Urinary neutotransmitters

Neurorelief.com * Increased glutamate, epinephrine, norepinephrine, or PEA levels are observed in patients with anxiety disorders. * Anxiety may result from inefficient GABA or Glycine receptors. * High GABA, Glycine, and frequently Taurine levels are observed in patients with anxiety disorders. * Neurotransmitter tests can help identify chemical imbalances that underlie anxiety. * Reducing excitatory neurotransmitters glutamate, norepinephrine, PEA, epinephrine etc., will reduce anxiety and GABA and Glycine levels. * Patients with high GABA levels need GABA support.

Lead inhibits the formation of GABA and increases the concentration of Glutamate/glutamine in the synapse.

Pubmed Laboratory of Pathobiochemistry of the Central Nervous System, Department of Neurochemistry, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego str., 02-106 Warsaw, Poland. lidkas@cmdik.pan.pl

Glutamine (Gln), glutamate (Glu) and gamma-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocytic-derived glutamine is the precursor of the two most important neurotransmitters: glutamate, an excitatory neurotransmitter, and GABA, an inhibitory neurotransmitter. In addition to their roles in neurotransmission these neurotransmitters act as alternative metabolic substrates that enable metabolic coupling between astrocytes and neurons. The relationships between Gln, Glu and GABA were studied under lead (Pb) toxicity conditions using synaptosomal fractions obtained from adult rat brains to investigate the cause of Pb neurotoxicity-induced seizures. We have found that diminished transport of [(14)C]GABA occurs after Pb treatment. Both uptake and depolarization-evoked release decrease by 40% and 30%, respectively, relative to controls. Lower expression of glutamate decarboxylase (GAD), the GABA synthesizing enzyme, is also observed. In contrast to impaired synaptosomal GABA function, the GABA transporter GAT-1 protein is overexpressed (possibly as a compensative mechanism).

Furthermore, similar decreases in synaptosomal uptake of radioactive glutamine and glutamate are observed. However, the K(+)-evoked release of Glu increases by 20% over control values and the quantity of neuronal EAAC1 transporter for glutamate reaches remarkably higher levels after Pb treatment. In addition, Pb induces decreased activity of phosphate-activated glutaminase (PAG), which plays a role in glutamate metabolism. Most noteworthy is that the overexpression and reversed action of the EAAC1 transporter may be the cause of the elevated extracellular glutamate levels. In addition to the impairment of synaptosomal processes of glutamatergic and GABAergic transport, the results indicate perturbed relationships between Gln, Glu and GABA that may be the cause of altered neuronal-astrocytic interactions under conditions of Pb neurotoxicity.

Amino Acids -- Cofactors and Relationships

Amino acid profiling clinical guidelines for determination of preferred specimen choice.

From: Townsend Letter for Doctors and Patients | Date: 12/1/2003 | Author: Feinerman, Judy

Introduction

Profiling of amino acids in plasma and urine has been used to elucidate a rapidly growing number of aminoacidopathies since the introduction of partition chromatography methods in 1945. (1) The question of whether plasma or urine may be the preferred specimen choice for amino acid testing is a frequent clinical concern in the evaluation of a patient's amino acid status. An informed decision must involve what principal clinical answers are sought and which amino acids are being tested. To state categorically that profiling of amino acids is best performed on plasma or urine is to oversimplify. The question of preferred specimen can be answered only when it is addressed to specific amino acids or to the specific type of information desired.

One commonly practiced method to judge the relative value of results from two specimen types is to ask which specimen has been most used for scientific studies. The majority of published studies have used plasma as the specimen for analysis (approximately a 3:1 plasma/urine ratio). (2) This is primarily because most investigations have been concerned with essential amino acid status. Urine is typically reserved for studies of dietary protein intake, digestive adequacy, bone loss and muscle protein catabolic states. The aminoacidemias and aminoacidurias associated with metabolic disorders are approximately equally divided in the published research. Inherited metabolic disorders generally result in extreme elevations, and the abnormality is easily detected in either specimen type. The branched chain amino acids (BCAAs), for example, are elevated in both plasma and urine in maple syrup urine disease. The newer application of amino acid profiling of older children and adults to determine amino acid status in chronic degenerative diseases is more pertinent for this article.

Amino Acid Dynamics

Plasma

A fasting plasma specimen reflects the state of the dynamic flux of amino acids leaving sites like skeletal muscle and flowing into sites of utilization in liver, brain, and other tissues (Figure 1). Amino acid levels in plasma reach their homeostatic balance point making a fasting specimen ideal for repeated measures to monitor progress. The principal factors effecting changes over time are dietary intake, digestive efficiency, hepatic uptake, and the ability of skeletal muscle to maintain sufficient rates of transamination. The amount of an essential amino acid in plasma determines the rate of any dependent process in the tissues. For example, low plasma tryptophan results in reduced formation of serotonin in the brain. (3)

[FIGURE 1 OMITTED]

Urine

Twenty-four hour urinary amino acids have been measured in the evaluation of specific clinical conditions. In many cases the research represents disruption of normal amino acid metabolism as a result of the disease process and the shortterm changes in plasma amino concentration. A 24 hour urine amino acid analysis reveals amino acid metabolism throughout the period of metabolic stress of digestion and daily activity. This aspect is of particular value for evaluating those amino acids that primarily reveal tissue degradation, such as hydroxylysine and hydroxyproline, which are released from collagen of connective tissue and bone.

Clinical Categories Assessed via Amino Acid Profiling

Gastrointestinal Function

Amino acids and their derivatives provide some useful markers that can reflect gastrointestinal function, specifically protein digestion capacity. The normal digestion of dietary protein results in free-form amino acids and short-chain peptides. Recent (i.e. 3 days) dietary protein intake has little influence on plasma amino acid profiling. A fasting plasma specimen highlights the dynamics of homeostatic maintenance of the free form amino acid pool, which is remarkably stable, independent of diet. In contrast, 24-hour urine analysis of amino acids more clearly elucidates recent protein intake based on the activities of the previous 24-48 hours. In feeding young men a protein mixture (patterned after egg protein) specifically devoid of methionine and cystine for eight days, fasting plasma methionine and cystine levels showed little change during the eight-day period. Urinary levels of methionine decreased markedly within a few days after feeding of the experimental diet, suggesting urinary amino acids are more useful to monitor short-term changes in protein intake. However, plasma levels are the preferred way to assess long-term adequacy and dynamics of amino acid utilization. (4), (5)

