Supplements for ADHD

ADD & ADHD ADD & ADHD Natural Control of ADD & ADHD Billie J. Sahley, Ph.D., CNC In Toxic Psychiatry, Peter Breggin, MD states, Hyperactivity is the most frequent justification for drugging children. Difficult-to-control children are certainly not a new phenomenon, but attempts to give them a medical diagnosis are the product of modern psychology and psychiatry. At first, psychiatrists called hyperactivity a brain disease: minimal brain dysfunction (MBD). When no minimal brain dysfunction could be demonstrated, the label became attention deficit disorder (ADD). Six million children in this country suffer some type of learning disability, ADD, or ADD with hyperactivity (ADHD). Over two million children currently take Ritalin for ADD/ADHD. ADD and ADHD may be caused by psychological problems, including trauma and abuse, nutritional deficiencies, chemical imbalances, allergic responses to food and chemicals, or a poor diet. A failure in the brains inhibitory system (the ability of the brain to inhibit and control itself) may also cause ADD/ADHD. Ritalin, the most commonly used drug for ADD and ADHD, is an amphetamine and a Schedule II class drug (other Schedule II drugs are morphine, opium, and medicinal cocaine). Doctors prescribe Ritalin for many children who do not need it, causing a number of adverse mental and physical side effects. Yet this potent, toxic drug is being used as a quick fix to quiet children. Surprisingly, prescription rates for Ritalin doubled between 1992 and 1996. Children demonstrating symptoms of anxiety, ADHD or ADD often have an imbalance in their brains biochemistry. A biochemical imbalance results from a deficiency of neurotransmitters, the chemical messengers of the brain. If a biochemical imbalance goes untreated, a child can display maladaptive behavior, followed by possible long-term physical and emotional problems. A childs state of health reflects his or her state of nutrition. When minerals, vitamins, amino acids, enzymes, or even hormones are deficient in a childs system, the result can be a disturbed biochemical homeostasis causing impaired functions in the brain. This, in turn, can cause an inability to focus, concentrate, and stay on task. At the Pain and Stress Center in San Antonio, we have successfully treated numerous children with orthomolecular therapy. Orthomolecular therapy corrects the brains biochemical imbalance, without toxic drugs that can produce adverse side effects. ADD/ADHD presents a major problem facing parents today. Most people think of hyperactivity as some type of behavioral problem (a child who is impatient, impulsive, and constantly moving); but not all hyperactive children are aggressive. Some are very passive, withdrawn, and find it hard to communicate their feelings. ADD/ADHD is not a condition that can be measured in precise scientific terms. Nor is it a situation with a quick fix, especially with powerful and addictive drugs such as Ritalin. ADD/ADHD is a complex and intricate condition in which children demonstrate maladaptive or disorganized behaviors, which put them out of sync with the world around them. Numerous clinical studies established that hyperactive children often have low serotonin levels. A proper combination of tryptophan or 5-HTP and B6, elevates the serotonin level and balances the brain; the childs symptoms diminish. The dosage, of course, depends on the childs age, weight, and the degree of hyperactivity. Effectiveness of Amino Acids Neurotransmitters affect behavior and learning. A neurotransmitter deficiency consequently has a dramatic effect on childrens or adults abilities to learn and function in an orderly manner. Most hyperactive and ADD children are born with a shortage of neurotransmitters, establishing a genetic link, most often on the male side. These children also do not manufacture the needed amount of these chemical messengers. Where do we get neurotransmitters? From the amino acids, GABA, glycine, taurine, tyrosine, glutamine and tryptophan. Do children or adults get enough aminos through diet? NO! Balanced amino-acid doses, in the right combination and formulas, produce the needed neurotransmitters naturally. Using a stimulant medication to try to produce neurotransmitters is like a shotgun going off in the childs brain. Our children were not born with Ritalin in their brain, so how can they have a Ritalin deficiency? Approximately fifty different neurotransmitters exist in the human brain, but communication between brain cells uses only ten (approximately) major neurotransmitters. How we feed the brain directly affects our production of neurotransmitters. With proper nutrition and supplementation, we can correct or enhance mind, mood, memory, and behavior. All major neurotransmitters are made from amino acids and dietary protein. One of the dangers of a low-protein diet is not ingesting enough amino acids to make adequate brain neurotransmitters. Apathy, lethargy, difficulty concentrating, loss of interest, and insomnia all result when the diet does not include adequate amounts of amino acids. Drugs do not produce or increase production of neurotransmitters. Drugs only address symptoms. Amino acids restore the balance nature intended. Some of the major symptoms of neurotransmitter deficiencies are ADD, ADHD, brain fog, mood swings, increased stress, anxiety, depression, insomnia, irritability, and aggression. Stress plays a major role in the depletion of neurotransmitters. Inhibitory neurotransmitters are the keys to behavior, emotions, and pain. Inhibitory amino acids include tryptophan, taurine, GABA, and glycine. Millions of people have turned to drugs known as SSRIs (Selective Serotonin Reuptake Inhibitors). These drugs, such as Prozac, Paxil, Zoloft, and Effexor work by selective enhancement of serotonin levels. SSRIs prevent the presynaptic nerve from reabsorbing serotonin that it previously secreted. Prozac causes an increase in brain serotonin levels; but Prozac and other prescription drugs do not increase neurotransmitters. (See Figure 1). 5-HTP is synergistic with other supplements that enhance neurotransmitters such as GABA, glutamine, tyrosine, phenylalanine, and glycine. Magnesium prolongs the benefits of 5-HTP. Chronic stress depletes available serotonin, as well as interferes with serotonins ability to control behavior. Research demonstrates that low serotonin levels can change brain function and impair learning. Low serotonin may be responsible for an increase in depression and drug use among teens and children. Most teens with low serotonin levels are more prone to try recreational drugs or even prescription drugs, for relief. A low brain serotonin level impairs the ability to focus and reason. 5-HTP shows a lot of promise as a natural answer to a multitude of problems that plague adults and children. Use caution with 5-HTP if your child is taking prescription antidepressant medications. GABA (Gamma-aminobutyric acid) GABA, an inhibitory neurotransmitter, is found throughout the central nervous system. GABA assumes an ever-enlarging role as a significant influence on ADD, ADHD, stress, anxiety, and depression, as well as stress-induced illnesses. According to Candace Pert, a neuroscientist who discovered the GABA receptor, every cell in the body has a GABA receptor, which is one reason why GABA has such positive effects. GABA inhibits the cells from firing, diminishing anxiety-related messages. Tranquilizers provide only temporary relief. We have seen many patients on Xanax that still experience anxiety. They have been told it is not addictive: it is! THERE IS NO SUCH THING AS A TRANQUILIZER DEFICIENCY! Nutrient deficiencies do occur, however; and they can and do change behavior. GABA, glutamine, and glycine prove vital for energy and the smooth running of brain functions. We have successfully used these three amino acids with patients to ease anxiety, irritability, and ADD. Research demonstrates a large number of children who display ADD/ADHD behavior actually experience anxiety. If they use all available GABA, then the receptors in the brain become empty, allowing the brain to be bombarded with random firings of excitatory messages. However, when adequate amounts of GABA are present, the reception of multiple random firings are blocked, so the brain does not become overwhelmed. At the Pain & Stress Center we regularly combine GABA and other amino acids to achieve positive results. Dose amounts vary, depending on the age and weight of the child. GABA now takes its place as a major influence on those taking drugs, and in many cases, replacing the drugs. We have found