Vegan Nutrition Testing Project: Interim Report

Introduction

Reducing consumption of animal products is a choice with both moral and practical consequences. Last summer I found myself in contact with many vegans who cared a lot about the moral consequences, but had put little effort into learning about or managing the practical consideration of removing animal products from their diet. I’ve suffered a lot due to bad nutrition, so this made me very concerned. With a grant from the Survival and Flourishing Fund, I launched small a pilot project to give nutritional tests to 5 vegans and near-vegans from the Lightcone Office, which they could use to choose supplements that would hopefully improve their health.

My long-term goal was for everyone to have accurate information on their personal nutritional costs of veganism and make informed choices about how to handle them, with the first line solution being supplements. My goal for the pilot was to work out practical issues in testing, narrow the confidence interval on potential impact, and improve the nutrition of the handful of people. This report is on phase 1: getting the testing done and supplements started. It is aimed at people who might want to run a similar program at scale; if you are interested in running this for yourself I recommend checking out Tuesday’s post on iron deficiency.

Tl;dr: I found rampant iron deficiencies, validating the overall concern. The procedure I used has a lot of room for improvement. 

The Experiment

I gave nutrition tests to 6 people in the Lightcone office. 

The ideal subject was completely vegan, had never put any effort or thought into their diet, and was extremely motivated to take a test and implement changes. This person does not volunteer for studies, so I ended up with 4 vegans or near-vegans who had put somewhere between 0 and a lot of thought into their diet, 1 vegetarian, and 1 extremely motivated omnivore I used to test out the process.  In addition, one hardcore vegan contributed results from private testing. I did not poll the ~vegans on their exact diets.

Unless otherwise stated the results exclude the omnivore.

I gave each of these six people a Genova Metabolomix+ test, ordered from walkinlabs.com, with the iron add-on. This test was selected for being recommended by doctors I trust (in part because they prefer urine to blood testing), having extremely easy-to-read results, being nearly comprehensive (with the unfortunate absence of vitamin D), and because I hoped urine collection at home would be easier than blood draws at a lab. Foreshadowing: I was wrong about that last part.

I also gave people the option of an add-on to determine what variant of the MTHFR gene they have. MTHFR can affect how one processes certain B vitamins, and certain variants can necessitate a more expensive form of supplements.

Several people (although not everyone) scored with undetectably low iron. I offered them follow-up blood tests, which one person accepted. An additional vegan contributed blood test results without urine results.

As of publication all subjects have received their first round of results and started supplements of their choosing. 

The original plan was to retest in 3-6 months after people began supplements, using the same urine tests.

My initial predictions

I expected the big shortages to be B12, iron, and vitamin D, the first of which has very few* natural vegan sources and the latter two of which are scarce, although not absent, in vegan sources. This makes it pretty unfortunate the original test did not include vitamin D. 

[*B12 is naturally found in some (but not all) seaweeds and algaes, in at least one kind of mushroom, and in nutritional yeast. It’s also added to many wheat products in the US, so if you eat enough wheat and aren’t going out of your way to get unfortified wheat that’s a strong source]

Relative to the mainstream I wasn’t very concerned about protein consumption. Vegan proteins are a little less abundant, a little harder to digest, and have a less ideal distribution of amino acids, but are basically fine as long as you don’t pile on additional constraints.

One reason I was concerned was that lots of people I polled were piling on additional constraints, like keto or gluten-free, and still not doing anything to manage nutrition. I expected a smattering of deficiencies from these people, and to a lesser extent from everyone, as their restrictions and tastes cut off random nutrients. These could have been in any almost nutrient.

I expected everyone to be fine on vitamin C because it is abundant in both produce and processed food (where it’s used as a preservative).

Results

(including only vegans and near-vegans)

  1. ¾  vegan testers had severe iron deficiencies in their urine tests.
    1. The one who didn’t had both a stunning dietary intake of iron, and a parent who 23andMe believes to have a genetic predisposition to excessive absorption of iron.
    2. An additional vegetarian tester was not deficient.
    3. One of these retested with a blood test and scored low normal (~30). However this person was already taking iron supplements at the time of the test. 
    4. A bonus blood-only participant tested between 13 and 20, meaning they’d be considered deficient by some standards but not others.
  2. There were no B12 deficiencies, probably because everyone was already on B12 supplements. 
  3. One tester had a lot of deficiencies, including vitamin C, to the point I suspect it’s a problem with digestion rather than diet. 
  4. Everyone had at least one amino acid deficiency, including the person eating over 100g of protein/day. I don’t know how big a deal this actually is.
  5. The urine test did not include vitamin D.  Of the 2 blood tests, both had low-normal vitamin D.
  6. Excluding the person with across-the-board deficiencies, there were scattered other deficiencies but nothing else to consistently worry about. People were mostly in their tests’ green zone, with occasional yellow and red.

What does this mean?

Only one near-vegan out of 5 had solidly good ferritin levels. As I discuss here, that’s a very big deal, potentially costing them half a standard deviation on multiple cognitive metrics. 

There’s no control group, so I can’t prove that this is a veganism problem. But I’m quite suspicious.

There were no other consistent problems, so broad-spectrum testing is probably overkill for people with no known problems. 

Retrospective on the project

What worked

I consider the core loop of the study as vindicated as can it be at this stage. 

  • Deficiencies were identified, and the primary one was one of the three I predicted.
    • And another of the three, B12, was probably absent because people treated it preemptively. Note that people were inconsistent in what they took so I can’t say definitively what they were on during testing.
  • In the counterfactual timeline the shortages were probably identified much later if at all. No one who participated had any plans for testing, including people with obvious symptoms and people whose doctors had previously recommended testing.

This will be less impressive if supplementation doesn’t turn out to fix anything, but it’s an extremely solid start.

Other things that went well:

  • Having the room in my budget for unplanned additional testing, so I could add in serum iron tests when it became obvious they were necessary.
  • Creating a shopping list with links. I was worried this was somehow taking advantage of people (since I used affiliate links), but removing a decision and several steps from the ordering process seems to have been pretty crucial. 
  • Bypassing the need for doctors’ visits to get a test. Given how long it took people to order tests I think doctors’ appointments would have killed the project entirely. 
  • The Lightcone ops team was extremely cooperative and got all of the vitamins I suggested into the office.

