A primer on Lithium, Lithium + Rapamycin, etc. potentially more stable and safer pharmacokinetics

[tongMD]

Seems like a few people here (ie @desertshores) take Lithium orotate as there is some suggestive evidence in animal models that it may extend lifespan when taken with rapamycin, while also reversing dyslipidemia from rapamycin.

I wonder if anyone has any blood work showing this in humans. If so, please do share dosing and bloodwork!

For those who are not very familiar, I suppose I can do a quick introduction on lithium from my second look at the combination and what lithium does:

Potential effects with rapamycin

This PNAS study found large synergistic effects of lithium, trametinib, and rapamycin in a fly model:

https://www.pnas.org/doi/10.1073/pnas.1913212116

The study noted given the complex nature of the aging process, it is extremely unlikely that the most effective “antiaging” therapy could be achieved by a single compound with a single target, as almost every other “antiaging” researcher has suggested. This study showed non-additive effects on lifespan with combination therapy being significantly greater than when taken separately. Essentially, “1+1=3” and “1+1+1=5”. Not only that, fertility was preserved.

Dosing in animals
Low doses of lithium extended lifespan in flies, but high doses shortened lifespan: Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis - PubMed

MOA related to anti-aging
Lithium has multiple possible targets and I will not go through every single one of them - just the relevant ones for anti-aging. It appears that micro-dose Lithium may induce mitohormesis and xenobiotic detoxification via the GSK-3 and NRF2 pathway. GSK-3 regulates the Wnt/B-catenin pathway. Lithium may increase stem cell activity and increase the transport of Vit B12 and folate. Lithium may also increase autophagy and mitochondria. However, some of these effects are not proven in humans. In humans, it appears to increase neurogenesis and neuroprotective factors, and increase cortical gray matter, white matter, and limbic structures (ie hippocampus, thalamus, amygdala) from MRIs of bipolar patients.

MOA in bipolar disorder/mania:
GSK-3 and inositol monophosphatase (inositol depletion hypothesis) are the proposed direct targets of lithium action in the CNS for bipolar disorder. The other proposed MOAs include: stimulating inhibitory neurotransmission and inhibiting excitatory transmission, inhibiting overactive PKC intracellular signaling, modulation of norepinephrine/dopamine/serotonin/GABA, and modulation of abnormal Ca activity at NMDA receptor.

Pharmacogenetics
In a GWAS for bipolar disorder patients, 4 linked SNPs on chromosome 21 met genome-wide significance criteria for an association to monotherapy lithium response in a large sample size.

Genetic variants associated with response to lithium treatment in bipolar...

Animal studies
Model organisms have revealed IMPA as a mediator of improved synaptic function in response to lithium. GSK-3 appears to be a conserved mediator of lithium action, required for increased longevity, improved cognition, and prevention of Alzheimer’s disease pathology across worm, fly, and mice models of neurodegeneration. Lithium chloride was shown to repress abdominal aortic aneurysm in rats via regulating the GSK3β/SIRT1/NF-κB signaling pathway: Lithium chloride represses abdominal aortic aneurysm via regulating GSK3β/SIRT1/NF-κB signaling pathway - PubMed

Humans studies
There is also a lower incidence of dementia in human patients with bipolar disorder and suggestive evidence from a very small study for lower dementia progression in human AD patients with low dose lithium (0.3 mg/day): Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease - PubMed

Safety studies
From my understanding, >5 mg lithium intake has not been tested for safety. There are observational studies that go up to 3 mg per day in drinking water. There are a lot of possible drug-drug interactions with lithium and doses can increase manyfold. Especially in older people, those with low salt intake, kidney impairments, and/or dehydration. There are plenty of interacting drugs, including but not limited to - NSAIDs, ACEi, and antibiotics. This letter implied that >5 mg of lithium orotate could be potentially unsafe:

Possible dangers of a "nutritional supplement" lithium orotate - PubMed

Here is one case report of lithium toxicity in supplemental lithium orotate 18 tablets of “3.83 mg of elemental lithium per 100 mg of (organic) lithium orotate” compared to “18.8 mg of elemental lithium per 100 mg of (inorganic) lithium carbonate” used in bipolar

Lithium toxicity from an internet dietary supplement

Pharmacokinetics
The half-life of lithium is ~24 hrs. It takes at least 4-5d for serum lithium concentrations to reach a steady state after dosing is changed. Fingerstick tests of lithium levels are available for 12-hr serum trough levels.

