Overmethylation and Undermethylation
These are descriptors applied within the Pfeiffer/Walsh Clinic in Chicago to describe a clear difference they observed in the patients attending the clinic. The descriptors are very useful in the clinic setting to describe to patients the basic reason for their specific biochemistry. They are not however accurate scientific terms. With modern equipment and technology research is in process aimed to illuminate the actual science. The core difference to be remembered is that hypo, or slow methylators respond to different biochemistry than hyper or fast methylators and if prescribed the incorrect nutrient may exacerbate symptoms and complicate recovery. Methylation issues are not related to Pyrrole measurements.
Here is a very simple explanation to enable basic understanding of the biochemistry.
Undermethylation or Hypo-Methylation
In the first half of the methylation cycle the amino acid Methionine is converted to homocysteine through the intermediaries SAMe [s adenosylmethionine], and SAH [s andenosyl homocysteine].
It is the SAMe that donates the methyl group to multiple biochemical reactions and the SAH that is a potent inhibitor of methylation.
When this side of the cycle is functioning poorly it is referred to as UNDERMETHYLATION.
The usual reason for poor functioning here is likely that the enzyme responsible for the initial conversion [MAT] carries a minor genetic defect [SNP] and thus cannot function at full measure.
This step is Magnesium dependant and the conversion should be aided by magnesium supplementation.
From observational data it seems likely these patients have certain personality traits that are very different to those without this defect. They are referred to as “undermethylators” and with training with experienced practitioners, and a degree of experience, clinicians can pick undermethylators with a carefully taken clinical history.
Biochemical confirmation is difficult. One of the multitude of biochemical reactions involving methylation is the metabolism of histamine which has to be “methylated” to be broken down. A slightly elevated histamine would be in keeping with “undermethylation”. Histamine is an indicative test, not fully accurate. There are now more detailed ways to measure methylation status. Other tests for methylation need to be done carefully due to the reactivity of the amino acids. It is also more expensive and not covered by medical rebate. Patients already on antidepressant/antihistamine medications will not get a reliable methylation test as they influence the result. All testing is an indicator, not a diagnosis.
For the reasons stated above ‘undermethylators” would be likely to show clinical improvement by supplementation with Magnesium, SAMe and in some cases methionine.
It is also hypothesised that this group are relatively low in serotonin and thus more likely to respond favourably to the SSRI type medication. Therefore, caution should be used as SNRI medication may create exacerbation of symptoms.
There is a theory that after treatment commences for undermethylation there may be changes which trigger oxidative stress which may trigger a short term high urinary pyrrole measurement. This is yet to be researched but can be observed by 6 monthly Urinary tests until the urine is clear of pyrrole.
It has been observed in the literature that a number of people with depression respond well to S adenosyl methionine. The Pfeiffer/Walsh clinic found these people that respond well to SAMe tended to be those with high histamine who they determined to be undermethylators.
Overmethylation or Hypermethylation
In the second half of the methylation cycle, Homocysteine is converted back to methionine by being remethylated. This methyl donation can be accomplished by 2 ways. The first involving methylfolate in conjunction with B12 and the second using trimethylglycine [TMG or Betaine].
In many patients it is this half of the methylation cycle that is functioning sub-optimally due to minor defects in the enzymes involved [MS, COMT, or MTHFR]. It must be emphasised that most enzymes still function fine even given these defects [SNPs].
So, whilst methyl groups are being produced the process is inefficient and the term “overmethylation” was used for these patients.
Again, with observational data these patients have different personality traits and a trained and astute clinician can suspect this issue with a carefully taken clinical history.
Biochemically this group would be expected to have a slightly depressed histamine and likely elevated homocysteine.
We would expect these patients to respond favourably supplementation with various forms of folate, B12, B3 and TMG.
We hypothesised these patients are likely to be low in noradrenalin and would be more likely to respond favourable to the SNRI type medication. Therefore, caution should be used as SSRI may cause exacerbation of symptoms.
There will be references in the reference section of this site for further reading.