Artificial and Non-sugar Sweeteners: the Good, the Bad, and the Science

We like sweet things. We are born with a sweet tooth. For thousands of years we satisfied that sweet tooth as soon as we were able to. This was never a problem, since sugar was not something readily available. Today, sugar-sweetened products surround us in every grocery store, and advertisements for candy and soft drinks bombard us. We also know that excessive amounts of sugar is not good for us.

In an effort to give us that sweet taste we desire, but without the calories, low-calorie or non-nutritive sweeteners have been developed. Sometimes they are the result of years of dedicated research, other times they are the result of pure chance.

Few things that we ingest give cause for more discussion and speculation than sweeteners. Artificial sweeteners are surrounded by myths, misconceptions, and fearmongering. They are accused of causing cancer and obesity and making us stupid. Media is often helping spread this misinformation, either through lack of knowledge about the subject or through failure to do proper research.

This article will discuss the most common sweeteners, the science behind them and their documented effects. The objective is to help bring clarity to what sweeteners are and do, and whether they actually do make us fat and sick or not.

Acesulfame potassium

Acesulfame potassium, or acesulfame K, where K stands for the chemical symbol for potassium, is an artificial and non-nutritive sweetener, discovered in 1967. A scientist discovered it by accident when he licked his fingers and connected the sweet taste he found to the chemicals he had been working with earlier.

Acesulfame potassium is approximately 200 times sweeter than sugar and stable both in heat and in acidic environments. Since it has a metallic aftertaste, it is rarely used alone.1 Combined with aspartame or sucralose, the metallic aftertaste is effectively neutralized, and especially in combination with aspartame, acesulfame potassium produces a sweetness close to that of real sugar, although some has reported this aftertaste regardless.

Unlike aspartame, acesulfame potassium stimulates insulin release. Rat studies have shown that acesulfame potassium stimulates insulin release of the same magnitude as a similar amount of glucose.2 While this might sound alarming, since acesulfame is 200 times sweeter than sugar, the amount used in acesulfame potassium-sweetened products is also 200 times less.

This means that the resulting insulin release is only measurable in a laboratory, not when consumed in normal amounts. In one study, the rats were administered 20 mg acesulfame potassium per kilogram of bodyweight and hour. That is the equivalent of drinking several bathtubs worth of diet soda in an hour.

In one study from 1997, acesulfame K induced a dose-dependent clastogenic effect in rats. Rats exposed to acesulfame potassium exhibited chromosome aberrations in the bone marrow.3 The doses given were within non-toxic levels as reported by the Joint Expert Committee for Food Additives of the World Health Organization and the Food and Agriculture Organization of the United Nations. These effects have not been replicated, and neither the FDA nor EFSA have considered the results significant enough to cause alarm.

Aspartame

Aspartame is an artificial high-intensity sweetener originally authorized as a food additive by the U.S. Food and Drug Administration (FDA) in 1981. The European Food Safety Authority (EFSA), the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the EU Scientific Committee for Food (SFC) have also evaluated it. An Acceptable Daily Intake (ADI) of 40 mg/kg body weight per day has been established in the EU, while the FDA has set the US equivalent to 50 milligrams per kilogram of body weight per day.

Aspartame is methyl ester of the dipeptide of the amino acids L-aspartic acid and L-phenylalanine. After oral ingestion, aspartame is fully hydrolyzed and broken down into 5-benzyl-3.6-dioxo-2-piperazine acetic acid (DKP), L-phenylalanine, aspartic acid and methanol. Ten percent of ingested aspartame is released as methanol. Because aspartame is metabolized effectively through hydrolysis, no amount of intact aspartame can be detected in the bloodstream following ingestion.

Those born with the rare genetic disorder phenylketonuria lack the ability to properly break down phenylalanine and need to avoid aspartame for this reason.

Aspartame is approximately 200 times sweeter than sucrose, and is not stable in heat.

