New Evidence for Lithium Deficiency

As I wrap up Cafer’s Pharmacology, 2nd Edition Series: Prescribing Lithium, I’m adding one last topic. Published this week in Nature, this study strengthens the case for lithium deficiency as clinically relevant, providing direct tissue and mechanistic support.

Summary – “Lithium deficiency and the onset of Alzheimer’s disease” (Aron et al, Nature, 2025)

Background

❖ Lithium is naturally present in blood and brain at low micromolar concentrations

❖ Lithium deficiency/essential mineral status is not yet formally recognized

❖ Normal ageing may impair brain lithium regulation

❖ Amyloid-β plaques are negatively charged and can attract/sequester cations (e.g., zinc, iron, lithium)

❖ Most ecological studies link higher natural lithium in drinking water with lower rates of dementia and suicide

❖ Microdose lithium slowed progression of mild cognitive impairment to dementia (Shim et al, 2023; Strawbridge et al, 2023)

❖ Clinical lithium carbonate use is limited by toxicity and narrow therapeutic window,  though such risks are negligible at proposed low doses

Human Findings

❖ Post-mortem prefrontal cortex in MCI and AD shows markedly reduced lithium levels

    ➤ cerebellar and serum levels normal

❖ Amyloid-β plaques are enriched in lithium compared to surrounding tissue

    ➤ non-plaque tissue shows lower lithium

    ➤ lower levels in prefrontal cortex correlate with worse cognition

Mouse Models

❖ Amyloid-overexpressing (AD) mice on a lithium-deficient diet show:

    ➤ exaggerated amyloid-β42 and phospho-tau accumulation

    ➤ pro-inflammatory microglial activation 

    ➤ synaptic, axonal, and myelin loss

    ➤ transcriptomic changes overlapping with human AD

    ➤ worsened cognitive performance

Lithium Orotate (LiO) vs Lithium Carbonate 

❖ LiO has the lowest conductivity among 16 salts tested

    ➤ binds amyloid less than lithium carbonate

❖ In AD mice, LiO was more effective than lithium carbonate at equivalent dose in  preventing/reversing:

    ➤ amyloid/tau pathology

    ➤ loss of microglial amyloid-clearing ability

    ➤ neuroinflammation

    ➤ cognitive deficits

❖ In wild-type ageing mice, LiO prevented age-related neuronal loss and memory decline

Conclusions

❖ Lithium depletion in brain tissue may be an early, reversible driver of Alzheimer’s disease

❖ Microdose LiO <1 mg elemental daily shows promise as a preventive or therapeutic option

FAQs

Does lithium deficiency cause Alzheimer's disease?

By definition, amyloid plaque–mediated lithium sequestration can’t be the initiating cause of Alzheimer’s, because plaques have to be present before they can trap lithium.

The process:

❖ Plaques begin forming for other reasons (genetics, APP processing, clearance failure, etc.)

❖ These plaques bind lithium, lowering its availability in surrounding brain tissue

❖ Lithium depletion then accelerates amyloid/tau pathology, neuroinflammation, and myelin/synapse loss

    ➤ promotes further plaque growth

So deficiency of lithium in the prefrontal cortex is probably an early accelerant of Alzheimer's rather than a primary trigger.

In Alzheimer's why are lithium levels normal in the cerebellum if low in the cortex?

Cerebellar lithium wasn’t reduced likely because:

❖ Cerebellar tissue has a distinct glial/neuronal ratio and metal ion handling

    ➤ may help maintain lithium homeostasis.

❖ The cerebellum is relatively resistant to amyloid-β plaque deposition

    ➤ so there is little sequestration of lithium there

No plaques, no lithium trapping, so levels stay normal.

Should individuals with mild cognitive impairment (MCI) take lithium? How much?

1 mg lithium orotate (equivalent of ~5 mg prescription lithium carbonate) may be sufficient.

The Nature study’s physiological range in mice corresponded roughly to <1 mg/day elemental lithium in humans.

Since there is no established optimal dose for MCI, given presumed safety of substantially higher lithium does, I suggest 5 to 10 mg elemental lithium / day (equivalent to 27 to 54 mg of prescription lithium carbonate).

Supporting Evidence for Microdose Lithium

❖ Several small trials (e.g., Seong Sool Shim et al, 2023; Strawbridge et al, 2023) found that microdose lithium slowed progression from MCI to dementia

❖ The new Nature study (Aron et al, 2025) shows lithium depletion accelerates amyloid/tau pathology in mice, and restoring physiological lithium prevents or reverses these changes

❖ Populations with higher natural lithium in drinking water show lower dementia incidence

Potential Risks

❖ Even low doses can increase TSH or cause hypothyroidism

❖ Though presumably safe, there are no long-term human safety trials in the microdose range

❖ OTC lithium orotate is not FDA-regulated

    ➤ possibility of inconsistent content and bioavailability or contaminants

Lithium orotate brand recommendations?

