Again I don’t know how to reconcile that with what you said before. Did you change your mind, or did I misunderstand you?
Benquo
Karma: 12,699
I don’t know how to reconcile that with your previous comment, which seemed to say that the expectation that people can explain and justify their public actions is antidemocratic and leads to kings.
That seems like Moldbug’s opinion, that participatory republics are fundamentally incapable of standards of behavior or problem-solving and therefore wanting standards pushes you inexorably kingwards, which I’ve argued against elsewhere.
I’m not aware of a clear hypothesis about what hazardous info Socrates might have had that would’ve caused that. It seems much more likely that partially organized and therefore dangerous people, moreso than empty shells of ambition, would actively seek out the fellow whom the Oracle at Delphi declared the wisest man in the world, and that his track record at dissuading them from doing crazy and dangerous things was much less than 100%.
I’d call that Jewish rather than proto-Christian. Christianity, at least in its canonical texts, moved away from this kind of insistence on legal accountability toward forgiveness and grace. The Hebrew Bible is much more interested in enforcing standards.
But more apropos here: What if there’s more to do here than take sides for or against Euthyphro? What if instead of deciding whether his moral feeling is correct, we’re curious about what’s going on procedurally?
I should mention here that I think the “improve sleep onset” dose of 3g just before bed is calibrated for NMDA receptor stimulation, not the improved ROS clearance etc that would improve sleep quality, for which 10g/day (ideally broken up into at least 2 doses with meals) seems like a good place to start. I see no strong reason not to try both, though. And if you want to see over a slightly longer period what 3g/night does instead, that seems like good data to have anyhow.
“Got to sleep quickly” is the main immediate easy to recognize benefit I’d expect from the 3g dose just before bed (unless, of course, you already usually got to sleep quickly).
I almost never have trouble getting to sleep; the glycine seems to improve the quality of sleep or reduce my need for it, which seems more likely to have to do with ROS clearance or possibly collagen repair than the NMDA signaling mechanism studied specifically for sleep onset.
What aspects of the post do you think it was a missed opportunity not to highlight?
Generally, as I understand it, the convention is for that sort of text to mean it’s 200 mg of magnesium, not 200 mg of the compound.
1.4g is more than a tenth of the typical shortfall and there’s a lot of heterogeneity, but also total magnesium need is often estimated at half a gram, so 200mg is a large percentage of that.
The issues should be fixed now.
Thanks for the independent check. I like the prompt you used and just used it to do an extra fact-checking pass of another draft post.
I too am more interested in the “treat the underlying cause, not the signal” thing that led directly to “glycine for reducing sleep need”, than the rabbit hole I went down about glycine and fever. I just thought the rabbit hole led somewhere productive (a much more detailed and therefore credible picture of glycine’s relation to sleep need), so I figured I’d share it; without that rabbit hole you just get my quoted comment, which I agree is more valuable word for word, but also isn’t the sort of thing that gets curated as a front-page post. (You could of course fix the incentive problem by curating my comment instead if the system allowed for that.)
To answer the question about motive: the story I told in this post is pretty much complete. I had recently started supplementing glycine for idiosyncratic metabolic reasons, but had no plans to write anything up until I got a crazy idea I decided to check out. In the course of checking it out I realized I had the material for an interesting article, so here it is!
By my count there are eight complaints in the Claude transcript you shared. I looked into all of them: three warrant corrections, two are plausible but wrong on closer inspection, and three are complaints where I can’t figure out what I should have done differently.
Corrections I’m making:
1. The 10-60g range conflates nutritional shortfall with pharmacological dosing. The 10g comes from Meléndez-Hevia et al. 2009, a metabolic flux analysis of what the body needs for normal function. The 60g is the dose used in schizophrenia trials targeting NMDA receptor modulation in the brain. Glycine is an obligatory co-agonist at NMDA receptors, and massive oral doses are needed to force enough across the blood-brain barrier to increase brain glycine levels. The schizophrenia application is fundamentally pharmacological, not supraphysiological compensation for unusual glycine need. I think the sourcing footnote itself is not misleading, but summarizing this in the body text as “Estimated total requirements” collapses an important distinction. I’ll think about how to fix that.
2. The pyroptosis description overstates macrophage integrity. “The macrophage can do its job without self-destructing” is too strong. The cell still dies. Pores still form in the membrane and the cell loses membrane potential. Glycine prevents the final membrane rupture that releases inflammatory contents into surrounding tissue, but the macrophage doesn’t survive. The inflammatory damage is deferred, not eliminated, which can still matter in acute infection, but the essay implies the macrophage walks away intact.
3. The essay says “macrophages have glycine-sensitive chloride channels” without specifying which macrophage populations. The anti-inflammatory chloride channel pathway (GlyR) operates in peripheral macrophages (Kupffer cells, alveolar macrophages) responding to infection and endotoxin. But Hendriks et al. 2010 found that microglia, macrophages that live exclusively in the brain, respond to glycine pro-inflammatorily via a mechanism that is not mediated by GlyR. Although microglia express GlyR subunit mRNA, Hendriks found that the immunomodulatory effect was GlyR-independent and instead operated through neutral amino acid transporters (NAATs), which aren’t even glycine-specific. NAATs respond to alanine, serine, glutamine, proline, and other small neutral amino acids. So the microglia aren’t responding to glycine per se; they’re responding to free amino acids, which the blood-brain barrier works hard to keep out. (That’s why schizophrenia treatment has to use oral glycine doses as high as 60g to force enough glycine into the brain to do anything interesting.)
