Neurotransmitters

Abstract

A composition and method for treating Attention Deficit/Hyperactivity Disorder (ADHD) is provided which can be used both with and without ethical drugs now used to treat ADHD. The composition contains dimethylaminoethanol (DMAE), omega 3-fatty acids, betaine, oligomeric proanthocyanidins (OPC), folic acid, vitamins C, E, B₁₂, B₆, B₅ and beta-carotene and minerals (calcium, magnesium, zinc and selenium). Ethical drugs such as amphetamines, methylphenidate HCl and pemoline are known to control ADHD, but each has significant side effects when used in their therapeutic dose. When combining the composition with such ethical drugs, the amount of the ethical drug can be lowered below a level which causes undesirable side effects which is an important feature. Preferred compositions contain one or more of lecithin, choline, 5-hydroxytryptophan, tyrosine, Reishi Extract, Kava Extract, Gingko, Ginseng and St. John's Wort.

DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

It is apparent that there is a need for the treatment of ADHD without the serious side effects of the aforementioned known drugs now used for treating ADHD. This invention provides a safe and efficacious combination of natural products which can be used with or without a reduced dosage of known ethical drugs used for ADHD. Dimethylaminoethanol (DMAE) is a natural chemical (found in fish) and has a p-acetamidobenzoate salt formerly prescribed for short attention span and hyperactivity. This drug is now available as an over-the-counter (OTC) nutrient supplement. Unlike most stimulant drugs, which tend to produce a short "up" cycle followed by a quick "come down", DMAE's effects are long lasting and more subtle. People who take DMAE report that after three or four weeks, they feel a mild stimulation continually, without side effects. The quintessential "nootropic" DMAE focuses on specific cortical brain functions associated with the direct intensification of consciousness. Side effects are very rare--high doses may result in insomnia, headache or tense muscles, which disappear if the dose is lowered. No serious adverse effects have been reported with DMAE. DMAE it is hypothesized accelerates the brain's synthesis and turnover of the neurotransmitter, acetylcholine, by redirecting choline synthesis to the cortex. Acetylcholine is the neurotransmitter that the brain uses for short term and long term memory and also helps in concentrating and focusing. Clinical studies including a double blind clinical study comparing DMAE and Ritalin, demonstrated significant test score improvements for both DMAE and Ritalin vs. placebo in ADHD children. DMAE has been shown to increase levels of choline in the brain due to DMAE's superior ability to cross the Blood-Brain Barrier. DMAE has been shown to elevate mood and allow a sounder sleep. DMAE has also been shown to decrease the accumulation of lipofuscin in the brain and to increase attention span and improved concentration. DMAE and derivatives thereof such as its p-acetamido benzoate salt and its bitartrate salt is an important component in the composition of this invention for treating Attention Deficit/Hyperactivity Disorder. Amounts of DMAE of up to 1000 mg, or more, preferably 200-800 mg are used. The brain consists of about 60% fat (lipids). In clinical studies with children with Attention Deficit/Hyperactivity Disorder, supplements of omega-3 fatty acids [eicosapentaenoic acid (EPA), and docosahexanoic acid (DHA)] vs. placebo, have demonstrated improved mood, enhanced clarity of thinking, more serenity and mental clarity of thinking, better concentration and better vision for those taking omega-3 fatty acids. Omega-3 fatty acids (e.g., EPA and DHA; fish oil) are an important component of the composition of the invention and are used in an amount of up to about 1200 mg or more, preferably 200-800 mg. Since the brain contains so much fat (lipids), it is hypothesized the brain has to be protected from free radicals forming "lipid peroxidation" which can cause brain disorders. Antioxidants such as vitamin C, E and A, preferably beta-carotene, improve memory performance and are included in the composition of the invention for this purpose. Vitamin C is used in an amount up to about 1500 mg or more, preferably 200-1000 mg; vitamin E up to about 800 IU or more, preferably 400 IU; and Vitamin A up to about 25,000 IU or more, preferably 10,000-25,000 IU. Recently, U.S. Pat. No. 5,719,178 claimed the use of proanthocyanidins (derived from the conifer bark), an antioxidant, in the treatment of APHD. The general class of oligomeric proanthocyanidins (OPC), which include conifer bark extract, grape seed extract, pine bark extract and the protective phenolic compounds from natural sources including