[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]

There are a number of interesting comments on the A Chemical Hunger Discussion Thread recently posted on r/slatestarcodex, so we wanted to feature and discuss a few of them here. Thanks to everyone who commented and asked questions, we appreciate all the feedback.

Some of these questions are meaty enough to deserve a post of their own, so we won’t discuss any of those comments here. But trust us, it’s (probably) coming.

When did Obesity Spike?

The OP of the Reddit thread, u/HoldMyGin/, asks:

My biggest criticism is the assertion that obesity rates started spiking around 1980. If you look at a graph of rates, sure, they did, but isn’t that what one would expect to see if you’re measuring the percent of a normal distribution above a certain threshold, and the mean of that distribution is slowly but consistently inching upward?

This is an interesting point, but the trends don’t look that way to us. 

To test this, we ran a simple simulation where a population of 1000 people with normally distributed BMI (mean 23, sd 4) all see an increase of 0.1 points of BMI per year for 200 years. They start at about 3% obese, which is around the premodern rate of obesity, and show a pretty gradual increase over time:

In reality, the US went from about 1-3% obese in 1890 to about 10% obese in 1980, then from about 10% obese in 1980 to about 36% obese today. This is an increase of 7-9 points over 90 years versus an increase of 26 points over 40 years. In the simulation it takes about 20 years to reach 10% obesity and then about 36 more years to reach 36% obesity. The time scale seems way off for a constant mean increase.

In any case, the spike isn’t just caused by an increase in the mean because the SD of BMI has increased as well. Analysis of data from the Framingham Heart Study found that the standard deviation of BMI increased “from 4.18 kg/m(2) to 6.15 for women and 3.31 kg/m(2) to 4.73 for men” between 1971 and 2008.

u/KnotGodel also chimed in with:

Just to add to this. u/slimemoldtimemold‘s chart of obesity over time is from the CDC. I took this chart, hand-transcribed it, and then assumed BMI followed a normal distribution. From this, I computed the implied mean and standard deviation for each sex over time. … You can see from the chart that (in this model) mean BMI didn’t really change until 1978. After this point it increased by ~4 points.

Here are KnotGodel’s lovely figures based on the CDC data. Thanks Knot! 

Those SD seem very different from the numbers in the Framingham Heart Study over a very similar period, but maybe this is because the variance in Framingham, Massachusetts is going to be lower than the variance in the country as a whole.

Diseases of Deficiency

u/leerylizard raised an interesting alternative theory:

Another idea I’ve considered is that the modern diet is simply missing some key nutrient(s) we haven’t learned about yet. Like how beriberi and scurvy had unknown etiologies until they were eventually identified as thiamine and vitamin C deficiencies, respectively. Modern agribusiness tends to use different methods than were common before 1900, what with the Haber process for soil fertilization, mono-cropping, etc. Maybe some particular nutrient is lost when we switch to a modern diet.

This would be very weird because, if obesity were anything like beriberi and scurvy, it would be easily reversed when people got access to the required nutrient. It would probably be more common in people who depended on unusual or limited food supplies, e.g. arctic explorers, astronauts, people during sieges, etc. But we don’t see any of that.

As usual, this would be hard to square with the altitude data, and the fact that there is a lot of variation in obesity between different professions. Barring strong evidence for a particular nutrient, it seems pretty unlikely.

Psychiatric Doses

u/ScottAlexander, who is a practicing psychiatrist, says:

If lithium is involved, it’s got to be pretty weird and inconsistent. Lithium given in psychiatric doses – about 1000x the background dose – sometimes makes patients gain weight, in the same way that any drug can potentially make you gain weight. But you can still find plenty of psychiatric lithium patients with normal BMI. I’m not sure really sure how to square “use water filters to decrease your lithium by 0.001 mg” with “but also some people take 1000 mg lithium and are fine”. I don’t want to say it’s impossible, because there are a lot of effects like this (some people exposed to secondhand smoke get lung cancer, but some smokers do not get lung cancer). I still feel like I would need a better model of what’s happening before I cared too much about microinterventions to decrease environmental lithium.

We agree that there is something weird going on here, so let’s

As far as we can tell, the weight gain is more consistent than “sometimes patients gain weight”. Most people who take lithium at psychiatric doses gain some weight, 45/70 in one example. The weight gain tends to be quite a bit, on average 22 lbs (10kg), and about 20% of patients gain more than that. But it’s true that some people gain no weight.

Of course, 75% of the variance in modern obesity is still genetic. People who are “immune” or resistant to lithium’s effects on weight gain won’t gain much weight on psychiatric doses for the same reason they don’t gain weight on trace doses — they’re immune or resistant. And in fact we see evidence that matches this; one study says, “the patients who increased in weight during the treatment were overweight already before the start.” From this perspective, it’s not surprising that some people don’t gain weight on psychiatric doses of lithium. If someone from Mississippi has a BMI of 23, they are lean despite (presumably) high levels of exposure and will probably remain lean no matter how much you throw at them (until dead).

