A Series of Unfortunate Omelettes: Lithium in Food Review & Survey Proposal

One thing that makes lithium a plausible explanation for the obesity epidemic is that clinical doses of lithium cause weight gain as a side-effect. A clinical dose of lithium is in the range of 1000 mg (“300 mg to 600 mg … 2 to 3 times a day”), and people pretty reliably gain weight on doses this high. In a 1976 review of case records, about 60% of people gained weight on clinical doses, with an average weight gain of about 10 kg.

But those are clinical doses, and it seems like the doses you’re getting from the environment are generally much smaller. There’s usually some lithium in modern drinking water, and there’s more lithium in drinking water now than there used to be. It seems to get into the water supply from things like drilled water wells, fracking, and fossil fuel prospecting, transport, and disposal. But even with all these sources of contamination, the dose you’re getting from your drinking water is relatively low, probably not much more than 0.2 mg per day. If you live right downstream from a coal plant, or you’re chugging liter bottles of mineral water on the regular, you could maybe get 5 or 10 mg/day. But no one is getting 1000 mg/day or even 300 mg/day from their drinking water. 

So what gives? 

Effects of Trace Doses

One possibility is that small amounts of lithium are enough to cause obesity, at least with daily exposure.

This is plausible for a few reasons. There’s lots of evidence (or at least, lots of papers) showing psychiatric effects at exposures of less than 1 mg (see for example meta-analysis, meta-analysis, meta-analysis, dystopian op-ed). If psychiatric effects kick in at less than 1 mg per day, then it seems possible that the weight gain effect would also kick in at less than 1 mg. 

There’s also the case study of the Pima in the 1970s. The Pima are a group of Native Americans who live in the American southwest, particularly around the Gila River Valley, and they’re notable for having high rates of obesity and diabetes much earlier than other groups. They had about 0.1 mg/L in their water by the 1970s (which was 50x the national median at the time), for a dose of only about 0.2-0.3 mg per day, and were already about 40% obese. All this makes the trace lithium hypothesis seem pretty reasonable.

Unfortunately, no one knows where the weight gain effects of lithium kick in. As far as we can tell, there’s no research on this question. It might cause weight gain at doses of 10 mg, or 1 mg, or 0.1 mg. Maybe 0.5 mg a week on average is enough to make some people really obese. We just don’t know.

Some people in the nootropics community take lithium, often in the form of lithium orotate (they use orotate rather than other compounds because it’s available over-the-counter), as part of their stacks. Based on community posts like this, this, and this, the general doses nootropics enthusiasts are taking are in the range of 1-15 mg per day. 

We haven’t done a systematic review of the subreddit (but maybe you should, that would be a good project for someone) but they seem to report no effects or mild positive effects at 1 or 2 mg lithium orotate and brain fog and fatigue at 5 mg lithium orotate and higher. Some of them report weight gain, even on doses this low. The fact that a couple extra mg might be enough to push you over the line suggests that the weight gain tipping point is somewhere under 10 mg, maybe a lot under. And for what it’s worth, all of this is consistent with the only randomized controlled trial examining the effects of trace amounts of lithium which found results at just 0.4 mg a day. 

Clinical and Subclinical Doses

Another possibility is that people really ARE getting unintended clinical doses of lithium. We see two reasons to think that this might be possible.

#1: Doses in the Mirror may be…

The first is that clinical doses are smaller than they appear. 

When a doctor prescribes you lithium, they’re always giving you a compound, usually lithium carbonate (Li2CO3). Lithium is one of the lightest elements, so by mass it will generally be a small fraction of any compound it is part of. A simple molecular-weight calculation shows us that lithium carbonate is only about 18.7% elemental lithium. So if you take 1000 mg a day of lithium carbonate, you’re only getting 187.8 mg/day of the active ingredient.

The little purple orbs are the pharmacologically active lithium ions, everything else is non-therapeutic carbonate

For bipolar and similar disorders, lithium carbonate has become such a medical standard that people usually just refer to the amount of the compound. It’s very unusual for an ion to be a medication, so this nuance is one that some doctors/nurses don’t notice. It’s pretty easy to miss. In fact, we missed it too until we saw this reddit comment from u/PatienceClarence/, which begins, “First off we need to differentiate between the doses of lithium orotate vs elemental lithium. For example, my dosage was 130 mg orotate which would give me 5 mg ‘pure’ lithium…” 

Elemental lithium is what we really care about, and when we look at numbers from the USGS or serum samples or whatever, they’re all talking about elemental lithium. When we say people get 0.1 mg/day from their water, or when we talk about getting 3 mg from your food, that’s milligrams of elemental lithium. When we say that your doctors might give you 600 mg per day, that’s milligrams lithium carbonate — and only 112.2 milligrams a day of elemental lithium. With this in mind, we see that the dose of elemental lithium is always much lower than the dose as prescribed. 

A high clinical dose is 600 mg lithium carbonate three times a day (for a total of 1800 mg lithium carbonate or about 336 mg elemental lithium), but many people get clinical doses that are much smaller than this. Low doses seem to be more like 450 mg lithium carbonate per day (about 84 mg/day elemental lithium) or even as little as 150 mg lithium carbonate per day (about 28 mg/day elemental lithium).

Once we take the fact that lithium is prescribed as a compound into account, we see that the clinical dosage is really closer to something like 300 mg/day for a high dose and 30 mg/day for a low dose. So at this point we just need to ask, is it possible that people might occasionally be getting 30 mg/day or more lithium in the course of their everyday lives? Unfortunately we think the answer is yes.

#2: Concentration in Food

The other reason to think that modern people might be getting clinical or subclinical doses on the regular is that there’s clear evidence that lithium concentrates in some foods. 

Again, consider the Pima. The researchers who tested their water in the 1970s also tested their crops. While most crops were low in lithium, they found that one crop, wolfberries, contained an incredible 1,120 mg/kg.

By our calculations, you could easily get 15 mg of lithium in a tablespoon of wolfberry jelly. If the Pima ate one tablespoon a day, they would be getting around 100 times more lithium from that tablespoon than they were getting from their drinking water.

The wolfberries in question (Lycium californium) are a close relative of goji berries (Lycium barbarum or Lycium chinense). The usual serving size of goji berries is 30 grams, which if you were eating goji berries like the ones the Pima were eating, would provide about 33.6 mg of lithium. This already puts you into clinical territory, a little more than someone taking a 150 mg tablet of lithium carbonate.

If you had a hankering and happened to eat three servings of goji berries in one day, you would get just over 100 mg of lithium from the berries alone. We don’t know how much people usually eat in one go, but it’s easy enough to buy a pound (about 450 g) of goji berries online. We don’t have any measurements of how much lithium are in the goji berries you would eat for a snack, but if they contained as much lithium as the wolfberries in the Gila River Valley, the whole 1 lb package would contain a little more than 500 mg of lithium.

So. Totally plausible that some plants concentrate 0.1 mg/L lithium in water into 1,120 mg/kg in the plant, because Sievers & Cannon have measurements of both. Totally plausible that you could get 10 or even 100 mg if you’re eating a crop like this. So now we want to know, are there other crops that concentrate lithium? And if so, what are they?

In this review, we take a look at the existing literature and try to figure out how much lithium there is in different foods. What crops does it concentrate in? Is there any evidence that foods are further contaminated in processing or transport? There isn’t actually all that much work on these questions, but we’ll take a look at what we can track down.

Let’s not bury the lede: we find evidence of subclinical levels of lithium in several different foods. But most of the sources that report these measurements are decades old, and none of them are doing anything like an exhaustive search. That’s why at the end of this piece, we’re going to talk a little bit about our next project, a survey of lithium concentrations in foods and beverages in the modern American food supply.

Because of this, our goal is not to make this post an exhaustive literature review; instead, our goal is to get a reasonable sense of how much lithium is in the food supply, and where it is. When we do our own survey of modern foods, what should we look at first? This review is a jumping off point for our upcoming empirical work.

Context for the Search

But first, a little additional context. 

There are a few official estimates of lithium consumption we should consider (since these are in food and water, all these numbers should be elemental lithium). This review paper from 2002 says that “the U.S. Environmental Protection Agency (EPA) in 1985 estimated the daily Li intake of a 70 kg adult to range from [0.650 to 3.100 mg].” The source they cite for this is “Saunders, DS: Letter: United States Environmental Protection Agency. Office of Pesticide Programs, 1985”, but we can’t find the original letter. As a result we don’t really know how accurate this estimate is, but it suggests people were getting about 1-3 mg per day in 1985.

These numbers are backed up by some German data which appear originally to be from a paper from 1991, which we will discuss more in a bit: 

In Germany, the individual lithium intake per day on the average of a week varies between [0.128 mg/day] and [1.802 mg/day] in women and [0.139] and [3.424 mg/day] in men. 

The paper also includes histograms of those distributions: 

Both of these say “mg/day” but we’re pretty sure that’s 1000x too high and they should say “µg/day”. If it were mg/day we think many of these people would be dead?

We want to call your attention to the shape of both of these distributions, because the shape is going to be important throughout this review. Both distributions are pretty clearly lognormal, meaning they peak early on but then have a super long tail off to the right. For example, most German men in this study were getting only about 0.2 to 0.4 mg of lithium per day, but twelve of them were getting more than 1 mg a day, and five of them were getting more than 2 mg a day. At least one person got more than 3 mg a day. And this paper is looking at a pretty small group of Germans. If they had taken a larger sample, we would probably see a couple people who were consuming even more. You see a similar pattern for women, just at slightly lower doses.

We expect pretty much every distribution we see around food and food exposure to be lognormal. The amount people consume per day should usually be lognormally distributed, like we see above. The distribution of lithium in any foods and crops will be lognormal. So will the distribution of lithium levels in water sources. For example, lithium levels in that big USGS dataset of groundwater samples we always talk about are distributed like this:

With scatterplot because those outliers are basically invisible on the histogram

Again we see a clear lognormal distribution. Most groundwater samples they looked at had less than 0.2 mg/L lithium. But five had more than 0.5 mg/L and two had more than 1 mg/L.

This is worth paying close attention to, because when a variable is lognormally distributed, means and medians will not be very representative. For example, in the groundwater distribution you see above, the median is .0055 mg/L and the mean is .0197 mg/L. 

These sound like really tiny amounts, and they are! But the mean and the median do not tell anywhere close to the full story. If we keep the long tail of the distribution in mind, we see that about 4% of samples contain more than 0.1 mg/L, about 1% of samples contain more than 0.2 mg/L, and of course the maximum is 1.7 mg/L. 

This means that about 4% of samples contain more than 20x the median, about 1% of samples contain more than 40x the median, and the maximum is more than 300x the median.

Put another way, about 4% of samples contain more than 5x the mean, about 1% of samples contain more than 10x the mean, and the maximum is more than 80x the mean.

We should expect similar distributions everywhere else, and we should expect means and medians to consistently be misleading in the same way. So if we find a crop with 1 mg/kg of lithium on average, that suggests that the maximum in that crop might be as high as 80 mg/kg! If this math is even remotely correct, you can see why crops that appear to have a low average level of lithium might still be worth empirically testing.

Another closely related point: that USGS paper only found those outliers because it’s a big survey, 4700 samples. Small samples will be even more misleading. Let’s imagine the USGS had taken a small number of samples instead. Here are some random sets of 6 observations from that dataset:

0.044, 0.007, 0.005, 0.036, 0.001, 0.002

0.002, 0.028, 0.005, 0.001, 0.009, 0.001

0.003, 0.006, 0.002, 0.001, 0.001, 0.006

We can see that small samples ain’t representative. If we looked at a sample of six US water sources and found that all of them contained less than 0.050 mg/L of lithium, we would miss that some US water sources out there contain more than 0.500 mg/L. In this situation, there’s no substitute for a large sample size (or, the antidote is to be a little paranoid about how long the tail is).

So if we looked at a sample of (for example) six lemons, and found that all of them contained less than 10 mg/kg of lithium, we might easily be missing that there are lemons out there that contain more than 100 mg/kg.

In any case, the obvious lognormal distribution fits really well with the kind of bolus-dose explanation we discussed with JP Callaghan, who said: 

My thought was that bolus-dosed lithium (in food or elsewhere) might serve the function of repeated overfeeding episodes, each one pushing the lipostat up some small amount, leading to overall slow weight gain. … I totally vibe with the prediction that intake would be lognormally distributed. … lognormally distributed doses of lithium with sufficient variability should create transient excursions of serum lithium into the therapeutic range.

In the discussion with JP Callaghan, we also said:

Because of the lognormal distribution, most samples of food … would have low levels of lithium — you would have to do a pretty exhaustive search to have a good chance of finding any of the spikes. So if something like this is what’s happening, it would make sense that no one has noticed. 

What we’re saying is that even if people aren’t getting that much lithium on average, if they sometimes get huge doses, that could be enough to drive their lipostat upward. If we take that model seriously, the average amount might not not be the real driver, and we should focus on whether there are huge lithium bombs out there, and how often you might encounter them. Or it could be even more complicated! Maybe some foods give you repeated moderate doses, and others give you rare megadoses. 

Two final notes before we start the review: 

First, if two sources disagree — one says strawberries are really high in lithium and the other says that strawberries are really low in lithium, or something — we should keep in mind that disagreement might mean something like “the strawberries were grown in different conditions (i.e. one batch was grown in high-lithium soil and the other batch wasn’t)” or even “apparently identical varieties of strawberries concentrate lithium differently”. There isn’t a simple answer to simple-sounding questions like “how much lithium is in a strawberry” because reality is complicated and words make it easy to hide that complexity without thinking about it.

Second, we want to remind you that whatever dose causes obesity, lithium is also a powerful sedative with well-known psychiatric effects. If you’re getting doses up near the clinical range, it’s gonna zonk you out and probably stress your kidneys. 

Ok. What crops concentrate lithium?

Lithium Concentration

Unfortunately we couldn’t find several of the important primary sources, so in a number of places, we’ve had to rely on review papers and secondary sources. We’re not going to complain “we couldn’t find the primary source” every time, but if you’re ever like “why are they citing a review paper instead of the original paper?” this is probably why.

We should warn you that these sources can be a little sloppy. Important tables are labeled unclearly. Units are often given incorrectly, like those histograms above that say mg/day when they should almost certainly say µg/day. When you double-check their citations, the numbers don’t always match up. For example, one of the review papers said that a food contained 55 mg/kg of lithium. But when we double-checked, their source for that claim said just 0.55 mg/kg in that food. So we wish we were working with all the primary sources but we just ain’t. Take all these numbers with a grain of salt.

Particularly important modern reviews include Lithium toxicity in plants: Reasons, mechanisms and remediation possibilities by Shahzad et al. (2016), Regional differences in plant levels and investigations on the phytotoxicity of lithium by Franzaring et al. (2016), and Lithium as an emerging environmental contaminant: Mobility in the soil-plant system by Robinson et al. (2018). Check those out if you finish this blog post and you want to know more.

It’s worth noting just how concerned some of these literature reviews sound. Shahzad et al. (2016) say in their abstract, “The contamination of soil by Li is becoming a serious problem, which might be a threat for crop production in the near future. … lack of considerable information about the tolerance mechanisms of plants further intensifies the situation. Therefore, future research should emphasize in finding prominent and approachable solutions to minimize the entry of Li from its sources (especially from Li batteries) into the soil and food chain.”

Older reviews include The lithium contents of some consumable items by Hullin, Kapel, and Drinkall — a 1969 paper which includes a surprisingly lengthy review of even older sources, citing papers as far back as 1917. Sadly we weren’t able to track down most of these older sources, and the ones we could track down were pretty vague. Papers from the 1930s just do not give all that much detail. Still, very cool to have anything this old. 

There’s also Shacklette, Erdman, Harms, and Papp (1978), Trace elements in plant foodstuffs, a chapter from (as far as we can tell) a volume called “Toxicity of Heavy Metals in the Environment”, which is part of a series of reference works and textbooks called “HAZARDOUS AND TOXIC SUBSTANCES”. It was sent to us by a very cool reader who refused to accept credit for tracking it down. If you want to see this one, email us.

A bunch of the best and most recent information comes from a German fella named Manfred Anke, who published a bunch of papers on lithium in food in Germany in the 1990s and 2000s. He did a ton of measurements, so you will keep seeing his name throughout. Unfortunately the papers we found from Anke mostly reference measurements from earlier work he did, which we can’t find. Sadly he is dead so we cannot ask him for more detail.

From Anke, in case anyone can track them down, we’d especially like to see a couple papers from the 1990s. Here they are exactly as he cites them:  

Anke’s numbers are very helpful, but we think they are a slight underestimation of what is in our food today. We’re pretty sure lithium levels in modern water are higher than levels in the early 1990s, and we’re pretty sure lithium levels are higher in US water than in water in Germany. In a 2005 paper, Anke says: “In Germany, the lithium content of drinking water varies between 4 and 60 µg/L (average : 10 µg/L).” Drinking water in the modern US varies between undetectable and 1700 µg/L (1.7 mg/L), and even though that 1700 is an outlier, about 8% of US groundwater samples contain more than 60 µg/L, the maximum Anke gives for Germany. The mean for US groundwater is 19.7 µg/L, compared to the 10 µg/L Anke reports.

So the smart money is that Anke’s measurements are probably all lower than the levels in modern food, certainly lower than the levels in food in the US.

Here’s another thing of interest: in one paper Anke estimates that in 1988 Germany, the average daily lithium intake for women was 0.373 mg, and the average daily lithium intake for men was 0.432 mg (or something like that; it REALLY looks like he messed up labeling these columns, luckily the numbers are all pretty similar). By 1992, he estimates that the average daily lithium intake for women was 0.713 mg, and the average daily lithium intake for men was 1.069 mg. He even explicitly comments, saying, “the lithium intake of both sexes doubled after the reunification of Germany and worldwide trade.”

That last bit about trade suggests he is maybe blaming imported foods with higher lithium levels, but it’s not really clear. He does seem to think that many foreigners get more lithium than Germans do, saying, “worldwide, a lithium intake for adults between [0.660 and 3.420 mg/day] is calculated.”

Anyways, on to actual measurements.

Beverages

Beverages are probably not giving you big doses of lithium, with a few exceptions.

Most drinking water doesn’t contain much lithium, rarely poking above 0.1 mg/L. Some beverages contain more, but not a lot more. The big exception, no surprise, is mineral water.

As usual, Anke and co have a lot to say. The Anke paper from 2003 says, “cola and beer deliver considerable amounts of lithium for humans, and this must be taken into consideration when calculating the lithium balance of humans.” The Anke paper from 2005 says that “amounts of [0.002 to 5.240 mg/L] were found in mineral water. Like tea and coffee, beer, wine and juices can also contribute to the lithium supply.” But the same paper reports a range of just 0.018 – 0.329 mg/L in “beverages”. Not clear where any of these numbers come from, or why they mention beer in particular — the citation appears to be the 1995 Anke paper we can’t find. 

In fact, Anke seems to disagree with himself. The 2005 paper mentions tea and coffee contributing to lithium exposure. But the 2003 paper says, “The total amount in tea and coffee, not their water-soluble fraction in the beverage, was registered. Their low lithium content indicates that insignificant amounts of lithium enter the diet via these beverages.”

This 2020 paper, also from Germany, finds a weak relationship for beer and wine and a strong relationship for tea with plasma concentrations for lithium. We think there are a lot of problems with this method (the serum samples are probably taken fasted, and lithium moves through the body pretty quickly) but it’s interesting.

Franzaring et al. (2016), one of those review papers, has a big figure summarizing a bunch of other sources, which has this to say about some beverages: 

For water, 1 ppm is approximately 1 mg/L

So obviously mineral water can contain a lot — if you drank enough, you could probably get a small clinical dose from mineral water alone. On the other hand, who’s drinking a liter of mineral water? Germans, apparently.

We think their sources for wine are Classification of wines according to type and region based on their composition from 1987 and Classification of German White Wines with Certified Brand of Origin by Multielement Quantitation and Pattern Recognition Techniques from 2004. The 1987 paper reports average levels of lithium in Riesling and Müller-Thurgau wines in the range of about 0.010 mg/L, and a maximum of only 0.022 mg/L. The 2004 paper looks at several German white wines, and reports a maximum of 0.150 mg/L. This is pretty unsystematic but does seem to indicate an increase. 

This paper from 2000 similarly finds averages of 0.035 and 0.019 mg/L in red wines from northern Spain. This 1994 paper and this 1997 paper both report similar values. We also found this 1988 paper looking at French red wines which suggests a range from 2.61 to 17.44 mg/L lithium. Possibly this was intended to be in µg/L instead of in mg/L? “All results are in milligrams per liter except Li, which is in micrograms per liter” is a disclaimer we’ve seen in more than one of these wine papers.

So it might be good to check, but overall we don’t think you’ll see much more than 0.150 mg/L in your wine, and most of you are hopefully drinking less than a full liter at a time.

She’s just so happy!

The most recent and most comprehensive source for beverages, however, is a 2020 paper called Lithium Content of 160 Beverages and Its Impact on Lithium Status in Drosophila melanogaster. Forget the Drosophila, let’s talk about all those beverages. This is yet another German paper, and they analyzed “160 different beverages comprising wine and beer, soft and energy drinks and tea and coffee infusions … by inductively coupled plasma mass spectrometry (ICP-MS).” And unlike other sources, they give all the numbers — If you want to know how much lithium they found in Hirschbraeu/Adlerkoenig, “Urtyp, hell” or the cola known as “Schwipp Schwapp”, you can look that up. 

They find that, aside from mineral water, most beverages in Germany contain very little lithium. Concentration in wine, beer, soft drinks, and energy drinks was all around 0.010 mg/L, and levels in tea and coffee barely ever broke 0.001 mg/L.

The big outlier is the energy drink “Acai 28 Black, energy”, which contained 0.105 mg/L. This is not a ton in the grand scheme of things — it’s less than some sources of American drinking water — but it’s a lot compared to the other beverages in this list. They mention, “it has been previously reported that Acai pulp contains substantial concentrations of other trace elements, including iron, zinc, copper and manganese. In addition to acai extract, Acai 28 black contains lemon juice concentrate, guarana and herb extracts, which possibly supply Li to this energy drink.”

BEWARE

We want to note that beverages in America may contain more lithium, just because American drinking water contains more lithium than German drinking water does. But it’s doubtful that people are getting much exposure from beverages beyond what they get from the water it’s made with. 

Basic Foods

We also have a few leads on what might be considered “basic” or “component” foods.

Anke mentions sugars a bit, though doesn’t go into much detail, saying, “honey and sugar are also extremely poor in lithium…. The addition of sugar apparently leads to a further reduction of the lithium content in bread, cake, and pastries.“ At one point he lists the range of “Sugar, honey” as being 0.199 – 0.527 mg/kg, with a mean of 0.363 mg/kg. That’s pretty low.

We also have a little data from the savory side. This paper from 1969 looked at levels in various table salts, finding (in mg/kg):

On the one hand, those are relatively high levels of lithium. On the other hand, who’s eating a kilogram of salt? Even if table salt contains 3 mg/kg, you’re just never gonna get even close to getting 1 mg from your salt.

Plant-Based Foods

It’s clear that plants can concentrate lithium, and some plants concentrate lithium more than others. It’s also clear that some plants concentrate lithium to an incredible degree. This last point is something that is emphasized by many of the reviews, with Shahzad et al. (2016) for example saying, “different plant species can absorb considerable concentration [sic] of Li.” 

Plant foods have always contained some lithium. The best estimate we have for preindustrial foods is probably this paper that looked at foods in the Chocó rain forest around 1970, and found (in dry material): 3 mg/kg in breadfruit; 1.5 mg/kg in cacao, 0.4 mg/kg in coconut, 0.25 mg/kg in taro, 0.4 mg/kg in yam, 0.6 mg/kg in cassava, 0.5 mg/kg in plantain fruits, 0.1 mg/kg in banana, 0.3 mg/kg in rice, 0.01 mg/kg in avocado, 0.5 mg/kg in dry beans, and 0.05 mg/kg in corn grains. Not nothing, but pretty low doses overall.