bioflavonoids it is hypothesized can reduce free radical damage causing APHD and are included in the composition of the invention. These "free radical inhibitors" can pass through the Blood-Brain Barrier to protect the brain. OPCs have been shown to possess antihistamine, anti-inflammatory and immune-boosting effects as well as inhibiting the breakdown of the catecholamine neurotransmitters. OPCs increase attention span, increase focus and decrease emotional activity in ADHD persons and are used in the composition of the invention in an amount of about 200 mg or more, preferably 50-150 mg. Faulty neurotransmission is considered the main reason for ADHD. Acetylcholine is involved with learning and memory. Serotonin is involved with mood, emotional balance and impulse control. Catecholamines speed up the rate at which one neuron signals another. It is an important feature of this invention that there be a proper balance between the neurotransmitters for "normal" mental and emotional function. ADHD is a complex disorder involving an unbalance in several neurotransmitters. This invention uses a multi-step approach to fully treat ADHD disorder and the body according to this invention must have "methyl donors" to synthesize the brain chemicals, which accounts for their mood elevating and cognitive effects. Betaine or trimethylglycine, folic acid and vitamin B₁₂ are methyl donors, which are included in the composition of the invention. Betaine is used in an amount up to about 750 mg or more, preferably 100-500 mg. Folic acid is used in an amount up to 1.2 mg or more, preferably 0.4-1 mg and Vitamin B₁₂ up to about 40 mcg or more, preferably 3-30 mcg. In addition to the vitamins mentioned, the body uses vitamin B₅ to form acetylcholine and vitamin B₆ to form serotonin and L-Dopa into Dopamine, which accounts for their effect of increased alertness and mood. These vitamins are included in the composition of the invention. Vitamin B₅ is used up to about 250 mg or more, preferably 50-250 mg and Vitamin B₆ up to about 25 mg or more, preferably 5-25 mg. There are some vital minerals that affect the functioning of the brain. Calcium is a second messenger in neuronal membranes and it acts like a traffic signal for uptake and release of neurotransmitters. A "green light" from calcium permits release of a neurotransmitter into the synaptic intersection and a "red light" halts its passage into the receiving neuron. Calcium regulates the speed, intensity and clarity of every message that passes between brain cells. Magnesium is the second most important mineral in the brain. A study found low magnesium levels in 95% of ADHD children. Supplements of magnesium at a level of 6 mg/lb. of the child showed a decrease in hyperactivity. Zinc is the third most important mineral in the brain, where it acts like an antioxidant and also acts on the surface of the neurons as an electrical "contact" for neurotransmission. Selenium has been shown to protect the integrity of message sending between neurons by preventing free-radical attacks. One or more of these minerals, preferably all, are included in the composition of the invention in amounts up to about 150% of their RDA or more, preferably 100%. Calcium is preferably used at a level of 200 to 1200 mg, magnesium 100 to 500 mg, zinc 5 to 50 mg and selenium 40 to 120 mcg. 5-Hydroxytryptophan (5-HT), the precursor of serotonin, is also included in a preferred composition of the invention in an amount up to 75 mg or more, preferably 25-50 mg. Tyrosine, an amino acid, is a precursor of the catecholamines and used as a food supplement and improves alertness and elevated mood. Tyrosine is included in the composition of the invention in an amount up to 300 mg or more, preferably 50-250 mg. Like omega-3 fatty acids, phospholipids are important for optimal brain health, and are found in high concentrations in the brain. They help the brain cells communicate and influence how well the receptors function. Lecithin is a phospholipid found in certain foods and available as a food implement. Lecithin provides a very available source of choline required for acetylcholine. Lecithin and cytidine 5-diphosocholine (CDP) supplements increase alertness and motivation. Lecithin is used in an amount up to 2000 mg or more, preferably 600-1800 mg. Choline is also included in a preferred composition of the invention in an amount up to 800 mg or more, preferably 100-500 mg. Another important component of a preferred composition of the invention is Reishi extract derived from mushrooms. Reishi extract calms the mind, eases tension, improves memory and sharpens concentration and focus which are all important effects for treating Attention Deficit/Hyperactivity Disorder according to this invention. Reishi extract is used in