that, when combined with other amino acids, GABA works exceptionally well with ADD children. L-Glutamine Glutamine, along with GABA and Glycine, is rapidly becoming an important therapeutic amino acid of the 21st century. Glutamine, found in many foods, is the third most abundant amino acid in the blood and brain. It also provides a major alternative fuel source for the brain when blood sugar levels are low. Glutamine functions as an inhibitory neurotransmitter, and is the precursor for GABA, the antianxiety amino acid. The amino acid trio of Glutamine, GABA, and Glycine plus B6 are among the major inhibitory neurotransmitters in the brain. Glutamine is found in the nerves of the hippocampus, the memory center of the brain, in the cranial nerves, and in many other areas of the brain. These three amino acids work together as inhibitory neurotransmitters. Anyone taking amino acids must take B6 to metabolize the amino acids. Intellectually impaired children and adults often show an increase in IQ after taking glutamine in combination with Ginkgo biloba and B6. Dr. Roger Williams demonstrated that children and adults diagnosed with ADHD showed a marked improvement when taking 250 mg to 1,000 mg of glutamine daily. GABA and glutamine are not only found in the brain, but also in the receptor sites throughout the body. Glutamine is the memory and concentration amino acid. Seventy five percent of hyperactive and ADD childrens blood tests showed low levels of glutamine. Dr. C. Fredericks research also demonstrated a definite increase in the IQs of children given glutamine. When glutamine was given daily, children showed impressive improvements in their abilities to learn, to retain, and to recall. Glutamine is a major part of my orthomolecular program for hyperactive and ADHD children. Glutamine is one of the amino acids that create the neurotransmitters in the brain that enhance learning and memory. Hyperactive and ADD children have low neurotransmitter levels, especially glutamine. Adding glutamine increases the level of neurotransmitters. Start with 500 mg of glutamine and gradually increase until you reach the optimal dose for your child, to a maximum of 3,000 mg per day. Taurine Taurine is now classified as a conditionally essential amino acid in the adult. In infants and children, however, taurine is an essential amino acid. As one of the sulfur amino acids, adults synthesize taurine from cysteine and methionine, provided B6 and zinc are present. Taurine is found abundantly throughout the body in the heart, olfactory bulb, central nervous system, and brain (hippocampus and pineal gland). As an inhibitory neurotransmitter, taurine, after GABA, is the second-most important inhibitory transmitter in the brain. Taurines inhibitory action in the brain equals that of GABA and glycine. Its inhibitory effect is one source of taurines anticonvulsant and antianxiety properties. Some children with Downs syndrome have shown an increase in IQ levels when taurine was added to their diet along with glutamine, B6, and vitamin E. The need for taurine increases whenever you experience more stress than usual, or have an illness. Tyrosine Tyrosine is the amino acid and inhibitory neurotransmitter that often helps overcome depression. Clinical studies show that tyrosine controls medication-resistant depression. In a 1980 issue of the American Journal of Psychiatry, a study by Dr. Alan Gelenberg of Harvard Medical School discussed the role of tyrosine in the control of anxiety and depression. Dr. Gelenberg postulated that the lack of available tyrosine results in deficiency of the hormone norepinephrine at a specific location in the brain that relates to mood problems such as depression. Children given tyrosine supplementation demonstrated a marked improvement in mental performance and mood stability. Tyrosine, because of its role in assisting the body to cope physiologically with stress and building the bodys natural store of adrenaline, deserves to be called the stress amino acid. Stress exhaustion requires tyrosine. During periods of stress, in order to continue coping with stress physiologically, the brain requires tyrosine. Tyrosine aids children and young teens, as well as adults, with recurrent depression and mood disorders. In children, dosage ranges from 200 to 500 mg daily. Glycine Glycine is a nonessential amino acid, with the simplest structure of all the amino acids resembling glucose (blood sugar) and glycogen (excess sugar converted in the liver for storage). Glycine is sweet to the taste, can be used as a sweetener, and can mask bitterness and saltiness. Pure glycine dissolves readily in water. As the third major inhibitory neurotransmitter in the brain, glycine readily passes the blood-brain barrier. Studies by the late Carl Pfeiffer, MD, Ph.D., demonstrated glycine as an important factor in psychiatric disorders. Glycine decreases the craving for sugar, and, in many cases, can replace sugar on foods such as cereal. Glycine calms aggression in both children and adults. When combined with GABA and glutamine, glycine influences brain function by slowing down anxiety-related messages from the limbic system. As a very nontoxic amino acid, both children and adults can use glycine. Glycine can be mixed with other amino acids. Doses for a child range between 500 to 2,000 mg daily, divided. Magnesium Hyperactive or ADD children are almost always deficient in magnesium. Magnesium proves necessary for proper brain energy and is the first mineral depleted when anyone (child or adult) is under stress. Magnesium is a stress mineral, and deficiency can lead to hyperactive or ADD behavior. Magnesium plays a significant role in sugar metabolism and in the proper utilization of carbohydrates to create energy. Magnesium is so very important in a childs diet, especially if he displays hyperactive behavior, ADD, or other behavioral problems. Magnesium can be taken in liquid form, tablet, or capsule. When added to the ADD/ADHD diet, calming effects sometimes occur immediately. Most magnesium exists inside the cells where it activates enzymes necessary for the metabolism of carbohydrates and amino acids. In 1988, a study published in Alternative Medicine Review linked the development of ADHD to low blood-serum magnesium levels. A group of children followed for six months were given 200 mg of magnesium a day. Researchers noted remarkably decreased hyperactivity in the children. As a major nutrient needed by ADD/ADHD children and adults, magnesium is the number one stress mineral needed by the body. Magnesium is responsible for over three hundred enzyme functions. It cannot be stored by the body, and it must be taken daily. Symptoms of magnesium deficiency include asthma, migraines, eye twitches, anxiety, confusion, muscle spasms, irritability, depression, nervousness, fatigue, mood swings, PMS, hypertension, and insomnia. Calcium A calcium deficiency can also induce ADD/ADHD behavior. A child deficient in calcium exhibits irritability, sleep disturbances, anger, and inattentiveness. The first signs of a calcium deficiency include nervous stomach, cramps, tingling in the arms and legs, and painful joints. A calcium deficiency can also lead to ADD/ADHD behavior. Children sensitive to dairy products must receive daily calcium supplementation in capsule, chewable, or liquid form. Children up to 10 years of age need 1000 mg of calcium daily; adolescents need 1,200 to 1,500 mg daily. For those involved in sports activities, calcium supplementation is a must. Huperzine Recent research reports that Huperzine A improves mental function and learning in adolescents. Chinese researchers designed a study to determine the efficiency of Huperzine on memory and learning. The clinical study included 34 matched pairs of junior middle school students that had significant complaints of poor memory and difficulty in learning. In the double blind trial, half of the students received a placebo while the other half received Huperzine A for four weeks. Academic performance was measured before and after the clinical trial. The Huperzine group scored significantly better on standard memory tests without side effects. Huperzine A is an extract derived from Chinese club moss. Huperzine can be combined with amino acids and other nutrients. The suggested dosage is one 50 mcg capsule in the morning and in the evening for children aged 12 and over. This information is excerpted from my book Control Hyperactivity/ADD Naturally. Other resources include Is Ritalin Necessary? Both are available through: Pain & Stress Center 5282 Medical Dr. #160 San Antonio, TX 78229-6023

