The Lithium Thread

[Guest]

...no I'm not talking about electric cars. But there have been some intriguing recent findings for taking lithium at clinical dosing to prevent dementia and maybe even lower mortality. Let's talk about that.

It all started quite a while ago with findings, that geographical areas in Asia, Europe and the US with higher lithium content in drinking water had a notably lower rate of suicide and a somewhat lower rate in all-cause mortality (i.e. not impressive at all). That was a curious finding, that lead people like Peter Attia or Michael Rae to supplement with that - it's nowadays actually fairly common in the "longevity" community to take a pill containing 5 mg of elemental lithium a day. That's above food/water intake in lithium rich areas. We gonna talk about dosing in a moment and I'm linking an informative video at the end of this post.

Researchers try to tease out the effect of lithium in cohort studies... because there is a group of people that take high dose lithium (900 mg up to 1800 mg lithium carbonate a day - that could be lethal dosing if you're no careful) for decades: folks with mood conditions such as bipolar disorder or severe depression. That's an obvious confounder - this population has a higher all-cause mortality. Not just by accidental deaths. Anything from cancer to cardiovascular disease - all related to sub-optimal lifestyle choices. They tend to eat more, exercise less, are heavier smokers and drug abusers. So take the following epidemiological studies with a big salt crystal, mined deep in the mountains of some alpine range.

A recent epidemiological study on dementia in lithium users found a 44% reduction in dementia comparing lithium users (that is: people affected by mood disorders) vs. the non-users in the general population - after adjusting for a common set of confounders:

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003941

This is essentially a follow up on a number of smaller or less sophisticated studies in the previous 20 years, finding lower levels of dementia in bipolar people using lithium vs. bipolar people using other kinds of medication. The recent result is interesting insofar, as mood disorders increase the risk of dementia. It's still not controlled study - and given the particularities of lithium users, there might some relevant confounders not covered in the common set of variables.

 

Curiously, a small randomized trial in people with mild cognitive impairment found a similar risk ratio. These folks didn't have mood disorders - but are at risk for Alzheimer's. Dosing ranged between 150 mg and 600 mg a day of lithium carbonate (18,8 mg of elemental lithium per 100 mg LiC), targeting a certain blood level. Substantially above "natural" exposure and common supplements - but also lower than therapeutic levels in mood disorders:

https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/clinical-and-biological-effects-of-longterm-lithium-treatment-in-older-adults-with-amnestic-mild-cognitive-impairment-randomised-clinical-trial/EF9931A98FFD7FA99F2202C19063EF77

As a result, there is a 47% reduction in progression from MCI to dementia - backed up by bio-markers for dementia and cognitive testing:

However - due to the small scale of the trial, the result wasn't quite statistical significant; a p-value of 0,06 instead of the commonly used metric of 0,05 or below. To resolve any doubts about that, a research group in Pittsburgh started a replication the trial - the LATTICE-trial - to achieve results to full statistical significance:

https://lldep.pitt.edu/projects-2/lattice/

The trial is probably going to publish it's main findings by the end of 2024.

 

Another very curious finding, and the immediate cause for this write up, is another epidemiological study published early this year (2023), based on data off the UK Biobank:

https://www.aging-us.com/article/204476/text

They are comparing people with mood-disorders using lithium alone or in combination with other drugs to mood-disorder affected people using other drugs, but not lithium. They create both sample groups with carefully matched demographic parameters - made possible by the over 500.000 participants in the UK Biobank. At the outset they're essentially the same - just differing in using lithium as a treatment or not. Follow-up time is 12 years.

The result is really stupid (meaning: almost unbelievable): a 72,6% reduction in all-cause mortality. After excluding any accidental deaths (as lithium is effective against suicide)and any early deaths. All causes of death seem to be heavily affected in favor of lithium, from cancer to cardiovascular. Now that's still not a controlled trial. That's still based on a general group with higher baseline-mortality. And unfortunately the authors are not calculating a direct mortality curve comparison between lithium users and the non-mood-disorder population in the database. Though examining the mortality curve for all mood-disorder affected people vs. non-affected people reveals, that the increase in mortality is not dramatic. So lithium using mood-disorder affected people almost certainly rank better for all-cause mortality than the general population.

