Why do we use histamine to determine serotonin and dopamine levels for treating depression naturally?

While genetics is the inherited characteristics of an organism’s genes, epigenetics is a term that describes the factors of influence on the genes, to cause the cells to increase or decrease their function. That function is the transcription and manufacture of proteins. Methylation is the dominant factor that influences cells to perform.

The science of methylation and epigenetics is a new and promising area for the future of healthcare and disease management.  It is particularly important in the field of psychiatry and treatment of depression.

Methylation influences all cells

Methylation is an epigenetic force that influences the performance of all cells in the body. In persons who are ‘undermethylated’ cellular activity is increased, while the cellular activity of overmethylated persons is decreased to a less than normal rate.

The function of cells in the body

The primary function of cells is to read various portions of our DNA and construct amino acids into specific proteins, depending on the particular cell line. For instance, endocrine cells produce hormones, immune cells produce immune globulins, digestion related cells produce digestive enzymes.

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


Depression and methylation

As it relates to depression, the evidence is clear, undermethylation is associated with low serotonin and dopamine activity. Overmethylation is associated with the increased functioning of serotonin and dopamine. The reason for this is due to the epigenetic influence on the body’s production of a neurotransmitter uptake enzymes referred to as serotonin reuptake transporter (SERT) and dopamine reuptake transporter (DERT).

The synthesis of serotonin and dopamine

Serotonin and dopamine are synthesized from 5-hydroxytryptophan (5HTP) and L-dopa. These protein ‘precursors’ are abundant in most persons and a deficiency or excess are not a significant influence on the neurotransmitters’ syntheses. A more significant influence on the synthesis of serotonin and dopamine is the presence of vitamins B6 and zinc. The rose of these two nutrients act as cofactors in the conversion of the precursors to the neurotransmitters is an important one. Vitamin B6 and zinc are directly responsible for converting 5HTP and L Dopa.

This is why doctors trained in the Walsh Protocol determine plasma zinc and urine pyrroles levels when diagnosing the cause of depression. Pyrroles are another epigenetic condition that leads to a significant depletion of zinc and vitamin B6. For the determination of the biochemical status of neurotransmitters, we rely on these tests instead of looking at the blood or serum levels of serotonin and dopamine.


The reuptake of serotonin and dopamine

The reuptake activity of serotonin and dopamine plays a more important role in brain function that does the synthesis of these neurotransmitters. When the SERT and DERT enzymes are in excess, the activity of serotonin and dopamine at the nerve junction is reduced. Reuptake is the dominant force in determining the status of serotonin and dopamine activity. Reuptake enzyme activity is regulated by folic acid which produces acetylase enzymes that alter the DNA histones. This competes with methyl compounds on the DNA and affects cellular epigenetics by reducing methylation.

Undermethylators have an excess these reuptake enzymes and so neurotransmitter activity is low. The opposite is the case for overmethylators. They have a lower reuptake enzyme activity and so they have higher serotonin and dopamine activity. Both individual types may be depressed but for opposite reasons; either due to elevated or depressed neurotransmitter activity.

Using 23andMe genetic tests to determine methylation SNPs treating with folates

There is a great deal of confusion surrounding the use of genetic testing to determine methylation status. Because there are over 70 genes involved in methylation, making assessments based on one or two SNP’s is an insufficient testing parameter.  This is the case with the commonly used MTHFR genetic SNP. A defective gene may certainly influence the rate of methylation but it does not necessitate the use methylated folic acid or any folates to improve methylation, in fact, such an approach is problematic. Genetics is not advanced enough in this area to use SNPs for determining a treatment course in the management of depression. Folates play a greater role in increasing the function of SERT and DERT transport enzymes.

Because folates increase the transport activity of these enzymes it lowers the functioning levels of serotonin and dopamine. For that reason alone, giving folates to someone already suspected of low serotonin and dopamine activity can be deleterious. Folates lower the activity of these important neurotransmitters.

Determining methylation status by testing whole blood histamine levels

SAMe is a compound that contains the most readily available form of methyl used to regulate DNA at the histone level. Because of the biochemical reaction illustrated below, SAMe is consumed in the breakdown of histamine.


When someone who is genetically predisposed to elevated histamine they will also have low levels of methylation. Because of that, symptoms associated with elevated histamine are also characterized as undermethylation symptoms. Low histamine symptoms are likewise characteristic of overmethylation.

Whole blood histamine is currently recommended by Dr. Walsh of the Walsh Research Institute as the most practical method for determining one’s methylation status. Of note, histamine results and methylation status can be masked when someone is taking antihistamines. For proper assessment, a physician will need to assess whether the results are reliable or if an alternative test should be done. Dr. Walsh also likes the Doctors Data Methylation Panel. This is a blood test that determines the ratio of SAMe/SAH (s-adenosyl methionine / s-adenosyl homocysteine). It is a bit more difficult to order and it is not useful for determining overmethylation status.

Second Opinion Physician offers whole blood histamine and the DD Methylation Panel. Also available is an SOP Methylation Panel that looks at histamine and homocysteine. This test combo is important for determining the best course of therapy. It is important to know homocysteine levels prior to treating undermethylators as methylation also increases homocysteine. An elevated homocysteine, which is a marker for cardiovascular inflammation must be corrected with supplementation prior to increasing methylation in persons who have other cardiovascular risk factors.

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


Treating with medications and supplements 

Any treatment plan that manages under or overmethylators must take into consideration whether the test performed is accurate and be sure to factor in current medications. When it is clear that someone is overmethylated in the presence of mood disorders, it is crucial that they are not given methylators or medications such as SSRI drugs (Prozac, Zoloft or Lexapro, etc) or DRI’s that inhibit dopamine reuptake (Modafinil, Diflouropine) and NDRI’s that increase dopamine and norepinephrine (Wellbutrin, Cymbalta and Effexor etc).

Persons who are undermethylated generally do well on these medications because they tend to have low levels of all three neurotransmitters. However, as many as 18% of depressed persons are overmethylators with low serotonin and dopamine. Increasing levels of these neurotransmitters would likely worsen their condition.

To determine the relative level of norepinephrine, Second Opinion Physician offers the Copper Overload Biotype test panel. Free copper causes the conversion of dopamine to norepinephrine. Lowered levels of dopamine and elevated norepinephrine can be corrected with the nutrient protocols taught by Dr. Walsh at the Walsh Research Institute.


According to the tens of thousands of cases studied at the Walsh Institute, as many as 22% of all depressives suffer from undermethylation and as many as 18% are with overmethylation.

With supplementation, undermethylators tend to show slow progress until month 2, with 6-12 months needed to achieve full effect.  Overmethylators show clear improvement by week 4, with 3-6 months for full effect. Continuous supplement therapy is recommended for both conditions.

Check with your doctor before using supplements.

“There’s promising evidence for certain supplements for depression” . Those include fish oil, folic acid, and SAMe. But more research needs to be done before we’ll know for sure. Always check with your doctor before starting any supplement, especially if you’re already taking medications.

SOP Doctor, David Epstein DO, is a Walsh-trained physician who provides a consultation for treating depression and Assessment patients are put on supplements and given lifestyle recommendations in a detailed report.



2 thoughts on “Histamine, Methylation and Serotonin. A natural approach to treat 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.

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