The essay’s argument about infection and inflammation holds for the peripheral macrophages it’s actually about, but the prose needs to specify that rather than saying “macrophages” unqualified.
Criticisms that are plausible but wrong:
4. Glycine vs cysteine as glutathione bottleneck. The fact-check complains this “oversimplifies a contested area where cysteine is traditionally considered the primary rate-limiting substrate” and asks why the post focuses more on glycine than cysteine.
The post focuses on glycine because it’s about glycine. It’s investigating a specific question (“is fever a symptom of glycine deficiency?”), not writing a comprehensive guide to glutathione precursors. The essay says explicitly that it’s “not comprehensive nutritional advice” and immediately goes on to illustrate that by flagging cysteine as the other glutathione bottleneck, noting that people with limited cysteine intake or elevated need for it may benefit from supplementing NAC. That’s the essay doing exactly what you’d want it to do: acknowledging the limitation of its own scope and pointing readers toward what it isn’t covering, rather than pretending cysteine doesn’t matter.
As to why I personally am more interested in glycine right now, my reasons are:
I already knew about NAC for preventing respiratory tract infections or recovering from them faster.
I recently started supplementing glycine based partly on idiosyncratic metabolic defects that likely mildly to moderately impair my glycine synthesis, and partly based on estimates that typical Westerners could use more anyway, and got surprisingly-to-me strong almost immediate apparent benefits (though it’ll be clearer in a year whether this is real or just coincidence).
The estimates that typical Westerners could use more anyway persuaded me that glycine’s benefits might be of particular relevance to a general audience, while my impression (as discussed in the linked comment thread) is that people who get enough animal protein generally get enough cysteine for when they’re not sick or injured.
On oversimplification, the essay says “in many contexts, glycine is the bottleneck.” The counterargument offered is that in many cases cysteine is the bottleneck. Yes.
Your fact-check turned up some evidence for glycine specifically that I hadn’t referenced in the post. Glutathione is made in two steps: glutamate-cysteine ligase (GCL) combines glutamate and cysteine, then glutathione synthase adds glycine. Each enzyme-substrate pairing has a Km, the concentration at which the reaction runs at half its maximum speed, and below which its output becomes increasingly sensitive to how much of that substrate is available. Glutathione synthase’s Km for glycine is about 900 µM (Luo et al. 2000), while red blood cell glycine concentrations have been measured at 218-529 µM (Kumar et al. 2023) — near or below the Km, suggesting that glycine availability can materially influence glutathione synthesis rates. Glutamate is typically well above GCL’s Km (Lu 2013). Cysteine varies more, ranging from near to well above its Km (Lu 2013).
5. Gersovitz 45g/day vs Meléndez-Hevia 3g/day. The fact-check flags this as a discrepancy that “complicates the deficit narrative.” They’re measuring different things.
Gersovitz’s ~44g/day and Meléndez-Hevia’s ~3g/day are not in conflict. Gersovitz measured glycine appearing from all biosynthetic sources. Much of that 44g is glycine being converted to serine and back; it shows up in the flux measurement but doesn’t add net new glycine to the pool. Meléndez-Hevia measured net new glycine created via that same enzyme (serine hydroxymethyltransferase): about 3g/day. Comparing dietary glycine and new glycine production with irreversible consumption and loss from collagen turnover, Meléndez-Hevia estimates a glycine deficit of about 10g/day.
Complaints where I can’t figure out what I should have done differently:
6. O’Hearn paper status. The fact-check says I should have flagged that O’Hearn is an independent researcher publishing a review rather than original experimental work. The essay describes it as synthesizing evidence, which is what reviews do. The fact-check seems to think “paper” implies “original experiment by someone at an institution,” but I don’t.
As for “independent researcher,” in case that’s a complaint about qualifications and credentials, I’ll note that the paper was published in a peer-reviewed academic journal.
7. The 127-volunteer infection study. The fact-check acknowledges “the study exists and the post’s description is accurate,” then says it’s “very weak, even beyond what the post acknowledges,” complaining that the essay doesn’t mention that the study involves self-selected groups, self-reported outcomes, and no viral confirmation.
The post’s characterization of the study explicitly tags the unrandomized and unblinded nature of the study, advises the reader to take it with a grain of salt, and says “the control group reported no change in infection frequency,” which would seem to suggest self-reporting, and would seem to preclude formal viral confirmation.
This seems to me like an appropriate level of detail on the flaws of a study invoked as illustrative, not load-bearing. Should I really have spent extra words on the fact that the specific form of selection bias the study failed to prevent via randomization was self-selection?
