Lithium’s Pivotal Role in Your Body

Lithium has been known for years to be useful for bipolar disorder. Despite all that is known about lithium and its impact on biochemical pathways, no one has defined the mechanism by which lithium has its impact. It is likely to be an effect on multiple pathways, since there are a number of enzymes in the body that are activated or inhibited by lithium.

Lithium comes together with methylation at COMT, the enzyme catechol-o-methyl-transferase. COMT breaks down dopamine and norepinephrine. Dopamine is a critical neurotransmitter for motivation, focus, and attention, among other functions. Norepinephrine is involved with modulating the impact of stressors. Both are central to nervous system function.

COMT uses methyl groups to accomplish this deactivation. COMT –/– breaks down dopamine at a steady even rate and uses significant numbers of methyl groups. COMT +/+ breaks down these neurotransmitters more slowly and uses fewer methyl groups.

We know that giving a patient more methyl groups than they can use produces symptoms. They get mood swings and start to look bipolar. Children will become hyperactive or “stimmy,” or get other symptoms when they are put on methyl B12 if it is too much for them.

Lithium may inhibit the production of a central enzyme in the sulfur system, thioredoxin reductase. It appears that lithium may be increasing the production of COMT and inhibiting the production of thioredoxin reductase. COMT and thioredoxin reductase have genes that are on opposite strands of chromosome 22. Their promoter regions overlap, which implies some mutual regulation. Having a shared promoter means that at any given time you can make either COMT or you can make thioredoxin, but you cannot make both.

This circumstance is analogous to a roadway being closed down to one lane. The line of traffic can move only in one direction at a time. One lane is stopped while the other one can go. A shared promoter generates the same situation in gene transcription. You can make either COMT or thioredoxin, but not both at the same time.

Dr. Amy emphasizes that this is her hypothesis; it is not scientific fact. But based on this hypothesis, she started looking carefully at lithium levels and opened up a whole new area in her program. Using this hypothesis makes a difference for patients. She noticed that MTR+ is associated with excess lithium excretion. An out-of-balance methylation cycle will also cause increased lithium excretion. The vast, vast majority of patients using this protocol come in with low lithium levels.

Dr. Amy suggests only low dose lithium support because lithium also inhibits ribonucleotide reductase. Ribonucleotide reductase takes ribonucleotides, i.e., RNAs, and breaks them down into building blocks for DNA and other RNAs. So one of the toxic impacts of high dose lithium is this impact on RNA breakdown. You need to support with DNA building blocks, for example using Nucleotide Immune Support. The RNA formulas also supply these building blocks.


Lithium is an essential trace element. You must get it from your diet. The average intake of lithium from the diet should be up to 3100 mcg, or 3.1 mg. Dr. Amy wants to supplement with very low level lithium, around 2.5 mg. She wants to do it consistently and she does not want to get near biologic doses. What it takes to actually increase a patient’s lithium levels can be significantly more, especially with sicker patients.

You have to keep watching the lithium and cobalt levels on a UEE. High lithium levels on a UEE may indicate excess excretion, but when cobalt, the oxidized form of B12, starts to show, you know the lithium level is coming into balance and you can start to push the long route instead of just the short route.

Why is this important?

There is a connection between lithium and COMT, bipolar disorder, and schizophrenia (SZ). It is possible that imbalances in the COMT pathway need regulation by low dose lithium in order to get the kind of levels of COMT that you need for proper dopamine processing. When the levels of COMT in the brains of patients with SZ and bipolar disorder were compared with normal controls, the levels of COMT in those affected were lower than in controls. Lithium seems to increase the activity of COMT.

Lithium induces B12 transport into the cells, thus driving the long route. This can happen with just the standing levels of B12 without additional supplementation. B12 binding capacity as well as white count will go up in the presence of lithium. B12 deficiency is known to lead to degeneration of the central nervous system and psychiatric disturbances such as affective disorders and manic psychosis. Violent criminals as a group have the lowest levels of lithium in hair. There is not only a relationship between lithium, B12, and folate, but also between low lithium and anxiety, aggression, bipolar disorder, and SZ.

In studies with patients known to be low in B12, the following psychiatric manifestations were reported to remit with vitamin B12 therapy: confusion , hallucinations, delusions, disorientation, confabulation, anxiety, restlessness, fatigue, depression, irritability, sleepiness, psychosis, stupor, slowed ability to process thoughts, decreased memory, acute delirium, mania, apathy, lack of energy, weakness, violent behavior, flight of ideas, negativism, and acute paranoid states. These symptoms may occur in the absence of hematological evidence of B12 deficiency.

So certain behavioral problems, depression, and learning disability could be caused or aggravated by low nutritional intake of lithium coupled with marginal deficiencies of B12.

Lithium has a direct effect on norepinephrine pathways. Lithium indirectly inhibits thioredoxin reductase. There is an inverse relationship between thioredoxin reductase and COMT, so it may be that lithium increases COMT leading to decreased norepinephrine.

Other positives of lithium:

  • Lithium stimulates tyrosine hydroxylase, which is a secondary pathway to dopamine production.
  • Lithium has neuroprotective actions against a variety of insults. It increases GABA activity. It helps to protect against glutamate excitotoxicity by inhibiting the NMDA receptor-induced calcium influx.
  • Lithium plays a role with sodium and potassium balance.
  • Lithium may help to repair neurons and reduce some of the trauma after injury.
  • It induces enhancement of mitochondrial oxidative phosphorylation in human brain tissue.
  • It plays a role with respect to myelination by enhancing the expression of brain-derived neurotrophic factor.
  • And finally, lithium has been shown to be protective in Alzheimer’s disease.

Check out my YouTube video:
Fine Tuning Your Treatment of Chronic Illness with MTHFR Genetics

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About Nancy Mullan, MD

Some people call Dr. Nancy Mullan the MTHFR genetic medicine expert. Dr. Mullan works with people who are struggling with chronic disease or other significant illness, who are willing to use diet and genetics-based nutritional supplementation, and who want to increase wellbeing and energy, enhance immunity, lift mood, fine-tune genetic function, and get their lives back. Dr. Mullan has studied at a number of exceptional institutions: the University of Pennsylvania, Tufts University School of Medicine, and the University of Chicago Hospitals and Clinics. She excels at integrating the results of biochemical and genetic testing into sustained clinical improvement for you. She has succeeded with patients who confounded the specialists at Massachusetts General Hospital, the Mayo Clinic, the Cleveland Clinic, Stanford, and many well-known integrative medical doctors. When recommending her, her patients say, “This is the woman you need to talk to. She really knows how to handle tough clinical problems.” Dr. Mullan's specialty areas are MTHFR+, methylation genetics, and genetics-based nutritional supplementation. Within this context, she most often works with Chronic Fatigue Syndrome, Lyme Disease, Psychiatric Disorders, Autism Spectrum Disorders, Women’s Health Issues, Thyroid Disorder, Gastrointestinal Disorder, and Heavy Metal Toxicity.
This entry was posted in Chronic Disease, Dopamine and Dopamine Signaling, Epigenetics, MTHFR+, Treating Chronic Illness Series, Uncategorized and tagged , , , , , , , . Bookmark the permalink.

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