Difficulties + possible changes

Potential changes are framed as recommendations because I am deeply hoping to hand off this project to animal advocates, who caused the veganism in the first place. 

  1. The test ordering workaround was not as good as I had hoped
    1. I’d originally hoped to just hand participants a box, but they had to order the tests themselves.
    2. In order to get iron + genetics tests people had to call rather than order online. This is non-standard for the provider and two people had to call twice to insist on what they wanted.
    3. Tests took a long time to ship, and a long time to return results after shipping. The lab alleges this is a supply chain issue and there’s nothing to be done about it. 
    4. Those two together turned into a pretty big deal because they made it very hard to plan and people lost momentum.
    5. In combination with the results showing few problems beyond iron I recommend deemphasizing full spectrum urine tests and focusing on blood tests for iron (and vitamin D), and making those convenient, perhaps by bringing a phlebotomist to the office.
    6. Another option would be to bring in a medical practitioner, who can order tests for other people, to manage tests so the office can be stocked with them. This of course fails to solve the problem for anyone not in the office.
    7. There are home tests for vitamin D and iron specifically, but I have no idea if they’re any good.
  2. Ideal test subjects (completely vegan, never done nutritional testing or interventions, promptly puts in the effort to do these tests and act on them once I suggest it) were even thinner on the ground than anticipated.
    1. I knew there wouldn’t be many, but I didn’t think it would be so hard to get five people pretty close to that profile. 
    2. I loosened restrictions and still consistently found problems, so recommend lowering the eligibility bar for testing in future rounds, especially since that was always the plan. The strict requirements in this round were an attempt to make the signal as loud as possible.
  3. Getting everyone tested was like herding cats. Beyond the problems with the test distributor, some participants needed repeated reminders to order, one lost a test, results went missing… it was kind of a nightmare.
    1. One advantage of focusing on blood tests would be to cut down on this, especially if you bring the phlebotomist to the office.
  4. At points I was uncomfortable with the deference some participants showed me. I was as clear as I possibly could be that this was a best-effort from a knowledgeable amateur kind of thing; they were responsible for their own health and I was a nonexpert trying to provide some logistics help. I nonetheless got more than one person bringing me problems not even related to the nutrition project, and insisting I tell them what to do.
    1. Recommendation: bring in a skilled nutritionist. They can both give better advice than me and devote more time to helping people. 
  5. I initially misread the protein results (which are delivered in terms of “how deficient are you?” rather than “what’s your current level?”, making 0 the best possible score). Luckily I knew I was confused from the beginning and no one had taken any actions based on my misinterpretation. More broadly, I’m just a woman who’s had some problems and read some stuff, I expect my suggestions to be better than nothing but far from the maximum good it would be possible to do.
    1. Recommendation: bring in a skilled nutritionist
  6. I underestimated the amount of time and especially emotional labor this project would need. I was hoping to bluff my way through that until people got on supplements, at which point the improvements in health would be their own motivation. I think I always overestimated how well that would work, but it was especially wrong because all the problems with the tests drained people’s momentum.
    1. Recommendation: I still think you should bring in a skilled nutritionist
  7. Many of the participants were moving frequently and not in the office by the time their results came in (because they took so long…), so they had to buy supplements themselves. Given the option I would have selected people consistently in the office, but as mentioned I was already managing trade-offs around participants.
    1. Recommendation: ask for more money to give everyone their first month of supplements and a convenient pill planner.

Next Steps

I previously planned to give people the same urine test 3-6 months after they started supplements. That no longer seems worth it, relative to the cheaper and more convenient blood tests. 

It’s not actually clear a formal follow-up is that useful at all. I initially planned that because I expected a wide range of shortages such that literature reviews wouldn’t be helpful. But there was only one real problem, and it has a richer literature than almost any micronutrient. So I don’t think another 5 people’s worth of scattered data is going to add much information. 

So the next step for this as a project would be mass blood testing for B12, iron, and vitamin D. 

Feeling motivated?

If this has inspired you to test your own nutrition, I haven’t done anything you can’t do yourself. Both the urine and blood tests are available at walkinlabs.com, and if you have a doctor they’re quite likely to agree to testing, especially if you’re restricting meat products or fatigued. I have a draft guide of wisdom on supplementation I’ve picked up over the years here, although again, I’m not a doctor and only learned how to digest food last May, so use at your own risk. 

Thank you to the Survival and Flourishing Fund for funding this project, Lightcone for hosting, and all the participants for their precious bodily fluids.

Iron deficiencies are very bad and you should treat them

In brief

Recently I became interested in what kind of costs were inflicted by iron deficiency,  so I looked up studies until I got tired. This was not an exhaustive search, but the results are so striking that even with wide error bars I found them compelling. So compelling I wrote up a post with an algorithm for treating iron deficiency while minimizing the chance of poisoning yourself. I’ve put the algorithm and a summary of potential gains first to get your attention, but if you’re considering acting on this I strongly encourage you to continue reading to the rest of the post where I provide the evidence for my beliefs.

Tl;dr: If you are vegan or menstruate regularly, there’s a 10-50% chance you are iron deficient. Excess iron is dangerous so you shouldn’t supplement blindly, but deficiency is easy and cheap to diagnose with a common blood test. If you are deficient, iron supplementation is also easy and cheap and could give you a half standard deviation boost on multiple cognitive metrics (plus any exercise will be more effective). Due to the many uses of iron in the body, I expect moderate improvements in many areas, although how much and where will vary by person. 

Note that I’m not a doctor and even if I was there isn’t good data on this, so it’s all pretty fuzzy. The following is an algorithm for treating iron deficiency that I’ve kludged together from various doctors. I strongly believe it is a lot better than nothing on average, but individuals vary a lot and you might be unlucky. 

