Let me cut to the chase:
– for some people, supplementing with low-dose lithium orotate helps with anxiety, mood, and anger issues,
– for others, lithium orotate supplements will have little or no noticeable effect on mood.
This article explains the research on lithium, digs into some of the genetic connections, and explores the link to cellular vitamin B12 levels.
What does lithium orotate do?
Before going any further, I want to clarify that I’m generally referring to the over-the-counter mineral supplement of lithium orotate in this article. This is different than the prescription doses of lithium carbonate used for bipolar disorder.
Lithium is a naturally occurring mineral found in foods at concentrations dependent upon the mineral content of the soil. It is also an essential element that people need – in small amounts. High amounts of lithium are toxic.[ref]
We typically get about 3 -4 mg in our food each day, but it varies a lot based on where you live and where your food was grown. In comparison, lithium orotate supplements come in doses that contain 5mg to 10 mg of elemental lithium.
Studies on lithium levels found naturally in drinking water:
Lithium is also found in drinking water in varying amounts depending on the lithium levels in the soil. Looking at the studies on areas with higher vs. lower lithium levels can give an idea of what a low-dose lithium supplement could affect.
Epidemiological studies find that areas of higher lithium are linked to decreased depression and decreased aggression.
- A meta-analysis of studies, which included 3.7M people, showed that suicide rates are more than 50% lower in areas with higher lithium in the drinking water.[ref]
- Another study found that homicide rates are lower in areas with higher levels of lithium in the water supply.[ref]
More than 800,000 people die each year of suicide, so the link between higher lithium and lower suicide rates is important — and backed by other research. In addition to the epidemiological studies of lithium in drinking water reducing suicide rates[ref], research on prescription lithium chloride also shows that it reduces suicide attempts, independent of its effect on mood in bipolar disorder.[ref]
Safety studies specific to lithium orotate:
A 2021 study investigated the safety of using lithium orotate. The researchers found that there were no genotoxic effects, meaning that it won’t damage DNA. In the animal study, there were no adverse effects found and no organ damage. The highest dose tested in animals was 400 mg/kg/day with no observable adverse effects.[ref]
Lithium, Polyunsaturated Fatty Acids (PUFA), and Choline
Several studies have found that lithium reduces arachidonic acid (inflammatory polyunsaturated fatty acid) production in the brain. Some researchers theorize is that this reduction of neuroinflammation is one way that prescription-strength lithium chloride works for bipolar disorder.[ref][ref]
Animal studies using higher levels of lithium, similar to levels from prescription lithium, show that within a month, there are changes in lipid levels in the brain. Specifically, choline and phosphatidylcholine levels increase while sphingomyelin levels decrease.[ref] Phosphatidylcholine and choline are well-studied for brain benefits and often used as supplements for boosting cognitive function.
What is the connection between lithium orotate, mood, and B-vitamins?
Dr. Amy Yasko, a naturopathic doctor with a Ph.D. in immunology, has written extensively on why she thinks some individuals need and use more of the mineral lithium than others. She recommends checking lithium levels for all autistic children and suggests supplementing with low levels of lithium for MTR/MTRR mutations. Dr. Yasko states that “Lithium not only plays a role in mood, glutamate control and limiting aggression but also has been shown to be involved in B12 transport.”[ref] She recommends making sure your lithium level is in balance before adding in B12.
In addition to Dr. Yasko’s clinical work associating B12 and lithium, there are several studies showing this as well.[ref]
- People who take prescription levels of lithium long-term for bipolar disorder tend to have lower serum levels of B12 (thus possibly more B12 in cells) than people using other medications.[ref]
- A study that analyzed lithium in hair samples in a variety of locations and populations “suggests a role of lithium in the transport and distribution of vitamin B12.”[ref]
- A recent study (Feb. 2020) finds that for animal models of manic/depressive disorder, lithium works better in conjunction with folate (vitamin B9).[ref]
Why is vitamin B12 important to your mood?
Vitamin B12, along with folate, is essential for the production of tetrahydrobiopterin (BH4) which, in turn, is involved in the production of the neurotransmitters serotonin, melatonin, dopamine, norepinephrine, and epinephrine.[ref]
A deficiency of vitamin B12 has been shown to cause symptoms which “may include agitation, irritability, negativism, confusion, disorientation, amnesia, impaired concentration and attention, and insomnia; while psychiatric disorders that may be diagnosed in patients having vitamin B12 deficiency include depression, bipolar disorder, panic disorder, psychosis, phobias, and dementia”.[ref]
GSK3B, lithium, circadian rhythm, and mood:
Another way that lithium interacts with mood is through inhibiting GSK3B (glycogen synthase kinase 3beta). Named for its initially discovered link to glycogen synthase, GSK3B acts on many different pathways in the body including circadian rhythm[ref] and neuronal plasticity.
