Critical Examiner

In a continuation of my coverage on artificial sweeteners, this post will be dedicated to one of the most controversial of them all: aspartame.  That’s because aspartame has been blamed for causing cancer and attributed to many other afflictions, which is evident in this chain email that circulated in 1998 during the early days of the internet.  In particular I remember the stories growing up, before I could even pronounce the word, that claimed aspartame causes cancer, and like many people, I automatically believed it was true.  I’ve dug through the scientific literature, there was a ton of it to look through…part of the reason it took so long for me to write this article.  Not surprisingly I’ve found that most of the claims are unsubstantiated by evidence, despite the fact that many of these studies are 20-30 years old – something that I do take issue with.  I did find some more recent compelling research, backed by a plausible mechanism on the potential neurotoxic effects of long-term aspartame consumption.  Those studies used large doses of aspartame, but were within the FDA acceptable daily intake limit, and I would urge you to read on for more context.  Aspartame may also have an affect on metabolic parameters related to diabetes and obesity, as well as composition of gut bacteria.  The evidence is conflicting, however, and many of these same issues are brought up surrounding other artificial sweeteners as well.

History

Aspartame was discovered through pure, dumb luck in 1965 by a scientist named James Schlatter, who was trying to discover an inhibitor to the gastric acid releasing hormone gastrin, presumably in an effort to create a treatment for peptic ulcers.  Instead, he spilled some of the material that he was working with on his hands and, like any good scientist (sarcasm), licked his fingers to pick up a piece of paper to discover the sweet taste of an intermediate in his organic reaction called aspartame.

Aspartame is a methyl ester dipeptide of aspartic acid and phenylalanine found in over 6000 products worldwide marketed under the brand name Equal.  Even though aspartame contains the same caloric intake as sugar on a weight by weight basis, it is 200 times sweeter than sugar. Therefore, recipes using aspartame require 200 times less of it than sugar as an ingredient and so it is classified as a non-nutritive sweetener on the basis that the small amount used in food translates to a negligible amount of energy.

Worldwide consumption of aspartame is estimated to be around 3mg/kg of body weight per day, corresponding to 210mg for a person weighing 70kg or 154lbs.  In the United States, consumers of aspartame are estimated to take in 330mg/day on the low and 940mg/day on the high end.  The US FDA has set the acceptable daily intake (ADI) of aspartame to be 50mg/kg of body weight per day, and using the 70kg person as an example this would be 3.5 grams a day, or 109 packets of Equal, or 17.5 cans of diet soda sweetened with aspartame.  The ADI is a number that the FDA defines as 100 times less the no observed adverse effect level in animal studies, so presumably you could drink 1,750 cans of diet soda before feeling any ill effects attributed to the aspartame.

Hundreds of studies have been cited in an industry review on the safety of aspartame published in 2007, one of the most thorough reviews I’ve seen on any subject, and I use it as a reference for this article unless otherwise stated.

Aspartame and Cancer

The reason for the mounds of studies that exist on the subject can probably be traced back to the 1980’s when it was thought that aspartame was responsible for an increase in brain tumors.  However aspartame was not approved for use until 1983 and according to the National Cancer Institute, the incidence of brain tumors was on the rise beginning in the early 1970’s.  Animal studies done during that period also found no link between aspartame and cancer.

The issue was brought up again in a 1996 epidemiological study that attributed the rise in brain cancer incidence post-1975 to aspartame use.  However, you could just as easily make that same connection with the increased use of sugar but neither assumption would be valid on its own.  Additionally, a separate review on the total incidence of brain cancers published in 1999 actually shows the number of cases has leveled off since the 90’s and mortality has actually declined in younger people, while there has been increased incidences in the elderly, both can be attributable to better detection and treatment methods.  There are also ways of manipulating data to get the result that you want without ever actually fabricating numbers and that seems to be what this study has done, as pointed out in one of the letters to the editor.  Several scientists have challenged the claims in that study and the European Food Safety Authority (EFSA) evaluated the study and concluded there was no plausible connection between aspartame and brain cancer.