  1. Take a serum ferritin test. If you have a doctor they will almost certainly say yes to a request, or you can order for yourself at walkinlab.com
  2. If your results show a deficiency (<20ug/L), increase iron intake through diet or supplements such as Ferrochel, taking the default dose once per day, with a meal.
    1. The definition of deficiency can vary by study, lab and goal. I picked <20ug/L because it’s the highest level I have concrete evidence is insufficient, but personally believe people are likely to benefit from iron beyond that and am taking pills accordingly.
  3. If you experience negative effects after taking the pills, stop immediately. Give yourself a week to recover, then you can try other brands, be more careful to eat with a full meal, etc. 
  4. If you are experiencing the symptoms of iron poisoning (listed below), stop pills and see a doctor now. Iron poisoning is a very big deal, which is why step 1 of this algorithm is “get tested” not “gobble pills”.  Unfortunately several of these are pretty generic, but I’m never going to feel bad about telling people with seizures to seak medical attention:
    1. Nausea
    2. Vomiting
    3. Abdominal pain
    4. Dizziness
    5. Low blood pressure and a fast or weak pulse
    6. Headache
    7. Fever
    8. Shortness of breath and fluid in the lungs
    9. Grayish or bluish color in the skin
    10. Jaundice (yellowing of the skin due to liver damage)
    11. Seizures
    12. Black or bloody stools
  5. Retest at 8-12 weeks, ideally at the same lab as before.
  6. Continue to retest every 8-12 weeks.
  7. If you increase by 20ug from your starting value without noticing any improvements to your cognition or overall energy levels; low ferritin is probably not your bottleneck.
    1. If you believe it’s not a problem at all, quit.
    2. If you believe it is a problem but another problem is limiting your gains, stay on a maintenance dosage but don’t put more time into managing this. Verrrrry roughly, divide your current dosage by your currently monthly gains (so If you take one RDA/day and gain 10ug/month, your result is 0.1), and take that much. This hopefully keeps you from losing ground, without gaining so quickly it could become a problem.
  8. If you’re getting improvements, keep going until those taper off. I personally would exercise caution and investigate the downsides of iron once I reached 80ug/L, but I’ve never gotten close to that so it hasn’t come up. 
  9. Continue to retest and adjust until you’ve found a dose on which your values are stable and healthy.

[Note: I provided links to supplements because I found people follow through more when I do, and because it’s easy to buy worthless supplements. There are other good supplements out there and if you have a reason to prefer one, take that instead. Links are affiliate.]

Research summary

Iron’s most famous use in the body is in hemoglobin, which your blood uses to transport oxygen. Oxygen is extremely important [citation needed], so it makes sense that low hemoglobin (aka anemia) gets a lot of attention, and everyone agrees anemia is very bad. But what the studies I read found was that even among people who started with adequate hemoglobin, a low ferritin score still predicted they would benefit from supplementation. And it’s not because of a bad definition of “adequate”; people saw benefits even when their hemoglobin didn’t change. So what else does iron do? 

Iron is one of a small number of elements that can safely accept electrons in reduction-oxidation reactions. Free electrons are quite damaging, so iron’s ability to safely contain them is important. Some specific usages:

  • The enzyme catalase, which converts caustic H2O2 to harmless water.
    • Fun fact: Catalase is the least important enzyme whose name and purpose I can recall offhand. Other enzymes achieved that status by being very important (DNA polymerase), or having self explanatory names (carbohydrase), but catalase achieved this by sounding kind of similar to a song I was into the summer I took microbiology, and I made up alternate lyrics about the enzyme.
  • Multiple points in DNA synthesis and repair, including keeping DNA polymerases in their correct shapes.
  • Myoglobin: similar to hemoglobin it binds oxygen, but instead of blood it stays in muscles, holding oxygen in reserve until it is needed.
  • Regulation of many components of the immune system.
  • Proline and lysyl hydroxylases, both used to build collagen.
  • Please enjoy this list of 80 enzymes that use iron as a cofactor.

I’d say “that’s a lot” but honestly it’s not, everything in the body is like this, it was not built to be understood.

Standard tests for anemia only look at hemoglobin. Ferritin tests are considered to be a much better measurement of cellular iron levels. There’s suspicion, although not proof, that your body prioritizes hemoglobin production above other uses of iron, so it will undersupply these other uses in order to maintain hemoglobin levels. This suggests that if you have normal hemoglobin but low ferritin, additional iron will find many uses. Unfortunately, those uses and their effects are so varied I can’t really predict what any particular person will experience.

There are any number of studies showing correlations between low ferritin and low functioning, but I don’t find those very useful. The people in those studies might have any number of deficiencies for multiple reasons, or low ferritin levels could just be a proxy for poverty. In my research I stuck to actual experiments, with controls, that gave iron to subjects and checked for an improvement in function, not just test scores. Unfortunately, there were not that many of them.

The only study I liked on the cognitive effects found an absolutely enormous effect. Successful iron supplementation led to improvements averaging >0.5 standard deviations in attention, learning, and memory. I have qualms about this study and expect the results are cherrypicked, but it’s also not necessarily the full size of the effect, because they stopped after a set amount of time rather than waiting for effects to plateau.

There were multiple studies on iron supplementation and exercise. In a nutshell: everyone’s endurance improves when they exercise. Giving people with iron deficiency but not anemia (IDNA) iron supplements increases that effect. In the strongest study, people treated for iron deficiency for 6 weeks improved their 15km time by 10%, compared to 5% in the control group. Another study (which didn’t involve exercise training) showed no improvement in time to complete a given distance, but did find the treatment group used about 5% less energy while doing so. 

Iron deficiency rates vary a lot by population, but with the patterns you’d expect. Vegans are more deficient than vegetarians, who are more deficient than omnivores. People who regularly menstruate (or give blood) are more likely to be deficient. I found the baseline rate of omnivorous men in rich countries to be somewhere between 0-11%. For a female omnivore it’s 9-22% (these numbers include people already taking supplements; it’s presumably higher if you don’t). Young female vegans who were not already supplementing were at least 50% deficient, plausibly more. Data for non-supplementing male vegans was not available, but let’s ballpark it at 5-25%, based on the ratio between men and women in the general public.

People in poor countries are much more likely to be iron deficient and anemic, due to poor diet and more physical exertion. 

Caveats

I am not a doctor, my most relevant credential is a BA in a different part of biology, the fact that I couldn’t find a decent resource and had to make it myself is a sign of civilizational inadequacy.

Normally not being a doctor inhibits me from giving medical advice, but I am going to go ahead and say that iron poisoning is extremely bad and not that hard to induce with pills, don’t do that. Iron poisoning is why you need to be careful your kid only gets one multivitamin a day, and why men can’t use women’s multivitamins (which should actually be “menstruator’s multivitamins”, since the relevant issue is monthly blood loss). 

