Urinary neurotransmitter analysis provides a non-invasive means of assessing a patient’s ability to synthesize and metabolize neurotransmitters, and may be used to evaluate patient responses to supportive nutritional therapies (Marc 2011). Central and peripheral nervous system functions are dependent upon normal synaptic transmission, mediated by neurotransmitters including the biogenic amines (catecholamines dopamine, norepinephrine, epinephrine; serotonin; histamine) (Eisenhofer 2004, Rothman et al. 2012). The incorporation of metabolic intermediaries such as 3-methoxyyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), normetanephrine, metanephrine and 5-hydroxyindoleacetic acid (5-HIAA), into the Comprehensive Neuro-biogenic Amines Profile may provide clinicians with the means to evaluate the function of monoamine oxidase (MAO) A and B, catechol-O-methyltransferase (COMT), and aldehyde dehydrogenase (ALDH). These enzymes are essential not only in the catabolism of neurotransmitters, but the detoxification of exogenous estrogens, pharmaceuticals and environmental amines. Targeted nutritional support may optimize enzyme function and support patient health. Given the recent advances in the understanding of nutritional biochemistry, inheritance, epigenetics, and environmental toxicology, as well as improved sensitivity and specificity in the analysis of urinary neurotransmitter levels (Li 2014) and their intermediaries, it may be time to reconsider the clinical utility of urinary neurotransmitters in functional medicine. The evaluation of only the end products of neurotransmitter metabolism, homovanillic acid (HVA) and vanillylmandelic acid (VMA), may not provide a complete picture of enzyme function for the clinician.
Urinary levels of neurotransmitters primarily reflect the activity of the peripheral and GIT enteric nervous systems. The majority of the neurotransmitters excreted in the urine reflect peripheral metabolism (Eisenhoffer 2004). However, with the exception of tryptophan-5-hydroxylase, the enzymatic machinery for neurotransmitter synthesis and metabolism is often similar (if not identical) on both sides of the blood-brain barrier (BBB) (Cansev 2007). Part of the metabolism of catecholamines takes place in the same cells where the amines are produced. Different enzymes may be used and different metabolites are generated if a neurotransmitter is processed within a neuron (MAO, ALDH), or outside of it (COMT). This occurs because catecholamines are constantly leaking out of vesicles and into the cytoplasm. Circulating neurotransmitters may also be metabolized in the liver or kidney. The metabolism of precursors or neurotransmitters results in intermediary metabolites. The metabolites may or may not be biologically active, and may provide important functional clues about catabolic transformation reactions.
Enzyme function may be affected by inheritance, nutritional status or environmental exposures. Mutations or single nucleotide polymorphisms (SNPs) may alter enzyme function and affect the metabolism of neurotransmitters. Dietary deficiency or gastrointestinal malabsorption may affect the availability of required nutrient cofactors. Toxic exposures may inhibit enzymatic functions and increase oxidative stress, resulting in altered neurological function and metabolism. The catabolic enzymes for neurotransmitters may be affected by any or all of these factors.
There are two forms of monoamine oxidase (MAO). Monoamine oxidase A (MAO-A) activity is necessary for intraneuronal neurotransmitter metabolism. It oxidizes the catecholamine neuro-biogenic amines dopamine, norepinephrine and tryptophan to an aldehyde intermediary. MAO-A also oxidizes dietary and environmental amines (dyes, pigments, insecticides and polymers). Dopamine is primarily oxidized by MAO-B. The degradation of dopamine creates reactive oxygen species, and increased MAO-B activity has been associated with aging and Parkinson’s disease. Animal studies indicate that MAO activity may up-regulated with stress. MAO is inherited with the X chromosome; males have one copy and females have two copies of the genetic code for MAO. MAO-A and MAO-B are coded by two separate genes. Inherited variations in MAO activity may affect neurotransmitters or neurochemistry. In addition to medications designed to inhibit MAO activity (MAOIs), MAO may be inhibited by cigarette smoke, and toxic elements such as cadmium, lead and mercury. Dopamine, if not converted into norepinephrine is degraded by intraneuronal MAO and extraneuronal COMT. MAO-A converts dopamine to 3,4-dihydroxyphenylacetic acid (DOPAC). COMT uses SAMe and magnesium to degrade dopamine into 3-methoxytyramine (3MT). MAOA and COMT further convert the intermediary metabolites to homovanilic acid (HVA). There is no way to tell, by the level of HVA, if one or both degradation enzymes are deficient. Differences in the levels of DOPAC and 3MT may easily distinguish which degradation enzyme, MAO or COMT, is not functioning optimally.
