Methylation Overview

http://www.alternativementalhealth.com/articles/pfeiffer.htm Methylation 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. 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. 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. 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. A quick way to test for need for methylation therapy is to carry out a cautious trial of SAMe. Within a week or two you should have your answer. If she clearly is improving on the SAMs (which is frightfully expensive)..... you can get usually the same benefits (albeit more slowly) using methionine plus calcium, magnesium, and B-6. This should be side-effect free unless (a) the methylation is begun too abruptly or (b) the patient has a rare genetic enzyme disorder which disrupts the SAM cycle. We've found that direct methylation is usually more successful than tinkering with the SAM cycle. The primary way humans receive most of their methyl groups is from dietary methionine. It's often hard to improve on Mother Nature. (Jan 20, 2003) 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. TMG generally provides some benefits to undermethylated persons, but tends to make oxidative stress protections worse by diminishing the amount of homocysteine which converts via the cystathione pathway of the SAM cycle. TMG certainly is a promising nutrient for such persons, and adding some cysteine or glutathione can overcome the cystathione pathway deficit. Personally, I believe the use of SAMe is the quickest way to help an undermethylated, high-histamine person. Most OCD patients (both obsessive thoughts AND compulsive actions) exhibit undermethylation and associated low levels of serotonin, dopamine, and norepinephrine. Choline is anti-dopaminergic and often makes OCD patients worse. Generally OCD patients respond nicely to methionine, SAMe, calcium, magnesium, B-6, inositol, TMG, and zinc. Most OCD patients get worse if given supplements of DMAE, choline, copper, or folic acid. 500 to 1000 mg/day of inositol will probably be needed to provide good response. (9 Jan, 2003) Over-methylation Conditions associated with overmethylation: Anxiety/Panic disorders, anxious depression, hyperactivity, learning disabilities, low motivation, "space cadet" syndrome, paranoid schizophrenia, hallucinations. High in serotonin, dopamine, and norepinephrine. Many persons who suffer from anxiety along with depression are over-methylated. Methyl is an important chemical group consisting of one carbon and three hydrogen atoms (CH3). Over-methylation (too many added methyl groups) results in excessive levels of the neurotransmitters dopamine, norepinephrine, and serotonin. Typical symptoms include chemical and food sensitivities, underachievement, upper body pain, and an adverse reaction to serotonin-enhancing substances such as Prozac, Paxil, Zoloft, St. John’s Wort, and SAMe6. They have a physical tendency to be very depressed in folates (a form of folic acid), niacin and Vitamin B-12, and biochemical treatment focuses on supplementation of these nutrients. These persons are also overloaded in copper and methionine (a sulfur-containing amino acid) and supplements of these nutrients must be strictly avoided. Choline Phosphatidyl choline is also very effective in protecting DHA/EPA from free radical oxidative stress..... another good reason to take it. In my experience DMAE is especially effective for increasing acetylcholine levels in the brain, since it passes the blood/brain barrier & converts to choline. I like to use this for overmethylated persons who have excessive dopamine and norepinephrine levels. However, enhancing acetylcholine activity must be avoided in persons who genetically are overloaded in this NT. Choline, DMAE, and phosphatidyl choline can cause nasty symptoms in these persons (about 10% of the population). Persons with innately high acetylcholine levels tend to be very tense and sometimes nearly catatonic. They have very high anxiety, but usually keep it inside. They also usually have a history of seasonal allergies, perfectionism, and OCD tendencies. Increasing acetylcholine activity can be a disaster for them. Those deficient in acetylcholine usually present with nervous legs, are prone to pacing, and are quite voluble. Their misery is plain to everyone. Therapies to increase acetylcholine activity can be extraordinarily helpful for this population. (March 6, 2003) Inositol can cause negative side effects in those who are overmethylated. Histapenia (Low Histamine - over-methylated) Low-histamine depressives are usually nervous, anxious individuals who are prone to paranoia and despair. No seasonal allergies, but many food allergies and chemical sensitivity. Low libido. Obsessions but not compulsions. Heavy body hair. Nervous legs. Grandiosity. Many have a history of hyperactivity, learning disabilities and underachievement. They are over-methylated which results in elevated dopamine and norepinephrine levels. Treatment focuses on B3, C, B12, with about 2-4 months required for correction of the imbalance. Also DMAE, choline, manganese, zinc, omega-3 essential oils, C and E. They should avoid methionine, SAMe, Inositol, TMG and DMG. One thing that is absolutely certain is that methionine and/or SAMe usually harm low-histamine (overmethylated persons). 