Impulse Control and Serotonin

Impulse Control Disorders Introduction Impulsivity is a fundamental aspect of the human personality in addition to being a prominent feature of many psychiatric disorders. Defined broadly, impulsivity can refer to: 1. acting on the spur of the moment without previous planning 2. rapid decision making without consideration of alternative action 3. carefreeness, taking each day as it comes. Other authors place impulsivity in a class of action oriented personality predispositions that includes extroversion, sensation seeking, and a lack of inhibitory controls. Difficulties with impulse control are present in a number of Axis I disorders, including intermittent explosive disorder (IED), kleptomania, pyromania, pathological gambling and trichotillomania. With the exception of IED, these impulse control disorders have the diagnostic feature of a tension release cycle and/or gratification after engaging in the behavior. Compulsive shopping falls within the DSM-IV category of Impulse-Control Disorders Not Otherwise Specified. Preoccupation with, and inability to resist purchasing unneeded items characterize compulsive shopping. There are many other disorders where impulsive behavior is secondary to a more primary problem. For example patients with dementia, psychosis, mania, and organic brain syndromesoften exhibit impulsive behavior but both pathological conceptualization as well as treatment focus on the primary disorder. In addition Cluster B personality disorders (borderline, antisocial, histrionic and narcissistic) also have prominent impulsive traits. For the purpose of this lecture we will concentrate on those conditions where impulse control is a core feature. Neurobiology The emerging view is that the serotonin system is important in the expression of impulsivity. Research over the past twenty years has been fairly consistent in finding lowered indices of serotonin function associated with behaviors characterized by impulsivity. One conceptualization of the function of serotonin is that it serves in a capacity of behavioral restraint checking for signals of nonreward, punishment and uncertainty. Pharmacologic manipulations support this model. For example, animals with impaired serotonin levels (due to blockade of serotonin synthesis or lesion of raphe nuclei) exhibit behavior described as hyperirritable and hyperexciteable. Approaches for studying serotonin function in this population have included measuring the serotonin metabolite 5-HIAA in CSF, neuroendocrine challenge studies, and studies of serotonin receptors and transporters on platelets. More recent methods have focused on second messenger signaling, genetic polymorphisms associated with important serotonin related proteins (eg. tryptophan hydroxylase) and application of brain imaging techniques. These studies have been generally consistent in finding low serotonin function in populations with impulsive behavior. It is not surprising that biologic factors may be important in this dimension of behavior as at least two studies support a heritable component of impulsiveness and aggressive behavior. Intermittent Explosive Disorder (IED) Diagnostic Criteria 1. Several discrete episodes of failure to resist aggressive impulses that result in serious assaultive acts or destruction of property. 2. The degree of aggressiveness expressed during the episodes is grossly out of proportion to any precipitating psychosocial stressors. 3. The aggressive episodes are not better accounted for by another mental disorder. Clinical Features IED is characterized by aggressive outbursts that typically have a rapid onset, are short lived (less than 30 minutes) and can involve verbal assault , assault against property or physical assault. The episode can be associated with a provocation but the response is out of proportion. This pattern of behavior leads to significant distress and impairment in the interpersonal and occupational spheres. In addition, legal or financial problems may result. Epidemiology Although IED can occur in childhood, the mean age of onset is 15. It is more common in males (3:1). The lifetime prevalence has been estimated to be about 2.4%. Differential Diagnosis 1. Substance Intoxication or Withdrawal: Aggressive outbursts can be associated with alcohol, cocaine, PCP, barbiturate and inhalant use. 2. Personality Change Due to a General Medical Condition: This diagnosis is made when behavior is associated with a diagnosable medical condition (eg. traumatic brain injury). 3. Oppositional Defiant Disorder, Conduct Disorder, Cluster B personality disorders: IED should be distinguished from the aggressive behavior associated with these disorders. 4. Purposeful behavior: In this case the aggressive behavior has a clear primary gain. 5. Malingering: Individuals may try to feign IED to avoid responsibility for their aggressive behavior. Treatment Serotonin reuptake inhibitors are a logical first choice in treating IED. Clinical trials indicate their efficacy in decreasing verbal and non-assaultive physical aggression in personality disordered subjects as well as in IED. Trials have generally used doses higher than what are typically used for treatment of depression. Among the anticonvulsants, valproate has been studied the most extensively. There is evidence, that like SSRIs, that valproate can reduce impulsive aggression in a variety of diagnostic categories. A number of studies have demonstrated efficacy of lithium in reducing impulsive aggressive acts in prison populations. Side-effects, however, have limited its use. There is some evidence that treatment response is maximized when pharmacological treatment is combined with psychological interventions. Psychological interventions center primarily on cognitive-behavioral group therapy. Specific treatments include relaxation training, problem-solving, negative thought reduction, cognitive therapy alone or in various combinations. While combination approaches appear to be more effective, there has been little ability to discriminate which specific treatment is superior to others. Kleptomania Diagnostic Criteria 1. Recurrent failure to resist impulses to steal objects that are not needed for personal use or for their monetary value. 2. Increasing sense of tension immediately before committing the theft. 3. Pleasure, gratification, or relief at the time of committing the theft. 4. The stealing is not committed to express anger or vengeance and is not in response to a delusion or a hallucination. 5. The stealing is not better accounted for by Conduct Disorder, Mania, or Antisocial Personality Disorder. Clinical Features & Epidemiology The diagnosis of kleptomania is reserved for a relatively rare group of individuals who engage in shoplifting of items they neither want nor need. Fewer than 5% of shoplifters are thought to represent this disorder. The diagnosis is made most frequently in women and the average age at presentation is about 35 years, although the age of onset is much younger (~20 years old). Patients with this disorder appear to have high rates of depression and social isolation. Bulimia also is associated with this disorder. Differential Diagnosis Ordinary theft, which is deliberate and motivated by primary gain (usefulness or monetary value of the object), should be distinguished from Kleptomania. Treatment Cognitive behavioral therapy has been used often in conjunction with medications such as lithium and antidepressants including SSRIs. Systematic long-term treatment studies are lacking. This disorder can have a chronic course despite repeated convictions for shoplifting. Pyromania Diagnostic Criteria 1. Deliberate and purposeful fire setting on more than one occasion. 2. Tension or affective arousal before the act 3. Fascination with, interest in, curiosity about, or attraction to fire and its situational contexts. 4. The fire setting is not done for monetary gain, as an expression of sociopolitical ideology, to conceal criminal activity, to express anger of vengeance, to improve one's living circumstances, in response to a delusion or hallucination, or as a result of impaired judgment. 5. The fire setting is not better accounted for by Conduct Disorder, Mania or Antisocial Personality Disorder. Little is known about this relatively rare disorder. While arson is a major source of property damage, studies indicate that patients with pyromania represent a small fraction of perpetrators, as little as 1%. Similarly, while childhood fire setting is quite common, rarely is the diagnosis of pyromania made. This suggests that efforts should be directed towards evaluating fire setters first for other diagnoses such as conduct disorder, antisocial personality disorder, substance abuse, or other conditions where judgement can be impaired (mental retardation, psychosis, etc). Because of its low prevalence, there is insufficient data in regard to treatment and outcome. Trichotillomania Diagnostic Criteria 1. Recurring pulling out of one's hair resulting in noticeable hair loss.\ 2. An increasing sense of tension immediately before pulling out the hair or when attempting to resist the behavior. 3. Pleasure, gratification, or relief when pulling out the hair. 4. The disturbance is not better accounted for by another mental disorder and is not due to a general medical condition. 5. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. Clinical Features While hair pulling can occur at any site on the body, and frequently at multiple sites, the most common sites are the scalp, eyelashes, eye brows and pubic hair. This behavior can be prompted by stressful circumstances, depressed mood or contemplative states (such as may occur during reading, driving, or lying in bed). Of particular note is the impact trichotillomania has on social functioning. Feelings of shame and embarrassment lead to avoidance behavior and the use of wigs, hats and scarves to disguise hair loss. Case reports describe patients that eat hair (trichophagia) resulting in the development of bezoars (hairballs) that can lead to abdominal pain, bowel obstruction, and vomiting. Patients with trichotillomania are more likely to suffer from mood, anxiety and substance abuse disorders. Eating disorders and body dysmorphic disorder have also been reported to occur at a higher frequency in this population. Epidemiology Available literature suggests the prevalence in the United States to be less than 1%. The prevalence, however, of chronic hair pulling that does not meet criteria for the disorder may be as high as 10%. Surveys suggest that it is more common in women than men. The mean age of onset is estimated to be 13 years. Hair pulling in children is typically considered a benign "habit" and is self-limited. Etiology In contrast to the current DSM-IV classification of trichotillomania as an impulse control disorder, there is an alternate view that it more closely resembles OCD in its phenomenology, pathophysiology, and reported response to serotonergic agents. Others focus on the reinforcing, anxiety-reducing aspects of the behavior and suggest that trichotillomania might be related to anxiety disorders. A third interesting view is that trichotillomania is best viewed as part of a spectrum of biologically determined "pathological 'grooming' behaviors" such as compulsive feather-picking in birds and acral lick dermatitis in dogs. Treatment Antidepressants with prominent serotonergic effects (such as clomipramine and SSRIs) are most often prescribed. There is not, however, a consistent literature supporting efficacy. Combination approaches with atypical antipsychotics have been used with some success. Evidence suggests that even in those patients who show a good response initially to medication treatment, the potential for relapse is quite high. A variety of behavioral techniques have been applied to treating this population. Habit reversal training is designed to increase awareness of the behavior and teach alternative coping skills. Cognitive behavioral therapy is also used. There is a lack of systematic studies to determine efficacy of these interventions. The course of trichotillomania is highly variable without a consistent pattern. Pathological Gambling 1. Persistent and recurrent maladaptive gambling behavior as indicated by five (or more) of the following: 1. preoccupation with gambling 2. needs to gamble with increasing amounts of money 3. has repeated unsuccessful efforts to control, cut back, or stop gambling 4. is restless or irritable when attempting to cut down or stop gambling 5. gambles as a way of escaping from problems or of relieving a dysphoric mood 6. after losing money gambling, often returns another day to get even 7. lies to others to conceal extent of involvement with gambling 8. has committed illegal acts to finance gambling (forgery, fraud, theft, etc) 9. has jeopardized or lost a significant relationship, job, or educational or career opportunity because of gambling 10. relies on others to provide money to relieve a desperate financial situation caused by gambling 2. The gambling behavior is not better accounted for by a Manic Episode Clinical Features The gambling related costs in the United States of gambling are estimated to exceed $5 billion annually. While 86% of the general adult population was estimated (in 1998) to have gambled at some point in their lives, less than 10% of adult gamblers develop a gambling problem (as defined by impairment in occupational, interpersonal or financial functioning). Individuals with this disorder tend to be competitive, energetic, restless and easily bored. Pathological gambling is complicated by high rates of mood, psychotic, anxiety, attention-deficit, personality (antisocial), and substance use disorders (alchohol, nicotine, and stimulants). Rates of attempted suicide are higher than the general population (17% to 24%) Epidemiology The lifetime prevalence of pathological gambling in adults is estimated to be between 1.1-1.6%. Not surprisingly, these rates are much higher in patrons of gambling venues. Similarly states with increased access to legalized gambling have an even greater prevalence. The rates of pathological gambling also appear to be higher in populations receiving mental health or substance abuse treatment. Males outnumber females 2:1 with females being less likely to receive treatment (perhaps reflecting greater stigma in females). Of interest is that individuals with a family history of gambling are more at risk (a number of twin studies support this conclusion). Neurobiology In addition to a link with the serotonin system (as is generally seen with impulsive behavior) other studies of gambling behavior have focused on limbic brain regions, such as the anterior cingulate cortex, that are also thought to be involved in the underlying drug craving in cocaine dependence. Dopamine, involved in mediating the rewarding and reinforcing aspects of drugs of abuse, has been implicated in biochemical studies of pathological gambling, with cerebrospinal fluid levels of dopamine and its metabolites that are suggestive of increased dopamine neurotransmission. This overlap with substance abuse is supported by studies of decision making, neuroimaging, and neuropsychological testing. Treatment Behavioral treatments that have been effective in substance abuse have also been applied in treating pathological gambling. These include Gamblers Anonymous, motivational interviewing techniques, and cognitive behavioral therapy. There have not been many studies to convincingly establish their efficacy. Studies suggest that drop out rates as high as 90% occur with self-help groups. A number of well-controlled studies, however, have been completed showing benefit from SSRI treatment. While not definitive, these results are encouraging. SSRI doses higher than typically used for treating mood disorders were required. Other pharmacological approaches have been with the opiod antagonist naltrexone. Course Without intervention, there is generally a progression of in the frequency of gambling, the amount wagered, and the preoccupations with gambling. References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC, American Psychiatric Association, 1994. Diefenbach, GJ; Reitman, D; Williamson, DA. Trichotillomania: a challenge to research and practice. Clinical Psychology Review. 20(3):289-309, 2000 Sarasalo, E; Bergman, B; Toth, J. Theft behaviour and its consequences among kleptomaniacs and shoplifters--a comparative study. Forensic Science International. 86(3):193-205, 1997 Potenza MN, Kosten TR, Rounsaville BJ. Pathological gambling. JAMA 11;286(2):141-144, 2001 Reist C. Serotonin and Impulsivity. Directions in Psychiatry. 17:297-301, 1997. Coccaro EF, Kavoussi RK. Fluoxetine and impulsive aggressive behavior in personality disordered subjects. Arch Gen Psychiatry 54: 1081-1088, 1997.