Abnormal amino acid patterns can correspond to what may be wrong in protein nourishment or digestion. The patterns seen may reflect dietary protein deficiency, and/or maldigestion. Hyperaminoacidemias and hyperaminoacidurias typically indicate genetically inherited metabolic enzyme impairments or transport problems, not digestive enzyme impairments or insufficient stomach acid secretion. Low levels measured among the essential and some of the semi-essential amino acids reflect dietary and uptake problems. For example, the essential amino acid histidine is required to make histamine, an important digestive function, which occurs early in the stomach. Low plasma or urinary histidine may then suggest impaired ability for optimal protein digestion. Low levels of the aromatic amino acids--tryptophan, phenylalanine, and tyrosine--may indicate inadequate stomach acid (HCl) secretion as this is critical to activate pepsin-mediated protein digestion. Clinicians must remember to consider renal function in evaluation of urinary amino acids, however, as patients with renal failure may show decreased creatinine measurements, resulting in skewed levels upon measurement and subsequent interpretation.

In select circumstances, elevations in urine amino acids can serve as disease markers. For example, hydroxyproline appears to be a hallmark for celiac disease and other malabsorption states, with the greatest hydroxyproline excretion occurring in those patients with the most pronounced steatorrhea. (6) This is believed to reflect an increased turnover of collagen and may be related to the osteomalacia sometimes accompanying malabsorption.

Cellular Energy Production

Fatigue may be one of the most commonly reported medical complaints heard by clinicians today. Amino acid deficits may be related to the cause of fatigue. Amino acids undergo transamination reactions which supply intermediates to the citric acid cycle in order to facilitate mitochondrial oxidative phosphorylation; or more meaningful to the patient, cellular energy production. (7) Citric acid cycle intermediates are produced from aspartate, tyrosine, phenylalanine, isoleucine, valine, methionine, glutamine, histidine, arginine, proline, glutamate, and beta-alanine. Despite a significant lack of clinical research on urinary amino acids for assessment of fatigue syndromes, one study of interest has emerged in which strong associations of beta-alanine in urine with chronic fatigue symptom expression has suggested a possible molecular basis in the development of an objective test for chronic fatigue syndrome. (8)

There has been increasing interest in the mechanisms behind central (brain-related) fatigue, particularly in relation to changes in brain monoamine metabolism and the influence of specific amino acids on fatigue. (9) Central fatigue has been implicated in both chronic fatigue syndrome (10) and postoperative fatigue. (11) Evidence continues to emerge demonstrating increased ratios of plasma tryptophan to branched-chain amino acids may be responsible for the central fatigue seen in long, sustained exercise and post-surgery. (12-14) The literature abounds with clinical studies on fatigue, with an overwhelming preponderance of these studies utilizing measurements of plasma amino acids.

Detoxification

Determination of detoxification capacity is an important clinical issue for many patients with chronic illness, especially if suspected to be environmentally induced. While the role of amino acids in phase II hepatic conjugation reactions is well established, assessment of amino acid availability for optimal conjugation warrants further clarification. Of particular interest are the amino acids, glycine, cysteine, glutamic acid, taurine, methionine, glutamine, and aspartate. As urinary levels are best reserved for evaluation of short-term dietary changes or protein digestion capability, profiling of plasma pool availability is relevant to detoxification capacity. Highly targeted urinary amino acid derivatives however, such as hydroxyproline, may serve as useful biomarkers of exposure to pollution. (15), (16)

Detoxification of ammonia is an important responsibility of the liver. The urea cycle involves a series of biochemical steps in which ammonia, a waste product of protein metabolism, is removed from the blood, converted to urea, and excreted in urine. In urea cycle dysfunction, ammonia (a highly toxic substance) accumulates, and is not removed from the body efficiently. Ammonia accumulation in the general circulation may go on to reach the brain, where it may cause neurologic damage and in severe cases can lead to irreversible brain damage and/or death. Mild hyperammonemia conditions are often seen as low plasma glutamic acid levels and high glutamine levels. (17) Symptoms include headache, irritability, fatigue, mental confusion, poor concentration, and food intolerance reactions, particularly to high protein foods. At the other end of the spectrum of urea cycle dysfunction are inherited urea cycle disorders. A urea cycle disorder is a distinct genetic disease caused by a deficiency of one of the enzymes in the urea cycle, which is responsible for removing ammonia from the bloodstream.

Removal of ammonia via the urea cycle can be an important clinical issue. A case of infantile autism has been associated with inefficient ammonia detoxification as evidenced by elevated plasma ammonia and elevated plasma and urine levels of gamma-aminobutyric acid (GABA). It was postulated that elevated ammonia levels may result in higher GABA concentrations and that a link between plasma ammonia and plasma GABA exist where the concentration of GABA in the plasma is directly related to plasma ammonia concentration. (18) Meanwhile, in elderly subjects, patients with Alzheimer's disease (vs. healthy controls) exhibited altered plasma ornithine and arginine concentrations, (19) perhaps highlighting the long term effect of altered urea cycle function on neurodegeneration.

Neurotransmitter Metabolism

The aromatic amino acids--phenylalanine, tyrosine, and tryptophan--are converted to catecholamines and serotonin by enzymes in adrenal, intestinal, and neronal tissue. GABA and glutamic acid exert CNS-active neurotransmission effects without any modification of their chemical structures. Plasma levels of these amino acids are known to influence CNS concentrations of the respective neurotransmitters. Schizophrenia treatments (and etiologic mechanisms) have been linked to the glutamatergic and dopaminergic excitatory amino acid systems. (20) Alterations in plasma levels of aspartate, glutamate, glycine, and taurine have been suggested as neurochemical markers of epilepsy. (21)

Plasma tyrosine has been proposed as a useful assessment of thyroid function. Low plasma levels of tyrosine have been associated with hypothyroidism. (22), (23) Tyrosine has been used as a treatment for depression and blood pressure modulation. (24) Possible additional symptoms of low plasma tyrosine would be chronic fatigue, learning, memory or behavioral disorders, and autonomic dysfunction. (1) High levels of stress lead to depletion of phenylalanine. (25) The inherited metabolic disorder of phenylketonuria results in greatly elevated phenylalanine in plasma and urine. Excessive protein intake or a metabolic block in the conversion of phenylalanine to tyrosine can also elevate phenylalanine in plasma or urine.