There are a few other old sources we can look at. Shacklette, Erdman, Harms, and Papp (1978) report a paper by Borovik-Romanova from 1965, in which she “reported the Li concentration in many plants from the Soviet Union to range from 0.15 to 5 [mg/kg] in dry material; she reported Li in food plants as follows ([mg/kg] in dry material): tomato, 0.4; rye, 0.17; oats, 0.55; wheat, 0.85; and rice, 9.8.” That’s a lot in rice, but we don’t know if that’s reliable, and we haven’t seen any other measurements of the levels in rice. We weren’t able to track the Borovik-Romanova paper down, unfortunately.

From here, we can try to narrow things down based on the better and more modern measurements we have access to.

Cereals

We haven’t seen very much about levels in cereals / grains / grass crops, but what we have seen suggests very low levels of accumulation.

Hullin, Kapel, and Drinkall (1969) mention an earlier review which found that the Gramineae (grasses) were especially “poor in lithium”, giving a range of 0.47-1.07 mg/kg. 

Borovik-Romanova reported, in mg/kg, “rye, 0.17; oats, 0.55; wheat, 0.85; and rice, 9.8” in 1965 in the USSR. Most of these concentrations are very low. Again, rice is abnormally high, but this measurement isn’t at all corroborated. And since we haven’t been able to find this primary source, there’s a good chance it should read 0.98 instead.

Anke, Arnhold, Schäfer, & Müller (2005) report levels from 0.538 to 1.391 mg/kg in “cereal products”, and in a 2003 paper, say “the different kinds of cereals grains are extremely lithium-poor as seeds.” Anke reports slightly lower levels in derived products like “bread, cake”. 

There’s also this unusual paper on corn being grown hydroponically in solutions containing various amounts of lithium. They find that corn is quite resistant to lithium in its water, actually growing better when exposed to some lithium, and only seeing a decline at concentrations around 64 mg/L. (“the concentration in solution ranging from 1 to 64 [mg/L] had a stimulating effect, whereas a depression in yielding occurred only at the concentrations of 128 and 256 [mg/L].”) But the plant also concentrates lithium — even when only exposed to 1 mg/L in its solution, the plant ends up with an average of about 11 mg/kg in dry material. Unfortunately they don’t seem to have measured how much ends up in the corn kernels, or maybe they didn’t let the corn develop that far. Seems like an oversight. (Compare also this similar paper from 2012.)

Someone should definitely double-check those numbers on rice to be safe, and corn is maybe a wildcard, but for now we’re not very worried about cereal crops.

Leafy Vegetables

A number of sources say that lithium tends to accumulate in leaves, suggesting lithium levels might be especially high in leafy foods. While most of us are in no danger of eating kilograms of cabbage, it’s worth looking out for. 

In particular, Robinson et al. (2018) observed significant concentration in the leaves of several species as part of a controlled experiment. They planted beetroot, lettuce, black mustard, perennial ryegrass, and sunflower in controlled environments with different levels of lithium exposures. “When Li was added to soil in the pot experiment,” they report, “there was significant plant uptake … with Li concentrations in the leaves of all plant species exceeding 1000 mg/kg (dry weight) at Ca(NO3)2-extractable concentrations of just 5 mg/kg Li in soil, representing a bioaccumulation coefficient of >20.” For sunflowers in particular, “the highest Li concentrations occurred in the bottom leaves of the plant, with the shoots, roots and flowers having lower concentrations.”

Obviously this is reason for concern, but these are plants grown in a lab, not grown under normal conditions. We want to check this against actual measurements in the food supply. 

Hullin, Kapel, and Drinkall (1969) report that an earlier source, Bertrand (1943), “found that the green parts of lettuce contained 7.9 [mg/kg] of lithium.” They wanted to follow up on this surprisingly high concentration, so they tested some lettuce themselves, finding: 

This pretty clearly contradicts the earlier 7.9 mg/kg, though the fact that lettuce can contain up to 2 mg/kg is still a little surprising. This could be the result of lettuce being grown in different conditions, the lognormal distribution, etc., but even so it’s reassuring to see that not all lettuce in 1969 contained several mg per kg.

In this study from 1990, the researchers went and purchased radish, lettuce and watercress at the market in Brazil, and found relatively high levels in all of them:

Let’s also look at this modern table that reviews a couple more recent sources, from Shahzad et al.:

FW = Fresh Weight and DM = Dry Matter, we think? 

None of these are astronomical, but it’s definitely surprising that spinach contains more than 4 mg/kg and celery and chard both contain more than 6 mg/kg, at least in these measurements.

So not to sound too contrarian but, maybe too many leafy greens are bad for your health. 

Fruits & Non-Leafy Veggies

Anke, Arnhold, Schäfer, & Müller (2005) say that “fruits and vegetables supply 1.0 to 7.0 mg Li/kg,” and report levels from 0.383 to 6.707 mg/kg in fruits. 

This is a wide range, and a pretty high ceiling. But as usual, Anke is much vaguer than we might hope. He gives some weird hints, but no specific measurements. In the 2003 paper, Anke says, “as a rule, fruits contain less lithium than vegetative parts of plants (vegetables). Lemons and apples contained significantly more lithium, with about 1.4 mg/kg dry matter, than peas and beans.”

More specific numbers have been hard to come by. We’ve found a pretty random assortment, like how Shahzad et al. report that “in a hydroponic experiment, Li concentration in nutrient solution to 12 [mg/L], increased cucumber fruit yield, fruit sugar, and ascorbic acid levels, but Li did not accumulate in the fruit (Rusin, 1979).” It’s interesting that cucumbers survive just fine in water containing up to 12 mg/L, and that suggests that lithium shouldn’t accumulate in cucumbers under any realistic water levels. But cucumbers are not a huge portion of the food supply.

What we do see all the time is sources commenting on how citrus plants are very sensitive to lithium. Anke says, “citrus trees are the most susceptible to injury by an excess of lithium, which is reported to be toxic at a concentration of 140–220 p.p.m. in the leaves.” Robinson et al. (2018) say, “citing numerous sources, Gough et al. (1979) reported a wide variation in plant tolerance to Li; citrus was found to be particularly sensitive, whilst cotton was more tolerant.” Shahzad et al. say, “Bradford (1963) found reduced and stunted growth of citrus in southern California, U.S.A., with the use of highly Li-contaminated water for irrigation. …  Threshold concentrations of Li in plants are highly variable, and moderate to severe toxic effects at 4–40 mg Li kg−1 was observed in citrus leaves (Kabata-Pendias and Pendias, 1992).” This Australian Water Quality Guidelines for Fresh and Marine Waters document says, “except for citrus trees, most crops can tolerate up to 5 mg/L in nutrient solution (NAS/NAE 1973). Citrus trees begin to show slight toxicity at concentrations of 0.06–0.1 mg/L in water (Bradford 1963). Lithium concentrations of 0.1–0.25 mg/L in irrigation water produced severe toxicity symptoms in grapefruit … (Hilgeman et al. 1970)”.

All tantalizing, but we can’t get access to any of those primary sources. For all we know this is a myth that’s been passed around the agricultural research departments since the 1960s.

The citrus is tantalizing, get it? 

Even if citrus trees really are extra-sensitive to lithium, it’s not clear what that means for their fruits. Maybe it means that citrus fruits are super-low in lithium, since the tree just dies if it’s exposed to even a small amount. Or maybe it means that citrus fruits are super-high in lithium — maybe citrus trees absorb lithium really quickly and that’s why lithium kills them at relatively low levels.

So it’s interesting but at this point, the jury is out on citrus.

Nightshades

Multiple sources mention that the Solanaceae family, better known as nightshades, are serious concentrators of lithium. Hullin, Kapel, and Drinkall mention that even in the 1950s, plant scientists were aware that nightshades are often high in lithium. Anke, Schäfer, & Arnhold (2003) mention, “Solanaceae are known to have the highest tolerance to lithium. Some members of this family accumulate more than 1000 p.p.m. lithium.” Shacklette, Erdman, Harms, and Papp (1978) even mention a “stimulating effect of Li as a fertilizer for certain species, especially those in the Solanaceae family.”

Shahzad et al. (2016) say, “Schrauzer (2002) and Kabata-Pendias and Mukherjee (2007) noted that plants of Asteraceae and Solanaceae families showed tolerance against Li toxicity and exhibited normal plant growth,” and, “some plants of the Solanaceae family, when grown in an acidic climatic zone accumulate more than 1000 mg/kg Li.” We weren’t able to track down most of their sources for these claims, but we did find Schrauzer (2002). He mentions that Cirsium arvense (creeping thistle) and Solanum dulcamara (called things like fellenwort, felonwood, poisonberry, poisonflower, scarlet berry, and snakeberry; probably no one is eating these!) are notorious concentrators of lithium, and he repeats the claim that some Solanaceae accumulate more than 1000 mg/kg lithium, but it’s not clear what his source for this was.

Hullin, Kapel, and Drinkall mention in particular one source from 1952 that found a range of 1.8-7.96 [mg/kg] in members of the Solanaceae. 7.9 mg/kg in some nightshades is enough to be concerned, but they don’t say which species this measurement comes from. 

The finger seems to be pointing squarely at the Solanaceae — but which Solanaceae? This family is huge. If you know anything about plants, you probably know that potatoes and tomatoes are both nightshades, but you may not know that nightshades also include eggplants, the Capsicum (including e.g. chili peppers and bell peppers), tomatillos, some gooseberries, the goji berry, and even tobacco. 

We’ve already seen how wolfberries / goji berries can accumulate crazy amounts under the right circumstances, which does make this Solanaceae thing seem even more plausible. 

Anke, Schäfer, & Arnhold (2003) mention potatoes in particular in one section on vegetable foods, saying: “All vegetables and potatoes contain > 1.0 mg lithium kg−1 dry matter.” There isn’t much detail, but the paper does say, “peeling potatoes decreases their lithium content, as potato peel stores more lithium than the inner part of the potato that is commonly eaten.”

That same paper that tries to link diet to serum lithium levels does claim to find that a diet higher in potatoes leads to more serum lithium, but we still think this paper is not very good. If you look at table 4, you see that there’s not actually a clear association between potatoes and serum levels. Table 5 says that potatoes come out in a regression model, but it’s a bit of an odd model and they don’t give enough detail for us to really evaluate it. And again, these serum concentrations were taken fasted, so they didn’t measure the right thing.

It’s much better to just measure the lithium in potatoes directly. Anke seems to have done this in the 1990s, but he’s not giving any details. We’ll have to go back all the way to 1969, when Hullin, Kapel, and Drinkall included three varieties of potatoes in their study (numbers in mg/kg):

These potatoes, at least, are pretty low in lithium. The authors do specifically say these were peeled potatoes, which may be important in the light of Anke’s comment about the peels. These numbers are pretty old, and modern potatoes probably are exposed to more lithium. But even so, these potatoes do not seem to be mega-concentrators, and Hullin, Kapel, and Drinkall did find some serious concentrators even back in 1969. 

This is especially interesting to us because it provides a little support for the idea that the potato diet might cause weight loss by reducing your lithium intake and forcing out the lithium already in your system with a high dose of potassium, or something. At the very least, it looks like you’d get less lithium in your diet if you lived on only potatoes than if you somehow survived on only lettuce (DO NOT TRY THE LETTUCE DIET).

Apparently the nightshade family’s tendency to accumulate lithium does not include the potatoes (unless the peeling made a huge difference?). This suggests that the high levels might have come from some OTHER nightshade. Obviously we have already seen huge concentrations in the goji berry (or at least, a close relative). But what about other nightshades, like tomatoes, eggplant, or bell peppers? 

Hullin, Kapel, and Drinkall do frustratingly say, “[The lithium content] of the tomato will be reported elsewhere.” But they don’t discuss it beyond that, at least not in this paper. We’ll have to look to other sources.

Shacklette et al. report: “Borovik-Romanova reported the Li concentration in [dry material] … tomato, 0.4 [mg/kg].” This is not much, though these numbers are from 1965, and from the USSR.

A stark contrast can be found in one of Anke’s papers, where they state, “Fruits and vegetables supply 1.0 to 7.0 mg Li/kg food DM. Tomatoes are especially rich in Li (7.0 mg Li/kg DM).” 

This is a lot for a vegetable fruit! It occurs to us that tomatoes are pretty easy to grow hydroponically, and you could just dose distilled water with a known amount of lithium. If any of you are hydroponic gardeners and want to try this experimentally, let us know! 

But tomatoes are obviously beaten out by wolfberries/goji berries, and they also can’t compare to this dark horse nightshade: tobacco.

SURPRISE

That’s right — Hullin, Kapel, and Drinkall (1969) also measured lithium levels in tobacco. They seem to have done this not because it’s another nightshade, but because previous research from the 1940s and 1950s had found that lithium concentrations in tobacco were “extraordinarily high”. For their own part, Hullin and co. found (mg/kg in ash): 

This is a really interesting finding, and in a crop we didn’t expect people to examine, since tobacco isn’t food.

At the same time, measuring ash is kind of cheating. Everything organic will be burned away in the cigarette or pipe, so the level of any salt or mineral will appear higher than it was in the original substance. As a result, we don’t really know the concentration in the raw tobacco. This is also the lithium that’s left over in the remnants of tobacco after it’s been smoked, so these measurements are really the amount that was left unconsumed, which makes it difficult to know how much might have been inhaled. Even so, the authors think that “the inhalation of ash during smoking could provide a further source of this metal”. 

This is also interesting in combination with the fact that people with psychiatric disorders often seem to self-medicate with tobacco. Traditionally schizophrenics are the ones drawn to being heavy smokers, but smoking is disproportionately common in bipolar patients as well. Researchers have generally tried to explain this in terms of nicotine, which we think of as being the active ingredient in tobacco, but given these lithium levels, maybe psychiatric patients smoke so much because they’re self-medicating with the lithium? Or maybe lithium exposure through the lungs causes schizophrenia and bipolar disorder? (For comparison, see Scott Alexander discussing a similar idea.)  

We didn’t find measurements for any other nightshades, but we hope to learn more in our own survey.

Animal-Based Foods

Pretty much everything we see suggests that animal products contain more lithium on average than plant-based foods. This makes a lot of general sense because of biomagnification. It also makes particular sense because many food animals consume huge quantities of plant stalks and leaves, and as we’ve just seen, stalks and leaves tend to accumulate more lithium than other parts of the plants.

toxic waste make bear sad

But the bad news is that, like pretty much everything else, levels in animal products are poorly-documented and we have to rely heavily on Manfred Anke again. He’s a good guy, we just wish — well we wish we had access to his older papers.

It’s like he’s toying with us!!!

Meat

Meat seems to contain a consistently high level of lithium. Apparently based on measurements he took in the 1990s, Anke calculates that meat products contain an average of about 3.2 mg/kg, and he gives a range of 2.4 to 3.8 mg/kg. 

In Anke, Arnhold, Schäfer, & Müller (2005) he elaborates just a little, saying, “Poultry, beef, pork and mutton contain lithium concentrations increasing in that order.”

In place of more detailed measurements, Anke, Schäfer, & Arnhold (2003) give us this somewhat difficult paragraph: 

On average, eggs, meat, sausage, and fish deliver significantly more lithium per kg of dry matter than most cereal foodstuffs. Eggs, liver, and kidneys of cattle had a mean lithium content of 5 mg/kg. Beef and mutton contain more lithium than poultry meat. Green fodder and silage consumed by cattle and sheep are much richer in lithium than the cereals largely fed to poultry. Sausage and fish contain similar amounts of lithium to meat. 

Beyond this, we haven’t found much detail to report. And even Anke can’t keep himself from mentioning how meat plays second fiddle to something else:

… Poultry, beef, pork and mutton contain lithium concentrations increasing in that order. Most lithium is delivered to humans by eggs and milk (> 7000 µg/kg DM). 

This is backed up by Hullin, Kapel, and Drinkall (1969), who said: 

Among foods of animal origin, those which have been found to contain lithium include eggs (Press, 1941) and milk (Wright & Papish, 1929; Drea, 1934).

So let’s leave meat behind for now and look at the real heavy-hitters.

Dairy

The earliest report we could find for milk was this 1929 Science publication mentioned by Hullin, Kapel, and Drinkall. But papers this old are pretty terse. It’s only about three-quarters of a page, and the only information they give about lithium is that it is included in the “elements not previously identified but now found to be present” in milk. 

Anke can do one better, and estimates an average for “Milk, dairy products” of 3.6 mg/kg with a range of 1.1 to 7.5 mg/kg. This suggests that the concentration in dairy products is pretty high across the board, but also that there’s considerable variation.

Anke explains this in a couple ways. First of all, he says that there were, “significant differences between the lithium content of milk”, and he suggests that milk sometimes contained 10 mg/kg in dry matter. This seems to contradict the range he gives above, but whatever. 

He also points out that other dairy products contain less lithium. For example, he says that butter is “lithium-poor”, containing only about 1.2 mg/kg dry matter, which seems to be the bottom of the range for dairy. “In contrast to milk,” he says, “curd cheese and other cheeses only retain 20–55% of lithium in the original material available for human nutrition. The main fraction of lithium certainly leaves cheese and curd cheese via the whey.”

This is encouraging because we love cheese and we are glad to know it is not responsible for poisoning our brains — at least, not primarily. It’s also interesting because 20-55% is a pretty big range; we’d love to know if some cheeses concentrate more than others, or if this is just an indication of the wide variance he mentioned earlier in milk. Not that we really need it, but if you have access to the strategic cheese reserve, we’d love to test historical samples to see if lithium levels have been increasing. 

What he suggests about whey is also pretty intriguing. Whey is the main byproduct of turning milk into cheese, so if cheese is lower in lithium than milk is, then whey must be higher. Does this mean whey protein is super high in lithium?

Whey protein display in The Hague, flanked by boars

Eggs

The oldest paper we could find on lithium in eggs is a Nature publication from 1941 called “Spectrochemical Analysis of Eggs”, and it is half a page of exactly that and nothing else. They do mention lithium in the eggs, but unfortunately the level of detail they give is just: “Potassium and lithium were also present [in the eggs] in fair quantity.”

Anke gives his estimate as always, but this time, it’s a little different: 

Anke gives an average (we think; he doesn’t label this column anywhere) of 7.3 mg/kg in eggs. This is a lot, more than any other food category he considers. And instead of giving a range, like he does for every other food category, he gives the standard deviation, which is 6.5 mg/kg.

This is some crazy variation. Does that mean some eggs in his sample contained more than 13.8 mg/kg lithium? That’s only one standard deviation above the average, two standard deviations would be 20.3 mg/kg. A large egg is about 50 g, so at two standard deviations above average, you could be getting 1 mg per egg. 

That does seem to be what he’s suggesting. But if we assume the distribution of lithium in eggs is normal, we get negative values quickly, and an egg can’t contain a negative amount of lithium.

Because lithium concentrations can’t be negative, and because of the distributions we’ve seen in all the previous examples, we assume the distribution of lithium in eggs must be lognormal instead.

A lognormal distribution with parameters [1.7, .76] has a mean and sd of very close to 7.3 and 6.5, so this is a reasonable guess about the underlying distribution of eggs in Germany in 1991.

Examination of the lognormal distribution with these parameters suggests that the distribution of lithium in eggs (at least in Germany in 1991) looks something like this: The modal egg in this distribution contains about 3 mg/kg lithium. But about 21% of the eggs in this distribution contain more than 10 mg/kg lithium. About 4% contain more than 20 mg/kg. About 1% contain more than 30 mg/kg. About 0.4% contain more than 40 mg/kg. And two out of every thousand contain 50 mg/kg lithium or more. 

That’s a lot of lithium for just one egg. What about the lithium in a three-egg omelette? 

ACHTUNG

To answer this Omelettenproblem, we started by taking samples of three eggs from a lognormal distribution with parameters [1.7, .76]. That gives us the concentration in mg/kg for each egg in the omelette.

Again, a large egg is about 50 grams. In reality a large egg is slightly more, but we’ll use 50 g because some restaurants might use medium eggs, and because it’s a nice round number. 

So we multiply each egg’s mg/kg value by .05 (because 50 g out of 1000 g for a kilogram) to get the lithium it contains in mg, and we add the lithium from all three eggs in that sample together for the total amount in the omelette.

We did this 100,000 times, ending up with a sample of 100,000 hypothetical omelettes, and the estimated lithium dose in each. Here’s the distribution of lithium in these three-egg omelettes in mg as a histogram: 

And here it is as a scatterplot in the style of The Economist

As you can see, most omelettes contained less than 3 mg lithium. In fact, most contained between 0.4 and 1.6 mg.

This doesn’t sound like a lot, but we think it’s pretty crazy. A small clinical dose is something like 30 mg, and it’s nuts to see that you can get easily like 1/10 that dose from a single omelette. Remember that in 1985, the EPA estimated that the daily lithium intake of a 70 kg US adult ranged from 0.650 to 3.1 mg — but by 1991 Germany, you can get that whole dose in a single sitting, from a single dish! 

Even Anke estimated that his German participants were getting no more than 3 mg a day from their food. But this model suggests that you can show up at a cafe and say “Kellner, bringen Sie mir bitte ein Omelette” and easily get that 3 mg estimate blown out of the water before lunchtime.

Even this ignores the long tail of the data. The omelettes start to peter out at around 5 mg, but the highest dose we see in this set of 100,000 hypothetical breakfasts was 11.1 mg of lithium in a single omelette.

The population of Germany in 1990 was just under 80 million people. Let’s say that only 1 out of every 100 people orders a three-egg omelette on a given day. This means that every day in early 1990s Germany, about 800,000 people were rolling the dice on an omelette. Let’s further assume that the distribution of omelettes we generated above is correct. If all these things are true, around 8 unlucky people every day in 1990s Germany were getting smacked with 1/3 a clinical dose of lithium out of nowhere. It’s hard to imagine they wouldn’t feel that. 

Processed Food

One thing we didn’t see much of in this literature review was measurements of the lithium in processed food.

We’re very interested in seeing if processing increases lithium. But no one seems to have measured the lithium in a hamburger, let alone a twinkie. 

There are a few interesting things worth mentioning, however — all from Anke, Schäfer, & Arnhold (2003), of course.

Mostly Anke and co find that processed foods are not extreme outliers. “Ready-to-serve soups with meat and eggs were [rich] in lithium,” they say, “whereas various puddings, macaroni, and vermicelli usually contained < 1 mg lithium/kg dry matter. Bread, cake, and pastries are usually poor sources of lithium. On average, they contained less lithium than wheat flour. The addition of sugar apparently leads to a further reduction of the lithium content in bread, cake, and pastries.”

Even in tasty treats, they don’t find much. We don’t know how processed German chocolate was at the time, but they say, “the lithium content of chocolates, chocolate candies, and sweets amounted to about 0.5 mg/kg dry matter. Cocoa is somewhat richer in lithium. The addition of sugar in chocolates reduces their lithium content.”

The only thing that maybe jumps out as evidence of contamination from processing is what they say about mustard. “Owing to the small amounts used in their application,” they begin, “spices do not contribute much lithium to the diet. It is surprising that mustard is relatively lithium-rich, with 3.4 mg/kg dry matter, whereas mustard seed contains extremely little lithium.” Mustard is generally a mixture of mustard seed, water, vinegar, and not much else. We saw in the section on beverages that wine doesn’t contain much lithium, so vinegar probably doesn’t either. Maybe the lithium exposure comes from processing?

Misc

We notice that for many categories of food, we seem to have simply no information. How much lithium is in tree nuts? Peanuts? Melons? Onions? Various kinds of legumes? How much is in major crops like soy? This is part of why we need to do our own survey, to fill these gaps and run a more systematic search.