The papers are very finicky and boring and this was really important, so I’ve tried to frontload my conclusion. This is a delicate balancing act of readability and accuracy. I did my best but some trade-offs are unavoidable. 

This lit review was done with a focus on people with low iron intake, especially vegans. None of the studies I looked at filtered on dietary intake versus absorption issues. This means they probably underestimate the impact of supplementing for healthy people.

Do not take the dosages in the studies literally, especially if you don’t menstruate. The right dosage depends on the form and your personal needs. I suggest operating based on RDA percentages rather than raw chemical weights.

Details

Definitions

There are a lot of ways to measure iron and iron-related levels in the body. The two most important are hemoglobin (the protein red blood cells use to carry oxygen) and ferritin (the protein your cells use to store oxygen, but also present in blood). There are some other numbers I’m going to ignore.

Hemoglobin and ferritin are both testable via blood sample, and the tests have something called “reference ranges”, which are supposed to be the healthy range of values. Whether the ranges actually capture that is a matter of great controversy, with various people alleging the minimum is what you need to avoid hardcore deficiency diseases, but won’t get you optimum functioning, to people claiming low scores are fine and anyone who says otherwise is a psyop from Big Vitamin. And then there’s individual variation.

Hemoglobin’s reference range is 120g/L-170g/L.  Ferritin’s reference range starts between 10 and 20 ug/L, and ends at 150-200ug/L, depending on who you ask.  It’s possible to have low hemoglobin (aka anemia) without an iron deficiency or vice versa. Low hemoglobin with adequate iron typically means you’re having trouble manufacturing hemoglobin and is beyond the scope of this post. Low iron with adequate hemoglobin is more controversial. Top explanations include “the tests aren’t that good”, “you’re deficient but your body is prioritizing hemoglobin production”, “you’re about to develop anemia” and “low iron is fine, actually”.  

Impact Data

When looking at studies I used the following selection criteria:

  • Examining iron deficiency without anemia. We can assume that anemic cases will benefit more from iron, unless the anemia is unrelated to the iron deficiency.
  • No co-morbidities.
  • On adult humans (in practice this almost always means women).
  • In the developed world.
  • RCTs only, no correlational studies.

This didn’t leave a lot of studies, and I had to accept some other flaws. 

Mental

Murray-Kolb and Beard (2007)

This study was by far the best study of cognitive function, maybe the only one that tested an intervention rather than merely looking at correlations. I don’t love it. The data presentation is obviously leaving a lot of information out, I assume to dramatize results. But those results are very dramatic. 

This study allowed for mild anemia (hb < 120 but >105), but separated anemic and non-anemic subjects. The paper, uh, doesn’t mention its threshold for iron deficiency; another paper from the same authors set it at serum ferritin <=12ug/L, which is in line with the aggregated averages.

The study included a double control group that started with sufficient iron and hemoglobin. Each group (no deficiency (n=42), iron deficiency without anemia (n=73), and iron deficiency with anemia (n=34)) was split into treatment and placebo groups. 

Iron supplementation increased ferritin levels in everyone. People with iron deficiency without anemia (IDNA) increased serum ferritin (sFt in the table) 2.5x more than their placebo group; people with iron deficiency and anemia (IDA) improved ferritin levels almost 4x more than their placebos. Neither group got anywhere close to the ferritin levels of the no-deficiencies group. The treatment group was given 160 mg of ferrous iron daily.

In baseline cognitive testing, IDNA women scored about the same or slightly worse as healthy women, and IDA women scored much worse than both. This is probably an underestimate of the effect, because the study was heavily recruited from students at a single university, who can be expected to be selected for the same range of competence.

The study separately evaluated treatment-group women who had increased ferritin levels from those who didn’t. The former group had large improvements in their cognitive test results, the latter very modest ones. I think separating out non-responders is fair: if there’s a problem interfering with iron absorption that doesn’t tell you anything about the effect of increasing ferritin levels, and I am studying this mostly for the benefit of people with insufficient dietary intake.

Among ferritin responders, attention, memory, and learning increased from .5 to .75 standard deviations (although somehow that .75 is at p<0.07). That effect size is the equivalent of 7.5-12.5 IQ points or 1.1-1.6 inches in height. Of course the test could be bullshit, but it’s not out of line with anecdotes I hear. Additionally, the treatment groups did not reach the ferritin levels of the healthy group, indicating potentially more gains to be had.

Hemoglobin responders also saw more improvement than non-responders, but the effect size was smaller than with ferritin, indicating an effect of iron beyond increasing hemoglobin.

(Note that the axis has changed from performance to time required, making negatives good. Yes, I am suspicious that they presented total score for one metric and time to completion for another).

Physical

Zhu and Haas (1998)

20 women with normal hemoglobin (Hb >120 g/l) but low ferritin (serum ferritin <= 16 ug/l) were given 135 mg ferrous iron supplements for eight weeks and instructed to take with citrus juice. 17 women were given placebos as a control (random assignment, double-blinded). They were given both blood and athletic tests before and after treatment.

Treatment group hemoglobin and iron binding capacity were unchanged. Serum ferritin was up 250% for the treatment group (compared to 30% for the control). Their athletic test results did not improve any faster than the controls, however they needed less energy (2.0kj/min) and oxygen (5%) to get those same results. 

Hinton et al (2000)

22 women with normal hemoglobin (Hb >12 g/dl) but low ferritin (serum ferritin <= 16 ug/l) were given 100mg ferrous iron supplements for six weeks. 20 women were given placebos as a control (random assignment, double-blinded). They were given both blood and athletic tests before and after treatment.

Iron supplementation did not change hemoglobin or iron binding capacity levels, but did increase serum ferritin by about 50%, and transferrin saturation by 70%. Note that their ending ferritin levels (19.4) were still barely above the bottom of the reference range, indicating there was probably much more room for growth. 

The control group went marginally up on some measurements and marginally down on others, I’ve treated their changes as noise.

Both treatment and placebo groups were given 4 weeks of exercise treatment; the treatment group showed about double the athletic improvement. Endurance saw a bigger improvement than initial performance.