Diamine oxidase breaks down histamine

Enzyme stimulation by S boulardii was associated with significant increases in diamine oxidase activity

Cofactors for neurotransmitters

Tourette Syndrome, B6 dependency, allergy BonnieGr bonniegr at aol.com Thu Feb 8 13:19:55 EST 1996 I have been putting the puzzle pieces together on the subject of Tourette Syndrome, using medline documents, college textbooks, etc. Please read the following long rationale document that I have prepared, and comment by e-mail (BonnieGr at aol.com). It is my hope that more research will be done to validate my theory. Enjoy! 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, epinephrine and norepinephrine. 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

Histamine's effects

Technical Bulletin - Issue 11 - Histamine July 28, 2004 Issue 11 Editor: Gottfried Kellermann, PhD Contributors for this issue: Mike Bull Joe Ailts Carol Arndt, Bill Wilson, M.D. The Technical Support staff at NeuroScience is proud to bring you another informative newsletter designed to keep you up to date with current developments taking place within our company. Here you will find product reviews, new test parameter announcements, neurotransmitter interpretation suggestions, and anything else relevant to the world of neurotransmitters. The NeuroScience Technical support staff has revised its Technical Guide which reviews of many of the aspects of neurotransmitter testing and amino acid therapy. NeuroScience has a New Website. Please take a moment to visit and review the new information and the new format. Our tenth newsletter reviewed the new biphasic approach to TAAT (Targeted Amino Acid Therapy) that is more effective for patients with fatigue and relevant to this newsletter, increases histamine. Here, in our eleventh issue, we will focus on the neurotransmitter, histamine, a relatively new addition to the NeuroScience testing menu. Feel free to send us your questions and comments to be addressed in this newsletter. Your input is appreciated! Histamine is a recent addition to the NeuroScience testing menu and is now being measured routinely. Research by NeuroScience in the development of assays for neurotransmitters has created this new cost-effective assay and histamine now joins GABA and PEA in our expanding test menu. (A neurotransmitter test for glutamate and a test for the amino acid glutamine have also been developed and are available in the panel listed below. They will be the subject of an upcoming Technical Bulletin.) The actions of histamine are very well-known in the immune system. However, the actions of histamine within the central nervous system (CNS) are less familiar. Immunologically, histamine is released from mast cells or formed via histidine decarboxylase an enzyme that is up regulated in response to inflammatory cytokines. It is the presence of the immune response that triggers the increase in histamine that revs up mucus production to incredible levels and causes runny noses and hacking coughs. Without the immunological assault, e.g. increased cytokines, allergens, or IgE, histamine is a mild-mannered hardworking Clark Kent. Histamine is a neurotransmitter and histamine containing neurons have been found to have a pacemaker function within the brain. The firing rate of these neurons correlate positively with brain activity levels and display distinct day-night rhythms. Within the posterior region of the hypothalamus there are a large number of neurons that synthesize and utilize histamine and these neurons provide the stimulation that maintains or modulates activity in many other regions of the brain. Histamine, like the other biogenic amines (serotonin, dopamine, norepinephrine, epinephrine, and PEA) is stored in presynaptic vesicles and is released into the synapse. Also like other amine neurotransmitters, histamine binds to transmembrane G-protein coupled receptors on the post-synaptic neurons to exert its function. Histamine crosses the blood-brain-barrier very poorly and is synthesized within histamine neurons via the decarboxylation of histidine. Histidine is an essential amino acid and readily crosses the blood-brain-barrier via the LNAAT (large neutral amino acid transporter). The histidine decarboxylase enzyme is not rate-limiting and increasing the availability of histidine will increase the synthesis of histamine. Unlike other monoamines, histamine does not appear to have a specific reuptake mechanism for inactivation. Instead, histamine is inactivated by the ubiquitously present histamine methyltransferase and subsequent deamination by monoamine oxidase B. Some of the effects of histamines are best known because of the effects of antihistamine medications. First generation antihistamines are an excellent example. These medications block (antagonize) the actions of histamine by binding to the histamine receptor and as such prevent histamine from gaining access. First generation antihistamines, by definition, cross the blood-brain-barrier and interact with histamine receptors in the periphery as well as the CNS. Typical examples are: Diphenhydramine (Benadryl), Carbinoxamine (Clistin), Clemastine (Tavist), Chlorpheniramine (Chlor-Trimeton), and Brompheniramine (Dimetane). First generation antihistamines are also associated with significant drowsiness and diphenhydramine is included in OTC sleep aids (Unisom, Sominex, Nytol, etc.), because of this effect. Second generation or the so-called "non-drowsy" antihistamines, in contrast, do not cross the blood-brain barrier. So, while second generation antihistamines block the same receptors, they do not interact with those in the brain and therefore do not block the excitatory activity of histamine. Common examples are: Fexofenadine (Allegra), Loratidine (Claritin), Cetirizine (Zyrtec), and Acrivastine (Semprex). The excitatory action of histamine agrees very well with the observed activity of histamine neurons, which are active during the day, less active at night, and almost completely inactive during REM sleep. There are at least four types of histamine receptors (H1...H4) numbered according to their order of discovery. H1 H1 receptors are located in the periphery in the smooth muscles of intestines, bronchi, and blood vessels, as well as the CNS and are the main target for the antihistamine medications used to address allergies and the immune response. H1 receptors within the central nervous system are also responsible for the stimulatory properties of histamine and the improvement in cognitive function, vigilance, and memory caused by histamine. H2 H2 receptors on neurons are primarily post-synaptically located and receptors are coupled to adenylyl cyclase and increase cAMP for energy production. High densities of H2 receptors are found within the CNS. Activation of these receptors has primarily an excitatory effect on neurotransmission via alterations in ion channel activity that favor neuron depolarization. The H2 receptors are also present in the periphery, including the gastric mucosa, immune cells, and myocytes. Drugs acting on the H2 receptors in the gut prevent histamine from stimulating the secretion of gastric acid and have been widely prescribed for the treatment of gastro-esophageal reflux and peptic ulcer disease. In general, H2 receptor blockers do not cross the blood-brain barrier. Common examples are: Cimetidine (Tagamet), Ranitidine (Zantac), Famotidine (Pepcid), Nizatidine (Axid). In patients with poor digestion increasing gastric acid production by increasing histamine can aid digestion by stimulating acid secretion. H3 H3 are believed to be auto-receptors that act to down-regulate histamine release and synthesis and thereby reduce the effects of H1 and H2 receptors. However the greatest concentration of H3 receptors exist in areas of the brain that have more non-histamine neurons. As such, histamine release, acting via the H3 receptor, can modulate the activity of serotonin and dopamine neurons as well. Behavioral animal studies have shown that enhancing the actions of histamine, through the use of H3 receptor blockers, causes significant improvements in memory and learning. H4 H4 receptors have only recently been discovered and seem in some ways to act like H3 receptors but are located in mast cells as well as in the CNS. They seem to increase calcium mobilization from intracellular calcium stores. Histidine is important in a number of biological functions. The imidazole ring of histidine allows it to act as either an acid or base at physiological pH. Because of this, histidine can catalyze many chemical reactions and is found in the reactive center of many enzymes. Similarly, it is the ability of histidine molecules in hemoglobin to buffer H+ ions in red blood cells that allows for the exchange of O2 and CO2 at the tissues or lungs, respectively. Histidine has also been found to have anticonvulsant properties. Animal models of epilepsy report that histidine will decrease the incidence of seizures. Supporting the importance of histamine are studies which find that histamine blockers can reduce the effectiveness if some antiseizure medication. Many supplements tout histidine supplementation as a way to increase sexual pleasure and orgasm intensity. We are not aware of any research published to support this claim. Permitting a few degrees of separation, histidine, which increases histamine, can increase the release of oxytocin, which is a neuropeptide that is also associated with orgasms. So, a theoretical link is possible. Please send us an email if you have any comments about this. Observations by NeuroScience regarding the use of histidine come from the product ExcitaCor. ExcitaCor and TravaCor have been used in therapy regimens for patients presenting with neurotransmitter deficiencies in epinephrine and dopamine and is chosen over other therapies specifically when these values are accompanied by complaints of fatigue. Details of this protocol were outlined in our tenth Technical Bulletin. We have seen through neurotransmitter testing that ExcitaCor, a histidine containing product will increase histamine levels. Subjects taking histidine containing therapies reported feeling less fatigued and more alert. No allergy symptoms were observed. Neurotransmitter tests in these studies also confirm that the histidine in ExcitaCor will, via the neuromodulatory role of histamine, increase the release of the catecholamines: epinephrine and norepinephrine. We have also seen that young patients with autism or ADHD have higher histamine levels. This could be a contributing factor in the hyperkinetic facet of ADHD as well as an influence in the clinical presentation of the autism patient. We have also observed that high histamine levels are reduced when TAAT products that increase serotonin are used and recommend increasing serotonin when histamine is high. Even if serotonin levels are not low. This is beneficial in two ways. First patients with high histamine levels are more likely to to have an excess of stimulatory neurotransmitter activity and increasing serotonin will minimize that excess. Second, increasing serotonin can reduce allergy symptoms. This has been reported by practitioners using NeuroScience products with their patients as well as in published reports of antidepressants being used in dermatology to eliminate skin rashes. It has been reported that patients with depression have histamine receptors that don't bind histamine as well as the receptors of non-depressed subjects. This reduced function may be overcome by increasing histamine levels. Our observations show that patients suffering from depression have lower histamine levels. * Histamine is an excitatory neurotransmitter * Histamine acts as a pacemaker to increase activity in many regions of the brain * Histamine increases the release of epinephrine and norepinephrine * Supplementation with histidine contributes to the modulation of fatigue and depression. * Neurotransmitter testing data shows that ExcitaCor will increase histamine * High histamine can be reduced by increasing serotonin The mechanism of spontaneous firing in histamine neurons. Stevens DR, Eriksson KS, Brown RE, Haas HL. Behav Brain Res. 2001 Oct 15;124(2):105-12. Review. The physiology of brain histamine. Brown RE, Stevens DR, Haas HL.Prog Neurobiol. 2001 Apr;63(6):637-72. Review. Importance of histamine in modulatory processes, locomotion and memory. Philippu A, Prast H. Behav Brain Res. 2001 Oct 15;124(2):151-9. Review Histidine induces lipolysis through sympathetic nerve in white adipose tissue. Yoshimatsu H, Tsuda K, Niijima A, Tatsukawa M, Chiba S, Sakata T. Eur J Clin Invest. 2002 Apr;32(4):236-41. Central histaminergic system and cognition. Passani MB, Bacciottini L, Mannaioni PF, Blandina P. Neurosci Biobehav Rev. 2000 Jan;24(1):107-13. Review. Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS. J Neurosci. 2002 Sep 1;22(17):7695-711. Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. John J, Wu MF, Boehmer LN, Siegel JM.Neuron. 2004 May 27;42(4):619-34. Histamine activates tyrosine hydroxylase in bovine adrenal chromaffin cells through a pathway that involves ERK1/2 but not p38 or JNK. Cammarota M, Bevilaqua LR, Rostas JA, Dunkley PR. J Neurochem. 2003 Feb;84(3):453-8. Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP. J Pharmacol Exp Ther. 2003 Jun;305(3):1212-21. Epub 2003 Mar 06. L-histidine is a beneficial adjuvant for antiepileptic drugs against maximal electroshock-induced seizures in mice. Kaminski RM, Zolkowska D, Kozicka M, Kleinrok Z, Czuczwar SJ. Amino Acids. 2004 Feb;26(1):85-9. Epub 2003 May 09. Neuronal histamine regulates food intake, adiposity, and uncoupling protein expression in agouti yellow (A(y)/a) obese mice. Masaki T, Chiba S, Yoshimichi G, Yasuda T, Noguchi H, Kakuma T, Sakata T, Yoshimatsu H. Endocrinology. 2003 Jun;144(6):2741-8. Histamine and prostaglandin interaction in regulation of oxytocin and vasopressin secretion. Knigge U, Kjaer A, Kristoffersen U, Madsen K, Toftegaard C, Jorgensen H, Warberg J.J Neuroendocrinol. 2003 Oct;15(10):940-5. Subcellular distribution of histamine, GABA and galanin in tuberomamillary neurons in vitro. Kukko-Lukjanov TK, Panula P.J Chem Neuroanat. 2003 Jul;25(4):279-92. The role of central histaminergic neuron system as an anticonvulsive mechanism in developing brain. Yokoyama H. Brain Dev. 2001 Nov;23(7):542-7. Review. The use of antidepressant drugs in dermatology. Gupta MA, Guptat AK. J Eur Acad Dermatol Venereol. 2001 Nov;15(6):512-8. Review. We hope you enjoyed this edition of The NeuroScience Technical Bulletin. Copyright 2003, 2004 by NeuroScience, Inc. No part of this newsletter shall be reproduced, stored, or transmitted by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the NeuroScience, Inc. ©NeuroScience,Inc. 2006 Disclaimer The information provided in this newsletter is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional or any information contained on or in any product label or packaging. You should not use the information in this newsletter for diagnosis or treatment of any health problem or for prescription of any medication or other treatment. You should consult with a healthcare professional before starting any diet, exercise or supplementation program, before taking any medication, or if you have or suspect you might have a health problem. You should not stop taking any medication without first consulting your physician.

