I read a lot of studies on health and genetics (a lot!), and I keep finding research on an unexpected mineral – lithium – popping up. Topics such as circadian rhythm dysfunction, Alzheimer’s disease, telomere length, type 2 diabetes, and obesity… not the subjects that I expected to lead me back to lithium!
Recent research on lithium and health
The rest of this article lays out the evidence that increasingly shows the importance of this mineral in our health and longevity.
I think it is important to examine the research and look at the long-term effects and safety questions that always come to mind when talking about lithium.
There is a stigma, at least in my mind, around lithium, and I’ve hesitated at times to talk with friends and family about it. Funny, isn’t it, that no one has a hesitation about talking about other minerals such as magnesium or potassium.
Lithium is a mineral that is naturally found in food and drinking water, as well as being available in low dose supplemental forma.
The difference between lithium orotate supplements and prescription lithium carbonate
Let’s first look at the different type and amounts of lithium that are being referenced in the research studies. There is quite a range – from low levels in water to high levels in prescription meds.
For a lot of people, lithium brings to min the prescription medication for bipolar disorder. This is almost always in the form of lithium carbonate.
Prescription doses of lithium carbonate are around 900-1200mg/day, although this can vary based on the individual. For lithium carbonate, there is about 18.8 mg of elemental lithium per 100mg of lithium carbonate. So a 900mg dose would give about 170mg elemental lithium.[ref]
Lithium orotate usually comes as a 120mg supplement that gives about 5mg of elemental lithium. There are also 10mg supplements available as well.
The amount of lithium that we get in foods and drinking water varies based on the mineral content of the soil, with estimates of .5 to 3mg/day.
A provisional RDA of 1 mg/day has been recommended.[ref]
Breaking this down, a standard lithium orotate (5mg elemental lithium) supplement would average around twice the normal daily consumption from food and water, while the prescription dosages are closer to 80 to 100 times normal daily intake.
Alzheimer’s Disease and Naturally Occurring Lithium Levels
A 2017 study investigated Alzheimer’s rates and natural lithium levels in the drinking water in Texas.[ref] In an article about the study (much quicker read than the full paper), the lead author of the study explains the findings.
Essentially, water samples from almost all of the counties in Texas were tested for their natural levels of the mineral lithium, which varies depending on the concentration in rock and soil.
While Alzheimer’s rates have been on the rise everywhere, the researchers found that Texas counties with higher levels of lithium in the groundwater had less of an increase in Alzheimer’s rates compared with counties that had lower levels of lithium.
The study results are not a total surprise since previous studies had linked lithium to a decreased risk of dementia, but it is a great confirmation at a large scale population level. Aadditionally, observational studies show that patients taking prescription lithium are at a lower risk of dementia.
Other recent studies on lithium and Alzheimer’s disease:
- A 2015 review in the Journal of Alzheimer’s Disease analyzed the data from three randomized placebo-controlled clinical trials of lithium for treating Alzheimer’s patients. The trials found that lithium “significantly decreased cognitive decline as compared to placebo”.
- An October 2017 article in JAMA Psychiatry details a nationwide study in Denmark on the exposure to lithium in drinking water and the incidences of dementia. This was a large study, with 73,000+ dementia patients and 733,000+ people without dementia as the control. The study found that there was a decreased rate of dementia in people with naturally higher levels of lithium in their water (measured since 1986).
- A March 2018 animal study looked into the mechanisms of how lithium chloride lowers the risk of Alzheimer’s. It found that lithium chloride caused an increase in soluble β-amyloid clearance from the brain. In mice genetically bred to be a model of human Alzheimer’s, lithium chloride restored the clearance of soluble β-amyloid to the levels of normal mice. One big thing to note from this study is that lithium chloride did not affect β-amyloid that had formed plaque already.
- A study in 2015 looked at the effects of microdoses of lithium on a mouse model of Alzheimer’s disease. The study found that small doses of lithium carbonate in the drinking water of mice carrying the genes for Alzheimer’s disease caused a “decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in the cortex, when compared to non-treated transgenic mice.” This was a follow-up study to the human study in 2013 which showed that microdoses of lithium stopped the cognitive decline in Alzheimer’s patients.