Numerous studies have demonstrated that plasma tryptophan is an indirect marker of changes in brain serotonin synthesis. (26) Tryptophan has been shown to help induce sleep in insomniacs due to increased serotonin production in the brain stem. Plasma tryptophan levels are increased with sleep deprivation because of decreased utilization. (27-29) Low plasma levels of tryptophan have been reported in depressed patients (30) and are correlated with the degree of depression. (31) Used alone or with amitryptyline, the amino acid is effective against depression in general practice. (32)

Serine is also a critical component in the biosynthesis of acetylcholine, an important CNS neurotransmitter used in memory function and mediator of parasympathetic activity. Patients suffering from episodic acute psychosis display a disturbance of serine-glycine metabolism, (33) and a higher serine/ glycine ratio is observed in depressed individuals. (34)

Muscle Catabolism

Specific amino acids measured in urine provide insight into protein catabolism. Urinary 1-methylhistidine (1-MeHis) is a marker of beef, chicken and poultry consumption. (35-37) High urinary excretion of 3-methylhistidine (3-MeHis), a component of muscle, indicates active catabolism of muscle and is an abnormal marker for excessive muscle breakdown. It has been used as such a marker in studies of clinical conditions associated with nitrogen loss, including trauma, surgery, (38) infection (39) and in uncontrolled diabetes. (40) A study in Sweden looked at 3-MeHis levels to evaluate effect of alphaketoglutarate-enriched enteral feeding on protein metabolism after major surgery. (41) Other numerous studies utilized urinary 3-MeHis in cases where limiting catabolism is the outcome being studied. Urine 3-MeHis was used to evaluate the anabolic effectiveness of supplementation with exercise. Muscle breakdown in resistance exercisers trying various post-exercise beverages was assessed via urinary 3-MeHis. (42)

Collagen

Proline is required for protein synthesis and is metabolized into hydroxyproline, an important component in connective tissue. Therefore, high urinary levels may reflect inadequate connective tissue synthesis. Low levels of proline can indicate a poor quality protein diet and consequently prevent optimal connective tissue maintenance. Hydroxyproline is a component of collagen. High levels in 24-hour urine or plasma correlate with the increased osteocalcin secretion that is characteristic of high bone turnover. (43) Also involved with collagen synthesis in connective tissue is the amino acid hydroxylysine (HLys), a derivative of lysine. HLys and Hydroxyproline are indicators of liver disease, however elevated HLys seems to be a stronger index of hepatic collagen metabolism in chronic liver disease. (44)

Nutritional Markers

Abnormal levels of amino acids in plasma and urine can also indicate insufficiencies of nutrients. Specific vitamins and minerals are required for amino acid metabolism. Abnormal results from amino acid profiling may be due to deficiencies of the nutrients required as cofactors for transformation into other compounds. Low levels of essential amino acids may indicate inadequate pancreatic enzyme activity. Because zinc is required as a cofactor in several digestive enzymes, a deficiency of this element can affect overall plasma amino acid levels. (45), (46) Individual amino acid abnormalities are indicators of specific nutrient insufficiencies.

Because the catabolism of amino acids is a heavily utilized pathway in the liver, breakdown of branched chain amino acids (BCAAs) affords an opportunity for detecting interruptions in the pathway caused by inadequacy of vitamin B6, thiamin and/ or other B vitamins. Leucine, isoleucine and valine are initially metabolized utilizing a pyridoxal-5-phosphate dependent enzyme. Continued deamination into keto-acids requires vitamins B1, B2, B3, B5 and lipoic acid. Plasma homocysteine elevations indicate a demand for vitamins B6, B12 and folate, necessary cofactors for the metabolism of this amino acid. A limitation of homocysteine as a marker for any one component in this vitamin triad is the fact that homocysteine will rise in the absence of B6, B12 and/or folate.

One study performed on cobalamin deficient rats, serine (Ser) and threonine (Thr) levels in plasma and urine were significantly elevated. After two weeks of B12 supplementation, in addition to decreased urinary methylmalonic acid, was normalization of plasma Ser and Thr. It appears that cobalamin deficiency results in impaired metabolism of Thr and Ser due to minimization of the enzymes responsible for the conversion of Ser and Thr to pyruvate. (47)

Vitamin C is the main cofactor involved in collagen synthesis-namely the conversion of proline to HPro. Acute or chronic deficiency of vitamin C produces a significant increase in the proline /HPro ratio in urine. (48) Supplementation with vitamin C has been used to successfully treat certain types of collagen disorders and to stimulate collagen synthesis. (49)

Vascular Function

Vascular tension involves the cell regulator nitric oxide (NO) and its precursor arginine. A sequence of events in the endothelial cells results in NO release. NO penetrates into the underlying layer of muscle cells where it elicits release of the final modulator of muscle relaxation, cyclic guanosine monophosphate. Many of the reported effects of arginine in human health are due to NO-related cell responses. Impairment of endothelium-dependent coronary microvascular function due to aging in particular, can be restored by Larginine supplementation. (50) NO plays a role in vascular homeostasis influencing vascular tone and structure. (51) NO-mediated pathways are also investigated in understanding erectile dysfunction. (52) In evaluating vascular function plasma arginine and/or urinary nitrates are measured. (53-55) Plasma asymmetric-dimethylarginine, a NO inhibitor is another index used in similar studies. (56-58) However, measurement of urine amino acids in assessment of vascular health is minimal. Homocystinuria, a genetic disorder caused by a cystathione beta-synthase deficiency, is associated with vascular events as a result of markedly elevated circulating homocysteine. (59) Human studies have shown that high levels of homocysteine are associated with impaired endothelial-dependent vasodilation in healthy subjects indicating that the bioavailability of NO is decreased in those with hyperhomocysteinemia. (60) Plasma homocysteine levels are preferred in studies investigating related disorders. (61-64)

Other Conditions

Urinary amino acids have been measured in the evaluation of specific clinical conditions. In many cases the research represents disruption of normal amino acid metabolism as a result of the disease process and the short-term changes in plasma amino concentration.