More controversy surfaced around 2005-06 when Soffritti et al published two reports on a single lifetime feeding study using Sprague-Dawley rats. The rats were given doses of aspartame as high as 125 times the Food and Drug Administration’s (FDA) acceptable daily intake (ADI), with the lowest dose being 4 times less than the ADI.

The first report by the Soffritti group in 2005 concluded that there was a statistically significant increase in blood related cancers (leukemias and lymphomas) in the females fed aspartame at all doses, except the lowest dose, but there was no difference between male rates or the overall population at all doses compared to the control group which was not fed aspartame.  In fact, some of the male groups at the highest doses had a lower incidence of cancer than the control group.  The same authors produced a second report in 2006, covering the same experiment and presenting the same data, with very different conclusions; stating that there was a statistically significant difference in males, females and the overall population that developed cancer.  For this reason and others, the study has been marred by criticism from other scientists and food regulating agencies.

It’s important to know that this particular strain of rat is used frequently in cancer research because they develop tumors naturally over their roughly 2 year lifespan at a rate of about 42-50% starting at approximately 130 days of age, a rate similar to that of humans.  So in order to conclude that a compound is carcinogenic you would expect rats given the treatment to have a greater number of tumor incidence and probably at an earlier age than that of control rats, and the rate should increase as the dose increases (a dose-dependent response). The data in this study clearly does not indicate a dose-dependent trend with aspartame in any group.  A study such as the one by Soffritti et al where the rats are allowed to die naturally also makes it difficult to assess whether tumors developed spontaneously or in response to treatment.  Cancer is primarily a disease that results from living to an old age.  As the rats are allowed to survive to an older age, it becomes more difficult to differentiate between spontaneous tumor development (background) and those caused by treatment.  Further, the incidence of tumor development in the female control group was unusually low at 8%.  On average, the actual percentage can fluctuate between 4-25% based on other experiments in the literature.  Even within the first paper, the authors themselves admit to seeing an average of about 12.4% incidence rate of lymphomas and leukemia’s in females of this strain of rat.  The rate of tumor development in aspartame-treated females never exceeded 25% for any dose range, in other words, never outside the historical average. Considering the disparity between these numbers and the reported 8% from the control group, it’s easy to see why they found a statistically significant response.

There are also changes that begin to occur in tissue soon after death if a necropsy is not performed immediately, and allowing for a natural death of the animals leaves a lot of potential time between death and necropsy, an independent review of the study confirmed the presence of these post mortem changes in the tissue of these animals which may have effected the interpretation of tissue histology.

And there were even more problems with the study…

The rats were housed in different rooms, but all groups were housed together rather than randomized individually to different rooms.  There were 5 animals per cage, it’s recommended to house only 2 together based on the reported size of the cage in this study.  The composition of the diet is not clearly stated and its unknown how the aspartame was added, even after the authors were questioned in an independent review.  The statistical methods used may not have been appropriate.  Most damning is the fact that the rats were apparently afflicted with respiratory infections, likely a result of the densely packed housing conditions, which would have increased the likelihood of tumor development in the lungs and brain.

The two reports were enough to cause the EFSA to reevaluate the safety of aspartame and they concluded that the study was too problematic to make any claims on aspartame based on the reasons that I summarized.

Several studies, ranging from 28 days to 2 years, have been conducted on animals including dogs, mice, rats and rabbits with doses as high as 125 times the ADI, have reported no adverse effects from aspartame treatment even at the highest doses.  Most of those studies took place in the early 1970’s and it seems they were plagued by problems too as pointed out in this review by the EFSA.  Quoted directly from that article:

“These studies were unsatisfactory in a number of ways, including the presence of infections requiring
antibiotic treatment in one study, and they were subjected to detailed investigation by the US Bureau
of Foods in the 1970s. The outcome of the investigation was that the studies were essentially reliable
but that they were limited by a number of shortcomings in terms of diet preparation, protocol
compliance and QA.“

It would be interesting to know if the results of the toxicity studies held up to modern standards and scrutinized under peer review the way the Soffritti reports were.  To my knowledge, no other recent lifetime feeding studies have been conducted with aspartame.  However, aspartame was evaluated by the National Toxicology Program (NTP) in 2005 using 3 different transgenic mouse models, strains that are used to detect cancer causing agents, in aspartame feeding trials at various doses for 40 weeks and found no evidence that aspartame was carcinogenic.

