Let’s see the end from the beginning: 

“Thus, low dose LiO prevents age-related pro-inflammatory changes, synapse loss and cognitive decline in mice without evidence of toxicity.” -Aron, et al. Nature 2025

WOWOWOW. I don’t get overly enthused about most rodent trials for human-related reasons, but I’m genuinely excited about this paper and wanted to share why. It is meaningful to the Attention, Please reader not for its immediate impact on productivity or focus but for the core Goldmind mission of helping people think their best. This means “best” across the entire lifecycle and thus addressing different issues with cognition at different ages. During a working career the strategies for optimized cognition are different from the tools to use at retirement age, but I’m still dedicated to identifying anything that might help someone feel more in control of his/her mind, and lithium (orotate) certainly appears to have great promise in being a tremendous tool. The publishing of the Aron paper feels like the moment that decades of research on lithium has built up towards, finally garnering this humble element attention on a population-wide level. Here I’ll discuss the paper, but also go a bit deeper into the other published data on lithium for cognition which, while I was aware of before Aron, I wasn’t giving the proper importance until I took the time to think through how all of these pieces fit together. 

In brief, Aron, et al just published a nuanced paper linking lithium deficiency to a higher risk of Alzheimer’s disease (AD). They used human genetics, post-mortem brain tissue, and animal work to argue that our cells need trace lithium to keep tau and amyloid in check and showed (in mice) that using physiologic lithium orotate (hereafter LiO) actually reversed signs of AD in a mouse model of the disease and improved cognition.¹ It’s not a call to immediately get everyone popping LiO like chicklets, lithium is toxic in high doses (which were not given in this trial, these were “physiologic” doses), and there still needs to be large-scale human trials (though some small ones have been done with LiO delivering 5mg elemental lithium without adverse events); it is a big wake up call to clinicians to stop treating lithium like a taboo and start treating it like what it might be for the brain: a required trace element that most of us barely get and may prevent or even reverse some hallmarks of AD at doses that are extremely unlikely to cause renal or thyroid issues.

How it started…

Lithium isn’t a lab invention. No brilliant big-pharma-employed molecular engineer crafted it to perfectly inhibit GSK3B, which is thought to be the primary mechanism that it exerts its far-reaching effects. As Dr. Ghaemi likes to remind us: God made it. It was forged in supernova explosions and it’s everywhere – deserts, brines, well water, and the old “healing” springs people used to travel to in search of miracles. It is quite literally elemental, in that it is the 3rd element in the periodic table. In the early 20th century, a lemon-lime soda your grandfather might have purchased at Ye Olde General Store catchily called Bib-Label Lithiated Lemon-Lime (later, 7UP for lithium’s atomic number, 7 – actually 6.94, hence the title of this post) used lithium citrate as a selling point; it stayed on shelves until 1948, when the U.S. clamped down on therapeutic claims in soft drinks.² Lithium (as LiO) remains available as a dietary supplement but cannot be sold in FOOD products. Trace lithium exposure (micrograms per liter) through water and food used to be unremarkable. It is still present at various levels in tap water in regions with high environmental concentrations with some remarkable consequences (see below).

From Gouty Guinea Pigs to Gold Standard

Modern psychiatry’s use of lithium began in 1949, right after 7UP had to dump it, when Australian psychiatrist John Cade stumbled onto its antimanic effects while trying to treat guinea pigs with gout.³ He noticed it didn’t treat their gout but did really chill them out. And pioneering psychiatrist that he was, he tested lithium on himself before he used it on any manic patients. Early use was, hmm, let’s generously call it well-intentioned-but-often-fatal. There were no serum levels, no basic guardrails and no standard dosing protocols which meant people frequently died of overdoses. The therapeutic window for lithium is quite small – which means there isn’t much room for error when you’re dealing with fully ionized lithium you get from most lithium salts. This might change with LiO (more below). But the initial rollercoaster with lithium leading to improvement in manic symptoms but often also death set psychiatry back a few decades. We gradually relearned how to use lithium carefully as lithium carbonate (LiC), with routine blood monitoring and well-defined therapeutic ranges. Today, lithium carbonate remains an FDA-approved mood stabilizer for bipolar disorder (BD), life-saving in the right patients, and decidedly not a casual supplement. It is still the gold standard for manic and mixed episodes in BD as well as maintenance phases of the disorder. Lithium carbonate is ~19% elemental lithium by weight, so the average 300 mg tab (which is the smallest it comes in) delivers 56 mg of elemental lithium. Most folks taking lithium for BD take 600-1800 mg daily of LiC, so 112-336 mg elemental lithium to maintain therapeutic blood levels. This is roughly 100x (not 100%, 100x!) times the doses used to supplement with LiO and the equivalent human dose studied in Aron (roughly 1.5 mg daily).

