Lithium is a well-known treatment for bipolar disorder at high therapeutic doses due to its neuroprotective and mood-stabilizing effects. However, emerging evidence suggests that lithium at much lower doses—naturally present in drinking water and food—may play an important role in supporting mental health and overall well-being. Some studies associate trace lithium intake with reduced suicide rates and lower levels of violence, prompting researchers to propose a provisional daily intake of 1000 μg for a 70-kg adult.

Although lithium is not officially recognized as a micronutrient, it may meet the criteria due to its diverse biological actions and potential role in nervous system function, metabolism, and neural communication.

Mechanism of Action: Complex and Multifactorial

The biochemical mechanisms underlying lithium’s actions are multifactorial and closely linked to enzymes, hormones, and vitamins. While many aspects remain unclear, lithium’s cellular effects may result from competition with Na+ and Mg2+ ions due to their similar atomic radii. This competition affects key enzymes and signaling pathways, altering neurotransmitter synthesis and release, as well as cellular metabolism.

Lithium has been shown to regulate intracellular signaling pathways by stabilizing sodium-potassium ATPase and modulating cAMP- and Ca2+-dependent cascades. It reduces intracellular calcium concentrations while enhancing the uptake of major neurotransmitters such as noradrenaline, serotonin, and dopamine. Moreover, lithium’s influence on phosphatidylinositol and adenylyl cyclase systems affects synaptic neurotransmitter signaling, while its inhibition of glycogen synthase kinases plays a role in cell proliferation, metabolism, and apoptosis.

Additional studies suggest that lithium can stimulate the expression of neuroprotective factors such as brain-derived neurotrophic factor (BDNF), regulate circadian rhythms by modulating clock genes, and normalize hypothalamic-pituitary-adrenal (HPA) axis function. It may also enhance the transport of vitamin B12 and folic acid to the brain, although findings on this remain controversial.

Lithium’s Role in Neuroprotection and Immunomodulation

Lithium therapy has been associated with increased gray matter density and enlargement of the amygdala and hippocampus. It promotes the production of neural stem cells and protects against oxidative stress. In addition to its neuroprotective properties, lithium has immunomodulatory effects, inducing granulocytosis and lymphopenia while enhancing the activity of monocytes, natural killer (NK) cells, and B lymphocytes. It stimulates the synthesis of IgG and IgM immunoglobulins, highlighting its complex role in immune regulation.

Lithium in the Diet

Lithium is naturally present in various foods, with nuts being the richest source, followed by cereals, fish, potatoes, tomatoes, cabbage, and certain mineral waters. Animal-based foods contain much less lithium, and cultivated mushrooms are nearly devoid of it if grown in lithium-deficient substrates. In many regions, dietary lithium intake depends on the soil’s lithium content, which varies geographically. A vegetarian diet rich in grains and vegetables generally provides more lithium than a diet focused on animal proteins.

Lifestyle, Medications, and Lithium Clearance

Lithium requirements may increase under certain physiological and lifestyle conditions. Stress and elevated cortisol levels, as well as dietary deficiencies in other micronutrients like magnesium, zinc, and B vitamins, can increase the demand for lithium. Several medications and dietary factors also affect lithium clearance:

• Reduced clearance: Low-sodium diets, dehydration, antihypertensive medications (e.g., ACE inhibitors, beta blockers), and non-steroidal anti-inflammatory drugs (NSAIDs, excluding aspirin) reduce lithium excretion, potentially increasing its retention.
• Increased clearance: High sodium intake, caffeine, theophylline, nifedipine, and certain diuretics accelerate lithium excretion and may raise the body’s lithium requirements.

Pregnancy is another state associated with increased lithium clearance, which could alter lithium needs during this period.

The Case for Lithium as a Micronutrient

Given its broad biological activity and potential neuroprotective and immunomodulatory effects, lithium might indeed act as a micronutrient. However, it is important to note that the majority of these effects have been observed with high, therapeutic doses. Whether similar outcomes occur at the much lower doses found in food and drinking water remains uncertain and requires further investigation.

Currently, no key biological function of lithium has been identified that is essential for the lifecycle of living organisms. Nonetheless, its wide spectrum of action and safety at low doses make it an intriguing candidate for further research. Understanding its role in human health could open new avenues for improving mental well-being and preventing mood disorders naturally.

Is Lithium a Micronutrient? From Biological Activity and Epidemiological Observation to Food Fortification