Aspartame: Once more unto the breach

Like it or not, there's a clear scientific consensus

(Note: This one is long enough that your email provider may cut it off. But if “too long for email” makes you think “still way too short”, well—good news! The web version has expandy boxes to make it even longer still: dynomight.net/aspartame )

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Look, I get it. Diet Coke tastes sweet because it has aspartame in it. Aspartame is a weird synthetic molecule that’s 200 times sweeter than sucrose. Half of the world’s aspartame is made by Ajinomoto of Tokyo—the same company that first brought us MSG back in 1909.

If you look on Wikipedia, you’ll see that aspartame is a methyl ester of the aspartic acid phenylalanine dipeptide, which isn’t, like, comforting.

It’s normal to have a prior that aspartame would be bad for you. Certainly, that was my prior. Without looking at any evidence, any reasonable person would think like this:

This makes the decision theory pretty simple: Consuming aspartame has little upside, but substantial downside.

The thing is, we do have evidence. We have a lot of evidence. The FDA calls aspartame “one of the most exhaustively studied substances in the human food supply”.

The other thing is, the alternative to aspartame often isn’t no aspartame but rather sugar or corn syrup or even perhaps even alcohol.

I don’t want to convince anyone to consume aspartame. But if we’re choosing between aspartame and other risky things, we should evaluate the relative risks.

What happens to aspartame after it goes into your body

Let’s forget about safety for a second, and just look at the causal chain. Say you drink a Diet Coke. What happens next?

Fact 1: Aspartame is quickly broken down in the gut.

After you drink a Diet Coke, the aspartame goes to your guts. After that, it’s very quickly broken down into:

• 50% phenylalanine

• 40% aspartic acid

• 10% methanol

For example, a can of Diet Coke contains 184 mg of aspartame. This becomes:

• 92 mg of phenylalanine

• 73.6 mg aspartic acid

• 18.4 mg methanol

This happens quickly and completely. No aspartame ever enters your bloodstream. The rest of your body only ever sees these three other chemicals.

Fact 2: Phenylalanine is a standard amino acid you consume all the time.

We recently talked about phenylalanine. It is an essential amino acid. If you didn’t consume any of it, then when your body tried to make certain proteins, those proteins would get truncated, and they wouldn’t do what they were supposed to do, and then you would die.

Fortunately, that’s almost impossible. Here are four ways to contextualize the 92 mg of phenylalanine you get from a Diet Coke:

1. Phenylalanine in food:

   

2. In fruits and vegetables, 2-4% of all protein is phenylalanine. In cereals and animal protein, it’s 5%.

3. RDA guidelines say an adult person should get at least 33 mg/kg per day of phenylalanine (or tyrosine, a metabolite of phenylalanine). For a 70 kg (154 lb) person, that would be 2130 mg.

4. Meat-eating men in the UK 3500 average mg per day. Vegetarians and vegans get slightly less.

Around 1 in 12,000 babies is born with phenylketonuria, a serious genetic disorder that results in low levels of the enzyme phenylalanine hydroxylase. This makes it difficult to metabolize phenylalanine. So, people with phenylketonuria need to carefully monitor their consumption of phenylalanine (from all sources). This is why there’s this scary ALL-BOLD WARNING.

If you had phenylketonuria, you would know it.

Fact 3: Aspartic acid is a standard amino acid you consume all the time.

Here’s a chart from Wikimedia with our friends circled:

Aspartic acid is not essential in humans, meaning that if you don’t eat it, your body can make it (usually from oxaloacetic acid). But that’s not likely, since almost everything that has protein in it has aspartic acid, including meat, grains, dairy, vegetables, and eggs.

Men in the UK average 6600 mg of aspartic acid per day. Recall that a Diet Coke gives around 74 mg.

Fact 4: Methanol is a simple alcohol you consume all the time.

Methanol (CH₃OH) is the simplest alcohol molecule. It’s in lots of food. Here are some foods with larger average amounts.

But this still vastly underestimates how much methanol you get. In land plants, the primary component of cells walls is pectin. Once in the body, pectin degrades into methanol. Here are some estimates of the indirect increase in methanol various fruits and vegetables cause in this way.

You get the idea. We eat things that contain methanol or metabolize into methanol all the time. It’s estimated that most people get between 130 and 1030 mg of methanol from food per day, much more than the 18 mg in a Diet Coke.

Now isn’t methanol toxic? Well, sure, if you consume enough of it. The LD₅₀ in rats is around 5600 mg/kg, as compared to 7300 mg/kg for good-old ethanol.

