New data on lithium for prevention and treatment of Alzheimer disease (AD) dementia raise the question: lecanemab, or low-dose lithium? Those data were summarized in Part 1 of this 2-part series, including evidence for the superiority of lithium orotate over lithium carbonate. Comparing the benefit/risk ratios for lecanemab vs lithium is an apples-and-oranges problem, but comparing options for prevention of dementia is easier.
Benefits: Lecanemab
Figure 1 presents the primary outcome measure results of the CLARITY randomized trial of lecanemab for patients with minimal cognitive impairment (MCI) and early AD dementia, roughly as shown in the New England Journal.1 The difference in CDR scores after 18 months is 0.4 points, which is statistically significant (P <0.0001) in this sample of 1795 patients.
These results look different when presented on the full 0-18 scale as in Figure 2.
Of course upon seeing a result like this one should ask “That’s statistically significant, but it is clinically significant?” A Minimally Important Clinical Difference has been defined for the CDR: 1 point for patients with MCI, and 2 points for those with AD dementia.2 The observed difference of 0.4 points falls well short of both. By comparison, the anticholinesterase donepezil can yield initial improvement for 6 to 9 months, but no further benefit. In the manufacturer’s report of an open-label extension of the CLARITY trial, the separation in CDR scores widened between lecanemab and untreated participants, reaching 1 point at 3 years and 1.75 points: more clinically significant, but still worsening with time.3
The US Food and Drug Administration (FDA) approved aducanumab, the first monoclonal antibody for AD dementia (lecanemab is the third) while its counterpart in the UK—the European Medical Agency—did not. These decisions were and remain highly controversial. Three of the 11 FDA committee members resigned. But the FDA decision “broke the dam,” such that subsequent monoclonal antibodies did not have to demonstrate clinical improvement for approval. 4
Benefits: Low-Dose Lithium
In brief: several small randomized trials in patients with MCI have shown slowing of cognitive decline with lithium carbonate. These results align with indirect and epidemiologic data suggesting lithium can lower the incidence of AD dementia.5 Recently, an important paper appeared in Nature reporting extensive experiments in AD-prone mice,6 summarized in Part 1 of this series. In these studies, lithium orotate prevented formation of amyloid plaques, phosphorylation of tau proteins, and cognitive decline; and reversed cognitive decline when started long after the development of these pathologies; all to a much greater extent than lithium carbonate. But no human trials of lithium orotate for the prevention of dementia have been conducted. Ironically, a novel form of lithium that has shown “better brain absorption” in mice is in phase 2 human trials, with millions of dollars in funding7, but nonprofit funding will be needed for lithium orotate research.8
Risks: Lecanemab
The main concern is amyloid-related imaging abnormalities (ARIA), including edema (ARIA-E) and hemorrhage (ARIA-H). Lecanemab has shown a lower overall ARIA incidence (21.3%) compared with aducanumab (41%) in phase 3 trials. Symptomatic ARIA is less frequent, occurring in less than 3% of lecanemab-treated patients, but risk is higher in APOE ε4 carriers, especially homozygotes.9
Infusion-related reactions are common (26% to 37%), typically mild, and often occur with the first dose. Finally, in the open-label extension of CLARITY-AD, a few deaths were considered possibly related to study drug, most commonly in the context of concomitant anticoagulant or thrombolytic therapy and intracerebral hemorrhage. 9
Risks: Lithium Orotate
A review of worldwide databases and toxicity studies found no evidence of adverse effects of lithium orotate in humans.10 The authors also examined data for the dissociated form, orotic acid, a precursor in pyrimidine synthesis consumed in dairy products, but long-term exposure to orotic acid has not been studied in humans. They note the absence of a “postmarket safety signal” for lithium orotate.
In a survey of users of lithium supplements including lithium orotate, there were no descriptions of serious adverse effects. Withdrawal problems were more common than expected but nocebo effects could not be differentiated.11
Finally, a single case report describes an intentional overdose of 18 capsules, presenting with nausea and vomiting, a peak blood level of 0.4 mEq/L, and resolution of adverse effects within 3 hours.12
Renal risk from lithium orotate appears to be very low, based on the several decades of human experience, and now 2 mouse studies suggesting that lithium orotate risks are no greater6 or possibly lower13 than with lithium carbonate. But hypothyroidism might have been less obvious to users and thus not associated with lithium orotate, either in surveys or in medical case reports. Low doses of lithium carbonate can affect thyroid function14 so for now, TSH testing before and early in use of lithium orotate seems warranted until we know more about its potential thyroid effects.
Comparing Lecanamab and Lithium Orotate
Comparing the risks of lecanemab and lithium for established MCI or AD dementia is an apples-and-oranges problem. What should drive decision-making: evidence for benefit, albeit very small and known substantial risks and costs; or absence of evidence for risk and low cost, but questionable evidence for benefit (given that absence of evidence is not evidence of absence)?
Comparing these medications for primary prevention of dementia is simpler. Certainly the first step is maintaining a healthy lifestyle as best one can.15 Beyond that, monoclonal antibodies are not candidates for primary prevention because of their risks. Is lithium orotate now worth considering? When the consequences of an illness are dire, any strategy for prevention with a plausible mechanism and at least some evidence for efficacy becomes worth considering.
Dose of Lithium Orotate
I do not have systematic data, and my excitement about the new lithium research surely exerts substantial influence, but I can report that after presenting a translation of Aron et al’s Nature paper in the context of previous studies,16 many people have asked “what dose of lithium orotate should I take?”