Patients with Cushing's disease exhibit changes in urinary and serum concentrations, and renal clearance of amino acids with relationship to glucose tolerance. Normalization of cortisol levels restores amino acid status. (65) Investigation of aminoaciduria of subjects with different types and severity or traumatic injuries shows that many amino acids are involved and that the aminoaciduria is correlated with a reduced total serum calcium. (66) Changes in plasma and urinary amino acids were seen during diabetic keto-acidosis (DKA). A strong correlation was found between the urinary excretion of several amino acids and that of the beta-2-microglobin characterizing tubular dysfunction, thus reflecting altered metabolic state and renal function due to DKA. (67) Urinary phosphoethanolamine (PEA) is typically elevated in the first few weeks of life and declines throughout childhood and adolescence. Higher than normal levels of urinary PEA were seen in infants and children with impaired central nervous systems, systemic skeletal affections and hepatopathies. (68) Urinary beta-aminoisobutyric acid has been used in several studies as a marker of urinary tract tumors and at helping to predict recurrences, (69,70) while other studies have correlated this amino acid derivative in urine with leukemias and lymphomas. (71,72)

Clinical Application

For evaluation of overall amino acid body status, plasma testing emerges as the method of choice. Urine amino acid assays appear to be most commonly used to diagnose genetic metabolic disorders. Muscle protein and collagen catabolism and integrity are evaluated by certain amino acids elevated in urine. Urine amino acids are typically not measured to indicate nutrient demands. For example, folate deficiency leads to increased catabolism of histidine (73,74) and consequent increased urinary histidine excretion and/or its metabolites. Although an elevated histidine may indicate need for folate, the urinary organic acid formiminoglutamate is a more specific marker for folate status within the tissues. (75,76)

Organic Acids in Urine

There are various methods of acquiring data about vitamin status. Concentrations of vitamins can be measured in serum or blood cells. The excretory products formed from vitamins may be measured in urine. Thirdly, functional adequacy of a particular vitamin can be revealed by the urinary levels of specific metabolic intermediates controlled by the action of the vitamin. For routine clinical purposes, the most useful assay gives a clear answer to the question of whether body pools are adequate to meet current tissue demands.

To demonstrate, increased plasma or urine isoleucine or appearance of significant levels of the branched chain keto acids (not BCAAs) in urine, are markers of thiamin deficiency. (77) Ultimately, the combination of markers most useful in assessing an individual need for a specific nutrient such as thiamin is plasma or urine isoleucine, urine pyruvate, alpha-ketoisovalerate, alpha-ketoisocaproate, and alpha-keto-betamethylvalerate. In addition, urinary levels of organic acids formed from amino acid catabolism can be extremely useful as markers of functional adequacy of amino acids. This should be considered when answering the question of specimen selection for direct testing of amino acids. The combination of amino acids in plasma with organic acids in urine provides a more complete picture of amino acid abnormalities and becomes an exciting prospect to further assess an individual's specific nutritional needs.

Conclusion

The overall conclusion to be drawn from this discussion is that a great majority of reports documenting clinically useful information from evaluation of essential amino acids have evaluated plasma levels. We can also say that for most, but not all clinical situations, the greatest array of useful information is derived from the measurement of plasma amino acids. Plasma is especially favored when the prime consideration is the supply of the essential amino acids for optimum balance to maintain or restore health. Amino acid testing is extremely valuable in establishing nutritional therapies and understanding cellular and metabolic needs of a patient. The choice of specimen for testing should be based upon what clinical information is being investigated.

Glutamate and Namenda

From Dr. Bock's new book: Page 184: "Another medication that appears to be promising in the treatment of autism is Namenda, which is FDA approved for the treatment of Alzheimer's disease. Although Namenda does not decrease inflammation directly, it may be helpful by acting on glutamate receptors on the cells to block the activity of glutamate, an excitatory amino acid that may act synergistically with inflammatory mediators." Page 335: "Namenda started out as an Alzheimer's drug, and is now being clinically investigated in the treatment of autism. In my practice, I've found that some kids respond well to it, but it makes others have sudden meltdowns, in which they become extremely emotional for no apparent reason. Why? It's probably because Namenda decreases the activity of the neurotransmitter glutamate, and some kids are already low in the activity of this neurotransmitter. In contrast, most autistic kids generally have high glutamate activity. No two kids are exactly alike, and no two kids need exactly the same medications. As doctors and parents, we need to be good detectives, and keep looking for adverse reactions, and positive responses." Page 347: "Namenda can be an effective drug among the subset of children who have an excess of the excitatory neurotransmitter glutamate. This can include children on the autism spectrum, and also those with ADHD. Excess glutamate tends to make children hyperactive. Namenda, however, blocks glutamate receptors, thereby decreasing the activity of glutamate. In one study of 39 children on the autism spectrum, Namenda showed moderate success in decreasing hyperactivity and inappropriate speech. Namenda is not appropriate for all kids with psychiatric disorders, but it can be of significant value to the high-glutamate kids

Glutamate "Blockers?"

Article that asks what things might be taken to block excess glutamates

Mike: Here's a practical question that's actually been burning in my head for about eight years: Is there anything that a person can take to block the absorption of MSG or glutamate as a defensive supplement?

Dr. Blaylock: Well, not necessarily to block it. You have other amino acids that can't compete for glutamic acid absorption. So that may be one way to help reduce the rate at which it would be absorbed.

Mike: Which aminos would those be?

Dr. Blaylock: Those would include leucine, isoleucine and lysine. They would compete for the same carrier system, so that would slow down absorption. There are a lot of things that act as glutamate blockers. You know, like silimarin, curcumin and ginkgo biloba. These things are known to directly block glutamate receptors and reduce excitotoxicity. Curcumin is very potent. Most of your flavonoids.

Magnesium is particularly important, because magnesium can block the MNDA glutamate type receptor. That's its natural function, so it significantly reduces toxicity. Vitamin E succinate is powerful at inhibiting excitotoxicity, as are all of your antioxidants. They found combinations of B vitamins also block excitotoxicity.

ADHD/Glutamates/Salicylates (from Australia)

My approach to ADD ADHD

Several factors involving cerebral Zinc (? and other metals), salicylates and glutamates.

For lists of these foods see http://www.zipworld.com.au/~ataraxy/Salic_03.txt

An overview is provided at http://209.1.158.41/b_nutrition/02solutions/03rx/food/food3.htm

What we know.

1] Tartrazine (food additive 102) can cause hyperactivity. Check out food colourings at http://ificinfo.health.org/brochure/foodcolr.htm

2] Tartrazine causes acute zinc loss in the urine (zincouria).

3] Those sensitive to 102 are usually sensitive to dietary (and prescribed) salicylates and glutamates.

