woman, 15 teaspoons. Still not enough to sweeten a bottle of Coke, but offers a little more leeway for sweetening tea or sprinkling on a grapefruit or something.

Allulose is claimed to provide health benefits, though, compared to erythritol. Fourth generation sweeteners like allulose are said to have as an advantage: additional functions. We’ll find out if that’s true, next.

Allulose is a kind of low-calorie sugar naturally existing in very small quantities, but now industrially produced as a commercial sweetener, said to have advantages that make it comparable to erythritol as a sugar substitute. It’s said to have anti-diabetic effects, but this was in obese mice. Allulose decreases LDL cholesterol levels in high-fat-fed hamsters, and is said to have a substantial impact on obesity in lard-munching mice, but what about men and women?

In a petri dish, allulose inhibits fat cell precursors from maturing into fat cells and reduced the amount of fat accumulation within fat cells. Here’s a before and after picture with the fat staining red, of swapping in some allulose for regular sugar. Therefore, the researchers conclude, allulose may be a promising sugar substitute for an anti-obesity diet. But you don’t know, until you put it to the test.

They gave people about a teaspoon of allulose a half hour before eating a meal, and compared to the no-sugar control group, the allulose group started burning more fat. The researchers concluded that allulose enhances after-a-meal fat burning, indicating that it could be a novel sweetener to control and maintain healthy body weight through enhanced energy metabolism. Okay, but first of all, it was only 15 calories of fat burned over that 4-hour period. And they didn’t burn more calories overall. They just switched from burning carb calories to fat calories, and so may have switched back later on and made up for it later in the day.

You can’t just look at one meal. You need to track people’s actual weight over time, and, here we go. A weight reducing effect of a syrup that included about 5 percent allulose, compared to high fructose corn syrup. The results showed significant decreases in body weight, body fat, and waist circumference, but it was some proprietary syrup mixture, and look, anything would look good against high fructose corn syrup.

This, is the study I’ve been looking for. Evaluating the effect of allulose for fat mass reduction in humans. Over a hundred individuals randomized to a placebo control, sucralose, or a teaspoon of allulose twice a day, or one-and-three-quarter teaspoons twice a day, and despite no change of physical activity or calorie consumption between the two groups, body fat was significantly decreased following allulose supplementation. They even took CT scans, so they could tell where the fat was disappearing from.

Now, the drop in body fat was only about 2 pounds over 12 weeks, and the drop in abdominal fat in the higher dose group was almost totally a drop in subcutaneous fat, the flabby superficial fat––not the dangerous visceral fat deeper down that really matters for health. But still, body fat loss despite no change in calorie intake similar to what was seen in the mice, but the hamster effect did not materialize. No significant change in LDL cholesterol in either of the allulose groups. What about the purported anti-diabetes effects?

If you have people chug a beverage with up to about two teaspoons of allulose alone, previously known as psicose, or with a big load of rapidly-digesting carbs, the allulose alone has predictably no influence on blood glucose or insulin concentration. Yet when you consume allulose along with the refined carbs, there was actually a suppression of the elevation of blood sugar and insulin, and by a significant amount: a 30 percent drop in blood sugar and insulin levels over a two-hour period.

We think it’s because the presence of allulose impairs the absorption of sugar through the intestinal lining, because they all might be competing for the same sugar transporter. Yeah, but who’s chugging maltodextrin? What about just like a regular meal?

And…here we go, and in borderline diabetics who could use some blood sugar spike suppression. A randomized double-blind placebo-controlled crossover experiment to see what drinking one and a quarter teaspoon of allulose in a cup of tea with a meal would do, and indeed a significant drop––though only about 15 percent. You can see how they tried to exaggerate the y-axis.

They also did a second experiment randomizing people to a little over a teaspoon of allulose three times a day with meals for 12 weeks. Nice to see there didn’t appear to be any adverse side effects, but they also didn’t find any weight loss effects in contrast with that other study. So, the body fat data are mixed, and so too are the sugar data. This study found no effects of allulose on blood sugars in healthy participants, though a similar study on diabetics did. A systematic review and meta-analysis of all such controlled feeding trials suggested that the acute benefit on blood sugars was of borderline significance, and it’s unclear whether or not this alone could translate into meaningful improvements in blood sugar control over time. So, maybe it’s not enough to just add allulose. You might actually have to also cut out the junk.

Although ability to suppress blood sugar responses is the most well studied aspect of allulose, I do just want to cover one last angle, the fact that allulose extends the lifespan of a tiny roundworm called C. elegans through a dietary restriction mechanism––even though they ate the same amount of food. Two months in, just a few percent of the control group were still alive, whereas twice as many in the low allulose group and about 25 percent still around in the higher allulose group. We think it worked by boosting the expression and activities of antioxidant enzymes in the body, extending lifespan by mopping up free radicals. But who cares about the survival curves of worms?