an amount up to 2000 mg or more, preferably 500-1500 mg. Kava (Piper Methysticum) is a plant grown in the South Pacific and contains kavalactones, which influence a number of brain receptors involved with relaxation and mental clarity. In a study the results showed kava superior to placebo, with improvements in anxiety, mood, tension and fears with increased alertness. With the anxiety that is part of ADHD, kava extract is included in the composition to provide a calming effect and increase concentration. Kava is used in an amount up to 200 mg or more, preferably 50-150 mg. Gingko Biloba extract contains flavonoids and terpene lactones. Gingko improves communication between nerve cells and enhances blood flow to the brain. It also acts as a powerful antioxidant. Ginseng extract has been found to improve blood circulation and provide mental clarity. Researchers have evaluated the cognitive effects of gingko/ginseng. A double blind, placebo controlled study showed improvements in memory and overall cognitive function for those taking both gingko and ginseng and both are in preferred embodiments of the invention. Gingko is used in an amount up to 200 mg or more, preferably 30-120 mg and Ginseng up to about 200 mg or more, preferably 50-150 mg. The herb, St. John's Wort, affects five neurotransmitters in the brain: serotonin, noradrenaline, dopamine, gamma-aminobutyric acid (GABA) and interleukin-6. Because St. John's Wort affects these neurotransmitters, it helps balance them to provide "normality" and is a preferred component in the composition of the invention for treating ADHD in an amount up to about 800 mg or more, preferably 100-600 mg. In the combination of the aforementioned "natural" therapy, with ethical drugs, in addition to amphetamines, methylphenidate HCl, and pemoline, the composition of the invention can be used also with fluoxetine, sertraline, paroxetine, fluoxamine, citalopram, venlafaxine, bupropion, nefazodone and mirtazapien, among others. While the above components as described are the preferred components to be used in the composition of the invention it will be appreciated to those skilled in the art that known derivatives, e.g., salts, may be employed. As set forth hereinabove, it is an important feature of the invention that the components act together to provide a synergistic effect by effecting different pathways of action, i.e., by normalizing the several neurotransmitters and receptor sites responsible for ADHD. While the present invention has been particularly described, in conjunction with a specific preferred embodiment, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art in light of the foregoing description. It is therefore contemplated that the appended claims will embrace any such alternatives, modifications and variations as falling within the true scope and spirit of the present invention.

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.

Digestive/metabolic problems in ADHD/Autism

From: Holistic Primary Care – online article Digestive, Metabolic Problems Abound In Patients with ADHD, Autism By Erik L. Goldman Editor in Chief PORTLAND, OR- Attention Deficit Hyperactivity Disorder and autism are multifactorial biological disorders requiring a multimodal therapeutic approach that addresses the gastrointestinal, immunologic and metabolic problems usually associated with the behavioral abnormalities, said Jeff Bradstreet, MD, at the annual meeting of the American Holistic Medical Association. "Conventional allopathic concepts define ADHD and autism as 'psychiatric' disorders. I think that's bunk. I look at ADHD and autism biologically," said Dr. Bradstreet, founder of the International Child Development Resource Center (ICDRC), a clinic and foundation that has treated over 2,000 children with ADHD or autism. "As an MD, I had to move toward naturopathic principles to learn how to treat these disorders." Over the years, Dr. Bradstreet has developed sophisticated therapeutic protocols centered on correcting digestive problems, eliminating allergens and environmental toxins, and improving nutrition. Whenever possible, he prefers to treat these kids without pharmaceuticals. "I only use drugs as a rescue modality." While ADHD and autism are related in many ways, and sometimes overlap, Dr. Bradstreet believes they are distinct conditions. He rejects the notion that autism is simply an extreme form of ADHD. However, he contends that both reflect altered brain and CNS function, which are the net result of environmental toxin overload, abnormal immunologic reactions, impaired hepatic detoxification, and GI dysfunction which can sometimes be extreme. There is still plenty of debate over how to define these conditions and even more regarding their etiologies. But there is little argument