4] Salicylates bind minerals such as copper (and probably zinc). Copper salicylates have been used in Rheumatoid Arthritis.

5] The compound Zinc-salicylate has similar biological appearance to glycine.

6] Glycine is an amino acid and inhibitory neurotransmitter.

7] Glutamate is an excitatory transmitter. MSG (additive 621) is a glutamate. Glutamates occur naturally in foods.

8] Salicylates require glycine for liver metabolism. Salicylglycine is the main excreted metabolite.

9] Salicylates accumulate in most fruits and some vegetables prior to ripening so as to defend themselves against being eaten. In the last 3 days of ripening, salicylate levels fall as antioxidants enter from the stem of the plant. For example, one large green apple will be converted to about 150mg of salicylate.

10] Green harvesting (picking fruit 7 days prior to ripening) will produce high salicylate, low antioxidant foods. Green harvesting is widely practiced in WA.

11] Because of generalized soil deficiencies, most of WA food sources are lower in zinc and selenium than ever before. Please note: The farmers know about this, the Agriculture Dept knows about this. The only group who do not know about this are the medical profession.

12] There are many foods that contain glutamates and salicylates. Apart from the obvious (additive 621 MSG), tomatoes, yeast extracts, tomato sauce, gravies, stock cubes, tomato paste, salami’s, meat pies, seasoned meats, grapes, plums, prunes, raisins, sultanas broccoli, mushrooms and spinach.

13] Hence, even "healthy eating" will result in low zinc, high salicylate condition. It will also put strain on glycine reserves.

Hypothesis.

1] Low or borderline low cerebral zinc levels will become further compromised by high salicylate diet.

2] Zinc-salicylate or Zinc-Tartrazine may competitively compete for glycine binding sites.

3] Glutamates are excitatory and so a combination of low zinc, high salicylate, high glutamate food such as pie and sauce or vegemite on toast could lead hyperactivity or another altered mental state.

4] If you combine the effect of Zinc soil deficiencies and high salicylate, high glutamate diet and no wonder WA has such a high rate of ADD/ADHD.

Diagnostic and treatment regimen.

1] Measure RBC zinc locally. I suggest Clinipath, but do not use their reference range as a guide. It is not useful for several reasons. If most of WA is deficient, then how can they provide a normal? Moreover, they have not (and cannot) sample randomly from the community at large to attain such values. In fact they use crossover testing. For example, if a patient's FBP is normal, they will assume that the RBC is also normal and include them in the melting pot of results. Now if the indication for the FBP was recurrent infections, then low zinc (despite a normal FBP) could well be the cause (not usually thought of by doctors although extremely well documented for about half a century now). If the physician is investigating hypoglycaemia, then zinc deficiency most often causes post-prandial hypoglycaemia, and glucose is usually normal (and hence put into the "normal" zincs) at the time of testing, because the doctor has not listened to the patient symptoms ("But doctor, I feel like my blood sugar is low 2-3 hours after a meal, not first thing in the morning"). The same is true for the investigation of joint pain, allergy, asthma, depression, infertility and hair loss. The FBP, LFT's and U&E's will be usually be normal and hence the zinc levels from these patients will bias the pool. If these are the type of samples being used for normals, then obviously they do not represent a normal population and make a mockery of any statistical approach to blood level testing.

2] If the level is less than 200 micromol/L, start zinc supplements. I use 1.5 to 2 mg/kg for the first month, usually in liquid form such as Metagenics "Zinc Drink" or "Orthoplex Zymin". Don't be squeamish, the toxic dose of zinc is 2000mg and most people will just vomit after 200mg.

3] Start a strict low salicylate diet. Beware, although most parents will flatly deny that they give their children anything unhealthy, most of these children will, in fact, be "addicted" to one of the high salicylate high glutamate foods (tomato sauce, peanut paste, muesli bars, gravies...), so be tough. Although unhappy at first, they'll thank you for it afterwards, I can promise you.

4] If you can, also measure RBC Magnesium, ferritin, Vitamin C, selenium and helicobacter serology.

5] Optimal levels, for RBC Mg is >2.30 mmol/L, ferritin is >30 micromol/L, Vitamin C is 50 micromol/L. Selenium is >1.0 micromol/L.

6] If you find helicobacter, treat it. It causes malabsorption years before it causes reflux, heartburn or ulcers. Iron deficiency precedes ulcers by at least 12 months!! Think of how many patients you've sent for endoscopies for investigation of iron deficiency who only had helicobacter with no ulcers and no occult faecal blood? How could this happen? Helicobacter causes parietal cell dysfunction. You need parietal cells to make the HCl to ionise Iron, Magnesium and Calcium. Your parietal cells need Vitamin B1, B6 and Zinc to make HCl. If you don't make acid then low acid food entering the duodenum will not stimulate the pancreas to make picolinic acid which is used to absorb zinc and chromium. Everyone knows this except the Gastroenterologists!

7] Just removing salicylates from the diet or just giving zinc will not always work. The other issues of low zinc low antioxidant intake and glutamates must be dealt with too.

Excitotoxins in food (Glutamates, etc.)

Foods to Avoid, Foods to Enjoy

This is one of the newest pages that I have added to the Website. Much of this information has been on the site for years but has been buried deep in the sections that have required tedious scrolling to find them. Thankfully, a Website upgrade has changed all of that. So, here are the lists of foods rich in glutamate/aspartate and those that are lower in these two non-essential, neurostimulating amino acids that we are restricting in the excitotoxin-related conditions.

First of all, Here are a couple of great sites for looking up the nutritional profiles of food, including their glutamate and aspartate content. The newest and most comprehensive that I have found to date is http://www.foodcomp.dk/fcdb_alphlist.asp. Another is http://www.whfoods.com/foodstoc.php . In the latter, simply click on the food you are inquiring about, then scroll down toward the bottom of the page until you see the chart in the Nutritional Profile section. There is a click-on link after that chart (just above the References section) that reads "In Depth Nutritional Profile for (chosen food)" . Click on that link and then just scroll done to the aspartate and glutamate listings. Make note of the serving size at the top of the chart so that you'll be making an accurate comparison. You will quickly see the huge difference between the glutamate/aspartate content of healthy fruits/vegetables versus items such soy, wheat, barley, and the bean family (with the exception of green beans).