Lithium orotate appears to be similar pharmacokinetics relative to Lithium carbonate: Lithium orotate, carbonate and chloride: pharmacokinetics, polyuria in rats - PubMed

To mitigate some effects of high doses especially since lithium has a very narrow therapeutic window in bipolar disorder - this study tested lithium salicylate and lithium lactate with very different results - very steady with lithium salicylate in both plasma and brain over 48 hrs, as opposed to lithium orotate which spikes:

For comparison, Lithium carbonate (Lithium orotate is probably similar) in different people:

Plasma and Brain Pharmacokinetics of Previously Unexplored Lithium Salts

[RapAdmin]

Yes - I take 5mg of lithium orotate on a fairly regular basis. Your coverage of potential benefits of lithium salicylate is interesting - but it doesn’t seem to be something that is easily available, at least on Amazon (as lithium orotate is).

Last year a study came out that put a bit of a damper on the speculation around lithium and aging, as can be seen here:

Lithium can mildly increase health during ageing but not lifespan in mice

https://onlinelibrary.wiley.com/doi/10.1111/acel.13479?fbclid=IwAR3-CynxoaV5z3E-KKlsPwZIytMx9Nj0cYeYPKg-XIUCaNVVQPx3sf7QepI

Still, I think 5mg of Lithium Orotate is a reasonable bet, and I’ve not noticed much positive or negative while taking it. I’ve not done any rigorous pre/post blood testing, that might reveal blood lipid benefits, etc.

There was a recent story on this topic of microdosing lithium:

Lithium: The Next Trend in Microdosing?

The Alzheimers Drug Discover Foundation did a good summary on the compound back in 2016, but it hasn’t been updated since:

Lithium-microdose-Cognitive-Vitality-For-Researchers.pdf

[desertshores]

As I have previously posted I have been taking lithium orotate since the late 80s or early 90s, can’t really remember. The brand I am taking claims to deliver 5mg elemental lithium per tablet.
I take 3 tablets daily.

I was taking it for “anger management” issues I was having while driving in Germany, at least my wife thought so,. I really do believe it reduces quickness to anger and dramatic mood swings.

So, I have been taking it with rapamycin since early November 2021.
I did notice my lipid levels increase after I started taking rapamycin.

Seems relatively safe, at least for me.

A toxicological evaluation of lithium orotate
“Lithium orotate, the salt of lithium and orotic acid, has been marketed for decades as a supplemental source of lithium with few recorded adverse events”

A toxicological evaluation of lithium orotate - PubMed

[tongMD]

There is just a whole lot of variability with Lithium levels as noted in bipolar patient populations, even when dosed carefully such that ER visits are common.

Now of course you are taking a much, much lower dose than bipolar patients (300 mg?), so the relative safety will likely be much higher. But just pointing out that there is no guarantee that this will apply to everyone (there is plenty of genetic variabilities) or that it will be safe, not to mention - a lot of possible drug-drug interactions - adding a new supplement or drug can increase the risk of bipolar patients going to the ED by 30x.

Did you check lithium levels via low-cost fingerprick and lipid panels with and without rapamycin? Have you noticed effects at lower doses? Would be curious if you can share.

If you also have any lab work with Urinalysis, eGFR / Creatinine / blood urea nitrogen, thyroid / TSH, and parathyroid / calcium function. Even ECG would be nice before and after.

[tongMD]

Interesting - great share - I missed that one.

It does seem to support some extra healthspan in male mice specifically with some clues to MOA corroborating other mice studies i.e. suggestive of prevention of renal inflammation and delayed age-related loss of glucose tolerance via GSK-3 inhibition and proteostasis. The GSK-3beta hippocampal data is in agreement with previous mice studies. The rotarod performance was increased which could be suggestive of neuroprotective effects, but the fat loss sort of threw it off.

They didn’t really check everything associated with other mice studies - there was anti-neuroinflammatory via NFKB from GSK-3 inhibition, reduced oxidative stress via NRF2, proteostasis via IMPA inhibition induced autophagy, neurogenesis via CREB/BDNF and Wnt.

I’d also note for context - mice tend to die of cancer especially based on their stated 20 C protocol (normally at ~30 C, so this is really cold for them) - not only that - the strain used is sensitive to cold conditions. This is important because they get cancer, but are less likely to die from CVD (see Lithium and GSK-3/Wnt). It might throw off lifespan results.

Mice also tend to lack external stress/lower ROS generation in those lab conditions (see Lithium and NRF2) while specifically, that strain doesn’t really have decent induction for NRF2. Mice also don’t get AD - so it’s kind of hard to say what to make of the human studies that suggest slowing of dementia.