You may be wondering at this point why all doctors aren’t handing out low doses of lithium to everyone at risk for Alzheimer’s. I think the quick answer is that it isn’t the ‘standard of care’ with enough clinical trials backing it up. A more cynical viewpoint is that lithium orotate (and aspartate) is a cheap, over-the-counter supplements without pharmaceutical companies sponsoring huge trials and pushing doctors to prescribe them. There seems to be a couple of ‘novel’ low-dose formulations in the works by pharmaceutical companies, though. [ref][ref][ref]
Telomeres, aging, and lithium?
Telomeres are the sequences of DNA that are found at the ends of each chromosome. This sequence protects the ends of the chromosome from deterioration. The common example given is to think of telomeres like the plastic on the end of shoelaces that protects the shoelace from fraying. When cells undergo cellular reproduction (mitosis), a little bit of the telomere is lost, and thus telomere length is considered a biomarker of cellular aging. Shorter telomere length is associated with several age-related chronic diseases including Alzheimer’s.
A recent transgenic mouse study found that lithium carbonate treatment leads to longer telomere length in mice that are bred to have Alzheimer’s disease. Interestingly, the normal mice had no effect on telomere length from lithium. A meta-analysis of 13 studies found that Alzheimer’s patients have shorter telomeres.
A human study looked at telomere length in patients with bipolar disorder. The study found that patients with bipolar disorder (not on lithium) and their relatives had shorter telomeres lengths than healthy, unrelated people. More interestingly, patients with bipolar disorder who were lithium-treated had longer telomere length than patients with bipolar disorder who were not taking lithium as well as relatives of bipolar patients.
Telomere length is a new field of investigation for researchers looking into so many different topics of aging, longevity, and disease. I don’t think the handful of studies on telomere lengthening from lithium can really lead to a conclusion; I look forward to seeing what future studies tell us on the topic.
Anti-Inflammatory action of lithium
Lithium exerts anti-inflammatory effects on the body — as well as pro-inflammatory effects under specific conditions. It has been known since the 1970’s that lithium inhibits prostaglandin synthesis and COX2 in some parts of the brain. While there is some debate on the topic, the majority of studies also point to lithium decreasing the production of TNF-α, a pro-inflammatory cytokine.[ref]
A recent cell study looked at the potential of lithium plus caffeine, theobromine, and catechin on the innate immune system and inflammation. The results showed that stacking lithium with caffeine, theobromine, and catechin was more effective as an anti-inflammatory than using them separately.
Another recent study looked at the anti-inflammatory effects of lithium on cells containing the SOD2 genetic variant rs4880. The study found that those with rs4880 alanine allele (G/G for 23andMe) had more of an anti-inflammatory response than those with the valine allele (A/A for 23andMe). This was a cell study though, so it is hard to know how well this translates to the whole body.
Obesity and Type 2 Diabetes
What surprised me about the Nov. 2017 study that I referenced above was that Texas counties with higher levels of lithium in their water also had lower levels of obesity and diabetes. I was surprised by this because one of the side effects of long-term, high dose lithium carbonate usage is an increased risk of hypothyroidism and possible weight gain.
Part of the explanation for the high levels of lithium in water correlating to lower levels of obesity and diabetes may be due to the effects on circadian rhythm. Another possible connection between lithium, obesity, and T2D may be the effect on blood glucose levels. In mice, certain levels of lithium reduced non-fasting blood glucose levels.[ref]
How is lithium affecting our body and brain?
For a long time, it wasn’t really understood how lithium worked for bipolar patients. (Quite a few psychiatric medications have been used for decades without fully understanding the mechanisms by which they work – or don’t work – for people.) Studies over the past decade or two have shed light on the neurobiological mechanisms of lithium and genetic studies have increased that knowledge.