It’s interesting, though not surprising, to see such a clear divide between plant and animal foods. In fact, we wonder if this can explain why vegetarian diets seem to lead to a little weight loss and vegan diets seem to lead to a little more, and also why neither of them work great.

Meat seems to contain a lot of lithium, but honestly not that much more than things like tomatoes and goji berries. Vegetarians will consume less lithium when they stop eating meat, but if they compensate for not eating meat by eating more fruit, they might actually be worse off. If they compensate by eating more eggs, or picking up whey protein, they’re definitely worse off! 

Vegans have it a little better — just by being vegan, they’ll be cutting out the three most reliable sources of lithium in the general diet. As long as they don’t increase their consumption of goji berries to compensate, their total exposure should go down. Hey, it makes more sense than “not eating dairy products gives you psychic powers because otherwise 90% of your brain is filled with curds and whey.”

But even so, a vegan can get as much lithium as a meat-eater if they consume tons of nightshades, so even a vegan diet is not a sure ticket to lithium removal. Not to mention that we have basically no information on plant-based protein sources (legumes, nuts) so we don’t know how much lithium vegans might get from that part of their diet.

In Conclusion

There’s certainly lithium in our food, sometimes quite a bit of lithium. It seems like most people get at least 1 mg a day from their food, and on many days, there’s a good chance you’ll get more.

That said, most of the studies we’ve looked at are pretty old, and none of them are very systematic. Sources often disagree; sample sizes are small; many common foods haven’t been tested at all. The overall quality is not great. We don’t think any of this data is good enough to draw strong conclusions from. Personally we’re avoiding whey protein and goji berries for right now, but it’s hard to get a sense of what might be a good idea beyond that. So as the next step in this project, we’re gonna do our own survey of the food supply.

The basic plan is pretty simple. We’re going to go out and collect a bunch of foods and beverages from American grocery stores. As best as we can, we will try to get a broad and representative sample of the sorts of foods most people eat on a regular basis, but we’ll also pay extra-close attention to foods that we suspect might contain a lot of lithium. Samples will be artificially digested (if necessary) and their lithium concentration will be measured by ICP-MS. All results will be shared here on the blog.

Luckily, we have already secured funding for the first round of samples, so the survey will proceed apace. If you want to offer additional support, please feel free to contact us — with more funding, we could do a bigger survey and maybe even do it faster. We could also get a greenhouse and run some hydroponic studies maybe.

If you’re interested in getting involved in other ways, here are a few things that would be really helpful:

1. If you would be willing to go out and buy an egg or whatever and mail it in to be tested, so we could get measurements from all over the country / the world, please fill out this form.

2. If you work at the FDA or a major food testing lab or Hood Milk or something, or if you’re a grad student with access to the equipment to test your breakfast for lithium and an inclination to pitch in, contact phil@whylome.org to discuss how you might be able to contribute to this project.

Peer Review: Obesity II – Establishing Causal Links Between Chemical Exposures and Obesity

A new paper, called Obesity II: Establishing Causal Links Between Chemical Exposures and Obesity, was just published in the journal Biochemical Pharmacology (available online as of 5 April 2022). Authors include some obesity bigwigs like Robert H. Lustig, and it’s really long, so we figured it might be important. 

The title isn’t some weird Walden II reference — there’s a Part I and Part III as well. Part I reviews the obesity epidemic (in case you’re not already familiar?) and argues that obesity “likely has origins in utero.”

“The obesity epidemic is Kurt Cobain’s fault” is an unexpected but refreshing hypothesis

Part III basically argues that we should move away from doing obesity research with cells isolated in test tubes (probably a good idea TBH) and move towards “model organisms such as Drosophila, C. elegans, zebrafish, and medaka.” Sounds fishy to us but whatever, you’re the doctor.

This paper, Part II, makes the case that environmental contaminants “play a vital role in” the obesity epidemic, and presents the evidence in favor of a long list of candidate contaminants. We’re going to stick with Part II today because that’s what we’re really interested in.

For some reason the editors of this journal have hidden away the peer reviews instead of publishing them alongside the paper, like any reasonable person would. After all, who could possibly evaluate a piece of research without knowing what three anonymous faculty members said about it? The editors must have just forgotten to add them. But that’s ok — WE are these people’s peers as well, so we would be happy to fill the gap. Consider this our peer review:

This is an ok paper. They cite some good references. And they do cite a lot of references (740 to be exact), which definitely took some poor grad students a long time and should probably count for something. But the only way to express how we really feel is:

Seriously, 43 authors from 33 different institutions coming together to tell you that “ubiquitous environmental chemicals called obesogens play a vital role in the obesity pandemic”? We could have told you that a year ago, on a budget of $0. 

This wasted months, maybe years of their lives, and millions of taxpayer dollars making this paper that is just like, really boring and not very good. Meanwhile we wrote the first draft of A Chemical Hunger in a month (pretty much straight through in October 2020) and the only reason you didn’t see it sooner was because we were sending drafts around to specialists to make sure there wasn’t anything major that we overlooked (there wasn’t).

We don’t want to pick on the actual authors because, frankly, we’re sure this paper must have been a nightmare to work on. Most of the authors are passengers of this trainwreck — involved, but not responsible. We blame the system they work under.

We hope this doesn’t seem like a priority dispute. We don’t claim priority for the contamination hypothesis — here are four papers from 2008, 2009, 2010, and 2014, way before our work on the subject, all arguing in favor of the idea that contaminants cause obesity. If the contamination hypothesis turns out to be right, give David B. Allison the credit, or maybe someone even earlier. We just think we did an exceptionally good job making the case for the hypothesis. Our only original contributions (so far) are arguing that the obesity epidemic is 100% (ok, >90%) caused by contaminants, and suggesting lithium as a likely candidate. 

So we’re not trying to say that these authors are a bunch of johnny-come-latelies (though they kind of are, you see the papers up there from e.g. 2008?). The authors are victims here of a vicious system that has put them in such a bad spot that, for all their gifts, they can now only produce rubbish papers, and we think they know this in their hearts. It’s no wonder grad students are so depressed! 

So to us, this paper looks like a serious condemnation of the current academic system, and of the medical research system in particular. And while we don’t want to criticize the researchers, we do want to criticize the paper for being an indecisive snoozefest.

Long Paper is Long

The best part of this paper is that comes out so strongly against “traditional wisdom” about the obesity epidemic:  

The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. … Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. 

In particular we like how they point out how, from the contaminant perspective, measures of how much people eat are just not that interesting. If chemicals in your carpet raise your set point, you may need to eat more just to maintain homeostasis, and you might get fat. This means that more consumption, of calories or anything else you want to measure, is consistent with contaminants causing obesity. We made the same point in Interlude A. Anyways, don’t come at us about CICO unless you’ve done your homework. 

We also think the paper’s heart is in the right place in terms of treatment: 

The focus in the obesity field has been to reduce obesity via medicines, surgery, or diets. These interventions have not been efficacious as most people fail to lose weight, and even those who successfully lose substantial amounts of weight regain it. A better approach would be to prevent obesity from occurring in the first place. … A significant advantage of the obesogen hypothesis is that obesity results from an endocrine disorder and is thus amenable to a focus on prevention. 

So for this we say: preach, brothers and sisters.

The rest of the paper is boring to read and inconclusive. If you think we’re being unfair about how boring it is, we encourage you to go try to read it yourself.

Specific Contaminants

The paper doesn’t even do a good job assessing the evidence for the contaminants it lists. For example, glyphosate. Here is their entire review:

Glyphosate is the most used herbicide globally, focusing on corn, soy and canola [649]. Glyphosate was negative in 3T3-L1 adipogenic assays [650], [651]. Interestingly, three different formulations of commercial glyphosate, in addition to glyphosate itself, inhibited adipocyte proliferation and differentiation from 3T3-L1 cells [651]. There are also no animal studies focusing on developmental exposure and weight gain in the offspring. An intriguing study exposed pregnant rats to 25mg/kg/day during days 8-14 of gestation [652]. The offspring were then bred within the lineage to generate F2 offspring and bread to generate the F3 progeny. About 40% of the males and females of the F2 and F3 had abdominal obesity and increased adipocyte size revealing transgenerational inheritance. Interestingly, the F1 offspring did not show these effects. These results need verification before glyphosate can be designated as an obesogen.

For comparison, here’s our review of glyphosate. We try to, you know, come to a conclusion. We spend more than a paragraph on it. We cite more than four sources.

We cite their [652] as well, but we like, ya know, evaluate it critically and in the context of other exposure to the same compound. We take a close look at our sources, and we tell the reader we don’t think glyphosate is a major contributor to the obesity epidemic because the evidence doesn’t look very strong to us. This is bare-bones due diligence stuff. Take a look: 

The best evidence for glyphosate causing weight gain that we could find was from a 2019 study in rats. In this study, they exposed female rats (the original generation, F0) to 25 mg/kg body weight glyphosate daily, during days 8 to 14 of gestation. There was essentially no effect of glyphosate exposure on these rats, or in their children (F1), but there was a significant increase in the rates of obesity in their grandchildren (F2) and great-grandchildren (F3). There are some multiple comparison issues, but the differences are relatively robust, and are present in both male and female descendants, so we’re inclined to think that there’s something here. 

There are a few problems with extending these results to humans, however, and we don’t just mean that the study subjects are all rats. The dose they give is pretty high, 25 mg/kg/day, in comparison to (again) farmers working directly with the stuff getting a dose closer to 0.004 mg/kg.

The timeline also doesn’t seem to line up. If we take this finding and apply it to humans at face value, glyphosate would only make you obese if your grandmother or great-grandmother was exposed during gestation. But glyphosate wasn’t brought to market until 1974 and didn’t see much use until the 1990s. There are some grandparents today who could have been exposed when they were pregnant, but obesity began rising in the 1980s. If glyphosate had been invented in the 1920s, this would be much more concerning, but it wasn’t.

Frankly, if they aren’t going to put in the work to engage with studies at this level, they shouldn’t have put them in this review. 

If this were a team of three people or something, that would be one thing. But this is 43 specialists working on this problem for what we assume was several months. We wrote our glyphosate post in maybe a week?

Some of the reviews are better than this — their review of BPA goes into more detail and cites a lot more studies. But the average review is pretty cruddy. For example, here’s the whole review for MSG:

Monosodium glutamate (MSG) is a flavor enhancer used worldwide. Multiple animal studies provided causal and mechanistic evidence that parenteral MSG intake caused increased abdominal fat, dyslipidemia, total body weight gain, hyperphagia and T2D by affecting the hypothalamic feeding center [622], [623], [624]. MSG increased glucagon-like peptide-1 (GLP-1) secretion from the pGIP/neo: STC-1 cell line indicating a possible action on the gastrointestinal (GI) tract in addition to its effects on the brain [625]. It is challenging to show similar results in humans because there is no control population due to the ubiquitous presence of MSG in foods. MSG is an obesogen.

Seems kind of extreme to unequivocally declare “MSG is an obesogen” on the basis of just four papers. On the basis of results that seem to be in mice, rats, mice, and cells in a test tube, as far as we can tell (two of the citations are review articles, which makes it hard for us to know what studies they specifically had in mind). Somehow this is enough to declare MSG a “Class I Obesogen” — Animal evidence: Strong. In vitro evidence: Strong. Regulatory action: to be banned. Really? 

Instead, we support the idea of — thinking about it for five minutes. For example, MSG occurs naturally in many foods. If MSG were a serious obesogen, tomatoes and dashi broth would both make you obese. Why are Italy and Japan not more obese? The Japanese first purified MSG and they love it so much, they have a factory tour for the stuff that is practically a theme park — “there is a 360-degree immersive movie experience, a diorama and museum of factory history, a peek inside the fermentation tanks (yum!), and finally, an opportunity to make and taste your own MSG seasoning.” Yet Japan is one of the leanest countries in the world.

As far as we can tell, Asia in general consumes way more MSG than any other part of the world. “Mainland China, Indonesia, Vietnam, Thailand, and Taiwan are the major producing countries in Asia.” Why are these countries not more obese? MSG first went on the market in 1909. Why didn’t the obesity epidemic start then? We just don’t think it adds up. 

(Also kind of weird to put this seasoning invented in Asia, and most popular in Asia, under your section on “Western diet.”)

Adapted from Fig. 3

Let’s also look at their section on DDT. This one, at least, is several paragraphs long, so we won’t quote it in full. But here’s the summary: 

A 2017 systematic review of in vitro, animal and epidemiological data on DDT exposures and obesity concluded the evidence indicated that DDT was “presumed” to be obesogenic for humans [461]. The in vitro and animal data strongly support DDT as an obesogen. Based on the number of positive prospective human studies, DDT is highly likely to be a human obesogen. Animal and human studies showed obesogenic transmission across generations. Thus, a POP banned almost 50 years ago is still playing a role in the current obesity pandemic, which indicates the need for caution with other chemical exposures that can cause multigenerational effects.

We’re open to being convinced otherwise, but again, this doesn’t really seem to add up. DDT was gradually banned across different countries and was eventually banned worldwide. Why do we not see reversals or lags in the growth of obesity in those countries those years? They mention that DDT is still used in India and Africa, sometimes in defiance of the ban. So why are obesity rates in India and Africa so low? We’d love to know what they think of this and see it contextualized more in terms of things like occupation and human exposure timeline.

Review Paper

With a long list of chemicals given only the briefest examination, it’s hard not to see this paper as overly inclusive to the point of being useless. It makes the paper feel like a cheap land grab to stake a claim to being correct in the future if any of the chemicals on the list pan out.

Maybe their goal is just to list and categorize every study that has ever been conducted that might be relevant. We can sort of understand this but — why no critical approach to the material? Which of these studies are ruined by obvious confounders? How many of them have been p-hacked to hell? Seems like the kind of thing you would want to know! 

You can’t just list papers and assume that it will get you closer to understanding. In medicine, the reference for this problem is Ioannidis’s Why Most Published Research Findings Are False. WMPRFAF was published in 2005, you don’t have an excuse for not thinking critically about your sources.

Despite this, they don’t even mention lithium, which seems like an oversight. 

Oh right, Kurt Cobain IS responsible for the obesity epidemic

We wish the paper tried to provide a useful conclusion. It would have been great to read them making their best case for pretty much anything. Contaminants are responsible for 50% of the epidemic. Contaminants are responsible for no more than 10% of the epidemic. Contaminants are responsible for more than 90% of the epidemic. We think phthalates are the biggest cause. We think DDT is the biggest cause. We think it’s air pollution and atrazine. Make a case for something. That would be cool.

What is not cool is showing up being like: Hey we have a big paper! The obesity epidemic is caused by chemicals, perhaps, in what might possibly be your food and water, or at work, though if it’s not, they aren’t. This is a huge deal if this is what caused the epidemic, possibly, unless it didn’t. The epidemic is caused by any of these several dozen compounds, unless it’s just one, or maybe none of them. What percentage of the epidemic is caused by these compounds? It’s impossible to say. But if we had to guess, somewhere between zero and one hundred percent. Unless it isn’t. 

Effect Size

The paper spends almost no time talking about effect size, which we think is 1) a weird choice and 2) the wrong approach for this question. 

We don’t just care about which contaminants make you gain weight. We care about which contaminants make you gain a concerning amount of weight. We want to know which contaminants have led to the ~40 lbs gain in average body weight since 1970, not which of them can cause 0.1 lbs of weight gain if you’re inhaling them every day at work. These differences are more than just important, they’re the question we’re actually interested in!

For comparison: coffee and airplane travel are both carcinogens, but they increase your risk of cancer by such a small degree that it’s not even worth thinking about, unless you’re a pilot with an espresso addiction. When the paper says “Chemical ABC is an obesogen”, it would be great to see some analysis of whether it’s an obesogen like how getting 10 minutes of sunshine is a carcinogen, or whether it’s an obesogen like how spending a day at the Chernobyl plant is a carcinogen. Otherwise we’re on to “bananas are radioactive” levels of science reporting — technically true, but useless and kind of misleading.

The huge number of contaminants they list does seem like a mark in favor of a “the obesity epidemic is massively multi-causal” hypothesis (which we discussed a bit in this interview), but again it’s hard to tell without seeing a better attempt to estimate effect sizes. The closest thing to an estimate that we saw was this line: “Population attributable risk of obesity from maternal smoking was estimated at 5.5% in the US and up to 10% in areas with higher smoking rates”.

Stress Testing

Their conclusion is especially lacking. It’s one thing to point out that what we’re studying is hard, but it’s another thing to deny the possibility of victory. Let’s look at a few quotes:

“A persistent key question is what percent of obesity is due to genetics, stress, overnutrition, lack of exercise, viruses, drugs or obesogens? It is virtually impossible to answer that question for any contributing factors… it is difficult to determine the exact effects of obesogens on obesity because each chemical is different, people are different, and exposures vary regionally and globally.”

Imagine going to an oncology conference and the keynote speaker gets up and says, “it is difficult to determine the exact effects of radiation on cancer because each radiation source is different, people are different, and exposures vary regionally and globally”. While much of this is true, oncologists don’t say this sort of thing (we hope?) because they understand that while the problem is indeed hard, it’s important, and hold out hope that solving that problem is not “virtually impossible”. Indeed, we’re pretty sure it’s not. 

They’re pretty pessimistic about future research options:

“We cannot run actual ‘clinical trials’ where exposure to obesogens and their effects are monitored over time. Thus, we focus on assessing the strength of the data for each obesogen.”

Assessing the strength of the data is a good idea, but this is leaving a lot on the table. Natural experiments are happening all the time, and you don’t need clinical trials to infer causality. We’d like to chastise this paper with the following words:

[Before] we set about instructing our colleagues in other fields, it will be proper to consider a problem fundamental to our own. How in the first place do we detect these relationships between sickness, injury and conditions of work? How do we determine what are physical, chemical and psychological hazards of occupation, and in particular those that are rare and not easily recognized?

There are, of course, instances in which we can reasonably answer these questions from the general body of medical knowledge. A particular, and perhaps extreme, physical environment cannot fail to be harmful; a particular chemical is known to be toxic to man and therefore suspect on the factory floor. Sometimes, alternatively, we may be able to consider what might a particular environment do to man, and then see whether such consequences are indeed to be found. But more often than not we have no such guidance, no such means of proceeding; more often than not we are dependent upon our observation and enumeration of defined events for which we then seek antecedents.

… However, before deducing ‘causation’ and taking action we shall not invariably have to sit around awaiting the results of the research. The whole chain may have to be unraveled or a few links may suffice. It will depend upon circumstances.

Sir Austin Bradford Hill said that, and we’d say he knows a little more about clinical trials than you do, pal, because HE INVENTED THEM. And then he perfected them so that no living physician could best him in the Ring of Honor– 

So we think the “no clinical trials” thing is a non-issue. Sir Austin Bradford Hill and colleagues were able to discover the connection between cigarette smoking and lung cancer without forcing people to smoke more than they were already smoking. You really can do medical research without clinical trials.

They did not do this

But even so, the paper is just wrong. We can run clinical trials. People do occasionally lose weight, sometimes huge amounts of weight. So we can try removing potential obesogens from the environment and seeing if that leads to weight loss. If we do it in a controlled manner, we can get some pretty strong evidence about whether or not specific contaminants are causing obesity.

Defeatism

Our final and biggest problem with this paper is that it is so tragically defeatist. It leaves you totally unsure as to what would be informative additional research. It doesn’t show a clear path forward. It’s pessimistic. And it’s tedious as hell. All of this is bad for morale. 

The paper’s suggestions seem like a list of good ways to spend forever on this problem and win as many grants as possible. This seems “good” for the scientists in the narrow sense that it will help them keep their tedious desk jobs, jobs which we think they all secretly hate. It’s “good” in that it lets you keep playing what Erik Hoel describes as “the Science Game” for as long as possible:

When you have a lab, you need grant money. Not just for yourself, but for the postdoctoral researchers and PhDs who depend on you for their livelihoods. … much of what goes on in academia is really the Science Game™. … varying some variable with infinite degrees of freedom and then throwing statistics at it until you get that reportable p-value and write up a narrative short story around it.

Think of it like grasping a dial, and each time you turn it slightly you produce a unique scientific publication. Such repeatable mechanisms for scientific papers are the dials everyone wants. Playing the Science Game™ means asking a question with a slightly different methodology each time, maybe throwing in a slightly different statistical analysis. When you’re done with all those variations, just go back and vary the original question a little bit. Publications galore.

If this is your MO, then “more research is needed” is the happiest sound in the world. Actually solving a problem, on the other hand, is kind of terrifying. You would need to find a new thing to investigate! It’s much safer to do inconclusive work on the same problem for decades.

This is part of why we find the suggestion to move towards research with “model organisms such as Drosophila, C. elegans, zebrafish, and medaka” so suspicious. Will this solve the obesity epidemic? Probably not, and certainly not any time this decade. Will it allow you to generate a lot of different papers on exposing Drosophila, C. elegans, zebrafish, and medaka to slightly different amounts of every chemical imaginable? Absolutely.

(As Paul Graham describes, “research must be substantial– and awkward systems yield meatier papers, because you can write about the obstacles you have to overcome in order to get things done. Nothing yields meaty problems like starting with the wrong assumptions.’”)

With all due respect to this approach, we do NOT want to work on obesity for the rest of our lives. We want to solve obesity in the next few years and move on to something else. We think that this is what you want to happen too! Wouldn’t it be nice to at least consider that we might make immediate progress on serious problems? What ever happened to that? 

Political Scientist Adolph Reed Jr. once wrote that modern liberalism has no particular place it wants to go. “Its métier,” he said, “is bearing witness, demonstrating solidarity, and the event or the gesture. Its reflex is to ‘send messages’ to those in power, to make statements, and to stand with or for the oppressed. This dilettantish politics is partly the heritage of a generation of defeat and marginalization, of decades without any possibility of challenging power or influencing policy.“

In this paper, we encounter a scientific tradition that no longer has any place it wants to go (“curing obesity? what’s that?”), that makes stands but has a hard time imagining taking action, that is the heir to a generation of defeat and marginalization. All that remains is a reflex of bearing witness to suffering. 

We think research can be better than this. That it can be active and optimistic. That it can dare to dream. That it can make an effort to be interesting. 

Why do we keep complaining about this paper being boring? Why does it matter? It matters because when the paper is boring, it suggests that the idea that obesity is caused by contaminants isn’t important enough to bother spending time on the writing. It suggests people won’t be interested to read the paper, that no one cares, that no care should be taken in the discussion. That nothing can be gained by thinking clearly about these ideas. It suggests that the prospect of curing obesity isn’t exciting. But we think that the prospect of curing obesity is very exciting, and we hope you do too!

Philosophical Transactions: Lithium in Scottish Drinking Water with Al Hatfield

Previous Philosophical Transactions:

Al Hatfield is a wannabe rationalist (his words) from the UK who sent us some data about water sources in Scotland. We had an interesting exchange with him about these data and, with Al’s permission, wanted to share it with all of you! Here it is:


Hi,

I know you’re not that keen on correlations and I actually stopped working on this a few months ago when you mentioned that in the last A Chemical Hunger post, but after reading your post today I wanted to share it anyway, just in case it does help you at all. 

It’s a while since I read all of A Chemical Hunger but I think this data about Scottish water may support a few things you said:

– The amount of Lithium in Scottish water is in the top 4 correlations I found with obesity (out of about 40 substances measured in the water)

– I recall you predicted the top correlation would be about 0.5, the data I have implies it’s 0.55, so about right.

– I recall you said more than one substance in the water may contribute to obesity, my data suggested 4 substances/factors had correlations of more than 0.46 with obesity levels and 6 were more than 0.41.

Method

– Scottish Water test and record how much of up to 43 substances is in each reservoir/water source in Scotland https://www.scottishwater.co.uk/your-home/your-water/water-quality/water-quality

– their data is in pdf format but I converted it to Excel

– Scottish Water don’t publish Lithium levels online but I did a Freedom of Information request and they emailed it to me and I added it to the spreadsheet.