Pyroluria info

Clinical Use and Diagnosis: Pyrrole disorder-characterized by elevated urine kryptopyrrole test, resulting in a dramatic deficiency of zinc and vitamin B6. Identified frequently in behavior disorders, autism, aspergers, adhd, add, depression, bipolar disorders,assaultive/aggressive/violent behavior, other mental and emotional conditions and schizophrenia. It is an inborn error of the pyrrole chemistry. Common symptoms include: Poor tolerance of physical and emotional stress, poor anger control, emotional mood swings, depression, anxiety, poor short term memory, frequent infections, inability to tan, poor dream recall, abnormal fat distribution, sensitivity to light and sound and tactile sensitivites. The decisive laboratory test is analysis of Kryptopyrrole in urine. Treatment: Treatment of pyroluria consists of a replacement of zinc and vitamin B6. Because the treatment is metabolic rather than pharmacologic, it needs to be titrated to individual requirements. A variety of factors are taken into consideration when developing a treatment regimen. Both zinc and B6 supplementation need to be directed by a practitioner as too much can be toxic, use of wrong form ineffective, and avoiding competing minerals and supplements may be necessary.

Testosterone, Aggression, Serotonin

Aggression: The Testosterone-Serotonin Link Forensic Psychiatric Division and 3Directorate, Be'er Yaakov Mental Health Center, Magen Prison, Ramleh, Israel 3Abarabnel Mental Health Center, Bat-Yam, Israel Both affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel Key words: aggression, biological component, serotonin, testosterone Abstract The relevance of central neurotransmission to aggressive and impulsive behavior has become more evident due to extensive research in humans and animals. Among other findings, there are abundant data relating low serotonergic activity ± as measured by low cerebrospinal fluid 5-hydroxyindolacetic acid, and a blunted response of prolactin to fenfluramine ± to impulsive behavior. Many studies on testosterone activity show a relation between high plasma levels and a tendency towards aggression. It is hypothesized that the interaction between low serotonin and high testosterone levels in the central nervous system has a significant effect on the neural mechanisms involved in the expression of aggressive behavior. It seems that testosterone modulates serotonergic receptor activity in a way that directly affects aggression, fear and anxiety. Our survey reviews the main findings on serotonin, testosterone and the possible interaction between them with regard to these behavioral phenomena. IMAJ 2003;5:653±658 For Editorial see page 667 Aggression is a complex social behavior with many definitions. The most suitable for clinical implications is that proposed by Moyer [1]: ``An overt behavior with the intention of inflicting damage or other unpleasantness upon another individual.'' Aggression may occur in a broad spectrum of human behaviors ranging from an episodic, normal reaction to more generalized, pervasive manifes- tations in severe psychopathologies. In both humans and animals, the term aggression comprises behaviors that are non-homogenous for clinical phenomenology and neurobiologic features, making simple extrapolation from animal subtypes to humans not feasible. Nonetheless, clinical observations, experimental laboratory para- digms and cluster/factor-analytic statistics have been used in attempts to subdivide aggression in both humans and animals, thus broadening our understanding of the similar and non-similar factors that underlie aggression [2]. Violence has been defined as the physical force exerted for the purpose of violating, damaging, or abusing [3]. In humans, aggressive antisocial behavior, which is a complex phenomenon, is defined as a conduct indicating indifference to another's person or property such as criminal behavior, dishonesty or abuse [4]. Individual differences in the temperamental traits of impulsivity are relatively stable throughout life. Impulsivity is defined as actions that cannot be stopped or altered once they are initiated, even if the consequences of the action might be undesirable or unpleasant [5]. These traits are likely to result from interactions of biological and environmental factors. Brain structur- al abnormalities that are caused by genetic, nutritional-environ- mental factors may produce neuropsychologic dysfunctions. Neurotransmitters, hormones, cytokines, enzymes, growth factors, and signaling molecules are all involved in this complex neuro- circuitry that leads towards pathologic aggression. A neural circuit composed of several regions of the prefrontal cortex, amygdala, hippocampus, medial preoptic area, hypothalamus, anterior cingu- late gyrus, insular cortex, ventral striatum and other interconnected structures has been implicated in emotion regulation. Functional or structural abnormalities in one or more of these regions or in the interconnections among them can increase the susceptibility for impulsive aggression and violence [6]. Abnormalities of 5-hydroxy-tryptophan and noradrenergic func- tioning have been implicated in aggressive behavior. The role of dopamine in human studies requires further investigation. Most studies suggest that impulsive aggression is related to lower 5-HT levels in the central nervous system. While some studies show that increased levels of norepinephrine correlate with impulsive aggres- sion, others demonstrate an opposite relationship. The role of norepinephrine in impulsive aggressive behavior is still unclear [7]. Among the various factors implicated in aggression in humans and animals, a distinct link between testosterone and serotonin has been hypothesized as a major contributor [8]. In the present study we review recent findings on the effect of serotonin and testosterone on aggressive behavior and the possible link between them [Figure 1]. Testosterone Testosterone and other neurosteroids lead to sexual differentiation in the CNS. In laboratory animals it is clear that the CNS is 5-HT = 5-hydroxy-tryptophan IMAJ . Vol 5 . September 2003 Aggression: The Testosterone-Serotonin Link 653 inherently female unless exposed to testicular hormones. Manip- ulation of the hormonal environment during perinatal development permanently alters both the structure and function of the CNS. Exposing females to testicular hormones masculinizes components of the CNS. Prenatal chemical castration or surgical castration of the male allows the development of a more female-like CNS. In mammals, the sexual differentiation of the CNS has a significant role in shaping sexual preference and other reproductive activities. In addition, it influences food intake and body weight, territorial marking and aggressive behavior, learning strategies, and play behavior. Most likely, in humans, other aspects of cognitive function are affected as well [9]. Testosterone appears to mediate its effects during a critical time period before and after birth, when it sensitizes certain neuronal circuits in the brain and guides the organization of the brain into a ``male-like'' pattern by inducing or preventing neural cell death. It has been suggested that as a result, in adulthood, when steroids stimulate these circuits again, aggressive behavior is elicited through modulation of specific neurotransmitter pathways. However, it must be remembered that hormones themselves do not directly cause behaviors; rather they induce chemical changes in certain neurons, affecting the likelihood of certain behavioral outcomes as a result of modulation of particular neural pathways [10]. Testosterone acts as a prohormone which, when converted into 5-alpha-dihydrotestosterone, acts on androgen receptors, or when converted to estradiol by the enzyme aromatase, acts on estrogen receptors. There is overwhelming evidence that most of the effects of testosterone in mediating aggression occur after aromatization [11]. Furthermore, the intensity of aggressive behavior was directly correlated with the aromatase activity in the posterior hypothala- mus [12]. Men, in general, are much more aggressive than women ± a fact that has led researchers to investigate possible links between levels of male hormones (particularly testosterone) and aggressive or criminal behavior. Testosterone may affect levels of aggression beginning early in life. In a study conducted among 28 male and 20 female preschoolers, children were videotaped while playing. Levels of aggression in social and play situations were observed and measurements of salivary testosterone levels evaluated. Results indicated a positive correlation in boys (but not in girls) between testosterone levels and serious aggression in social situations, but no correlation with playful aggression [13]. A study of 4,462 men revealed that the overall picture among the high testosterone men is one of delinquency, substance abuse and a tendency toward excess aggressive behavior. These men have more trouble with people like teachers while they are growing up, have more sexual partners, are more likely to show disciplinary problems during their military service and to have used ``hard'' drugs, particularly if they had a poor education and low incomes [14]. Measurements of testosterone saliva levels in 692 adult male prisoners showed that inmates who committed violent or sexual crimes had higher testosterone levels than inmates who were incarcerated for property crimes or drug abuse. This study also shows that inmates with higher testosterone levels violated more prison rules, especially those involving overt confrontation [15]. When salivary testosterone levels of young adult delinquents were compared with levels in a group of college students, matched for age, gender and race, the delinquent subjects had higher testosterone levels than the student controls, a finding that was true for both male and female subjects [16]. It can thus be concluded that high testosterone levels play a role in some criminal behavior, particularly when other risk factors such as low socioeconomic status are present. High testosterone levels have also been found in cases of antisocial behavior in a subtype of alcoholics. Levels of free testosterone, total testosterone, and sex hormone-binding globulin (which influences total testosterone concentration) were measured in 61 men undergoing forensic psychiatric examination. All subjects had been detoxified from drugs and alcohol while hospitalized or in prison. High concentra- tions of total testosterone and SHBG were related to type II alcoholism (a strongly genetically influenced type of alcoholism seen primarily in males, and associated with earlier onset, a more severe course, and criminality). In addition, total testosterone and SHBG were related to antisocial personality disorder and to socially deviant behavior, as reflected by scores on the Psychopathy Checklist, and free testosterone was strongly associated with the psychopathy-related scales of the Karolinska Scales of Personality [17]. In general, women