For example, recently my wife started eating peanuts and raisins as a late night television snack. Almost immediately, she started having very restless sleep and was complaining about soreness in her muscles and back. A quick trip to the chart showed very high levels of glutamate and asparate in peanuts.

I'm just glad that my canine patients don't eat peanut butter and jelly sandwiches and down it with a big glass of milk like our ADHD kids do. Let's see: wheat bread (with gliadorphins and plenty of glutamate and aspartate), peanut butter (LOTS more glutamate and asparate), jelly ("sugar gel"), and all of it washed down with cow milk (casomorphins and plenty of glutamate. Oh yeah. Don't forget the arachadonic acid for you pain sufferers).

Hmmmm..... It does all make sense, doesn't it?

Foods rich in glutamate and aspartate: 1) Grains: Wheat, barley, and oats are highest. Corn and rice are lower than the previous three but higher than potatoes. 2) Dairy Products: All Cheeses (cheddar, Swiss, Monterey Jack, Mozzarella, PARMESAN) are very high. Casein is very concentrated in cheese and is 20% glutamic acid by composition. 3) Beans: Soy, Pinto, lima, black, navy, and lentils 4) Seeds: Sunflower, pumpkin, etc. 5) Peanuts: Very high, as are cashews, pistachios, and almonds. I have more detailed charts on the site to show exact values for the various nuts. Everything in moderation applies when eating nuts of any kind. So, I do not recommend you reach for nuts when you are really hungry unless you can stop after a few. Nuts are very good for you..in moderation. For example, seven almonds a day gives you what you need . 6) Diet drinks: Primary source of aspartate (aspartame) 7) Prepared foods, soups: 70% of prepared foods and many soups have MSG 8) Meats: Note- All meats are naturally rich in glutamate and aspartate. Lamb (and eggs) are the lowest, while rabbit and turkey are the highest. However, I believe that the amount in a normal serving of meat should not be enough to cause problems. I think that it is all of the other "unnatural" sources when combined with the meats that are causing the problems. One of my newest concerns is the presence of glutamate in the flesh of grain-fed animals, especially chickens, turkeys, and cattle. This is a topic of discussion on the celiac forums and we are now believing that this is a real concern and could explain why some celiacs are not responding to elimination diets. Catfish are also grain fed. The fact is that 60-70% of the American Diet is wheat and dairy (with heavy emphasis on cheese). This combined with the amount of artificial sweeteners being consumed and the addition of SOY has led this country into an epidemic of pain syndromes, including fibromyalgia. Epilepsy is definitely on the rise in pets and the combination of wheat and soy in pet foods is playing a huge role. I am seeing first time epileptic dogs within three weeks of starting such diets. Food low in glutamate and asparate: 1) Fruits 2) Vegetables 3) Potatoes 4) Lamb and eggs are relatively low. 5) Tree nuts (e.g. pecans, walnuts, macadamias) NOTE: These are relatively low when compared to peanuts and cashews. I have more detailed charts on the site to show exact values. Pecans, for example, have half the amount of glutamate that peanuts have but that is still quite a bit. Again, everything in moderation applies when eating nuts of any kind. I do not recommend you reach for nuts when you are really hungry unless you can stop after a few. Nuts are very good for you..in moderation. 7 almonds a day gives you what you need .

Now, for the GOOD news:

On these dietary restrictions, I just want to make one thing very clear. We are restricting the level of glutamate and aspartate in the diet because the neurons of the brain (and their associated supportive cells called glial cells, or astrocytes) are diseased and cannot handle the high levels of this non-essential, neurostimulating amino acid in our typical diet. By eating what has become the Standard American Diet (S.A.D.), we are absolutely bombarding our brain with these “excitotoxins” in the form of grains, dairy, soy, and the rest.

But, it is the fact that the brain is unhealthy that explains why we are seeing the syndromes such as epilepsy, ADHD, insomnia, fibromyalgia, and various neurodegenerative diseases. I need to reemphasize this point for a number of reasons but mainly to establish why a person would develop one of these conditions and another not while eating the same foods. There must be something that distinguishes that person from the other…and there is…there always is. These things are covered elsewhere on the Website, but this might be a good time to check out my newest section, Viruses-Friend or Foe?

Here’s the point: When we are in the throws of one of the excitotoxin-related disorders, we need to reduce our consumption of the foods rich in these amino acids as much as possible. Doing so places a big Band-Aid on the situation and yields notable and often remarkable results in a short period of time. Dogs have stopped seizing in 24 hours. I felt noticeably better in four days. My fibromyalgia was improved in less than a week and gone in a month.

The phenomenal thing is that the long-term recovery also comes from the same diet. The principle reason this disease-producing cycle was set into motion to begin with was the damage effects of the “big 4” (gluten, casein, soy, and corn) on the intestinal villi and their ability to absorb vital nutrients. This combined with the showering of the body with exctotoxins, allergens, lectins, estrogens, and other substances from these same foods sets us up for the disease states that follow. Once the immune system starts to suffer from the same process, we are pretty much done.

The good news (yes, there is some good news) is that once we are off the “big 4” long enough, the process does reverse. Imagine the benefits of your body properly absorbing the calcium, iron, iodine, B complex, vitamin C, and trace minerals it so desperately needs. Imagine a brain, liver, and entire body that is getting what it needs to repair and thrive and in an environment free of the top four human, dog, and cat food allergens (cow milk, wheat, soy, and corn), which are also providing major quantities of allergens, damaging lectins, estrogens, depressants (casomorphins/gliadomorphins), and excitotoxins. Do you think you might just start feeling better??? (Smile)

But there’s more good news (and this is the main reason for placing this information here on this page). Once you have recovered…your brain, liver, and immune system are back to normal or close to it…then you can go back to eating some of those sources of glutamate and aspartate that are not one of the “big 4”. Again, the reason for the more severe restriction of these other foods was to place a Band-Aid on the situation- to provide relief for your ailing brain and liver (which regulates the glutamate in the bloodstream) by reducing the load of these potentially harmful neuroactive amino acids on these unhealthy organs. Once the nervous system and liver have recovered, most of us can go back to eating the nuts, seeds, beans, and meats that we were limiting in the beginning.