Oxidative deamination by MAO produces hydrogen peroxide and a reactive aldehyde, which may increase oxidative stress and put excessive demand on the cell’s glutathione pool. Aldehyde dehydrogenase (ALDH) converts aldehydes to fatty acids. Aldehyde dehydrogenase (ALDH) activity contributes to a variety of vital biochemical reactions in the body. Mutations or single nucleotide polymorphisms (SNPs) may occur in the dehydrogenase or reductase enzymes, and may affect enzyme function. Environmental aldehydes that must be processed by aldehyde dehydrogenases include cigarette smoke, formaldehyde, polyurethane, polyester plastics, and many medications. Aldehyde excess due to enzymatic insufficiency may be associated with symptoms of dizziness, nausea, rapid heartbeat (tachycardia) and “alcohol flush”. ALDH is part of the metabolic pathway for dopamine and serotonin. The dopamine intermediaries may elevate and have neurotoxic effects (increased oxidative stress) if ALDH or MAO-B activity is compromised. Serotonin may elevate and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) may decrease, if either MAO-A or ALDH activities are insufficient. Comparison of serotonin and 5-HIAA levels against dopamine, DOPAC and 3MT levels may distinguish insufficiencies in the activities of MAO-A, MAO-B or ALDH.
Catechol-O-methyltransferase (COMT) activity is necessary for extra-neuronal neurotransmitter metabolism. COMT methylates both catecholamines and catecholamine metabolites oxidized by MAO. COMT is not found in sympathetic nerves, but is abundant outside the neuron in other cells and tissues. High levels of COMT are found in the liver, kidneys; COMT is also present in red blood cells and in adrenomedullary chromaffin cells. Inherited or acquired factors may affect enzymatic activity. Various mutations and SNPs in the genes coding for COMT have been associated with some types of mood disorders, obsessive-compulsive disorder and schizophrenia. COMT requires magnesium and S-adenosyl methionine (SAM) cofactors. Low levels of the metabolites metanephrine and normetanephrine, and (perhaps) elevated levels of epinephrine and norepinephrine, may occur if catechol-O-methyltransferase (COMT) function is insufficient. The conversion of norepinephrine and epinephrine to their metabolites had been considered a major pathway leading to VMA, but it is now known that this is a minor pathway. Most VMA (94%) is formed from the transient aldehyde metabolite 3-methoxy-4-hydroxyphenylglycolaldehyde (MOPEGAL) in the liver.
Only 10-20% of urinary neurotransmitters and their intermediaries may originate in the central nervous system. However, while the majority of the urinary neurotransmitters and metabolites in urine originate in the peripheral nervous system, normalizing urinary neurotransmitter levels based on laboratory analysis has been shown to result in the improvement of some mood and behavior symptoms (Marc 2010). The evaluation of peripheral neurotransmitters and intermediaries may also assist in the evaluation of physiological conditions such as cardiovascular disease, metabolic syndrome, thyroid or parathyroid disease, adrenal disorders or hormone imbalances, as all of these conditions may alter mental status or contribute to metabolic encephalopathy.
In 2011, an article in The Lancet (Kurian, 2011) stated “The monoamine neurotransmitter disorders consist of a rapidly expanding heterogeneous group of neurological syndromes characterized by primary and secondary defects in the biosynthesis degradation, or transport of dopamine, norepinephrine, epinephrine, and serotonin”. The article also noted that “many neurotransmitter disorders mimic other neurological disorders, and may be misdiagnosed”. The article recommended the analysis of neurotransmitters in cerebrospinal fluid for accurate clinical diagnosis. However, the collection of cerebrospinal fluid for the assessment of urinary neurotransmitters and metabolites is expensive, uncomfortable and simply not practical in most cases. Urinary neurotransmitters are easily collected by patients and the results may be readily integrated into routine practice. Urinary neurotransmitters are stable during collection and transportation (other methods of evaluating neurotransmitters, such as platelets, may not be as stable), and urinary neurotransmitter intermediaries may best reflect enzyme functions.
The proper collection and handling of urine specimens prior to laboratory receipt is necessary for accurate results. As the purpose of urinary neurotransmitter testing is to evaluate clinically significant elevations or deficiencies in neurotransmitter status, either true first morning void (i.e., after being in bed without arising x 8 hours) or 24-hour urine neurotransmitters and intermediaries may be most clinically relevant. The ingestion of certain foods may affect the results of urinary neurotransmitter testing, and the avoidance of specific foods is recommended, as certain foods may affect serotonin and other neurotransmitter levels. Any medication that is meant to affect neurotransmitters (such as reuptake inhibitors, etc.) may alter neurotransmitter or intermediary levels from baseline levels; it is the clinical decision of the prescribing physician whether or not to discontinue (by safely tapering off), any such medications prior to testing.
Alterations in urinary neurotransmitter status may be associated with a variety of conditions including metabolic disorders, mood/behavioral disorders, environmental exposures, or (rarely) the presence of certain tumors. Analysis of both neurotransmitters and their intermediaries may provide the clinician with greater clarity about patient health, functional status, and nutritional needs.
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