One “conspiracy theory” you hear about aspartame is that it becomes formaldehyde once it’s in the body. This is absolutely true: When metabolizing methanol, formaldehyde is created. But small amounts of formaldehyde are also completely normal. The half-life of formaldehyde in human blood is around 1 minute, meaning it disappears almost immediately. You get more formaldehyde (via methanol) by eating an apple than by drinking a Diet Coke. Formaldehyde itself is also present in lots of foods, like meat, seafood, fruits, vegetables, and coffee.

Fact 5: This doesn’t prove aspartame is safe.

To summarize the above:

1. Aspartame is quickly broken down in the gut into phenylalanine, aspartic acid, and methanol. Aspartame itself never enters your bloodstream or touches any other part of the body.

2. Phenylalanine is normal.

3. Aspartic acid is normal.

4. Methanol is normal.

(Incidentally, this same logic does not apply to other artificial sweeteners which mostly aren’t broken down at all.)

While informative, this does not prove aspartame is safe. Biology is crazy. But it should inform our priors. Speaking for myself:

Previous model: Consuming aspartame results in a crazy unknown synthetic chemical circulating around your body and doing god-knows-what.

Updated model: Consuming aspartame results in slightly larger amounts of some totally normal chemicals.

But even if normal, could these chemicals still cause harm? Sure. Fortunately for us, aspartame was invented a long time ago.

The scientific consensus

How to think about this situation

Aspartame was first made in 1965 and was approved by the FDA in 1981. In all the decades since, there have been hundreds of studies.

How should we best make use of all this information? Given so many studies, focusing on individual papers is a mistake. With enough monkeys pounding away at enough typewriters scientists pounding away at enough science, lots of weirdness is expected.

The right strategy is to look at the entire pool of evidence. Some tiny number of people have the time and expertise to comb through the entire literature and synthesize everything. For the rest of us, the only sane attitude is to read other people who have done that synthesis.

The US Food and Drug Administration (FDA)

In typical US government fashion, the FDA doesn’t go to great lengths to explain its reasoning to the public. The best you can find is this rather lame page:

The history of aspartame and the FDA is contentious and sort of infuriating. For the scientific question of “is aspartame safe?” the main thing to know is that the FDA approved it a long time ago, and continues to stand by those decisions.

But it must be said that the history and public communication of the FDA on this issue is kind of a train wreck, and if I wanted to optimize it to serve as conspiracy theory fuel, I could scarcely do any better. The FDA says it continues to monitor new studies and remains confident aspartame is safe. So why doesn’t it explain its reasoning to a skeptical public? How is it possible the newest document the FDA can point people to is from 26 years ago? When a concerned citizen writes in, why does the FDA respond 12 years later, and act like that’s perfectly normal? Not helpful.

The European Food Safety Authority (EFSA)

Fortunately, other countries exist. The EFSA has a nice page that summarizes things this way:

The bottom of the page has a timeline that clearly presents all past activities, and clearly links to all ongoing studies and reports. (The fact that I’m impressed by such basic things drives home just how low the FDA sets the bar.)

There’s also an extremely nice-263 page risk assessment. This document is the single best (most clear, credible, thorough, and up-to-date) source of information I could find on the safety of aspartame. Here are some quotes from the summary:

there was no epidemiological evidence for possible associations of aspartame with various cancers in the human population.

The Panel considered the database on the genotoxicity of methanol and concluded that the data set was limited but that the available reliable in vitro and in vivo data did not indicate a genotoxic potential for methanol.

the calculated [No Observed Adverse Effect Level]s for methanol by oral exposure are 140 and 515-fold higher than the maximum amount of methanol that could be released when aspartame is consumed at the [Acceptable Daily Intake]

the data on reproductive and developmental toxicity did not suggest that there was a risk from methanol derived from aspartame at the current exposure estimates or at the [Acceptable Daily Intake] of 40 mg/kg bw/day.

based on recent measurements of basal levels of formaldehyde in blood and on the modelling of its biological turnover and steady state concentration in cells, formaldehyde formed from aspartame-derived methanol was not of safety concern at the current exposure estimates or at the ADI of 40 mg/kg bw/day.

It ends this way:

Health Canada

Canada is one of the clearer communicators:

Here are their conclusions in a handy table:

New Zealand Food Safety Authority

From an archived page:

Joint Expert Committee on Food Additives (JECFA)

The UN and WHO “jointly” run the JECFA. The only public reports I can find from them are really old, like 1980. For what it’s worth, this was the conclusion:

As far as I can tell, this 1981 update is the last word on aspartame from the JECFA. However, the JECFA currently has aspartame on the priority list of substances proposed for evaluation, as requested by Columbia, Costa Rica, and—somehow—the United States of America.