Chronic Stress

A perceived challenge can activate the mind/body system, resulting in increased alertness and stronger action, but chronic activation of this response leads to abnormal responses to stress characterized by 1) the inability of the body to return to baseline levels of catecholamines and cortisol, and 2) the inability of the body to activate the biochemical changes associated with a perceived challenge. When either of these response patterns develops due to continual activation of the stress response, then stress becomes debilitating.

Stress and Cortisol -- long lasting effects

Original source: A perceived challenge can activate the mind/body system, resulting in increased alertness and stronger action, but chronic activation of this response leads to abnormal responses to stress characterized by 1) the inability of the body to return to baseline levels of catecholamines and cortisol, and 2) the inability of the body to activate the biochemical changes associated with a perceived challenge. When either of these response patterns develops due to continual activation of the stress response, then stress becomes debilitating.

Stress and Immuned

Wikipedia: Cortisol

In normal release, cortisol (like other glucocorticoid agents) has widespread actions which help restore homeostasis after stress. (These normal endogenous functions are the basis for the physiological consequences of chronic stress - prolonged cortisol secretion.) * It acts as a physiological antagonist to insulin by promoting glycogenolysis (breakdown of glycogen), breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood). There is a decreased glycogen formation in the liver . [2] Prolonged cortisol secretion causes hyperglycemia. * It can weaken the activity of the immune system . Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor.[3] It reflects leukocyte redistribution to lymph nodes, bone marrow, and skin. Acute administration of corticosterone (the endogenous Type I and Type II receptor agonist), or RU28362 (a specific Type II receptor agonist), to adrenalectomized animals induced changes in leukocyte distribution. * It lowers bone formation thus favoring development of osteoporosis in the long term. Cortisol moves potassium into cells in exchange for an equal number of sodium ions.[4] This can cause a major problem with the hyperkalemia of metabolic shock from surgery. * It helps to create memories when exposure is short-term; this is the proposed mechanism for storage of flash bulb memories. However, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning. * It increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine. In the absence of cortisol, widespread vasodilation occurs. * It inhibits the secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH secretion. Some researchers believe that this normal feedback system may break down when animals are exposed to chronic stress. * It increases the effectiveness of catecholamines. * It allows for the kidneys to produce hypotonic urine.

Effects of Therapeutic Interventions for Foster Children on Behavioral Problems, Caregiver Attachment, and Stress Regulatory Neural Systems

Abstract: Young children in foster care are exposed to high levels of stress. These experiences place foster children at risk for poor social, academic, and mental heath outcomes. The role of adverse events in stimulating neurobiological stress responses presumably plays a role in shaping neural systems that contribute to these problems. Systematic and developmentally well-timed interventions might have the potential to change developmental trajectories and promote resilience. Moreover, understanding how specific dimensions of early adversity affect underlying stress response systems and how alterations in these systems are related to later psychosocial outcomes might facilitate more precise and targeted interventions. Data are drawn from two ongoing randomized trials involving foster infants/toddlers and preschoolers. Consistent with prior animal models of early adversity, these studies have shown that early adversity—particularly neglect, younger age at first foster placement, and higher number of placements—is associated with altered hypothalamic-pituitary-adrenal (HPA) axis function. The interventions under investigation have produced evidence that it is possible to impact many areas that have been negatively affected by early stress, including HPA axis activity, behavior, and attachment to caregivers.

Low Cortisol, not high, after stress in childhood?

Development and Psychopathology (2001), 13: 515-538 Cambridge University Press doi:10.1017/S0954579401003066 Low cortisol and a flattening of expected daytime rhythm: Potential indices of risk in human development MEGAN R. GUNNAR a1 c1 and DELIA M. VAZQUEZ a2 a1 University of Minnesota a2 University of Michigan Abstract Since the work of Hans Selye, stress has been associated with increased activity of the limbic–hypothalamic– pituitary–adrenocortical (LHPA) axis. Recently, a number of studies in adults have shown that this neuroendocrine axis may be hyporesponsive in a number of stress-related states. Termed hypocortisolism, the paradoxical suppression of the LHPA axis under conditions of trauma and prolonged stress presently challenges basic concepts in stress research. Adverse conditions that produce elevated cortisol levels early in life are hypothesized to contribute to the development of hypocortisolism in adulthood. However, as reviewed in this paper, hypocortisolism also may be a common phenomenon early in human childhood. Although preliminary at this point, the ubiquity of these findings is striking. We argue that developmental studies are needed that help explicate the origins of low cortisol and to determine whether the development of hypocortisolism is, in fact, preceded by periods of frequent or chronic activation of the LHPA axis. We also argue that developmental researchers who incorporate measures of salivary cortisol into their studies of at-risk populations need to be aware of the hypocortisolism phenomenon. Lower than expected cortisol values should not necessarily be relegated to the file drawer because they contradict the central dogma that stress must be associated with elevations in cortisol. Lastly, we note that evidence of low cortisol under adverse early life conditions in humans adds to the importance of understanding the implications of hypocortisolism for health and development.

Dopamine, Norepinephrine, and aggression

Although biochemical studies in antisocial children (Kruesi et al., 1990, 1992; Rogeness, Javors, & Pliszka, 1992) have not provided clear evidence of a relationship between NE or DA, on the one hand, and aggressive behavior, on the other, clinical findings have supported an involvement of these monoamines in aggressive behavior. One study (Klein et al., 1997) showed that methylphenidate, which stimulates the release of NE and DA, reduced antisocial behavior reports in children with CD independent of ADHD symptoms. Moreover, the knowledge that the reward system in the brain and DA are implicated in the neurobiology of addiction (Dackis & O’Brien, 2001) and that children with CD are at considerable risk of substance abuse (Kazdin, 1995) is consistent with an involvement of DA in the modulation of aggressive behavior in children. More research is needed to clarify the precise role of NE and DA in the instigation and regulation of aggressive behavior in children.

Serotonin and behavior -- from vanGoozen article

5-HT and Aggression In an influential thesis, Spoont (1992) argued that 5-HT stabilizes information processing in neural systems, resulting in controlled behavioral, affective, and cognitive output, whereas disturbances in 5-HT activity result in altered information processing tendencies. High levels of 5-HT were proposed to lead to excessive restraint, cognitive inflexibility and anxiety, whereas low levels were thought to lead to behavioral disinhibition and distractibility. Coccaro and Kavoussi (1996) proposed a model for impulsive aggression in which the threshold for aggressive action, given the proper environmental circumstances, is modulated by overall 5-HT system function. Diminished serotonergic function is thought to disinhibit aggression directed against the self and others, perhaps by sharpening sensitivity to stimuli that elicit irritation and aggression and blunting sensitivity to cues that signal punishment(Spoont, 1992). =============== To date, only three studies have measured 5-HIAA in CSF in children (Castellano´s et al., 1994; Kruesi et al., 1990, 1992; see Table 3). Kruesi et al. (1990) found that children with DBD and/or ADHD had lower 5-HIAA levels compared with children suffering from obsessive-compulsive disorder. CSF 5-HIAA concentrations were also inversely correlated with ratings of aggressive behavior in the disruptive group. At the 2-year follow-up, CSF 5-HIAA levels were found to be a predictor of the severity of physical aggressive behavior and poor outcome (Kruesi et al., 1992). In contrast, Castellano´s et al. (1994) found in their study of 29 boys with ADHD that CSF 5-HIAA levels were positively correlated with measures of aggression and impulsivity.

Maltreatment and neurotransmitters

Child maltreatment and the developing HPA axisstar, open Amanda R. Tarulloa and Megan R. GunnarCorresponding Author Contact Information, a, E-mail The Corresponding Author aInstitute of Child Development, 51 East River Road, University of Minnesota, Minneapolis, Minnesota, USA Received 12 May 2006; revised 6 June 2006; accepted 7 June 2006. Available online 28 July 2006. Abstract The developing HPA axis is under strong social regulation in infancy and early childhood and is vulnerable to perturbation in the absence of sensitive, responsive caregiving. Child maltreatment has complex, long-term influences both on basal cortisol levels and on HPA responsivity to pharmacological and psychological stressors, depending on current psychiatric status, current life adversity, age, and most likely, genetic factors. Among the more consistent findings, maltreated children with internalizing problems have elevated basal cortisol most often detected in early AM concentrations, whereas adults maltreated as children often exhibit low basal cortisol levels and elevated ACTH response to psychological stressors. To disentangle these complicated interactions, future research must take the above qualifiers into account, study the transition to puberty, explore the moderating role of candidate genes, and utilize animal models and pharmacological challenges, when ethical, to localize changes in the HPA axis. Post-institutionalized children may provide a model to separate early adverse care histories from current adversity. Keywords: Glucocorticoids; Hypothalamic–pituitary–adrenal axis; Stress; Maltreatment

Comparative absorption of zinc picolinate, zinc citrate and zinc gluconate in humans.

