Lithium Orotate and Vitamin B12: Benefits for Mood and Cognitive Support

Key takeaways:
~For some people, supplementing with low-dose lithium orotate helps with anxiety, depression, and anger issues.
~For others, lithium orotate supplements seem to have little or no noticeable effect on mood.
~Research shows that small amounts of lithium (natural mineral) influence mood, aggression, neuroinflammation, and more.
~Vitamin B12 comes into play here as well, and lithium orotate along with B12 may help with mood and cognition.

In this article, we will explore the potential lithium orotate benefits, backed by research studies, and discuss its impact on mood, anxiety, and cognition.

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What is low-dose lithium orotate?

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.

Lithium orotate is a type of natural mineral supplement, and it comes in doses ranging from 5 to 10 mg of elemental lithium. (Just to be clear — I’m not talking about the high-dose prescription lithium carbonate that is used for bipolar disorder. Lithium orotate is a different formulation and a whole lot lower dose.)

Naturally occurring levels of lithium impact depression and aggression:

Lithium is found in drinking water in varying amounts, depending on the naturally occurring lithium levels in the soil.

Researchers have looked at areas that have higher levels of lithium in the water and compared them to areas with low lithium levels.

Several studies show that areas with higher lithium levels in their drinking water have lower levels of depression and decreased aggression.

A meta-analysis of studies on lithium in water showed that suicide rates were >50% lower in areas with higher lithium in the drinking water.[ref]
Another study found that homicide rates were lower in areas with higher levels of lithium in the water supply.[ref]

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

USGS map of lithium levels in drinking water

The science behind lithium orotate’s benefits:

Studies show that low amounts of lithium, such as what is found in lithium orotate supplements, can help with mood, neuroinflammation, circadian rhythm, ADHD, and more.

Let’s dive into the research on lithium for mood, explore the cellular changes, and understand the mechanisms of action in the brain.

Lithium is thought to act in multiple ways to affect mood:

alters GSK3B expression, impacting circadian rhythm
reduces neuroinflammation
increases BDNF
interacts with vitamin B12 and folate

1.) Lithium orotate: Impact on circadian rhythm and sleep

One way that lithium interacts with mood is by inhibiting GSK3B (glycogen synthase kinase 3beta). GSK3B acts on many different pathways in the body, including circadian rhythm and neuronal plasticity.[ref]

Dysregulation of GSK3B is linked to bipolar disorder, depression, and Alzheimer’s disease.[ref]

Lithium competes with magnesium in binding with GSK3B and inhibiting GSK3B. Through its impact on GSK3B, researchers think lithium can modulate the activity of many different pathways including circadian rhythm. Additionally, lithium may take the place of magnesium in other proteins that need magnesium.[ref]

GSK3B interacts with circadian rhythm and sleep issues, which can be at the heart of depression and mood disorders. Thus, lithium may impact mood and sleep by modifying GSK3B.

Additionally, lithium has been shown in animal and cell studies to upregulate PER2, a core clock gene.[ref]

2.) Lithium reduces neuroinflammation:

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 in neuroinflammation is one of the ways prescription-strength lithium chloride works for people with bipolar disorder.[ref][ref]

The reduction in arachidonic acid 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 decreased.[ref]

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

Related article: Types of Supplemental Choline

3.) Lithium impacts BDNF

Brain-Derived Neurotrophic Factor (BDNF) is important in mood, memory, and learning. It helps the brain to form new connections.

In people with bipolar disorder, BDNF levels are often reduced. Lithium has been shown in multiple studies to increase BDNF levels.[ref]

4.) The connection between lithium orotate, mood, and B vitamins

Clinicians for more than a decade have recognized that lithium orotate and vitamin B12 act synergistically.

For example, Amy Yasko, PhD, 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] 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 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..” Additionally, vitamin B12 deficiency increases the relative risk of depression, bipolar disorder, panic disorder, psychosis, phobias, and dementia.[ref]

Lithium orotate supplements and doses:

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.

Note: If you have medical questions about lithium orotate as a supplement, talk to your doctor or pharmacist. This is especially important if you are on medications for a mood disorder.

Safety studies specific to lithium orotate:

While lithium has been used for more than a century for bipolar disorder, there are possible side effects with the high-dose prescription levels of lithium.

But what about low-dose lithium orotate?

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]

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. However, not everyone notices a difference in mood.

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.

In addition to improving anxiety and irritability symptoms, there may be other benefits to low-dose lithium, such as Alzheimer’s prevention.

What is ‘microdosing’ lithium?

Several recent peer-reviewed studies reference microdosing of lithium for Alzheimer’s disease prevention or treatment. Essentially, the term microdosing just means a low dose compared to prescription lithium.

For example, clinical trials using a 300 mcg dose of lithium refer to it as microdosing. However, trials using up to 5 mg of elemental lithium also refer to it as microdosing.[ref][ref][ref]

I am bringing up microdosing because the right dose of lithium for Alzheimer’s prevention may be different than for someone who is using lithium orotate for mood regulation.

ADHD and lithium orotate:
Some clinicians recommend low-dose lithium orotate for ADHD.[ref] In adults with ADHD, a study using high-dose lithium found that it was as effective as methylphenidate in reducing irritability, aggressive outbursts, and more.[ref] In animals, lithium increases working memory.[ref]

Related article: ADHD Genes

Lithium Orotate Genotype Report:

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The MTR and MTRR genes are important in vitamin B12 usage in the methylation cycle. Dr. Yasko explains 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 – not peer-reviewed research studies. There are no research studies connecting lithium orotate to specific B12 variants.

MTR Polymorphisms (SNPs):

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 Polymorphisms (SNPs):

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):

Keep in mind that the amount of lithium in the prescription medication is orders of magnitude higher than supplemental lithium orotate. What I find interesting is that genome-wide genetic studies (GWAS) link lithium as an ion to 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 —.

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Safety and Side Effects:

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]

Lithium Supplement Details:

Lithium orotate is available in health food stores and online in 5 mg – 20mg doses. Everyone is unique in whether lithium will affect mood and which dosage is going to be most effective. You may want to start with the lowest available dosage (usually 5mg) and go from there.

Caution: 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:

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