Also, importantly, this is not the censoring effect of metformin. Metformin users in 2 important epidemiological studies performed ever so slightly better than non-users - despite the users being (pre-)diabetic. The problem: metformin is the first line drug for every early diabetic patient. And in these studies, every person adding another drug to metformin, because their diabetes got worse, was exluded from the group of metformin users (despite still taking metformin). So it compared only the self-selected best performing (pre-)diabetics who due to lifestyle changes didn't progress, with the general population. Best performing pre-Diabetics, that in addition got much more frequent medical check-ups than the general population.

Lithium is NOT a first line drug - because of the need for close monitoring of lithium levels. Also in this study ANY lithium intake counted as taking lithium - no censoring or self-selection of the sample.

 

Finally, it bears repeating that we are not talking about that weak-ass "longevity" lithium dosing of 5 mg a day in the recent studies just presented. To make that point and give a detailed insight into the different dosing regimens, I highly recommend this youtube video:

 

 

Now... I'm mostly doing this superficial summary to have a post that I can reference for my own purposes later. Nonetheless: let's discuss!

 

Edited May 17 by Guest
clarity

[IgorF]

Thanks for posting, I googled quickly the topic and it seems local media in my country of residence wrote about it in 2020 but somehow I missed it completely.

The idea is interesting but this:

Quote

The drug itself is also known to be nephrotoxic, opening up the possibility of spontaneous emergence of toxicity at doses that were previously well-tolerated.

made me a bit unhappy. This is a quot from wikipedia, I did not found quickly what does it mean - spontaneous but ordinary description of nephrotoxicity e.g. in https://d-nb.info/1239497113/34 looks a bit unpleasant. AFAIR kidney damage is the worst thing to have with almost any other usual comorbidity, with covid it acted as 3x modifier for the grim scenario. 

And another thing that is a bit questionable - here https://www.ncbi.nlm.nih.gov/books/NBK499992/ it is described that li will accumulate in many places (well, it destroys kidney structure of those, unhappy to be vulnerable to the intoxication mechanism) and the only countermeasure is hemodialisys which I suspect will not poll it out from all the unwanted places. So irreversibility of some intoxications is not a question rather a risk/gain ratio.

While this ratio for people at risk of dementia and other neurological disorders seems reasonable, for those not at risk (sadly it is not possible to assess it easily as doc on the video describes) maybe it could make sense to assess own li status (and do a thyroid pannel) and maybe raise own consumption to something like on the most li-soils studies produces.

I consume almost no local water so I am curious to do a serum test and think of getting some very low amounts probably..

Br,

Igor

[Guest]

Yes, as used in therapeutic dosing for mood-disorders - that is about 170 mg to 340 mg of elemental lithium per day - there is a requirement for regular monitoring for lithium levels and kidney blood parameters. Just to be clear: most people in this therapeutic range do not develop any problems with their kidneys. Nonetheless, it would be foolish to take such a high dose without close monitoring of blood parameters.

More interesting would be the question of sub-therapeutic dosing, such as in the small trial in patients with mild cognitive impairment - so 28 mg to 112 mg of elemental lithium per day. We know that the 5 mg of lithium typical used as a supplement is probably very safe, unless you are a special case. So what about 28 mg (sub-therapeutical) instead of 170 mg for bipolar disorder (Swanson's even offers 20 mg in pill as supplement)? Unfortunately I'm not able to find studies on side-effect for this "intermediate" dosing regimen.