Aspartame and cancer

When aspartame was approved and introduced to the market in 1981, as the third artificial sweetener after saccharine and cyclamate, it was not suspected of any carcinogenic activity. It had been thoroughly studied before approval, and long-term studies using high doses of aspartame had failed to produce any signs of genotoxicity.

In 1996, Olney et al published an article that changed the public opinion of aspartame and received massive attention, from both media and the scientific community. In the paper, titled Increasing brain tumor rates: Is there a link to aspartame?4 the authors published data showing that the rate of brain tumors in humans had increased dramatically since the introduction of aspartame on the market.

This paper hypothesized that this increased rate of brain tumors might be linked to, and even caused by, aspartame. The same authors also published the results of a trial in which Sprague-Dawley rats had been administered aspartame-containing feed for 2 years. They demonstrated an abnormally high incidence of brain tumors in the aspartame-fed rats, while the control group rats remained tumor free.

Media picked up on these findings and the statements of Olney et al and suggested the public stayed away from aspartame and called for a reassessment of the carcinogenicity of aspartame in some cases, and for an outright ban in others.

Other scientists, however, criticized the paper and the findings it presented, noting that it relied on flawed methodology.

While Olney had linked the introduction of aspartame to the increase in brain tumors during the same time, they pointed out that this kind of correlation is not one allowed in proper epidemiology. No information about the aspartame consumption of the individuals who had developed brain tumors were available, so the increase could just as likely been the result of any other factor or combination of factors.

In addition, the increase in brain tumor frequency occurred at the same time as the introduction of aspartame. This alone makes it impossible to point out aspartame as the one cause for the increase. It takes time for brain tumors to develop and be diagnosed, so the introduction of aspartame at the same time as the increase in brain tumors cannot be used to argue cause and effect.

In 2006, a study followed 473,984 persons for up to 5.2 years for diagnoses of hematopoietic cancers and malignant gliomas.5 This time, however, the researchers also examined the intake of aspartame and the daily frequency of aspartame-containing beverage consumption. Consumption of aspartame was not associated with any risk of overall hematopoietic cancer, gliomas or glioblastomas. These findings did not change after adjusting for sex, age, family history of cancer, smoking, alcohol, and several other factors.

These findings are consistent with the majority of animal studies and human case-control studies on brain cancer.6 7

Also in 2006, Soffritti et al published a study in which Sprague-Dawley rats were administered aspartame in feed from 8 weeks of age until time of death.8 The results showed an increased incidence of malignant tumors in multiple organs, and the study concluded that aspartame is a multipotential carcinogenic agent, even at doses much lower than the current Acceptable Daily Intake.

Later assessments of the Soffritti study have called into question the validity of the results and the methodology used in the study. European regulatory authorities examined the findings and concluded that the lymphomas found in the aspartame study were actually lesions caused by Mycoplasma Pulmonis, a common and naturally occurring respiratory pathogen in rodents, completely unrelated to aspartame.

The leukemias and lymphomas in the aspartame-treated rats were considered to be unrelated to aspartame in an EFSA assessment, instead attributed to the inflammatory chances in the lungs of the rats and the contamination by Mycoplasma Pulmonis.9

A new histological evaluation found no evidence of tumorigenic effects of aspartame in any organ group and concluded that there is no evidence that aspartame is carcinogenic in rats.10

A review article from 2004 found no evidence that aspartame is carcinogenic in humans, and in 2013 EFSA published an extensive re-evaluation of aspartame, concluding that, based on scientific research, there is no evidence that aspartame bears a carcinogenic risk or any need for a revised ADI.

Glycemic impact of aspartame

Aspartame is often recommended as an alternative to sugar for diabetics. Four decades worth of studies have extensively examined the effect of aspartame on blood glucose control and insulin release in humans. They have invariably shown that aspartame does not raise blood sugar levels, cause insulin release or otherwise affect blood glucose control in diabetics or non-diabetics.