What the population data say

Across cities and countries, from Texas (Li ≈70–170 µg/L) to Greece (at the high range of Li ≈0.1–121 µg/L) to Denmark (Li above ~15 µg/L), places with slightly higher natural lithium in drinking water tend to show lower rates of suicide, homicide and AD in the population. The effect is small, but it repeats across ecological datasets and a 2020 meta-analysis.⁴ ⁵ On the best-designed study on dementia, Denmark’s national registry found higher trace levels (still micrograms per liter, here >15 µg/L which translates into ~1 mg elemental lithium circulating in a 70kg human or consuming about 0.75 mg elemental Li daily given half-life and volume of distribution assumptions) correlated with roughly 17% lower dementia incidence.⁶ Other work at extremely low levels finds no association, so dose clearly matters and more work needs to be done here.⁷ But we wouldn’t necessarily expect any result from <1 µg/L, would we? If this is an essential element that we gradually become deficient of and we get it naturally through diet (water/food), there must be levels below which we are already “deficient.”  Again, this is not proof of causation because these are epidemiological studies; but they are a consistent signal that tiny amounts of lithium (but not too tiny) likely matter over decades. And this is without any conscious effort to supplement or the form of lithium salt ingested. How such a small, simple molecule reduce self-harm, aggression and cognitive impairment? It sounds too good to be true. And this is data that has been known for decades before the most recent paper was published. It points to what Aron tried to build on: lithium deficiency is likely bad for mental health–so what happens when we just take a deficiency and make it non-deficient? This isn’t dosing for BD, this is micrograms-to-milligrams.

Human trials strengthen the signal

Randomized trials using low, monitored LiC tell a pretty consistent story. In patients with amnestic mild cognitive impairment, year-long lithium at serum 0.25–0.5 mmol/L slowed cognitive decline versus placebo and reduced CSF phospho-tau.⁸ An extension study following participants for up to three years showed stabilization of memory/attention and biomarker shifts consistent with less Alzheimer’s pathology.⁹ In frank Alzheimer’s disease, microdosed lithium (300 µg/day elemental) halted MMSE decline over 15 months compared with placebo.¹⁰ These are not miracle cures; they are small, clinically visible effects that warrant larger, well-funded trials that have yet to really materialize. Though given the popular attention Aron has earned, the time for lithium might have finally come. Someone will fund, or hopefully has already started, a trial looking at larger (but still small) doses of LiO in AD, MCI and normal, healthy older adults (and possibly middle-aged adults, where the process of AD begins). It has to happen. We don’t know when AD pathology actually starts. It’s likely beginning in people in their 40s or 50s and only manifesting with amnestic symptoms in the 60s-80s age range. Maybe we should be starting low-dose LiO before significant disease progression? 

Aron, abridged, in plain English

The Nature paper weaves together several clever lines of inquiry: genetics that point from low lithium to Alzheimer’s risk; human brain tissue showing lithium-sensitive pathways misregulated in AD; and animal/neuronal models where restoring trace lithium normalizes tau phosphorylation and synaptic markers.¹ The implication is straightforward: in a subset of humans, relative lithium deficiency is biologically plausible and may accelerate Alzheimer-type changes. Taking it one step further from their data: reversing that deficiency with physiologic levels of lithium from LiO may slow, stop, or actually REVERSE those AD-type changes. That fits with a long-standing nutrition proposal: lithium should be treated as an essential trace nutrient with an intake around 1 mg/day elemental for a 70-kg adult.¹³-¹⁵ U.S. dietary estimates sit between 0.6 and 3.1 mg/day depending on water and food; some people will be at the low end, maybe Aron is the jumpstart we all need to start integrating low-dose protocols of LiO more widely.¹⁶ ¹⁷

Aron wasn’t megadosing LiO, it was providing a level of elemental lithium designed to get back to the physiological range that could easily be attained with diet, and this was enough to have a substantial impact on AD-like progression in the studied mice. This was the equivalent of human consuming just what the nutritionists proposed above, about 1-1.5 mg elemental lithium daily, or 20-30 mg of LiO daily. And Aron also showed that even at 10x this low (but effective) physiological dose that kidney and thyroid function wasn’t adversely affected. This is not the same as LiC. Orotate offers lithium a better anionic partner, one that we may have been overlooking because of an early proponent’s bad rep and a deeply flawed study that made LiO look more dangerous than LiC.

So what’s all this about lithium orotate, then?