Agents Actions. 1987 Jun;21(1-2):223-8. Comparative absorption of zinc picolinate, zinc citrate and zinc gluconate in humans. Barrie SA, Wright JV, Pizzorno JE, Kutter E, Barron PC. The comparative absorption of zinc after oral administration of three different complexed forms was studied in 15 healthy human volunteers in a double-blind four-period crossover trial. The individuals were randomly divided into four groups. Each group rotated for four week periods through a random sequence of oral supplementation including: zinc picolinate, zinc citrate, and zinc gluconate (equivalent to 50 mg elemental zinc per day) and placebo. Zinc was measured in hair, urine, erythrocyte and serum before and after each period. At the end of four weeks hair, urine and erythrocyte zinc levels rose significantly (p less than 0.005, p less than 0.001, and p less than 0.001) during zinc picolinate administration. There was no significant change in any of these parameters from zinc gluconate, zinc citrate or placebo administration. There was a small, insignificant rise in serum zinc during zinc picolinate, zinc citrate and placebo supplementation. The results of this study suggest that zinc absorption in humans can be improved by complexing zinc with picolinic acid.

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.

Graphic for presentation -- serotonin pathway

Neurotransmitters and alcoholism (levels similar to our kids)

The HPA Axis The “Home” of Alcoholism in the Body and Mind Research has concluded that the “home” of alcoholism resides in the HPA (hypothalamus, pituitary, adrenal) axis of the neuroendocrine system. Now that we have the well-defined markers of addictive chemistry and we know where they live, scientists have developed extremely sophisticated tests which monitor the performance of this axis under various conditions by measuring dopamine, serotonin, GABA, glutamate, epinephrine (adrenaline), norepinephrine (noradrenalin), cortisol and DHEA which are the six big neurotransmitters and two key hormones which define either the health of the neuroendocrine system or its state and depth of illness. In Alcoholism: The Cause & The Cure you learn that addictive or addicted biochemistry is essentially the body's inability to adequately self-medicate with the natural, feel-good transmitters such as serotonin, GABA, dopamine and endorphins (as well as enkephalins) which predisposes an individual to “seek” relief in external ways such as alcohol. Addictive biochemistry is intricately associated with an upregulated (in excess) sympathetic nervous system where, due to low GABA, serotonin, and endorphins; excitatory neurotransmitters such as glutamate, norepinephrine and epinephrine are overexpressed which cause the many symptoms problem drinkers are known to self-medicate. It is also the bedrock of the progression of alcoholism in active drinkers because the longer one drinks, the more damage is done to the neuroendocrine system rendering it progressively unable to medicate the body naturally which intensifies symptoms which then causes one to drink more. To help you understand the root of this phenomenon I will go into a little more detail regarding genetic addictive biochemistry and active addiction and how they affect the HPA axis. The endocrine system is the network of glands in the body comprised of the hypothalamus, pituitary, pineal, adrenals, thyroid, parathyroid and the sex glands; ovaries and testes. These glands secrete hormones throughout the body to each and every organ via the blood which are received by their complimentary receptors. Hormones are “messengers” which carry messages coded by our DNA with the intention of keeping an organ regulated and healthy, essentially functioning as it should. A hormone's message will stimulate, suppress or maintain functional cell or tissue activity of the organ it is received by. The hypothalamus is the center piece of the endocrine system and is located in the middle of the base of the brain. The hypothalamus' ultimate purpose is to establish and maintain homeostasis; balance within the body. It regulates all the functions of the autonomic system of breathing, heart rate, etc… but also hunger, thirst, sexual drive, sleep urination and metabolism which includes blood sugar control. Although technically the hypothalamus is part of the endocrine system it is really central to both the endocrine and nervous system; in fact, it is in the hypothalamus that these two extremely complex systems of the body intersect. As the Master Accountant, the hypothalamus performs checks and balances and responds to chemical messages of deficient or excess by sending various hormones and neurotransmitters to “adjust” to the requirements of your internal and / or external environments to maintain status quo. The hypothalamus is able to do this because it houses receptor sites for both hormones from the endocrine system and neurotransmitters from the nervous system and it utilizes the information it receives from those sites to do its job of not only controlling the entire endocrine system, including having a profound influence on the liver, heart and kidneys, but establishing healthy brain chemistry and nervous system performance by correcting neurotransmitter imbalances by either slowing production of what is in excess, ingesting or degrading them faster, or in cases of deficiency, producing and releasing them as required. The door to addictive biochemistry opens when either the hypothalamus or one of the organs which serve the hypothalamus in accomplishing this job is injured, or if the nutrients required are not available. In any one of these conditions the entire system will fall off the “point zero” (homeostasis) that the HPA system tries to maintain, and the door for addictive biochemistry is opened. It is a well known fact that addictive biochemistry and full out alcoholism are associated with over expression of the sympathetic nervous system; low serotonin, GABA, dopamine, endorphins and enkephalins and it is in the hypothalamus where the delicate job of balancing this network of hormones and neurotransmitters to achieve physical and mental health is supposed to be done - whether it be directly from the hypothalamus or via the pituitary and adrenals under the control of the hypothalamus. The only difference between addictive biochemistry and full out alcoholism is that addictive biochemistry becomes aggravated, meaning that the deficient condition within the hypothalamus, pituitary or adrenals is made more profound by the damaging effects of alcohol toxicity and the medicating effects which, while drinking, overexpress serotonin, endorphins and dopamine which magnifies the negative impact of an already upregulated brain chemistry. The symptoms the problem drinker experiences intensify in direct relationship to the diminishing health of the neuroendocrine system which further encourages the person to drink more thus causing even more damage. This cycle progressively intensifies until intervention which discontinues and heals the damage is required to stop it. The pituitary gland is located below the hypothalamus and is directly connected to it via nerve and circulatory pathways. The hypothalamus regulates the function of the pituitary gland which in turn controls hormonal secretions of all other glands; however, specific to alcoholism we are concerned with the function of the adrenals and the secretion of cortisol which is under control of ACTH (adrenocorticotrophin) secreted by the pituitary, and epinephrine and norepinephrine which is also released by the adrenals due to a rise in CRH and/or signals from the sympathetic nervous system. In the case of cortisol release, when the hypothalamus registers low blood sugar it will send CRH (corticotrophin releasing hormone) to the pituitary which then releases ACTH which will cause cortisol to be secreted from the adrenals. This chain of events will also cause the release of epinephrine and to a lesser degree norepinephrine. Prolonged increased levels of epinephrine will block insulin receptors which leads to insulin resistance and lowered serotonin, endorphin, enkephalin and GABA levels which impairs HPA functions and increases compulsive / addictive behavior. The adrenals sit on top of the kidneys and are directly controlled by the pituitary gland. The adrenals are comprised of two sections; one is the medulla which is the inner core and the second is the adrenal cortex which is the outer layer. The medulla relates to the sympathetic nervous system and produces the catecholamines epinephrine and norepinephrine. The adrenal cortex produces sex hormones, aldosterone, and what we're most concerned with cortisol. The adrenals receive chemical messengers (hormones) from the pituitary and signal from the sympathetic nervous system which determines how much of its hormones it will release. However, if they are injured, diseased or fatigued they will not be able to keep up with the demands from the hypothalamus to maintain homeostasis and mild to severe mental disorders will surface as symptoms of compromised adrenal health. Although it is hard to imagine because they are docked on our kidneys, adrenal health is fundamental to our mental health. Proper levels of cortisol, epinephrine and norepinephrine are crucial to our mental well-being so concentrated focus needs to be applied to their health when healing addictive biochemistry and alcoholism. How They All Work Together I will use stress as an example of how the organs of the HPA work together and then we will take a look at how excessive alcohol use causes alcoholism and how to correct the metabolism so the addictive biochemistry and conditions for alcoholism are no longer present. During periods of acute stress special serotonin receptors on the hypothalamus are stimulated which cause the hypothalamus to produce CRF (corticotrophin release factor). The CRF is sent directly to the pituitary which causes ACTH to be sent to the adrenals which triggers release of cortisol. Cortisol is sent throughout the body on a number of different missions with the primary one to reduce the stress by stimulating serotonin (inhibitory neurotransmitter) in the amygdala which has an inhibitory effect on amygdala glutamate (excitatory neurotransmitter) which helps to calm the person down. The amygdala is directly connected to the hypothalamus and is a component of the limbic area of the brain where processing of emotions, fear, panic and long term memories occur. Many forms of depression, anxiety and panic disorders