Low-Dose Lithium: A New Frontier in Mental Health Treatment

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Rethinking Lithium

Lithium has long remained at the forefront of effective treatments for bipolar disorder.¹ However, due to safety concerns, a stigma often hangs over its use. For decades, data have slowly been building that lithium has a much wider dose-response curve with potential utility at lower doses. With my own patients, low and microdose lithium has been invaluable for helping with irritability, anger, and addiction. As a treatment, low-dose lithium can act like a bridge between medications and integrative approaches, supporting well-being with reduced adverse effects.

While not generally accepted as a nutrient, some authors have made strong arguments—based on animal research and ecological studies—that lithium may fit the definition of a mineral.² This may help explain why microdoses of lithium are often helpful: patients may actually be struggling with a lithium deficiency.

Arguably, the strongest evidence for low-dose or even nutritional doses of lithium is for the prevention of dementia and suicide. Recent research and my own clinical experience have demonstrated additional clinical applications, including for depression, substance use disorder, and irritability (Table).

Table. Positive Studies on Low-Dose Lithium

Defying Cognitive Decline: How Low-Dose Lithium May Prevent Dementia

Initial evidence for the effects of lithium on cognitive decline and dementia were uncovered in patients with bipolar disorder. Bipolar is well known to increase the risk of developing dementia. An analysis from 2020 found that a diagnosis of bipolar disorder tripled the risk.³

In contrast, studies on patients with bipolar disorder who were on lithium as a mood stabilizer found that lithium treatment significantly reduced the risk of dementia.⁴ Based on the findings, clinical trials started exploring the use of lithium as a direct treatment for Alzheimer disease. While some of the initial studies were mixed,^5,6 further clinical trials have found benefits for slowing or halting the progression of cognitive decline with lithium treatment.

A trial by Nunes et al even found potential benefits with 300 µg of lithium per day.⁷ At this microdose, patients with Alzheimer disease remained stable over 15 months as patients on placebo continued to decline. At the end of the study, Mini-Mental State Examination (MMSE) scores had dropped to 14 in the placebo group, whereas the lithium group held steady at just below 20.

In 2011, a trial of low-dose lithium for cognitive decline also found benefits.⁸ Treatment included 12 months of low-dose lithium, with blood levels between 0.25-0.5 mmol/L. As compared with placebo, lithium-treated subjects had a decrease in phosphorylated tau in cerebrospinal fluid (CSF) and better cognitive function.

After additional data was collected on the same subjects over the next 2 years, outcomes were further improved.⁹ Placebo patients worsened, whereas the patients on low-dose lithium remained mostly stable. Memory and attention were significantly better with lithium. Lithium also increased levels of amyloid-beta peptide in the CSF at 3 years. The increase was hypothesized to be due to an increased clearance of amyloid plaques with long-term lithium treatment.

The final analysis of these patients was published in 2024.¹⁰ While a significant subset of patients had died, the patients who had received lithium had higher MMSE scores vs those who were given placebo: 25.5 vs 18.3, respectively. Verbal fluency testing also showed marked advantages with lithium treatment with scores of 34.7 vs 11.6.

One of the most recent meta-analyses for patients with bipolar disorder found that pharmaceutical lithium reduces dementia risk by half.³ A separate meta-analysis of both the preclinical and clinical research found that lithium displays neuroprotective effects with clinical data showing positive results in patients with Alzheimer disease.¹¹

Increasing cases of Alzheimer disease and dementia are one of the more sobering realities we face in medicine, as cases are projected to increase precipitously over the coming decades.¹² Considering the challenges of our aging population, lithium may be a cost-effective augmentation strategy to fill treatment gaps for dementia prevention initiatives.

A Life-Saver in Microdoses: The Potential of Lithium in Suicide Prevention

Beyond the potential benefits for cognitive health, lithium may also be useful for another significant unmet need: suicide prevention. Suicide rates have been mostly on the increase in the United States since 2001.¹³ Suicide is the second leading cause of death among individuals aged 10 to 34.¹³ And while there is controversy around the research, in total, it strongly suggests that lithium has antisuicidal properties.

Evidence for microdoses reducing suicide risks comes from a large and growing number of ecological studies exploring suicide rates and lithium levels in tap water.¹⁴ Lithium is naturally found in the environment, with tap water being a significant component of the lithium present in the diet.² Tap water levels can vary dramatically from locality to locality providing natural variations in exposure.¹⁵ Lithium levels in drinking water are usually measured in micrograms per liter, suggesting that lithium may have relevant neurological effects even at these low levels.

In 1970, the first report about lithium concentrations in tap water and local state mental health hospital admissions found an inverse correlation.¹⁶ As lithium exposure from groundwater increased, local hospital admissions were reduced. Over the ensuing decades, numerous research groups analyzed local water supplies and mental health outcomes, most often as suicide rates. A meta-analysis of this data was published in 2021, including 113 million individuals from 2678 regions around the world.¹⁴ The study found that higher groundwater lithium was correlated with reduced suicide and mental hospital admissions. Since the meta-analysis, most of the additional studies have continued to confirm the relationship.^17,18

For patients with bipolar disorder, standard pharmaceutical doses of lithium have also shown consistent effects for lowering suicide risk.¹⁹ Tentatively, the results of the research suggest that lithium’s antisuicidal effects occur through a broad range of dosage levels. Considering the rising tide of suicides in this country and the safety of lithium when utilized in lower doses, lithium may deserve additional consideration as one component in a multiprong approach for suicide prevention.