 

However, so far it seems okay in term of effectiveness and side effects (provided regular monitoring of blood markers), compared to the alternative drugs - if the results are confirmed in the LATTICE trial. Because alternative drugs do not really work. Aducanumab is the only approved drug that showed some effectiveness:

https://www.nytimes.com/2021/06/07/health/aduhelm-fda-alzheimers-drug.html

 

There were 2 trials. One trial showed no effect. The other trial showed a delay in progression of 22% over 18 month; that is the intervention group takes about 22% more time to have the same level of Alzheimers progression (4 month over 18 month). Note: that's a different metric as the Alzheimer's conversion rate in the small lithium trial. The intervention group in lithium didn't reach the 13-month dementia conversion level of the placebo group even after 40 months (still being well above that level). In the same metric as in the Aducanumab trial that would be more than 200% delay in progression.

Also lithium isn't billed as 56.000 USD per year and doesn't cause brain swelling/bleeding (in unisono with headaches, nausea and fainting) as a side effect in 40% of the patients.

If I would be diagnosed with mild cognitive impairment, I sure as hell would try out lithium at 150 mg lithium carbonate (28 mg elemental lithium) and combination with some regular blood test. And provided that serious side effects are sufficiently rare, I would think about it even now.

 

Also note:

mood-disorder people taking therapeutic dosing had a 72% reduced all-cause mortality compared to carefully matched mood disorder people using different drugs, after 12 years of epidemiological observation. Just to put into perspective the dangers of a high dose regimen. At the very least that tells you how shitty the alternative drugs for mood disorder are. Of course, these lithium users have regular checks on their kidney function. That's a smart idea for any dose that goes substantially above the 5 mg supplement level.

Edited May 18 by Guest

[IgorF]

Well, I intuitively agree with the logic described and I will seriously think about my own strategy on this topic due to my age and possibility to go with really small dosing of it, the only one concern I have regarding long-term low dosage is based on this:

- the things that are doing something usually are doing something different also and in many cases it could be undesired, thus - the better the benefit of some artificial intervention drug the more careful we have to look in other areas. If I understand the mechanics behind li correct it is mainly connected to its size - it is 1+ ion significantly smaller then na and perhaps comparable with h3o+ when it is not tunneling proton over the membrane complexes - thus it will be a "key" to many molecular "locks" and even without studies it is easy to predict wide coverage of potential interactions with biological molecules

- tolerance. Probably it should not be generalized too wide but there is known effect of adaptation observed in biological systems to drug interventions in particular. It could be the case that neuroprotection effect will be ceased in those who will start with very low doses in the midage. To investigate it a more complicated study hardly possible to construct will be required and it will perhaps not come in the next decades

In any case, the benefits looks too attractive comparing to risks, so I think the only thing to be added for those under subclinical doses is TSH as a part of regular bloodwork, some doctors are selecting it as a cheap but sensitive thing to be  part of regular check for otherwise healthy people and with li it makes even more sense to keep an eye on it.

 

Edited May 19 by IgorF

[Guest]

Again - there is essentially no effective treatment for Alzheimer's and other types for dementia. The 2 new anti-body therapies would hardly count as effective for clinical outcomes in almost any other field of medicine.

And they demonstrate far worse side-effects than is documented for sub-therapeutic or low-range therapeutic dosing of lithium. In Alduhelm, side effects are almost a feature, with 40% of patients diagnosed with either brain bleeding or brain swelling. Serious lithium problems generally build-up over time, particularly with lower doses, and can be easily identified in bi-annually blood work. In addition there is data of patients using lithium for decades, and at up to 10 times higher dosing than the small placebo trial in lithium. They're doing fine in comparison - the drastically lower all-cause mortality compared to mood-disorder patients using other medications was also found in 2 studies on population data in Finland and Taiwan.

 

In fact, I'm puzzled about the lack of reporting about the favorable data situation regarding lithium and dementia. Even dedicated Alzheimer's advocacy societies hardly report about it (according to a google site-search of their webpages). None of the major English-language Alzheimer sites seem to report the small placebo trial. Most also don't report the recent epidemiological study of bipolar patients on lithium vs. general population. Instead some rat study from 2 years ago seems to be weirdly popular on alzheimer's webpages that report about lithium at all.