– I used the website to get the water quality data for a reservoir for every city/big town in Scotland and lined it up in the spreadsheet.

– I used Scottish Health Survey – Local Area Level data to find out what percentage of people are obese in each area of Scotland and then matched it as well as I could to a reservoir/water source.

– I then used the Data Analytics add-on in Excel to work out the correlations between the substances in the water and obesity.

Correlations with obesity (also in attachment)

Conductivity 0.55

Chloride 0.52

Boron 0.47

Lithium 0.47

Total Trihalomethanes 0.42

Sodium 0.42

Sulphate 0.38

Fluoride 0.37

Colony Counts After 3 Days At 22øc 0.34

Antimony 0.33

Gross Beta Activity 0.33

Total organic carbon 0.31

Gross Alpha Activity 0.30

Cyanide 0.26

Iron 0.26

Residual Disinfectant – Free 0.23

Arsenic 0.23

Pesticides – Total Substances 0.23

Coliform Bacteria (Total coliforms) 0.23

Copper 0.19

PAH – Sum Of 4 Substances 0.19

Nitrite 0.17

Colony Counts After 48 Hours At 37øc 0.16

Nickel 0.13

Nitrite/Nitrat e formula 0.13

Nitrate 0.12

Cadmium 0.11

Turbidity 0.08

Bromate 0.08

Colour 0.06

Lead -0.10

Manganese -0.12

Hydrogen ion (pH) -0.12

Aluminium -0.15

Chromium -0.15

Ammonium (total) -0.22

2_4-Db -0.25

Residual Disinfectant – Total -0.36

2_4-D -0.42

Dicamba -0.42

MCPB -0.42

MCPP(Mecoprop) -0.42

Scottish Water definition of Conductivity

Conductivity is proportional to the dissolved solids content of the water and is often used as an indication of the presence of dissolved minerals, such as calcium, magnesium and sodium.

Anyway, not sure if that’s any help to you at all but I enjoy your blog and thought I would send it in. Let me know if you have any questions.

Thanks 

Al


Hi Al,

Wow, thanks for this! We’ll take a look and do a little more analysis if that’s all right, and get back to you shortly. 

Do you know the units for the different measurements here, especially for the lithium? We’d be interested in seeing the original PDFs as well if that’s not too much hassle.

Thanks! 

SMTM


Hi,

You’re welcome! That’s great if you can analyse it as I am very much an amateur. 

The units for the Lithium measurements are µgLi/l. I’ve attached the Lithium levels Scottish Water sent me. I think they cover every water source they test in Scotland (though my analysis only covered about 15 water sources).

Sorry I don’t have access to the original pdfs as they’re on my other computer and I’m away at the moment. But I have downloaded a couple of pdfs online. Unfortunately the online versions have been updated since I did my analysis in late November, but hopefully you can get the idea from them and see what measurements Scottish Water use.

Let me know if you’d like anything else.

Thanks,

Al


Hey Al,

So we’ve taken a closer look at the data and while everything is encouraging, we don’t feel that we’re able to draw any strong conclusions.

We also get a correlation of 0.47 between obesity and lithium levels in the water. The problem is, this relationship isn’t significant, p = 0.078. Basically this means that the data are consistent with a correlation anywhere between -0.06 and 0.79, and since that includes zero (no relationship), we say that it’s not significant.

This still looks relatively good for the hypothesis — most of the confidence interval is positive, and these data are in theory consistent with a correlation as high as 0.79. But on the whole it’s weak evidence, and doesn’t meet the accepted standards.

The main reason this isn’t significant is that there are only 15 towns in the dataset. As far as sample sizes go, this is very small. That’s just not much information to work with, which is why the correlation isn’t significant. For similar reasons, we haven’t done any more complicated analyses, because we won’t be able to find much with such a small sample to work with. 

Another problem is that correlation is designed to work with bivariate normal distributions — two variables, both of them approximately normally distributed, like so: 

Usually this doesn’t matter a ton. Even if you’re looking at a correlation where the two variables aren’t really normally distributed, it’s usually ok. And sometimes you can use transformations to make the data more normal before doing your analysis. But in this case, the distribution doesn’t look like a bivariate normal at all:  

Only four towns in the dataset have seriously elevated lithium levels, and those are the four fattest towns in the dataset. So this is definitely consistent with the hypothesis.

But the distribution is very strange and very extreme. In our opinion, you can’t really interpret a correlation you get from data that looks like this, because while you can calculate a correlation coefficient, correlation was never intended to describe data that are distributed like this.

On the other hand, we asked a friend about this and he said that he thinks a correlation is fine as long as the residuals are normal (we won’t get into that here), and they pretty much are normal, so maybe a correlation is fine in this case? 

A possible way around this problem is nonparametric correlation tests, which don’t assume a bivariate normal distribution in the first place. Theoretically these should be kosher to use in this scenario because none of their assumptions are violated, though we admit we don’t use nonparametric methods very often. 

Anyways, both of the nonparametric correlation tests we tried were statistically significant — Kendall rank correlation was significant (tau = 0.53, p = .015), and so was the Spearman rank correlation (rho = 0.64, p = .011). Per these tests, obesity and lithium levels are positively correlated in this dataset. The friend we talked to said that in his opinion, nonparametric tests are the more conservative option, so the fact that these are significant does seem suggestive. 

We’re still hesitant to draw any strong conclusions here. Even if the correlations are significant, we’re working with only 15 observations. The lithium levels only go up to 7 ppb in these data, which is still pretty low, at least compared to lithium levels in many other areas. So overall, our conclusion is that this is certainly in line with the lithium hypothesis, but not terribly strong evidence either way.

A larger dataset of more than 15 towns would give us a bit more flexibility in terms of analysis. But we’re not sure it would be worth your time to put it together. It would be interesting if the correlation were still significant with 30 or 40 towns, and we could account for some of the other variables like Boron and Chloride. But, as we’ve mentioned before, in this case there are several reasons that a correlation might appear to be much smaller than it actually is. And in general, we think it can sometimes be misleading to use correlation outside the limited set of problems it was designed for (for example, in homeostatic systems).

That said, if you do decide to expand the dataset to more towns, we’d be happy to do more analysis. And above all else, thank you for sharing this with us!

SMTM

[Addendum: In case anyone is interested in the distribution in the full lithium dataset, here’s a quick plot of lithium levels by Scottish Unitary Authority: 

]


Thanks so much for looking at it. Sounds like I need to brush up on my statistics! Depending how bored I get I may extend it to 40 towns some time, but for now I’ll stick with experimenting with a water filter.

All the best,

Al

Control and Correlation

I.

A thermostat is a simple example of a control system. A basic model has only a few parts: some kind of sensor for detecting the temperature within the house, and some way of changing the temperature. Usually this means it has the ability to turn the furnace off and on, but it might also be able to control the air conditioning. 

The thermostat uses these abilities to keep the house at whatever temperature a human sets it to — maybe 72 degrees. Assuming no major disturbances, the control system can keep a house at this temperature indefinitely.

In the real world, control systems are all over the place.

Imagine that a car is being driven across a hilly landscape.

A man is operating this car. Let’s call him Frank. Now, Frank is a real stickler about being a law-abiding citizen, and he always makes sure to go exactly the speed limit. 

On this road, the speed limit is 35 mph. So Frank uses the gas pedal and the brake pedal to keep the car going the speed limit. He uses the gas to keep from slowing down when the road slopes up, and to keep the car going a constant speed on straightaways. He uses the brake to keep from speeding up when the road slopes down.

The road is hilly enough that frequent use of the gas and brake are necessary. But it’s well within Frank’s ability, and he successfully keeps the needle on 35 mph the whole time. 

Together, Frank and the car form a control system, just like a thermostat, that keeps the car at a constant speed. You could also replace Frank’s brain with the car’s built-in cruise control function, if it has one, and that might provide an even more precise form of control. But whatever is doing the calculations, the entire system functions more or less the same way. 

Surprisingly, if you graph all the variables at play here — the angle of the road, the gas, the brake, and the speed of the car at each time point — speed will not be correlated with any of the other variables. Despite the fact that the speed is almost entirely the result of the combination of gas, brake, and slope (plus small factors like wind and friction), there will be no apparent correlation, because the control system keeps the car at a constant 35 mph. 

High precision technical diagram

Similarly, if you took snapshots of many different Franks, driving on many different roads at different times, there would be no correlation between gas and speed in this dataset either.

We understand something about the causal system that is Frank and his car, and how this system responds to local traffic regulations, so we understand that gas and brake and angle of the road ARE causally responsible for that speed of 35 mph. But if an alien were looking at a readout of the data from a bunch of cars, their different speeds, and the use of various drivers’ implements as they rattle along, it would be hard pressed to figure out that the gas makes the car speed up and the brake makes it slow down. 

II. 

We see that despite being causally related, gas and brake aren’t correlated with speed at all.

This is a well-understood, if somewhat understated, problem in causal inference. We’ve all heard that correlation does not imply causation, but most of us assume that when one thing causes another thing, those two things will be correlated. Hotter temperatures cause ice cream sales; and they’re correlated. Fertilizer use causes bigger plants; correlated. Parental height causes child height; you’d better believe it, they’re correlated. 

But things that are causally related are not always correlated. Here’s another example from a textbook on causal inference

Weirdly enough, sometimes there are causal relationships between two things and yet no observable correlation. Now that is definitely strange. How can one thing cause another thing without any discernible correlation between the two things? Consider this example, which is illustrated in Figure 1.1. A sailor is sailing her boat across the lake on a windy day. As the wind blows, she counters by turning the rudder in such a way so as to exactly offset the force of the wind. Back and forth she moves the rudder, yet the boat follows a straight line across the lake. A kindhearted yet naive person with no knowledge of wind or boats might look at this woman and say, “Someone get this sailor a new rudder! Hers is broken!” He thinks this because he cannot see any relationship between the movement of the rudder and the direction of the boat.

Let’s look at one more example, from the same textbook: 

[The boat] sounds like a silly example, but in fact there are more serious versions of it. Consider a central bank reading tea leaves to discern when a recessionary wave is forming. Seeing evidence that a recession is emerging, the bank enters into open-market operations, buying bonds and pumping liquidity into the economy. Insofar as these actions are done optimally, these open-market operations will show no relationship whatsoever with actual output. In fact, in the ideal, banks may engage in aggressive trading in order to stop a recession, and we would be unable to see any evidence that it was working even though it was!

III.

There’s something interesting that all of these examples — Frank driving the car, the sailor steering her boat, the central bank preventing a recession — have in common. They’re all examples of control systems.

Like we emphasized at the start, Frank and his car form a system for controlling the car’s speed. He goes up and down hills, but his speed stays at a constant 35 mph. If his control is good enough, there will be no detectable variation in the speed at all. 

The sailor and her rudder are acting as a control system in the face of disturbances introduced by the wind. Just like Frank and his car, this control system is so good that to an external observer, there appears to be no change at all in the variable being controlled.

The central bank is doing something a little more complicated, but it is also acting as a control system. Trying to prevent a recession is controlling something like the growth of the economy. In this example, the growth of the economy continues increasing at about the same rate because of the central bank’s canny use of open-market operations, bonds, liquidity, etc. in response to some kind of external shock that would otherwise cause economic growth to stall or plummet — that would cause a recession. And “insofar as these actions are done optimally, these open-market operations will show no relationship whatsoever with actual output.”

The same thing will happen with a good enough thermostat, especially if it has access to both heating and cooling / air conditioning. The thermostat will operate its different interventions in response to external disturbances in temperature (from the sun, wind, doors being left open, etc.), and the internal temperature of the house will remain at 72 degrees, or whatever you set it at.

If you looked at the data, there would be no correlation between the house’s temperature and the methods used to control that temperature (furnace, A/C, etc.), and if you didn’t know what was going on, it would be hard to tell what was causing what.

In fact, we think this is the case for any control system. If a control system is working right, the target — the speed of Frank’s car, the direction of the boat, the rate of growth in the economy, the temperature of the house — will remain about the same no matter what. Depending on how sensitive your instruments are, you may not be able to detect any change at all. 

If control is perfect — if Frank’s car stays at exactly 35 mph — then the system is leaking literally no information to the outside world. You can’t learn anything about how the system works because any other variable plotted against MPH, even one like gas or brake, will look something like this: 

This is true even though gas and brake have a direct causal influence on speed. In any control system that is functioning properly, the methods used to control a signal won’t be correlated with the signal they’re controlling. 

Worse, there will be several variables that DO show relationships, and may give the wrong impression. You’re looking at variables A, B, C, and D. You see that when A goes up, so does B. When A goes down, C goes up. D never changes and isn’t related to anything else — must not be important, certainly not related to the rest of the system. But of course, A is the angle of the road, B is the gas pedal, C is the brake pedal, and D is the speed of the car. 

If control isn’t perfect, or your instruments are sensitive enough to detect when Frank speeds up or slows down by fractions of an mph, then some information will be let through. But this doesn’t mean that you’ll be able to get a correlation. You may be able to notice that the car speeds up a little on the approach to inclines and slows down when it goes downhill, and you may even be able to tie this to the gas and brake. But it shouldn’t show up as a correlation — you would have to use some other analysis technique, but we’re not sure if such a technique exists.

And if you don’t understand the rest of the environment, you’ll be hard pressed to tell which variation in speed is leaked from the control system and which is just noise from other sources — from differences in friction across the surface of the road, from going around curves, from imperfections in the engine, from Frank being distracted by birds, etc.

IV.

This seems like it might be a big problem, because control systems are found all over biology, medicine, and psychology.

Biology is all about homeostasis — maintaining stability against constant outside disturbances. Lots of the systems inside living things are designed to maintain homeostatic control over some important variable, because if you don’t have enough salt or oxygen or whatever, you die. But figuring out what controls what can be kind of complicated. 

(If you’re getting ready to lecture us on the difference between allostasis and homeostasis, go jump in a pond instead.)

Medicine is the applied study of one area of biology (i.e. human biology, for the most part), so it faces all the same problems biology does. The human body works to control all sorts of variables important to our survival, which is good. But if you look at a signal relevant to human health, and want to figure out what controls that signal, chances are it won’t be correlated with its causes. That’s… confusing. 

Lots of people forget that psychology is biological, but it obviously is. The brain is an organ too; it is made up of cells; it works by homeostatic principles. This is an under-appreciated perspective within psychology itself but some people are coming around; see for example this recent paper.

If you were to ask us what field our book A Chemical Hunger falls under, we would say cognitive science. Hunger is pretty clearly regulated in the brain as a cognitive-computational process and it’s pretty clearly part of a number of complicated homeostatic systems, systems that are controlling things like body weight and energy. So in a way, this is psychology too.

It’s important to remember that statistics was largely developed in fields like astronomy, demography, population genetics, and agriculture, which almost never deal with control systems. Correlation as you know it was introduced by Karl Pearson (incidentally, also a big racist; and worse, a Sorrows of Young Werther fan), whose work was wide-ranging but largely focused on genetic inheritance. While correlation was developed to understand things like barley yields, and can do that pretty well, it just wasn’t designed with control systems in mind. It may be unhelpful, or even misleading, if you point it at the wrong problem.

For a mathematical concept, correlation is not even that old, barely 140 years. So while correlation has captured the modern imagination, it’s not surprising that it isn’t always suited to scientific problems outside the ones it was invented to tackle.

Philosophical Transactions: JP Callaghan on Lithium Pharmacokinetics

In the beginning, scientific articles were just letters. Scholars wrote to each other about whatever they were working on, celebrating their discoveries or arguing over minutiae, and ended up with great stacks of the things. People started bringing interesting letters to meetings of the Royal Society to read aloud, then scientists started addressing their letters to the Royal Society directly, and eventually Henry Oldenburg started pulling some of these letters together and printing them as the Philosophical Transactions of the Royal Society, the first scientific journal.

In continuance of this hallowed tradition, in this blog post we are publishing some philosophical transactions of our own: correspondence with JP Callaghan, an MD/PhD student at a large Northeast research university going into anesthesia. He has expertise in protein statistical mechanics and kinetic modeling, so he reached out to us with several ideas and enlightened criticisms.

With JP Callaghan’s help we have lightly edited the correspondence for clarity, turning the multi-threaded format of the email exchange into something more linear. We found the conversation very informative, and we hope you do as well! So without further ado: 


JP Callaghan:  Hi guys, great work on A Chemical Hunger

I’m sure someone already suggested this but the Fulbright program executes the “move abroad” experiment every year. In fact, they do the reverse experiment as well, paying foreigners to move to the US. The Phillipines Fulbright program seems especially active.

(The Peace Corps is already doing this experiment as well, but that’s probably probably more confounded since people are often living in pretty rustic locations.)

You could pretty easily imagine paying these folks a little extra money to send you their weight once a month or whatever.

SLIME MOLD TIME MOLD:  Thank you! Yeah, we’ve been trying to figure out the best way to pursue this one, using existing data if possible. Fulbright is a good idea, especially US <–––> Philippines, and especially because we suspect young people will show weight changes faster. We’ve also thought about trying to collect a sample of expats, possibly on reddit, since there are a lot of anecdotes of weight loss in those communities.

The tricky thing is finding someone who has an in with one of these groups. We probably can’t just cold call Fulbright and ask how much all their scholars weigh, though we’ll start asking around. 

JPC: Unfortunately my connection with the Fulbright was brief, superficial, and many years ago. I can ask around at my university, though. I’m not filled with unmitigated optimism, but the worst they can do is say no/ignore me.

Also, I wanted to mention that lithium level measurements are extremely common measurements in clinical practice. It’s used to monitor therapeutic lithium (for e.g. bipolar folks). (Although I will concede usually they are measuring .5 – 1.5 mmol/L which would be way higher than serum levels due to contamination.) Also, it’s interesting that the early pharmacokinetic studies also measured urine lithium (see e.g. Barbara Ehrlich’s seminal 1980 paper) so there’s precedent for that as well. I’m led to understand from my lab medicine colleagues that it’s a relatively straightforward (aka cheap) electrochemical assay, at least in common clinical practice.

SMTM:  We’ve looked into measurement a bit. We’re concerned that serum levels aren’t worth measuring, since lithium seems to accumulate in the brain and we suspect that would be the mechanism (a commenter suggested it might also be accumulation in bone). But if we were to do clinical measurements, we’d probably measure lithium in urine or maybe even in saliva, since there’s evidence they’re good proxies for one another and for the levels in serum, and they’re easier to collect. Urine might be especially important if lithium clearance rate ends up being a piece of the puzzle, which it seems like it might. 

JPC: It is definitely true that lithium accumulates inside cells (definitely rat neurons and human RBCs, probably human neurons, but maybe not human muscle; see e.g. that Ehrlich paper I mentioned). The thing is, lithium kinetics seem to be pretty fast. Since it’s an ion, it doesn’t partition into fat the way other long-lasting medications and toxins do, and so it’s eliminated fairly quickly by the kidneys. (THC is a classic example of a hydrophobic “contaminant”; this same physical chemistry explains why a long-time pothead will test positive for THC for months, but you can stop using cocaine and, 72 hours later, screen negative.)

It might be worth your time to look at some of the lithium washout experiments that have been done over the years (e.g. Hunter, 1988 where they see lithium levels rapidly decline after stopping lithium therapy that had been going on for a month).

I suppose, though, that I’m not aware of any data that specifically excludes the possibility that there is a very slow “third compartment” where lithium can deposit (such as, as your commenter suggested, bone; although I don’t know much about whether or not lithium can incorporate into the hydroxyapatite matrix in bone. It’s mostly calcium phosphate and I’m not sure if lithium could “find a place” in that crystalline matrix).

Anyway, though, my understanding is that lithium kinetics in the brain are relatively fast. (For instance, see Ebadi, et al where they measure [Li] in rat brains over time.) So even if you have a highly accumulated slow bone compartment, the levels of lithium you’d get in the brain would still be super low, because it equilibrates with the blood quickly and therefore is subject to rapid elimination by the kidneys.

However, I don’t think you need to posit accumulation for your hypothesis. If you’re exposed to constant, low levels of lithium, you reach an equilibrium. There’s some super low serum concentration, some rather-higher intracellular concentration, and it’s all held in steady state by the constant intake via the GI tract (say, in the water) and constant elimination by the kidneys. Perhaps this is what you’re getting at when you say the rate of elimination might be very important?

Instead, consider some interesting pharmacodynamics: low-level (or maybe widely fluctuating, since lithium is also quickly cleared?) exposure to lithium messes with the lipostat. This process is probably really slow, maybe because weight change is slow or maybe because of some kind of brain adaptation process or whatever. We have good reason to suspect low-level lithium has neurological effects already anyway through some of the population-level suicide data I’m sure you’re aware of.

Urine and serum levels of lithium are only good proxies for one another at steady state. I really strongly suggest you guys look at that Ehrlich paper. She measures serum, intra-RBC, and urine [Li] after a dose of lithium carbonate (the most common delayed-release preparation of pharmaceutical lithium).

Another good one is Gaillot et al which demonstrates how important the form of lithium (lithium carbonate vs LiCl) is to the kinetics. (As an aside, this might be a reason for lithium grease to be so bad; lithium grease is apparently some kind of weird soap complex with fatty acids, maybe it gets trapped in the GI tract or something.)

SMTM: The rat studies are interesting but don’t rats seem like a bad comparison for determining something like rate of clearance? Besides just not being human, their metabolisms are something like 6-8x faster than ours and their lifespans are about 20 times shorter. Also human brains are huge. What do you think?

JPC: Certainly I agree that rats are not people and are bad models in many ways. I think that renal function is the key parameter you’d want to compare. The most basic measure of kidney function is the GFR (glomerular filtration rate), which basically measures how much fluid gets pushed through the “kidney filter” per unit time. Unfortunately in people we measure it in volume/time/body surface area and in rats volume/time/mass which makes a comparison less obvious than I was hoping. To be honest, I am not sure how well rat kidney function and human kidney function is comparable. (Definitely more comparable than live and dead human kidney function, though 😉.)

What do you mean by ”their metabolisms are something like 6-8x faster than ours”? Like, calories/mass/time? Usually when I think about “metabolic rate” I am thinking of energy usage. When we think about drug elimination, the main things that matter are 1) liver function (for drugs that are hepatically metabolized) 2) various tissue enzyme function (e.g. plasma esterases for something like esmolol) and 3) renal function. I don’t generally think about basal metabolic rate as being a pertinent factor, really, except perhaps in cases where it’s a proxy for hepatic metabolism.

Lithium is eliminated (“cleared”) almost exclusively by the kidney and it undergoes no metabolic transformations, so I wouldn’t worry about anything but kidney function for its clearance.

You’re right, though, the 20x lifespan difference could be an issue. If we are worried about accumulation on the timescale of years, then obviously a shorter rat life is a problem. But (if I read your blog posts right) rats as experimental animals are also getting fatter so presumably the effect extends to them on the timescale of their life? (Did you have data in rats? I don’t remember.)

Indeed, if it’s actually just that there a constant low-level “infusion” of lithium via tapwater, grease exposure at work, etc giving rise to a low steady-state lithium (rather than actual bioaccumulation) this would explain why the effect does extend to these short-lived experimental animals.

SMTM: You make good points about laboratory animals. There are data on rats and they do seem to be getting heavier. Let’s stick a pin in this one for a now, you may find this next bit is relevant to the same questions:

In your opinion, are the studies you cite consistent or inconsistent with the findings of Amdisen et al. 1974 and Shoepfer et al. 2021? Also potentially relevant is Amidsen 1977. We describe their findings near the end of this section — basically they seem to suggest that Li accumulates preferentially in the bones, thyroid, and parts of the brain. The total sample size is small but it seems suggestive. We agree accumulation may not be essential to the theory but doesn’t this look like evidence of accumulation? We’ve attached copies of Amdisen et al. 1974 and Amdisen 1977 as PDFs in case you want to take a closer look. [SMTM’s Note: If anyone else wants to see these papers, you can email us.]