Brownlie et all (2004)

~20 women, with serum ferritin concentration < 16 ug/L and a hemoglobin concentration > 120 g/L were given 100mg ferrous iron/day for 6 weeks. Of that, 4 weeks also included exercise training.

Once again we see an improvement in ferritin but not hemoglobin or binding capacity.

The treatment group experienced ~30% more improvement in their trial times than the control, or 800% if they started with elevated ferritin. I’m suspicious of this posthoc subgroup analysis, but on the other hand, the bar in this graph is very big.

Hinton and Sinclair (2006)

The good news: this study has men! I did not think I was going to find any of those!

The bad news: this study has 20 people, total.

No meaningful change in hemoglobin or binding capacity, near doubling of serum ferritin in the treatment group, 15% drop in ferritin in the control group. 

Results are basically identical for the control and placebo groups.

Prevalence Data

Estimates for the prevalence of iron deficiency vary a lot by study and population. 

In the first paper I found, the estimate was 9-22% among menstruating women in the general public, and 1-2% among adult men (non-menstruating women were not included but I expect “do you lose 2-4 tablespoons of blood every month?” and “do you occasionally host demanding parasites?” to be more important than hormones or gender identification). Note that this number includes both anemic and non-anemic iron deficiency. 

Vegans are at much more risk. One German study of vegan women found a median serum ferritin level of 14 ug/L, a level that is above their reference range and LabCorp’s but below the cut-off in several of the studies cited above. They found 40% of young women fell below their threshold for deficiency (12ng/ml) and 11% of older women (presumably mostly post-menopausal) did so. Women taking iron supplements were excluded from this study.

A second German study (why are they all from Germany?) that allowed supplements and had an even gender split found rates of iron deficiency slightly lower in vegans than omnivores, but both had higher means than anyone in any of the impact studies I found. Nonetheless, 10% of vegans were iron deficient.

My own study (data forthcoming) had 3-4 male vegans and a deficiency rate of 25%-75%, depending on how you count. 

Thank you Survival and Flourishing Fund for funding this research and Lightcone Infrastructure for providing a home for it.

Thanks to Andrew Rettek for help making my normally very in-the-weeds style more accessible.

Review of Examine.com’s vitamin write-ups

There are a lot of vitamins and other supplements in the world, way more than I have time to investigate. Examine.com has a pretty good reputation for its reports on vitamins and supplements. It would be extremely convenient for me if this reputation was merited. So I asked Martin Bernstoff to spot check some of their reports. 

We originally wanted a fairly thorough review of multiple Examine write-ups. Alas, Martin felt the press of grad school after two shallow reviews and had to step back. This is still enough to be useful so we wanted to share, but please keep in mind its limitations. And if you feel motivated to contribute checks of more articles, please reach out to me (elizabeth@acesounderglass.com).

My (Elizabeth’s) tentative conclusion is that it would take tens of hours to beat an Examine general write-up, but they are not complete in either their list of topics nor their investigation into individual topics. If a particular effect is important to you, you will still need to do your own research.

Photo credit DALL-E

Write-Ups

Vitamin B12

Claim: “The actual rate of deficiency [of B12] is quite variable and it isn’t fully known what it is, but elderly persons (above 65), vegetarians, or those with digestion or intestinal complications are almost always at a higher risk than otherwise healthy and omnivorous youth”

Verdict: True but not well cited. Their citation merely asserts that these groups have shortages rather than providing measurements, but Martin found a meta-analysis making the same claim for vegetarians (the only group he looked for).

Toxicology

Verdict: Very brief. Couldn’t find much on my own. Seems reasonable.

Claim: “Vitamin B12 can be measured in the blood by serum B12 concentrations, which is reproducible and reliable but may not accurately reflect bodily vitamin B12 stores (as low B12 concentrations in plasma or vitamin B12 deficiencies do not always coexist in a reliable manner[19][26][27]) with a predictive value being reported to be as low as 22%”

Verdict: True, the positive predictive value was 22%, but with a negative predictive value of 100% at the chosen threshold. But that’s only the numbers at one threshold. To know whether this is good or bad, we’d have to get numbers at different threshold (or, preferably, a ROC-AUC).

Claim: B12 supplements can improve depression

Examine reviews a handful of observational studies showing a correlation, but includes no RCTs.  This is in spite of there actually being RCTs like Koning et al. 2016 and a full meta analysis, neither of which find an effect. 

The lack of effect in RCTs is less damning than it sounds. I (Elizabeth) haven’t checked all of the studies, but the Koning study didn’t confine itself to subjects with low B12 and only tested serum B12 at baseline, not after treatment. So they have ruled out neither “low B12 can cause depression, but so do a lot of other things” nor “B12 can work but they used the wrong form”.

I still find it concerning that Examine didn’t even mention the RCTs, and I don’t have any reason to believe their correlational studies are any better. 

Interactions with pregnancy

Only one study on acute lymphoblastic leukemia. Seems a weird choice. Large meta-analyses exist for pre-term birth and low birth weight, likely much more important. Rogne et al. 2016.

Overall

They don’t seem to be saying much wrong but the write-up is not nearly as comprehensive as we had hoped. To give Examine its best shot, we decided the next vitamin should be on their best write-up. We tried asking Examine which article they are especially confident in. Unfortunately, whoever handles their public email address didn’t get the point after 3 emails, so Martin made his best guess. 

Vitamin D

Upper respiratory tract infections.

They summarize several studies but miss a very large RCT published in JAMA, the VIDARIS trial. All studies (including the VIDARIS trial) show no effect, so they might’ve considered the matter settled and stopped looking for more trials, which seems reasonable.

Claim: Vitamin D helps premenstrual syndrome

”Most studies have found a decrease in general symptoms when given to women with vitamin D deficiency, some finding notable reductions and some finding small reductions. It’s currently not known why studies differ, and more research is needed”

This summary seemed optimistic after Martin looked into the studies:

  • Abdollahi 2019:
    • No statistically significant differences between groups.
    • The authors highlight statistically significant decreases for a handful of symptoms in the Vitamin D group, but the decrease is similar in magnitude to placebo. Vitamin D and placebo both have 5 outcomes which were statistically significant.
  • Dadkhah 2016:
    • No statistically significant differences between treatment groups
  • Bahrami 2018:
    • No control group
  • Heidari 2019:
    • Marked differences between groups, but absolutely terrible reporting by the authors – they don’t even mention this difference in the abstract. This makes me (Martin) somewhat worried about the results – if they knew what they were doing, they’d focus the abstract on the difference in differences.:
  • Tartagni 2015:
    • Appears to show notable differences between groups, But terrible reporting. Tests change relative to baseline (?!), rather than differences in trends or differences in differences. 