Well, C. elegans is a well-studied model of aging and longevity, but mostly just for convenience sake, but does share most of the longevity genes or pathways we’re interested in. It would be nice to see experiments on at least human cells, and here we go. The effect of allulose on free radicals and oxidative stress in human coronary artery endothelial cells––the cells that line the inside of our arteries. Add a bunch of sugar, and free radical levels shoot up, but add the same amount of sugar along with some allulose, and it’s as if you never even added the sugar, and this then translates to inhibiting the expression of an inflammatory marker that plays a role in the buildup of atherosclerotic plaque. However, it is still too early to draw conclusions about the clinical relevance of these data.

To conclude, are these rare sugars like allulose a healthy alternative for traditional sweeteners? Well, considering the variety of potentially beneficial effects of allulose without known disadvantages from metabolic and toxicological studies, allulose may currently be the most promising rare sugar. But how much is that saying? We just don’t have a lot of good human data. As a result of the absence of these studies, it may be too early to recommend rare sugars for human consumption.

Please consider volunteering to help out on the site.

• Hossain A, Yamaguchi F, Matsuo T, et al. Rare sugar D-allulose: Potential role and therapeutic monitoring in maintaining obesity and type 2 diabetes mellitus. Pharmacol Ther. 2015;155:49-59.
• Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514(7521):181-6.
• Swithers SE. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements. Trends Endocrinol Metab. 2013;24(9):431-41.
• Oshima H, Kimura I, Izumori K. Psicose Contents in Various Food Products and its Origin. Food Sci Technolo Res. 2006; 12:137-43.
• Jiang S, Xiao W, Zhu X, et al. Review on D-Allulose: In vivo Metabolism, Catalytic Mechanism, Engineering Strain Construction, Bio-Production Technology. Front Bioeng Biotechnol. 2020;8:26.
• Ran G, Tan D, Zhao J, et al. Functionalized polyhydroxyalkanoate nano-beads as a stable biocatalyst for cost-effective production of the rare sugar d-allulose. Bioresour Technol. 2019;289:121673.
• Van Laar ADE, Grootaert C, Van Camp J. Rare mono- and disaccharides as healthy alternative for traditional sugars and sweeteners? Crit Rev Food Sci Nutr. 2021;61(5):713-41.
• Chung MY, Oh DK, Lee KW. Hypoglycemic health benefits of D-psicose. J Agric Food Chem. 2012;60(4):863-9.
• Nishioka K, Katayama I, Sano S. Urticaria induced by D-psicose. Lancet. 1983;2(8364):1417-8.
• Hayashi N, Iida T, Yamada T, et al. Study on the postprandial blood glucose suppression effect of D-psicose in borderline diabetes and the safety of long-term ingestion by normal human subjects. Biosci Biotechnol Biochem. 2010;74(3):510-9.
• Memorandum. U.S. Food & Drug Administration. February 28, 2019.
• Iida T, Hayashi N, Yamada T, et al. Failure of d-psicose absorbed in the small intestine to metabolize into energy and its low large intestinal fermentability in humans. Metabolism. 2010;59(2):206-14.
• Nishii N, Nomizo T, Takashima S, Matsubara T, Tokuda M, Kitagawa H. Single oral dose safety of D-allulose in dogs. J Vet Med Sci. 2016;78(6):1079-83.
• Eapen AK, de Cock P, Crincoli CM, Means C, Wismer T, Pappas C. Acute and sub-chronic oral toxicity studies of erythritol in Beagle dogs [published correction appears in Food Chem Toxicol. 2017 Dec;110:443]. Food Chem Toxicol. 2017;105:448-55.
• Nishii N, Takashima S, Kobatake Y, Tokuda M, Kitagawa H. The long-term safety of D-allulose administration in healthy dogs. J Vet Med Sci. 2017;79(11):1780-4.
• Han Y, Choi BR, Kim SY, et al. Gastrointestinal Tolerance of D-Allulose in Healthy and Young Adults. A Non-Randomized Controlled Trial. Nutrients. 2018;10(12):2010.
• How much sugar are you drinking? City of Meridan Department of Health and Human Services. April 2009.
• Bowman SA, Clemens JC, Martin CL, et al. Added sugars intake of Americans: what we eat in America, NHANES 2013-2014. Food Surveys Research Group. Dietary Data Brief No. 18. May 2017.