regarding the sharply increasing incidence and prevalence. The most recent estimate is that one in every five school aged boys in the US must take a stimulant to go to school. There are over 350 million doses of methylphenidate given to US schoolchildren every year. Federal registries suggest there are between 9 and 12 million children with ADHD. Data from California indicate one in 160 school age children have some form of autism; the figures have doubled over the last four years. "Some of this may be overdiagnosis, but I think that most of it is not. It is very, very real." Dr. Bradstreet and his colleagues believe ADHD arises from a combination of immunologic, allergic and digestive dysfunction that begins with damage to the child's immune system early in development. The injury may be due to environmental toxin exposure, but in the majority of cases, he believes mercury-containing vaccines do play a role. Thimerosal and aluminum in vaccines are intrinsically neurotoxic, and they can also modulate immune function. Live viral vaccines contain as much as 25 mcg of mercury (as thimerosal) per dose. Young children receiving serial live viral vaccines get quantities of mercury that, on a body weight basis, exceed safe levels for US adult fish consumption. Dr. Bradstreet and his colleagues recently completed a case control study showing a statistically significant correlation between mercury exposure at an early age and autism. Those who had the highest levels of mercury exposure had a 6.4-fold increased prevalence of autism than those at the lowest levels. There was no correlation between autism and lead or cadmium exposure. "It is not just vaccine mercury, but environmental mercury as well." The vaccine etiology, though still highly controversial, has been gaining credence in recent years. A CDC-funded study recently showed a statistically significant difference in the prevalence of ADHD, autism, and tick disorders between individuals who received mercury-containing vaccines at 3 months, and those who did not. Analysis of data from the federal Vaccine Adverse Events Reporting System (VAERS) and the US Department of Education do show a linear correlation between the odds ratio for neurodevelopmental disorders and thimerosal exposure (Geier DA, Geier MR. Pediatr Rehab. 2003. 6 (2): 97-102). However, two recent Danish population-based studies comparing rates of these disorders between hundreds of thousands of individuals vaccinated with thimerosal-containing versus thimerosal-free vaccines, failed to show any correlation (Hviid A, et al. JAMA. 2003; 290 (13): 1763-6, Madsen KM, et al. Pediatrics. 2003; 112 (3 pt. 1): 604-6). Most conventionally-trained pediatricians hold that there is little risk of autism from vaccines, especially thimerosal-free vaccines. They argue that if there is any risk, it is probably very small, and that the benefits of vaccination far outweigh any potential risks. Dr. Bradstreet, the father of an autistic child, strongly disagrees. "There are still no truly mercury-free vaccines," he said, suggesting that this may explain the absence of a correlation in the Danish studies. "We are making progress and they are getting better. But there's still a lot of mercury out there." Live virus vaccines, such as the one for measles are particularly problematic, said Dr. Bradstreet. "The way it is injected, the virus gets immediate access to the tissues in which it prefers to proliferate the lymph nodes and CNS-and escapes immune system clearance. As a result, residual virus can become a problem. In one recent study, 50% of a cohort of children with autism had cerebrospinal fluid antibodies to measles virus proteins found in the MMR vaccine. Many ADHD/autism children also have a unique form of irritable bowel disease in which proteins traceable to vaccine strains of measles are found. While there is still much room for debate about the connection between vaccines and neurodevelopmental disorders, there is a growing consensus that children with ADHD and autism typically have gastrointestinal problems, and that the two are related. The GI tract in most of these patients is, to put it bluntly, a total mess, said Dr. Bradstreet. He insisted that without cleaning up the gut problems, it is impossible to make headway in resolving ADHD and autism. Lower GI dysfunction, enzyme deficiencies and impairments of hepatic detoxification pathways are very common. Patients typically excrete large amounts of sulfate in their urine, sometimes as much as 10 times more than normal children. The cause is yet not known, but it results in impairment of sulfate-dependent hepatic detoxification pathways. These patients also excrete cysteine, a key amino acid for glutathione production. Cysteine wasting is a characteristic of residual