In conclusion, only the poorest research finds effects – not a great indicator of a promising intervention. But Examine didn’t miss any obvious studies.

Claim: “There is some evidence that vitamin D may improve inflammation and clinical symptoms in COVID-19 patients, but this may not hold true with all dosing regimens. So far, a few studies have shown that high dosages for 8–14 days may work, but a single high dose isn’t likely to have the same benefit.”

The evidence Martin found seems to support their conclusions. They’re missing one relatively large, recent study (De Niet 2022). More importantly, all included studies are about hospital patients given vitamin D after admission, which are useless for determining if Vitamin D is a good preventative, especially because some forms of vitamin D take days to be turned into a useful form in the body. 

  • Murai 2021:
    • The regimen was a single, high dose at admission.
    • No statistically significant differences between groups, all the effect sizes are tiny or non-existent.
  • Sabico 2021:
    • Compares Vitamin D 5000 IU/daily to 1000 IU/daily in hospitalized patients.
    • In the Vitamin D group, they show faster
      • Time to recovery (6.2 ± 0.8 versus 9.1 ± 0.8; p = 0.039)
      • Time to restoration of taste (11.4 ± 1.0 versus 16.9 ± 1.7; p = 0.035)
        • The Kaplan-Meier Plot looks weird here, though. What happens on day 14?!
    • All symptom durations, except sore throat, were lower in the 5000 IU group:

All analyses were adjusted for age, BMI and type of D vitamin – which is a good thing, because it appears the 5000 IU group was healthier at baseline:

  • Castillo 2020:
    • Huge effect – half of the control group had to go to the ICU, whereas only one person in the intervention group did so (OR 0.02).
    • Nothing apparently wrong, but I’m still highly suspicious of the study:
      • An apparently well-done randomized pilot trial, early on, published in “The Journal of Steroid Biochemistry and Molecular Biology”. Very worrying that it isn’t published somewhere more prestigious.
      • They gave hydroxychloroquine as the “best available treatment”, even though there was no evidence of effect at the time of the study.
      • They call the study “double masked” – I hope this means double-blinded, because otherwise the study is close to worthless since their primary outcomes are based on doctor’s behavior.
      • The follow-up study is still recruiting.

Conclusion

I don’t know of a better comprehensive resource than Examine.com. It is alas still not comprehensive enough for important use cases, but still a useful shortcut for smaller problems.

Thanks to the FTX Regrant program for funding this post, and Martin for doing most of the work.

I Caught Covid And All I Got Was This Lousy Ambiguous Data

Tl;dr I tried to run an n of 1 study on niacin and covid, and it failed to confirm or disprove anything at all.

You may remember that back in October I published a very long post investigating a niacin-based treatment protocol for long covid. My overall conclusion was “seems promising but not a slam dunk; I expect more rigorous investigation to show nothing but we should definitely check”. 

Well recently I got covid and had run out of more productive things I was capable of doing, so decided to test the niacin theory. I learned nothing but it was a lot of effort and I deserve a blog post out of it null results are still results so I’m sharing anyway.

Background On Niacin

Niacin is a B-vitamin used in a ton of metabolic processes. If you’re really curious, I describe it in excruciating detail in the original post.

All B vitamins are water-soluble, and it is generaly believed that unless you take unbelievably stupid doses you will pee out any excess intake without noticing. It’s much harder to build up stores of water-soluble vitamins than fat vitamins, so you need a more regular supply.  Niacin is a little weird among the water-solubles in that it gives very obvious signs of overdose: called flush, the symptoms consist of itchy skin and feeling overheated. Large doses can lead to uncontrolled shaking, but why would you ever take that much, when it’s so easy to avoid?

People regularly report response patterns that sure look like their body has a store of niacin that can be depleted and refilled over time. A dose someone has been taking for weeks or months will suddenly start giving them flush, and if they don’t lower it the flush symptoms will get worse and worse. 

Some forms of niacin don’t produce flush. Open question if those offer the same benefits with no side effects, offer fewer benefits, or are completely useless.

Niacin And Long Covid

There’s an elaborate hypothesis about how covid depletes niacin (and downstream products), and this is a contributor to long covid. My full analysis is here. As of last year I hadn’t had covid (this is antibody test confirmed, I definitely didn’t have an asymptomatic case) but I did have lingering symptoms from my vaccine and not a lot else to try, so I gave the protocol a shot.

My experience was pretty consistent with the niacin-storage theory. I spent a long time at quite a high dose of the form of niacin the protocol recommends, nictonic acid. My peak dose without flush was at  least 250mg (1563% RDA) and maybe even 375mg (2345% RDA). When I hit my limit I lowered my dose until I started getting flush at the new dose, and eventually went off nicotnic acid entirely (although I restarted a B-vitamin that included 313% RDA of a different form). That ended in September or early October 2021. It made no difference in my lingering vaccine symptoms.

In early 2022 I tried nicotinic acid again. Even ¼ tablet (62.5mg, 390% RDA) gave me flush.