have low testosterone levels. In order to learn more about the effects of this "male" hormone in females, saliva testosterone levels in 87 female inmates in a maximum security prison were compared with the violence levels of the crimes the subjects had committed, as well as the levels of aggressive dominant behavior they exhibited in prison. A direct link between testosterone and aggressively dominant behavior in prison was found. Further analysis indicated that increasing age is linked to reduced criminal violence and aggressive dominance in female prisoners, both directly and indirectly through lower levels of testosterone that come with age. Five women with the lowest testosterone levels were described by prison staff members to be "sneaky" and "treacherous." Observing the well-established link Reviews SHBG = sex hormone-binding globulin 654 M. Birger et al. IMAJ . Vol 5 . September 2003 between testosterone and dominance, it is hypothesized that when dominant high testosterone inmates face confrontation, they act openly and directly, while low testosterone inmates, because they are less dominant, need to be more ``sneaky'' in dealing with others [18]. The conclusion derived from accumulating evidence in humans and animals indicates that high testosterone levels are related to dominance-related aggression implicated in normal and pathologic behaviors. Serotonin The brainstem raphe 5-HT system is the most widely distributed neurotransmitter system in the brain. Serotonergic raphe neurons project diffusely to a variety of brain regions (e.g., cortex, amygdala, and hippocampus). In addition to its role as a neurotransmitter, 5- HT is an important regulator of morphogenetic activities during early brain development as well as during adult neurogenesis and plasticity, including cell proliferation, migration, differentiation and synaptogenesis [19]. In humans, non-human primates and other mammals, preclini- cal and clinical studies have accumulated an overwhelming body of evidence indicating that 5-HT signaling is a major modulator of emotional behavior, including anxiety and impulsivity as well as aggression, and integrates complex brain functions such as cognition, sensory processing and motor activity [20]. The diversity of these functions is due to the fact that 5-HT orchestrates the activity and interaction of several other transmitter systems. 5-HT may be viewed as a master-control neurotransmitter within a highly complex system of neural communication mediated by at least 14 pre- and postsynaptic receptor subtypes and subunits. 5-HT synthesizing and metabolizing enzymes, and the 5-HT transporter, play an important role in the regulation of 5-HT, which acts as a chemical messenger. 5-HT-mediated behaviors may be diversely expressed and range from minor personality accentuations (char- acterized by impulsivity, hostility, irritability, psychopathic deviance or violence, or by more clear-cut personality dysfunction such as antisocial, borderline, narcissistic and histrionic personality traits or disorders) to major psychiatric disturbances (suicidal behavior, overt aggressive behavior, intermittent explosive disorder, patholo- gic gambling, pyromania, bulimia, and some types of substance or alcohol abuse) [21]. One of the most replicated findings in psychobiology is the observation of lower 5-hydroxyindolacetic acid in the brain and cerebrospinal fluid of subjects with impulsive aggression and suicidal behavior. Low or lower than average 5-HIAA concentrations in cerebrospinal fluid have been reported in individuals who display inappropriate aggression as children, engage in frequent impulsive and violent criminal behavior, exhibit excessive alcohol abuse and dependence, and in high lethality suicide attempters as opposed to low lethality suicide attempters. Lifetime levels of aggression were found to be higher among individuals with lower CSF levels of 5-HIAA suffering from depression. In contrast, the dopamine and norepinephrine systems do not appear to be as significantly involved in suicidal acts, aggression, or depression. [22]. In a study of wild and captive primates, 49 male rhesus monkeys were studied for 4 years. During this time, young monkeys were undergoing a very dangerous period of life during which they migrated from their own groups to new social groups. Between 30% and 50% of the monkeys died during this period, often from violent encounters with other monkeys. (This particular colony of monkeys has no natural enemies.) At the beginning of the study, 5-HIAA levels were measured and the monkeys were divided into four groups: low, mid-low, mid-high, and high 5-HIAA. Twenty-seven of the monkeys were observed in the wild and the monkeys' aggressive acts were recorded. The aggressive acts of all 49 monkeys while in captivity, as well as the monkeys' fight-related scars and wounds, were also recorded. Low CSF 5-HIAA concentrations were predictive of the early death of 11 subjects of the monkey group that were either known or presumed dead. Direct observations of aggressive behavior showed that subjects that died had engaged in high rates of escalated aggression and exhibited a trend to engage in more overall aggression. Of the six dead monkeys whose bodies were recovered, all four who died violently had low 5-HIAA levels, while the two monkeys that died of illnesses had 5-HIAA levels similar to those of the surviving monkeys. While monkeys with low 5-HIAA levels were more violent than the high 5-HIAA monkeys, they also had other dangerous personality traits. They migrated at earlier ages when they were less prepared to defend themselves, were more likely to take life-threatening risks such as spontaneous jumping at dangerous heights when moving from tree to tree, and were most likely to be caught repeatedly in traps. [23]. The increased death rate among monkeys with low 5-HIAA levels is consistent with the results of a 1993 study conducted in a mixed- diagnosis group of 73 male psychiatric patients examined between 1976 and 1990 and diagnosed as suffering predominantly from schizophrenia and depression. Seven of these patients later died before the age of 40. All seven had markedly lower CSF 5-HIAA levels than the surviving patients, and six of the seven died either in homicides, suicides, or "suspicious" accidents [24]. An increase in plasma prolactin when the drug fenfluramine is administered is one measure of the responsiveness of the serotonergic system. The administration of the serotonin-releasing agent D-fenfluramine to 35 healthy subjects (20 females and 15 males) caused an inverse correlation between measures of serotonin function and measures of hostility and aggression in male subjects [25]. These data provide modest support for the theory of a link between reduced serotonergic activity and increased trait aggression in healthy males. No similar correlation was seen in female subjects. A fenfluramine challenge to 97 personality- disordered patients revealed that those with a history of self-injury or suicide attempts displayed evidence of abnormalities of the serotonergic system [26]. Research on deactivation of 5-HT receptors also indicated that 5-HT is connected to impulsivity and aggression-related behavior. The 5-HT1B receptor was the first subtype to have its gene deactivated. These receptors are located predominantly at presynaptic terminals where they can inhibit release of 5-HT. Wild-type and homozygous null mutant (5-HT1B) Reviews 5-HIAA = 5-hydroxyindolacetic acid CSF = cerebrospinal fluid IMAJ . Vol 5 . September 2003 Aggression: The Testosterone-Serotonin Link 655 showed more rapid, more intense, and more frequent attacks when being intruded than the non-isolated male wild-type [27]. In contrast to 5-HT1B knockout in mice, 5-HT1A knockouts are less reactive and possibly less aggressive but show more anxiety-related behavior than control mice [28]. In humans, significant sib-pair linkage of antisocial alcoholism was associated with 5-HT1B gene HTR1B G861C polymorphism and the short-tandem repeat locus D6S284 [29]. The first step in 5-HT biosynthesis in 5-HT neurons is catalyzed by the rate-limiting enzyme tryptophan hydroxylase. Involvement of L-tryptophan availability and of TPH activity in impulsivity, aggressiveness, and associated suicidality has been reported in several studies of psychiatric patients or offender populations [30]. An increase was recently observed in aggressive responses on a free-operant laboratory measure of aggression following experi- mental tryptophan depletion in healthy males, supporting the hypothesis that low plasma tryptophan concentration and asso- ciated decrease in brain 5-HT facilitates aggression-related behavior [31]. Although some studies show a controversial trend, i.e., that elevated serotonergic activity leads to increased aggression [32], the majority of research data in humans and animal models do show a correlation between aggressive behavior and low CNS serotonergic activity. This is demonstrated by low CSF 5-HIAA levels, fenfluramine challenge, tryptophan depletion, and mice knockout paradigms. The relation between testosterone and serotonin A study that measured CSF testosterone and 5-HIAA showed that: . CSF free testosterone concentrations were positively correlated with overall aggressiveness, but not with measures of impulsiv- ity. . CSF 5-HIAA concentrations were negatively correlated with impulsive behavior and with severe, unrestrained aggression, but not with overall rates of aggression. High rates of impulsive behavior were positively correlated with severe, unrestrained aggression, but not overall rates of aggression. . Dimensional analyses showed that while subjects with low CSF 5-HIAA exhibited high rates of aggression, high CSF testosterone further augmented rates and intensity of aggression in subjects with low CSF 5-HIAA [33]. It is thus concluded that high CSF free testosterone concentrations are associated with competitive aggression, while low CSF 5-HIAA concentrations are associated with severe aggression, which results from impaired impulse control and perseverance [34]. The relationship between impulsivity, aggression, 5-HT function and testosterone in male offenders with personality disorders was investigated in 60 male offenders with personality disorders and 27 healthy controls, using the Special Hospital Assessment of Personality and Socialization score. Non-psychopaths and those with schizoid personality disorders according to SHAPS had enhanced 5-HT function (prolactin response to d-fenfluramine). Reduced 5-HT function was found in offenders with borderline personality disorders and those with a history of repeated self-harm or alcohol misuse. The 5-HT function was inversely correlated more strongly with impulsivity than with aggression. Plasma testosterone correlated positively with aggressive acts. The SHAPS primary psychopaths had lower initial cortisol and higher testosterone concentrations than controls [8]. Acute administration of testoster- one in male rats caused a significant increase in the