Aspartame Metabolism, Phenylketonuria, and Methanol

Another reason aspartame remains a contentious issue with scientists is because of the breakdown products that it produces when metabolized by the body.  Aspartame is converted to aspartic acid, phenylalanine, and methanol.  There’s no debate that phenylalanine is bad and should be avoided by those with phenylketonuria, a genetic condition in which the enzyme that metabolizes phenylalanine is impaired. Therefore, people with this condition know they have to avoid certain foods in their diet that are high in phenylalanine and all foods containing aspartame are supposed to be labeled with a warning to phenylketonuriacs.

What remains a subject of debate is whether the methanol produced as a breakdown product is harmful.  Methanol toxicity can result in vision loss, even though some methanol is made naturally in the fermentation process of alcohol, some moonshiners have historically used methanol to dilute the final product and increase the apparent “strength.” This is where the anecdote for moonshine causing blindness originates.  It can also lead to neurological impairment and death, with a high number of survivors of methanol poisoning reporting to have Parkinson’s disease later in life.

The industry would contend that the methanol from aspartame is harmless because we ingest more methanol from natural products than from aspartame.  The estimated amount of methanol that is generated from average consumption of aspartame sweetened beverages is 55 mg/L.  The equivalent amount of fruit juice would contain 680mg/L and citrus fruits 180mg/L, its worth mentioning that this information was taken from the industry review I cited at the beginning of this article and within that article this reference is cited as (Anonymous, 1991). Even though I suspect the information is true, you never want to see an anonymous source cited as a reference in a scientific article.  Although I can’t access the paper to verify, another source estimates that an equivalent amount of tomato juice would have 6 times the amount of methanol than from aspartame.

Looking at these numbers, clearly, aspartame makes a negligible contribution to human intake of methanol.  However, methanol metabolism and toxicity can be complicated by other factors.  For example, treatment of methanol poisoning involves consumption of ethanol, ie ordinary drinking alcohol, because ethanol and methanol share a common enzyme in the liver that metabolizes these compounds.  Ethanol would serve as a competitive inhibitor of this enzyme, thereby, slowing methanol metabolism.  Its unknown how much methanol exposure is required to cause acute effects but the general range for a lethal dose is thought to be 0.3 to 1g/kg of body weight.

So does our body handle methanol differently from sources such as fruit and vegetables than from aspartame containing sources?  Certainly alcoholic beverages contain ethanol that would slow oxidation of any methanol present, potentially negating the harmful effects of rapid methanol metabolism. Do other sugary sources contain a corresponding amount of ethanol and would it even matter in such small amounts?  I don’t know the answer and I don’t think anyone does.

Aspartame and Neurotoxicity

I think its safe to say that it would be virtually impossible to ingest enough aspartame to produce acute symptoms of methanol poisoning.  I would be more concerned about chronic exposure to aspartame, the people in the highest percentile consuming several diet beverages sweetened with aspartame on a daily basis for several years, especially in regards to the effects that it may be having on the brain.