Lithium orotate was promoted in the 1970s by “the controversial” Hans Nieper as a way to deliver lithium at lower serum levels. He mixed his reasonable arguments and direct clinical experience of LiO’s effectiveness with sweeping, grandiose claims and later fringe oncology ideas, which is why many clinicians may have thrown the baby out with the bathwater. LiC just sort of became the standard and no one looked back at LiO. But just because a dude is a bit cracked in the end doesn’t necessarily mean all of his ideas are wrong. He understood there something fundamental about lithium use that has been consistently overlooked: the anion (here, orotate) matters that the lithium is delivered with. There was another problem though: early animal work raised a red flag about safety of LiO. At high injected doses, LiO produced higher tissue lithium and worse renal clearance than lithium carbonate.¹⁸ Let’s put what Smith & Schou actually found in their 1979 study: they injected 2mmol Li / kg into rats, which in a 70kg human, is equivalent to 972 mg elemental Li given at once. This is 194 capsules of 5 mg elemental LiO (the dosage commonly used as a supplement) or 17 tabs of LiC (300mg each, delivering 56 mg elemental lithium) and immediately put the rodents in a toxic blood level of 2.9 mmol/L (when therapeutic is 0.6-1.2 mmol/L) and almost 1000x higher than the blood levels Aron targeted (2–4 µmol/L). The fact the mice were overdosed doesn’t teach us anything about LiO’s inherent kidney risks. Smith & Schou’s clownish conclusion that it’s “inadvisable to use lithium orotate” was based on an acute, supra-therapeutic, intraperitoneal comparison, then generalized to patients despite being nowhere near human-relevant. More recently, a mouse model suggested LiO achieves its behavioral effects at significantly lower serum lithium levels versus carbonate, implying very different pharmacokinetics.²⁰ Pacholko & Bekar (2023) showed LiO blocked a lithium-sensitive behavioral assay at ~10x lower lithium doses than LiC, and organic-anion transporter (OAT) blockade eliminated LiO’s effect but not LiC’s, i.e. there is distinct transport/compartmentalization (using the OAT) rather than “more nephrotoxicity.” At behaviorally effective doses over 14 days, LiC showed classic renal/TSH liabilities; LiO did not. So take that old S&S study and throw it in the trash. But why does the delivery vehicle of the lithium ion appear to matter so much?

Lithium orotate is not just “lithium carbonate with a different molecular weight.” The anion really appears to matter biologically – not because LiO stays mostly neutral (i.e. the lithium stays bound to the orotate molecule) in plasma – it doesn’t; both salts dissociate > 99.95% once ingested). But because Li-orotate ion pairs are 10-50x higher concentration than Li-carbonate, this changes how lithium is partitioned in brain tissue, how much gets sequestered by amyloid, and which transport pathways move it across membranes.

Aron screened all of the commonly used lithium salts and found that lithium carbonate binds avidly to amyloid-β plaques, which traps lithium and depletes it from the rest of the brain. In contrast, lithium orotate shows reduced amyloid binding, preserves “free” lithium, and – at microdose levels – prevented amyloid/tau accumulation, synapse and myelin loss, and memory decline in AD mouse models and aging wild-type mice, without detected toxicity. The authors explicitly describe LiO as an “amyloid-evading” lithium salt and propose lithium replacement with amyloid-evading salts as a prevention/treatment strategy. This is what makes dosing with LiO so appealing: something about it (likely the 10-50x increased ion pair binding allowing the organic anion transporter to shuttle bound lithium intracellularly where it can then inhibit GSK3B) makes it MUCH better than the gold standard at MUCH lower doses. I don’t think it’s a coincidence that LiO has ~10x more ion-pair binding and a biologically active dose at 10x lower than LiC. That seems like a clue as to why. Maybe just having the orotate molecule in solution in plasma then getting a lucky catch of a free Li+ ion as it jumps onto the OAT to get dumped intracellularly is all we need to tip the scales in favor of LiO. I don’t know. But I’m so excited that we’ll find out soon enough.

And if you want to be sceptical about how mouse data translates to humans, we already have human plausibility from a study that used ^7Li-MRI to detect brain lithium signal in healthy adults after low-dose LiO (~5 mg elemental/day for weeks) – again, orders of magnitude below therapeutic LiC exposure – confirming that nutritional-range LiO reaches the CNS. That doesn’t prove superiority on outcomes in humans yet, but it nails deliverability at the doses Aron frames as “replacement.” 21 We know it gets in, even at low doses, just like it does in mice. It’s a reasonable assumption to think it acts similarly once it gets there.

And how, exactly, does Li+ act once it gets in there?