A Subtle Shift: The Promise of Low-Dose Lithium for Resistant Depression

While the data shows that doses close to and including standard pharmaceutical levels are more effective for treating mania and depressive episodes in bipolar disorder,²⁰ the research also has shown that lower doses are well-tolerated and may provide benefits in some cases of major depressive disorder.

An open-label study in severely depressed patients who were unresponsive to an initial trial of venlafaxine found significant benefits with low-dose lithium augmentation.²¹ Lithium, at doses between 300 and 450 mg, does not require blood monitoring and was well tolerated. The authors argue that low-dose lithium may be a preferable first choice in “non-emergent situations'' due to its ease of use and higher tolerability. A separate, small, dose-response trial using lithium augmentation for treatment-resistant depression that was unresponsive to sertraline found that both 400 mg and 800 mg of lithium were equivalent in their clinical response.²² In patients with severe depression, a subset of patients on citalopram plus 300 mg of lithium carbonate achieved therapeutic blood levels and had significantly higher remission rates of suicidal thoughts.²³ In patients with multiple sclerosis, low-dose lithium (between 150 and 300 mg) improved depression symptoms better than an observation period without lithium.²⁴

However, not all research findings on low-dose lithium treatment for depression have found benefits. In patients on tricyclic antidepressants who were resistant to treatment, lithium at 750 mg provided significant benefits whereas doses of 250 mg did not.²⁵

Breaking Chains: Lithium’s Role in Addiction Recovery

Substance use and addiction are typically difficult to treat. Clinical trials are often plagued with high dropout rates, a predictor of relapse.²⁶ As such, interpreting the data can be difficult. While the results are mixed, some research and my own clinical experience suggests that low-dose lithium may have a role for helping to treat addiction.

An early study using an integrative medicine approach for treatment using 6 mg of lithium (as 150 mg of lithium orotate), combined with other supplements and dietary recommendations, found benefits for patients with alcohol use disorder.²⁷ Of the treated patients who stayed on lithium, 36 of 42 had a history of hospitalization due to severe alcohol use. With lithium treatment, almost a quarter of patients remained alcohol free for up to 3 to 10 years. None of the patients needed additional hospitalizations. However, the study had numerous limitations, including a high drop-out rate and only included patients who managed to continue lithium treatment.

In patients recently detoxed from alcohol, low-dose lithium (defined as blood levels between 0.3 and 0.5 mmol/L) or a vitamin placebo were administered.²⁸ Due to a previous study noting that patients who detoxified from alcohol often displayed manic-type symptoms, the study was implemented to see if lithium could address these symptoms. For the detoxed patients on lithium, manic symptoms significantly decreased, fully normalizing over a 2-week period. For controls, manic symptoms did not significantly change and remained elevated.

The most recent study of interest utilized 150 mg of lithium carbonate for patients at a residential addiction center as a replacement for antidepressants or benzodiazepine medications.²⁹ With the implementation of low-dose lithium, opiate doses dropped by 50%, benzodiazepine use was almost eliminated, and atypical antipsychotics were reduced by more than two-thirds. Polypharmacy, or the use of 5 or more psychiatric medications in a treatment regimen, was reduced by almost 80%. For patients on lithium, program completion rates increased by almost 100%. In total, low-dose lithium effectively reduced medication use and improved residential addiction treatment outcomes.

Cooling the Fire: Microdose Lithium for Anger and Irritability

Irritability and anger are not official diagnoses in the DSM. As such, they are often considered as secondary to other conditions like depression or bipolar disorder and not treated directly. In children, disruptive mood dysregulation disorder (DMDD) encompasses problems with anger and irritability.

From my own clinical experience, irritability often has roots in metabolic, environmental, and nutritional factors. While older studies on prison inmates suggest that lithium may have utility for decreasing anger and aggressive behaviors,^30-32 in my experience, irritability is one of the most powerful indicators that a patient will benefit from low-dose or microdoses of lithium. For any patient struggling with irritability, especially when there is a family history of addiction, bipolar disorder, or depression, elemental lithium between 2 and 10 mg, typically as lithium orotate, has often provided significant relief. For children with DMDD, lithium can sometimes provide profound benefits, helping to safely decrease symptoms when used in such low doses.

The Untapped Potential of Low-Dose Lithium

Lithium has long had a starring role in standard medicine as a therapeutic option for bipolar disorder and as an adjunctive treatment for depression. Nonetheless, research and my own clinical practice with thousands of patients have found that lithium’s efficacy is still very relevant at lower doses. From an integrative medicine perspective, microdoses of lithium may act more like a nutrient,³³ improving mood, reducing irritability, and supporting cognitive function. These low-dose benefits of lithium extend from hundreds of micrograms up through the standard dosage range of lithium used for bipolar disorder treatment.

Dr Greenblatt is the chief medical officer of Psychiatry Redefined, an online educational platform for integrative and functional psychiatry.

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