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 nonepinephrine persons, who usually respond beautifully to folate/B-12 therapy [1 Dec -03] SAMe is likely to cause great worsening of symptoms, including mania, if given to an OVER-methylated person. The incidence of overmethylation in our patient database of 1,500 bipolar cases is about 18%. Bipolar disorder is not a single condition, but a collection of very different biochemical disorders under the same umbrella diagnosis. SAMe works great for truly undermethylated patients, but all hell breaks out if given to someone who is overloaded (genetically) with methyl groups. The right way to do this is to (a) first determine the person's innate methylation tendency & then (b) act accordingly. (Jan 31, 2003) Histadenia - (High Histamine - Under-methylation) 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.) Low in serotonin, dopamine, and norepinephrine. Conditions associated with undermethylation: Anorexia, Bulemia, shopping/gambling disorders, depression, schizo-affective disorder, delusions, oppositional-defiant disorder, OCD. Many patients with obsessive-compulsive tendencies, "oppositional-defiant disorder," or seasonal depression are under-methylated, which is associated with low serotonin levels. They generally exhibit seasonal allergies and other distinctive symptoms and traits. They have a tendency to be very depressed in calcium, magnesium, methionine, and vitamin B-6 with excessive levels of folic acid. These under-methylated persons can have a positive effect from Paxil, Zoloft, and other serotonin-enhancing medications, although nasty side effects are common. A more natural approach is to directly correct the underlying problem using methionine, calcium, magnesium, and B-6. SAMe, St. John’s Wort, Kava Kava, and inositol (a natural sugar alcohol) are also very useful in treating these individuals. 40-70 is optimum histamine range for mental health considerations. Histamine is an important neurotransmitter which affects human behavior. This syndrome often involves seasonal variations in depression, obsessive-compulsive behavior, inhalant allergies, and frequent headaches. In severe cases involving psychosis, the dominant symptom is usually delusional thinking rather than hallucinations. They tend to speak very little and may sit motionless for extended periods. They may appear outwardly calm, but suffer from extreme internal anxiety. Most OCD patients with both obsessive thoughts and compulsive actions are in this category. Associated with under-methylation, which results in low levels of important neurotransmitters such as serotonin, dopamine and norepinephrine. Treatment focuses on the use of antifolates such as calcium, methionine, SAMe, magnesium, zinc, TMG, omega-3 essential oils, B6, inositol, and A, C and E. The dose of inositol is 500 to 1000mg. Choline is anti-dopaminergic and often makes undermethylated patients worse. Also bad are DMAE, copper and folic acid. Three to six months of nutrient therapy are necessary to correct this chemical imbalance. Symptoms will return if treatment is stopped. Two good labs for whole blood histamine are LabCorp and Quest. Also use a special absolute basophil count as a methlyation marker. The count must be direct and not differential. Alcian blue dye is the preferred staining agent. Best lab for this test is Direct Healthcare Access in Glenview IL 847 299 2440 One thing that is absolutely certain is that methionine and/or SAMe are wonderful for high-histamine (undermethylated) persons. Histadelic (undermethylated) persons thrive on methionine, SAMe, Ca and Mg..... but get much worse if they take folates & B-12 which can increase methyl trapping. The bottom line is that undermethylated persons generally exhibit very elevated folate levels.... and these persons get worse if additional folate is given SAMe is very promising for undermethylated persons and a bad idea for those who suffer from a genetic tendency for overmethylation. I don't particularly like the "allopathic" method you referred to which is simply trial & error. SAMe can do great harm if given to the wrong person. I hate going to funerals. (17 Dec, 2002) The mechanisms of action of SAMe and TMG are quite different. Most of our methyl groups come from dietary methionine. The methionine is converted to SAMe in a reaction with magnesium, ATP, methionine-adenosyl-transferase, and water. SAMe is a relatively unstable carrier of methyl groups and is the primary source of methyl for most reactions