Lithium isn’t one switch; it participates in a bunch of actions that nudge the brain toward stability and protection. The best-established push is by inhibiting GSK-3 (glycogen synthase kinase-3). Lithium lowers GSK-3 activity directly (by competing with magnesium at the catalytic site) and indirectly (by increasing inhibitory serine phosphorylation).22 23 That matters because GSK-3 sits at the crossroads of Wnt/β-catenin, synaptic plasticity, and tau phosphorylation. Turn it down and you stabilize β-catenin, reduce pro-apoptotic signaling, and blunt the pathological phosphorylation of tau – useful in any effort to reduce the aging of brains.22 23 This is one of the hallmarks of AD. It’s no surprise that by blocking something that phosphorylates tau you might be doing something good.

A second action is on inositol/IP₃ signaling. Lithium inhibits inositol monophosphatase (IMPase) and related enzymes. That lowers free inositol, reduces PIP₂/IP₃ cycling, and promotes autophagy independent of GSK-3. In cells and animal models, that autophagy boost clears aggregate-prone proteins (mutant huntingtin, α-synuclein), which is relevant to neurodegeneration where autophagy is often dialed down.24 25

Lithium also alters the circadian clock (probably at least part of why it is so effective in BD). Through GSK-3 and casein-kinase pathways, it lengthens circadian period and increases rhythm amplitude in cellular and animal models. It is thought that by shifting someone’s internal clock toward stronger, more regular oscillations it makes neural systems less likely to switch into more pathological, disordered states.26 27

At the synapse level, lithium dampens excessive glutamate/NMDA signaling and biases the system toward GABAergic inhibition. Remember the chilled out guinea pigs that Cade stumbled upon? Maybe they were just extra GABAergic. Chronic lithium reduces NMDA-coupled arachidonic-acid signaling in vivo (a proxy for pathologic excitatory drive) and enhances GABAergic synaptic activity. Less excitotoxic chitter-chatter; more inhibitory tone.28 29

At the neuron level, Li increases neurotrophic (new neurons) and anti-apoptotic (cell death) effects. Chronic lithium exposure increases BDNF and VEGF, up-regulates Bcl-2/Bcl-xL, and dampens pro-apoptotic mediators. In animals, that translates into more resilient hippocampal circuitry and enhanced synaptic plasticity; in humans, structural imaging repeatedly finds larger gray-matter volumes in lithium-treated patients versus matched controls. More actual brain. Lithium pushes the complex cortical system toward survival and plasticity instead of shrinkage and loss.30-32

FinaLi+

Should you go out and buy Lithium orotate 5mg (elemental) and start taking it today? I mean, not to be overly disclosing, but I did. I did the day that I read the Aron study, started to put all of the disparate pieces together that I’d been pretty dismissive of through my training, and considered the risks and benefits for myself at age 44 with a family history of AD. You should certainly not take this as a recommendation for you to do the same, because it is not that. LiO is neither a panacea nor without possible real harms, even at low doses. It is definitely worth thinking about and considering for your individual situation. It’s a topic your personal doctor should feel comfortable discussing with you, and in my opinion, you should have that conversation before starting it.

I prescribe lithium (carbonate) all the time to patients. I’ve always known it was extremely effective for the people willing to take it, but I’ve had many challenging cases where the side effects forced me to stop it or my patient just couldn’t tolerate it. It is under-utilized in psychiatry despite being the gold standard for BD. What Aron, et al. really did for me was fully open my eyes to the decades of research that had come before it, along with the genuinely good science that they did in their study. Orotate and carbonate are not the same. And stupid me, I’d never really thought deeply about why the carrier of the lithium ion mattered, even though people have been exploring this for 50+ years. I’m very optimistic we might have a well-studied, evidence-based tool in LiO in the near future that may offer unique benefits for people dealing with MCI/AD or even those at risk of developing it in the coming decades. For now, we have many good bits of knowledge, but no robust human trials that can change the practice of medicine. They’ll come, and the sooner the better.

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References

1. Aron L., et al. Lithium deficiency and the onset of Alzheimer’s disease. Nature. 2025; doi:10.1038/s41586-025-09335-x.

2. Fountoulakis KN. The Rise of a Legend: Lithium and the Extraordinary Story of Its Discovery. Pharmaceuticals (Basel). 2025 Aug 20;18(8):1230.

3. Cade J. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2:349–352.

4. Memon A., et al. Association between naturally occurring lithium in drinking water and suicide rates: systematic review and meta-analysis of ecological studies. Br J Psychiatry. 2020;217:667–678.

5. Kohno K., et al. Lithium in drinking water and crime rates in Japan: cross-sectional study. BJPsych Open. 2020;6:e8.

6. Kessing L.V., et al. Association of lithium in drinking water with the incidence of dementia. JAMA Psychiatry. 2017;74(10):1005–1010.