Dysregulation of GSK3B is linked to bipolar disorder, depression, and Alzheimer’s disease.[ref]
Lithium competes with magnesium in binding with GSK3B, and through this binding inhibits GSK3B. Through its impact on GSK3B, researchers think lithium can modulate the activity of many different pathways. Additionally, lithium may take the place of magnesium in other proteins that need magnesium. [ref]
Does lithium orotate work for everyone?
Quick answer: lithium orotate does not seem to improve mood issues for everyone.
Anecdotally, for some people, a 5 or 10mg lithium orotate supplement makes them less irritable, angry, or anxious. It may take a week to notice the effect on mood. But other people don’t find a noticeable difference in mood. (There may be other benefits to lithium, though, such as Alzheimer’s prevention.)
It is likely that genetics, diet, stress level, and daily exposure to lithium through drinking water/foods all come together to determine whether supplemental lithium affects mood for an individual.
What is ‘microdosing’ lithium?
I’ve seen several articles lately talking about microdosing lithium. Essentially, this seems to mean taking a low dose of lithium.
While it seems like some people just like the buzzword (perhaps with the connotation of microdosing LSD), several research studies reference microdosing of lithium for Alzheimer’s disease. For example, clinical trials using a 300 mcg dose of lithium refer to it as microdosing, which makes sense in comparison with trials that used 150 – 600mg doses.[ref][ref][ref]
I bring up microdosing, because the right dose of lithium for Alzheimer’s prevention or mood regulation is likely to be different for everyone. If you decide to try lithium orotate as a supplement, you may want to experiment with a range of different doses to see what works best for you.
Genetic variants that could affect lithium orotate:
Dr. Yasko lays out her research on the effects of lithium. She makes the case that lithium, through the inhibition of thioredoxin, can increase COMT, which is an enzyme that regulates and degrades dopamine, epinephrine, and norepinephrine.
I want to be really clear here… This information is based on online recommendations for clinicians. There are no research studies that specifically show that lithium orotate works to improve mood for people with these variants.
MTR Genetic Variants:
Check your genetic data for rs1805087 (23andMe v4, v5; AncestryDNA):
- A/A: typical
- A/G: increased enzyme activity, possibly more responsive to lithium orotate supplements for irritability, anxiety
- G/G: increased enzyme activity[ref] possibly more responsive to lithium orotate supplements for irritability, anxiety
Members: Your genotype for rs1805087 is —.
The rs1805087 variant is also known as A2756G. The G allele causes an increase in activity, thus possibly causing a decrease in methyl groups available for other pathways to use and also using up methylB12 more quickly than normal.[ref]
MTRR Genetic Variants:
Methionine synthase reductase has several fairly common variants that affect the production of the MTRR enzyme which regenerates vitamin B12 (methylcobalamin) for use by MTR and other enzymes. The variant rs1801394 is also known as A66G, and it decreases this enzyme’s efficiency. It is a fairly common variant carried by about half the population.
Check your genetic data for rs1801394 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs1801394 is —.
COMT genetic variant: rs4680
One well-studied variant of the COMT gene is rs4680, often referred to as Val158Met. In looking at research studies, the G is “Val” and the A allele is usually noted as “Met”.
- The G allele (Val) has higher COMT enzymatic activity, causing a more rapid breakdown of the neurotransmitters and thus lower levels of dopamine. In most populations, the G allele is the most common.[ref]
- The A allele (Met) has lower COMT enzyme activity and thus higher levels of dopamine. This variant of the COMT enzyme seems to have lower activity because it breaks down faster at normal body temperature.[ref]
Check your genetic data for rs4680 (23andMe v.4 and v.5; AncestryDNA):
- G/G: higher COMT activity, lower dopamine & norepinephrine, higher pain tolerance (Val)
- A/G: intermediate COMT activity (most common genotype)
- A/A: 40% lower COMT activity, higher dopamine & norepinephrine, lower pain tolerance (Met), reduced stress resiliency
Members: Your genotype for rs4680 is —.