viral infection, and it results in compromise of glutathione-dependent detoxification pathways. The net result is that these individuals can't break down and excrete toxins. Pancreatic enzyme deficiency is very common; Dr. Bradstreet noted that approximately 75% of the children he treats have significant deficiencies of key pancreatic enzymes. As a result, they do not digest proteins properly, setting the stage for both upper and lower GI problems. Researchers at the department of pediatric gastroenterology, University of Maryland studied 36 autistic children via endoscopy, biopsy, and intestinal and pancreatic enzyme analysis. They found that 69% had grade I or II esophageal reflux and inflammation, 42% had chronic gastritis, 67% had duodenitis, and 58% had low carbohydrate digestive enzyme levels (Horvath K, et al. J Pediatr. 1999; 135 (5): 559-63). Diarrhea and constipation are common in these patients. Some kids tend to have more diarrhea, while others have constipation so extreme they develop impactions. "You can sometimes feel these huge fecal masses if you palpate their abdomens," said Dr. Bradstreet. This can be particularly problematic because in essence, they are storing large loads of toxins, further burdening their already compromised hepatic detoxification pathways. Many ADHD/autism patients have "leaky gut" syndrome, characterized by a breakdown of the tight junctions between endothelial cells in the gut lumen. This is evidenced by the presence of lactulose in their fecal material (D'Eufemia P, et al. Acta Pediatr. 1996; 85 (9): 1076-9). A highly permeable gut wall allows passage of all sorts of antigenic proteins, toxins, and pathogens into the circulation. Dr. Bradstreet is particularly concerned about "exorphins," protein fragments from the incomplete digestion of grain gluten and casein. Some of these protein fragments, like beta-casomorphins and gluteomorphins, are neuroactive and able to bind to opioid receptors in the brain. In a child with a leaky gut, these exorphins easily pass into circulation, and since hepatic clearance of opioid neurotransmitters is already compromised, the exorphins hang around for a long time. He believes they are driving factors in the cognitive symptoms and abnormal behaviors of ADHD and autism (Wakefield AJ, et al. Aliment Pharmacol Ther. 2002; 16 (4): 663-74). Some of the most compelling work linking digestive system problems with neurobehavioral disorders like ADHD and autism comes from the work of Andrew J. Wakefield and his Inflammatory Bowel Disease Study Group at the Royal Free and University College Medical School, London. His team performed ileocolonoscopy with biopsies on 60 children with developmental disorders including autism, ADHD and Asperger's syndrome, as well as 50 unaffected control subjects. They found ileal lymph node hyperplasia in 93% of the affected children, but in only 14% of the controls, and colonic node hyperplasia in 30% of the affected kids, but 5% of the controls. Close to 90% of the kids with developmental disorders had chronic colitis, versus only 4% of the controls (Wakefield AJ, et al. Am J Gastroenterol. 2000; 95 (9): 2285-95). This builds on an earlier study of 12 children, all of whom showed nodular hyperplasia and colitis (Wakefield AJ, et al. Lancet. 1998; 351 (9103): 637-41). Clostridium, which can secrete a number of neuroactive toxins, also plays a role in some patients. Patients with late onset autism sometimes have increased numbers of clostridial species in the gut. Dr. Bradstreet described the bizarre case of a dog that inadvertently ate feces from an autistic child: the dog went into a coma for 7 days. "Researchers at the University of Michigan are studying feces from this child to see what might have caused this extreme reaction. We think it might be clostridial toxins." Management of the complex multi-system problems characteristic of ADHD, autism and other developmental problems is a major challenge for physicians and families of these children. Dr. Bradstreet centers his approach on the following goals: improvement of GI function, restoration of normal immune function, elimination of heavy metals and other toxins, and supplementation to optimize hepatic, immunologic, neurologic, and cognitive function. He does use DMSA chelation to eliminate mercury and other heavy metals, and said that over 70% of these children will show major improvements in behavioral symptoms just from this alone. "It is the number one treatment as rated by the parents; no drug even comes close." Other treatments that help with detoxification include: Selenium: At a dose of 25 mcg/day, this mineral facilitates detoxification by binding to mercury by forming selenium-mercury complexes that can be safely excreted in the urine. It is also an