content of 5- HT2A receptor mRNA and serotonin transporter mRNA in the dorsal raphe nucleus and the density of 5-HT2A receptor and serotonin binding sites in higher centers of the brain. The lack of effect of 5- alpha-dihydrotestosterone, a potent androgen that cannot be converted to estrogen, suggests that the action of testosterone depends upon its conversion to estrogen by aromatase. This may also explain why estrogen, but not testosterone, increased the density of 5-HT2AR binding sites in the caudate-putamen, a brain region where aromatase is scarce. These findings provide a potential topochemical handle with which to investigate testosterone/estrogen regulation of serotonin- related gene expression. The possible role of interactions between sex steroids and serotonin mechanisms might serve as an etiologic model to psychopathology leading to aggression [35]. The administration of paroxetine, a selective serotonin reuptake inhibitor, did not have any effect on night-time testosterone profiles in healthy male volunteers [36]. In a study examining the relationship between 5-HT, testosterone and alcoholism in the etiology of domestic violence, it was shown that: . Healthy controls and domestic violence in the non-alcoholic group differed in 5-HIAA concentrations and physical violence scores. . Healthy controls and domestic violence alcoholic groups differed in testosterone concentrations, alcohol dependence and physical violence scores. . The domestic violence non-alcoholic and domestic violence alcoholic groups differed in 5-HIAA, testosterone concentra- tions, physical violence scores and alcohol dependence [37]. Although studies link high levels of testosterone to aggression, this hormone alone does not account for aggressive behavior. In fact, successful athletes and businessmen tend to have high testosterone levels, without being any more violence-prone than their low testosterone counterparts, indicating that testosterone may not act alone in promoting aggression. Rather, aggressive men's behavior may be influenced by high testosterone levels combined with low levels of the brain chemical serotonin. Testosterone is linked more strongly to dominance in general than to aggression. High testosterone levels encourage dominance- seeking behaviors, which put the individual into situations in which frustration of dominance can occur. It is postulated that when a high testosterone man is frustrated in his attempts to achieve dominance, serotonin comes into play, because low serotonin activity is associated with hyper-responsiveness to aversive stimuli and therefore results in a greater likelihood of an intensely negative emotional reaction and, thus, a greater chance of aggressive behavior. It is speculated that the hypothalamus and amygdala, which are prominently associated with both testosterone and Reviews TPH = tryptophan hydroxylase SHAPS = Special Hospital Assessment of Personality and Socialization 656 M. Birger et al. IMAJ . Vol 5 . September 2003 serotonin, play a key role in aggressive responses to situations in which efforts at dominance are frustrated. In comparison to non- aggressive animals, aggressive animals were found to have lower serotonin levels in the hypothalamus and the amygdala. Testoster- one action in both of these brain structures was shown to increase aggression in various animal species [38]. Conclusions Biological influences are not the only pathway leading to individual differences in personality dimensions, behavior, and psychopathol- ogy. Complex traits are most likely generated by a complex interaction of environmental and experiential factors with a number of biological factors, among which testosterone and serotonin play a major role. Recent genetic studies on 5-HT receptors, transpor- ters, and modifying enzymes have shown that although these substances have only a modest impact, they affect many develop- mental processes throughout ontogeny as well as compensatory mechanisms. The therapeutic application of these findings includes the use of agents that increase 5-HT, either by facilitating its release such as fenfluramine or by blocking its reuptake by the various selective serotonin reuptake inhibitors [39]. Chemical castration by antian- drogenic agents, although inefficient for treating general aggres- sion, is used for the treatment of paraphilic sex offenders [40]. It is becoming increasingly evident that many neurotransmitters and hormones are expressed at early periods of neural development and it is likely that they participate in the structural organization of the nervous system. A major challenge is therefore the identifica- tion of specific neural mechanisms that underlie aggressiveness and impulsivity for the purpose of early identification, prevention and the treatment of individuals who are prone to violent acts. References 1. Moyer K. Kinds of aggression and their physiological basis. In: Buglass R, Bowden P, eds. Principles and Practice of Forensic Psychiatry. Community and Behavioural Biology. Part A. Edinburgh: Churchill Livingstone, 1968. 2. Scarpa A, Raine A. Psychophysiology of anger and violent behavior. Psychiatr Clin North Am 1997;20:375±94. 3. The American Heritage Dictionary of the English Language. 4th edn. New York: Houghton Mifflin, 2000. 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edn. Washington, DC: American Psychiatric Association, 1994. 5. Logan GD, Schachar RJ, Tannock R. Impulsivity and inhibitory control. Psych Sci 1997;8:60±4. 6. Davidson RJ. Dysfunction in the neural circuitry of emotion regulation ± a possible prelude to violence. Science 2000;289:591±4. 7. Oquendo MA, Mann JJ. The biology of impulsivity and suicidality. Psychiatr Clin North Am 2000;23:11±25. 8. Dolan M, Anderson IM, Deakin JF. Relationship between 5-HT function and impulsivity and aggression in male offenders with personality disorders. Br J Psychiatry 2001;178:352±9. 9. Gorski RA. Development of the cerebral cortex. XV: Sexual differentiation of the central nervous system. J Am Acad Child Adolesc Psychiatry 1998;37:1337±9. 10. Ewen B. Endocrine effects on the brain and their relationship to behavior. In: Siegel G, ed. Basic Neurochemistry. 5th edn. London: Raven Press, 1994:1007±26. 11. Schlinger BA, Callard GV. Aromatization mediates aggressive behavior in quail. Gen Compar Endocrinol 1990;79:39±53. 12. Schlinger BA, Callard GV. Aromatase activity in quail brain: correlation with aggressiveness. Endocrinology 1989;124:437±43. 13. Sanchez-Martin E, Fano L, Ahedo J, et al. Relating testosterone levels and free play social behavior in male and female preschool children. Psychoneuroendocrinology 2000;8:773±83. 14. Dabbs JM, Morris R. Testosterone, social class, and antisocial behavior in a sample of 4,462 men. Psychol Sci 1990;1:209±11. 15. Dabbs JM, Carr TS, Frady, Rl, et al. Testosterone, crime, and misbehavior among 692 male prison inmates. Person Individ Diff 1995;18:627±33. 16. Banks T, Dabbs JM. Salivary testosterone and cortisol in a delinquent and violent urban subculture. J Soc Psychol 1996;136:49±56. 17. Stalenheim EG, Eriksson E, von Knorring L, et al. Testosterone as a biological marker in psychopathy and alcoholism. Psychiatr Res 1998;77:79±88. 18. Dabbs JM, Hargrove MF. Age, testosterone, and behavior among female prison inmates. Psychosom Med 1997;59:477±80. 19. Azmitia EC, Whitaker-Azmitia PM. Development and adult plasticity of serotonergic neurons and their target cells. In: Baumgarten HG, Gothert M, eds. Serotonergic Neurons and 5-HT Receptors in the CNS. New York: Springer, 1997:1±39. 20. Westenberg HG, Murphy DL, Den Boer JA. Advances in the Neurobiology of Anxiety Disorders. New York: Wiley, 1996. 21. Staner L, Mendlewicz J. Heredity and role of serotonin in aggressive impulsive behavior. Encephale 1998;24:355±64. 22. Asberg M. Neurotransmitters and suicidal behavior: the evidence from cerebrospinal fluid studies. Ann NY Acad Sci 1997;836:158±81. 23. Higley JD, Mehlman PT, Higley SB, et al. Excessive mortality in young free-ranging male nonhuman primates with low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations. Arch Gen Psychiatry 1996;53: 537±43. 24. Faustman WO, Ringo DL, Faull KF. An association between low levels of 5-HIAA and HVA in cerebrospinal fluid and early mortality in a diagnostically mixed psychiatric sample. Br J Psychiatry 1993;163:519±21. 25. Cleare AJ, Bond, AJ. Does central serotonergic function correlate inversely with aggression? A study using D-fenfluramine in healthy subjects. Psychiatr Res 1997;69:89±95. 26. New AS, Trestman RL, Mitropolou V, et al. Serotonergic function and self-injurious behavior in personality disorder patients. Psychiatr Res 1997;69:17±26. 27. Ramboz S, Saudou F, Amara DA, et al. 5-HT1B receptor knock out- behavioral consequences. Behav Brain Res 1996;73:305±12. 28. Zhuang X, Gross C, Santarelli L, et al. Altered motional states in knockout mice lacking 5-HT1A or 5-HT1B receptors. Neuropsychopharma- cology 1999;21:52±60S. 29. Lappalainen J, Long JC, Eggert M, et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch Gen Psychiatry 1998;55:989±94. 30. LeMarquand DG, Benkalfat C, Pihl RO, et al. Behavioral inhibition induced by tryptophan depletion in nonalcoholic young men with multigenerational family histories of paternal alcoholism. Am J Psychiatry 1999;156:1771±9. 31. Wingrove J, Bond AJ, Cleare AJ, et al. Trait hostility and prolactin response to tryptophan enhancement/depletion. Neuropsychobiology 1999;40:202±6. 32. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274:1527±31. 33. Higley JD, Mehlman PT. CSF testosterone and 5-HIAA correlate with different types of aggressive behaviors. Biol Psychiatry 1996;40:1067±82. 34. Higley JD, Mehlman PT. Comment on the article: CSF testosterone and 5-HIAA correlate with different types of aggressive behaviors Biol Psychiatry 1997;42:305±7. 35. Fink G, Sumner B, Rosie R, et al. Androgen actions on central serotonin Reviews IMAJ . Vol 5 . September 2003 Aggression: The Testosterone-Serotonin Link 657 neurotransmission: relevance for mood, mental state and memory. Behav Brain Res 1999;105:53±68. 36. Schlosser R, Wetzel H, Dorr H, et al. Effects of subchronic paroxetine administration on night-time endocrinological profiles in healthy male volunteers. Psychoneuroendocrinology 2000;25:377±88. 37. George DT, Umau JC, Philips MJ, et al. Serotonin, testosterone and alcohol in the etiology of domestic violence. Psychiatr Res 2001;104:27± 37 38. Bernhardt PC. Influences of serotonin and testosterone in aggression and dominance: convergence with social psychology. Curr Direc Psychol Sci 1997;6:44±8. 39. Coccaro EF, Kavoussi RJ. Fluxetine and impulsive aggressive behavior in personality disordered subjects. Arch Gen Psychiatry 1997;54:1081±8. 40. Rosler A, Witztum E. Pharmacotherapy of paraphilias in the next millennium. Behav Sci Law 2000;18:43±56. Correspondence: Dr. M. Birger, Forensic Psychiatric Services, Magen Prison, P.O. Box 2058, Ramleh 72100, Israel. Phone: (972-8) 977-6142 Fax: (972-8) 977-6141 email: bymoshe@beer-ness.health.gov.il Reviews