8. Rabbit ICV glycine. The fact-check notes this is intracerebroventricular injection and questions its relevance to dietary supplementation. But the essay already says “glycine injected directly into the brain’s fluid-filled cavities.”
More importantly, the rabbit study is not presented in support of the primary argument, but to flag a potential confounder of the essay’s proposed experimental test.
5g in AM, 5g in PM, rounding up a bit. When I’m sick, double the dose plus 1⁄4 tsp NAC powder. in AM and PM.
Colds immediately got noticeably shorter and milder and moderate sleep loss just didn’t bother me that much, you might say I had much more sleep credit to spend.
Shorter sleep periods and longer wake periods with no new health, mood, energy, or cognitive problems, or improved recovery from stressors like exercise, infection, or injury with no longer sleep periods.
That’s … a stronger effect than I expected. Whoa.
It’s 33% of the amino acids in collagen counting amino acids. It’s less if you count them by weight/mass as glycine is lighter than other amino acids.
This was a mistake on my part and I’ll correct the article.
Masterjohn’s lower bound of 10g matches Meléndez-Hevia et al. 2009, which explicitly accounts for glycine recycling, while 60g is the highest dose used in schizophrenia treatment. He didn’t cite sources in the linked piece, though, so I’ll add a footnote with the sourcing I could find.
I haven’t been able to find evidence that typical oral supplement doses of NAC meaningfully reduce hypertrophy. I did find one paper reporting that an NAC infusion can blunt some ROS signaling after exercise, and a 2017 meta-analysis found no benefits from NAC supplementation on exercise performance, but I can’t find evidence of harm at oral doses.
I still endorse the very limited recommendation I made that people with specific reason to think they have elevated need or meaningfully limited supply of cysteine “may benefit” from the supplement.
The 1971 GRAS rescission was a precautionary regulatory action during a broad FDA review of GRAS substances. The regulation (21 CFR 170.50) cites unspecified animal studies at “high levels” and concern about increasing industrial use of glycine as a food additive.
I did not rely on glycine’s historical GRAS status in the first place, and I don’t think it’s reasonable to ask me to put words in the FDA’s mouth about why glycine was shifted from one category of permissible food ingredients to another category of permissible food ingredients in order to argue with them.
I have not been able to identify which pre-1971 studies the FDA was referring to, and neither apparently have subsequent reviewers. The rescission did not amount to an across-the-board ban; glycine is currently permitted for certain food uses under later regulations (21 CFR 172.320).
The most plausibly concerning animal finding I’ve found is a 1994 carcinogenicity study (Kitahori et al.) that found renal papillae necrosis in Fischer 344 rats given 2.5% or 5.0% glycine in drinking water for 108 weeks. Those concentrations work out to roughly 6-12 g/kg/day in rats, which scales to roughly 70-150g/day in a human. Fischer 344 rats are known for high rates of spontaneous chronic progressive nephropathy, a renal disease with no strict human counterpart, which complicates interpretation of renal findings in this strain. A follow-up study by the same group (Kitamura et al. 1996) found that glycine at 5% did not promote chemically initiated urinary lesions, while sodium aspartate did, suggesting the original renal findings may have been about chronic osmotic or pH stress from very concentrated solutions rather than glycine toxicity per se. The authors of a later 2013 study (Shibui et al.) reached the same interpretation.
That 2013 study, specifically designed to establish a toxicity threshold, found no adverse effects at the maximum tested dose of 2 g/kg/day (scaling to ~23g/day in humans). Human schizophrenia trials have used 30-60g/day for weeks to months; the main reported side effects are gastrointestinal.
While you’re sorting out the peptide formulation, here are two experiments you could try in the interim:
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Figure out what dosage of sleep deprivation sends a clear statistical signal over what time period in what metrics. Without this, it doesn’t matter how good the rest of your protocol is.
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Test whether glycine + NAC reduces rebound sleep need after your deprivation nights. Same design (except for whatever changes are implied by the results to 1), but instead of orexin, take 15g glycine (5g with breakfast, 5g with dinner, 5g before bed) + 600mg NAC with dinner.
The rationale for 2: A key function of sleep appears to be clearing reactive oxygen species that accumulate during wakefulness, and glycine is rate-limiting for glutathione, the main antioxidant that does that clearing. Most people on modern diets are substantially glycine-deficient. If the bottleneck on recovery from sleep deprivation is partly substrate availability for ROS clearance, then supplying the substrates should make shortened sleep more efficient, which is the thing you actually want orexin to do. It would then be interesting to see how this compares with orexin alone, or all three together.
I wrote this up in more detail here. Glycine powder is ~$0.03/g with no stability or delivery concerns, and NAC is cheap too, so the cost is basically your time.
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It’s always gratifying to learn that the information I offered helped someone orient, and especially gratifying to get that validation so quickly. Please let me know what you find out.
I don’t know how much we disagree here. A lot of people use accountability as a euphemism for punishment, but I literally just mean accountability. I agree that moral competence is the core issue, although I think Plato was either naïve or self-censoring about the causes of moral incompetence. His description of tyranny as coordination around transgressiveness comes close, though.