I Get Covid

Once I developed symptoms and had done all the more obviously useful things like getting Paxlovid, I decided it would be fun to test myself with niacin (and the rest of the supplement stack discussed in my post) and see if covid had any effect. So during my two weeks of illness and week of recovery I occasionally took nicotinic acid and recorded my results. Here’s the overall timeline:

  1. Day -2: am exposed to covid.
  2. Day 0: test positive on a cue test (a home test that uses genetic amplification).
    1. Lung capacity test: 470 (over 400 is considered health).
    2. Start Fluvamoxine and the vitamin cocktail, although I’m inconsistent with both the new and existing vitamins during the worst of the illness. Vitamin cocktail includes 313% RDA of no-flush niacin, but not nicotinic acid. 
  3. Day 1: symptomatic AF. 102.3 degree fever, awake only long enough to pee, refill my water, and make sure my O2 saturation isn’t going to kill me. I eat nothing the entire day.
    1. I monitored my O2 throughout this adventure but it never went into a dangerous zone so I’m leaving it out of the rest of the story.
  4. Day 2: start with 99 degree fever, end day with no fever. Start Paxlovid.
    1. Every day after this I am awake a little bit longer, eat a little bit more, and have a little more cognitive energy, although it takes a while to get back to normal. 
    2. Try ¼ tab nicotinic acid (62.5 mg/ 375% RDA), no flush.
    3. Lung capacity troughs at 350 (considered orange zone).
  5. Day 4: ½ tablet nictonic acid, mild flush.
  6. Day 7: lung capacity up to 450, it will continue to vary from 430-450 for the next two weeks before occasionally going higher.
  7. Day 9: ½ tablet nictonic acid, mild flush
  8. Day 10-17: ⅓ tablet nictonic acid, no flush
    1. Where by “⅓” tablet I mean “I bit off an amount of pill that was definitely >¼ and <½ and probably averaged to ~⅓ over time”
  9. Day 12: I test positive on a home antigen test
  10. Day 15: I test negative on a home antigen test (no tests in between) 
  11. Day 17: ⅓ tablet produces flush (and a second negative antigen test)
    1. This was also the first day I left my house. I had thought of myself as still prone to fatigue but ended up having a lot of energy once I got out of my house and have been pretty okay since.

Conclusions

My case of covid was about as bad as you get while still technically counting as mild. Assuming I went into it with niacin stores such that 62.5mg nicotinic acid would generate flush, it looks like covid immediately took a small bite out of them. Or it reduced my absorption of vitamins, such that the same oral dosage resulted in less niacin being taken in. There’s no way to know covid had a larger effect on niacin than other illnesses, because I don’t have any to compare it to. Or maybe the whole thing was an artifact of “not eating for two days, and then only barely, and being inconsistent with my vitamins for a week”.

Kencko Fruit Powder: Better Than Anything I’m Actually Going to do

UPDATE: As much as I love the concept of Kencko, if I drink them too fast they make me vomit, even when very diluted. I reluctantly withdraw my seal of approval.

 

Sometimes the modern economy really delivers.

As longtime readers know, I have two strikes against me when it comes to food: it requires both chewing and digesting. Chewing is painful for me due to nerve damage in my jaw. Digesting… well some of the problems with digestion are caused by insufficient stomach acid, but those are easily treated with a pill. I still have problems when I take the pills and no one knows why. So I eat a lot of things that require minimal chewing and are easy to digest. This set of things has very little overlap with the set of things my nutritionist wants me to eat, such as produce. I eat some fruits and veggies, especially in the summer, but not nearly enough.

Enter Kencko.

 

 

Kencko produces small packets of powderized fruits and vegetables. This requires no chewing and substantially less digestion. They taste fine. Not amazing, but fine. You could probably make them taste better by adding sugar or honey. Because they’re produced by freeze drying, they’re better nutritionally than other preserved fruit. Not as good as fresh, but, in the words of my nutritionist, “better than anything you’re actually going to do.” 

Nutritionists are hit-or-miss, so I double checked the nutrition claim myself. Based on a rushed review (primary source), I find that freeze drying has some nutritional loss, exact amount depending on the nutrient, but within the range that could conceivably counterbalanced by the increased digestibility of powder (this also means the sugar hits faster), and also the fact that I’m eating them at all. I suspect the biggest loss is the absence of probiotic flora in the sterilized powder packets.

There’s the issue of price. I was originally going to apologize for the price, chalk it up to convenience, and plead necessity for myself, but it turns out the packets are not that expensive relative to comparables. Ordered in the largest size, Kencko is $3.07/ounce. I spent 45 minutes finding prices for other freeze dried fruit powders, and that’s as good as you can do short of wholesale (spreadsheet). There are cheaper powders, but they’re inevitably something other than freeze-dried.

How about compared to actual fruit? It takes .44 lbs of fruit to produce one 20 g Kencko packet (price: $2.16-$3.30, depending on quantity ordered). According to this USDA report (chart on page 3), .5 lbs is $0.66-$0.90 cents worth of apples, $2.16 worth of blueberries, or $2.10-$2.85 worth of cherries. Note that those are advertised prices, so probably less than what you’d pay on average and certainly less than what you’d pay out of season, and for conventional produce rather than the organics Kencko uses. Kencko is definitely more expensive than in-season, on-sale produce, but not ridiculously so. Plus it never goes bad so you’re not paying for produce you throw away.

The worst thing I will say about Kencko is that their mixer bottle sucks. It mixes less well and is harder to clean than a Blender Bottle (affiliate link), buy one of those or use a spoon.

Obviously if you can just eat a vegetable you should do that. But if you find that untenable for some reason, Kencko is a reasonable way to turn money into consumed produce. This is an incredibly good trade for me and I’m really happy it exists.

[Kencko has not paid me for this post and I’m not in contact with them beyond ordering the product and following them on Twitter.]

Manganese

In summary: Manganese is an essential nutrient and too much will kill you.

On one hand we have people exposed to manganese is the air from industrial processes. These people definitely get Parkinson’s like symptoms, and in the aggregate score lower on various intellectual tasks. Monkey infants on soy formula (which has more manganese than milk based formulas) had mild neurological effects, so you can take in enough from food alone to be dangerous.

On the other hand, manganese superoxide dismutase is the only thing keeping your mitochondria from melting, and it does several other things besides. So we can’t just throw up our hands and say “no more manganese”, we have to actually figure out a safe level.

The World Health Organization has set the No Observed Adverse Effects Level at 11mg/day, based on the observation that some humans naturally get that much through their diet. As mentioned previously, we know you can get manganese poisoning through food alone, so this is not very reassuring to me.

The most comprehensive source I found on this was this thread on the soylent message boards (they cite several of the same things I did above, all correctly, so I trust their work ). According to their sources, most adults already eat enough Manganese to meet the RDA. I don’t want to put too much stock in the RDA, because neither I nor they could find out how the FDA (or the Linus Pauling Institute) set it. However even if you accept the number, if people are already getting it through diet, and too much is toxic, it doesn’t belong in a multivitamin.