originate in the amygdala due to low serotonin and its inhibitory effects on the glutamate pathways of the amygdala. The HPA and Addictive / Addicted Biochemistry The genetic markers in the brain chemistry which spell alcoholism are the same for those that earned the condition through alcohol abuse; they are low endorphin, enkephalin, GABA, serotonin and dopamine expression which results in the over expression of the sympathetic nervous system; glutimate, epinephrine and norepinephrine. It doesn't necessarily have to be all of these; it could be just one or two that can engage the practice of self-medicating once a person, regardless of age, is exposed to a substance that helps balance their deficiencies. Albeit for a short time with known ramifications but it seems to be worth it because they will continue the habit until they find a way to stop the mild to severe symptoms they suffer through another means. The symptoms those with inherited capacity for addictive biochemistry are not as pronounced as the active drinker, however they are indeed debilitating and extremely mentally and physically uncomfortable. These symptoms can vary depending on the exact deficiencies of these neurotransmitters combined but they can include everything from depression, mental / physical fatigue and cravings for simple carbs to low self-esteem / confidence and low grade anxiety or restlessness. Alcohol can fix all of these in one fell swoop because it immediately raises all of the deficient neurotransmitters. The price to pay is high though, because on the other end comes the bottoming out of the already inherently low levels of neurotransmitters. Long-term drinking causes exaggerated over expression of the sympathetic nervous system due to overexpression of excitatory neurotransmitters glutamate, epinephrine, and norepinephrine; and underexpression of the inhibitory neurotransmitters; serotonin, GABA and dopamine, and the opioids endorphins and enkephalins during periods of sobriety which cause the “excitatory” symptoms I mentioned earlier which the individual is encouraged to self medicate. They will suffer their own combination of these now magnified symptoms due to the similar, now magnified neurotransmitter deficiencies. Due to the continual extreme demands on the adrenals, problem drinking invariably fatigues the adrenals and brings the problem drinker to a serious stress syndrome due depletion of cortisol, epinephrine and DHEA in concert with the depressive effects of low serotonin. Due to low cortisol / epinephrine, they will suffer from overexpression of norepinephrine which is known to cause irritability, anxiety, aggression, hypertension, and bipolar disorder. What happens within the body of those that have been abusing alcohol for a while and have damaged their neuroendocrine system is this: while the person is drinking, GABA, endorphins, dopamine and serotonin are overexpressed and literally emptied out from the CNS and hypothalamus which gives them the relaxation and medication for their symptoms they desire (which causes one to drink even more to achieve relief they found with far less alcohol early in their habit). This extreme depletion of inhibitory neurotransmitters leaves stores “empty” the next morning when they wake up which causes the overexpression of glutamate and the catecholamines. The symptoms of this condition are any of those I've mentioned including anxiety, restlessness, worry, short attention span, inability to focus, can't sit in one place for long, jitters, insomnia; basically most any feeling that is associated with being too “amped” up internally - this doesn't necessarily mean you feel like running a marathon; you don't. It means you are internally overexcited. Your endorphins and enkephalins were also over produced and emptied out so you won't have much of your natural pain killers available to mediate the condition you're in; ergo, soon you will have another drink. The internal scene with most people who rarely drink excessively is quite different; they have ample healthy stores of serotonin, dopamine, GABA, endorphin and enkephalin and they will immediately rise to the job of balancing the overexpressed glutamate and catecholamines. In the long-term drinker this is impossible because their body's ability to manufacture and replenish healthy levels of these neurotransmitters has been diminished from the damage of alcohol toxicity and the resulting malnutrition. The possible genetic handicap of not being able to naturally balance the autonomic sympathetic and parasympathetic nervous system by producing ample amounts of inhibitory neurotransmitters may also be involved which means there was a precondition of low levels of the natural feel-goods which will serve to accelerate the progression of alcohol abuse. Once the damage is established in the HPA by long-term drinking the cycle becomes deeply embedded in the person's biochemistry because this condition renders them entirely dependent on alcohol to achieve peace, relaxation and the natural euphoria of life because they can't feel good inside their own skin naturally anymore within a reasonable amount of time, and not without a bout of severe withdrawal which they are not inclined to endure. Inherited and acquired imbalanced, upregulated sympathetic neuroendocrine hormones and neurotransmitters are predominately caused by weakened or injured organs of the HPA caused by extreme blood sugar fluctuations over a considerable period and / or malnutrition. Alcohol metabolites such as acetaldehyde will also injure all of these organs in variable degrees making a considerable contribution to the addiction. A family history of unmet need for brain sugars due to a number of reasons such as famine or dietary restrictions due to location or climate which caused an excess of grains to be consumed over protein has been identified as contributing factors for weakened adrenals and injury to the hypothalamus and pituitary which can result in inheriting the predisposition to seek alcohol, other simple sugars and stimulants to self medicate. Another contributor to a genetic predisposition to addictive biochemistry is an early adoption of the industrialized food craze which began in the 40s and 50s which has now manifested in nearly 95% of what is at your supermarket being adulterated with sugars, hydrogenated fats, or foods so processed that there really isn't any food in the product anymore. These so called “foods” cause malnutrition and also damage the delicate workings of the HPA axis. Excessive dietary sugars, OTC, prescription and street drugs, malnutrition, disease and environmental toxins (especially acetaldehyde) can create a deficiency of neurotransmitters and imbalance or even damage the neuroendocrine system, creating an immediate requirement to replete and balance them before illness and possibly disease sets in. Alcoholism is extremely responsive to neurotransmitter repletion since it is their deficiencies and imbalance that is at the very root of alcohol addiction. In the Brain - a drink in a long time problem drinker (simplified) ? serotonin, GABA, endorphins and dopamine > hypothalamus produces ? CRF > pituitary produces ? ACTH > adrenals produce ? Cortisol. Sympathetic nervous system produces ? norepinephrine and epinephrine. 20 to 30 min. later, sharp drop in blood sugar, serotonin, endorphins and dopamine. Individual begins to feel “excitatory” symptoms. Has another drink, cycle begins again. Next day: Individual experiences symptoms of low levels of the feel-good neurotransmitters: serotonin, GABA, dopamine, endorphins, enkephalins and GABA. Concurrently, he/she will suffer symptoms of high cortisol (due to low blood sugar this time), glutamate, norepinephrine and epinephrine. The “tank” for the parasympathetic, feel-good neurotransmitters is emptied out and mental and physical capacities are diminished while the person suffers resulting symptoms. The individual begins to cultivate his/her habits around repletion of these neurotransmitters through the use of alcohol which progressively damages the person's ability to produce them and an addiction is born. The biochemistry of alcohol related symptoms exposed: Symptoms of long-term alcohol abuse directly related to HPA function: Stress Disorder There are possibly a hundred pathways for the various symptoms caused by alcohol toxicity and damage. I am provided a simplified one to demonstrate the very real fundamental message of this section: that alcohol toxicity and the results of its metabolism in the brain cause the psychological symptoms they suffer which triggers the survival mechanism to reduce pain and since they can't do it naturally, will seek it relief in alcohol. Due to alcohol toxicity damage and malnutrition, adrenal fatigue causes low cortisol output which leads to high norepinephrine levels (overexpressed). I've mentioned the debilitating symptoms of this condition earlier. The cause is because cortisol is required (along with SAMe) to produce epinephrine from norepinephrine. When this doesn't occur, norepinephrine is overexpressed while epinephrine and cortisol are diminished. Note here that cortisol is required in some areas of the brain to activate serotonin so when it is low it can also inhibit serotonin expression. This condition delivers one to the “alarm” stage of stress disorder due to the profound states of mind that can result from elevated norepinephrine including extreme anxiety, panic attacks, exaggerated fear (paranoia), insomnia, aggression, irritability, hypertension and even bipolar disorder. All of these conditions center on the deregulation of the HPA axis. How The 101 Program Corrects Addictive Biochemistry (simplified) Through the use of HPA axis testing, measuring the key neurotransmitters known to facilitate addictive biochemistry: dopamine, serotonin, GABA, glutamate, epinephrine, and norepinephrine. Cortisol and DHEA levels are also tested to establish the degree to which the adrenals are damaged so that an appropriate treatment for the adrenals can be developed. Once the neurotransmitter deficiencies are exposed, the practitioner can develop a personalized, targeted nutritional therapy (TNT) and aggressive nutriceutical protocol to bring the neuroendocrine system back into balance, optimizing the HPA axis and relieving the individual of the symptoms they self-medicate. Other contributing factors such as liver and GI damage are considered and addressed as well to provide the system with the best possible environment to heal and correct the “broken” metabolism.