A recent meta-analysis found that consumption of zero- or low-calorie sweeteners, including aspartame, did not elevate blood glucose levels compared to placebo.11

Another systematic review and meta-analysis of randomized clinical trials concluded that aspartame is not associated with altered blood glucose levels, insulin levels, triglyceride concentrations, body weight or energy intake compared to control.12

A recent consensus statement concluded that low- and non-calorie sweeteners, including aspartame, might contribute to improved glycemic control.13

Aspartame, weight gain and obesity

Aspartame and other sweeteners have been implicated in weight gain and obesity. Even though they are non-caloric, artificial sweeteners might not activate the rewards system like natural sweeteners. Non-caloric sweeteners might also impair the predictive relationship between sweet taste and the energy content of food, which could lead to a compensatory increase in caloric intake.

Human studies do not support any significant direct effect of aspartame on weight gain. In one of the original studies on aspartame and body weight, subjects lost similar amounts of weight during a calorie restricted diet with or without high daily doses of aspartame.14

In a new study from 2018, beverages containing aspartame did not differ significantly from water in their effects on appetite, energy intake and food choices.15

Compared to water, some studies have indicated that aspartame leads to a higher energy intake due to compensatory mechanisms, but replacing beverages sweetened with sugar with aspartame-sweetened beverages does not. Regular intake of sugar-sweetened beverages leads to weight gain over time, but the same does not hold true when beverages sweetened with aspartame is given instead.

Aspartame and oxidative stress in the brain

A number of studies indicating inflammation, oxidative stress and activation of the apoptotic pathway in the brain neurons in rats have been published in the last few years.16 17 18

These studies have not caused regulatory organizations to take any action, and it is unclear if the results are relevant to humans. Since there have been a number of studies reaching similar conclusions, the results warrant further research.

Aspartame and gut microbiota

One recent study showed that the administration of artificial sweeteners disrupted the gut microbiota of mice and humans, causing glucose intolerance.19 Test subjects were given saccharin and aspartame, but only saccharin had any disruptive effect. Aspartame did not affect gut microbiota more than tap water. Regardless of this, media reported that aspartame had been implicated in the disruption of intestinal microbiota. While it does seem like some sweeteners can alter gut microbiota, so far aspartame has not been shown to be one of those.

Cyclamate

Of all the common artificial sweeteners, sodium cyclamate is the least potent. Cyclamate is only 20 to 40 times sweeter than sucrose. Like many other sweeteners, it was discovered by accident. A University of Illinois student in 1937 had put his cigarette on a table where he had been working with chemicals for an anti-fever medicine, and when he put it back in his mouth, he discovered that it suddenly tasted sweet.

In a long-term study, monkeys were fed cyclamate in the diet from birth and continuing for up to 24 years.20 Malignant tumors were diagnosed in three of the monkeys. The tumors were colon carcinoma, hepatocellular carcinoma, and adenocarcinoma of the prostate. Benign tumors were found in three other monkeys. These were adenoma of the thyroid gland and two cases of leiomyoma of the uterus. No tumors were found in the monkeys in the control group that were not fed any cyclamate.

In spite of these findings, it was concluded that no toxic or carcinogenic effect of cyclamate could be established. Since the tumors affected different organs, no cause and effect relationship between cyclamate and the cancers could be determined.

Cyclamate is completely banned in the USA since 1970, although it is approved as a sweetener in more than 125 countries in the rest of the world. The ban in the USA came into effect after the combination of cyclamate and saccharin was found to increase the incidence of bladder cancer in rats.21 The FDA has since issued statements that the evidence does not support cyclamate being carcinogenic, but the ban on cyclamate in the USA stands to this day.

High doses of cyclamate have been shown to induce testicular atrophy in rats, but there does not seem to be any connection between cyclamate and fertility in humans.22

Erythriol

Erythriol is a sugar alcohol discovered almost 170 years ago. It can be found naturally in fermented foods and in certain kinds of fruit. Other sugar alcohols will be covered later in the article, but since erythriol is metabolized differently and, unlike other sugar alcohols, provides no energy, it merits its own discussion.

