Lithium Orotate, Vitamin B12, and Mood

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 seem to have little or no noticeable effect on mood.

This article explains the research studies on lithium, digs into the genetic connections for mood response, and explores the link to cellular vitamin B12 levels.

What does low-dose 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 get roughly 3 -4 mg of lithium per day naturally in our food and water, although this varies depending on where you live and where your food was grown. In comparison, lithium orotate supplements come in doses ranging from 5 to 10 mg of elemental lithium.

Lithium orotate as a supplement:

Low-dose lithium orotate supplements are available in many health and supplement stores. They are also readily available online. Supplemental doses of lithium range from 5 mg to 20mg of elemental lithium.

If you have medical questions about lithium orotate as a supplement, talk to your doctor, especially if you are on a mood-altering medication.

Safety studies specific to lithium orotate:

Let’s talk about safety first. 

A 2021 animal study investigated the safety of using lithium orotate. The results showed no genotoxic effects, meaning that it wouldn’t damage DNA. There were no adverse side effects or organ damage in the animal trial. 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 production in the brain.  Arachidonic acid is an inflammatory lipid. Some researchers theorize that this reduction of neuroinflammation is one of the ways prescription-strength lithium chloride works for people with bipolar disorder.[ref][ref]

This isn’t an immediate change, though. Animal studies using higher lithium levels, similar to levels found in prescription lithium, show that lipid levels in the brain change within a month. Specifically, choline and phosphatidylcholine levels increased, while sphingomyelin levels decreases.[ref]

Phosphatidylcholine and choline are well-studied for brain benefits and are frequently used as supplements to improve cognitive performance.

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 epidemiological 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 3.7 million 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]

With over 800,000 people dying by suicide every year, the link between higher lithium levels and lower suicide rates is important!

In addition to epidemiological studies showing that lithium in drinking water reduces suicide rates[ref], research on prescription lithium chloride also indicates that it reduces suicide attempts, independent of its effect on mood in bipolar disorder.[ref]

GSK3B, lithium, circadian rhythm, and mood:

Another way that lithium interacts with mood is by 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]

GSK3B also interacts with circadian rhythm and sleep issues.

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 children with autism 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 ensuring your lithium level is in balance before adding in B12.

In addition to Dr. Yasko’s clinical work associating B12 and lithium, several studies are showing this as well.[ref]

Research studies on lithium and B-vitamins:

  • 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 various 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 bipolar disorder, lithium works better in conjunction with folate (vitamin B9).[ref]

Why is vitamin B12 important to your mood?

Vitamin B12 and with folate (B9) are required to produce tetrahydrobiopterin (BH4), which 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 that “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]

How long does lithium orotate take to work?

Anecdotally, a 5 or 10mg lithium orotate supplement helps some people feel less irritable, angry, or anxious. It may take a week to notice the effect on mood. But other people don’t find much of a difference in mood. (There may be other benefits to low-dose lithium, 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 an individual’s mood. The genetics part is explained in more detail below.

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 ‘microdosing’ 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, as to trials using up to 5 mg of elemental lithium.[ref][ref][ref]

I bring up microdosing, because the right dose of lithium for Alzheimer’s prevention or for 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:

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The MTR and MTRR genes are important in vitamin B12 usage in the methylation cycle.

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, an enzyme that regulates and degrades dopamine, epinephrine, and norepinephrine.

I want to be really clear here… This information is based on online recommendations from clinicians and not on peer-reviewed research studies. There are no research studies that specifically show that lithium orotate improves mood specifically 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 (MTRR) 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):

  • A/A: typical
  • A/G: somewhat decreased enzyme efficiency
  • G/G: decreased enzyme efficiency[ref][ref]

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 dopamine levels. In most populations, the G allele is the most common.[ref]
  • The A allele (Met) has lower COMT enzyme activity and thus higher dopamine levels. 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 v4, v5; 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. Keep in mind that the amount of lithium in the prescription medication is orders of 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 .

GADL1 gene: encodes glutamate decarboxylase-like protein 1

Check your genetic data for rs17026688 (23andMe v4; AncestryDNA):

  • C/C: Typical
  • C/T: more likely to respond to lithium carbonate for bipolar disorder
  • T/T: more likely to respond to lithium carbonate for bipolar disorder[ref]

Members: Your genotype for rs17026688 is .


Lifehacks:

Lithium Supplements:

Lithium orotate is available in health food stores and online in 5 mg – 20mg doses.

Talk with your doctor if you have any questions on whether a supplement is right for you, especially if you are on prescription medications.

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 recent studies 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.

It is also being investigated and used to slow the progress of ALS, dementia, and Alzheimer’s disease.

Related article: Low dose lithium and Alzheimer’s prevention

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 the SLC1A2 -181A>C variant (rs4354668), T/T homozygotes had fewer 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 orotate supplements:

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 with an adverse reaction:

  • A case study of an 18-year-old who took 18 tablets at once containing 120mg of lithium orotate. This dose would be the equivalent of 90mg of elemental lithium (along with a lot of excipients and capsule coatings). After a trip to the emergency department with nausea, she was discharged within a few hours to a psychiatric hospital.[ref]

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.