Just remember- "Everything in moderation". Some individuals will recover to such a degree that they could go back to eating all of the peanuts, lima beans, and steak they want without experiencing a seizure, pain episode, or bad night's sleep. BUT, most will fall into a category somewhere in between this level of recovery and where they were to start with, depending on several secondary factors, such how much we cheat with the "big 4", our age, local pollution, and more. And after all, loading up on peanuts is not good for anyone. (All you need is about 6 peanuts or almonds to get all that you need from them for the day. BUT, who does that???) Similarly, we do not need the cowboy-sized serving of steak they throw at us at your favorite restaurant. (I have to keep telling myself that.)

So, please do not think that I am saying you cannot eat any of the foods on the glutamate-rich list ever again. The formal name of the diet is the glutamate-aspartate restricted diet. That is a relative term, with some individuals requiring a more severe restriction than others. But when it comes to the "big 4", I use the term elimination. If you are gluten, casein, soy, and/or corn intolerant, elimination is the key to your optimal recovery. These are the guys that set us up for all of this mess. That is why I now "lovingly" call them the four horsemen of the apocalypse. The effects they can have on man and animals is potentially catastrophic and hopefully the reader now has a much better idea of why I have dedicated my life to this mission.

I hope this helps.

Dogtor J.

Oxytocin and behavior

http://www.healing-arts.org/children/autism-overview.htm Oxytocin is produced through the influence of the cholecystokinin-A (CCKA) receptor, which requires its substrate, cholecystokinin, to be sulfated (see the free sulfate theory of autism). If there is insufficient ability to sulfate compounds (a finding in some autistic people), the receptor will not work well, and many CCKA mediated functions will be afffected. The presence of opioid peptides and opiate receptors in the hypothalamo-neurohypophysial system, as well as the inhibitory effects of enkephalins and beta-endorphin on release of oxytocin and vasopressin has been well documented 6. Opioid peptides inhibit oxytocin release and thereby promote the preferential secretion of vasopressin when it is of functional importance to maintain homeostasis during dehydration and hemorrhage. Both neuromodulators and a neurohormones co-exist in the same neuron, as demonstrated for vasopressin with dynorphin or leucine-enkephalin, which serves to regulate the differential release of two biologically different, yet evolutionarily-related, neurohormones, e.g. oxytocin and vasopressin, from the same neuroendocrine system. Stress: Human immune function is mediated by the release of cytokines, nonantibody messenger molecules, from a variety of cells of the immune system, and from other cells, such as endothelial cells. There are Th1 and Th2 cytokines. Autoimmune and allergic diseases involve a shift in the balance of cytokines toward Th2. The autoimmune aspect of autism has been related to excessive Th2 cytokines resulting, in part, from vaccination. Gulf War syndrome and asthma have been similarly linked to excess immunization in the presence of increased environmental toxins and pollutants (high antigenic load). http://www.healing-arts.org/children/index.htm Please also see our new article, "Imaging Children with ADHD: MRI Technology Reveals Differences in Neuro-signaling". In this report, it was found that children with attention deficit-hyperactivity disorder (ADHD) may have significantly altered levels of important neurotransmitters in the frontal region of the brain, according to a study published in the December 2003 issue of the Journal of Neuropsychiatry and Clinical Neurosciences. "Our data show children with ADHD had a two-and-half-fold increased level of glutamate, an excitatory brain chemical that can be toxic to nerve cells," said lead author Helen Courvoisie, M.D., assistant professor, division of child and adolescent psychiatry, department of psychiatry and behavioral sciences at the Johns Hopkins Medical Institutions, Baltimore. "The data also suggest a decreased level of GABA, a neuro-inhibitor. This combination may explain the behavior of children with poor impulse control." Environmental factors associated with ADHD include low birth weight, hypozia (too little oxygen) at birth, and exposure in utero to a number of toxins including alcohol, cocaine, and nicotine. Other studies have found correlations between certain toxic agents / nutrient deficiencies and learning disabilities. These include: * Calcium deficiency * High serum copper * Iron deficiency can cause irritability and attention deficits * Magnesium deficiency, which is characterized by fidgeting, anxiousness, restless, psycho- motor inability, and learning difficulties * Malnutrition in general is related to learning disabilities; the child does not have to look malnourished, a fact forgotten in affluent countries * Dyslexic children seem to have abnormal zinc and copper metabolism - low zinc and high copper * Iodine deficiencies have been linked to learning difficulties http://osiris.sunderland.ac.uk/autism/owens.htm CHOLECYSTOKININ Lack of availability of sulfate would also seriously effect the performance of the major gut hormone and neurotransmitter called cholecystokinin. Two types of CCK receptors have been described: the first one, the CCKA receptor, is predominant in the alimentary canal; and the second, the CCKB receptor, is more abundant in the brain. Both receptors are found in both systems, however, and can be co-localized. (95,70) Many forms of CCK are active, but the octapeptide form of CCK which is a chain of eight amino acids, is able to promote the same degree of signal at the CCKB receptor regardless of whether sulfate has attached to it or not. On the other hand, the CCKA receptor is a thousand times more responsive to sulfated octapeptide than it is to the octapeptide's unsulfated form. (44,23) In a condition of low sulfate, CCK's maturation might be affected (24), and the delivery of its signal at the CCKA receptor would be unreliable.When one looks at the function of the CCKA receptor, the possible relevance to autism begins to become clear. Though it is clear there are some regions where the CCKA receptor does not regulate the production of serotonin, it clearly does have effects in the hypothalamus (34,56), and it is also clear that CCK has very powerful effects on serotonin in other regions where the receptor has not been differentiated. It may consequently have effects on serotonin's metabolite, melatonin, in the pineal gland. The CCKA receptor powerfully regulates dopamine(23,92,117); and also intrinsic factor (114), a substance in the digestive system which allows the body to absorb B12. When B12 is lacking it will result in elevations in methylmalonic acid in the urine (31), which was found to be consistently elevated in the children in Wakefield's recent study.(119) Dysregulation of these pathways in autism have been described by others. (7,82) The CCKA receptor also governs the release of oxytocin (64), dubbed "the social hormone" whose inadequacy may relate to the social deficits in autism. http://209.85.165.104/search?q=cache:NxDcVeCDi1EJ:www.eas.asu.edu/~autism/Additional/SummaryofDefeatAutismNow.doc+zinc+CCK+oxytocin&hl=en&ct=clnk&cd=3&gl=us Sulfation: Susan Owens substituted for Rosemarie Waring, and presented Dr. Waring's data on sulfate in autism. Basically, people with autism were found to excrete roughly twice as much sulfate in their urine, so that they had only 1/5 the normal level of sulfate in their bodies. Sulfur is an essential mineral, and is needed for many functions in the body. AIDS patients have also been found to exhibit a loss of sulfur in their urine, leading to a loss of extracellular sulfated structures in the brain. This has not yet been investigated in autism, but may be the same. In AIDS patients, treatment with N-acetyl cysteine was found to be beneficial. In autism, TNF (tumor necrosis factor) is elevated, which can inhibit the conversion of cysteine to sulfate. Low sulfur levels could cause many problems. o Sulfur is needed to sulfate the hormone CCK, which stimulates oxytocinergic neurons to release oxytocin. So, a lack of sulfur could explain the low oxytocin levels found in autism, which is important for socialization. o Sulphate is important for detoxification of metals and other toxins. o Sulphation requires activated sulfate, which requires magnesium. o Boys excrete more sulfur than girls, so they may be more susceptible to sulfation problems. o Wakefields group found that the ileum of the intestine lacks sulfur, which would lead to a leaky gut. o Sulphate is needed to release pancreatic digestive enzymes. o Many enzymes would be impaired if sulfur levels were low. o The perineuronal nets around neurons, which modulate their function, are primarily composed of chondroitin sulfur. Low sulfur would thus yield less modulation of neurons o The hepatitis B vaccine was found to inhibit sulphation chemistry for one week in typical people.

