Not a causative finding in humans but darn interesting
Even if they did you'd have to run huge samples then do post testing necropsies to see which mice had AD which which didn't, then filter your data, then try to find results in what remains.
Otherwise you can inject the mice with a chemical known to cause AD, which is not reliable on it's own, so you can get genetically modified mice which express _some_ of the known plaques and misfolds that are associated with human AD.
Animal testing is still, largely, a very unethical and cruel affair. AD testing in mice is especially fraught with hazard.
> Since lithium has not yet been shown to be safe or effective in protecting against neurodegeneration in humans, Yankner emphasizes that people should not take lithium compounds on their own
I reject this kind of blind safetyism. A cursory search suggests that lithium orotate has been used for decades, and the article suggests that "profound effects" were seen at an "exquisitely low dose" which should be safe. They're going to need a much better explanation of why people shouldn't try it.
You said you searched to learn more about lithium, but somehow missed that it's highly recommended to be administered by doctors due to side effects after long term use. Anything that damages your kidneys or thyroids can kill you, so calling it "blind safetyism" is silly.
Most experts who have been recommending lithium supplementation to support general health recommend doses about 100 or 300 times lower.
The problem is that a subset of self-experimenters have the mindset "the more, the better" -- I still remember the Covid-era vitamin D discussions, with people openly reporting taking stupendous daily doses. (Lithium and vit. D are not in the same category, but you'll recognize the approach.)
So someone goes overboard, maybe damages their health, and traces it back to an article without the caveat. Lawsuit time! We're talking about fractions of a percent here, but with a wide enough potential readership you have a non-trivial chance of a hit. Common sense doesn't work at scale. Hence the CYA rhetoric.
It would be more useful and effective for the article to say “don’t do this to yourself because it can damage your guts, see these links, there’s tradeoffs here”
The former just fades into the modern world’s background noise of unchecked ass-covering.
The missing piece of this argument is just what the probability of different legal risks is here.
Wether or not their ass-covering is reasonable hinges on that and on their risk tolerance.
Drinking water is a good idea.
*check with your doctor if you are allergic to water, have a history of drowning, or are unable to distinguish water from ethanol. Do not consume water while intubated. People with rabies may have adverse reactions to water. Use caution when drinking water if you cannot swallow or are currently vomiting. Water from some sources may be contaminated. Salt water may contain jellyfish.
—-
My legal exposure from the initial statement went down with every little stupid disclaimer I added there, and there’s no penalty for each one. But you probably didn’t even read the full thing. We’ve created a culture of everyone feeling like they need to cover their ass, and the real important things get drowned out.
This is at a clinical dose which is somewhat high. It is the dosage fund reliable as treatment for bipolar type 1. As long as you get your kidney numbers checked twice a year, at that dose, its mostly unproblematic as issues show themselves in the numbers before major damage.
The error of the concerned 3rd party is particularly egregious with a disease like Alzheimer's, which presents a significant risk of ruin in the form of information death. It is totally rational to use an intervention that will cause you significant harm if it preserves your mind another few years.
I believe its also in the water supply in certain places, so if it works for dementia there are natural experiments already running on this.
https://www.psychiatrictimes.com/view/low-dose-lithium-a-new...
https://www.cambridge.org/core/journals/the-british-journal-...
I would think naturally occurring lithium in some people's water would give pretty good control conditions to do a wide study of this effect on Alzheimers as well?
Results
The literature search identified 415 articles; of these, 15 ecological studies were included in the synthesis. The random-effects meta-analysis showed a consistent protective (or inverse) association between lithium levels/concentration in publicly available drinking water and total (pooled β = −0.27, 95% CI −0.47 to −0.08; P = 0.006, I2 = 83.3%), male (pooled β = −0.26, 95% CI −0.56 to 0.03; P = 0.08, I2 = 91.9%) and female (pooled β = −0.13, 95% CI −0.24 to −0.02; P = 0.03, I2 = 28.5%) suicide mortality rates. A similar protective association was observed in the six studies included in the narrative synthesis, and subgroup meta-analyses based on the higher/lower suicide mortality rates and lithium levels/concentration.