Appendix
- Calculate the equivalent in mg/liter for 4.3 microequivalents per liter (the dose their mice were given in the study showing reversal of cognitive decline). Answer: 0.0298 mg/L.
- Next: how many liters of water does a mouse drink per day? Answer: it ranges from 3.9 to 8.2 milliliters. Call it 6 ml.
- Plug that in for daily lithium the Nature mice received, answer: 0.2 micrograms.
- Convert to mg/kilogram of body weight. How much does a mouse weigh, specifically the J20 mouse used in these studies? Answer: females, 15 to 20 grams; males, 20 to 40 grams. Call it 25 grams.
- So the dose was 0.2 mcg per 25 grams, or 0.008 mg/kg.
- In a human weighing 70 kg (154 lbs), that would be a daily consumption of 0.56 mg/day of elemental lithium.
- How much lithium orotate does it take to deliver 0.56 mg of elemental lithium? Divide the molar mass of lithium orotate by the molar mass of elemental lithium: 162/6.94, or 23.3.
- 23.3 * 0.56 = 13 mg of lithium orotate per day
- (More careful rounding yields 11.7 mg in the hands of my math friends. So call it 12 mg/day, to match a mouse.)
The most effective dose of lithium orotate in Aron et al’s mice was the smallest: 4.3 microequivalents per liter. The human equivalent, affirmed by 3 competent mathematicians, is 12 mg/day (calculations in the Appendix). This may provide an anchor point in the absence of dose-finding studies. Patients might consider a smaller dose if starting younger (eg, a 5 mg pill daily), or a larger dose (eg, a 20 mg pill daily) if starting older, and especially if some cognitive decline is already evident. Beyond the latter there is far less human experience11 on which to judge long-term safety.
What About Treating MCI and AD?
When cognitive decline prompts use of the newly approved pTau217/ß-Amyloid 1-42 blood test and the result is positive, most patients and families will want to consider treatment options. Donepezil, lecanemab, or another monoclonal antibody, or lithium orotate? Informed consent should include account of the lithium studies, including the new mouse data; followed by careful shared decision-making.
Dr Phelps is retiring from 30 years of treating complex mood disorders, and recently founded another website, DepressionEducation.org. He is the bipolar disorder section editor for Psychiatric Times® and the author of A Spectrum Approach to Mood Disorders for clinicians and Bipolar, Not So Much for patients and their families.
References
1. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9-21.
2. Muir RT, Hill MD, Black SE, Smith EE. Minimal clinically important difference in Alzheimer's disease: rapid review. Alzheimers Dement. 2024;20(5):3352-3363.
3. Early Alzheimer’s patients continue to benefit from four years of LEQEMBI® (lecanemab-irmb) therapy new clinical data presented at AAIC. News release. July 31, 2025. Accessed November 14, 2025. https://www.eisai.com/news/2025/news202554.html
4. Hunter P. The controversy around anti-amyloid antibodies for treating Alzheimer's disease : the European Medical Agency's ruling against the latest anti-amyloid drugs highlights the ongoing debate about their safety and efficacy. EMBO Rep. 2024;25(12):5227-5231.
5. Mauer S, Vergne D, Ghaemi SN. Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits. Aust N Z J Psychiatry. 2014;48(9):809-818.
6. Aron L, Ngian ZK, Qiu C, et al. Lithium deficiency and the onset of Alzheimer's disease. Nature. 2025;645(8081):712-721.
7. Alzamend Neuro announces dosing of first patient in its phase II clinical trial of AL001 “lithium in brain” study taking place at Massachusetts General Hospital. News release. May 29, 2025. Accessed November 12, 2025. https://ir.alzamend.com/news-events/press-releases/detail/93/alzamend-neuro-announces-dosing-of-first-patient-in-its
8. Ghaemi SN. The need for non-profit psychiatric drug discovery and development. J Clin Psychopharmacol. 2022;42(6):518-522.
9. Honig LS, Sabbagh MN, van Dyck CH, et al. Updated safety results from phase 3 lecanemab study in early Alzheimer's disease. Alzheimers Res Ther. 2024;16(1):105.
10. Murbach TS, Glávits R, Endres JR, et al. A toxicological evaluation of lithium orotate. Regul Toxicol Pharmacol. 2021;124:104973.
11. Strawbridge R, Myrtle S, Carmellini P, et al. A survey exploring people's experiences with lithium bought as a supplement: Une enquête sur l'expérience des personnes avec le lithium en supplément. Can J Psychiatry. 2025;70(10):782-795.
12. Pauzé DK, Brooks DE. Lithium toxicity from an Internet dietary supplement. J Med Toxicol. 2007;3(2):61-62.
13. Pacholko AG, Bekar LK. 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.
14. Phelps J, Coskey OP. Low and very low lithium levels: thyroid effects are small but still require monitoring. Bipolar Disord. 2024;26(2):129-135.
15. Lazar RM, Howard VJ, Kernan WN, et al. A primary care agenda for brain health: a scientific statement from the American Heart Association. Stroke. 2021;52(6):e295-e308.
16. Phelps J. Preventing dementia. YouTube/@PsychEducation. Accessed November 12, 2025.https://www.youtube.com/playlist?list=PL1lTWq-FqdPITRNa5844EEcnQujuDe3KZ