One effect of chronic, low-dose lithium is an increase in BDNF, which is a protein that promotes the growth of nerve cells.[ref]
The American Chemical Society published a great overview of the topic in 2014, “Neuroprotective Effects of Lithium: Implications for the Treatment of Alzheimer’s Disease and Related Neurodegenerative Disorders“. One of the effects of lithium is its inhibition of GSK-3β (glycogen synthase kinase-3 beta), which is involved in neuronal cell development and energy metabolism. Genetic mutations of GSK-3β increase the risk of bipolar disease.
Lithium ions compete with sodium and magnesium ions in the body for binding sites in certain circumstances. Lithium’s inhibitory effect on GSK-3β is thought to be due, in part, to binding to a site that is normally occupied by magnesium. For a very thorough overview of the biochemical properties of lithium, including its effect on the activation energy of water within a cell and its effect on mitochondrial function, please read through “Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology“.
One action of GSK-3β is its inhibition of glycogen synthase, which is an enzyme involved in the reaction that takes excess glucose and turns it into glycogen for storage. Thus inhibiting GSK-3β increases glycogen synthesis and increases insulin sensitivity.[ref][ref]
GSK-3β and Circadian Rhythm:
Our body’s core circadian clock is run by a couple of core genes that are expressed during the day and a couple of core circadian genes that rise at night. It is this daily rise and fall of gene expression that then drives our internal daily cycles of waking and sleeping, temperature, and energy metabolism. GSK-3β is involved in phosphorylation of both the day and night core circadian genes.
Genetic variants that change our circadian rhythm are linked to increased risk for bipolar disorder. People with bipolar disorder who respond well to lithium therapy have changes in their circadian gene expression when they take lithium.[ref][ref][ref][ref]
Alzheimer’s disease is also strongly linked to circadian disruption. [ref]
Prevention of lead toxicity:
A recent article hypothesized that some of the benefits reported for higher lithium levels in the drinking water (lower suicide rate, lower homicide, and crime rates) could be due to lithium mitigating the effects of lead toxicity. “Animal studies demonstrated that lithium pre-treatment mitigates lead toxicity.”
Toxicity of lithium:
Lithium is considered by some to be an essential trace element, and complete elimination of lithium causes a decline in fertility, higher mortality rates, and behavioral abnormalities.[ref] But, like all substances, there is always a toxic upper limit.
Patients taking lithium carbonate or lithium chloride for mood stabilization show a variety of side effects, depending on dosing. Most patients taking prescription lithium carbonate get blood tests done at regular intervals to determine their serum lithium levels. Plasma lithium levels above 1.2 mM cause nausea, diarrhea, and tremor. [ref] Other side effects noted by patients taking lithium chloride include increased thirst and urination, weight gain, and mental dullness. It was theorized that bipolar patients taking lithium may drink more calories due to increased thirst, thus causing weight gain.[ref] Other side-effects of higher doses of lithium include increased risk of kidney problems and interaction with hypothyroidism.
Lithium orotate, as a supplement, comes in much, much lower doses than the lithium in prescription lithium carbonate. There is one case report, though, of nausea and mild tremor from a teenager taking 18 tablets of a supplement that contained 100mg of lithium orotate.
Side effects of Lithium Orotate:
There aren’t any recent research studies or case reports (other than the one above) on lithium orotate side effects, so this section is n=1 personal experiences and internet hearsay. A couple of people that I’ve talked with have reported that lithium may make them tired or a little sleepy during the day. An article from a holistic doctor who suggests lithium orotate to most of his patients notes that very few have any side effects. He does suggest taking lithium orotate before bed instead of during the day. This makes sense in light of the circadian rhythm effects via GSK-3B inhibition. A study from 1986 on using lithium orotate for alcoholism listed minor side effects to the treatment (included more than just lithium orotate -e.g. low carb diet and other supplements) as loss of appetite, mild apathy, and muscle weakness. [ref]
As with any supplement, I suggest talking with your doctor if you are on any medications or if pregnant or nursing.
The study on stacking lithium with caffeine, theobromine, and catechin for an increased anti-inflammatory effect was interesting. If you are considering this combo, a good source of theobromine is cacao nibs. Catechins and caffeine are found in green tea.
Originally published April 2018.