MTHFR+ and Lithium

MTHFR+ and Lithium


For a comprehensive review of this subject, click on this link:


These are your Cliff Notes:

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 on bipolar disorder. It is likely to be an effect on multiple pathways. There are a number of enzymes in the body that are known to be impacted and inhibited by lithium.

Lithium comes together with methylation at COMT, the enzyme catechol-o-methyl-transferase. COMT breaks down dopamine and nor epinephrine. Dopamine is a critical neurotransmitter for motivation, focus and attention, among other functions. Nor epinephrine 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, 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. The detail and complexity surrounding this issue is explained in the presentation you can access at Dr Amy’s webinar link posted above.

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 the COMT transcript 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 certain SNPs are associated with excess lithium excretion. They are MTR+, SHMT+, and MTHFR C677T +. An out of balance methylation cycle will also cause increased lithium excretion.

Dr Amy suggests only low dose lithium support because lithium also inhibits ribonucleotide reductase. Ribonucleotide reductase takes ribonucleotides, ie, RNAs, and breaks them down into building blocks for DNA and other RNAs. So one of the toxic impacts of high dose lithium is its 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 as I discussed last week. The replay link to my discussion last week is available on my blog at
All of the replays will ultimately are cataloged there.


Why is this important?

There is a connection between lithium and COMT, bipolar disorder and 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 both B12 and folate transport into the cells thus driving the long route. This can happen with just the standing levels of B12 and folate 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 and folic acid, the transport of this latter vitamin also being modulated by lithium.

Lithium has a direct effect on nor epinephrine 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 nor-epinephrine.


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.


Lithium and thyroid.

Lithium has an impact on thyroid hormone production because it competes with iodine for uptake from the GI tract. We suggest getting around this problem by painting a 2’’ square of iodine on your skin and watching how long it takes for your body to absorb it.

If it is gone in 1 hour, you need iodine. Keep painting it on daily for transdermal supplementation.

If it stays on for 24 hours, you have enough iodine in your system. You can extrapolate the times between those two limits. Given all that has been said about the positives of using lithium if you are low in it, it is best not to just toss it aside because someone told you it was bad for thyroid. You may need both lithium and iodine. You can get both in the way just described.

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.
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5 Responses to MTHFR+ and Lithium

  1. I’m a bit confused about whether to use lithium after reading this and comparing it to the talk of April 30. I am MTHFR C677T +/+ and COMT V158M +/+. I have battled depression for 20+ years and was dx as atypical bipolar 6 months ago. In the webinar you seem to be saying everyone needs to be on lithium but reading above, it appears those with COMT mutations may not need lithium or as much lithium. Can you please clarify this for me?

  2. Thanks for following this blog and taking the time to comment. I have been slow to respond because I have been overwhelmed by the time consuming nature of Facebook, blogging, dealing with a teleconference, etc, etc. Summer holidays are coming, things are quieting down a bit, and I have the time to look for items that have been falling through the cracks.

    Everyone who has come into my practice in the past five years has been low lithium. I am not exaggerating this. Get a serum lithium level. See for yourself.

    You are MTHFR +/+. Your health is certain to be compromised. You should study this issue carefully so that things do not get worse as you get older. You need to be very proactive and you need a doctor who really knows about genetics. MTHFR +/+ will be misdiagnosed as many things. You owe it to yourself to get informed recommendations or you will end up on a plethora of pharmaceuticals and still not be well.

    COMT +/+ can actually be an advantage, but you have to limit the number of methyl groups that you take in supplements. COMT and lithium are mostly unrelated. If I said something that sounded different, ask me again. Send me an email with your question and then come on the call.

    Happy Mother’s Day everyone!

  3. Ted Hu says:

    How are COMT and lithium mostly unrelated? It appears the article’s thesis is their interrelationship.

  4. lind7 says:

    I’ve read elsewhere the iodine patch test is not a good way to determine deficiency.
    BTW, homozygous COMT V158M & COMT V158M, plus heterozygous MTHFR C677T, and some others.

    I appreciate the input on the need for lithium. Reminds me to start taking it again.

  5. Desperate for guidance here. Is it possible to consult you via phone or Skype? I have suffered with anxiety since age 5. Some depression mainly related to my levels of incessant anxiety and irritability which have been life long. I am now 56 and for the first time in my life having thoughts of suicide as the anxiety has surpassed panic levels and I’ve been hospitalized 4 times in less than a year, once for ” psychosis”. This has never happened to me before!!!! I was an RN for 30 years, now on disability. My serum levels of folic acid and b12 are always high even though I eat no gluten, processed foods, sugar nor dairy. I’ve lost 40# in the past 5 months, I’m afraid to eat anything! I really need someone who has a handle on these genetic issues. My psychiatrist is impatient with me because I need clonazepam to barely hoop on and no SSRIs seem to help. My PCP looks at me as if I have 3 heads. How do I get b12 into my cells and avoid over methylation? I take Tasks All In One, Mthfr Liver Support and CBS/ NOS kideny support. Oh please reply! I am double heterozygous for the 2 main MTHFR mutations, I am also COMPT +/+ @ A26166G, A1324G, T13376G, T24075C as well as heterozygous on 2 other COMPT mutations. NOS 3 all +/+, homozygous for MTRR A66G & A664A, heterozygous CBS C699T & A360A,, heterozygous on BHMT 02 & 08. I have many other MTRR & MTR mutations as well.

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