These things are simple enough to advise the populace to use on their own. The government should never play nanny, ever.
I repeated this a couple more times with a repeatable outcome.
It’s very hyped in supplement communities with claims that it’s perfectly safe and side effect free. I didn’t get any kidney damage or anything, but I also didn’t get a positive benefit from it. Only subtle negatives that built up over a week.
A paper is not like a religious commandment or something. It's, best case, some mortals honestly trying to learn something. Scolding them for admitting the limits of their knowledge is not reasonable.
Having seen a few family members succumb to dementia, it's not a path I want to take. Fuck up my kidneys and give me an early death, fine, but if I start showing the signs of that type of mental decline, I'm taking the lithium orotate.
My related biggest concern about this is that since it's a cheap supplement that can't be patented, it won't be a priority for the drug industry to study. Another reason to not necessarily trust the "Just slowly die by Alzheimers until we find the perfectly safe (patentable) antidote" crowd.
Sure, maybe lithium orotate can be bad in high doses.
You know what's super-bad for sure? Alzheimer's!
If I have Alzheimer's, please let me try whatever long-shot you have. I'll be your gunnie pig.
You are free to try it, it's over the counter, no one is oppressing you here, Darwin is your friend.
It does reach a point of diminishing returns for me and I become too sedated. I now take it irregularly.
I like the idea but can only imagine the anti-flouride crowd would freak out.
Definitely not something to start pouring into the water supply.
Shit, that's my baseline. I'd pay for supplements that produced the opposite effect, even by placebo. In the meantime, I'll continue trying to Jedi mindtricking myself into caring, motivation, and productivity.
Clinical trials need many participants and take a long time, and they require a control group which doesn't take lithium orotate. Finding these people might be hard if everyone is taking it anyway.
Would you be willing to die of Alzheimer's in order to serve as a placebo for the control group? What about your parents?
I don't really understand this mindset.
I already ordered 5mg tablets of lithium orate as soon as I read this. I'll just add them to the handfuls of other supplements I take each day just in case they may protect against common degenerative ailments.
I very much adhere to the better safe than sorry or yolo approach to supplementation.
And if it actually makes Alzheimer's worse?
We are talking about a mouse model of a disease that very famously doesn't work the same way in mice and humans. The most likely scenario is it does nothing. With this level of evidence you might as well just eat random garbage off the ground in the off chance it helps.
https://pubmed.ncbi.nlm.nih.gov/31954065/
"Conclusion: Individuals with BD [Bi Polar Disorder] are at higher risk of dementia than both the general population or those with MDD. Lithium appears to reduce the risk of developing dementia in BD."
It's called evidence-based medicine and it's useful for answering questions such such as 'with taking Lithium prevent Alzheimer's by ensuring you die of kidney disease first.
Taking a bunch of unnecessary supplements isn't inherently "safe".
This by default means there must be a large supply of people not on it for a long period of time who will suffer and die from Alzheimer's instead of just taking the supplement. That was my issue. It seemed to call for the self sacrifice of many in order to allow for a long term study. But I think you already know that if you read my response and just chose to focus on a single sentence.
"Would you be willing to die of Alzheimer's in order to serve as a placebo for the control group? What about your parents?"
Since that is essentially what you are asking the people that would have ordered low dose lithium based on this article to do.
Although that means you avoided answering my question directly multiple times although I think you strongly alluded that the answer would be no in your last response.
I look at my life and those of my family as precious and more valuable than all other lives (their lives over mine). I expect others to operate in a similar manner and that is why I am always taken aback at posts that seem to advocate for the sacrifice of one's self for the benefit of strangers. This is different of course from in the moment actions such as running into a burning building to save someone or stepping up to protect a woman you have never met from an aggressive man.
Your response while vague appears to indicate that you would not sacrifice yourself for this experiment either. Which is what I would expect from everyone.
I understand your general advocation for the clinical study and I agree with the need overall but not at the cost of intentionally sacrificing oneself.
So I'll pop a low dose lithium tablet along with a baby aspirin each night and hope you do the same. Wishing you a long life my friend.
> Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice.
