Why MTHFR genetic test and therapy with methylated folates is not advisable for treating undermethylated persons with depression or other mood disorders.

It is important to recognize that there is a more accurate indicator of methylation status than the MTHFR genetic test and that improving methylation alone is not all that is needed when considering medicines or nutrient therapy for managing depression.   

There is a great deal of confusion on the internet and in clinical practices among those who advocate methylated folate treatments for low serotonin depression. In many cases, patients have been tested for genetic mutations and found to have the MTHFR gene SNP. The argument has been that by increasing methylation with folates, in particular methylated folates, that serotonin levels will improve. Biochemically this is correct, supplementing with folic acid will increase methylation. And improving methylation will increase the production of serotonin. But functionally this is incorrect - treating depression with folic acid is not a good idea. The reason is as follows:

Pharmacological Research History: Since biochemistry revolution in psychiatry began in the mid 1960’s, it was learned that many persons with depression and mood disorders had low serotonin. Treatment regimens focused on medicines that increase serotonin at the nerve synapse, where the impulse from one nerve is carried to the next by the presence of serotonin once released at the junction. Drugs like MAO inhibitors increased serotonin at the synapse. Cofactors such as 5HTP and tryptophan were given to increase the production of serotonin. To some degree this was effective. However, in the mid 1980’s it was learned that a greater influence on serotonin neurotransmission is the rate of serotonin reuptake from the synapse after neuron firing. Psychiatry once again changed and treatment focused on serotonin reuptake by medicines classified as SSRI’s, such as Prozac, Lexapro, Celexa, Paxil Zoloft and Viibryd. These “selective serotonin reuptake inhibitors” increase the time that the neurotransmitter activates the receptors at the synapse, once released into the synaptic space.

Conventional Nutrient Therapy: Since the advent of epigenetic research and the influence on DNA expression by methylation, it has been learned that a far more powerful impact can be had with nutrients that alter the gene expression of serotonin reuptake transporter proteins, “SERT proteins. SERT proteins can be regulated by nutrients that have an epigenetic influence on the DNA that releases these reuptake proteins.  Methylators, such as SAMe and methionine inhibit the genetic expression of the transport proteins and thereby cause serotonin to remain present at the synapse longer. In other words, they behave similarly to how we believe SSRI drugs work, only they do so naturally. Methionine and SAMe are products of a biochemical process that takes place in all cells of the body, called the One Carbon Cycle.


Methylation is important in the product of serotonin and we now understand that it is even more important in the function of the DNA among brain cells that produce SERT proteins.

By increasing methylation, serotonin increases through production, and it also increases by the action of inhibiting the SERT reuptake transporter proteins.

Where the problem arises is that while many seem to understand that increasing methylation improves serotonin production, most do not recognize that folates, do more than improve methylation production within the one-carbon cycle. They also accelerate the expression of SERT transport proteins. By doing so, they reduce serotonin presence at the synapse and so lower the activity of serotonin. In other words, they increase production of serotonin, but lower the activity of it at the synapse.

Treating depression with folates, methylated or otherwise, is not advisable unless it is clear whether or not the depressed patient is experiencing overmethylated depression or undermethylated depression. Undermethylated depressives have an excess of serotonin reuptake and so low serotonin activity. Overmethylated depressives have low serotonin reuptake and a high level of serotonin activity.

It is extremely important that folates are not given without clarification of one’s methylation status. Nutritional therapy for undermethylated persons involves supplements that support the One-Carbon Cycle throughout the cycle.

While we understand that genetic mapping helps us predict the likelihood methylated folates will be important to improve methylation, it does not accurately reflect the actual methylation status. There are more that 70 genes involved in the influence of methylation.

A more useful test is whole blood histamine and homocysteine, plus a detailed history of symptoms and medications use. Low whole blood histamine is typically associated with high levels of serotonin and may be treated with supplements that increase SERT protein activity. High whole blood histamine correlates with low serotonin. For these we treat with methylation therapy and restriction of folates, acetylators and other nutrients. This must be done carefully since lowering serotonin of someone who is depressed with low serotonin will likely worsen their condition. As will increasing serotonin in a depressed person with elevated depression.

Another test for methylation status is offered by Doctors Data. This provides values for SAMe, methionine, adenosine and homocysteine. This test is not influenced by medicines such as antihistamines and anti-depressants that lower histamine test scores. It is however not so useful for persons who are taking methionine and SAMe or for overmethylators

There are very useful tests for determining methylation status

In summary:

  • Methylation increases serotonin production
  • Methylation reduces SERT transporter protein action
  • One Carbon Cycle is a biochemical pathway that produces methylators SAMe and methionine
  • Folates are involved in the methylation cycle, thereby increasing methionine and SAMe
  • Folates, methylated or not, have a more pronounced influence on increasing the activity of SERT transporters and thereby lower serotonin activity. Without a proper test, treating depression with folic acid is not advisable.
  • It is important to utilize a test such as whole blood histamine and homocysteine along with a good history taking prior to attempting to treat a patient with methylation therapy.

(Video of William Walsh PhD from the Walsh Research Institute elaborating on depression and methylation)




A good history can help determine one’s methylation status

In addition to the complexities of interpreting a methylation lab test, there are a good number of similar symptoms shared by overmethylators and undermethylators and for that reason alone it is important to get a qualified physicians impressions.

While it is not advisable to treat with medications or even nutritional supplements, some symptoms can be predictive of methylation status.

Common Signs and Symptoms among Undermethylators

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


Common Signs and Symptoms among Overmethylators

  • 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

10 thoughts on “Histamine, Methylation and Serotonin. Treating depression with folic acid is usually not a good idea!

  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.

  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.

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