In Walsh’s Commentary on Nutritional Treatment of Mental Disorders he gives a thorough explanation of methylation and it correlation to mental health. He is also the first scientist I have heard who specifically discusses trichotillomania in relationship to undermethylation. For this reason, I am very interested in finding out more about his work. In the following excerpt from his work, I have highlighted the information I found post pertinent. Walsh describes a treatment plan using 3-4 grams of inositol in combination with 2,000-3,000 mg of I-methionine.
Effective “markers” for methylation are (1) whole blood histamine (ref. levels 40-70 mcg/dL), available from Quest and LabCorp; (2) Absolute Basophils (ref. levels 30-50), available from Direct Healthcare, Inc in the Chicago area.
Elevated histamine and/or elevated basophils indicate undermethylation. Review of symptoms and medical history can bolster the diagnosis. For example, most undermethylated persons exhibit seasonal allergies, perfectionism, strong wills, slenderness, OCD tendencies, high libido, etc. Overmethylated persons generally exhibit anxiety, absence of seasonal allergies, presence of food/chemical sensitivities, dry eyes, low perspiration, artistic/music interests/abilities, intolerance to Prozac and other SSRI’s, etc.
Conditions associated with undermethylation: Anorexia, Bulemia, shopping/gambling disorders, depression, schizo-affective disorder, delusions, oppositional-defiant disorder, OCD.
Conditions associated with overmethylation: Anxiety/Panic disorders, anxious depression, hyperactivity, learning disabilities, low motivation, “space cadet” syndrome, paranoid schizophrenia, hallucinations. (Oct 3, 2003)
One-carbon (methyl) groups are involved in numerous important biochemical reactions in the body, including genetic expression, neurotransmitter synthesis and metabolism, etc. Methylation (more properly, the methyl/folate ratio) is a major factor in the rate-limiting step (the tetrahydrobiopterin reaction) in the synthesis of serotonin, dopamine, and norepinephrine in the brain. Undermethylated persons tend to be depleted in these 3 neurotransmitters, and the opposite is true for overmethylation.
The SAM cycle in which dietary methionine is converted to SAMe (the primary CH3 donor in the body), and then to homocysteine, is a dominant cascade of reactions in methylation and also is very important in production of glutathione, cysteine, and other aspects of sulfur chemistry.
Most persons with depression, oppositional defiant disorder, OCD, bipolar disorder, or schizophrenia exhibit a genetic abnormality in methylation….. which appears to be central to their illness. Carl Pfeiffer, MD, PhD of Princeton, NJ was a pioneer in this field. (Oct 3, 2003)
About 25 years ago, Dr. Carl Pfeiffer (Princeton, NJ) identified the condition he called “histapenia” or histamine deficiency. After studying the metabolism of more than 20,000 schizophrenics he learned that this “low histamine” syndrome was common in anxiety, panic disorders, and classical paranoid schizophrenia. His enormous biochemistry database revealed that most histapenics suffered from (1) copper overload and (2) deficiency of folic acid and/or B-12. More importantly, he found that aggressive therapy using folic acid, B-12, and B-3 usually produced dramatic improvements in these persons. Pfeiffer thought the improvements were largely due to elevating histamine levels in the body & brain.
Subsequent research has indicated that the improvements are due to normalizing the methyl/folate ratio. This ratio is important in the BH4 rate-controlling step in catecholamine synthesis (dopamine & norepinephrine). Also, methyl/folate abnormalities can impact genetic expression of many biochemicals. At any rate, too much methyl results in overproduction of DA and NE, and vice versa.
Also, a serious overload of homocysteine (homocysteinuria) can result in symptoms quite identical to paranoid schizophrenia. Folic Acid & B-12 serve to lower HCy levels.
One thing that is absolutely certain is that methionine and/or SAMe usually harm low-histamine (overmethylated persons)….. but are wonderful for high-histamine (undermethylated) persons. The reverse in true for histadelic (undermethylated) persons, who thrive on methionine, SAMe, Ca and Mg….. but get much worse if they take folates & B-12 which can increase methyl trapping.
I guess the bottom line is that undermethylated persons generally exhibit very elevated folate levels…. and these persons get worse if additional folate is given.
This is a fairly complex subject, and some of my medical staff are still struggling with the concept. However, they have the solace of knowing the clinical impact of methylation or folate therapy on persons with specific methylation/histamine disorders.
