MTHFR Positive? Undermethylated? Here’s why some methylated B vitamins are not good for depression:

mthfr methylation depression

MTHFR positive means that there is a deficiency of an enzyme (called Methylenetetrahydrofolate reductase) that breaks down homocysteine and folates. 

With this MTHFR genetic mutation (heterozygous or homozygous), as determined common genetic test with 23andMe, one may also have undermethylation. But treating depression with folic acids, inlcuding methylated folate B vitamins, should not be recommended for depression.

The MTHFR genetic mutation could potentially result in high homocysteine and low folates which may be problematic if not properly addressed. The understanding of this genetic SNP is very ambiguous.

Yes, high homocysteine is a risk factor for cardiovascular inflammation and yes, folates are one mechanism to lower homocysteine. But they are only one mechanism.

Other B-vitamins and dietary changes can be taken to lower this amino acid and simultaneously improve methylation.

However, folates should not be given to anyone with undermethylation depression unless it is determined that they are low in folates. The reason is that folates lower lower serotonin activity, and most people with depression have low serotonin and dopamine levels and function.

Folic acid for methylation and MTHFR postive gene mutations can be a difficult subject to grasp. Before taking B Vitamins for depression one should know how folates affect serotonin. Dr Walsh, who trains physicians on this subject, explains it well.

Dr William Walsh, PhD, discussing MTHFR, methylation,
folates and mood disorders.

Walsh heads the non-profit Walsh Research Institute in Chicago. Thanks to his educational workshops on the topic of epigenetics, depression  and methylation, physicians have  better grasp on the impact of folic acid and depression.

Before ever taking B vitamins for depression it is important to know that most persons with mood disorders are low in serotonin.

Folic acid may help with MTHFR positive gene mutations, but it dramatically reduces serotonin activity.

MTHFR depression methylation
Photo credit: William Walsh PhD

Folates may help with homocysteine and methylation. But it lowers serotonin activity.

  1. Methylation status is not determined by the MTHFR positive genetic mutations.
  2. High homocysteine does not mean someone is low in folates.
  3. Folates (methylated or not - including folinic acid and folic acid) may all improve methylation, yet persons who are undermethylated do not usually have low folic acid levels.
  4. Folates lower serotonin acvitity by increasing SERT or serotonin reuptake transport proteins.
  5. Folates can be taken to lower serotonin in overemethylators but should not be given to to undermethylators. While they may slightly increase serotonin PRODUCTION they will greatly lower ACTIVITY of serotonin.
  6. If people are genuinely experiencing undermethylation then they are likely suffering from mood disorders due to low serotonin activity.

Most common mood and behavior manifestations attributed to methylation imblance.


Low serotonin, normal folate depression

  • Chronic depression
  • Autism
  • Oppositional Defiance
  • Obsessive Compulsive Disorders
  • Psychosis prior to the onset of depression or other conditions.
  • Strong willed
  • Seasonal allergies
  • High libido
  • Competitive in sports
  • Overachiever prior to the onset
  • Protein deficiency and vegetarian diets
  • Tends to do better on SSRI medications
  • Responds well to antihistamines


High serotonin, low folate depression

  • Acute depression
  • Panic disorders
  • ADHD
  • High anxiety
  • Paranoia
  • Schizophrenia with auditory hallucinations
  • Dry eyes
  • Highly artistic, sociable and empathetic
  • Poor response to SSRI medications
  • Poor response to antihistamines
  • Food and chemical sensitivities
  • Not typically competitive
  • Builds muscle mass easily

Tests and consultation options to determine methylation status and manage mood disorders.

  • A whole blood histamine and homocysteine test, may be ordered here to be drawn at Lab Corp. It is, according to Walsh's research, the go-to test to determine one's true methylation status.  That's because of the methyl dependent enzyme which maintains whole blood histamine levels. This is an excellent indicator of methylation status vs a genetic predictor such as MTHFR.
  • A Walsh Approach takes this different approach to increasing serotonin activity in undermethylators, while carefully avoiding folates. 
  • A history of symptoms and medicines helps your Walsh trained doctor prepare the best supplement regimen for your unique biochemical levels.