7. Duthie A.C., et al. Low-level lithium in drinking water and subsequent risk of dementia. Int J Geriatr Psychiatry. 2023;38(1):e5890.

8. Forlenza O.V., et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomized controlled trial. Br J Psychiatry. 2011;198(5):351–356.

9. Forlenza O.V., et al. Clinical and biological effects of long-term lithium treatment in older adults with amnestic MCI: randomized clinical trial. Br J Psychiatry. 2019;215(5):668–674.

10. Nunes M.A., et al. Microdose lithium treatment stabilized cognitive impairment in Alzheimer’s disease. Curr Alzheimer Res. 2013;10(1):104–107.

11. Damri O., et al. Lithium, inflammation and neuroinflammation: clinical and mechanistic links. Brain Sci. 2024;14(6):613.

12. Gitlin M., et al. Lithium: current state of the art and future directions. Mol Psychiatry. 2024;29:1204–1222.

13. Schrauzer G.N. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr. 2002;21(1):14–21.

14. Szklarska D., Rzymski P. Is lithium a micronutrient? From biological activity and transport to the kinetics of excretion. Nutrients. 2019;11(7):1600.

15. Naeem A., et al. Lithium content and its nutritional beneficence, dietary intake, and biofortification. Biol Trace Elem Res. 2023;201:1089–1107.

16. U.S. EPA. Technical Fact Sheet: Lithium in Drinking Water. 2023.

17. Marshall T. Lithium as a nutrient. Institute of Mineral Research (review of intake estimates). 2015.

18. Smith D.F., Schou M. Kidney function and lithium concentrations of rats given lithium orotate or lithium carbonate. J Pharm Pharmacol. 1979;31(1):161–163.

19. Pacholko A.G., Bekar L.K. Lithium orotate: a superior option for lithium therapy? Brain Behav. 2021;11:e2262.

20. Pacholko A.G., Bekar L.K. Different pharmacokinetics of lithium orotate inform why it is more potent, effective, and less toxic than lithium carbonate in a mouse model of mania. J Psychiatr Res. 2023;164:192–201.

21.  Neal MA, et al. Human brain 7Li-MRI following low-dose lithium dietary supplementation in healthy participants. J Affect Disord. 2024 Sep 1;360:139-145.
    

22. Snitow ME, Ardito CM, Arrillaga-Romany IC, et al. Lithium and therapeutic targeting of GSK-3. Trends in Molecular Medicine. 2021;27(9):836–852.
    

23. Chuang D-M, Manji HK. GSK-3 as a target for lithium-induced neuroprotection. Bipolar Disorders. 2011;13(5-6):577–586.
    

24. Sarkar S, Floto RA, Berger Z, et al. Lithium induces autophagy by inhibiting inositol monophosphatase. Journal of Cell Biology. 2005;170(7):1101–1111.
    

25. Sarkar S, Rubinsztein DC. Inositol and IP₃ signaling in autophagy. Autophagy. 2006;2(3):132–134.
    

26. Noguchi T, Wang CW, Pan H, Welsh DK. Lithium effects on circadian rhythms in fibroblasts and suprachiasmatic nucleus. Molecular Psychiatry. 2016;21(4):537–549.
    

27. Kaladchibachi SA, Doble BW, Anthopoulos N, Woodgett JR, Manoukian AS. GSK-3 links lithium to the circadian clock. Journal of Circadian Rhythms. 2007;5:3.
    

28. Basselin M, Chang L, Chen M, et al. Chronic lithium blocks NMDA-linked signaling in rat brain in vivo. Neuropsychopharmacology. 2006;31(7):1659–1674.
    

29. Rijal S, Kim M-J, Park J, et al. Lithium enhances GABAergic synaptic activities. International Journal of Molecular Sciences. 2021;22(9):4891.
    

30. Young W. Review of lithium effects on brain and blood: neurotrophins and plasticity. Cell Transplantation. 2009;18(9):951–975.
    

31. Puglisi-Allegra S, Andolina D. Translational evidence for lithium-induced brain plasticity. Translational Psychiatry. 2021;11:461.
    

32. Sassi RB, Brambilla P, Hatch JP, et al. Increased gray matter volume in lithium-treated bipolar patients. Psychiatry Research: Neuroimaging. 2002;119(1-2):49–58.

Note: Nutritional lithium (micrograms to low milligrams of elemental lithium per day) is categorically different from prescription lithium therapy. Decisions about the latter require a physician, serum levels, and renal/thyroid monitoring.