Another source on lithium orotate:
> LiOr is proposed to cross the blood–brain barrier and enter cells more readily than Li2CO3, which will theoretically allow for reduced dosage requirements and ameliorated toxicity concerns.
If cells in the brain are being deprived of lithium due to sequestration by amyloid beta plaques, then a bioavailable form of lithium that is resistant to sequestration may treat the pathology.
> We reasoned that the electrostatic interaction of the Li ion with Aβ deposits would be a function of the ionization capacity of the salt, and that Li salts with reduced ionization might show reduced amyloid sequestration. To assess ionization directly, we measured the conductivity of 16 lithium salts. Inorganic Li salts, including the clinical standard lithium carbonate (Li2CO3, hereafter LiC), showed significantly elevated conductivity, indicative of increased ionization, relative to organic Li salts (P = 8 × 10−4; Fig. 5a and Extended Data Fig. 7a). Of the organic Li salts, lithium orotate (C5H3LiN2O4, hereafter LiO) showed the lowest conductance across a broad Li concentration range (Fig. 5a and Extended Data Fig. 7a) and was therefore selected for further comparison with the clinical standard LiC.
From my not-exactly-expert understanding: lithium is a teeny tiny cation, and it can form compounds on a whole spectrum from ionic to covalent-ish. The authors are observing that lithium orotate does not fully dissociate in water.
The headline right now "Lithium Reverses Alzheimer's in Mice"
Those are two quite different statements. Someone should fix that.
Maybe if you took lithium carbonate after clearing the plaques then you would get a recovery. But if just taking lithium orotate instead comprehensively fixes the deficiency regardless of plaques, as it seemed to do in this study, then maybe we don't need to bother treating the plaques at all.
Can't wait for human trials!
I don't know why so many people differentiate between lithium orotate and the lithium carbonate in psychiatry. Although they differ in absorption the active component is the lithium ion in both cases. Dosage is done according to lithium content, there are tables for converting from orotate to carbonate and back.
Then the effects of lithium orotate and carbonate can't be that different. And thus, above a particular dose blood monitoring is mandatory.
There are benefits of low dose lithium for sure. And the dosages in psychiatry have been on a steady decline. With lower doses come less side effects. It is definitly not the hammer of psychiatry that turns people into zombies or messes. It feels quite natural.
In addition the reduction of Alzheimers cases is not unique to lithium. Many meds cause Alzheimers rates in mentally ill people to decline to general population levels.
I went to visit my aunt one day, and my favourite uncle couldn't recognize me. It made me think that Alzheimer's is probably the worst thing that could happen to a person. I mean, what's worse than not being able to recognize those closest to you? You work a lifetime, and then you go out in such an undignified manner.
I pray for a cure in my lifetime.
You won't even remember whether or not you had lunch. I met a grandma that was distraught that nobody was feeding her and she was hungry. Except she had had lunch already but couldn't remember. You forget where you live so if you get out of the house you can't get back. And many have 'sundowning', they get scared if they are outside and the night falls. It's not just the forgetting either, you start losing fundamental functions and eventually die. Not to mention the aggression and mood swings, which are aggravated if you try to point out that they are forgetting things.
It's a terrible disease. You cease to be you.
I've had relatives die of Alzheimer's, and others die from other causes. Let me assure you that there are worse fates than the one you describe.
Alzheimer's is slowly destroying the person, but this might in some cases be not as bad as diseases which leave the person in place but make them suffer intensely, e.g. from pain or depression. Though it's hard to compare.
Seems like a good real world example that should prove out if lithium works as we know people with BD take it.
Turns out there is a study that says there is.
https://pubmed.ncbi.nlm.nih.gov/31954065/
"Conclusion: Individuals with BD are at higher risk of dementia than both the general population or those with MDD. Lithium appears to reduce the risk of developing dementia in BD."
Overall people with Bi-Polar have a much higher rate of dementia but lithium treatment appears to reduce that.
People treated with valproate instead (a mood stabilizer) do not enjoy the same benefit.