Especially interesting that Ebadi et al. say, “it has been shown that sodium intake exerts a significant influence on the renal elimination of lithium (Schou, 1958b)”, somewhat in line with our speculation here. We’ll have to look into that. 

Brains

JPC: Thanks for the papers. As you predicted, I’m finding them super interesting.

Shoepfer et al, 2021 is a lovely, very interesting paper (complete with some adorable Deutsch-English). I was aware of it but had not taken the time to read it yet.

By my read, it is primarily seeking to establish this new, nuclear fission based approach to measuring lithium in pathology tissue. After spending some time with it, I don’t really know how to interpret their findings. The main reason I am not sure what to do with this paper is that the results are in dead peoples’ brains. Indeed, they specifically note in their ‘limitations’ section: “The lithium distribution patterns so far obtained with the NIK method, thus in no way contradicting given literature references, are based on post mortem tissue.” The reason this is pertinent is that there is a lot of active transport of other monovalent cations (K, Na) and so I would worry that this is true for lithium as well and (obviously) this is almost certainly disrupted in dead people.

The second thing is that the tissue was fixed in (presumably) formalin and stained with hematoxylin and eosin before measuring lithium, which then comes out in units of mass/mass. Obviously in living tissue there’s lots of water and whatnot, and the mass-density of water and formalin is going to be pretty different.

So, as the authors say, I would say it’s neither consistent nor inconsistent with other data.

SMTM: It’s true that all the brain samples we have in humans are in dead brain tissue, but this seems like an insurmountable issue, right? Looking at dead tissue is the only way to get even a rough estimate of how much lithium is in the brain, since as far as we know there’s no way to test the levels in a living human brain, or if there is, no one has taken those measurements and it’s outside our current budget. 

In any case, the most relevant findings from these studies, at least in our opinion, are 1) that lithium definitely reaches brain tissue and sticks around for a while, and 2) regardless of absolute levels, there seems to be relatively more lithium in parts of the brain that regulate appetite and weight gain. These conclusions seem likely to hold even given all the reasonable concerns about dead tissue. What do you think?  

JPC: I agree. In my mind, the main question is whether or not lithium persists in the brain after cessation of lithium therapy. Put more rigorously, what is the rate of exchange between the “brain compartment” and (probably) the “serum compartment.” (I guess it could also be eliminated by CSF too maybe? Or “glymphatics”? idk I guess nobody really understands the brain.)

The main issue I have is this: if you’re exposed, say, to 20 ppb lithium and your serum has 20 ppb lithium and so does the cytoplasm in your neurons, this is actually the null hypothesis (that lithium is an inert substance that just flows down its concentration gradient). It’s obviously false (we know lithium concentrates in RBCs of healthy subjects, for instance), but this paper doesn’t help me decide if lithium 1) passively diffuses throughout the body 2) is actively concentrated in neurons, or even 3) is actively cleared from cells, simply because I don’t really know what to do with the number.

The second issue is the preparation. Maybe formalin fixation washes lithium away, or when it fixes cell membranes maybe the lithium is allowed to diffuse out. Maybe it poorly penetrates myelin sheaths, and has a tendency to concentrate the lithium inside cells by making the extracellular environment more hydrophobic (nature abhors an unsolvated ion).

Another reason I am so skeptical of the “slow lithium kinetics” hypothesis is just the physical chemistry of lithium. It’s a tiny, charged particle. Keeping these sorts of ions from moving around and distributing evenly is actually really hard in most cases. There are a few cases of ionic solids in the human body (various types of kidney stones, bones, bile stones] but for the most part these involve much less soluble ions than lithium and everything is dissolved and flows around at its whim except where it’s actively pumped.

SMTM: This is a good point, and in addition, the fact that tourists and expats seem to lose weight quickly does seem to be a point in favor of fast lithium over slow lithium. If those anecdotes bear out in some kind of more systematic study, “slow lithium kinetics” starts looking really unlikely. Another possibility, though, is that young people are the only ones who lose weight quickly on foreign trips, and there’s something like a “weight gain in the brain, reservoir in the bone” system where people remain dosed for a long time once enough has built up in their bones (or some other reservoir).

JPC: Very possible. Also young people generally have better renal function. There are tons of people walking around with their kidneys at like 50% or worse who don’t even know it.

A third and distant issue what I mentioned about the active transport of Na and K that happens in neurons (IIRC something like 1/3 of your calories are spent doing this) ceasing when you’re dead. This is also a fairly big deal, though, since there are various cation leak channels in cell membranes (for electrical excitability reasons, I think; ask an electrical engineer or a different kind of biophysicist) through which Li might also escape. (Since, after all, a reasonable hypothesis for the mechanism of action is that Li uses Na channels.)

Between these three difficulties, I do actually see this as borderline insurmountable for ascertaining how much lithium is in an alive brain based on these data. Basically, it comes down to “I don’t know how much lithium I should expect there to be in these experiments.”

However, “relatively more lithium in parts of the brain that regulate appetite and weight gain” is a good point. I think that this is something you actually can reasonably say: it seems like there is more lithium in these areas than other areas. The within-experiment comparisons definitely seem more sound. It would also be consistent with the onset of hunger/appetite symptoms below traditionally-accepted therapeutic ranges.

I do also want to clarify what I mean by “no accumulation.” There is of course a sort of accumulation for all things at all times. You take a dose of some enteral medication, it leaches into your bloodstream from your gut, accumulating first in the serum. It then is distributed throughout the body and accumulates in other compartments (brain, liver, kidney, bone, whatever). Assuming linear pharmacokinetics, there’s some rate that the drug goes in to and out of each of these compartments. 

If you keep taking the drug and the influx rate (from the serum into a compartment) is higher than the efflux rate (back to the serum from the compartment), the steady state in the compartment will be higher than the serum at steady state. In some sense, this could be called “accumulation.” But in another sense, if both these rates are fast, your accumulation is transient and quickly relaxes to zero if you clear the serum compartment of drug (which we know happens in normal individuals in the case of lithium). Although the concentration in the third compartment is indeed higher than in the serum, if you stop taking the drug, it will wash out (first from the serum then, more slowly, from the accumulating compartment).

SMTM: Thanks, this clarification is helpful. To make sure we understand, “accumulation” to you means that a contaminant goes to a part of the body, stays there, and basically never leaves. But you’re open to “a sort of accumulation” where 50 units go into the brain every day and only 10 units are cleared, leading to a more-or-less perpetual increase in the levels. Is that right? 

JPC: Yes. I would frame this in terms of rates, though. So 5 x brain concentration units go to the brain and 1 x brain concentration units go out of the brain per unit time, such that you get a steady state concentration difference between the serum in the brain of in_rate / out_rate (in this case).

You guys seem mathy so I’ll add: for an arbitrary number of compartments this is just a first-order ODE. You can represent this situation as rate matrix K where element i, j represents the rate (1/time) that material flows from compartment i to j (or maybe j to i, I can never remember). Anyway this usually just boils down to something looking like an eigenvector problem to get the stationary distribution of things. (Obviously things get more complicated when you have pulsatile influx.)

The key question, though, is what effect does this high concentration in the accumulating compartment have on the actual physiology? If we have slowly-resolving, high concentration in the brain, then I think we could call this clinical (ie neuropharmacologically significant) accumulation. However, I think the case in the brain is that you have higher-than-serum concentrations, but that these concentrations quickly resolve after cessation of lithium therapy. My reasoning for this is that lithium pharmacokinetics are classically well-modeled with two- and three-compartment models, which mostly have pretty fast kinetics (rate parameters with half lives in the hours range).

SMTM: This is interesting because our sense is sort of the opposite! Specifically, our understanding is that most people who go off clinical doses of lithium do not lose much weight and tend to keep most of the weight they gained as a side effect (correct us if we’re wrong, we haven’t seen great documentation of this). 

This seems at least suggestive that relatively high levels of lithium persist in the brain for a long time. On the other hand, clinical doses are really, really huge compared to trace doses, so maybe there is just so much in the brain compartment that it sometimes takes decades to clear. Ok we may not actually disagree, but it seemed like an interesting minor point of departure that might be worth considering.

JPC: I don’t know about this! I agree that slower (months to years) kinetics of lithium in the brain could explain this. An alternative (relatively parsimonious) explanation would be that, as Guyenet proposes, there simply is no mechanism for shedding excess adiposity. So if you gain weight as the result of any circumstance, if it stays on long enough for the lipostat to habituate to it, you just have a new, higher adiposity setpoint and have great difficulty eliminating that weight. That is, not being able to get the weight off after lithium-related weight gain might just be normal physiology.

The idea that clinical doses are just huge is sort of interesting. Normally, we think of the movement of ions in these kinetics models as having first-order kinetics (i.e. flux is proportional to concentration), but if you have truly shitboats of lithium in the brain, you could imagine that efflux might saturate (i.e. there are only so many transporters for the lithium to get out, since I imagine the cell membrane itself is impenetrable to Li+). This could be interesting. Not sure how you’d investigate it though. Probably patch-clamp type studies in ex vivo neurons? These are unfortunately expensive and extremely technical.

Amidsen

JPC: I see Amdisen et al. 1974 describes a fatal dose of lithium, which is very different pharmacokinetically from therapeutic doses. Above about 2.0 mmol/L (~2x therapeutic levels), lithium kinetics become nonlinear—that is, the pharmacokinetics are no longer fixed and the drug begins to influence its own clearance. In the case of lithium, high doses of lithium reduce clearance, leading to a vicious cycle of toxicity. This is a big deal clinically, often leading to the need for emergent hemodialysis.

So this is consistent with the papers I mentioned earlier (Ehrlich et al, Galliot et al) in the sense that cannot really conflict because they are reporting on two very different pharmacokinetic regimes.

You can’t directly compare the lithium kinetics in this patient to those in healthy people. You can see in figure 1 that the patient’s “urea” (I assume what we’d call BUN today?) explodes, which is a result of renal failure. It sounds like the patient wasn’t making any urine, i.e. has zero lithium clearance.

Figure 1 from Amdisen et al. 1974

SMTM: True, it’s hard to tell. But FWIW lithium also seems to be cleared through other sources like sweat, so even renal failure doesn’t mean zero lithium clearance, just severely reduced. (Though not sure the percent. 50% through urine? 80%? 99%?)

JPC: Yes this is true, of course. My intuition would be that it’s closer to 99% or even like 99.9%. The kidney’s “function” (I guess you have to be a bit careful not to anthropomorphize/be teleological about the kidney here, but you know what I mean) is to eliminate stuff from the blood via urine, which it does very well, whereas sweat and other excreta have other functions.

Let’s assume for a second that lithium and sodium are the same and that the body doesn’t distinguish (obviously false; all models are wrong but some are useful) and let’s do some math.

In the ICU we routinely track “ins and outs” very carefully. Generally normal urine output is 0.5 – 1.5 mL/kg body weight/hr. In a 70 kg adult call it >800 mL/day. But because we also know how much fluid is going in, we know how much we lose to evaporation (sweat, spitting, coughing up gunk, etc), which we call “insensible losses.” This is usually 40-800 mL/day.

A normal sweat chloride (which we use to check for cystic fibrosis) is <29 mM. Because sweat doesn’t have a static charge, we know there’s some positive counterion. Let’s assume it’s all sodium. So call it 30 mM NaCl, and calculate 800 mL x 30 mM = 24 mmol NaCl and 40 mL x 30 mM = 1.2 mmol. These are collected using (I think) topical pilocarpine to stimulate sweat production, so this would be an upper bound probably. It’s pretty close to what they find here which is in athletes during training (full disclosure I didn’t read the whole thing), which seems like it would be similar to the pilocarpine case (i.e. unlikely to be sustained throughout the day).

We also measure 24-hour sodium elimination when investigating disorders of the kidney. A first-reasonabe-google-hit normal range is 40-220 mmol Na/24 hours. (Of course, this is usually done when fluid-restricting the patient, so this would be on the low end of normal. If you go to Shake Shack and eat a giant salty burger your urine urea and Na are going to skyrocket. If you’re in a desert, your urine will be WAY concentrated, but maybe lower volume. It’s hard to generalize so this is at best a Fermi estimation type of deal.)

Anyhow, we’re looking at somewhere between 2x and 250x more sodium eliminated in the urine. Again my guess is that we’d be closer to the 250x number and not the 2x number for some of the reasons I mention above. Also I worry you can’t just multiply insensible losses * sweat [Na] because as water evaporates it gets drawn out of the body as free water to re-hydrate the Na, or something.

In writing this up, I also found this paper which also does some interesting quantification of sweat electrolytes (again we get a mean sweat [Na] of 37 and [Cl] of 34), but in some of the later plots (Figure 2) we can see that [Na] and [Cl] go way low and that the average seems to be being pulled up by a long tail of high sweat electrolytes.

So not sure what to take away from that but I thought I’d share my work anyway. 🙂

Bone

JPC: In the case of bone, however, there might be something here! You could imagine the bone being a large but slowly-exchanging depot of lithium. I’d be interested to see if anyone has measured bone lithium levels in folks who were, say, on chronic therapeutic lithium. I’m not aware of anything like that.

SMTM: It seems to fit Amdisen et al. 1974. That case study is of a woman who was on clinical levels of lithium for three years, and had relatively high concentrations in her bones. Like you say, a fatal dose of lithium is very different pharmacokinetically from therapeutic doses, but the rate at which lithium deposits in bone is presumably (?) much slower than for other tissues, so this may be a reasonable estimate of how much had made it into her bones from three years of clinical treatment. Sample size of one, etc., but like you say there doesn’t seem to be any other data on lithium in bones. 

JPC: I think it’s hard to say for sure if high concentration in her bones is due to the chronic therapy or the overdose. However, they note higher (0.77 vs 0.59 mmol/kg) in dense bone (iliac crest) than in spongey bone (vertebral body; there’s a better name than spongey… maybe cumulus? I don’t remember.). That’s interesting because it suggests to me (assuming that the error in the measurement is << 0.77-0.59) there is more concentrating effect in mineralized bone than all the cellular components (osteoclasts, osteoblasts, hematopoietic cells etc). 

Anyway it’s suggestive that maybe there is deposition in bone. I wouldn’t hang my hat on it, but it is definitely consistent with it. I also agree that bone mineralization/incorporation seems like it ought to be on a longer timescale than cellular transport, so that is consistent as well. Obviously n=1, etc etc, but it’s kind of cute.

SMTM: Maybe we should see if we could do a study, there must be someone out there with a… skeleton bank? What do you call that? 

JPC: A cadaver lab? I think most medical schools have them (ours does). In an academic medical setting, I would just get an IRB to collect bone samples from all the cadavers or maybe everyone who gets an autopsy that’s sufficiently extensive to make it easy to collect some bone. This would be a convenience sample, of course, but it would be interesting. Correlate age, zip code, renal function if known?

Because the patient is dead, there’s no risk of harm, and because they’re already doing the autopsy/dissection/whatever it should be relatively straightforward to collect in most cases (I mean, they remove organs and stuff to weigh and examine them so grabbing a bit of bone is easy). Unfortunately all these people got sick and died so you have a little bit of a problem there. For example, if someone had cancer and was cachectic, what can you learn from that? Idk.

In vivo bone biopsies are also a relatively common procedure done by interventional radiology under CT guidance (it’s SUPER COOL). You also have the problem that people are getting their biopsies for a reason, and usually the reason boils down to “we think that this bone looks weird,” so your samples would be almost by definition abnormal.

SMTM: Great! Maybe we can find someone with a cadaver lab and see if we can make it happen. This is a very cool idea.

Control Systems

SMTM: Earlier you mentioned the idea that the body’s set point can only be raised, but it seems really unlikely to us that there’s no mechanism for shedding excess adiposity. 

JPC: Hmm. You guys are definitely better read on this subject than I am, but do I fear I have oversimplified the Guyenet hypothesis somewhat. My recollection is that it is more that there’s no driving force for the lipostat setpoint to return to a healthy level if it has habituated to a higher level of adiposity.

I like the analogy to iron. (I don’t think that Guyenet makes this connection, but I read The Hungry Brain years ago so I’m not sure.) It turns out that the body has no way of directly eliminating iron, so when iron levels get high, the body just turns off the “get more iron” system. Eventually, iron slowly makes its way out of the body because bleeding, entropy, etc etc and the iron-absorption system clicks back on. (This is relevant because patients who receive frequent transfusions, such as those with sickle cell, get iron overload due to their inability to eliminate the extra iron.)

I guess, by analogy, it would be that the mechanism for shedding adiposity would be “turn off the big hunger cues.” It’s not no mechanism, it’s just a crappy, passive, poorly-optimized mechanism. (Presumably because, like how nobody got transfusions prior to the 20th century, there was never an unending excess of trivially-accessible and highly palatable food in our evolutionary history.)

SMTM: Well, overfeeding studies raise people’s weights temporarily but they quickly go back to where they were before. Anecdotally, a lot of people who visit lean countries lose decent amounts of weight in just a few weeks. And occasionally people drop a couple hundred pounds for no apparent reason (if the contamination hypothesis is correct, this probably happens in rare cases where a person serendipitously eliminates most of their contamination load all at once). And people do have outlets like fidgeting that seem to be a mechanism beyond just “turn off the big hunger cues.” All this seems to suggest that weight is controlled in both directions.

JPC: Proponents of the above hypothesis would explain this by saying that the lipostat doesn’t have time to habituate to the new setpoint during the timescale of an overfeeding study, and so they lose the weight by having their “acute hunger cues” turned off. Whereas as weight creeps up year after year, the lipostat slowly follows the weight up. You do bring up a good point about fidgeting, though.

My thought was that bolus-dosed lithium (in food or elsewhere) might serve the function of repeated overfeeding episodes, each one pushing the lipostat up some small amount, leading to overall slow weight gain. 

I think combining the idea that the brain concentrates lithium with an “up only” lipostat might give you this effect? If we say 1) lithium probably concentrates first in areas controlling hunger and thirst, leading to an effect on this at lower-than-theraputic serum concentrations, you might see weeks of weight-gain effect from a bolus 2) that we know that weight gain can occur on this timescale and then not revert (see the observation, which I read about in Guyenet, that most weight is gained between thanksgiving and NYE). What do you think?

SMTM: To get a little more into the weeds on this (because you may find it interesting), William Powers says in some of his writing (can’t recall where) that control systems built using neurons will have separate systems for “push up” and “push down” control. If he’s right, then there are separate “up lipostats” and “down lipostats”, and presumably they function or fail largely separately. This suggests that a contaminant that breaks one probably doesn’t break the other, and also suggests that the obesity epidemic would probably be the result of two or more contaminants.

JPC: Yes! Super interesting. There are lots of places in the brain where this kind of push-pull system is used. I remember very clearly a neuroscience professor saying, while aggressively waving his hands, that “engineers love this kind of thing and that’s probably why the brain does it too.” I wonder if he was thinking of Powers’ work when he said that.

SMTM: Let’s say that contaminant A raises the set point of the “down lipostat”, and contaminant B raises the set point of the “up lipostat”. Someone exposed to just A doesn’t necessarily get fatter, but they can drift up to the new set point if they overeat. At the same time, with exercise and calorie restriction, there’s nothing keeping them from pushing their weight down again. 

Someone exposed to both A and B does necessarily get fatter, because they are being pushed up, and they have to fight the up lipostat to lose any weight, which is close to impossible. (This might explain why calorie restriction seems to work as a diet for some people but doesn’t work generally.) 

Someone exposed to just B, or who has a paradoxical reaction to A, sees their up and down lipostats get in a fight, which looks like cycles of binging and purging and intense stress. This might possibly present as bulimia.

There isn’t enough evidence to tell to this level of detail, but a plausible read based on this theoretical perspective is that we might see something like, lithium raises the set point of the down lipostat and PFAS raise the set point of the up lipostat, and you only get really obese if you get exposed to high doses of both. 

JPC: Very interesting! It’s definitely appealing on a theoretical level. (See: your recent post on beauty in science.) I just don’t know anything about the state of the evidence in the systems neuroscience of obesity to say if it’s consistent or inconsistent with the data. (Same is of course true of the lipostat-creep hypothesis above.)

I’m not sure about why you think the two systems would function separately? Certainly, for us to see a change, there would have to be a failure of one or the other population preferentially but I’m not sure why this would be less common than one effect or the other. They’d be likely anatomical neighbors, and perhaps even developmentally related. I guess it would all depend on the actual physiology. I’m thinking, for instance, of how the eye creates center-surround receptive fields using the same photoreceptors in combination with some (I think) inhibitory interneurons (neural NOT gates). The same photoreceptor, hooked up a different way, acts to activate or inhibit different retinal ganglion cells (the cells that make up the optic nerve… I think. It’s been a while.). Another example might be the basal ganglia, which (allegedly) functions to select between different actions, but mostly our drugs act to “do more actions” by being pro-dopaminergic (for instance to treat Parkinsons) or “do fewer actions” by being antidopaminergic (as in antipsychotics like haloperidol).

SMTM: Yeah good points and good question! We have reasons to believe that these systems (and other paired systems) do function more or less separately, but it might be too long to get into here. Long story short we think they are computationally separate but probably share a lot of underlying hardware. 

Dynamics

SMTM: What do you think of a model based on peak lithium exposure? Our concern is that most sources of exposure are going to be lognormally distributed. Most of the time you get small doses, but very rarely you get a really really large dose. Most food contains no lithium grease, but every so often some grease gets on your hamburger during transport and you eat a big glob of it by accident. 

Lognormal Distribution

Or even more concerning: you live downriver from a coal power plant, and you get your drinking water from the river. Most of the time the river contains only 10-20 ppb Li+, nothing all that impressive. But every few months they dump a new load of coal ash in the ash pond, which leaches lithium into the river, and for the next couple of days you’re drinking 10,000 ppb of lithium in every glass. This leads to a huge influx, and your compartments are filled with lithium. 

This will deplete over time as your drinking water goes back to 10 ppb, but if it happens frequently enough, influx will be net greater than efflux over the long term and the general lithium levels in your compartments will go up and up. But anyone who comes to town to test your drinking water or your serum will find that levels in both are pretty low, unless they happen to show up on one of the very rare peak exposure days. So unless you did exhaustive testing or happened to be there on the right day, everything would look normal.

JPC: I totally vibe with the prediction that intake would be lognormally distributed. From a classic pharmacokinetic perspective, I would expect lognormally-distributed lithium boluses to actually be buffered by the fact that renal clearance eliminates lithium in proportion to its serum concentration–that is, it gets faster as lithium concentrations go up.

But I’m a big believer that you should shut up and calculate so I coded up a three compartment model (gut -> serum <-> tissue), made up some parameters* that seemed reasonable and gave the qualitative behavior I expected). Then either gave the model either 300 mg lithium carbonate three times a day (a low-ish dose of the the preparation given clinically), or three-times-a-day doses drawn from a lognormal distribution with two parameter sets (µ=1.5 and σ=1.5 or σ=2.5; this corresponds to a median dose of about 4.4 mg lithium carbonate in both cases, since the long tail doesn’t influence the median very much).

* k_gut->serum = 0.01 per minute

* k_serum->brain = 0.01 per minute

* k_brain->serum = 0.0025 per minute

* k_serum->urine = 0.001 per minute

* V_d,serum = 16 L

In my opinion, this gives us the following hypothesis: lognormally distributed doses of lithium with sufficient variability should create transient excursions of serum lithium into the therapeutic range.

Because this model includes that slow third compartment, we can also ask what the amount of lithium in that compartment is:

My interpretation of this is that the third compartment smooths the very spiky nature of the serum levels and, in that third compartment, you get nearly therapeutic levels of lithium in the third compartment for whole weeks (days ~35-40) after these spikes, especially if you get two spikes back to back. (Which it seems to me would be likely if you have, like, a coal ash spill or it’s wolfberry season or whatever.)