Which is all very odd, given the dire situation for any medical treatments for dementia. The anti-body trials easily receive 100 times that coverage - well, infinite for the dementia societies that don't report about lithium at all. Despite the overall data situation for lithium being much more promising. Importantly, there is no null finding.

So far:

- there is comprehensive population data from even 20 years ago showing much lower dementia in bipolar lithium users vs. bipolar non-lithium users

- an association for dementia and ground-water lithium levels in studies from Denmark and Texas; it's a pretty weak effect (not so much lithium) - but statistically significant

- the recent study comparing bipolar people on lithium with the general population in a UK-cohort (strong association in favor of lithium)

- 2 pre-clinical trials over 12 weeks and 15 weeks, showing favorable effects on dementia bio-markers

- 2 small placebo controlled trials over a couple of years; both showing much (really: MUCH) better effect than the 2 recent anti-body drugs; albeit not quite statistically significant

...and then there is the ongoing replication trial - LATTICE - powered to achieve full statistical significance.

 

Given the dire situation on the Alzheimer's/dementia front, you might assume that lithium would get some attention. Maybe not on Reddit or other social media. But at least among dedicated advocacy and research societies. Some of whom seem to not report it at all - in particular not the placebo controlled trials.

Edited May 20 by Guest

[IgorF]

Quote

Given the dire situation on the Alzheimer's/dementia front, you might assume that lithium would get some attention.

Perhaps antibody approach is more attractive because it is about something that could bring a lot of money, has no side-effects that are not detacheable from things with so "generic" power (lithium physical properties) and so on.

A life-long lithium researcher mentions this decline in lithium prescriptions in the last years:

https://www.sciencedirect.com/science/article/pii/S0304394022001471

Despite his own experience dealing with lithium he uses very accurate wording regarding AH and dementias:

https://inhn.org/inhn-projects/books/books/janusz-rybakowski-lithium-therapy-a-personal-tale-of-the-recent-decade

But he talks as a practitioner rather about treatments for better-established areas like bipolar disorder, so it could be the case that prevention with early start and lower doses could bring more benefits that attempt to use higher doses when the stage is advanced and too many things are broken. Actually antibodies solutions if I understand the things right are failing for the same reason - they are dealing with some consequences of a bigger "broken engine" when either interventions in other areas (not studied deep enough?) are needed or it is too late for such an approach, maybe similarly like with other known-to-be-breakable homeostasys body systems.

Also even if the idea about herpesviruses connection to dementias will not be confirmed anyhow I personally think it is very beneficial to have an additional suppressor for them, they are not co-evolved long enough with us thus their effects with age perhaps are more and more undesirable.

Br,

Igor

[IgorF]

Chased the danish study:

Quote

RESULTS A total of 73 731 patients with dementia and 733 653 controls (median age, 80.3
years; interquartile range, 74.9-84.6 years; 44 760 female [60.7%] and 28 971 male [39.3%])
were included in the study. Lithium exposure was statistically significantly different between
patients with a diagnosis of dementia (median, 11.5 μg/L; interquartile range, 6.5-14.9 μg/L)
and controls (median, 12.2 μg/L; interquartile range, 7.3-16.0 μg/L; P < .001). A nonlinear
association was observed. Compared with individuals exposed to 2.0 to 5.0 μg/L, the
incidence rate ratio (IRR) of dementia was decreased in those exposed to more than 15.0 μg/L
(IRR, 0.83; 95% CI, 0.81-0.85; P < .001) and 10.1 to 15.0 μg/L (IRR, 0.98; 95% CI, 0.96-1.01;
P = .17) and increased with 5.1 to 10.0 μg/L (IRR, 1.22; 95% CI, 1.19-1.25; P < .001). Similar
patterns were found with Alzheimer disease and vascular dementia as outcomes.
CONCLUSIONS AND RELEVANCE Long-term increased lithium exposure in drinking water may
be associated with a lower incidence of dementia in a nonlinear way; however, confounding
from other factors associated with municipality of residence cannot be excluded