Studying the effects of methanol on the brain has been difficult.  Rodents can metabolize formic acid more efficiently, one of the end products of methanol metabolism, owing to the presence of higher folate concentrations in the liver than humans.  However, a model for rat feeding has recently been designed to deal with this shortcoming in research by giving the rats methotrexate (MTX), which inhibits an enzyme involved in folate production.  MTX treatment allows rats given methanol to experience a state of methanol poisoning that more closely resembles human methanol poisoning.  A 2006 study gave rats a single 3 g/kg per body weight of methanol (much more than you would ever receive with aspartame consumption in one dose) along with MTX given for 7 days.  Rats given methanol+MTX had greatly increased markers of oxidant stress in specific regions of the brain compared to rats given MTX alone or sterile saline as a control.  I managed to find only two studies that have used this model to study the effects of chronic aspartame consumption on the brain.  The first, published in 2012, shows that rats fed MTX+aspartame at a concentration of 75mg/kg of body weight for 90 days, almost twice the amount of the acceptable daily intake limit set by the US FDA, found a marked increase in blood methanol concentrations in the rats fed aspartame+MTX over MTX alone and the control group, as well as markers of oxidative stress in the brain similar to what was found in the methanol study.  Another study, using the same conditions but with the US FDA acceptable intake of 40mg/kg of body weight of aspartame, found that this concentration was not only enough to produce oxidative damage in the brain but also induced apoptosis (programmed cell death).  Apoptosis is also an effect that was observed in a dose-dependant manner with neuronal cells in vitro that were treated directly with aspartame.  Still yet, another study found that aspartame and insulin injections, together, induced detoxifying cytochrome p450 enzymes in the brain but not in the liver of diabetic rats.

It’s difficult to say what exactly this means, but destruction of neurons is never a positive sign.  The caveat to remember here is that 40mg/kg of aspartame, while within the acceptable daily intake, is still an absurd amount over 90 days.  It would be equal to about 15 cans of diet soda a day.  Still, I can’t imagine this bodes well for chronic/lifetime consumers of aspartame containing products and I’m sure more studies will trickle out using smaller doses.  Unfortunately, it would be difficult to attribute neurodegenerative disease to aspartame use in the general population, since the diseases do not manifest until later in life, often with little or difficult to diagnose acute symptoms.  Additionally, there are too many lifestyle factors that simply could not be controlled.  It may be too early, but I haven’t seen any responses from the industry online regarding these studies the way they have combated the Soffritti study and others.  Admittedly, I don’t know enough to evaluate the soundness of the brain studies, but on a basic level I’m not seeing any obvious red flags.

Aspartame for Weight Loss, Diabetes, and Obesity

There’s one more aspect of aspartame that I would like to touch on before concluding this article, and that is the issue of obesity and diabetes since that is the primary reason people turn to artificial sweeteners.

There is an emerging body of evidence showing that artificial sweeteners and, specifically, aspartame consumed in doses equivalent to 2-3 soft drinks a day for 8 weeks in mice are effecting the composition of bacteria in the gut.  Bacteria that are associated with obesity and insulin resistance.  Another recent study showed that mice consuming the EFSA defined aspartame ADI of 40mg/kg of body weight a day (again, this is around 15 diet sodas a day) not only experienced states of hyperglycemia and hyperlipidemia, both hallmarks of obesity, but also showed signs of oxidative stress which generally contributes to inflammation and disease.  To be sure, there are studies that show aspartame and artificial sweeteners can help with weight loss.  This review covers multiple studies showing that substituting sugar for aspartame can aid in weight loss.  However, I suspect that energy intake was carefully controlled for in those studies and probably do not take satiety into account.  In an uncontrolled environment, for example, if you feel hungry after consuming an aspartame-containing product you’re probably going to eat more until you feel full or satisfied.  There are studies that show this is happening as well, such as this review, which can be seen as a counterpoint to the previous review covering weight loss.  I find this evidence to be more compelling than the weight loss review, since they focus on very specific metabolic disturbances on the level of protein expression with strong implications for diabetics, rather than just looking at energy intake/output and examining weight loss.

Conclusion

I will end by saying the usual: all things in moderation.  Personally, I would not consume aspartame on a regular basis and I believe if there is anyone at risk for health problems, it is only for the group chronically drinking large amounts of aspartame sweetened beverages a day.  However, I suppose If I had to have an artificial sweetener to get through my day, I would prefer sucralose because it does not seem to undergo any chemical reactions in the body, is likely completely eliminated from the body, and I’ve seen no plausible mechanism to date that would suggest any serious problems.