ConsumerLab’s review of low-dose lithium supplements indicates several brands passed testing for correct lithium content and absence of heavy metal contaminants: Advanced Research, American Biologics, Good State Health Solutions, KAL, Life Extension, and others

Do I need to monitor serum lithium levels or watch interactions with OTC lithium orotate?

Not if taken as directed. Serum levels will usually be undetectable with the standard assay, even at the maximum OTC lithium orotate strength of 20 mg (equivalent to 107 mg prescription lithium carbonate, if you trust the brand). TSH should be monitored annually.

Does it have to be lithium orotate?

No.

The Nature study found lithium orotate effective while equivalent physiologic doses of lithium carbonate were not. However, lithium carbonate at slightly higher strength should overcome amyloid sequestration to provide lithium to the surrounding cortex.

Prescription lithium carbonate has the advantage of being FDA-regulated. 300 mg is the smallest Rx tablet. 75 mg is achievable with ¼ of Rx 300 mg tab (#90 = 1 year, $12 GoodRx). I have instructed some patients to chop the 300 mg tabs into ~8 small fragments for 30 to 40 mg /day = slightly stronger than 5 mg OTC lithium orotate.

For cognition, is lithium superior to Prevagen (apoaequorin)?

Prevagen has no credible evidence of benefit. The mechanism unlikely to work in humans. It even faced FTC action for false advertising.

For MCI and early Alzheimer's, is lithium superior to Kisunla (donanemab-azbt)?

Kisunla has proven (though modest) clinical effect in a large randomized trial, while lithium’s potential remains promising but unproven in this setting.

This infographic highlights concerns about donanemab. This antibody is effective at clearing amyloid, but the clinical benefits are minimal. This implies that simply clearing amyloid may not be the solution, or that any potential benefits are offset by neurotoxicity, as indicated by accelerated brain volume decline.

CaferMed monograph on Kisunla

For MCI and early Alzheimer's, is lithium more promising than donepezil or memantine?

Current data make lithium the more biologically plausible candidate for slowing progression in MCI/early AD, but unlike Aricept or Namenda, it still lacks large, definitive clinical proof.

Aricept / Namenda – These are symptomatic drugs. In early AD, they can provide modest, temporary improvement in cognition or function but do not alter underlying disease progression. In MCI, trials have shown no significant prevention of dementia onset.

Additional Info on Lithium Strengths and Formulations

Lithium Formulations

Compound	Product	Strengths	Cost/mo	FDA	Key Points
Lithium carbonate (Eskalith)	IR capsules/ tablets	150mg, 300mg, 600mg	$4-$26	Rx	❖ Immediate release (IR) ❖ Label instructs TID dosing ❖ Current expert consensus is once daily dosing at evening /HS with either IR or ER formulation ❖ ER is generally preferred over IR, but 12-hour serum levels are similar
Lithium ER	Sustained Release (SR)	300mg, 450mg	$10-$30	Rx	❖ Order “lithium ER” (extended release)     ➤ Lithobid is SR (sustained release) 300 mg unscored film-coated ER tabs         ◇ label instructs BID dosing but modern standard is one daily dose at HS     ➤ Eskalith CR (controlled release) is 300 and 450 mg scored ER tabs     ➤ Most generics are simply “lithium ER”            ◇ CR and SR are marketing terminology rather than standardized pharmaceutical classifications           ◇ In the case of lithium, the FDA considers CR and SR therapeutically equivalent and interchangeable unless otherwise specified by the prescriber
Lithium citrate oral solution	Oral solution 300mg/5mL	150mg, 300mg, 450mg, 600mg (8 fl oz, 500mL bottle)	$28-$200	Rx	❖ Equivalent to IR lithium carbonate
Lithium orotate (LiO)	OTC supplement	1mg, 5mg, 10mg, 20mg elemental lithium	$3-$20	OTC	❖ Not FDA-regulated ❖ Lower ionization than lithium carbonate → “amyloid-evading”— less lithium bound to amyloid-β plaques, more retained in plaque-freebrain tissue (Aron et al, 2025) ❖ In Alzheimer’s mouse models, a human-equivalent dose of <1 mg elemental LiO prevented/reversed amyloid-β and tau pathology, reduced neuroinflammation, and restored cognition — effects absent with equal-dose lithium carbonate (Aron et al, 2025) ❖ Human benefit unproven but suggested ❖ Orotic Acid     ➤ no longer considered a vitamin (formerly “vitamin B13”)     ➤ no known direct biological effect on Alzheimer’s pathology once lithium is dissociated ❖ LiO is not bioequivalent to prescription Li carbonate/citrate     ➤ 1 mg elemental = 5 mg Rx     ➤ 5 mg elemental = 27 mg Rx     ➤ 10 mg elemental = 54 mg Rx     ➤ 20 mg elemental = 107 mg Rx ❖ Do not exceed one capsule/day ❖ Any dose can affect thyroid function
Lithium aspartate	OTC supplement	1mg, 5mg, 10mg, 20mg elemental lithium	$5-$25	OTC	Aspartic Acid  ❖ Likely irrelevant to effect of Li+Aspartate ❖ Amino acid naturally produced in body ❖ Can function as a neurotransmitter at NMDA receptors in the brain ❖ The amount of aspartic acid in these supplements contributes minimally to       overall dietary aspartate intake