It’s certainly true that whole blood histamine is compromised by AH treatments (including antigens and many psychiatric medications). We’ve gotten quite proficient in taking these factors into account. Fortunately, the ABC test doesn’t suffer from this disadvantage. Also, the syndromes of over-methylation and under-methylation are well defined…. and a medical history & review of symptoms greatly aids the diagnosis. (Oct 6, 2003)
The generalization that perfume and other chemical sensitivities are associated with overmethylation, low blood histamine, and elevated norepinephaine… is exactly that…a general rule with many exceptions. However, the correlation seems to be above 90 percent in the case of perfume sensitivity. Whenever a patient enters our clinic wearing a mask to filter out inhalant chemicals, we immediately suspect the overmethylation syndrome. The chemical testing usually confirms this diagnosis, but there definitely are a few persons who have severe perfume sensitivity for other reasons. We’ve evaluated about 19,000 persons, including about 1500 with anxiety disorder or panic disorder. Hundreds of these patients reported sensitivity to perfumes. Nearly 90 percent of the perfume-sensitive group were overmethylated, and reported multiple chemical and food sensitivities. usually in the absence of seasonal inhalant allergies. Perfume sensitivity is a classic symptom of these high nonepinephaine persons, who usually respond beautifully to folate/B-12 therapy [1 Dec -03]
Inositol is especially helpful for undermethylated persons (for example most persons with OCD), but can cause negative side effects in those who are overmethylated. Since Inositol is one of the primary second messengers in neurotransmission, it’s surprising is isn’t more commonly used. It’s especially useful in reducing anxiety and enhancing sleep.
To enhance sleep for a 160 lb person, we usually recommend 650 mg tablets, 1-3 as needed for sleep. Persons who have difficulty falling asleep should take it 30-60 minutes before sleep. Persons whose main problem is waking up in the middle of the night should take it at bedtime.
We’ve often given as much as 3-4 grams/day to undermethylated persons who respond beautifully to Inositol, and these persons take it morning, noon, and evening.
I once gave an invited presentation at a symposium at an APS annual meeting… in which data on megadoses (15-30 g) of Inositol were reported by another speaker. The volume of Inositol used seemed extreme to me, and would present daunting compliance problems. I believe such huge doses of Inositol are unnecessary, if methionine, calcium, B-6, and other nutrients to combat undermethylation are used. However, massive doses of Inositol might be needed if one tries to combat OCD with Inositol alone.
Regardless of the form of inositol, its use should be started as a trial, with close monitoring of patient. We’ve found that persons who achieve improved sleep after inositol are excellent candidates for taking it throughout the day also. I recommend you be alert for adverse side effects, especially with persons with severe anxiety or panic symptoms
Trichotillomania has been associated with OCD and undermethylation. If you can confirm the presence of undermethylation, the patient should benefit from (1) aggressive doses of l-methionine, calcium, magnesium, along with augmenting nutrients zinc, B-6, Inositol, Vitamin A & C and (2) strict avoidance of folic acid, choline, DMAE, and copper supplements
Aggressive methylation therapy can be very successful, but usually involves a very slow response. Typically, treatment with methionine, calcium, magnesium, B-6, etc requires about 2 months before the patient before any progress is evident — and 6-12 months are required for all of the benefits to be attained. Please note that whole blood histamine is a marker for innate methylation tendency, but is not an indicator of wellness or the degree to which undermethylation has been overcome. Undermethylated patients can become quite well without their histamine lab results changing at all.
One way to speed up the process of recovery is to use SAMe supplements in the beginning. Undermethylated patients usually report nice progress after the first week or two. SAMe is quite expensive, and can be gradually replaced by methionine after a couple of months.
Nearly all severely undermethylated persons have low serotonin levels and present with a history of depression, internal anxiety, and OCD. Many have a history of perfectionism and high accomplishment in the early years. Unfortunately this population also has a tendency for non-compliance with any treatment.
The late and great Carl Pfeiffer would occasionally resort to use of the anti-histamines Benedryl or Dilantin in high-histamine persons who were slow to respond. Avoidance of folate supplements is essential for most undermethylated persons, an exception being autism.
Some practitioners like to tinker with the SAM cycle to promote conversion of homocysteine to methionine, but this can deplete the cystathione pathway and result in deficiencies of glutathione, cysteine, etc. Some persons have a genetic enzyme weakness which can disrupt the SAM cycle
Undermethylated adults typically require 2,000 – 3,000 mg/day of methionine for several months to see good results. Also, augmenting nutrients such as calcium, magnesium, B-6, and zinc are essential.