There clearly are a ton of limitations here: the parameters are made up by me, real kinetics are more like two slow compartments (this has one), lithium carbonate is a delayed preparation that almost certainly has different kinetics from food-based lithium, and I have no idea how realistic my lognormal parameters are, to name a few. However, I think the general principle holds: the slow compartment “smooths” the spikes, and so doing seems to be able to sustain highish [Li] even when the kidney is clearing it by feasting when Li is plentiful and retaining it during famine periods.

I’m not sure if this supports your hypothesis or not (do you need sustained brain [Li] above some threshold to get weight gain? I don’t think anyone knows…) but I thought the kinetics were interesting and best discussed with actual numbers and pictures than words. What do you guys think? Is this what you expected?

SMTM: Yes! Obviously the specifics of the dynamics matter a lot, but this seems to be a pretty clear demonstration of what we expected — that it’s theoretically possible to get therapeutic levels in the second compartment (serum) and sometimes in the third compartment (brain?), even if the median dose is much much lower than a therapeutic dose. 

And because of the lognormal distribution, most samples of food or serum would have low levels of lithium — you would have to do a pretty exhaustive search to have a good chance of finding any of the spikes. So if something like this is what’s happening, it would make sense that no one has noticed. 

It would be interesting to make a version of this model that also includes low-level constant exposure from drinking water (closer to 0.1 mg per day) and looks at dynamics over multiple years, getting an impression of what lifetime accumulation might look like, but that sounds like a project for another time.

Thyroid

JPC: Another thought is that thyroid concentrations may also matter. If lithium induces a slightly hypothyroid effect, people will gain weight that way too, since common (even classic) symptoms of hypothyroidism are weight gain and decreased activity. (It also proposes an immediate hypothesis [look at T3 vs TSH] and intervention [give people just a whiff of levothyroxine and see if it helps].) There’s also some thought that lithium maybe impacts thirst (full disclosure have not read this article except the abstract)?

SMTM: Also a good note, and yes, we do see signs of thyroid concentration. Some sort of thyroid sample would also be less invasive than a brain sample, right? 

JPC: Yes. We routinely biopsy thyroid under ultrasound guidance for the evaluation of thyroid nodules (i.e. malignant vs benign). These biopsies might be a source of tissue you could test for lithium, but I’m not sure. The pathologists may need all the tissue they get for the diagnosis, they may not. Doing it on healthy people might be hard because it’s expensive (you need a well-trained operator) and more importantly it’s not a risk free procedure: the thyroid is highly vascular and if you goof you can hit a blood vessel and “brisk bleeding into the neck” is a pretty bad problem (if rare).

That said, it is definitely less invasive than a brain biopsy, and actually safer than the very low bar of “less invasive than a brain biopsy” implies.

Clinical

SMTM: Do you have clinical experience with lithium? 

JPC: Minimal but non-zero. I had a couple of patients on lithium during my psychiatry rotation and I think one case of lithium toxicity on my toxicology rotation. I do know a lot of doctors, though, so I could ask around if they’re simple questions.

SMTM: Great! So, trace doses might be the whole story, but we’re also concerned about possible lithium accumulation in food (like we saw in the wolfberries in the Gila River Valley). We wonder if people are getting subclinical or even clinical doses from their food. We do plan to test for lithium in food, but it also occurred to us that a sign of this might be cases of undiagnosed lithium toxicity. 

Let’s make up some rough numbers for example. Let’s say that a clinical dose is 600,000 µg and lithium toxicity happens at 800,000 µg. Let’s also say that corn is the only major crop that concentrates lithium, and that corn products can contain up to 200,000 µg, though most contain less. Most of the time you eat fewer than four of these products a day and get a subclinical dose of something like 50,000 – 300,000 µg. But one day you eat five corn products that all happen to be high in lithium, and you suddenly get 1,000,000 µg. You’ve just had an overdose. If common foods concentrate lithium to a high enough level, this should happen, at least on occasion. 

If someone presents at the ER with vomiting, dizziness, and confusion, how many docs are going to suspect lithium toxicity, especially if the person isn’t on prescription lithium for bipolar? Same for tremor, ataxia, nystagmus, etc. We assume (?) no one is routinely checking the lithium blood levels of these patients for lithium, that no one would think to order this blood test. Even if they did, there’s a pretty narrow time window for blood levels detecting this spike, as far as we understand. 

So our question is something like, if normal people are occasionally presenting with lithium toxicity, would the medical system even notice? Or would these cases be misdiagnosed as heavy metal exposure / dementia / ischemic stroke / etc.? If so, is there any way we can follow up with this? Ask some ER docs to start ordering lithium tests in any mystery cases they see? Curious to know what you think, if this seems at all plausible or useful.

JPC: I have a close friend who is an ED doc! She and I talked about it and here’s our vibe:

With a presentation as nonspecific as vomiting, dizziness, and confusion, my impression is that most ED docs would be unlikely to check a lithium level, especially if the patient is well enough to say convincingly “no I didn’t take any pills and no I don’t take lithium.” At some point, you might send off a lithium level as a hail-Mary, but there are so many things that cause this that a very plausible story would be: patient comes to ED with nausea/vomiting, dizziness, and altered mental status. The ED gives maybe fluids, checks some basic labs, does an initial workup, and doesn’t find anything. Admits the patient. The next day the admitting team does some more stuff, checks some other things, and comes up empty. The patient gets better after maybe 24-48h, nobody ever thinks to check a lithium level, and since the patient is feeling better they’re discharged without ever knowing why.

Another version would go: patient is super sick, maybe their vomiting and diarrhea get them super dehydrated and give them an AKI (basically temporary kidney failure). People think “wow maybe it’s really bad gastritis or some kind of primary GI problem or something?” The patient is admitted to the ICU with some kind of gross electrolyte imbalance because they’re in kidney failure and they pooped out all their potassium, someone decides they need hemodialysis, and this clears the lithium. Again the patient gets better, and everyone is none the wiser.

Tremor, ataxia, nystagmus, etc. are more focal signs and even if someone doesn’t have a history of lithium use, and in this case our impression is that people would be more likely to check a lithium level. We also think it wouldn’t always happen. Even in classic presentations of lithium toxicity, sometimes people miss the diagnosis. (Emergency medicine is hard; people aren’t like routers where they blink the link light red when the motherboard is fried or power light goes orange if the AC is under voltage. Things are often vague and complicated and mysterious.)

Something you’d have to explain is how this isn’t happening CONSTANTLY to people with really borderline kidney function. Perhaps one explanation might be that acute lithium intoxication (i.e. not against a background of existing lithium therapy) generally presents late with the neuro stuff (or so I hear).

We think that this is plausible if it is relatively uncommon or almost always pretty mild. If we were having an epidemic of this kind of thing (like on the scale of the obesity epidemic) I think it would be weird that nobody has noticed. Unless of course it’s a pretty mild, self-resolving thing. Then, who knows! AFAIK still nobody really knows why sideaches happen—figuring it out just isn’t a priority.

On occasion, the medical-scientific community also has big misses. There’s an old line that “half of what you learn in medical school is false, you just don’t know which half.” We were convinced until 1982 that ulcers were caused by lifestyle and “too much acid”; turns out that’s completely wrong and actually it’s bacteria. I saw a paper recently that argued that pretty much all MS might be due to EBV infection (no idea if it’s any good).

I think you could theoretically “add on” a lithium level to anybody that’s getting a head CT with the indication being “altered mental status.” “Add on” just means that the lab will just take the blood they already have from the patient and run additional testing, if they have enough in the right kind of tube. The logic is that patients with new-onset, dramatic, and unexplained mental status changes often get head CTs to rule out a bleed or other intracranial badness, so a head CT ordered this way could be a sign that the ordering doc may be feeling stumped.

If you wanted to get fancy, you could try to come up with a lab signature of “nausea/vomiting/diarrhea of unclear origin” (maybe certain labs being ordered that look like a fishing expedition) and add on a lithium there as well. 

SMTM: Good point, but, isn’t it possible that it IS happening constantly to people with really borderline kidney function? The symptoms of loss of kidney function have some overlap with the symptoms of lithium intoxication, maybe people with reduced kidney function really do have this happen to one degree or another whenever they draw the short straw on dietary lithium exposure for the day. Lots of people have mysterious ailments that lead to symptoms like nausea and dizziness, seemingly at random.

Or we could look at it from the other angle — lithium can cause kidney damage, kidney disease is (very roughly) correlated with obesity at the state level, and as far as we can tell, rates of kidney disease are going up, right? Is it possible that many cases interpreted as chronic kidney disease are “actually” chronic lithium intoxication?

JPC: I guess it’s definitely possible. The “canonical” explanation to this would be that diabetes (which is obviously linked to obesity) destroys your kidneys. But, if it’s all correlated together as a vicious cycle (lithium → obesity → CKD → lithium) that’s kind of appealing too. I bet a lot is known about the obesity-diabetes-kidney disease link though and my bet without looking into it would be that there’s some problem with that hypothesis.

My thought here was that if people with marginal/no kidney function are getting mild cases, I would expect people with normal kidney function to be basically immune. Or, if people with normal kidney function get mild cases, people with marginal kidneys should get raging cases. This is because serum levels of stuff are related to the inverse of clearance. The classic example is creatinine, which is filtered by the kidney and used as a (rough) proxy for renal function.

SMTM: This is super fascinating/helpful. For a long time now we’ve been looking for a “silver bullet” on the lithium hypothesis — something which, if the hypothesis is correct, should be possible and would bring us from “plausible” to “pretty likely” or even “that’s probably what’s going on”. For a long time we thought the only silver bullet would be actually curing obesity in a sample population by making sure they weren’t consuming any lithium, but that’s a pretty tall order for a variety of reasons, not least because (as we’ve been discussing) the kinetics remain unclear! But recently we’ve realized there might be other silver bullets. One would be finding high levels of lithium in food products, but there are a lot of different kinds of foods out there, and since the levels are probably lognormal distributed you might need an exhaustive search. 

But now we think that finding people admitted to the ER with vague symptoms and high serum lithium, despite not taking it clinically, could be a silver bullet too. Even a single case study would be pretty compelling, and we could use any cases we found to try to narrow down which foods we should look at more closely. Or if we can’t find any of these cases, a study of lithium levels in thyroid or in bone could potentially be another silver bullet, especially if levels were correlated with BMI or something. 

JPC: I’m always hesitant to describe any single experiment as a silver bullet, but I agree that even a single case report, under the right conditions, of high serum lithium in someone not taking lithium would be pretty suspicious. You’d have to rule out foul play and primary/secondary gain (i.e. lying) but it would definitely be interesting. As far as finding lithium in bone or thyroid (of someone not taking lithium), I’d want to see some kind of evidence that it’s doing something, but again it’d definitely be supportive.

SMTM: Absolutely. We also don’t really believe in definitive experiments. The goal at this stage is to look for places where there might be evidence that could promote this idea from “plausible” to “likely”.

A Chemical Hunger – Interlude F: Demographics

[PART I – MYSTERIES]
[PART II – CURRENT THEORIES OF OBESITY ARE INADEQUATE]
[PART III – ENVIRONMENTAL CONTAMINANTS]
[INTERLUDE A – CICO KILLER, QU’EST-CE QUE C’EST?]
[PART IV – CRITERIA]
[PART V – LIVESTOCK ANTIBIOTICS]
[INTERLUDE B – THE NUTRIENT SLUDGE DIET]
[PART VI – PFAS]
[PART VII – LITHIUM]
[INTERLUDE C – HIGHLIGHTS FROM THE REDDIT COMMENTS]
[INTERLUDE D – GLYPHOSATE (AKA THE ACTIVE INGREDIENT IN ROUNDUP)]
[INTERLUDE E – BAD SEEDS]
[PART VIII – PARADOXICAL REACTIONS]
[PART IX – ANOREXIA IN ANIMALS]

Income

The stereotype is that poor people are more obese than rich people, but rich countries are definitely more obese on average than poor countries:

This same trend of wealth being related to obesity is also mirrored within many countries. In poor countries, upper-class people are generally more likely to be obese than lower-class people. For example, in India rich people are fatter than poor people.

We see that the general pattern between countries is that wealth is associated with obesity, and we see the pattern within most poor countries is also that wealth is associated with obesity. Given this, it would be kind of surprising if the relationship ran the other way around in wealthy countries. 

Still, common-sense beliefs say that — in America at least — poor people are more obese than rich people, maybe a lot more obese. But evidence for this idea is pretty elusive. 

The National Health and Nutrition Examination Survey (NHANES) is an ongoing project by the CDC where every year they take a nationally representative sample of about 5,000 Americans and collect a bunch of information about their health and lifestyle and so on. In 2010 a NCHS team led by Cynthia Ogden examined the NHANES data from 2005-2008. They wanted to find out if there was any relationship between socioeconomic status and obesity, the exact same question we have in this post.

The results of their analysis were mixed, but there certainly wasn’t a strong relationship between socioeconomic status and obesity. Their key findings were: 

Among men, obesity prevalence is generally similar at all income levels, however, among non-Hispanic black and Mexican-American men those with higher income are more likely to be obese than those with low income.

Higher income women are less likely to be obese than low income women, but most obese women are not low income.

There is no significant trend between obesity and education among men. Among women, however, there is a trend, those with college degrees are less likely to be obese compared with less educated women.

Between 1988–1994 and 2007–2008 the prevalence of obesity increased in adults at all income and education levels.

Cynthia Ogden got to do it again in 2017, this time looking at the NHANES data from 2011-2014, trying to figure out the same thing. Again the picture was complicated — in some groups there is a relationship between socioeconomic status and obesity, but it sure ain’t universal. This time her team concluded:

Obesity prevalence patterns by income vary between women and men and by race/Hispanic origin. The prevalence of obesity decreased with increasing income in women (from 45.2% to 29.7%), but there was no difference in obesity prevalence between the lowest (31.5%) and highest (32.6%) income groups among men. Moreover, obesity prevalence was lower among college graduates than among persons with less education for non-Hispanic white women and men, non-Hispanic black women, and Hispanic women, but not for non-Hispanic Asian women and men or non-Hispanic black or Hispanic men. The association between obesity and income or educational level is complex and differs by sex, and race/non-Hispanic origin.

If you don’t trust us but do trust the Washington Post, here’s their 2018 article on Ogden’s work.

The studies that do find a relationship between income and obesity tend to qualify it pretty heavily. For example, this paper from 2018 finds a relationship between obesity and income in data from 2015, but not in data from 1990. This suggests that any income-obesity connection, if it exists, is pretty new, and this matches the NHANES analysis above, which found some evidence for a connection 2011-2014 but almost no evidence 2005-2008. Here’s a pull quote and relevant figure:

Whereas by 2015 these inverse correlations were strong, these correlations were non-existent as recently as 1990. The inverse correlations have evolved steadily over recent decades, and we present equations for their time evolution since 1990.

Another qualifier can be found in this meta-analysis from 2018. This paper argues that while there seems to be a relationship between income and obesity, it’s not that being poor makes you obese, it’s that being obese makes you poor. “Obesity is considered a cause for lower income,” they say, “when obese people drift into lower-income jobs due to labour–market discrimination and public stigmatisation.” 

Anyone who is familiar with how we treat obese people should find this theory plausible. But we don’t even have to bring discrimination into it — being obese can lead to fatigue and health complications, both of which might hurt your ability to find or keep a good job. 

This may explain why Cynthia Ogden found a relationship between income and obesity for women but not for men. It’s not that rich women tend to stay thin; it’s that thin women tend to become rich. A thin woman will get better job offers, is more likely to find a wealthy partner, is more likely to find a partner quickly, etc. Meanwhile, there’s a double standard for how men are expected to look, and so being overweight or even obese hurts a man’s financial success much less. This kind of discrimination could easily lead to the differences we see.

But the biggest qualifier is the relationship between race and income. If you’re at all familiar with race in America, you’ll know that white people make more money, have more opportunities, etc. than black people do. Black Americans also have slightly higher rates of obesity. The NHANES data we mentioned earlier contain race data and are publicly available, so we decided to take a look. In particular, we now have complete data up to 2017-2018, so we decided to update the analysis.

Sure enough, when we look at the correlation between BMI and household income, we see a small negative relationship, where people with more income weigh less. But we have to emphasize, this relationship is MEGA WEAK, only r = -.037. Another way to put this is that household income explains only one-tenth of a percent of the variance in BMI! Because the sample size is so huge, this is statistically significant — but not by much, p = .011. And as soon as we control for race, the effect of income disappears entirely.

We see the same thing with the relationship between BMI and family income. A super weak relationship of only r = -.031, explaining only 0.07% of the variance in BMI, p = .032. As soon as we control for race, the effect of income disappears.

We see the same thing with the relationship between BMI and education. Weak-ass correlation, r = -032, p = .022, totally vanishes as soon as we control for race. 

Any income effect needs to take into account the fact that African-Americans have higher BMIs and make less than whites do, and the fact that Asian-Americans have lower BMIs and make slightly more than whites do.

We don’t see much of a connection between income and obesity. If there is a link, it’s super weak and/or super idiosyncratic. Even if the connection exists, it could easily be that being obese makes you poorer, not that being poor makes you obese. 

Race

Race actually doesn’t explain all that much about BMI either. A simple model shows that in the 2017-2018 data at least, race/ethnicity explains only 4.5% of the variance in BMI. The biggest effect isn’t that African-Americans are heavier than average, it’s that Asian-Americans are MUCH leaner than everyone else. In this sample, 42% of whites are obese (BMI > 30), 49% of African-Americans are obese, but only 16% of Asian-Americans are obese! 

On the topic of race, some readers have tried to argue that race can explain the altitude and/or watershed effects we see in the Continental United States. But we don’t think that’s the case, so let’s take a closer look. Here’s the updated map based on data from 2019:

US Adults

This map is for all adults, and things have not changed much in 2019. Colorado is still the leanest state; the states along the Mississippi river are still among the most obese. Now, it’s true that a lot of African-Americans do live in the south. But race can’t explain this because the effect is pretty similar for all races. 

For non-hispanic white Americans, Colorado is still one of the leanest states (second-leanest after Hawaii) and states like Mississippi are still the most obese:

Non-Hispanic White Adults

For non-hispanic black Americans, Colorado is still one of the leanest states, and while you can’t see it on this map because the CDC goofed with the ranges, states like Mississippi and Alabama are still the most obese: 

Non-Hispanic Black Adults

In fact, here’s a hasty photoshop with extended percentile categories: 

Non-Hispanic Black Adults

If the overall altitude pattern were the result of race, we wouldn’t see the same pattern for both white and black and Americans — but we do, so it isn’t.


[Next Time: Li+]


A Chemical Hunger – Part IX: Anorexia in Animals

[PART I – MYSTERIES]
[PART II – CURRENT THEORIES OF OBESITY ARE INADEQUATE]
[PART III – ENVIRONMENTAL CONTAMINANTS]
[INTERLUDE A – CICO KILLER, QU’EST-CE QUE C’EST?]
[PART IV – CRITERIA]
[PART V – LIVESTOCK ANTIBIOTICS]
[INTERLUDE B – THE NUTRIENT SLUDGE DIET]
[PART VI – PFAS]
[PART VII – LITHIUM]
[INTERLUDE C – HIGHLIGHTS FROM THE REDDIT COMMENTS]
[INTERLUDE D – GLYPHOSATE (AKA THE ACTIVE INGREDIENT IN ROUNDUP)]
[INTERLUDE E – BAD SEEDS]
[PART VIII – PARADOXICAL REACTIONS]

A natural prediction of the idea that anorexia is the result of a paradoxical reaction to the same contaminants that cause obesity is that we should observe anorexia nervosa in animals as well as in humans. 

We’ve previously reviewed the evidence that pets, lab animals, and even wild animals have gotten more obese over the past several decades. We’ve also argued that anorexia is a paradoxical reaction of the compound or compounds that cause obesity. Since nonhuman animals are getting more obese when exposed to these contaminants, we should expect that some of them will experience a paradoxical reaction and become anorexic instead, just like humans do.

All the animals we have data on are getting fatter, but some species are gaining weight faster than others. It’s very likely that there will also be major differences in the rate and degree of paradoxical reactions. It would be very surprising if these contaminants affect mice in the exact same way they affect lizards or stingrays.

When we look at obesity data for animals, we see that primates appear to be gaining more weight than other species, and this makes sense. Primates are more closely related to humans than other animals are, so anything that causes obesity in humans is more likely to cause obesity in primates than in other mammals, and more likely cause obesity in mammals than in non-mammals, etc. As a result, we expect that anorexia is also most likely to be found in other primates.

Testing this prediction is a bit tricky. A wild animal that develops anorexia will likely die. As a result it won’t be around for us to observe, and won’t end up in our data. While pets and lab animals receive a higher standard of care, they may not survive either. 

As far as we can tell, when veterinarians notice that an animal is underweight and not eating, they don’t generally record this as an instance of an eating disorder. Instead, when a young animal doesn’t eat and eventually wastes away, this is often classified as “failure to thrive.” This is further complicated by the fact that veterinarians use the term anorexia to refer to any case where an animal isn’t eating, treating it as a symptom rather than a disorder. For example, a dog might not eat because it has an ulcer, or has accidentally consumed a toxic substance, and this would be recorded as anorexia. In humans, we would call this something like loss of appetite, which is itself a symptom of many disorders — including anorexia nervosa. (We’d love to hear from any vets with expertise in this area.)

As a consequence of all this, we don’t expect to find much direct evidence for anorexia in different species of animals. We do however expect there to be plenty of statistical evidence, because there are many statistical signatures that we can look for.

One thing we can look for is increased variance in body weights. Everyone knows that the average BMI has been going up for decades, but what is less commonly known is that the variance of BMI has also increased since 1975. When expressed in standard deviation, it has almost doubled in many countries. As correctly noted in The Lancet, this “contributed to an increase in the prevalence of people at either or both extremes of BMI.”

We should expect that animals today will have higher variation of body weights than they did in the past, just like humans do. We can similarly expect that animals that live in captivity will have higher variation of body weights than animals that live in the wild.

A particularly telling sign of this will be that while animals today (or in captivity) will on average be fatter than animals in the past (or in the wild), the leanest animals will actually be in the modern (or captive) group. We may not see animals with recognizable anorexia, but we should expect to see animals that are thinner than they would be naturally, which is presumably thinner than is healthy for them.

We might also expect to see different patterns by sex. In humans, women have higher variance of body weights than men do, which may explain why anorexia is more common in women than in men. This may not be the case in all species — it may even reverse. But a gender effect is what we see in humans and so we might also expect to see it in other animals as well.

Obesity in English Adults. Note that the distribution for women has a higher variance, which leads to more underweight AND more morbidly obese women than men.

Long-Tail Macaques 

In nonhuman animals, we use BMI equivalents. Sterck and colleagues developed a weight-for-height index for long-tail macaques which they called WHI2.7, which can function much like BMI does for humans.

For BMI in humans, values above 25 are considered overweight and values below 18.5 are considered underweight. For WHI2.7, the authors suggest that values above 62 indicate the macaque is overweight and values below 39 indicate the macaque is underweight.

Sterck and colleagues developed this measure by looking at macaques in their current population of research subjects, but they also compared the measurements of their research population to the measurements of the founder generation at Utrecht University from 1987 to 1989, and to some measurements of wild macaques from Indonesia in 1989.

Consistent with other observations of lab animals, we see that the macaques in the research population in 2019 are quite a bit fatter than the wild macaques in the 1980s (see table & figure below). The current population has an average WHI2.7 of 53.95, while the wild macaques had an average WHI2.7 of only 38.26. The current macaques are also quite a bit fatter than their ancestors, the founder group from the 1980s, who had an average WHI2.7 of 48.76.