Erythriol is manufactured as a sweetener using glucose as part of a fermentation process. This means that unlike other sweeteners discussed in this article, the process by which erythriol is manufactured is completely natural. Also unlike artificial sweeteners, erythriol does not taste sweeter than sugar, but only 60-70 % as sweet. This gives erythriol a bulk of its own, which means that it can be used in cooking in the same way as sucrose without added bulking agents like maltodextrin.

After ingestion, erythriol is absorbed into the blood from the small intestine and excreted through the urine, although a small part, around 10 %, enters the colon. Since only a small part of the ingested erythriol reaches the colon and since human intestinal bacteria cannot ferment erythriol, it does not cause bloating or diarrhea like other sugar alcohols when consumed in large amounts. This also means that erythriol is energy free.

Erythriol does not affect blood glucose or insulin levels. It also has no negative impact on dental health. No negative health effects have been attributed to erythriol intake.23 It is lethal to fruit flies, but does not seem to have any adverse effects on human health.24

Neotame

Sweetest of the sweet, neotame is an artificial sweetener chemically similar to aspartame. Neotame is a comparatively new artificial sweetener approved for general use by the FDA in the USA in 2002. It is a methyl ester 7,000 to 13,000 sweeter than sucrose and 40 times sweeter than aspartame. Unlike aspartame, individuals with the genetic disorder phenylketonuria can use neotame.

After intake of neotame, 20-30 % is absorbed and rapidly converted to the metabolite N-[N-(3.3-dimethylbutyl)-L-alpha-aspartyl]-L-phenylalanine. Both this metabolite and the remaining neotame pass through the system quickly and is eliminated completely though urine and feces without leaving any traces behind.

Neotame is more stable in heat and acidic environments than aspartame and can be used in cooking using relatively high temperatures.

Short-term and long-term toxicology studies using mice, rats and dogs have not shown any negative health effects of neotame. No toxic, carcinogenic, reproductive or hormonal side effects have been reported in animals given various amounts of neotame over long periods.

Human observations have shown that neotame is tolerated well both by diabetics and non-diabetics, without any blood glucose or insulin effect. The only human side effect reported in studies is headaches, but these cases have not been conclusively linked to neotame specifically.

Nothing suggests adverse health effects from long-term neotame ingestion. The ties to aspartame has given cause for negative rumors about neotame, but there is no scientific evidence supporting any such claims.25

Saccharin

Saccharin is the oldest non-caloric sweetener, discovered in 1870 by chemists at Johns Hopkins University. Like with other sweeteners, the discovery was by accident. A scientist had been working with benzoic sulfimide earlier in the day, and when he later happened to lick one of his fingers, he discovered a sweet taste.

Both the calcium and the sodium salt of saccharin can be used as a sweetener, although the most common variant is the sodium salt. It is 300 to 700 times sweeter than sucrose and provides virtually no energy. The energy content is measurable in a laboratory, but it is so minimal that saccharin can be classified as a non-caloric sweetener.

Saccharin has been approved as a sweetener for food and drink since 1900 and has been the main sweetener of many sugar-free and diet variants of soft drinks, including Coca-Cola. Today, most soft drink manufacturers have switched to other sweeteners for their products, but saccharin lives on as a table top sweetener.

Saccharin is heat stable and usable in hot drinks like coffee and tea without the sweetness disappearing, unlike aspartame for example. It has a bitter metallic aftertaste, but when combined with cyclamate or aspartame, this aftertaste is effectively masked. Saccharine is rarely used as the sole sweetener for this reason.

Saccharin and health

There has been a number of health-related controversies involving saccharin. In the 1970s, a connection between saccharin and bladder cancer in rats was discovered, which led to all saccharin-sweetened products being labeled as possibly carcinogenic.26 This warning label has since been removed, as later studies found that rats metabolize saccharine differently from humans. Humans excrete saccharin salts through the urine, but in rats, they stay in the bladder and cause cytological abnormalities. Saccharin is still suspected to cause cancer in rats, but not in humans.27

In 2010, the Environmental Protection Agency in the USA officially declared that saccharin is not to be considered a potential hazard to human health.