This is also pretty much what we would expect with the classic dose-response curve. If the inflection (EC50 or something) is at trace-level doses, then psychiatric doses blow past the inflection point and just max people out, and make them as obese as their genetics allows. For some people this is very obese, and for others it’s not obese at all.

Maybe the Silent Spring angle is correct, and lithium itself doesn’t cause obesity. Lithium is reactive, and it’s possible it forms some other compound that causes obesity, and that compound is created at higher levels in groundwater than when lithium carbonate reacts with stomach acid. 

Or it could just be that different lithium compounds lead to different levels of weight gain. Different lithium salts are used clinically, usually lithium carbonate or lithium citrate, but there are many other lithium salts, and many avenues of exposure. Has anyone ever checked to see if different salts lead to different levels of weight gain? 

As just one example, lithium bromide was used as a sedative back in the day, and is currently used as a desiccant in air conditioning and air purification systems. In a test of the oral toxicity of lithium bromide the European Chemicals Agency found that on a dose of 500 mg/kg no rats died, but “all rats gained weight by day 14 of the study.” On a dose of 2000 mg/kg, one rat died on the first day, but the rest survived, and “all surviving rats gained weight by day 14 of the study.” These doses are higher than psychiatric doses of lithium chloride, and we don’t know how much weight gain lithium bromide would cause in humans, but maybe psychiatric results aren’t a good indicator of how much weight gain can be caused by other lithium compounds.

Pima

In another comment, u/evocomp raises a number of points, the most interesting being:

The famous Pima Indians of Arizona had a tenfold increase in diabetes from 1937 to the 1950s, and then became the most obese population of the world at that time, long before 1980s. Mexican Pimas followed the trend when they modernized too. 

The Pima people, sometimes called Pima Indians, are a group of Native Americans from the area that is now southern Arizona and northwestern Mexico. In the United States, they are particularly associated with the Gila River Valley.

What evocamp describes is well-documented. The Pima seem to have had normal rates of diabetes and obesity in 1937, but both increased enormously by 1950, and by 1965 the Arizona Pima Indians had “the highest prevalence of diabetes ever recorded.” By 1970 the diabetes rate was around 40%, and by 2016, around 50%. The numbers on obesity are less specific, but it was also increasing and also very high by the 1970s.

The timeline here is very surprising — before 1970, obesity rates worldwide were almost always 10% or less. This is clearly a mystery that needs to be accounted for, so we really appreciate evocamp pointing us to this example.

If the contamination theory is right, we should be able to find evidence that the Pima were exposed to some contaminants, maybe from mining, as early as 1937. If the contamination theory is REALLY right, then we should be able to find evidence that the Pima were exposed to livestock antibiotics, PFAS, or lithium. We know that PFAS hadn’t been invented back then and antibiotics weren’t rolled out until a bit later, so that kind of leaves lithium.

Lithium was first mined in the United States in 1889. As far as we can tell, none of the early mines were in Arizona, but records from that period are spotty. There are lithium deposits in Arizona, so maybe there was a way for it to somehow get into the water supply. Around 1924, the government built a dam on the Gila river which halted the river waters, which caused the Pima to seek new water sources. Maybe it led to them switching to a water source that contained more lithium.

Or lithium could have been introduced some other way. For example, this report says, “In the Gila River Valley, deep petroleum exploration boreholes were drilled during the early 1900’s through the thick layers of gypsum and salty clay found throughout the valley. Although oil was not found, salt brines are now discharging to the land surface through improperly sealed abandoned boreholes, and the local water quality has been degraded.” Hm, that’s interesting. Did you know lithium is common in clays and oil-field brines?

The report also notes that “lithium is found in the groundwater of the Gila Valley near Safford.” There’s also this USGS report which says a Wolfberry plant (genus Lycium) “was sampled on lands inhabited by the Pima Indians in Arizona; it contained 1,120 ppm lithium in the dry weight of the plant.” To give that number some context, “an average of 150 ppm lithium in the ash and 25.8 ppm in the dry weight of all plants that were collected in both closed and open arid basins is considerably higher than the average of 1.3 ppm in dry weight reported for plants growing in a nonarid climate.” There was serious lithium contamination in this valley as early as 1974!

Also regarding the 1974 source, another USGS report says, “Sievers and Cannon (1974) expressed concern for the health problem of Pima Indians living on the Gila River Indian Reservation in central Arizona because of the anomalously high lithium content in water and in certain of their homegrown foods.”

We couldn’t have cherry-picked this example, because u/evocomp proposed it. The early and extreme incidence of obesity in the Pima is clearly a mystery that needs explaining, and sure enough, we found strong evidence for lithium contamination that fits the timeline of diabetes and obesity in the Pima. 

This seems like additional strong evidence that lithium causes obesity even at nonclinical levels. In fact, it is especially strong evidence that trace lithium alone can cause extremely high rates of obesity! There were many other groups of Native Americans living in largely similar conditions all over the country, but none of these groups were around 40% obese by 1970. It can’t be food or shelter or oppression by the US government because these things were more or less common to all groups — the difference between the Pima and other Native Americans is that the Pima were being exposed to huge doses of lithium in their food and water and other groups weren’t.

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[Next Time: ROUNDUP?]

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