essential cofactor for synthesis of glutathione peroxidase, a key antioxidant enzyme. Milk Thistle (Silybum marianum): Standardized preparations of 70-80% silymarin, an important bioactive component of this plant, were shown to improve liver function in patients with solvent-induced liver damage. There is also a study of 166 children with chronic liver disorders, 70% of whom showed liver function improvements while taking silymarin. N-Acetyl Cysteine (NAC): Since most patients with ADHD or autism are cysteine deficient, this is a cornerstone of treatment. NAC is a precursor of glutathione, an essential player in hepatic detox pathways. Dr. Bradstreet recommends starting with a low dose of 25 mg/day and gradually increasing up to 200 mg daily. Calcium-D-glucarate (as Betaine): This salt of D-glucaric acid inhibits beta-glucuronidase, and increases net elimination of toxins and steroid hormones via glucuronidation, a critical step in Phase II hepatic detoxification. Begin with 150 mg, and increase to 1,000 mg per day. Alpha Ketoglutarate (AKA): These patients often show elevated ammonia levels, derived from abnormal GI flora. AKA helps detoxify ammonia. It is also a precursor of glutamine which helps heal the gut mucosa. The dose range is 250-750 mg/day. Taurine: This sulfonic amino acid is involved in formation of bile salts, which are essential for toxin elimination. Taurine also plays a role in neuromodulation, and tends to have a calming effect on ADHD patients. Begin with 100 mg and build up to 1,000 mg/day. Methionine: This amino acid binds heavy metals, and adds methyl groups to xenobiotics, aiding in their excretion. Supplemental methionine increases production of several cytochrome P450 enzymes. The dose range is 100-400 mg. Given that many of these patients have enzyme deficiencies, enzyme replacement using fixed combinations of plant-based enzymes is a cornerstone of therapy. A recent clinical trial in which 29 children with autism spectrum disorders were given an enzyme formula containing exo- and endo-peptidases, showed measurable improvements on 13 cognitive and behavioral parameters. Dr. Bradstreet strongly recommends a gluten and casein-free diet. While not a "cure," this can certainly have a big impact (Knivsberg AM, et al. Nutrit Neurosci. 2002; 5 (4): 251-261). He also advised eliminating as many common allergenic foods as possible. This includes corn, wheat, soy and nuts. Other important nutrients and supplements that can improve digestive, immunologic and neurologic function in these patients include: Omega-3 Fatty Acids: "This is a must. These patients are almost always deficient." Omega-3s are critical components of neuronal membranes and they are essential for normal neurologic development. 1,000 mg per day is a reasonable starting dose, but don't hesitate to go as high as 3,000 mg. Probiotics: Once the severe GI abnormalities are cleared, it is important to re-seed the gut with healthy flora. Probiotic supplements are the easiest way to accomplish this. Vitamins A, C, and E: These "letter" vitamins, as well as beta-carotene are all important antioxidants, and patients with ADHD/autism are usually deficient. While a good multivitamin will probably provide most of what these patients need, it doesn't hurt to add additional vitamin C, which supports glutathione-mediated detoxification pathways. B Vitamins: B6 is probably the most well-studied vitamin in management of ADHD/autism. It is essential for healthy brain function, and patients are typically deficient. Since 1965, there have been 18 trials of high-dose B6. Overall, the data suggest that this will help 50%, while the other 50% show no benefit. Some studies suggest that B6 should be taken with magnesium. Zinc and other mineralsk: Both serotonin and melatonin are synthesized via zinc-dependent enzymes. Zinc-deficient children are often irritable, sullen and difficult to soothe. ADHD/autistic patients are usually deficient in zinc, as well as magnesium, iron and calcium. Dr. Bradstreet has also found pycnogenol, a derivative of French maritime pine trees, and L-theanine, derived from green tea, to be effective in improving cognitive function and helping to produce a calm but focused attention in these patients. Co-enzyme Q10, L-carnitine, L-carnosine and dimethyl aminoethanol (DMAE) are also helpful in improving cognitive function. Recently, Dr. Bradstreet formulated a line of products called Learner's Edge , that brings together many of these diverse nutrients and botanicals in an easy-to-use system. The line is manufactured by Integrative Therapeutics (www.learners-edge.com), and is the subject of a longitudinal clinical trial jointly sponsored by Arizona State University, Southwest College of Naturopathic Medicine, and Dr. Bradstreet's ICDRC.