[desertshores]

Unfortunately, don’t have any before and after data to share. Because of Covid shot reactions, variable rapamycin, and a mild case of Covid. My blood work has been all over the place for the last two years. Also, factoring in other changes in my supplements I don’t think I have anything meaningful to share. These are some of my most recent results from 07/21/22

[tongMD]

Ah no worries, that’s still helpful.

I’d be interested to look at a fingerprick test for Li, say 1-2 hours after taking it if you happen to have a convenient option nearby.

It’s pretty low cost (~$12) though if you happen to be interested too:

https://www.mdsave.com/amp/procedures/lithium/d583f9c8

[desertshores]

I just uploaded the thyroid panel. In the interest of science, I will look into lithium tests.

[desertshores]

Quest Diagnostics has the test. It is $38, I will get it tested next time it is convenient, probably towards the end of the month.

[RapAdmin]

Peter’s thoughts on lithium supplementation (AMA #3)

Peter's thoughts on lithium supplementation (AMA #3)

[L_H]

Lithium treatment extends human lifespan: findings from the UK Biobank - PubMed

Interesting uk biobank data showing a 3.6 times reduction in mortality rates for those on lithium vs other antipsychotics.

Obviously not conclusive research but highly encouraging

[RapAdmin]

@DrM noted in this other post in a different thread on Lithium, about this study the following

"I have to put on my Psychiatrist hat here and just mention that; 1. These are individuals with serious mental health conditions, and those conditions carry an increased probability of having a metabolic syndrome (increased lipids, obesity, etc.) (even if these individuals are untreated). 2. The “Other antipsychotic drug users” are likely on what we call “typical or atypical antipsychotics (risperidone, olanzapine, etc.),” which carry a markedly increased likelihood of metabolic syndrome and early death.
Lithium, by itself, for bipolar disorder, does not typically increase the risk of metabolic syndrome. So, in summary, I am saying that showing an increased lifespan in these subjects only on lithium compared to subjects taking typical or atypical antipsychotics cannot necessarily be generalized to adult subjects without one of these psychiatric conditions, if that makes sense.

[Kandice]

This article has some good information on lithium. NOVOS includes 1mg of lithium in one of their products.

What’s the best low-dose (microdosed) lithium supplement? Why does NOVOS...

[DeStrider]

I think that the biggest argument for micro-dosed lithium is that it improves your mood and therefore probably reduces stress levels. It is definitely beneficial for healthspan. If you get some extra lifespan mixed in there, then that’s a bonus. Remember, less stress is shown to lead to increased longevity.

[teadrinker88]

Do you take Lithium Orotate on the same day you take Rapamycin, or do you stop taking lithium orotate on the day of or after? I am only taking 5mg Lithium Orotate but it helps me immensely. I saw here a potential interaction with lithium, but I am guessing that’s more of a problem with higher doses of lithium carbonate?

[RapAdmin]

I take lithium orotate every day, including the days I take rapamycin. I take a very small dose or Lithium orotate. The drug interactions you link to are, I believe, most relevant for people taking high doses (100 to 600 times more than my dose) of lithium for other applications, like mental health issues. I don’t think its very relevant to the tiny doses we are taking. But - perhaps not a bad idea to skip lithium on rapamycin dosing days to be extra cautious.

[John_Hemming]

I don’t think Lithium metabolises in the same way that other things do. Hence I would not think if taken daily it would really impact on Rapamycin taken weekly.

Its serum half life is around a day so you are going to have quite a bit hanging around from the previous days anyway. (roughly the same as the amount from the dose you miss out if indeed you do)

Lithium: updated human knowledge using an evidence-based approach. Part II:...

“Lithium is almost exclusively excreted via the kidney as a free ion and lithium clearance is considered to decrease with aging. No gender- or race-related differences in kinetics have been demonstrated. Renal insufficiency is associated with a considerable reduction in renal clearance of lithium and is considered a contraindication to its use, especially if a sodium-poor diet is required.”

[Danlalane]

FWIW Bryan Johnson also takes Lithium daily and he publishes his blood biomakers. You may get him to be more specific in the spirit of science. He has been responsive to me in the past.

I take Lithium too and will gladly ask my Dr to test for it next time I get my blood drawn. I am lucky the Dr pretty much tests for anything I want and insurance has been generous with covering pretty much everything so far.

[teadrinker88]

I figured that the interaction potential was for high doses. I noticed a difference in my mood after just 2 days of taking 5mg. I’ll pause now and then when I take my rapamycin dose.

[teadrinker88]

Do you contact Bryan through twitter? I see (according to blueprint) he takes 1mg. Maybe I can consider taking less and see how that goes. Been on 5mg/daily for almost a week and it has noticeably improved my mood!