So I'll commit to adding low dose lithium to my daily supplements
High-dose lithium is extremely hard on your kidneys and may well lead to kidney failure in a decade or so. Medium-dose lithium is a lot more gentle but still requires monitoring. Many people can go down in dose after initial treatment, and good psych prescribers will attempt to do this after a while. (Or patients will request it, after the other side effects of lithium become noticable after the bipolar has settled down.) Low-dose lithium is much harder to study and may well be pretty safe. May.
It is not quite true that people have no idea how it cures bipolar disorder. It's definitely affecting the ion channels (sodium, potassium, etc), just like many other anticonvulsant drugs also used for treating bipolar. So the mechanism for action is not totally insane and unique. Now, why the ion channels are the place to go for certain people, that's an open question....
As a matter of fact, lithium patients aren't much worse off when it comes to kidney function. Especially with modern levels of around 0.6 to 0.8 mmols.
Lithium has many modes of action, ion channels like you said, but also GSK3 function, BDNF changes and many more. It even changes the DNA methylation.
If you read a literature review for lithium's mechanism of action, it's a wild ride [0] that clearly demonstrates exactly how little we know. More importantly, though, is that all of this is made up ex post facto. Nobody can take a _new_ drug and tell you anything concrete about what it will do or how it will work: instead, we look at what happens and _then_ we make crude guesses. It is essentially modern miasma theory. For those who have forgotten, the application of miasma theory built our first sanitation systems, which eliminated more deaths from disease than the entirety of vaccines. That is to say: just because we are groping in the dark does not make the work useless, and indeed, our first vaccines were also constructed with very primitive methods.
I think that a more concrete understanding of the human body can only come when we start to understand all the many pathways of life in/on/around the body. Right now, our technology constrains us to investigate only individual points in mostly static ways. Give it a few decades of advancement and I bet we'll have some fascinating insights. I would also bet that, as with any complex system, there will be no simple answers to how things work.
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For what it's worth, in the specific case of lithium, the American Society of Health-System Pharmacists would agree with me that the mechanism of action is unknown: https://www.drugs.com/monograph/lithium.html
[0] https://link.springer.com/article/10.1007/s40263-013-0039-0
Lithium is one of a large class of drugs that modulate the chemical potentials of the body's voltage-gated ion channels. There are a lot of drugs in this class, and most have been used with at least some degree of success to treat bipolar disorder. This class is also first-line treatment for many forms of epilepsy. The GABA system is directly tied in here too, and GABAergic agents are generally considered part of this class... and, guess what, they often help in bipolar as well. Lithium is a unique member of this class, and it is completely obvious (to a biochemist) that adding another species of alkali metal in sufficient concentration will disrupt the chemical potentials of sodium and potassium ion transport in the ion channels.
My point is: the first-level effect of lithium is well understood, and it affects an area that is well known to be affected by other drugs that have similar effects. So it is not total voodoo. However, you are also very correct that our understanding starts to break down after this. We can come up with new ion channel modulating drugs, and can reasonably expect them to be effective candidates for helping bipolar patients. What we cannot do is predict other targets or classes of drugs that might be interesting. That is where our understanding breaks down.
Here is where we can both agree: we know a few things about the mechanism, which allow us to make some useful judgments in a few limited cases. We can also both agree that we know so little that, if a new, similar drug were proposed, with only a small change to its chemical structure, neither of us would dare make any confident statements about its action. We also cannot accurately predict what would happen if given to a patient with a well-studied but different disorder. In other words: most of the useful judgments about lithium - those that would be economically or socially interesting, for example - cannot be made from the model, because our understanding of the mechanism of action is too crude.
All of that is also, however, true about my hypothetical Corolla from my first example: we can say a few things, but most of the useful judgments that could be made from a full understanding cannot be made. It would be obvious to anyone that we do not understand the Corolla. So why, then, would we claim to understand lithium?
Personal theory: these things are like "global constants" for the brain's GPU. Somewhat similar to the temperature constant in an LLM. There is no real "explanation" for why they work, they just have an effect. Various chemicals have various effects, often depending on the patient (because other constants vary, training data varies...) and we pick the chemical we like the effect of most.
Also, to my knowledge, we are not entirely sure why most, if not all, of the psychiatric drugs work. Plenty of hypotheses though.