Biotype Lab Panels

Free “Pre-Consultation”


Biotype Individual Tests

Histamine, Whole Blood


Biotype Individual Tests

Homocysteine, Plasma


20 thoughts on “MTHFR Positive? Undermethylated? Here’s why some methylated B vitamins are not good for depression:

  1. Linda says:

    I have the MTHFR C677T gene mutation.
    I have been taking B12, methylfolate & 800 mg per day of SAMe. It worked to get some health issues cleared up.
    I have done well with this treatment for several years but have recently developed constant diarrhea which I have had for 3 mos. Nothing seems to help. I’m currently on medical leave from teaching. I also have always had high levels of inflammation in my gut, allergies & food sensitivities. Help! I have lost over 15 lbs and did not have much weight anyway, being a competitive distance runner athlete. I’m not doing much exercise lately which may contribute to issue. Have taking care of aging parents. They are doing better than me! Some family members have had bouts w depression. I’m doing ok in that aspect.
    Any suggestions that might help me to clear up diarrhea?

    • Epstein says:

      Hi Linda, SAMe and folate have opposing effects on serotonin and dopamine activity. Suggest testing histamine levels to determine status of methylation before taking either of these supplements.

  2. Kristen Dutcher says:

    What test do you run to check histamine levels
    What about whole blood histamine to determine methylation status?

  3. David says:

    My gf is bipolar and we started the Walsh nutrient therapy 3 months ago. She is undermethlated with a slight copper overload. We did the blood test to determine these results with a nuturalpath who does the Walsh protocol. She has had three psychosis breaks since Jan 2018 and each resulted in hospitalization. She is taking 80mg of latuda at supper, 1200mg of lithium and 15mg of olanzapean at night. The nutrient protocol recommendations are 10,000IU vitamin A, P5P, Vitamin E, liposimol Glutithione, Sam-e, Zinc. Her has
    Complained about stomach upset for months
    And still has some psychotic thoughts such a spirits and demons needing to be fought. Can I do more the help with her stomach and brain functions now that we know she is under methylated? I’m thinking shamanic healer for emotional trauma in conjunction with psychologist and olive leaf with a probiotic? She wants to lose weight and has had a very difficult time doing that.

    • Epstein says:

      What you describe is not a full protocol for undermethylators. Further complicating the issue are these medications. I suggest you coordinate with the Walsh Practitioner and your prescribing physician to determine if medicine levels can or should be adjusted. Before changing doseages of medications or supplements it would be helpful to see how the labs and symptoms have changed, if at all, since she has started supplementation.

    • Sonu says:

      Hello . I m from india . First i dignosed with ocd , sexual obsessions . Got 150mg sertaline and aripiprazole 5 mg . Took 4 years . I thought i m ok with these medicines but it was hypomania . I realized and stopped medicines . Then i got bipolar 2 dignosis . No lithium lamictal worked for me . Just made me more depressed . I tried vitamin minerals then but nothing working . My folate level is 0.8 and b12is 238. What should i do . Plz tell.

      • Epstein says:

        Folates are not recommended for persons who are depressed or with similar symptoms unless a whole blood histamine test or methylation panel has definitively shown that one is OVERmethylated. We do not use folates in undermethylated persons because it acts on the reuptake protein production, lowering production and thereby increasing reuptake, which is good for overmethylators, who have high levels of serotonin and low folates.

  4. Bonnie says:

    This article currently states that 18 percent of depressed patients are overmethylators with low serotonin and dopamine. I believe this should say elevated levels of serotonin and dopamine with low levels of histamine.

  5. Amanda Toussaint says:

    I had a minor surgery 3 years ago and woke up in a state of panic and felt like nothing was real for about 7 days. When the acute episode ended I started becoming depressed, suffered from chronic anxiety and panic attacks daily, i took a pediatric dose of xanax just so I didn’t feel like I was dying 24/7. I eat very well, am a whole foods nutritionist but nothing worked naturally. I thought I was loosing my mind. I finally started zoloft and after 2-3 months it started to work. For 2.5 years I was fine and I was titrating off the whole time because I felt normal again, I had a history of anxiety but kept it in check for 20 years with diet and exercise, absolutely no medication. So I thought that 3 months was just an episode, I had recently moved 1000 miles away from any family with 3 children, just had my 3rd when it happened and I was lowered to 25 mg then 15 mg of zoloft over the course of a year . When I finally stopped the zoloft all of the symptoms reappeared. I tried everything, exercise, a host of natural supplements, b vitamins, rhodiola, ashwaganda, mag taurate but nothing worked and I was again in the same state. I am now on 50 mg of zoloft and feeling better but I went to a functional medical doctor and had extensive testing done. No smoking gun, my protein was low, some viral concerns and inflammation and my kidneys were not doing that well but everything else was fine, my B vitamins, vit D, my hormones. I want off this medication because I know it is not correcting the real issue but I am so afraid to go through that again. This doctor says he is going to work on methylation and my neurotransmitters. It is going to cost 4-5 thousand dollars and I just feel so defeated.

