Lithium

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Oxidative metabolism

Evidence suggests that mitochondrial dysfunction is present in patients with bipolar disorder.[72] Oxidative stress and reduced levels of anti-oxidants (such as glutathione) lead to cell death. Lithium may protect against oxidative stress by up-regulating complex I and II of the mitochondrial electron transport chain.

Dopamine and G-protein coupling

During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression.[72] Additionally, the post-synaptic actions of dopamine are mediated through G-protein coupled receptors. Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. Studies found that in autopsies (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder.[72] Lithium treatment alters the function of certain subunits of the dopamine associated G-protein, which may be part of its mechanism of action.

Glutamate and NMDA receptors

Glutamate levels are observed to be elevated during mania. Lithium is thought to provide long-term mood stabilization and have anti-manic properties by modulating glutamate levels.[72] It is proposed that lithium competes with magnesium for binding to NMDA glutamate receptor, increasing the availability of glutamate in post-synaptic neurons.[72] The NMDA receptor is also affected by other neurotransmitters such as serotonin and dopamine. Effects observed appear exclusive to lithium and have not been observed by other monovalent ions such as rubidium and caesium.

GABA receptors

GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission.[72] It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss). Lithium has been shown to increase the level of GABA in plasma and cerebral spinal fluid.[74] Lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotective proteins.[72] Lithium's regulation of both excitatory dopaminergic and glutamatergic systems through GABA may play a role in its mood stabilizing effects.

Cyclic AMP secondary messengers

Lithium's therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms.[76][77] The cyclic AMP secondary messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impair receptor coupled stimulation of cyclic AMP production.[72] It is hypothesized that the dual effects of lithium are due to the inhibition of G-proteins that mediate cyclic AMP production.[72] Over a long period of lithium treatment, cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors.

Inositol depletion hypothesis

Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, involved in degrading inositol monophosphate to inositol required in PIP2 synthesis. This leads to lower levels of inositol triphosphate, created by decomposition of PIP2.[78] This effect has been suggested to be further enhanced with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction is affected by lithium.[79] myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigating the function of SMIT.[72] Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle.

https://en.wikipedia.org/wiki/Lithium_(medication)#Glutamate_and_NMDA_receptors

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Psychology Today: Could You Have a Lithium Deficiency?
https://www.psychologytoday.com/us/blog/evolutionary-psychiatry/201201/could-you-have-lithium-deficiency

TL;DR [Too Long; Didn't Read]

Lithium was the original "up" ingredient in 7-UP soda

Greek physicians thousands of years earlier were treating mental disorders with mineral water now thought to be high in lithium.

when lithium does work, it is a wonderful thing. Suicidal depression and mood swings relieved within the week. To this day, lithium is one of the few medications proven to decrease the risk of suicide.

When rats are given lithium-laced or lithium-free food for 6 weeks, the lithium-dosed rats had less arachidonic acid, and more 17-OH DHA, which is an anti-inflammatory metabolite of the fish oil, DHA. 17-OH DHA seems to inhibit all sorts of inflammatory proteins in the brain.

Interestingly enough, lithium has been shown to be the only effective drug (at least to slow the progression down) in another inflammatory, progressive, and invariably fatal neurotoxic disease, ALS, which is also known as Lou Gerhig's disease (2), and lithium is being studied in HIV, dementia and Alzheimer's disease.

Seems that counties with higher lithium levels in the water had a statistically significant decrease in the incidence of homicide, suicide, arrests for opiates and cocaine, and violent criminal behavior. Now to put things into perspective, a high lithium water content translates to about 2mg of lithium a day. Pharmacologic psychiatric doses typically start at 300mg daily.

Furthermore, lithium has been found to [improve] distractibility... and produce improvement of selective attention to stimuli... it prevents behavioral alterations owing to social isolation, lowers [aggressive behavior] owing to confinement...and causes a normalization of spontaneous motor activity.

In another paper studying lithium in the Japanese water supply, human longevity increased with the amount of trace lithium in the water.

the addition of a bit of lithium to the matrix will decrease the overall sodium gradient in the brain, decreasing neuroxicity, and increasing the efficiency of brain energetics. From the Japanese drinking water, lithium, and suicide study:
"It can be speculated that very low but very long lithium exposure can enhance neurotrophic factors, neuroprotective factors and/or neurogenesis."

On the negative side, Swedish researchers tested thyroid effects of trace lithium in the water in some villages in the Peruvian Andes. Some of these villages had some 10-20X the natural lithium in the food and water of the Japanese subjects, up to a maximum of 30mg daily (which is, of course, within an order of magnitude of the pharmacologic dose of 300mg).  They found that lithium in the water seemed to decrease active thyroid hormone levels and increase thyroid stimulating levels—lithium as a medicine will tend to cause hypothyroidism.

side effects: lithium is toxic to the thyroid and kidneys (and heart in high amounts), causes weight gain, is fatal in overdose

https://www.psychologytoday.com/us/blog/evolutionary-psychiatry/201201/could-you-have-lithium-deficiency