Natural treatments for Anxiety.

IS ANXIETY A FACT OF LIFE? I don't think so. Readers have requested we address the subject of relieving anxiety by using the amino acids Taurine, & GABA, and Vitamin B3 (Niacin). Though setting out to do this, by the time anxiety & taurine were finished, the news was too long, so GABA & B3 will have to wait. Taurine has many other benefits, so if anxiety is not your interest you may want to skip ahead to the Taurine section. I would not begin helping someone with anxiety by giving these single agents alone, & indeed they may not need to be given. Suffice it to say, when you are physically healthy & biochemically balanced you should have no symptoms of anxiety unless you find yourself in an extremely emergent situation. Those under 18 or over 38 who suddenly develop anxiety which disrupts their normal activity may have one of the medical illnesses which can include anxiety & should have appropriate medical evaluation. Apparently, many in our society are anxious because minor tranquilizers are one of the most widely prescribed group of drugs & among the most problematic when regularly used long term, which, unfortunately, they often are. They are highly addicting & over time risk adding to the very symptoms they were originally intended to alleviate. Though the Physicians Desk Reference warns of their addictive potential & suggests only intermittent or short term usage, these warnings are often ignored. Some of these tranquilizers are Xanax, Klonopin, Ativan, Valium, Librium. Tranxene, as well as some of the sleeping meds. PHYSIOLOGICAL OR PSYCHOLOGICAL ANXIETY, OR BOTH? It helps to distinguish whether the anxiety begins with physical symptoms such as racing heart, sweaty palms, shaking, nervous stomach, restlessness, tension, etc. & then perhaps spreads to associated thoughts & fears. Or does it begin with fearful anxious thoughts & spread to become a physiological reaction? Or is it only manifested by thoughts with no physical component or physical symptoms with little associated fear thoughts. When there is a usual thought onset to the symptoms, besides doing all of the next recommended items, it is important to decondition your thought patterns. There are many techniques for doing this. My current favorite is the use of Hypnoperipheral Processing reprogramming tapes. This is a combination of hypnosis & Neurolinguistic Programming. It is a powerful & effective tool for change! You can find such tapes at http://www.metamodels.com/maps/hpp.html. I would suggest the series "Changing Emotions" & "Feeling Better". We also clarify the timing of the anxiety. Is it all the time, or at certain times of the day or night? Is it only in very specific situations? I had a patient who only had severe anxiety when going out in the car. We found she was sensitive to auto fumes & when we had her wear a carbon filtered mask to keep out the fumes, she was able to go out without any anxiety. What percentage of agoraphobics are having their symptoms as a reaction to a specific chemical environment? All of this detective work helps to clarify how much is physical, how much is psychological, or even how much is a psychological conditioned response to a physical trigger. Is the problem related to blood sugar instabilty, which I see quite often & commonly has a pattern of middle of the night, early a.m. or mid-afternoon symptoms. Or is it related to food sensitivities? Is there is a personal or family history of allergies or is a person repetitively eating the same foods, or many of the high allergen foods, such as milk, cheese, wheat, eggs? We also look for a history of high caffeine, alcohol, or sugar intake , or a general junk food diet. Is there a premenstrual or menopausal component? Is the person on medications which can cause anxiety as a side effect? WHAT DOES NUTRITION HAVE TO DO WITH ANXIETY? It is known that deficiencies of certain nutrients can cause anxiety, so begin by improving your diet. Those nutrients are: Vitamins B1, B3, B6, B12, folic acid, calcium, magnesium, phosphorus, omega-3-fatty acids, such as fish or flax seed oil, & certain amino acids, such as L-tryptophan, taurine, GABA. Too much calcium can also cause anxiety. First, clean up your diet. With your diet improvement you may want to add a good multivitamin mineral, an extra B complex, & an omega-3-fatty acid to basically cover most of the above listed nutrients. You would then only add extra items if all of the above failed to make a difference after 2 weeks. My first choice would be extra magnesium & the next choice would be taurine. WHAT IS TAURINE? Taurine is an amino acid which plays a major role in the brain as an "inhibitory" neurotransmitter & neuromodulator. It is similiar in structure to the amino acids GABA & L-Glycine, which are also neuroinhibitory. This means it helps to calm or stabilize an excited brain. Taurine stabilizes nerve cell membranes thus depressing the firing of brain cells & dampening the nerve cell action of the excitatory amino acids, glutamate, aspartate, & quinolinate. Taurine acts by regulating the sodium & potassium concentration in the cells & the magnesium level between the cells. This has everything to do with the electrical activity of the cells & subsequent communication between cells. By this mechanism, it has anti-anxiety & anti-convulsant activity. It has also been found useful in some cases of migraine, insomnia, agitation, restlessness, irritability, alcoholism, obsessions, depression, hypomania/mania. Dosage is from 500 mg twice daily to a total of 5000 mg daily in 3-4 divided doses, though I rarely recommend that high a dose. The total ideal body pool of taurine for adults is 12,000- 18,000 mg. Since taurine also affects the hypothalamus to help regulate body temperature, a higher dose can decrease your temperature & give chilliness, so be aware of that. Taurine also plays a role in memory & increases the level of a memory neurotransmitter, acetylcholine, in the brain (in animal studies). HOW DO YOU GET TAURINE? Taurine is highly concentrated in animal & fish protein or organ meats. Strict vegetarians can be at risk for taurine deficiency. Your body can make taurine in the liver & brain from the amino acids, L-Cysteine, & L-Methionine. Three enzymes are involved in the conversion, all requiring the pyridoxal-5-phosphate form of Vitamin B6 for this conversion. A B6 deficiency can thus cause a taurine deficiency. Some studies suggest humans are dependent upon dietary taurine to maintain "adequate" taurine reserves. Females tend toward lower taurine levels than males as their production pathways don't work as efficiently. Taurine is closely bound to zinc & manganese so deficiencies of either of these can interfere with its' utilization. Likewise, zinc & manganese enhance the effects of taurine. Taurine is the amino acid present in highest concentration of all amino acids in the fetal & newborn brain, which is the most dependent upon taurine & the least able to synthesize it.. The developing infant must derive taurine from the placenta, the newborn, from breast milk or taurine fortified formula. It is low in cow's milk. Taurine is essential for proper development of the central nervous system & the eyes. Nursing mothers especially need taurine as it stimulates prolactin to promote lactation, which is an interesting twist of nature, since infants need it so much. ( We could speculate that a mother unable to lactate may be taurine deficient, among other possibilites, & the infant is thus protected from receiving taurine deficient breast milk) Premature infants are especially prone to taurine deficiency. WHAT ELSE INFLUENCES TAURINE LEVELS? MSG can decrease taurine. Trauma, surgery, radiation therapy, burns, muscle diseases, steroid use, intestinal dysfunction with bacterial overgrowth of the small bowel can all lead to excess loss of taurine in the urine & subsequent deficiency. The medications Thorazine (a major tranquilizer) & Chloroquine (an antimalarial) can reduce taurine levels. Some depressed patients have decreased taurine. WHAT ELSE DOES TAURINE DO? EYES: It is in high concentration in the eyes where it has multiple functions to maintain normal retinal structure & function. Depletion leads to degeneration of the photoreceptor cells. Degenerative changes in the retinas of taurine deficient cats & dogs resemble retinitis pigmentosa. Taurine may be helpful in preventing cataracts. Age related macular degeneration has responded favorably to "injected" taurine as reported by American Biologics Mexico Hospital. CARDIOVASCULAR: Taurine is the most abundant amino acid in the heart, a particularly electrically excitable tissue, as are the brain & eye. Since taurine participates in electrical stabilization of the cell membranes & the normal regulation of nerve-muscle interaction, it is useful in heart irregularities & mitral valve prolapse, acting similarly to a calcium channel blocker (a class of drugs used in CV Disease) Taurine also helps control high blood pressure & is useful in congestive heart failure. DIABETES: Taurine affects carbohydrate metabolism. It potentiates the effect of insulin, enhances glucose utilization & glycogen (stored glucose) synthesis. FAT METABOLISM: Taurine reduces cholesterol by forming bile acids which are the end products of cholesterol breakdown & are the only route for eliminating cholesterol from the body. This action requires a functioning gall bladder. Taurine has an inhibitory effect on the formation of cholesterol gall stones. It is required for efficient fat absorption & solubilization. It is helpful in states of fat malabsorption such as with cystic fibrosis & other pancreatic deficiency syndromes. DETOXIFICATION: Taurine conjugates & detoxifies various internal & external toxic compounds & may help chemical sensitivities. ANTIOXIDANT: Taurine plays a major role in protecting cell membranes from oxidative attack. STRESS: It can inhibit the release of adrenalin & thus help with anxiety in this way, as well as protecting from other adverse effects of too much adrenalin. MISC: Acts as an immune stimulant to increase Natural Killer Cell Activity & Interleukin 2. Controls cell volume & osmolality. Is involved in the regulation of iron metabolism. Modulates levels of serum copper. TAURINE CAN ALSO STIMULATE RELEASE OF STOMACH ACID SO YOU SHOULD AVOID IF YOU HAVE ULCERS OR GASTRITIS. BE HAPPY!! Priscilla Slagle M.D.

Lack of B6 and tics, food allergies, behaviors...