    • Epstein says:

      The history is relevant in order to determine symptoms, medication history and past results. However, to get a good idea of the biochemistry associated with neurotransmitter levels a Walsh-trained physician and a Biotype blood panel should provide actionable information.

  6. Christy says:

    I am definitely high in histamine, and low in neurotransmitters. I am an undermethylator. My test results came back high in methyl-histamine; I have all the symptoms of an undermethylator (ie…previous diagnosis of Interstial cystitis that went away after time, flusing, itching skin when I run, anxiety, racing thoughts, etc…… However, when I try to supplement such as SAMe or 5HTP, I get very nauseous and wired. I am already wired from being undermethylated and can’t take more anxiety from SAMe and Nausea from 5 HTP. What other supplements should one take if the suggested supplements for an undermethylator make him/her wired and nauseous? Is this common?

    • Epstein says:

      It is important when treating elevated histamine to know copper/free copper status, vitamin D levels and to know one’s homocysteine levels and cardiac risk factors. Treating with SAMe or methionine is not a complete methylation program and may cause problems if other issues are not addressed first. Best to start a treatment plan with these possible issues addressed. Once corrected, if imbalanced, it is easier to handle SAMe and methionine. Nausea is common with digestive inflammation, yeast and leaky gut. 5HTP is not part of our protocol even with undermethylators.

  7. Kris Alexander says:

    17 year old son, recently diagnosed with depression, OCD. He hid it for several months, until suicidal ideation became a factor & he informed us. We immediately sought treatment via psychological & psychiatric avenues. Evaluation recommendations include weekly counseling sessions & medication (currently 2mg/day Abilify for past 2weeks). I’ve insisted on getting to the root cause, which is a slow, painful process. So far only managed to get MTHFR test (no abnormality there) & neurotransmitter panel, which showed elevated histamine, yet normal to slightly high serotonin, dopamine & norepinephrine. However, epinephrine & PEA were low. Began supplementation, before getting testing, with magnesium (insomnia), D3, C, multivitamin, B complex, inositol, & fish oil. Within last 2weeks, per Dr. recommendation, added adrenal support, benedryl, phenelyalanine & Abilify. His mood has seemingly improved in the last week 1/2. I still want to get to the root issue, as I believe depression is a symptom & not a diagnosis, & wonder what further testing is recommended, as I have to push to get it done. Also regarding methylation status, he has conflicting symptoms. So, I’m trying to determine cause of histamine elevation(allergy, stress, dehydration, etc…) & should I be more concerned with why it’s not being broken down. Also, benedryl? He exhibits no allergy symptoms. Sorry, this is so long, I’m trying so hard to advocate for my son & get him well & happy again. Any advice would be greatly appreciated. Thank you.

    • Epstein says:

      There are a number of conflicting strategies here. While histamine is a co-factor in depression, it is not likely the cause. MTHFR does not tell us much about methylation status, nor should it be a recipe for supplementation. Suggest the methylation panel of histamine/homocysteine – this will tell us if your histamine is elevated due to undermethylation. Supplements that improve methylation, sans folates, will be best if your whole blood histamine is elevated.

  8. John says:

    Hi! Could you explain why neurotransmitter precursors such as tryptophan/5-HTP or Tyrosine/Phenylalanine are not mentioned in your protocols? Undermethylators are said to be low on neurotransmitters and it would seem like they could only help in their production. Is it OK to take them?

    • Epstein says:

      As Walsh describes in his physician trainings, the issue is not with insufficient levels of neurotransmitters; the issue is with reduced activity. With undermethylation the problem is due to an excessive expression of SERT and DERT neurotransmitter reuptake promoters. Excessive reuptake is why SSRI drugs, reuptake inhibiters have become the main focus of antidepressant medicine research and therapy. When we thought diminished levels of neurotransmitters were the issue, the treatment was MAO inhibitors; this is no longer the desired approach.

    • Epstein says:

      Yes, that’s a great questions. We don’t useS serotonin precursors in the Walsh approach for a similar reason that pharmaceutical MAO inhibitors are used less often these days than SSRI drugs. The production levels are less important than the activity or reuptake activity of the neurotransmitters. Methylation is important with regards to serotonin activity from the epigenetic influence it has on the DNA that transcribes serotonin reuptake transport proteins. Undermethylators produce a high amount of these reuptake proteins, which lowers the effectiveness of the neurotransmitters. Most undermethylators respond better to methylation for its epigenetic influence on increasing methionine or methyl groups that act on the DNA.

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