The Academy of Nutrition and Dietetics

This is a seemingly respectable organization of more than 100 thousand food and nutrition professionals, albeit one funded by food industry lobbying groups. Their position report states:

Literature reviews

Again, I don’t think it’s productive to look at individual papers. But we can look at reviews of all the evidence.

Here, some judgment is required. If I type “review aspartame safety” into Google scholar, many of the papers that come up have several of the following factors:

1. Paper is published in an obscure journal

2. Authors are from obscure institutions

3. Paper only engages with a tiny slice of the literature

4. Paper just “doesn’t look right”

For full transparency, here are the papers I found less credible for the above reasons, given as hopefully-offense-minimizing numbers: 1 2 3 4 5 6 7 8. Note that many of these do suggest health concerns with aspartame, but I am discounting their conclusions because I don’t think they are credible. If you don’t trust me, you should definitely look at those papers yourself. I have linked (here or below) everything I found that was published after the year 2000 and claimed to be a review of aspartame.

Butchko et al.

Paper: Butchko et al. Aspartame: Review of Safety. Regulatory Toxicology and Pharmacology, 2002.

Our first is a 93-page monster from a team of 24 scientists (three of whom, note, are employed by The NutraSweet Company). As I write this, it’s been cited 344 times. In their summary, you can feel the frustration:

Here’s a table from this paper:

This is helpful to put things in perspective. If you drink a Diet Coke, you get 2.6 mg/kg of aspartame, assuming you weight 70 kg. That’s around 20 times less than the government recommended limits. It’s also around 1000 times less than doses that do not show harms in animals.

Magnuson et al.

Paper: Magnuson et al. Aspartame: A Safety Evaluation Based on Current Use Levels, Regulations, and Toxicological and Epidemiological Studies. Critical Reviews in Toxicology, 2007.

This is a 99-page paper that’s been cited 430 times so far. The conclusions are kind of feisty.

Note that this study was funded by Ajinomoto via some kind of blind-trust arrangement.

Rogers et al.

Rogers et al. Does low-energy sweetener consumption affect energy intake and body weight? A systematic review, including meta-analyses, of the evidence from human and animal studies. International Journal of Obesity, 2016.

This paper has 320 citations and 11 authors (four of whom—sigh—have gotten grants from or worked at sweetener companies). It focuses on on metabolism and weight. Here is their conclusion, where LES = Low-Energy Sweeteners, EI = Energy Intake, and BW = Body Weight.

Other reviews

There are many other reviews that seem scientifically solid, but aren’t nearly as comprehensive as those above. Here’s a representative snippet from each:

Why write this?

I write this with some trepidation, as my previous mentions of aspartame caused a surprising amount of rancor.

But whatever, I’ll die on this hill: After aspartame is consumed, it immediately breaks down into three naturally occurring chemicals. Even large amounts of aspartame cause smaller fluctuations in those chemicals than normal food. The current science says that the health impact of aspartame is essentially zero. Every credible body that has studied this question has reached the same conclusion.

Is it possible that some harms have been missed? Of course! That’s how science works: Evidence accumulates slowly. It never becomes a sure thing, we just eventually decide it’s sure enough and move on with our lives.

So why are we still talking about aspartame? Why worry about it rather than, say, sugar or alcohol? I know many people who avoid diet soda but drink sugar-sweetened soda or large amounts of alcohol. That’s choosing a known harm over something that’s appears harmless.

Or, why not worry about:

• Lightning

• Q-tips

• Fireplaces

• Bathtubs

• Generators

• Lawn mowers

• Umbrellas

• Cruise ships

• Air in subways

• Blood clots in planes

• Cosmic rays in planes

• Charred meat

• Anticholinergics

• Cocoa

• Perfluorooctanoic acid

• Helicobacter pylori

To me, most skepticism of aspartame looks like an isolated demand for rigor—an impossibly high standard of evidence that isn’t applied to other things. Most of us have finite bandwidth for things to worry about, and the evidence we have for aspartame puts it very low on the list of sensible worries.

Many of the same people who claim aspartame is risky exhort to Follow the Science in other domains. I wonder: what evidence would be convincing proof of aspartame’s safety, but doesn’t already exist? Is it even possible? If not, well, OK! But if you only follow the science when the conclusions are intuitive, it’s not science that chooses your destination.