in the body. Once the methyl group has been donated, the residual molecule is s-adenosyl-homocysteine which converts to homocysteine. TMG (betaine) is a biochemical which can donate a methyl group to homocysteine, thus converting it back to methionine. The TMG route is secondary to the 5-methyl-tetrahydrofolate/B-12 reaction which the primary route for restoring methionine. Methionine and SAMe supplements directly introduce new methyl groups into the body. TMG can provide a methyl group only to the extent that there is insufficient folate/B-12 to do the job. In some persons, the methylation effect of TMG is very minimal. In addition, persons who are undermethylated have a SAM cycle which is "spinning very slowly", much like a superhighway with little traffic. The answer for them is NOT to more efficiently convert the small amount of homocysteine to methionine (using TMG), but rather to directly introduce more methionine or SAMe into the body. A small percentage of persons with sufficient dietary methionine cannot efficiently produce SAMe --- These persons need supplemental SAMe, and not methionine or TMG and are the exception to the rule. In most other cases, methionine supplements alone are sufficient. TMG is a great way to treat individuals with dangerously high homocysteine levels. TMG can be very useful in augmenting methionine therapy along with B-6/P-5-P , serine, etc. The challenge is to supply enough methyl groups to help the patient, without creating dangerously high levels of homocysteine. Use of TMG is an "insurance policy" against this happening. (Jan 22, 2003) OTHER Pyroluria A stress disorder characterized by pronounced mood swings, temper outbursts, anxious depression. Inability to eat breakfast, absence of dream recall and frequent infections. The biochemical signature of this disorder includes elevated urine kryptopyrroles, a double deficiency of zinc and B-6, and low levels of arachidonic acid. Devastated by stresses including physical injury, emotional trauma, illness, sleep deprivation. Sensitivity to light and loud noises, dry skin, abnormal fat distribution, rage episodes, histrionic behavior. They also have low levels of arachidonic acid. Treatment centers on correcting a double deficiency of B-6, zinc essential fatty acids and augmenting nutrients. It is believed to result from abnormal hemoglobin synthesis which depletes the body of these nutrients. A positive response often occurs within the first seven days of treatment, with 1-2 months usually required for correction of the imbalance. Omega 3s can worsen mental symptoms in bipolar or schizophrenic patients.... if they have a pyrrole disorder. This phenotype is dramatically short of arachidonic acid & giving omega 3 oils aggravates the situation since omega 3 and omega 6 EFA's are in competition for delta 5,6 desaturases. We use red blood cell membrane analysis for EFA's if we suspect this problem. Pyroluric mental patients will usually get worse if given fish oils, DHA, EPA, etc. They thrive on Primrose Oil, a good source of AA and other omega 6s. (June 23, 2003) Most persons with pyroluria respond very quickly to the B-6, Zn, C, E therapy..... Major improvements are often seen by the 2nd day, and almost always by the end of the first week. The exceptions are: (1) persons with severe mental illness (schizophrenia or bipolar), (2) persons with other significant chemical imbalances, and (3) patients with a major malabsorptive condition. When pyroluria is diagnosed along with another chemical imbalance, I like to track a patient during the first 6-8 weeks to determine which is the dominant imbalance. If major improvement occurs immediately, it's because pyroluria has been corrected. Some patients report a nice early improvement followed by a plateau, and then another advance. Schizophrenic and bipolar pyrolurics usually report some progress after a few weeks, but it may take 3-6 months to get to steady state. The biggest problem with the Kp analysis is getting a proper sample to the lab. The kryptopyrrole molecule is unstable and will disappear rapidly at room temperature or if exposed to bright light. The urine sample must be placed in a freezer immediately after acquisition. Kp can be lost in the freezer if the temperature isn't well below 32 degrees F. We've also learned that exposure to bright light results in breakdown of the Kp molecule. Finally, the sample must be maintained in a frozen condition during shipment. I would greatly suspect any Kp value below 3.0. Usually this means the sample didn't get to the lab in proper condition. With respect to reference levels: We consider a healthy level to be between 4-8 mcg/dL. We consider persons between 10 and 20 to have mild pyroluria, and a good response to treatment is usually reported. Persons exhibiting 20 to 50 mcg/dL have moderate pyroluria, which can be a devastating condition. Persons above 50 mcg/dL have severe pyroluria.