Pairing it with a quote from book "Lithium and Cell Physiology" by "Ricardo O. Bach Vincent S. Gallicchio":

Quote

Another survey (31), which focused on lithium
water content, found a moderate correlation with cardiovascular mortality
without examining subpopulations by race or gender. In a third study based in
western Texas (32), similar results were obtained. While all of these studies used
water lithium as their index of population lithium exposure, none examined the
intake of lithium through foodstuffs-a source that is felt to provide up to 35
times more dietary lithium than water (33)

I tried to follow this "33. Livingston, H.D. (1970). Lithium depletion and atherosclerotic heart disease. Lan-
cet, 2, 99." and it is a letter, quotting:

Quote

SIR,-In his reply 1 to my letter 2 on this subject Dr.
Voors misquotes my figure for the average daily human
intake of lithium from food. My letter gives a figure of 0-7
mg. of lithium-not of lithium chloride. This implies a
normal lithium intake from food of not five or more times
but thirty-five times the amount from water intake in a
hard-water area with the highest water-lithium levels.

Well, it perhaps does not matter what exact figures are, but if the intake from food is reallly an order of magnitude higher than from drinking water (including washing the fruits-vegs perhaps) than it makes statistical significance mentioned in danish study not so attractive from ah perspective.

But it does not cancelling out the point that despite li is not proved to be neccessary it could be beneficial because it interacts with many places in our biology and we evolved in the environment where it definitely did it for millions of years, so artificial shift to depleted environment could be desirable to be fixed. But with care)

 

Br,

Igor

[IgorF]

From "Drinking Water Minerals and Mineral Balance" Ingegerd Rosborg, Springer 2015

Quote

Suggested Range Risk reducing Li range appears to be 0.05–0.2 mg/L.

From the 2019s version of study by Orestes V. Forlenza et al.

Quote

Another relevant methodological aspect is the therapeutic
window of lithium utilised in the trial. Lithium treatment was admi-
nistered at doses sufficient to yield serum levels of 0.25–0.5 mM/L.
This decision was taken for the sake of safety and tolerability, given
the high discontinuation rate in previous studies of lithium in
Alzheimer’s disease using therapeutic doses.11

0.2 mg/L -> 0.0288 mmol/l so the suggested by the book author's value in water is an order of magnitude lower than the minimum minimorum therapeutic value in serum used by dr Forlenza.

Here I can try to speculate on this (from "Lithium and Cell Physiology"):

Quote

It is quite apparent that in medical practice,
in order to achieve therapeutic action, the bodily systems are usually loaded close
to toxic levels. It is also known that lithium does not easily transgress the blood-
brain barrier and that the concentrations needed to bring the adrenergic/cholinergic
systems into equilibrium resembling "normalcy" are one order of magnitude lower
than the one created in the serum. If special vehicles could be designed that carry
the lithium ion to the sites of its designed action, one would not have to overload
the whole intracellular and intercellular systems with lithium near toxic levels.

+

Quote

It is interesting to note that the driving force established in inorganic sys-
tems by the voltage across the membranes of concentration cells bears little
resemblance to the transport phenomena in biological systems, where we often
observe ''uphill, against the gradient" migration.

Maybe this describes the requirement to "concentrate" "environmental" levels of li in the blood of patients, so it will fit into the narrow window where the uptake of li into the different cells will grow and it will outperform na/k/ca/mg and based on this it will change some pathways that will bring the effects.

 

It is also interesting that in the extension phase of dr. Forlenza's trial several people also decided to exit lithium after the first phase, it could be the case that they did not felt it worse continuation but that is just my speculation, I could easily be wrong with this.

Br,

Igor

Edited May 21 by IgorF

[Guest]

It seems Lithium can even be protective for the kidneys at sub-therapeutic dosing.

