Overview of Lithium
Found primarily in plant-derived foods, as well as drinking water, lithium has multiple benefits on nervous system functioning, as well as supporting healthy inflammation pathways, and promoting positive mood and outlook.
Interest in lithium affecting human behavior dates back to the mid-19th century, but continued research keeps the conversation about its clinical applications more engaging than ever.
Take, for example the studies on drinking water. Data published in 1990 showed that counties in Texas with little to no lithium in their drinking water had significantly higher incidences of violent crime than counties with water lithium levels ranging from 70-170 mcg/L. In a later study in Japan, lithium levels in drinking water were also significantly and negatively associated with suicide rates.
Again, as recently as 2017, an individual cross-sectional survey investigated the association between lithium levels in tap water and overall mental health problems with adolescents. A total of 3,040 students responded to a self-reported questionnaire and lithium levels in tap water were measured. Again, lithium levels in tap water were inversely associated with depressive symptoms and interpersonal violence.
These results all suggest that lithium at low doses has a generally beneficial effect on human behavior, which “may be associated with the functions of lithium as a nutritionally-essential element.”
From a chemical perspective, lithium looks a lot like sodium, but is actually a smaller molecule. Lithium’s exact biochemical mechanisms of action are multifactorial, and seem to interplay with a number of enzymes, hormones, vitamins and growth factors.
Lithium’s Functions
Although evidence has been sufficient enough to give lithium its status as an essential trace element, with a provisional RDA of 1,000 mcg/day for a 70kg adult, our understanding of lithium’s role in the body continues to evolve.
For example, we now understand that lithium’s main mechanisms of action appear to come from its ability to inhibit glycogen synthase kinase-3 activity (GSK-3β), and also to induce signaling mediate by brain-derived neurotrophic factor (BDNF). GSK-3 is being explored as an integral component in inflammatory processes that plays a role in the cascade of degenerative diseases. The inhibition of GSK-3 may provide protection from inflammatory conditions, suggesting that targeting the inhibition of GSK-3, in some cases, may prove beneficial.
A recent animal study looking at the degeneration of the central auditory system due to aging found an increased GSK-3β activity and a corresponding decrease in Wnt/β-catenin signaling. The administration of lithium chloride (Licl), an “activator” of Wnt signaling pathway, was found to “attenuate the neurodegeneration and auditory cortex apoptosis.”
The link between GSK-3β and lithium seems well-established, with lithium directly inhibiting GSK-3β activity by competitively inhibiting Mg2+ binding to the active site of the enzyme. This has been the primary mechanism of action investigated in choosing lithium as a mood stabilizer. Inhibition of GSK-3, however, does not fully explain lithium’s neuroprotective effects. Lithium also has transcriptional effects.
In one study, the transcriptional effects of lithium were investigated using Drossophila S-2 cells and adult fly heads. Lithium was found to regulate transcription of immune, neuronal and metabolic pathway genes.
Lithium inhibits GSK-3β activity, and it also appears to augment GluN2A receptor expression in the prefrontal cortex. GluN2B might be important for neural plasticity, making synapses “bidirectionally malleable.”
One study suggests the presence of GluN2B subunits may strengthen individual synapses and currents in the prefrontal cortex. It appears that GSK-3β activity seems to negatively regulate GluN2A expression, and lithium may influence prefrontal-related circuits through intricate mechanisms associated with neuronal plasticity and neuromodulation.
Implications for Mood Health
As a modulator as well as inhibitor of the body’s primary excitatory receptor, N-methyl-D-aspartate receptor (commonly referred to as NMDA-R), lithium has demonstrated both mood-elevating and anti-anxiolytic properties as well as having a role in gut health. Given these roles of lithium, it makes sense that this trace element has implications for mood health.
Lithium’s role in both B12 and folate utilization is an indication of this. Vitamin B12 helps to maintain healthy nerve cells and functioning. Vitamin B-12 deficiency can manifest in compromised digestion, which in turn can cause neurological disorders and inflammation. A range of evidence points to increased inflammation in stress-related and mood disorders. Also, adequate levels of Vitamin B-12 are significant for maintaining homeostatic homocysteine levels, which help to reduce depression and anxiety, as well as cognitive decline. In summary, lithium’s role in helping to reduce inflammation has also been associated with promoting mood health. Lithium also allows for folate utilization having additional implications for mood health. Folate plays a significant role in serotonin neurotransmission, further associated with positive mental health.
Antioxidant Properties
Long-term and low-dose exposure to lithium may exert anti-aging capabilities and has been found to decrease mortality. Lithium helps to strengthen the health and resilience of neurons, demonstrating neurotrophic and neuroprotective effects in a wide range of clinical and translational models. In small amounts, Lithium has been suggested to have strong antioxidant properties in cells compromised by stress and toxins.
Antioxidants have been suggested to have calming effects on adrenal gland functioning, and may help to reduce distress. Antioxidants also help to protect the body by counteracting free radicals. Research demonstrates this may improve upon symptoms of emotional distress and compromised mood.
Individual Responses to Lithium
Its role as an active homeostatic regulator seems without question. However, a recent literature search for biomarkers associated with lithium’s effects found that people respond differently to varied amounts of lithium. In other words, one size does not fit all. A person’s diet, lifestyle and genetics must be considered, as well as their brain cells, as some people’s neurons show weakened excitability and some hyper-excitability when exposed to lithium.
In this ongoing conversation surrounding lithium and its clinical relevance, one must duly note this lightest of the alkali metals has a critical role in optimal health as an essential trace element, and a provisional RDA of 1 mg/day.
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