The following addresses TS/OCD/ADD. The diagnosis would lie in the degree of vitamin B6 dependency/deficiency, and how long the person has been in this state. Carl Hansen, Jr. M.D. of Minneapolis describes celiac disease in several of his TS patients. This could be a pathway to vitamin B6 deficiency via malabsorption. Streptococcal infections have also been associated with TS. This could be a combination of the hyaluronidase's (an enzyme produced by the hemolytic strep that depolymerizes the ground substance of tissue) or streptokinase's actions on the blood brain barrier, the drain of vitamin B6 from the bacteria's own useage, the body's requirement of B6 for immunity, and the antibiotic's B6 antagonistic properties. A pre-exising B6 dependency/deficiency could be uncovered. TOURETTE SYNDROME, ALLERGY AND THE B6 DEPENDENCY STATE I have my Bachelor's degree in Biology, specializing in Medical Technology, and in graduate school, I took graduate courses in biochemistry. I work as a medical technologist performing and verifying clinical laboratory tests in Chemistry, Hematology and Blood Bank at Mt.Carmel East Medical Center in Columbus, Ohio. I do not have TS but my son, Jason (13 yrs old) has TS with OCD. ADD has not been formally diagnosed, although he has problems with organization, distractibility, and the ability to switch gears. My son has had allergies since he was a baby. He is sensitive to red dye #40 with tired splitting headaches which make him scream until he is exhausted and sleeps. This, of course, hasn't happened in several years since he has avoided the dye. He also is allergic to sulfa, molds, dust, grass, trees, and most airborn allergens. He has been on the vitamins below for 1.5 months and the teachers have said that he is a different kid. Medications that he had been on made him progressively worse, and so we made a personal decision to discontinue meds altogether. He now is motivated in school, concentrates and finishes his work, and is less disruptive with his tics in class. At home he still has his tics and compulsions, but they are shorter lived and occur less often. He has had a set back this week due to a new semester with a new schedule, plus a very moldy, rainy few days. We gave him a little extra calcium-magnesium and one extra vitamin B3. He said that this gave him relief from his symptoms (he has never said this before with anything else). I solidified my theory on the premise that Jason is probably mildly vitamin B6 dependent. He was either born requiring high amounts of B6, and/or B6 antagonists attacked early in his first year of life. B6 antagonists are hydrazines (plant growth regulators, tartrazine, etc), DOPA found in certain beans, penicillinamine, antioxidants in petroleum, many drugs including penicillin, erythromycin, phenobarbital, tetracycline, corticosteroids, sulfamethoxazole, etc. Amino acids began building up in his system, from decreased transamination, etc. Serotonin became decreased from tryptophan not being able to be utilized. Allergies developed (which is in association with low B6), I believe allergy produces swings in histamine levels which causes a constant fluctuation in neurotransmitters capable of producing mood swings and rages. The conservation of vitamin B6 (when not abundantly available) causes it to be used by the prevailing neurotransmitter system at any given time, leaving other neurotransmitter systems less than optimally functional. Histamine receptors have been found to trigger dopamine receptors directly. Histamine is also a neurotransmitter affected by deficient vitamin B6. Its receptor sites are probably increased to compensate. Kinins released into the body's tissues in response to immune complexes can damage the blood brain barrier, thus altering the sensitivity of brain cells to acetylcholine, serotonin, dopamine, histamine, epineprine and norepineprine. I found that L-dopa doesn't readily form dopamine in B6 deficiency, so probably dopamine is reduced causing an increase in dopamine receptor sites along with an increase the norepinephrine and epinephrine (which are formed from dopamine) receptors sites. These increased receptor sites make the nerves more excitable and false transmitters or true neurotransmitters can set them off with explosive qualities. These false transmitters can be phenolic substances, such as food additives, drugs, etc. The enzyme, phenol sulfotransferase (PST), detoxifies and eliminates phenolics (drugs, food additives, serotonin, dopamine (to name a few). In the brain, sulfation is used while glucuronidation prevails elsewhere. Cysteine requires B6 to enzymatically release sulfur for sulfation of these phenols by PST. Considering this, the neurotransmitters would would be conserved to a certain extent (their sulfation and elimination would be slowed down). ADD may happen when these false transmitters create background "noise", and if there is a real message to get through via other neurons, it is masked. When a true message is fired, it may have too strong of a signal, creating a strong impulsion, which can lead to the development of a tic or compulsion if the impulsion is acted upon and repeated creating a sort of conditioned reflex network of nerves. Mental, motor, and vocal tics can develop this way. According to my_ Biochemistry_ by Lehninger textbook from my graduate student in Biology days, tryptophan is broken down in Vitamin B3 deficiency to make nicotinic acid. Tryptophan is found in meat and is plentiful, if you are a meat eater. Tryptophan is the precursor for serotonin. I also looked up Vitamin B3 and how it could be connected to the issues of allergy and serotonin defiency in the brain. I found that Vitamin B3 is used to make NAD, NADP, which are coenzymes used in making histamine and serotonin (to name a few), and are essential in oxidative-reductive cellular metabolism. The B3 is needed due to tryptophan's inability to be broken down to nicotinic acid without adequate B6. So, if Vitamins B3 and B6 are being used for histamine production, then serotonin production suffers. Tryptophan then must be used in a higher frequency to make nicotinic acid. In Vitamin B6 deficiency, this cannot happen, because the enzyme kynurinase, that catalyzes the cleavage of 3 hydroxykynurine (an intermediate in tryptophan catabolism), contains pyridoxal phosphate (an active coenzyme form of Vitamin B6). In Vitamin B6 deficiency, large amounts of L-kynurenine are excreted in the urine, because of its high plasma levels. This is described in "Elevated plasma kynurenine in Tourette syndrome", _Molecular & Chemical Neuropathology_21(1): 55-60,1994 Jan. Kynurenine itself is metabolised to other substances, several of which are known to have effects on neurones. (per a research study done at University College London Medical School Harlow, England by Sheila L. Handley, BPharm, Ph.D. 1994) Large amounts of tryptophan which is broken down to ineffectively try to produce nicotinic acid reduces the amount of serotonin produced. Ineffective tryptophan utilization also uses alot of oxygen with tryptophan 2,3-dioxygenase. Low serotonin levels could cause obsessive compulsive behaviour, depression, and other mood related disorders. B6 is also required for the decarboxylase step of serotonin, histamine, and catecholamine pathways in the brain. In low B6, conservation takes place, so that B6 is used for fewer enzymes. When allergy strikes, the production of histamine causes a further imbalance of neurotransmitters, causing serotonin and/or catecholamine production to be further depleted. Sherry A Rogers, M.D., a specialist in environmental medicine, reports that all of the TS cases she has seen have a least one nutrient deficiency, and usually several. And she notes that all of these patients have hidden mold, dust, chemical and food sensitivities. ("Tourette Syndrome", _Health Counselor_, Vol.7, No.4) Acetylcholine is produced by acetyl CoA and choline. The choline is supplied through lecithin in Jason's supplements. In vitamin B6 deficiency, acetyl CoA would be made by fatty acid oxidation. So acetycholine could be functional with an adequate supply of fatty acids (evening primrose oil or flax oil might be useful). Acetylcholine could be in shorter supply in the parasympathetic system (relaxation) due to overuse in the sympathetic system where norepinephrine usually rules. The parasympathetic nervous system would need to have more acetylcholine in TS and associated disorders, it seems. Relaxation through the parasympathetic nervous system (which uses acetylcholine), where the heart rate is slowed, the blood pressure is lowered, the food is digested well, etc. is difficult in TS. Acetylcholine is probably overactive in the sympathetic autonomic nervous system, trying to stimulate the low supply of catecholamines, which would be decreased due to B6 deficiency/dependency. The receptors sites for catecholamines would be hyperexcitable and increased in number. The net usage of catecholamines could be normal to decreased due to increased stimulation by acetylcholine, depending on the availability of B6 in the body, and the conservation by low sulfation by PST. Conditions of emotional stress are known to produce more ticcing in TS. In short term stress, norepineprine, dopamine, and epineprine should be able to be produced by the conservation tactics of the body, but in long term stress, these would be exhausted, especially when another B6 dependent system is triggered. Likewise, the same would happen when histamine and serotonin are produced in short term and long term allergy. But as you might expect, the short term conditions would be explosive events with all of those increased receptor sites! Acetylcholine is also involved in the contraction of voluntary muscle cells and many other motor nerves, which are in heavy use in TS. Many people with TS are helped by exercise, where cardiac output and increased body temperature over a period of time inhibit the sympathetic nervous system. It may also help to clear toxic waste, such as kynurenine. Adequate water intake would be required to catabolize acetylcholine by cholinesterase. In my opinion acetylcholine is needed in B6 deficiency/dependency to run the nervous system. Fatty acids are essential to its success in this situation. Fatty acids require NADPH2, and NADH2 for their synthesis, and thus Vitamin B3. Water is also an utmost requirement in keeping acetylcholine from becoming a continuous firecracker. Jason has a water bottle close by most times and drinks tons of water. Water has always calmed him down. It may also dilute the kynurenine, excess amino acids and promote their excretion. If you look at the material written on the Canadian Mennonite families that have been studied with Tourette's disorder, you will see a high frequency of autoimmune and rare conditions. These findings are consistent with what one can expect with other Tourette's patients. For example, there is a high frequency of allergic conditions. My informal survey of TS and allergy results from the online TS support group are: With a total of 25 respondents with TS: 96% have allergies (24 out of 25) 56% have mold allergies 72% have obsessive complulsive traits (18 out of 25) 67% of those with obsessive compulsive traits have mold allergies 3 respondents thought they may have mold allergies, but weren't sure 52% have pollen allergies (ragweed, grass, tree, etc) 56% of those with obsessive compulsive traits have pollen allergy 48 % have animal allergies (cats, dogs, horse) 39% of those with obsessive compulsive traits have animal allergies 40% have dust allergy 39% of those with obsessive compulsive traits have dust allergy 20% have penicillin allergy 28 % of those with obsessive compulsive traits have penicillin allergy 20 % have miscellaneous allergies 11% of those with obsessive compulsive traits have miscellaneous allergies 16 % have food allergies 22 % of those with obsessive complulsive traits have food allergies 8% have sulfa allergy 11% of those with obsessive compulsive traits have sulfa allergy All of our frequent posters responded. The types of allergies are typically respiratory and airborne. Molds and pollens are the top allergens. 79% of the people with mold allergies also had pollen allergies, which are seasonal. Bonnie Grimaldi, BSMT (ASCP) 11283 Meadowcroft St. Pickerington, Ohio 43147 (614) 837-7545

Low Dopamine in Neglected/Abused kids?

Gerra G, Leonardi C, Cortese E, Zaimovic A, Dell'agnello G, Manfredini M, Somaini L, Petracca F, Caretti V, Saracino MA, Raggi MA, Donnini C Homovanillic acid (HVA) plasma levels inversely correlate with attention deficit-hyperactivity and childhood neglect measures in addicted patients. J Neural Transm. 2007 Aug 10; Background. Attention deficit hyperactivity disorder (ADHD) seems to be a risk condition for substance use disorders, possibly in relationship to common neurobiological changes, underlying both addictive and externalising behaviour susceptibility. Although this vulnerability has been primarily attributed to gene variants, previous studies suggest that also adverse childhood experiences may influence neurotransmission, affecting in particular brain dopamine (DA) system and possibly concurring to the development of behavioural disorders. Therefore, we decided to investigate ADHD symptoms and plasma concentrations of the DA metabolite homovanillic acid (HVA) in abstinent addicted patients, in comparison with healthy control subjects, evaluating whether ADHD scores were related with HVA levels, as expression of DA turnover, and whether HVA values, in turn, were associated with childhood emotional neglect. Methods. Eighty-two abstinent drug dependent patients, and 44 normal controls, matched for age and sex, completed the Wender Utah Rating Scale (WURS), measuring ADHD symptoms, and the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). Blood samples were collected to determine HVA plasma levels. Results. Addicted individuals showed significantly higher ADHD scores and lower HVA levels respect to control subjects. ADHD scores at WURS in addicted patients negatively correlated with plasma HVA values. In turn, plasma HVA levels were inversely associated with childhood neglect measures, reaching statistical significance with "mother-antipathy" and "mother neglect" scores. Conclusions. These findings suggest the possibility that childhood experience of neglect and poor mother-child attachment may have an effect on central dopamine function as an adult, in turn contributing to both ADHD and substance abuse neurobiological vulnerability.