Dopamine study -- negative behaviors due to low dopamine

In our study, dopamine depletion was achieved by oral administration of 4.5 g AMPT in 25 hours, as described earlier (1). Striatal D2 receptors were assessed at baseline and after acute dopamine depletion by using the bolus/constant infusion [123I]IBZM technique (1). Acquisition, reconstruction, and analysis of the single photon emission computed tomography data were performed as described previously (2). * Mr. A was a healthy, extraverted, very well functioning 21-year-old medical student without even minor psychological difficulties or psychiatric disorders in his family. His Global Assessment of Functioning Scale score was 97. Written informed consent was obtained from Mr. A. We will describe the spontaneous reported subjective experiences after he started the first dose of 750 mg AMPT at t=0 hours (1). * After 7 hours, Mr. A felt more distance between himself and his environment. Stimuli had less impact; visual and audible stimuli were less sharp. He experienced a loss of motivation and tiredness. After 18 hours, he had difficulty waking up and increasing tiredness; environmental stimuli seemed dull. He had less fluency of speech. After 20 hours, he felt confused. He felt tense before his appointment and had an urge to check his watch in an obsessive way. * After 24 hours, Mr. A had inner restlessness, flight of ideas; his ideas seemed inflicted, and he could not remember them. He felt a loss of control over his ideas. After 28 hours, he felt ashamed, frightened, anxious, and depressed. He was afraid that the situation would continue. At that time, blepharospasm, mask face, and tremor were noted. After 30 hours, he was tired and slept 11 hours. After 42 hours, he had poor concentration. In the next hours, he returned to normal.

5-htp for hot flashes?