WHI2.7 means and standard deviations for the three populations of long-tailed macaques described in Sterck et al., 2019

When we look at the standard deviations of these weight-height indexes, we find that the wild macaques in 1989 had a standard deviation of only 3.35, while the current population in 2019 had a standard deviation of 8.68! The founder population was somewhere in between, with a standard deviation of 8.07 (and this is slightly inflated by one extreme outlier). As macaques in captivity become more overweight and obese, the variance in their weight also increases. We can note that the standard deviation more than doubled between wild macaques and the current research population, and this is similar to the change in the standard deviation of human BMIs from 1975 to now, which approximately doubled.

WHI2.7 means and standard deviations for the three populations of long-tailed macaques described in Sterck et al., 2019

The wild monkeys were the leanest on average, with most of the wild females slightly underweight by the WHI2.7 measure. But the very leanest monkeys are actually in the current population, just as predicted. The leanest wild macaque had a WHI2.7 of 34.0, but the two leanest monkeys overall are both in the current population, and had WHI2.7 of 33.8 and 31.0. All of these leanest individuals were female.

As these observations suggest, there are consistent sex effects. In all three groups, male macaques have higher average WHI2.7 scores than females. In the wild group, the distributions barely overlap at all — the leanest male has a score just barely below that of the heaviest female.

Taking sex into account, the change in variance is even more pronounced. The wild macaques had a standard deviation in WHI2.7 scores of 3.35, but because the male and female distributions were largely separate, the standard deviation for males was 2.48 and the standard deviation for females was only 1.80.

This means that for the female macaques, the standard deviation of body composition scores increased by a factor of more than 4.5x, from 1.80 in the wild population to 8.14 in the current population.

We can use these data to make reasonable inferences about what we would see with a larger population. Weight and adiposity tend to be approximately normally distributed, and when we look at the distribution for WHI2.7 in these data, we see that the scores are indeed approximately normally distributed.

For these analyses, we’ll limit ourselves to the female macaques exclusively. Every underweight macaque in this dataset is female — not a single male macaque is classified as underweight. In every group, the mean WHI2.7 is higher for males than it is for females. Just as in humans, being underweight seems to be more of a concern for females than for males.

We could use this information to estimate what percent of macaques are underweight (WHI2.7 of 39 or less). But this doesn’t make sense because we already know that the wild macaques are underweight on average (mean WHI2.7 of 38.26). This is because that threshold, a WHI2.7 of 39, is based on the body fat percentage observed in these same wild macaques.

(This is quite similar to humans who don’t live a western lifestyle. On the Trobriand Islands, the average BMI was historically around 20 for men and around 18 among women, technically underweight by today’s standards.)

The authors also suggest that a WHI2.7 of 37 is perfectly healthy. Even though some of the macaques have WHI2.7 scores below 37, all macaques were examined by veterinarians as part of the study, and seem to be perfectly healthy (99% had BCS scores above 2.5, which indicates “lean” but not thin and certainly not emaciated). Other sources suggest that macaques can still be healthy even when they are thinner than this. Essentially, the threshold of 39 or even 37 isn’t appropriate for our analysis, because macaques appear to be largely healthy in this range.

While it’s hard to determine what WHI2.7 would indicate that a macaque is dangerously underweight, we’ve based our analysis on the leanest macaques we have data for. All the macaques we have data for have WHI2.7 scores above 30. We know that they were all surviving at this weight and the leanest were rated by the vets as merely thin, not emaciated. As a result, 30 seems like a good cutoff, and we can calculate approximately how many macaques would have a WHI2.7 below 30 in a larger population.

The wild female macaques have an average WHI2.7 of 36.16 with a standard deviation of 1.80. Based on this, in a larger population about 0.03% of wild female macaques would have a WHI2.7 below 30.0.

The female macaques from the current research population have an average WHI2.7 of 53.14 with a standard deviation of 8.14. Based on this, in a larger research population about 0.22% of current macaques would have a WHI2.7 below 30.0.

Theoretical distribution of WHI2.7 scores for female macaques in two distributions.

This shows an increase in the mean WHI2.7 and an enormous increase in the variation, just what we would expect to see if anorexia were the result of a paradoxical reaction. In addition, we see that the increase in variation also leads to an increase in the number of extremely underweight macaques (see below). If we tentatively describe a WHI2.7 of 30 or below as anorexic, then the rate of anorexia in female macaques in the current population is about ten times higher than the rate of anorexia in the wild population. The prevalence in the current female research macaques, 0.22%, is also notably similar to the prevalence of anorexia in humans, which is usually estimated to be in the range of 0.1% to 1.0% among women.

Lower tail of the theoretical distribution of WHI2.7 scores for female macaques in two distributions.

Another way to put this is that if we had a group of 10,000 wild macaques, we would expect about 7 wild macaques with a WHI2.7 of 30, 1 wild macaque with a WHI2.7 of 29, and no wild macaques with a WHI2.7 of 28 or below. In comparison if we had 10,000 macaques from a contemporary research population, we would expect about 8 macaques with a WHI2.7 of 30, about 6 macaques with a WHI2.7 of 29, about 4 macaques with a WHI2.7 of 28, about 3 macaques with a WHI2.7 of 27, about 2 macaques with a WHI2.7 of 26, about 1 macaque with a WHI2.7 of 25, about 1 macaque with a WHI2.7 of 24, and probably no macaques with WHI2.7 scores of 23 or below.

A different cutoff wouldn’t change the effect. For any arbitrary threshold, there will be more modern macaques at the extreme ends of the distribution. Based on what we know about healthy weights for these animals, 30 is a conservative cutoff, and the disparity only increases if we look at lower WHI2.7 scores.

Expected number of macaques with various extremely underweight WHI2.7 scores in different populations of 10,000 macaques.

It seems clear that a macaque with a score of 25 would be an extremely underweight animal, and from a simple analysis of the distributions, we should only expect to see these animals in a modern research population. In short, it’s clear that modern captive macaques have higher rates of anorexia than wild macaques from the 1980s, just the kind of paradoxical reaction this theory predicts.


[Next Time: DEMOGRAPHICS]


A Chemical Hunger – Part VIII: Paradoxical Reactions

[PART I – MYSTERIES]
[PART II – CURRENT THEORIES OF OBESITY ARE INADEQUATE]
[PART III – ENVIRONMENTAL CONTAMINANTS]
[INTERLUDE A – CICO KILLER, QU’EST-CE QUE C’EST?]
[PART IV – CRITERIA]
[PART V – LIVESTOCK ANTIBIOTICS]
[INTERLUDE B – THE NUTRIENT SLUDGE DIET]
[PART VI – PFAS]
[PART VII – LITHIUM]
[INTERLUDE C – HIGHLIGHTS FROM THE REDDIT COMMENTS]
[INTERLUDE D – GLYPHOSATE (AKA THE ACTIVE INGREDIENT IN ROUNDUP)]
[INTERLUDE E – BAD SEEDS]

We come up with theories to try to make sense of the world around us, and we start by trying to come up with a theory that can explain as much of the available evidence as possible.

But one of the known problems with coming up with theories is that sometimes you are overenthusiastic, and connect together lots of things that aren’t actually related. It can be very tempting to cherry-pick evidence to support an idea, and leave out evidence that doesn’t fit the picture. It’s possible to make this mistake honestly — you get excited that things seem to fit together and don’t even notice all the evidence that is stacked against your theory.

But sometimes noticing that things seem to fit together is how an important insight comes to light. The theory of continental drift was invented when Alfred Wegener was looking through a friend’s new atlas and noticed that South America and Africa seemed to have matching coastlines, “like a couple spooning in bed”. He wasn’t even a geologist — at the time, he was an untenured lecturer in meteorology — but he thought that it was important, so he followed up on the idea. “Why should we hesitate to toss the old views overboard?” he said when his father-in-law suggested that he be cautious in his theorizing. He was criticized by geologists in Germany, Britain, and America, in part because he couldn’t describe a mechanism with the power to shuffle the continents around the globe. But in the end, Wegener was right.

The true power of a theory is its ability to make testable predictions. One obvious prediction of the theory that obesity is caused by a contaminant in our environment is that we should also expect to see paradoxical reactions to that contaminant.

Predicting Paradoxical Reactions

Sometimes drugs have what’s called a paradoxical reaction, where the drug does the opposite of the thing it normally does. For example, amphetamines are usually a stimulant, but in a small percent of cases, they make people drowsy instead. Antidepressants usually make people less suicidal, but sometimes they make people more suicidal.

Normally when we talk about paradoxical reactions, we’re talking about the intended effect of the drug, not the side effects. But from the drug’s point of view, there’s no such thing as side effects — all effects are just effects. As a result, we should expect to sometimes see paradoxical reactions in side effects as well.

And in fact, we do. A common side effect of the sedative alprazolam is rapid weight gain. But another common side effect is rapid weight loss. Clinical trials show both side effects regularly. One trial of 1,388 people found that 27% of patients experienced weight gain and 23% of patients experienced weight loss. In those who do lose weight, weight loss is correlated with the dose (r = .35, p = .006).

Severe weight gain is a common side effect of psychiatric drug clozapine. People can and do regularly gain ten or twenty pounds on this drug. But some people actually lose weight on clozapine instead.

Lithium increases leptin levels in most patients, and this is presumably part of the mechanism that causes people to gain weight on lithium. But in some patients, lithium reduces leptin levels instead.

Normally the weight loss from these paradoxical reactions is pretty limited. But occasionally people lose huge amounts. People can gain 4 lbs (1.8 kg) over only 17 days on alprazolam. In comparison, anecdotal reports from admitted abusers suggest that high doses of alprazolam can lead you to eventually lose 10 or even 40 lbs.

On clozapine, people usually gain 10-15 lbs. But some people lose huge amounts of weight instead, up to 50% (!!!) of their body weight. One patient, a woman in her 30s, went from about 148 lbs (67 kg) to about 75 lbs (34 kg) on clozapine.

AGRP neurons are a population of neurons closely related to feeding. One of the ways researchers established this connection was by showing that activating these neurons in mice led to “voracious feeding within minutes.” Another way they showed this connection was by destroying these neurons, a process called ablation. “AGRP neuron ablation in adult mice,” reviews one paper, “leads to anorexia.”

If weight gain is the main effect of a drug, the paradoxical reaction is weight loss. If the obesity epidemic is caused by one or more contaminants that cause weight gain, we should expect that there will be some level of paradoxical reaction as well. If obesity is the condition, the paradoxical condition would be anorexia.

If it’s possible to turn the lipostat up, leading to serious weight gain, it’s certainly possible to turn the lipostat down as well, leading to serious weight loss. For most people, these environmental contaminants cause weight gain. But just like with other drugs, in some people there’s a paradoxical reaction instead.

This is biologically plausible. People with anorexia have extremely low leptin levels, and some reports suggest that leptin levels are correlated with symptoms other than just BMI. Anorexia risk is genetically heritable and some of the genes involved have already been identified. The authors of one genetic analysis close by saying,

Low BMI has traditionally been viewed as a consequence of the psychological features of anorexia nervosa (that is, drive for thinness and body dissatisfaction). This perspective has failed to yield interventions that reliably lead to sustained weight gain and psychological recovery. Fundamental metabolic dysregulation may contribute to the exceptional difficulty that individuals with anorexia nervosa have in maintaining a healthy BMI (even after therapeutic renourishment). Our results encourage consideration of both metabolic and psychological drivers of anorexia nervosa when exploring new avenues for treating this frequently lethal illness.

Brain lesions alone can cause anorexia nervosa, complete with the characteristic psychopathologies like fear of fatness, drive for thinness, and body image disturbance. Many cases present as “typical” anorexia nervosa, complete with weight and shape preoccupations. When tumors are surgically removed, these symptoms go away and the patients return to a healthy weight.

Brain lesions are not the only purely biological issue that can cause anorexia. In some cases, it appears to be closely related to the gut microbiome. In one case study a patient with anorexia had a BMI of only 15 even after undergoing cognitive-behavioral therapy, medication, and short-term force feeding, and despite maintaining a diet of 2,500 calories per day. Physicians gave her a fecal microbiota transplant from an unrelated donor with a BMI of 25. Following the transplant she gained 6.3 kg (13.9 lbs) over the next 36 weeks, despite not increasing her calorie intake at all. This is only one case, but the authors indicate that they are planning to conduct a randomized controlled trial to investigate the effects of fecal transplants in individuals suffering with anorexia. To the best of our knowledge this next study has not yet been published, but we look forward to seeing the results.

Eating and maintaining weight is a central cognitive problem. “The lipostat does much more than simply regulate appetite,” says Stephan Guyenet, “It’s so deeply rooted in the brain that it has the ability to hijack a broad swath of brain functions, including emotions and cognition.”

Remember those children we mentioned in Part II, who were born without the ability to produce leptin? Unlike normal teenagers, they aren’t interested in dating, films, or music. All they want to talk about is food. “Everything they do, think about, talk about, has to do with food,” says one of the lead researchers in the field. A popular topic of conversation among these teens is recipes.

These teenagers have a serious genetic disorder. But if you put average people in a similar situation, they behave the same way. The Minnesota Starvation Experiment put conscientious objectors on a diet of 1,560 calories per day. Naturally, these volunteers became very hungry, and soon found themselves unable to socialize, think clearly, or open heavy doors.

As they lost weight, these men developed a remarkable obsession with food. The researchers came to call this “semistarvation neurosis”. Volunteers’ thoughts, conversations, dreams, and fantasies all centered on food. They became fascinated by the paraphernalia of eating. “We not only cleaned our plates, we licked them,” recalled one volunteer. “Talked about food, thought about it. Some people collected as many as 25 or 30 cookbooks” (one such collection is pictured below). Others collected cooking utensils. “What we enjoyed doing was to see other people eat,” he continued. “We would go into a restaurant and order just a cup of coffee and sit and watch other people eat.”

Subjects became overwhelmingly preoccupied with food, and some collected dozens of cookbooks, like the collection shown above. 

These are the neuroses of people whose bodies believe that they are dangerously thin, either correctly (as in the starvation experiment) or incorrectly (as in the teenagers with leptin deficiency). The same thing happens when your mind, correctly or incorrectly, believes that you are dangerously fat. You become obsessed with food and eating, only in this case, you become obsessed with avoiding both. A classic symptom of anorexia is “preoccupations and rituals concerning food”. If that doesn’t describe the behavior above, I’m not sure what would.

But avoiding food and collecting cookbooks isn’t the lipostat’s only method for controlling body weight. It has a number of other tricks up its sleeve.

Many people burn off extra calories through a behavior called “non-exercise activity thermogenesis” (NEAT). This is basically a fancy term for fidgeting. When a person has consumed more calories than they need, their lipostat can boost calorie expenditure by making them fidget, make small movements, and change posture frequently. It’s largely involuntary, and most people aren’t aware that they’re burning off extra calories in this way. Even so, NEAT can burn off nearly 700 calories per day.

When most people eat less than they need, they become sluggish and fatigued, like the volunteers in the Minnesota Starvation Experiment. But people with anorexia fidget like crazy. A classic symptom of anorexia is excessive physical activity, even in the most severe stages of the illness. When one group measured fidgeting with a highly accurate shoe-based accelerometer, they found that anorexics fidget almost twice as much as healthy controls.

This kind of fidgeting is the classic response in people whose bodies are fatter than they want to be. In studies where people were overfed until they were 10% heavier than their baseline, NEAT increased dramatically. All of this is strong evidence that people with anorexia have lipostats that mistakenly think they desperately need to lose weight.

Of course, this does sound a little far-fetched. If anorexia were really a paradoxical reaction to the same contaminants that cause obesity, then in the past we would see almost no anorexia in the population, up to a sharp spike around 1980…

While there’s not as much historical data as we would like, the pattern we observe is just about that (see figure below). Cases were quite low until about 1970, when prevalence suddenly shot up. When we look at specific sections of historical data, finding evidence of an increasing trend (often only in young women) is pretty common.

Registered yearly incidence of anorexia nervosa in mental healthcare in northern Europe in the 20th century

In general the data is pretty scattered and spotty. Rarely does a study look at rates in the same area for more than five years. When there are such comparisons, they are usually for periods before 1980. For example, van’t Hof and Nicolson, writing in 1996 and arguing that rates of anorexia are not increasing, at one point cite studies that showed no increase from 1935-1979, 1935-1940, 1975-1980, and 1955-1960. But data from the Global Health Data Exchange (GHDx) shows that rates of eating disorders have been increasing worldwide since 1990, from about 0.185% to 0.215%. This trend is small but reliable — 87.5% of countries saw their rates of eating disorders increase since 1990.

(If that’s not enough for you, we can mention that in 1985 the New York Times reported, “before the 1970’s, most people had never heard of anorexia nervosa.” Writing in the 1980s, presumably they would know.)

There are other ways to look at the relationship. For example, we can compare the most obese countries to the countries with the highest rates of eating disorders:

Share of Adults that are Obese, 2016. Reproduced from ourworldindata.org under the CC BY 4.0 license.
Share of Population with an Eating Disorder, 2016. Reproduced from ourworldindata.org under the CC BY 4.0 license. 

With the exception of a few notable outliers (genetically homogeneous South Korea and Japan), these match up really well. The fit isn’t perfect, but we shouldn’t expect it to be. There are large genetic differences and differences in healthcare practices between these countries. They may use different criteria to diagnose eating disorders. But even given these concerns, we still see pretty strong associations — Chile, Argentina, and Uruguay are the most obese countries in South America, and they also have the highest rates of eating disorders.

We can go one step further. Looking at the data, we see that these are statistically related. In 2016, rates of eating disorders were correlated with obesity in the 185 countries where we have measures for both, r = .33, p < .001. If we remove the five tiny island nations with abnormally high (> 45%) obesity (Kiribati, Marshall Islands, Micronesia, Samoa, and Tonga), all of them with populations of less than 200,000 people, the correlation is r = .46:

Prevalence of eating disorders and obesity, 2016. Kiribati, Marshall Islands, Micronesia, Samoa, and Tonga not shown.

We see the same correlation between rates of obesity and rates of eating disorders when we look at the data from 1990, r = .37, p < .001.

Perhaps most compelling, we find that the rate of change in obesity between 1990 and 2016 is correlated with the rate of change in eating disorders between 1990 and 2016. The correlation is r = .26, p = .0004, and it’s r = .30 if we kick out Equatorial Guinea, a country where the rates of eating disorders tripled between 1990 and 2016, when none of the other countries even had their rates double. You can see those data (minus Equatorial Guinea) below:

 Increase in the prevalence of eating disorders and obesity, 1990-2016. Equatorial Guinea not shown.

That’s no joke. The countries that are becoming more obese are also having higher and higher rates of eating disorders.

We even see signs of a paradoxical reaction in some of the contaminants we reviewed earlier. You’ll remember that when mice are exposed to low doses of PFOA in-utero, they are fatter as adults — but when mice are exposed to high doses as adults, they lose weight instead. The dose and the stage of development at exposure seems to matter, at least in mice. It’s notable that anorexia most often occurs in teenagers and young adults, especially young women. Are young women being exposed to large doses all of a sudden, just as they start going through puberty? Where would these huge doses come from? It may not be that much of a stretch — PFAS are included in many cosmetics.

In one study of 3M employees, higher PFOS levels led to a higher average BMI, but also to a wider range in general. The lightest people in the study had some of the highest levels of PFOS in their blood. The quartile with the least PFOS in their blood had an average BMI of 25.8 and a range of BMIs from 19.2 to 40. The quartile with the most PFOS in their blood had an average BMI of 27.2 and a range of BMIs from 17.8 to 45.5. Remember, a BMI of below 18.5 is considered underweight.

In the study of newborn deliveries in Baltimore that we mentioned earlier, researchers found that obese mothers had babies with higher levels of PFOS than mothers of a healthy weight. But underweight mothers also had babies with higher levels of PFOS. In fact, babies from underweight mothers had the highest levels of PFOS exposure, 5.9 ng/mL, compared to 5.4 ng/mL in obese mothers, and 4.8 ng/mL in mothers of normal weight. “The finding that levels were higher among obese and underweight mothers is interesting,” they say, “but does not have an obvious explanation.” Knowing what we know now, the obvious explanation is that PFOS usually causes weight gain, but like all drugs, it sometimes has a paradoxical reaction, resulting in weight loss instead.


[Next Time: ANIMAL ANOREXIA]


A Chemical Hunger – Part VI: PFAS

[PART I – MYSTERIES]
[PART II – CURRENT THEORIES OF OBESITY ARE INADEQUATE]
[PART III – ENVIRONMENTAL CONTAMINANTS]
[INTERLUDE A – CICO KILLER, QU’EST-CE QUE C’EST?]
[PART IV – CRITERIA]
[PART V – LIVESTOCK ANTIBIOTICS]
[INTERLUDE B – THE NUTRIENT SLUDGE DIET]

Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals that are used to make a wide variety of everyday products, including food packaging, carpets, rugs, upholstered furniture, nonstick cookware, water-repellant outdoor gear like tents and jackets, firefighting foams, ski wax, clothing, and cleaning products. Many are also used in industrial, aerospace, construction, automotive, and electronic applications.

The PFAS family is enormous, containing over 5,000 different compounds. But only a couple of these compounds are well-studied. The rest remain rather mysterious. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are two of the original PFAS, are especially widespread in the environment, and we tend to have the most information on them.

PFAS are practically indestructible. They repel oil and water and are heat-resistant, which is part of why they have so many applications, but these features also ensure that they degrade very slowly in the environment, if they degrade at all. Short-chain PFAS have half-lives of 1-2 years, but longer-chain equivalents like PFOS are stable enough that we haven’t been able to determine their half-life. As a result, they stick around in the environment for a very long time, and soon make their way into soil and groundwater. The full picture is complicated, but there’s evidence that they accumulate in rivers as they flow towards the ocean.

They not only stick around for a long time in the environment, they stick around for a long time in your body. If you’re reading this, there’s probably PFAS in your blood. A CDC report from 2015 found PFAS in the blood of 97% of Americans, and a 2019 NRDC report found that the half-life of PFAS in the human body is on the order of years. They estimate 2.3 – 3.8 years for PFOA, 5.4 years for PFOS, 8.5 years for PFHxS, and 2.5 – 4.3 years for PFNA. “PFOS, PFNA, PFHxS, and related PFAS,” they write, “are known to bioaccumulate in the bodies of people of all ages, even before birth.”

How do these chemicals get into our bodies? Every route imaginable. “People are concurrently exposed to dozens of PFAS chemicals daily,” the NRDC report explains, “through their drinking water, food, air, indoor dust, carpets, furniture, personal care products, and clothing. As a result, PFAS are now present throughout our environment and in the bodies of virtually all Americans.” Looking at one map of PFAS measurements, we see that PFAS has been detected at military sites in 49 states (no measurements given for Hawaii) and in drinking water in Utqiagvik, Alaska, the northernmost incorporated place in the United States. Unfortunately, only a few states have done comprehensive testing.

This exposure isn’t just limited to humans. There’s bioaccumulation in the remote lichen-caribou-wolf food chain in northern Canada, and in part of the Arctic Ocean, with animals higher in the food chain showing higher concentrations of PFAS in their bodies. 

If we look at the history of PFAS (below), we see that the timeline for PFAS introduction lines up pretty well with the timeline for the obesity epidemic. PFAS were invented in the 1930s, 40s, and 50s, and were rolled out over the next couple decades. This gave them some time to build up in people’s bodies and in the environment. By the 1980’s many types, including some new compounds, were in circulation. In the 2000s, some of them began to be banned, but many of them are still widely used. After all, there are more than 5,000 of them, so it’s hard to keep track.

Discovery and manufacturing history of select PFAS.