The effecs of saccharin on blood glucose and insulin kinetics in both diabetics and non-diabetics have been studied. No significant acute effects on either blood glucose or insulin were found after consumption of one liter of a saccharin-sweetened beverage.28

The last few years, another health-related issue has been linked to saccharin. Saccharin seems to disrupt the gut bacteria of both mice and humans and induce glucose intolerance.29 Saccharin in itself does not affect insulin or glucose, but an effect on glucose tolerance could indirectly have an effect on normal post-prandial insulin and blood glucose levels.

The mechanisms behind this effect on glucose tolerance could potentially translate into an increased risk of diabetes type 2, although the long-term effects have not yet been properly studied and evaluated.

Stevia

The leaves of the stevia plant have been used to sweeten teas and treats for more than 1,500 years. In 1899, a Swiss botanist traveling in Paraguay described the sweet properties of the leaf, but it was not until the 1930s that the compounds responsible for the sweet taste of stevia were isolated.

The sweet compounds extracted from stevia leaves are called steviol glycosides. The FDA in the USA and EFSA in the EU have evaluated and approved stevia glycosides as a sweetener and as an ingredient in food products.

Steviol glycosides are not absorbed in the upper gastrointestinal tract. When they reach the large intestine, the glucose is used for energy by gut bacteria. The remaining steviol is quickly absorbed, metabolized by the liver and excreted through the urine.

There are many different kinds of steviol glycosides, and they can be up to 350 times sweeter than sucrose. They do not provide any metabolizable energy.

In commercial contexts, stevia is often claimed to be “natural”, but this is in reality only true when talking about the leaves of the stevia plant. Stevia glycosides are extracted through several chemical processes. This does not mean that they are bad or harmful, but calling them natural is stretching the truth.

Stevia and health

The World Health Organization has also evaluated the safety of stevia and concluded that is has no known adverse health effects. Within the EU, the leaves of the stevia plants can be used to sweeten teas, but not as an ingredient in other foods. In the USA, the leaves are not allowed in food products or as any kind of sweetener, due to inadequate toxicological information.

Stevia has no effect on blood glucose or insulin, and is considered safe for use by adults and children, in pregnancy and when breast-feeding.30 There are no indications of adverse effects on gut microbiota, but one study found that steviol glycosides inhibited the growth of probiotic gut bacteria.31 Whether or not this can be replicated in vivo remains to be seen.

Sucralose

Sucralose is manufactured from regular sucrose by removing three hydroxyl groups from sucrose and substituting them with chlorine atoms. The result is a non-caloric sweetener up to 1,000 times sweeter than sucrose. Sucralose is currently one of the most widely used artificial sweeteners in the world.

After ingestion, sucralose largely passes through the body and is excreted through the feces without being absorbed. Around 85 % of ingested sucralose is excreted this way. The remaining 15 % is absorbed and quickly eliminated through urine.

Sucralose in stable in heat and in acidic environments and can be used in cooking and in hot liquids, unlike for example aspartame.

Sucralose and health

More than 100 studies over 20 years have determined sucralose to be safe, and it is approved by all international health authorities, from EFSA to the WHO. No genotoxic, neurological or reproductive effects, regardless of dose, have been observed.32 Very high doses seem to reduce the body weight of rats, and the Acceptable Daily Intake (ADI) is set with this observation in mind, with a large safety margin for human consumption.

Sucralose does not affect blood glucose or insulin. However, two new studies have shown that sucralose can decrease insulin sensitivity in healthy humans.33 34 This could potentially be a risk factor for insulin resistance and diabetes type 2 in the long term. Long-term studies are needed to confirm these findings, but they indicate that sucralose might not be as biologically inert as once thought.

Another new study showed that rats given sucralose within ADI levels exhibited damaged intestinal microbiota and hepatic inflammatory response.35 No human studies have replicated this.