FindArticles > Alternative Medicine Review > Sept, 2005 > Article > Print friendly The potential role of 5-hydroxytryptophan for hot flash reduction: a hypothesis Jessica J. Curcio Abstract Hormone replacement therapy (HRT) is contraindicated in women with a history of breast cancer or a high risk of breast cancer development. Recent results from large clinical trials, such as the Women's Health Initiative, have demonstrated increased risks of thromboembolic events and a moderate increased risk of breast cancer in women using conjugated estrogens and progestogens. There is a need for viable non-hormonal alternative treatments to HRT, such as nutritional and botanical therapies, in this population of women, who tend to experience more significant vasomotor symptoms. Safe and effective therapies that do not stimulate breast cell proliferation could prove extremely useful for the management of such symptoms for women in both low- and high-risk breast cancer populations. As a non-hormonal treatment, anti-depressants, such as selective serotonin reuptake inhibitors (SSRIs), have been shown to improve hot flash symptoms in women. The proposed mechanism is related to an increase in serotonin allowing for an increase in the set point of the brain's thermoregulator. In small clinical studies, the administration of tryptophan and 5-hydroxytryptophan (5HTP), the precursors of serotonin, have been shown to reduce depressive symptoms, possibly by enhancing the synthesis of serotonin. Thus, increased serotonin levels may have the ability to decrease hot flashes in a mechanism similar to that of SSRIs without the risks of breast cell stimulation. This would be particularly desirable for menopausal women with breast cancer or with risks of breast cancer. This article discusses the background information on hot flashes, SSRIs, tryptophan, and 5HTP, and possible clinical application of 5HTP for menopausal women with breast cancer risk. (Altern Med Rev 2005;10(3):216-221) Introduction At menopause a woman's ability to produce her own endogenous hormones is greatly reduced. Menopause is recognized by the cessation of menses for at least one year and, although it is not a disease, the transition into menopause is often accompanied by symptoms. While the etiology of these symptoms is not completely understood, they can affect women both physically and psychologically, and can vary in frequency as well as intensity. (1) The most common symptoms include hot flashes, mood changes, depression, cognitive changes, vaginal dryness, decreased libido, dyspareunia, decreased energy, sleep disturbances, and weight gain. Hot flashes are the hallmark symptom of estrogen fluctuation, which occurs during the menopausal transition. A hot flash is generally characterized by a sudden sensation of intense body heat, often with profuse sweating of the head, neck, and chest. Hot flashes often occur at night, lasting several seconds to minutes, and can result in significant sleep deprivation. Hot flashes may be accompanied by heart palpitations, anxiety, irritability, and panic. Although not life threatening, hot flashes can significantly impact a woman's quality of life, functional ability, sexuality, and self-image. (2, 3) HRT has been the mainstay of treatment for menopausal symptoms. The options include estrogen replacement therapy (ET) alone in women who have undergone hysterectomy or estrogen and progestogen replacement therapy (EPT) in women with an intact uterus. The estrogens often prescribed and examined in larger clinical trials are conjugated estrogens and come from an equine source. Progesterone or progestogen, which include synthetically derived progestins such as medroxyprogesterone acetate (MPA), and natural progesterone such as oral micronized progesterone, are administered to counteract estrogen's proliferative effect on the uterus. (4) The addition of progestogens to the estrogen regimen for hormone replacement may be associated with patient inconvenience as they can produce the undesirable effect of vaginal bleeding and premenstrual symptoms when a cyclic regimen of these hormones is used. (5) A recent study performed by the Women's Health Initiative (WHI) suggests that women receiving HRT in the form of Prempro [R], a combination of conjugated equine estrogens and MPA, are at an increased risk for stroke and a moderate increased risk of breast cancer. (6) In the mouse, progestin plus estrogen was found to be more mitogenic in the adult mammary gland than estrogen alone. (7) Estrogen plus progesterone replacement therapy also substantially increases the percentage of women with abnormal mammograms due to increased breast density, suggesting that estrogen plus progesterone may stimulate breast cancer growth and hinder breast cancer diagnosis. (7) Menopausal Symptoms in Breast Cancer Patients Breast cancer survivors may experience menopausal symptoms due to a variety of reasons. Newly diagnosed, postmenopausal breast cancer patients are counseled to stop any hormone replacement therapy. The abrupt discontinuation of estrogen therapy usually results in a return of menopausal symptoms. Many newly diagnosed, premenopausal breast cancer patients undergo premature menopause secondary to chemotherapy or therapeutic ovarian ablation. Tamoxifen also produces or enhances menopausal symptoms. (8) It has been reported that menopausal symptoms may be more severe in some breast cancer patients compared with healthy women experiencing natural menopause. (9) In addition, decreased physical and emotional quality of life in breast cancer survivors has been correlated with a higher prevalence and severity of menopausal symptoms, particularly hot flashes. (9) Anti-depressants for Hot Flashes Anti-depressants such as SSRIs are currently being used as a treatment option for women with hot flashes when estrogen replacement is contraindicated (Table 1). The efficacy of anti-depressants for the treatment of menopausal hot flashes has been demonstrated in phase III trials. (10, 11) Venlafaxine was evaluated at three different doses in a randomized, double-blind, crossover design. Daily oral intake of 37.5 rag, 75 mg, 150 mg, or placebo, resulted in a significant reduction of hot flashes compared to placebo at all dose levels, with the most efficacy observed with the 75- and 150-mg doses (61% reduction in both groups). (11) A similar trial was performed evaluating fluoxetine at 20 mg daily compared to placebo. (12) A 50-percent reduction in hot flashes was observed compared to 36 percent for placebo (p=0.02). Similar trials examining the effects of other anti-depressants, such as citalopram and mirtazapine, have also demonstrated a reduction in hot flashes. (13, 14) However, anti-depressant drugs such as SSRIs are not without side effects and therefore may not be an ideal therapeutic intervention. Common bothersome side effects include insomnia, somnolence, nausea, vomiting, anorexia, and decreased libido. (15, 16) Physiology of Hot Flashes Although anti-depressant medications have demonstrated efficacy, the exact mechanism of action remains unknown. One of the theories of hot flash physiology is that a reduction in endorphin production decreases the set point of the thermoregulatory center in the hypothalamus. A reduction in the thermoregulatory set point will lead to heat loss, resulting in a hot flash as the body attempts to maintain a temperature within the set point. (17) It has been postulated that norepinephrine levels are directly correlated with this reduction in the thermoregulatory set point. (18) Studies have demonstrated an increase in norepinephrine levels in the brain both prior to and during a hot flash. (17, 19) Estrogen enhances the synthesis of serotonin and endorphins, (17, 19, 20) and serotonin and endorphins are believed to inhibit the production of norepinephrine. (17) According to one hot flash model, estrogen withdrawal leads to decreased blood levels of endorphins and serotonin and an increase in serotonin receptors, (18, 21) resulting in a loss in the feedback inhibition of norepinephrine production and a reduction in the thermoregulatory set point. (17, 18) Thus, agents that increase estrogen, serotonin, and endorphin levels or that decrease central norepinephrine release would be expected to reduce hot flashes. (17, 21) SSRIs block serotonin receptor subtype 2a and stimulate receptor subtype 1a, thereby increasing serotonin levels. This prevents hyperthermia and inhibits hypothermia, (18, 20) providing a potential mechanism by which SSRIs reduce hot flashes. Maintaining serotonin levels would attenuate the rise in norepinephrine associated with hot flashes. Tryptophan and 5-Hydroxytryptophan (5HTP): Serotonin Precursors Tryptophan is the amino acid precursor of serotonin. The amount of tryptophan that can be shunted into serotonin production is dependent on many variables, including the amount of niacin present and the availability of the substrate. Only free plasma tryptophan can cross the blood brain barrier via a carrier protein to enter the