This is worrisome enough to me that I’m tossing my multivitamin and focusing on getting individual missing nutrients through specific supplements (if anyone knows of a balanced B supplement, please let me know). It’s not so bad I’m tossing my protein/vitamin powder, because it has a lower volume of manganese and I don’t eat much at a time- however when it’s gone, I’ll probably switch to a straight protein powder.

 

Bone Broth

Bone broth is having its moment- paleo likes it, nut jobs who believe vaccines cause autism like it*, whoever the hell these people are like it, my nutritionist is a big fan.  The idea seems obvious- bones are full of nutrients that hard to get, especially in the typical American diet, surely drinking bones would be good.  Especially for calcium.  Everyone knows bones have calcium.

I got suspicious when I noticed that the nutritional label on my broth** reported 0% of my RDA of calcium.  I checked a few more brands, the top contender lists 2% calcium RDA and 4% iron/6 grams of protein.  Most list 0.  nutritiondata.self.com gives considerably better numbers, but no source.  Their listing contains a good deal more fat (9g, as opposed to 0 in any of the commercial broth I’ve found) and a non-zero amount of carbs.  None of the micronutrients they listed (vitamin C, a few Bs, iron, calcium, manganese) are fat soluble, but maybe there is something to preparing it at home.

Some of the websites touting bone broth list other substances that aren’t on nutritional labels but they believe are important.  I am well disposed to believe this claim.  There is no reason to believe science knows all the micronutrients we need, much less a USDA oriented towards the well being of farmers, not consumers.  The specifically mention glycosaminoglycans, a class protein/sugar hybrid found in joints.  This seems utterly plausible, but I was unable to find any numbers of this. At all.

I found one scientific paper on bone broth.  It is in Korean***.  It has some English but not enough for me to actually determine the micronutrient:protein ratio.  Beyond that you have studies about the components of bone broth and the assumption that it will be absorbed in this form.  For example this paper on collagen and rheumatoid arthritis (PDF).  Given it has 60 people and RA is a cyclic disease, their results are actually pretty good, but that still leaves it open to any number of manipulations.  The second best paper is a press relief on an informal study of chicken soup.

That leaves protein.  Everyone agrees bone broth has serious protein, but unfortunately not the most important kind.  Protein is made up of amino acids, of which there are two kinds: non-essential (which your body can manufacture) and essential (which you must take in via diet).  The RDA for protein is 0.8 g/kg body weight, of which 0.1 g should be of the essential amino acids (there are per-acid requirements but I’m not tracking 9 individual requirements), so 20% is putting  you ahead of the game, except that broth is missing two EAAs entirely.  After 20  hours of cooking (see korean) paper, 25% of the amino acids are glycine.  For comparison:

  • The pumpkin-based protein powder in front of me is 20% essential amino acids (and has way more iron than broth)
  • Whey protein is 60% EAAs.
  • Soy is 34%

I have trouble digesting protein and find bone broth stunningly easy to digest, so this is still a win for me, but it’s a slam dunk.

While traveling I’m using bone broth powder, which I’m increasingly convinced is a fancy way of saying “bone-based protein powder”.  I’m okay with bone based protein powder, although I might not have packed the pumpkin if I’d realized this.

Do you know what else is basically a protein powder?  Cricket flour.  They taste similar, cricket has a better amino acid profile (25% essential) and more trace nutrients (although I’m still tracking down how many more).  It is also cheaper, which should make !broth feel bad.

I find it more plausible than the average miracle food that bone broth has effects beyond what you’d expect from a naive read of the nutrition facts, because I expect animal bone + meat to fulfill a broader range of requirements than some berry.   I do feel better when I drink it, but a lifetime of digestive and chewing problems has given me a tendency to develop food security blankets, and broth is currently filling that role.   Simply by being a security blanket that is not jelly beans or peanut butter cups****, broth is a health food for me, personally, but I can’t really extrapolate beyond that. The current press around it appears to be almost entirely groundless.

Once again, the state of nutritional knowledge is embarrassingly bad and I would like us to shift money towards increasing it.  Also why the hell can’t I test the  nutritional content of broth I make myself?

 

*To their credit, they have an explanation that doesn’t rely on mercury, which has been extremely thoroughly disproven.  If they had presented it as a fringe thing they needed to prove, I would have entertained their hypothesis.  They presented it as fact, without any attempt to distances themselves from the atrocious denialism of the mercury-based anti-vaxxers.

**I buy it frozen on the theory that my time and not having my house continually smell of meat was worth the extra money.

***I don’t think this would be hard to determine if you read Korean, volunteers would be welcome.

****Trader Joe’s brand- I’m not an animal.

ETA: I only just learned that bone broth means “bones + connective tissue”.  Clean bones give you hardly any protein, even if there’s marrow in them.  Apparently I don’t need to pay $10/bag for store made stuff, I can use $8 worth of chicken feet and liver and eat for a week.

100% Food versus Soylent

I really, really wanted to like 100% food.  It has so much going for it- made of actual grown food, high protein variants, convenient portable single serve containers, shipping time measured in days rather than months… Unfortunately, it is inedible.

And if I’m saying inedible, it must be pretty bad.  I drink Soylent at room temperature, and for a long time didn’t bother mixing up the little protein clumps that formed (although once I realized how easy to clean my blender was, I did mix it).  As I write this I’m consuming my smoothie with a spoon because I put in too many chia seeds and it turned into a gel.  I cannot drink 100% food.  I ordered the six-variant mixer (chocolate/plain and regular/high protein/low carb), but I’ve only managed to try two (one low carb, one regular) and one of those was a mere pinch.  Extremely diluted the taste is tolerable, but still leaves this unbelievably gross oil aftertaste/film in your mouth.  I won’t drink it and you can’t make me.

The single serve containers were a disappointment too. There’s not enough room in them to really shake up the mix, so you end up with a lot of dry mix protected by a layer of wet mix.  So 100% food’s only real selling point is that it ships quickly.

I’m not 100% happy with Soylent.  I would really prefer fewer digestible carbs and more protein and fiber, but that’s addressable with some flax seeds and additional protein powder.  I would also love it if they shipped in < 3 months, and didn’t tell me they were going to ship a month before they did.  But it is better than starving to death, which is more than I can say for 100% food.