• Mäkinen KK. Gastrointestinal Disturbances Associated with the Consumption of Sugar Alcohols with Special Consideration of Xylitol: Scientific Review and Instructions for Dentists and Other Health-Care Professionals. Int J Dent. 2016;2016:5967907.
• Jiang S, Xiao W, Zhu X, et al. Review on D-Allulose: In vivo Metabolism, Catalytic Mechanism, Engineering Strain Construction, Bio-Production Technology. Front Bioeng Biotechnol. 2020;8:26.
• Maeng HJ, Yoon JH, Chun KH, et al. Metabolic Stability of D-Allulose in Biorelevant Media and Hepatocytes: Comparison with Fructose and Erythritol. Foods. 2019;8(10):448.
• Han Y, Kwon EY, Choi MS. Anti-Diabetic Effects of Allulose in Diet-Induced Obese Mice via Regulation of mRNA Expression and Alteration of the Microbiome Composition. Nutrients. 2020;12(7):2113.
• Kanasaki A, Jiang Z, Mizokami T, et al. Dietary d-allulose alters cholesterol metabolism in Golden Syrian hamsters partly by reducing serum PCSK9 levels. J Funct Food. 2019; 60:1-6.
• Han Y, Yoon J, Choi MS. Tracing the Anti-Inflammatory Mechanism/Triggers of d-Allulose: A Profile Study of Microbiome Composition and mRNA Expression in Diet-Induced Obese Mice. Mol Nutr Food Res. 2020;64(5):e1900982.
• Moon S, Kim YH, Choi K. Inhibition of 3T3-L1 Adipocyte Differentiation by D-allulose. Biotechnol Bioproc E. 2020; 25:22-8.
• Kimura T, Kanasaki A, Hayashi N, et al. d-Allulose enhances postprandial fat oxidation in healthy humans. Nutrition. 2017;43-44:16-20.
• Hayashi N, Yamada T, Takamine S, et al. Weight reducing effect and safety evaluation of rare sugar syrup by arandomized double-blind, parallel-group study in human. J Funct Food. 2014;11:152-9.
• Han Y, Kwon EY, Yu MK, et al. A Preliminary Study for Evaluating the Dose-Dependent Effect of d-Allulose for Fat Mass Reduction in Adult Humans: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2018;10(2):160.
• Iida T, Kishimoto Y, Yoshikawa Y, et al. Acute D-psicose administration decreases the glycemic responses to an oral maltodextrin tolerance test in normal adults. J Nutr Sci Vitaminol (Tokyo). 2008;54(6):511-4.
• Hishiike T, Ogawa M, Hayakawa S, et al. Transepithelial transports of rare sugar D-psicose in human intestine. J Agric Food Chem. 2013;61(30):7381-6.
• Hayashi N, Iida T, Yamada T, et al. Study on the postprandial blood glucose suppression effect of D-psicose in borderline diabetes and the safety of long-term ingestion by normal human subjects. Biosci Biotechnol Biochem. 2010;74(3):510-9.
• Braunstein CR, Noronha JC, Glenn AJ, et al. A Double-Blind, Randomized Controlled, Acute Feeding Equivalence Trial of Small, Catalytic Doses of Fructose and Allulose on Postprandial Blood Glucose Metabolism in Healthy Participants: The Fructose and Allulose Catalytic Effects (FACE) Trial. Nutrients. 2018;10(6):750.
• Noronha JC, Braunstein CR, Glenn AJ, et al. The effect of small doses of fructose and allulose on postprandial glucose metabolism in type 2 diabetes: A double-blind, randomized, controlled, acute feeding, equivalence trial. Diabetes Obes Metab. 2018;20(10):2361-70.
• Noronha JC, Braunstein CR, Blanco Mejia S, et al. The Effect of Small Doses of Fructose and Its Epimers on Glycemic Control: A Systematic Review and Meta-Analysis of Controlled Feeding Trials. Nutrients. 2018;10(11):1805.
• Chung MY, Oh DK, Lee KW. Hypoglycemic health benefits of D-psicose. J Agric Food Chem. 2012;60(4):863-9.
• Shintani T, Sakoguchi H, Yoshihara A, Izumori K, Sato M. d-Allulose, a stereoisomer of d-fructose, extends Caenorhabditis elegans lifespan through a dietary restriction mechanism: A new candidate dietary restriction mimetic. Biochem Biophys Res Commun. 2017;493(4):1528-33.
• Mooradian AD, Haas MJ, Onstead-Haas L, Tani Y, Iida T, Tokuda M. Naturally occurring rare sugars are free radical scavengers and can ameliorate endoplasmic reticulum stress. Int J Vitam Nutr Res. 2020;90(3-4):210-20.
• Murao K, Yu X, Cao WM, et al. D-Psicose inhibits the expression of MCP-1 induced by high-glucose stimulation in HUVECs. Life Sci. 2007;81(7):592-9.
• Van Laar ADE, Grootaert C, Van Camp J. Rare mono- and disaccharides as healthy alternative for traditional sugars and sweeteners?. Crit Rev Food Sci Nutr. 2021;61(5):713-41.

Motion graphics by Avo Media