central nervous system (CNS). Once in the CNS, tryptophan is converted to 5HTP and then is decarboxylated to serotonin (Figure 1). (22) The levels, and possibly function, of several neurotransmitters can be influenced by the supply of their dietary precursors. (23) A reduction in tryptophan has been correlated to a reduction in serotonin. (24) Tryptophan increases serotonin synthesis in the brain and may stimulate serotonin release. (25) [FIGURE 1 OMITTED] 5HTP and other Serotonin Precursors as Substitutes for Anti-depressant Medications Altering the metabolism of and biotransformation processes for serotonin may be an important feature for the treatment of depression. (26) Meta-analyses and reviews of both 5HTP and tryptophan suggest there is clinical benefit in the administration of these serotonin precursors for the treatment of depression. (27) Tryptophan has been shown to be useful in mild depression with bipolar disorder resistant to pharmacological treatment and to enhance the effect of other anti-depressant drugs. (22) Tryptophan has also demonstrated efficacy in the treatment of premenstrual dysphoric disorder (PMDD). (28) PMDD is a specific disorder associated with a cluster of symptoms, including sadness, hopelessness, self-deprecation, tension, anxiety, emotional lability, tearfulness, anger, and irritability, that are present in the last luteal week and resolve with menses onset. The magnitude of the reduction of symptoms from baseline in maximum luteal phase was 34.5 percent with tryptophan compared to 10.4 percent with placebo. (28) A review of 15 clinical trials using 5HTP, in dosages ranging from 50-800 mg for depression, demonstrated improvement of depressive symptoms by 56 percent. (29) Observational studies and a few randomized trials have demonstrated that 5HTP and tryptophan both have therapeutic value in patients with mild or moderate depression (30) with few adverse effects. (26) Although the studies are few, the evidence suggests that treatment with either tryptophan or 5HTP is better than placebo for depression. (31,32) While there are unconfirmed reports that the use of 5HTP may be associated with some side effects such as headache, nausea, drowsiness and lightheadedness, 5HTP is generally considered a safe dietary supplement. Rationale for using 5HTP for Hot Flashes Anti-depressants have been shown to improve hot flash symptoms in women with breast cancer or an increased risk of breast cancer, although as noted the exact mechanism is unknown. (10,11,13,13) Given the current understanding of hot flash physiology, the mechanism is likely due to increased serotonin and endorphin production, thereby increasing the set point of the brain's thermoregulator. Clinical trials of 5HTP for depression and related disorders show that the mechanism for improvements in symptoms may be due to an increase in serotonin levels. Theoretically 5HTP supplementation would have the ability to increase the amount of serotonin available, thus producing a similar effect to the SSRIs without the potential drawbacks. To date there are no direct comparative studies available to support this theory. Conclusion There is a growing need for alternatives to HRT for hot flashes, especially in at-risk breast cancer populations where HRT is contraindicated. Due to inconclusive findings, the evidence thus far on 5HTP and depression limits its use to patients with mild depression who are contraindicated to take antidepressant drugs. (27) Considering the biochemical theoretical impact of 5HTP on serotonin levels and subsequent thermoregulator centers and the lack of adverse events reported, the use of 5HTP for hot flashes poses an interesting hypothesis that warrants investigation. Agents that modulate neurotransmitters should be explored to not only evaluate the clinical significance of use for women experiencing debilitating symptoms that reduce their quality of life, but also to better understand the causes of hot flashes. Scientific insight into serotonin and endorphins in hot flashes could provide innovative management of menopausal symptoms and a possible new armamentarium of treatments that do not include hormone replacement therapy, which has demonstrated morbidity and mortality. While 5HTP is generally considered safe, (33) until adequately powered efficacy and safety studies with a large sample size and randomized controlled trials are conducted in menopausal women, recommendation of 5HTP for hot flashes can not be substantiated at this time. Evidence of safety, including dose-response studies, is needed to consider this non-hormonal alternative for women with risk of breast cancer. References (1.) Avis NE, Stellato R, Crawford S, et al. Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups. Soc Sci Med 2001;52:345-356. (2.) Couzi RJ, Helzlsouer KJ, Fetting JH. Prevalence of menopausal symptoms among women with a history of breast cancer and attitudes toward estrogen replacement therapy. J Clin Oncol 1995; 13:2737-2744. (3.) Finck G, Barton DL, Loprinzi CL, et al. Definitions of hot flashes in breast cancer survivors. J Pain Symptom Manage 1998;16:327-333. (4.) No authors listed. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1996;275:370-375. (5.) Mendoza N, Pison JA, Fernandez M, et al. Prospective, randomised study with three HRT regimens in postmenopausal women with an intact uterus. Maturitas 2002;41:289-298. (6.) Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333. (7.) Haslam SZ, Osuch JR, Raafat AM, Hofseth LJ. Postmenopausal hormone replacement therapy: effects on normal mammary gland in humans and in a mouse postmenopausal model. J Mammary Gland Biol Neoplasia 2002;7:93-105. (8.) Carpenter JS, Andrykowski MA, Cordova M, et al. Hot flashes in postmenopausal women treated for breast carcinoma: prevalence, severity, correlates, management, and relation to quality of life. Cancer 1998;82:1682-1691. (9.) Carpenter JS, Johnson D, Wagner L, Andrykowski M. Hot flashes and related outcomes in breast cancer survivors and matched comparison women. Oncol Nurs Forum 2002;29:E16-E25. (10.) Loprinzi CL, Pisansky TM, Fonseca R, et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 1998; 16:2377-2381. (11.) Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000;356:2059-2063. (12.) Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578-1583. (13.) Barton DL, Loprinzi CL, Novotny P, et al. Pilot evaluation of citalopram for the relief of hot flashes. J Support Oncol 2003; 1:47-51. (14.) Perez DG, Loprinzi CL, Barton DL, et al. Pilot evaluation of mirtazapine for the treatment of hot flashes. J Support Oncol 2004;2:50-56. (15.) Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry 2004;65:959-965. (16.) Masand PS, Gupta S. Selective serotonin-reuptake inhibitors: an update. Harv Rev Psychiatry 1999;7:69-84. (17.) Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL. Pathophysiology and treatment of hot flashes. Mayo Clin Proc 2002;77:1207-1218. (18.) De Sloover Koch Y, Ernst ME. Selective serotoninreuptake inhibitors for the treatment of hot flashes. Ann Pharmacother 2004;38:1293-1296. (19.) Fitzpatrick LA. Menopause and hot flashes: no easy answers to a complex problem. Mayo Clin Proc 2004;79:735-737. (20.) Notelovitz M. Hot flashes and androgens: a biological rationale for clinical practice. Mayo Clin Proc 2004;79:S8-S13. (21.) Weir E. Hot flashes ... in January. CMAJ 2004;170:39-40. (22.) Boman B. L-tryptophan: a rational anti-depressant and a natural hypnotic? Aust N Z J Psychiatry 1988;22:83-97. (23.) Young SN. Behavioral effects of dietary neurotransmitter precursors: basic and clinical aspects. Neurosci Biobehav Rev 1996;20:313-323. (24.) Russo S, Kema IP, Fokkema MR, et al. Tryptophan as a link between psychopathology and somatic states. Psychosom Med 2003;65:665-671. (25.) Sandyk R. L-tryptophan in neuropsychiatric disorders: a review. Int J Neurosci 1992;67:127-144. (26.) Byerley WF, Judd LL, Reimherr FW, Grosser BI. 5-Hydroxytryptophan: a review of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol 1987;7:127-137. (27.) Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev 2002(1):CD003198. (28.) Steinberg S, Annable L, Young SN, Liyanage N. A placebo-controlled clinical trial of L-tryptophan in premenstrual dysphoria. Biol Psychiatry 1999;45:313-320. (29.) Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev 1998;3:271-280. (30.) Meyers S. Use of neurotransmitter precursors for treatment of depression. Altern Med Rev 2000;5:64-71. (31.) Young SN. Are SAMe and 5-HTP safe and effective treatments for depression? J Psychiatry Neurosci 2003;28:471. (32.) Shaw K, Turner J, Del Mar C. Are tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysis. Aust N Z J Psychiatry 2002;36:488-491. (33.) Das YT, Bagchi M, Bagchi D, Preuss HG. Safety of 5-hydroxy-L-tryptophan. Toxicol Lett 2004;150:111-122. Jessica J. Curcio, ND--Research Associate, Southwest College Research Institute Correspondence address: Southwest College of Naturopathic Medicine, 2140 E. Broadway Road, Tempe, AZ 85282 E-mail: j.curcio@scnm.edu