A study from the Red Cross worked with blood donor data and measured serum levels in samples from 2000-2001 and plasma levels in samples from 2006, 2010, and 2015. In general, they found serious declines in serum levels of the PFAS they examined. For example, the average PFOS concentrations went from 35.1 ng/mL to 4.3 ng/mL, a decline of 88%, and PFNA concentrations went from 0.6 ng/mL to 0.4 ng/mL, a decline of 33%. The National Health and Nutrition Examination Survey (NHANES) data from the same period matches these trends pretty closely.

These studies show that levels of PFAS in American blood are declining, but they’re only looking at the PFAS that we already know are declining. Many of these PFAS are no longer in production. PFOS and PFOA, among other compounds, were phased out in the US between 2006 and 2015. But new compounds with similar structures were brought in to replace them. The companies that make these compounds say that the new PFAS are safer, but unsurprisingly this is very controversial.

Notably absent from both the Red Cross and the NHANES data is PTFE. This is somewhat surprising given that it is the original PFAS, and it is still in production. Granted, many sources claim that PTFE is extremely inert — including the paper Polytetrafluoroethylene Ingestion as a Way to Increase Food Volume and Hence Satiety Without Increasing Calorie Content, which goes on to argue that we should replace 25% of our food with Teflon (PTFE) powder so that we feel more full while eating fewer calories, which they say will help us make “the leap into the realm of zero calorie foods.” Personally, we’d stick to celery.

Maybe PTFE really is that inert. (We find it a little hard to believe. “Word was that the compounds were inert,” said one scientist of his choice not to study PFOA and PFOS in 2000.) Either way, the safety research on these substances is pretty ridiculous. Usually the exposure period is very short and the dose is extremely high. This may be relevant to exposure for industrial workers, but it doesn’t tell us much about the long-term effects of relatively low doses on the rest of us.

Advertisement for the Happy Pan, a Teflon-coated pan from the 1960s.

In one study they gave monkeys various amounts of PFOS for 182 days, and found “significant adverse effects” only in the 0.75 mg/kg/day dose group. Effects in this group included “mortality in 2 of 6 male monkeys, decreased body weights, increased liver weights, lowered serum total cholesterol, lowered triiodothyronine concentrations (without evidence of hypothyroidism), and lowered estradiol levels.”

This is interesting, but there are some problems. First of all, 0.75 mg/kg/day is an insanely high dose. Serum concentrations in the 0.15 mg/kg/day dosage group were 82,600 ng/mL for males and 66,800 ng/mL for females. The comparable rate in human blood samples is about 20-30 ng/mL. Second, 182 days is not a very long or realistic exposure period for most humans.

At these extremely high, short-term doses, weight loss is actually a relatively common side effect. This is the opposite of obesity, of course, but it does suggest that PFAS can affect body weight.

The type of exposure might make the difference. Mice have very different developmental trajectories than we do, but mice exposed to low doses of PFOA in-utero had higher body weights at low exposures, while mice exposed to high doses as adults lost weight. ”Exposure during adulthood was not associated with later-life body weight effects,” they write, “whereas low-dose developmental exposure led to greater weight in adulthood and increased serum leptin and insulin levels. Animals exposed to higher doses of PFOA, on the other hand, had decreased weight.” Note also that while half-life of PFOA in humans is about 3.8 years, in mice it is around 18 days.

A study of 665 pregnant Danish women, recruited in 1988–1989 with the researchers following up with the children 20 years later, found that in-utero PFOA exposure was related to greater BMI and waist circumference in female but not in male children. There are some issues with multiple comparisons — they measured more than one PFAS and they subdivided by gender, both of which are degrees of freedom — but the effects are strong enough to survive reasonable corrections for multiple comparisons, and are consistent with the results from mice, so let’s mark this one down as “suggestive”.

Other studies have found small but reliable effects where male babies, but not female babies, were a few grams lighter at birth when their mothers had higher serum PFOS levels. Again this study suffers from multiple comparison issues, but again it is relatively consistent with animal research.

It doesn’t seem likely that the effect in humans can be exclusively prenatal, however, because we know that people often gain weight when they move to a more obese country. There’s pretty good evidence that different environments are exposing you to different levels of contamination, and that it makes a difference.

Your drinking water is not the only way to be exposed. Many foods are contaminated with PFAS. PFAS are also found in clothes, carpets, and upholstered furniture, so you could be exposed even if there’s no PFAS in your diet. If your favorite beer or pasta sauce is bottled at a factory where the water source is high in PFAS, you’ll be exposed even if your own drinking water is uncontaminated. And since most major brands are bottled in more than one location, there wouldn’t even be a reliable by-brand effect—you’d need to track it by factory.

A better way to do this comparison might be between countries. In fact, we see what appears to be a pattern: There’s more PFAS in tapwater in the United States than there is in tapwater in China, and there’s more PFAS in tapwater in China than there is in tapwater in Japan. The pattern isn’t perfect, however: There’s even more PFAS in tapwater in France than in the United States, and more in Japan than in Thailand.

Occupational Hazard

One place you might get a lot of reliable exposure, though, is at your job. Looking at the uses of PFAS, we see that they’re common in:

  • Firefighting foams
  • Cookware and food packaging
  • Paints and varnishes
  • Cleaning products
  • Automotive applications, including components in the engine, fuel systems, and brake systems, as well as automotive interiors like stain-resistant carpets and seats
  • Healthcare applications, both in medical devices like pacemakers and in medical garments, drapes, and curtains

This suggests that if PFAS are linked to obesity, we should expect to see disproportionate levels of obesity in:

  • Firefighters
  • Food workers (especially cooks)
  • Construction workers
  • Professional cleaners
  • Auto mechanics and others who work closely with vehicles
  • Medical professionals who work closely with medical devices and garments / drapes / curtains, though probably not medical desk jobs.

In the 2000’s, the Washington State Department of Labor and Industries surveyed more than 37,000 workers. They found that on average 24.6% of their sample was obese, which we can use as our baseline. The rate of obesity in “protective services”, which includes police, firefighters and emergency responders, was 33.3%. Among cleaning and building services workers, 29.5% were obese. Truck drivers were the most obese group of all, at 38.6%, and mechanics were #5 at 28.9% obese. Health service workers (excluding doctors and nurses) were 28.8% obese. On the other hand, only 20.1% of food preparation workers were obese, and only 19.9% of construction workers:

Table 1: Washington State Department of Labor and Industries Data, 2003-2009

We can also look at national data from US workers in general. Looking at data between 2004 and 2011, we see that the average rate of obesity went from 23.5% in 2004 to 27.6% in 2011, and was 26.2% on average in that range. Unfortunately they break these numbers down by race, so we have to look at each race separately. 

When we look at the occupations of interest for non-hispanic white adults, we see that 30.4% of firefighters, 32.0% of cooks, 35.1% of food processing workers, 29.7% of building cleaning workers (and for some reason a whopping 37.3% of cleaning supervisors), 39.2% of motor vehicle operators, 27.7% of vehicle mechanics, 36.3% of people working in healthcare support, and 29.8% of health technicians were obese (see Table 2 below). Some construction occupations were slightly less obese than average (“Construction trades workers” at 25.0%), and some were much more obese than average (“Helpers, construction trades” and “Other construction and related workers” at 31.2% and 38.6%, respectively).

 Table 2: National Health Interview Survey Data, Non-Hispanic White Adults, 2004-2011

For non-hispanic white adults, individuals with the highest age-adjusted prevalence of obesity were motor vehicle operators, “other construction and related workers”, law enforcement workers, and nursing, psychiatric, and home health aides. It’s not clear why law enforcement workers are in there, but it’s pretty remarkable that the PFAS explanation can predict the other three.

Patterns are largely similar for the other racial groups. Among black female workers, the occupations with the highest age-adjusted prevalence of obesity were health care support (49.2%), transportation and material moving (46.6%), protective service (45.8%), personal care and service (45.9%), community and social services (44.7%), food preparation and serving (44.1%), and health care practitioners and technicians (40.2%). Some of these don’t seem to fit — why is “transportation and material moving” in there? — until you realize that “transportation and material moving” includes air traffic controllers, pilots, and other transportation workers, and you remember that PFAS-based firefighting foams are still widely used at airports.

Overall when we look at professions we would expect to have high exposure to PFAS, we see that workers in those professions are more obese than average. When you look at the professions with the highest rates of obesity, we see that most of them are related to mechanical work, healthcare, cleaning, or firefighting, all professions that have disproportionate exposure to PFAS on the job.

If on-the-job PFAS exposure really does lead to obesity, we should also see higher levels of obesity in people who work with PFAS directly. This is exactly what we find.

In 1993 and 1995, 3M conducted an internal study of PFOA exposure in a group of production workers. In the mid 90s, about 20-25% of the population was obese. About 40% of these workers were obese in 1993, and about 48% were obese in 1995.

Looking closer, they found that the group with the highest amount of PFOA contamination also had the highest BMI. The authors even take a moment to draw attention to this point. “It should be noted,” they say, “that all five employees in 1995 with serum PFOA levels [30,000 ng/mL] had BMIs 28.” BMI was slightly correlated with PFOA contamination (r = .11), though with only 111 people, the correlation was not significant. The authors seem unaware of the implications of this, however, and treat BMI as a confounder for other analyses.

Of course, this was not a normal group. They had insanely high serum PFOA levels, up to 115,000 ng/mL, though a few people had no PFAS in their blood.

A later 3M paper published in 2003 looked at serum levels of both PFOA and PFOS. In these data, there is a very clear relationship between PFOS levels and BMI. Men in the lowest quartile of PFOS exposure (mean 270 ng/mL) have an average BMI of 25.8, while men in the highest quartile of PFOS exposure (mean 2,690 ng/mL) have an average BMI of 27.2. The effect is even more pronounced for female employees. Women in the lowest quartile of PFOS exposure (mean 70 ng/mL) have an average BMI of 22.8, while women in the highest quartile of PFOS exposure (mean 1,510 ng/mL) have an average BMI of 28.7. They don’t report a correlation, but they do say, “the fourth quartile had significantly higher mean values than the first quartile for … BMI.”

Dose-Dependent Relationships in the Population

This is somewhat confusing, however, because PFAS serum levels aren’t all that correlated with BMI in the general population. This paper on 2003-2004 NHANES data (a large sample intended to be nationally representative) looked at PFAS concentrations in a final sample of 640 (down from 2,368) people and found only weak evidence of PFAS having an influence on body weight. The strongest relationship they report is for PFOS levels among male participants over 60. Some analyses even report significant negative relationships between PFAS levels and BMI.

Both of these approaches, however, are looking at coefficients in regression equations where they have included many covariates. While in principle this technique can be used to adjust for confounders, in practice the resulting estimates are difficult to interpret. Without a strong model of the causal structure involved, it’s hard to know what the relationship between two variables means when it is adjusted by 20 other variables. Including covariates in an unprincipled way can even cause estimates of an effect to reverse direction. It’s not a panacea, and in fact it can be misleading.

The NHANES data is publicly available, so we decided to check for ourselves. Sure enough, PFOS levels aren’t correlated with BMI — though they are correlated with both weight and height individually.

There’s an issue with looking at simple correlations of PFAS levels, of course, because they are highly correlated with one another. If you have high serum levels of one PFAS, you probably also have high serum levels of another. This means that they may interact or mask one another’s effects in potentially complicated ways.

For example, let’s look at PFHS. A quick correlation shows that serum PFHS levels are negatively correlated with BMI. As far as we can tell, no one has ever reported this, but it’s right there in the NHANES data. In the 2003-2004 data, the correlation is r = -0.090, p < .000045. This effect is small but extremely robust — people exposed to more PFHS are slightly skinnier.

PFHS levels are also correlated with PFOS (r = .29). When we look at the relationship between PFOS and BMI controlling for PFHS, the relationship between PFOS and BMI becomes significant, p = .035, showing that people with higher PFOS exposure are more obese.

“Just wait a minute,” you say, “that’s barely significant at all! How many relationships did you look at before you found that, anyways? This sounds a lot like p-hacking.” We had the same concern, which is why it’s great that we have NHANES data from many different years that we can use to validate this result.

We can go backwards to the 1999-2000 data (we can’t use the 2001-2002 data because the PFAS data for that year are missing ID numbers) where we find a significant relationship between PFOS and BMI controlling for PFHS, p = .008. We can also go forwards to the 2005-2006 data, where we also find a significant relationship between PFOS and BMI controlling for PFHS, p = .007. It seems to be pretty reliable. Now, it’s not a huge effect — the influence of PFOS is only about a half a point of BMI for the average person. But that’s a lot more than nothing.

This isn’t the place for doing a full analysis of the relationships between the different PFAS and how they interact. The NHANES doesn’t even measure every kind of PFAS, so we wouldn’t be able to find every relationship. The point is simply that the influence on BMI may be more complicated than a simple association, and this is proof that at least one of these surprises is hiding in publicly available data.

Why is the association so apparent in the 3M workers but harder to detect in the general population? It has to do with the issues with dose-dependence that we identified earlier. The 3M studies are the sort of samples where we should be able to detect a dose-dependent effect, if one exists. The NHANES data, however, is the sort of sample where it should be hard to detect a dose-dependent effect, even if a strong one exists.

The NHANES data is intended to be nationally representative, while the 3M data is looking at a few hundred people at a couple factories. As a result, the 3M sample is much less diverse than the NHANES sample, which means that it will also be less genetically diverse. Since there’s less genetic diversity, genetics will have less influence on people’s body weight. With less variation coming from people’s genetics, there’s less noise for the dose-dependent signal to be lost in, and it will be easier to detect. Looking at other populations that are not so diverse — like pregnant Danish women between 1996 and 2002 or newborn deliveries at the Johns Hopkins Hospital in Baltimore, MD — we also find that PFAS levels are related to BMI. Similarly, a study from 2021 found a dose-dependent relationship between PFOA — but not PFOS — and obesity in children living in the United States.

The 3M studies are also looking at a much wider range of dosages than are observed in the general population. In the 2003-2004 NHANES data, the range of serum PFOA levels was 0.1 to 77 ng/mL, and the range of serum PFOS levels was 0.3 to 435 ng/mL. In comparison, the range of serum PFOA levels in the 1993 and 1995 3M study was 0 to 115,000 ng/mL. In the 2003 3M study, the range of serum PFOA levels was 10 to 12,700 ng/mL and the range of serum PFOS levels was 40 to 10,060 ng/mL. Analyzing a less restricted range makes the correlation more accurate, which is what we see in the 3M data.

In the 3M sample, some employees participated in both 1993 and in 1995, and PFOA serum levels were highly correlated among the 68 employees who appeared in both samples (r = .91, p = 0.0001). This means that levels of exposure were extremely consistent across the two years between the measurements, possibly because people’s level of exposure was related to the role they had in the production process. Normally, it takes a while for someone’s weight to catch up to the dose of a compound that influences their weight — this is clear from studies of weight gain in people taking antipsychotics. But the 3M employees had serum levels that had been stable for many years. We should expect this to reduce noise and make the correlation between serum levels and BMI more accurate, and it appears to have done just that.

Other Considerations

Dose-dependence is strong evidence that PFAS are a contributor to the obesity epidemic. Is there any other lingering evidence?

One paper looking at a dieting study from 2003 found that PFAS concentration wasn’t related to body weight or weight lost during dieting. However, it was associated with greater weight regain over the months following the diet. People with the highest plasma concentrations of PFAS gained back about 8.8 lbs (4 kg), while people with the lowest plasma concentrations of PFAS gained back only about 4.4 lbs (2 kg). This is a relatively minor but statistically significant difference, and it is consistent with an account where these compounds don’t simply cause weight gain, but damage the lipostat and lead people to defend a higher body weight.

West Virginia is usually an obesity outlier. It’s the #1 or #2 most obese state (depending on your source), and it’s been one of the most obese states for as long as we’ve been keeping statewide records for this sort of thing. But it’s also high in elevation (19th highest after Washington state and Texas) and pretty far upriver. Most of the neighboring states — Ohio (#11), Pennsylvania (#24), Maryland (#26) and Virginia (#28) — are not nearly so obese.

DuPont built the very first Teflon (PTFE) plant in Parkersburg, West Virginia. By 1948, the plant was manufacturing 2 million pounds of PTFE per year. Some sources claim that they were using PFOA as part of the manufacturing process by 1951. Unfortunately we don’t have obesity data for West Virginia in 1948 or 1951, or the years immediately following. But we can note that many years later, West Virginia was at the center of the first legal action surrounding PFAS.

This kind of legal action has come about because PFAS have been linked to a variety of harmful health effects, including cancer, thyroid hormone disorder, and immune system effects. As a result, governments have begun to regulate and sometimes ban these compounds. New York, Maine, and Washington state have all banned or restricted PFAS in various ways, and in 2021, Vermont and Connecticut both passed legislation to remove PFAS from firefighting foams, food packaging, and other consumer products. There’s even some international regulation — PFOS have been regulated under the international Stockholm Convention since 2009, which was expanded to include PFOA and PFOA-related compounds in 2019. There was also a movie about PFAS bans, starring Mark Ruffalo.

Some people are hopeful that these bans will form a sort of natural experiment that can allow us to see what happens when PFAS are removed from the environment. Unfortunately, we’re less optimistic. First off, these compounds are very durable, so even if we ban them, huge doses will still be in the environment. Second, statewide bans won’t keep these substances from entering the state in food or goods produced elsewhere. 

Finally, these bans restrict only a tiny percentage of all PFAS. As a recent report from the European Commission notes, “The ban of widely used long-chain PFAS has led to their substitution with a large number of shorter chain PFAS. Several of these alternatives are now under regulatory scrutiny in the REACH Regulation because of the concern they pose for the environment and for human health.” Efforts to limit exposure to PFAS are a great idea, but the continued use of short-chain PFAS limits the usefulness of bans as natural experiments to determine the role of PFAS in obesity.


[Next Time: SUSPECT NUMBER THREE]


Drugs Fun, Heroin Still Dangerous

Carl Hart is a parent, Columbia professor, and five-year-running recreational heroin user, reports The Guardian. “I do not have a drug-use problem,” he says, “Never have. Each day, I meet my parental, personal and professional responsibilities. I pay my taxes, serve as a volunteer in my community on a regular basis and contribute to the global community as an informed and engaged citizen. I am better for my drug use.”

Hart makes it pretty clear he thinks drug use is a good thing. Good not only for himself, but for people in general. “Most drug-use scenarios cause little or no harm,” he says, “and some reasonable drug-use scenarios are actually beneficial for human health and functioning.” He supports some basic safeguards, including an age limit and possibly an exam-based competency requirement, “like a driver’s licence.” But otherwise, he thinks that most people can take most drugs safely.

The article mentions Hart’s research in passing, but doesn’t describe it. Instead, these claims seem to be based largely on Hart’s personal experiences with drugs. He’s been using heroin for five years and still meets his “parental, personal and professional responsibilities”. He likes to take amphetamine and cocaine “at parties and receptions.” He uses MDMA as a way to reconnect with his wife

When Hart wondered why people “go on [Ed.: yikes] about heroin withdrawal”, he conducted an ad hoc study on himself, first upping his heroin dose and then stopping (it’s not clear for how long). He describes going through an “uncomfortable” night of withdrawal, but says “he doesn’t feel the need or desire to take more heroin and never [felt] in any real danger.”

This is fascinating, but it seems like there’s a simple individual differences explanation — people differ (probably genetically) in how destructive and addictive they find certain substances, and Hart is presumably just very lucky and doesn’t find heroin (or anything else) all that addictive. This is still consistent with heroin being a terrible drug that ruins people’s lives for the average user.

Let’s imagine a simplified system where everyone either is resistant to a drug and can enjoy it recreationally, or finds it addictive and it ends up destroying their life. For alcohol, maybe 5% of people find it addictive (and become alcoholics) and the other 95% of us can enjoy it without any risk. In this case, society agrees that alcohol is safe for most people and we keep it legal. 

But for heroin, maybe 80% of people would find it addictive if they tried it. Even if 20% of people would be able to safely enjoy recreational heroin, you don’t know if it will destroy your life or not until you try it, so it’s a very risky bet. As a result, society is against heroin use and most people make the reasonable decision to not even try it.

Where that ruins-your-life-percentage (RYLP) stands for different drugs matters a lot for the kinds of drugs we want to accept as a society. Certainly a drug with a 0% RYLP should be permitted recreationally, and almost as certainly, a drug that ruined the lives of 100% of first-time users should be regulated in some way. The RYLP for real drugs will presumably lie somewhere in between. While we might see low-RYLP drugs as being worth the risk (our society’s current stance on alcohol), a RYLP of just ten or twenty percent starts looking kind of scary. A drug that ruins the lives of one out of every five first-time users is bad enough — you don’t need a RYLP of 80% for a drug to be very, very dangerous.

Listen, we also believe in the right to take drugs. We take drugs. Drugs good. Most drugs — maybe all drugs — should be legal. But this is very different from pretending that many drugs are not seriously, often dangerously addictive for a large percentage of the population. 

As far as we know, drugs like caffeine and THC aren’t seriously addictive and don’t ruin people’s lives. There’s even some fascinating evidence, from Reuven Dar, that nicotine isn’t addictive (though there may be other good reasons to avoid nicotine). But drugs like alcohol and yes, heroin, do seem to be seriously addictive, and recognizing this is important for allowing adults to make informed choices about how they want to get high off their asses.

Hart’s experience with withdrawal, and how he chooses to discuss it, seems particularly clueless. It’s possible that Hart really is able to quit heroin with minimal discomfort, but it’s confusing and kind of condescending that he doesn’t recognize it might be harder for other people. When people say things like, “I find heroin very addictive and withdrawal excruciating,” a good start is to take their reports seriously, not to turn around and say, “well withdrawal was a cakewalk FOR ME.”

This seems to be yet another example of the confusing trend in medicine and biology, where everyone seems to assume that all people are identical and there are no individual differences at all. If an exercise program works for me, it will work equally well for everyone else. If a dietary change cures my heartburn, it will work equally well for everyone’s heartburn. If a painkiller works well for me when I have a headache, it will work equally well for the pain from your chronic illness. The assumption seems to be that people’s bodies (and minds) are made up of a single indifferentiable substance which is identical across all people. But of course, people are different, and this should be neither controversial nor difficult to understand. This is why if you’re taking drugs it’s important to experiment — you need to figure out what works best for you.

This is kind of embarrassing for Carl Hart. He is a professor of neuroscience and psychology. His specialty is neuropsychopharmacology. He absolutely has the statistical and clinical background necessary to understand this point. At the risk of being internally redundant, different people are different from each other. They will have different needs. They will have different responses to the same drugs. Sometimes two people will have OPPOSITE reactions to the SAME drug! Presumably Carl Hart has heard of paradoxical reactions — he should be aware of this.

On the other hand, anyone who sticks their finger in Duterte’s eye is my personal hero. We should cut Hart some slack for generally doing the right thing around a contentious subject, even if we think he is dangerously wrong about this point.

Less slack should be cut for the article itself. This is very embarrassing for The Guardian. Hart is the only person they quote in the entire article. They don’t seem to have interviewed any other experts to see if they might disagree with or qualify Hart’s statements. This is particularly weird because other experts are clearly interested in commenting and the author clearly knows that they might disagree with Hart. They might have asked for a comment from Yale Professor, physician, and (statistically speaking) likely marijuana user, Nicholas Christakis, who would have been happy to offer a counterbalancing opinion. The Guardian was happy to print that Hart is critical of the National Institute on Drug Abuse (NIDA), “in particular of its director, Nora Volkow”, but there’s no indication that they so much as reached out to NIDA or to Volkow for comment (incidentally, here’s what Volkow has to say on the subject).

We can’t be sure, but it’s even possible they somewhat misrepresented Hart’s actual position. It’s disappointing but not surprising when a newspaper doesn’t understand basic statistics, and it would be unfair to hold them to the same standard we hold for Carl Hart. But it is fair to hold them accountable for the basics of journalistic practice, and it seems to us like they dropped the bong on this one.