Genetic variants that impact lithium carbonate (prescription lithium):
Lithium carbonate in prescription doses for bipolar disorder has several interesting genetic studies on it. Keep in mind that the amount of lithium in the prescription medication is orders or magnitude higher than supplemental lithium orotate, so the genetic studies may not correlate.
What I find interesting about these genome-wide genetic studies is the link between lithium acting on the ion channels that directly affect neurons.
ACCN1 gene: codes for a cation channel in neurons that is responsive to sodium, potassium, and lithium
Check your genetic data for rs11869731 (23andMe v5):
- C/C: may be more likely to respond to lithium for bipolar disorder[ref][ref]
- C/G: typical response
- G/G: typical response
Members: Your genotype for rs11869731 is —.
CACNG2 gene: calcium channel gamma-2 subunit
Check your genetic data for rs2284018 (23andMe v4, v5):
- C/C: may be more likely to respond to lithium for bipolar disorder[ref][ref]
- C/T: may be more likely to respond to lithium for bipolar disorder
- T/T: typical response rate
Members: Your genotype for rs2284018 is —.
BDNF gene: codes for brain-derived neurotrophic factor, which is important in the way neurotransmitters work and in neuroplasticity.
Check your genetic data for rs6265 Val66Met (23andMe v4, v5; AncestryDNA):
- T/T: decreased BDNF[ref] referred to in studies as Met/Met; introversion, resilient to adverse events, a quicker decline in Alzheimer’s[ref][ref][ref] may have a better response to lithium carbonate for bipolar disorder[ref]
- C/T: somewhat decreased BDNF, referred to as Val/Met;
- C/C: typical BDNF, referred to as Val/Val
Members: Your genotype for rs6265 is —.
Lithium orotate is available in health food stores and online in 5 mg – 20mg doses.
Natural Sources of Lithium:
Lithium occurs naturally in spring water in certain areas and can range from less than 1 mcg/l to well over 100 mcg/l. Additionally, it is also found in the soil and can be taken up by plants depending on the concentration in the soil. Here is a map of a few places in the US showing lithium levels in the well water.
A Texas study showed that counties with higher lithium levels in their water had significantly lower violent crime rates and suicide rates.[ref] There have been several more studies completed more recently in other countries that show the same decrease in suicide and homicide with higher levels of naturally occurring lithium.
High dose, prescription lithium carbonate
For well over a century, lithium has been used in high pharmacological doses (typically 300-1200+ mg per day) to treat bipolar disorder and other mood disorders.
Studies on lithium carbonate (prescription) and genetic variants
- People with a BDNF (brain-derived neurotrophic factor gene) variant known as Val66Met had a better response to lithium for bipolar mood disorder.[ref] (Check your BDNF variants here.)
- In looking at the SLC1A2 -181A>C variant (rs4354668) T/T homozygotes had a lower number of manic/depressive episodes while on lithium.[ref]
- A study showed that those with the serotonin transporter gene 5-HTTLPR variant known as the short/short variant had a worse response to lithium for mood disorders.[ref] (Check your serotonin genes here)
Safety of taking lithium:
Prescription levels of lithium do come with long-term side effects including higher risks of hypothyroidism and kidney problems.
- A meta-study on side effects from prescription dosages of lithium carbonate used for mood disorders showed that lithium increased the risk for hypothyroidism and weight gain. It also showed an increased risk of renal failure, with the overall risk being 0.5%.[ref]
Lithium orotate has one case study (of one patient):
- Lithium toxicity from an internet dietary supplement, 2007 — case study of an 18-year-old who took 18 tablets at once containing 120mg of lithium orotate. After a trip to the emergency department with nausea, she was discharged within a few hours to a psychiatric hospital.
Up your zinc intake? A recent animal study showed that increasing zinc intake eliminated the deleterious thyroid effects of lithium carbonate.[ref]
Lithium in the News
There have been a couple of really good articles recently explaining the benefits of a little lithium.
- Should We All Take a Bit of Lithium – New York Times article
- Could You Have a Lithium Deficiency? – Psychology Today article
Related Articles and Topics:
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Depression, Genetics, and Circadian Rhythm
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Anxiety and Genetics
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Cortisol and HPA Axis Dysfunction
Cortisol is a hormone produced by the adrenal glands in times of stress, and it also plays many roles in your normal bodily functions. It is a multi-purpose hormone that needs to be in the right amount (not too high, not too low) and at the right time. Your genes play a big role in how likely you are to have problems with cortisol.
Updated on 2/4/2020