Melatonin protects against lead exposure?

Abstract "The nervous system is the primary target for low-levels of lead (Pb) exposure and the developing brain appears to be especially vulnerable to Pb neurotoxicity. Chronic low-level Pb exposure causes growth retardation and intellectual impairment. In the present study the protective effect of melatonin during exposure to low-levels of Pb in human SH-SY5Y neuroblastoma cell cultures was assessed. The cells were exposed to Pb (0.01 to 10 M) for 48 h. Pb inhibited the proliferation of neuroblastoma cells significantly in a concentration-dependent manner. A 50% inhibition (IC50) of cell proliferation was observed at about 5 M Pb. Pb decreased (16% to 62%) the levels of total cellular glutathione (GSH) in a concentration (0.1 to 10 M)- dependent manner. Exposure of cells to Pb (5 M) for 48 h resulted in an eightfold increase in caspase-3 activity and prostaglandin E2 (PGE2) level. Pretreatment with melatonin (10 M) blocked the effects of Pb on GSH content and caspase-3 activity, and showed significant improvement in reducing the level of PGE2. The results suggest that some of the neurotoxic effects of Pb may be partly mediated by apoptosis and pretreatment with melatonin can prevent these effects. The present study asserts the neuroprotective effect of melatonin in conditions of Pb-induced toxicity in neuroblastoma cell cultures." Published in: International Journal of Toxicology, Volume 25, Issue 6 September 2006 , pages 459 - 464

Dopamine and NADH

In France, scientists found administration of NADH (ENADA™) caused more than a 40% increase in production of dopamine and norepinephrine, which are vital for strength, coordination, movement, cognitive function, mood, and sex drive (Birkmayer 1996). The amino acid tyrosine builds dopamine and norepinephrine also.

B6/P5P is a pseudo phenolic

Title: The effects of pyridoxal-5-phosphate on sulfotransferase activity: actions on tyrosyl protein sulfotransferase and phenol sulfotransferase. Authors: Rosemary H Waring, Robert M Harris and Victoria L Griffiths, School of Biosciences, University of Birmingham, Birmingham. B15 2TT. UK Introduction Sulfotransferase enzymes use PAPS (3’-phospho-adenosive-5’-phosphosulfate) to transfer sulfate residues onto a wide variety of substrates. TPST substrates require sulfation for efficient function while sulfation by SULT 1A1 greatly alters substrate properties, usually decreasing their activity. a) Tyrosylprotein sulfotransferase (TPST) Substrates - tyrosine residues on gastrin, cholecystokinin, mucin proteins Methods TPST activity was measured (using gastrin as substrate) with radiolabelled 35S-PAPS as sulfate donor; assays were incubated at 37°C for 40 minutes. All assays were performed in quadruplicate). Enzyme sources were a) platelet pellets prepared by centrifugation from time-expired platelet packs from the Birmingham Blood Transfusion Service and b) human colon adenocarcinoma HT-29 cells which synthesise mucin proteins and are thought to be the best model for the human g.i. tract. These were grown in McCoys 5A medium supplemented with 10% fetal bovine serum and glutamine/penicillin/streptomycin at 37°C till confluent, then harvested and centrifuged to give a cell membrane pellet. This was resuspended in phosphate buffered saline, then sonicated before assay. Cells were also grown after confluence for 24 hours with varying concentrations of P5P. P5P was also added directly to the platelet assay (0-2.5μM) MgCl2 was added at varying concentrations (0-5μM) before the start of the TPST assay. Results TPST activity was present in both human platelets and HT-29 cells. This enzyme activity was inhibited in the presence of P5P (Fig. 1). Direct effects of MgCl2 on the assay are shown in Fig. 2. As can be seen, MgCl2 concentration had no significant effects on the TPST activity of HT-29 cells but activated TPST activity in platelets (there are different isoforms of the enzyme). The concentration of 0.4μM P5P was then chosen as showing clear reduction of TPST activity in initial experiments (See Fig. 1). Human platelets were treated directly with this concentration while the HT-29 cells were incubated with it for 24h. Varying amounts of MgCl2 were then added to the assays (see Fig. 3). As can be seen, levels of MgCl2 at 0.5μM or greater removed the inhibition caused by 0.4μM P5P. Enzyme assays and Western blotting with specific anti-TPST antibodies showed that P5P did not affect the expression of TPST. All results were carried out in quadruplicate and are expressed as means ± SD. (SD <= 5.3%). b) SULT1A1 (Phenolsulphotransferase) Substrates – Phenols, catecholamines, flavonoids, steroids. Methods SULT1A1 activity was measured using 4-nitrophenol as a substrate (this also picks up any of the SULT1A2 isoform, although this is only present to a small extent in platelet preparations). Again radiolabelled 35S-PAPS was used in the assay as a sulfate donor. The enzyme sources were cytosols from platelets and HT-29 cells, prepared as before and assayed under standard conditions. Results SULT1A1 activity was present in both human platelets and HT-29 cells. This activity was inhibited by P5P (Fig. 4). However, this inhibition was only significant in the platelets; the HT-29 cell SULT1A1 seemed relatively unaffected. Treatment with MgCl2 (1.0μM) on cells exposed to 1.0 μM P5P restored the activity in platelets (Fig. 6) but had no significant effects in the HT-29 cells, which in any case were not greatly affected by the P5P (Fig. 4) SULT1A1 activity in platelets was almost unaffected by MgCl2 although SULT1A1 activity in HT-29 cells decreased slightly with increasing Mg (Fig. 5). Our previous studies have shown that the isoenzymes in these tissues have different activities and slightly different properties. Incubation of HT-29 cells with P5P had no effect on enzyme expression, as seen by Western blotting and enzyme activity. All results were carried out in quadruplicate and are expressed as means ±SD. (SD <= 5.4%). Conclusions 1. Platelet and HT-29 cells show TPST activity which is inhibited by P5P, though only the platelet isoform is greatly affected. This inhibition is reversed by MgCl2 in roughly equimolar amounts. 2. Platelet and HT-29 cells show SULT1A1 activity which is inhibited by P5P, although only the platelet isoform is greatly affected. Again this inhibition is reversed by MgCl2 in roughly equimolar amounts. 3. Neither TPST nor SULT1A1 expression is altered by P5P, which only affects the enzyme activity directly. 4. From the literature, P5P has a pseudo-phenolic structure which is believed to interact with those phenol sulfotransferases for which phenolic rings are a substrate. However, addition of Mg2+ may form a complex which no longer interacts with the enzyme. From the therapeutic point of view, Mg2+ ions should be supplied in at least a 2:1 ratio with P5P to reverse any inhibition and activate those sulfotransferases which respond to increased magnesium levels particularly the platelet enzymes.

Dopamine and Serotonin sulfation decreased by low PST

European Journal of Clinical Pharmacology Reduced platelet phenolsulphotransferase activity towards dopamine and 5-hydroxytryptamine in migraine Journal European Journal of Clinical Pharmacology Publisher Springer Berlin / Heidelberg ISSN 0031-6970 (Print) 1432-1041 (Online) Issue Volume 49, Numbers 1-2 / November, 1995 Biomedical and Life Sciences Monday, November 29, 2004 Pharmacokinetics And Disposition Reduced platelet phenolsulphotransferase activity towards dopamine and 5-hydroxytryptamine in migraine A. L. Jones1, G. L. Rubin1, M. W. H. Coughtrie1 Contact Information, R. C. Roberts2, 3 and W. Colvin3 (1) Department of Biochemical Medicine, University of Dundee, Ninewells Hospital and Medical School, DD1 9SY Dundee, Scotland, UK (2) Department of Medicine, University of Dundee, Ninewells Hospital and Medical School, DD1 9SY Dundee, Scotland, UK (3) Department of Neurology, Dundee Royal Infirmary, DD1 9ND Dundee, Scotland, UK Received: 1 August 1994 Accepted: 31 May 1995 Abstract Objective: The sulphation of the neurotransmitters dopamine and 5-hydroxytryptamine, and of the prototypical xenobiotic 4-nitrophenol, by phenolsulphotransferases was measured in platelet homogenates prepared from a group of migraine sufferers and a group of control subjects. Results: The activity of the M form of phenolsulpho-transferase, responsible for the sulphation of dopamine and 5-hydroxytryptamine was significantly reduced in the migraine population, by 28% with dopamine as substrate and by 20% with 5-hydroxytryptamine. The activity of the P form of the enzyme towards 4-nitrophenol was the same in both groups. We also report that the selective inhibition of P form phenolsulpho-transferase by red wine is much more potent than previously thought, with a 2000-fold dilution of dealcoholised red wine having the ability to inhibit sulphation by this enzyme by 50%. Conclusion: Our findings suggest that a reduced capacity for sulphation and inactivation of biogenic amines and catecholamines may be related to susceptibility to migraine.