Researchers in a post-hoc study in humans found, that people taking therapeutic dosing of lithium for 20 years had somewhat better kidney function than bipolar folks using different medication (note: lithium is supposed to be the therapy that puts kidneys at risk - not the other way around)

https://news.utoledo.edu/index.php/04_11_2022/low-dose-lithium-may-slow-kidney-aging-utoledo-study-finds

https://www.jci.org/articles/view/141848

 

They also found, that mice treated with a dose-equivalent of about 1/3 the therapeutic dose in humans (so: sub-therapeutic as in the placebo dementia studies) had a substantially better preserved kidney function during aging. Just like humans, mice loose about 50% of their kidney function until old age. But much less so with an intermediate lithium dose, comparable to sub-therapeutic dosing in humans.

So it may be, that yes - lithium at therapeutic doses can cause toxicity in the kidneys for vulnerable patients, if used over years. At the same time it also exerts a protective effect. This protective effect might already be present at sub-therapeutic dosing, where the toxic effects are much less of a concern.

 

Edit:

To be extremely on point - that is NOT A FREE PASS to use sub-therapeutic lithium without any concerns. If you're taking 150 mg or 300 mg of Lithium carbonate you absolutely have to do blood tests for:

- lithium levels achieved

- kidney function

- thyroid function

Lithium DOES INTERACT WITH OTHER MEDICATION. In particular common stuff like blood pressure medication and pain killers. Therefore, if you start lithium, every doctor will tell you to MEASURE the parameters just mentioned one week after starting a new dose of lithium. And subsequently at least annually.

Edited May 22 by Guest

[mccoy]

I've had no time to contribute to this post so far but I'm going to start now, since it's a topic I'm interested into as well. The treatise 'Sthal's essential psychopharmacology' suggests basically that lithium is part of the compounds inhibiting the GSK-3 enzyme (Glycogen Synthase Kinase). Such enzimes are part of a cascade of signals triggering proapoptotic processes. Since lithium (and possibly other mood stabilizers as well, like valproate) inhibit apoptosis, this would boost neuroprotection and plasticity, besides stabilizing mood. My problem with such description is that apoptosis in our context is usually seen as a positive occurrence, a protection from malfunctioning cells, cancer and so on. I don't know why this is not the case in the CNS.

 

 

[mccoy]

[mccoy]

[mccoy]

Starting therapeutic dosages according to 'Stahl's prescriber's guide' are 300 mg Li2CO3 2-3 times a day, this corresponds to about 113 to 169 mg elemental lithium per day initially, doses by far larger than the microdose of 5 mg or the minidose of 28 mg per day hinted at in previous posts.

Always for therapeutic purposes, Li plasma levels are closely monitored, the adviced concentration is more for mania and less for depression, the maintenance range is usually 0.7 to 1.0 mEQ/L.

It seems that sub-subtherapeutic dosages are probably not going to impinge significantly on renal and thyroid functions, but caution would suggest to monitor the functionality of such organs (part of a routine checkup) and to ensure that plasma levels are well below 0.5 mEQ/L (a small addition to the basic checkup).

Again, lithium can be dangerous since toxic doses are not much higher than therapeutic doses. Mini doses should not constitute a problem but of course, always consult a specialist.

 

 

Edited June 14 by mccoy

[IgorF]

My lab reported me as <0.04 mmol/l with therapeutic window 0.6-1.2 and toxic as >1.5.

So my fruits and vegs (3+kg daily) are almost empty of it and even if the tap water could have it relatively high (I am lazy to call the lab and measure it since I am not drinking it) I am definitely far below the possible "biological expectation". So in my case some small supplement could be added for the daily routine without doubts, as well as doing eGFR checks regularly which is anyway one of the best thing to be done for anyone.

I think the way it could compete with other ions at least could have something like hormetic effect, as a disturbance that trains the subsystems to be fit. But that is offcourse just a speculation))

[mccoy]

It's interesting to notice, as the medical knowledge underlines, that therapeutic dosages are pretty close to the toxicity threshold, Stahl's prescribers guide reccomends a 1.0 to 1.5 mEq/L = mmol/L for mania. That's probably the main reason for frequent plasma concentration checks