12-hr serum level is similar between IR and ER formulations

Important for Renal Outcomes

Current expert consensus favors once daily dosing at evening/HS for both IR and ER formulations

Five Strengths of Lithium

Strength	Blood level (mEq/L)	Approximate total daily dose	Status	Comments
Acute mania	0.8–1.2 (0.6–0.8 in older adults)	900–1,800 mg (may divide dose in acute phase)	FDA-approved	❖ The goal is to reach a serum level of 0.8–1.2 mEq/L as quickly as possible  ❖ As mania improves, decrease dose and consolidate dose to HS ❖ Target 0.8–1.0 for hypomania if monotherapy ❖ Lithium toxicity is typically defined as a serum level above 1.5      ➤ In older adults, toxicity can manifest at levels as low as 1.0–1.2
Maintenance of bipolar I disorder	0.6–0.8 (0.4–0.6 if older)	600–1,200 mg (single HS / evening dose)	FDA-approved	❖ Should be given as a single daily dose at HS / evening ❖ Levels are checked at 12 hours post dose  ❖ Maintenance target of 0.4–0.6 in older adults ❖ Some may need 0.8–1.0, but do not exceed 1.0 for maintenance ❖ Levels above 0.75 offer additional protection only against manic symptoms (Severus et al, 2008)
Maintenance of bipolar II or major depression	0.4–0.8	600 mg	Off-label	❖ Individualized, given as a single dose at ~HS per expert consensus  ❖ The lowest effective level to prevent mood episodes may be around 0.4 (Nolen et al, 2013) ❖ Target level may transiently increase to 0.8–1.0 for 2–3 weeks in the acute phase of depression or hypomania, individualized guided by tolerability
Neuroprotection, dementia, suicide prevention, cancer prevention	0.1–0.4	150–600 mg	Off-label	❖ “Low dose lithium” (no standard definition) ❖ The minimal or optimal effective dose for these indications is unestablished (may be higher or lower) ❖ 150 mg (smallest Rx capsule) is unlikely to require special monitoring unless renal impairment, age, or interacting meds. Side effects at this dose are not expected to exceed those of OTC microdose supplements. ❖ Hypothyroidism may be the only realistic risk at 150 mg
Nutritional supplement	<0.1	1–20 mg elemental lithium (5–107 mg Rx carbonate/citrate)	Off-label / non-FDA regulated OTC forms	❖ “Microdose lithium” (no standard definition) ❖ Typical intake ~0.5–3 mg elemental lithium/day from food and water (≈3–15 mg lithium carbonate/citrate equivalents) ❖ Physiological lithium supports synaptic, myelin, and microglial health; depletion may be an early, reversible driver of AD (Aron et al, 2025) ❖ Most ecological studies link higher natural lithium in drinking water with lower suicide and dementia rates ❖ Microdose lithium slowed progression of mild cognitive impairment to dementia (Shim et al, 2023; Strawbridge et al, 2023) ❖ 75 mg achievable with ¼ of Rx 300 mg tab (#90 = 1 year, $12 GoodRx) ❖ 60 mg QD with 1 mL of 300 mg/5 mL lithium citrate liquid ➤ available in bottles of 150, 300, 450, 473, 500 mL ❖ Lithium orotate outperformed lithium carbonate in an AD mouse model (Aron et al, 2025) ❖ 1 mg elemental OTC lithium orotate/aspartate ≈ 5 mg lithium carbonate/citrate

Prepublication access to Cafer’s Pharmacology, 2nd Edition Series: Prescribing Lithium will be available to subscribers very soon.

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