Lithium and its effects: does dose matter?

The scientific paper Lithium and its effects: does dose matter? by Manchia et al. examines the long-standing use of lithium in treating bipolar disorder and explores whether its clinical and biological effects are tied to dose levels. Traditionally, therapeutic benefits have been associated with serum concentrations above 0.6 mEq/L, particularly for stabilizing mood and preventing manic episodes. However, the authors question this threshold and investigate growing evidence suggesting that lower doses—or even microdoses—may also provide significant benefits, including reducing suicide risk and protecting cognitive function. The paper reviews clinical studies, epidemiological data, and biological mechanisms to assess lithium’s effects across a spectrum of doses.

For many years, lithium has been a trusted treatment for bipolar disorder (BD). It's well known for helping with both manic and depressive episodes and for preventing mood swings from coming back. One thing that makes lithium special is its ability to reduce suicide risk—a benefit that goes beyond just mood stabilization.

Doctors usually aim for a blood level of lithium above 0.6 mEq/L because that’s thought to be the most effective. But there’s a catch: lithium has a narrow therapeutic range, meaning the difference between an effective dose and a toxic one is small. This requires regular blood tests to keep levels safe. Despite this, recent research suggests that lower doses—or even tiny microdoses—may also have helpful effects, including protecting the brain and improving mental health.

This new scientific paper dives deep into the idea that lithium can still be useful at lower levels. It looks at the current research on standard doses, low doses, and microdoses of lithium and how each might affect bipolar disorder, cognitive decline, and suicide risk.

The study is a narrative review, meaning the authors examined a wide range of existing research without conducting new experiments. They used scientific databases like PubMed/Medline and searched for studies using terms such as “lithium,” “serum levels,” “bipolar disorder,” and “neuroprotective effects.” There were no time limits or strict filters on what studies to include. Instead, they used expert judgment and a strategy called “pearl-growing,” where key studies are used to find more related research.

Many clinical studies show that lithium levels of 0.6 mEq/L or higher are best for preventing manic episodes in people with bipolar disorder. In one study, patients taking standard lithium levels (0.8–1.0 mEq/L) had fewer relapses than those on lower doses. As the study explains, “standard levels (0.8–1.0 mEq/L) of lithium were associated with higher psychosocial functioning compared to low levels.”

However, some research suggests that lower levels—around 0.4 to 0.6 mEq/L—may still help prevent depressive episodes, especially in older adults or those more sensitive to lithium’s side effects. That said, lower levels might not be enough to stop manic symptoms.

One surprising finding is that trace amounts of lithium in drinking water could lower suicide rates. These lithium levels are far below what is used in medical treatment—just 70–170 µg/L. One early study from 1990 found a “negative correlation between lithium levels in drinking water and suicide incidence rates.”

Although these results are not consistent across all studies, and there are concerns about factors like socioeconomic status, they suggest that even very small amounts of lithium might have meaningful effects on mental health.

The study also found strong evidence that small doses of lithium could help protect the brain, especially in people at risk for Alzheimer’s disease or other types of cognitive decline. In a 12-month clinical trial, people with mild memory problems who took low-dose lithium (0.25–0.5 mEq/L) performed better on memory tests and showed fewer Alzheimer’s-related markers in their spinal fluid.

In another trial that lasted two years, lithium improved memory and attention in older adults. The study states, “low-dose lithium significantly outperformed donanemab, aducanumab, and placebo” on memory tests.

Some early trials have looked at lithium in amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disease. While results are mixed, some showed that low lithium levels (around 0.4–0.45 mEq/L) might help when combined with other drugs.

Animal studies back this up. In mouse models of Alzheimer’s disease, lithium microdoses helped improve memory, reduce brain inflammation, and even regrow brain cells. One study found that “low doses of lithium were able to reduce the expression of genes coding for pro-inflammatory cytokines while increasing anti-inflammatory cytokines.”

Researchers think that low-dose lithium helps by targeting specific pathways in the brain. It may boost a brain-protecting protein called BDNF (brain-derived neurotrophic factor) and block GSK-3β, an enzyme linked to Alzheimer’s and mood disorders. It also seems to reduce brain inflammation, which plays a role in both depression and cognitive problems.

Even tiny amounts of lithium in lab tests using rat brain cells increased BDNF levels significantly. In one test, BDNF in hippocampal neurons increased by 44% at a lithium dose of just 0.02 mM.

These biological effects give scientists a reason to believe that microdose lithium could be helpful even when blood levels are too low to treat bipolar disorder in the traditional sense.

This study opens the door to rethinking how lithium is used in mental health and brain care. While high doses are still needed to treat and prevent manic episodes, low or microdose lithium may work for other goals—like preventing depression in the elderly, lowering suicide risk, and protecting the brain from cognitive decline.

There’s also the hope that low-dose lithium might be safer, especially for people who can’t tolerate the side effects of standard lithium. As the study notes, “a subset of individuals with BD may present an optimal response to lithium therapy even at relatively lower lithium concentrations.”

These findings also highlight the need for more personalized treatment plans where lithium levels are tailored to each person’s unique health profile.

This scientific paper shows that lithium may have helpful effects at a range of doses—not just the standard levels used in bipolar disorder treatment. High-dose lithium remains the most effective for stabilizing mood, especially manic symptoms. However, lower doses may help prevent depressive episodes in older adults, reduce suicide risk, and even slow cognitive decline.

The big takeaway? Lithium might not be a one-size-fits-all treatment. Tiny doses could offer considerable benefits, especially in brain health, without the risks tied to higher levels. That makes lithium a promising area for future research in personalized medicine, neuroprotection, and mental health care.

As researchers continue to uncover how lithium works in the brain, low-dose and microdose options may one day become safe and effective tools for protecting mental wellness across a person’s lifetime.