Recently, it was discovered that a sip of a 48 mg sucralose solution increased serum insulin and induced imbalance in monocyte subpopulations in healthy young adults.36

Sucralose ingestion resulted in a significantly higher insulin response after a 75 gram oral glucose tolerance test compared to placebo.

In addition, dynamic changes in classical and nonclassical monocyte subsets could be observed following sucralose administration. The exact mechanisms by which sucralose affects monocyte subpopulations are not clearly understood, but they might be mediated by the increase in serum insulin.

Because sucralose is not metabolized completely, it passes through the body and into the environment when it is excreted through the urine. It has been detected in rivers, streams and lakes, and has been speculated to affect the environment and the wildlife in the long term, although current studies have not shown this to be the case.

Sugar alcohols

Sugar alcohols are polyols usually manufactured from sucrose. These include xylitol, sorbitol, maltitol, lactitol, erythriol, mannitol, and others. Erythriol is metabolized differently from the rest and is discussed separately.

Unlike other sweeteners discussed in this article, sugar alcohols provide energy and affect blood glucose and insulin. The energy content of sugar alcohols varies from 1.6 to 3 calories per gram. They taste less sweet and raise blood sugar and insulin levels less than sucrose. The exception regarding sweetness being xylitol, which is as sweet as sucrose.

Sugar alcohols have no adverse health effects.37 The only side effects are bloating and possible diarrhea. Sugar alcohols are not completely absorbed in the small intestine, which means that excessive amounts can cause harmless but uncomfortable gastrointestinal disturbances.

Sugar alcohols are non-cariogenic, and xylitol even decreases the incidence of dental caries by increasing salivary flow and pH13.

Conclusion and discussion

Low- or non-calorie and artificial sweeteners are some of the most studied and researched additives to our food and drink. Many decades of research have concluded that they are generally safe for human consumption and have established how much we can safely consume, based on animal studies.

This recommended maximal intake is called Acceptable Daily Intake and is a calculation of how much of a substance can be ingested on a daily basis during an entire life without adverse effects, based on current scientific knowledge.

The ADI value has a large safety factor, 10 if based on human research, 100 if based on animal studies. For example, the ADI of aspartame allows for a daily intake of about 4 liters of aspartame-sweetened beverages for an average human adult. The actual amount needed to reach harmful levels of the sweetener would kill through water poisoning first.

Even when isolated studies have shown adverse effects, the combined data from multiple studies is what is important. The effect or effect size needs to be consistent from one study to the next for the results to be viable as a basis for recommendations and scientific consensus. Regarding sweeteners, the consensus based on scientific research is that they, when consumed within ADI levels, do not have adverse health effects, do not affect insulin kinetics, do not cause obesity, and are not carcinogenic.

The sweeteners that do raise concerns, like cyclamate, are hardly used any longer or in so few products that they generally do not contribute significantly to the average intake of sweeteners.

When sweeteners are implicated in disease, obesity and other negative health conditions, it is important to remember that correlation does not imply causation. No one knows what future research might discover, but current scientific evidence does not support a causative relationship between sweeteners and various adverse health effects. A recent review did not find any significant association between non-sugar sweeteners and most health outcomes.38

There are new fields of research, like the impact on gut microbiota, which might have implications that will call for a need to revise the ADI of certain sweeteners. Currently, however, there is not enough research available to base any such revisions on.

Sweeteners have no nutritional value, so those who want to play it safe and avoid them do not miss any benefits beyond the sweet taste itself. However, artificial sweeteners have been a part of daily life for millions of people for decades, and so far, nothing has happened. Certain types of cancer have become more common since aspartame was introduced, and obesity is much more prevalent, but there are no differences between groups consuming aspartame and those that are not.

No one needs sweeteners. But for those who want to be able to eat and drink sweet foods without the calories and the possible health effects of regular sugar, sweeteners provide that opportunity, without apparent adverse health effects.

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