GABA Potentiators

Neurosciences Newsletter on GABA GABA is a true neurotransmitter and is involved in many clinical conditions. These include anxiety disorders such as panic attacks, seizure disorders like epilepsy, and numerous other conditions including addiction, headaches, Parkinson's Syndrome, and cognitive impairment. GABA's role is that of the primary inhibitory neurotransmitter and functions by down-regulating neurotransmission. Neurons are electrically charge cells. Ion pumps actively transfer Na+ ions out of the neuron and a overall negative charged known as the cells resting potential is attained. Two opposing forces work to alter the neurons electrical potential. The neurotransmitter glutamate increases the flow of positively charged Na+ ions into the neuron and reduce the neurons electrical charge. If the electrical potential is reduced to a critical point , called the action potential, the neuron will fire. In contrast, the neurotransmitter GABA opposes the effects of glutamate and prevents the neuron from firing. GABA achieves this by effecting the actions of the GABA receptor, a 5 subunit ion transporter. When GABA binds to the GABA receptor, the subunits of the receptor "open" and there is an influx of chloride ions. This influx restores the electrical potential of the neuron and thereby decreases the likelihood that the neuron will depolarize and relay the incoming signal. Essentially, weak or irrelevant signals are more likely to be terminated or "ignored." GABA receptor and the putative binding site for a number of agents that affect GABA function. This diagram shows the GABA-A receptor and the putative binding site for a number of agents that affect GABA function. The GABA receptor is a relatively large molecule and has binding sites not only for GABA but also for many modulatory compounds. Many of these modulatory compounds are useful therapeutic agents. Positive GABA modulators, like the benzodiazepines, do not cause the ion channel to open and an influx of chloride ions to occur on their own. They only enhance the activity of naturally occurring GABA by potentiating its function and therefore have vastly reduced potential for overdose or side effects than receptor agonist compounds, like barbiturates. While much safer than barbiturates benzodiazepine use frequently leads to dependence and withdrawal syndrome effects. This limits their utility for mild/moderate symptoms as well as for long-term therapy. Because of the important role for GABA and positive GABA modulators NeuroScience has developed a number of products that address GABA and are beneficial for patients with GABA related disorders. The following ingredients have been found to increase GABA or have a positive GABA modulating effect and have been combined in specific amounts and ratios depending on the results of laboratory tests and the clinical application. Taurine Taurine is an amino acid that is present at significant levels in the CNS and is positive modulator of GABA that does not have any adverse side-effects. Taurine also potentiates glycine - the inhibitory neurotransmitter in the spinal cord. The role of taurine as an inhibitory amino acid has been confirmed in many studies. Not surprisingly, brain tissue and cardiac tissue, which are susceptible to high levels of neurotransmitter stimulation, maintain high levels of taurine. Taurine has been shown to prevent the neuronal damage that can occur when there is an exposure to increased levels of the excitatory neurotransmitter glutamate. Over stimulation by excitatory neurotransmitters is the primary cause of neuron death in ischemic stroke. Taurine has been found to significantly reduce neuron death caused by over stimulation. The calming effects of taurine have been well studied. Other studies of taurine have found that it can reduce epileptic seizures and that low taurine levels are associated with anxiety. Glutamine Significant quantities of glutamine are normally present in the brain to support the complex process of GABA synthesis. Glutamine is an amino acid and a common precursor for the biosynthesis of GABA and glutamate. Glutamine is transported into the presynaptic terminals of inhibitory neurons by the glutamine transporter (GlnT) and is catalyzed by the actions of the enzyme glutamine deaminase to form glutamate. Glutamate in turn is converted into GABA through the actions of glutamic acid decarboxylase (GAD). (NOTE: This biosynthetic route is somewhat more complex than originally thought. Some studies have demonstrated that the glutamate formed from glutamine may enter the tricarboxylic acid (TCA) cycle before being converted to GABA.) 5-HTP Serotonin is a neurotransmitter, or more correctly a neuromodulator, that is widely distributed throughout the brain and generally enhances GABA and therefore has inhibitory activity. Therefore, as a precursor to serotonin, 5-HTP can further increase the activity of GABA. Low serotonin levels are frequently an underlying component of many clinical conditions that are also related to GABA function, e.g. insomnia, depression, & anxiety. Neurotransmitter tests show that GABA needs serotonin to function properly. Normally, GABA increases and acts through a negative feedback mechanism to reduce elevated excitatory neurotransmitters. However, this feedback mechanism requires the neuromodulating effects of serotonin. This is evident in patients with symptoms related to low GABA who have adequate GABA levels but low serotonin. Theanine Theanine is another amino acid that affects GABA. Initial interest in theanine arose due to the seemingly paradoxical calming effect of a caffeine containing drink. Theanine is a naturally occurring amino acid present at significant levels in tea leaves and is the component responsible for this discord. Theanine has been found to alter glutamate transport and actually increase GABA levels. Further studies reveal that theanine reduces hypertension in models of hypertension, increases the effectiveness of some chemotherapy compounds, reduces the stimulatory effect of caffeine, and calms patients.