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From the Townsend Letter
May 2016

Review: The Clinical Utility of Urinary Biogenic Amines and Other Neurotransmitters
by Andrea Gruszecki, ND
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Central and peripheral nervous system functions depend on normal synaptic transmission, which is mediated by a variety of neurotransmitters, including the biogenic amines (the catecholamines dopamine, norepinephrine, epinephrine, serotonin, histamine; Eisenhofer 2004; Rothman et al. 2012). Analysis of urinary biogenic amines and other neurotransmitters may provide a noninvasive assessment of neurotransmitter metabolism. Urinary neurotransmitters are easily collected by patients and the results may be readily integrated into current practice patterns. Urinary neurotransmitter evaluations may be used to identify neurotransmitter imbalances and evaluate the function of enzymes on synthesis and catabolic pathways (Fryar-Williams 2015). Alterations in neurotransmitter metabolism may reflect the neurological effects of environmental exposures to toxicants and may serve in the assessment of a variety of physiologic conditions (Castro-Diehl 2014; Kaidanovich-Beilin 2012). They provide a noninvasive 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). A review of the current scientific literature evaluates the utility of urinary neurotransmitters for clinical assessment.

A recent review of biomarker development for neuropsychiatric disorders (Enaw 2013) stated in its conclusion, "The need for biomarkers in the field of psychiatry is clear, but progress towards their development has been limited." In the article's conclusion, Enaw and Smith claim that "the successful identification of biomarkers will advance the field of psychiatry towards the goal of biological tests for diagnosis, symptom management and treatment response." The review failed to consider urinary neurotransmitters as a viable biomarker for neurologic health, despite the associations between urinary neurotransmitter levels and some mental health conditions that have been documented in scientific literature (Marc 2011). Enaw and Smith may have legitimate skepticism regarding urinary neurotransmitters, perhaps due to the fact that less than 20% of measured neurotransmitter metabolites in peripheral circulation originate in the central nervous system (CNS; Eisenhofer 2004). Or perhaps due to reports from some laboratories claiming, in spite of the evidence, that urinary neurotransmitters may be directly correlated with CNS neurotransmitter levels? If the notion that urinary neurotransmitters are a direct assessment of CNS neurotransmitter levels must be discarded, how might urinary neurotransmitters be of clinical value? Urinary neurotransmitter evaluations may be used to identify neurotransmitter imbalances, evaluate the function of enzymes on synthesis and catabolic pathways, monitor the effect of therapeutic interventions, and serve in the assessment of a variety of physiologic conditions. 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), it may be time to reconsider the clinical utility of urinary neurotransmitters in functional medicine.

Urinary Neurotransmitters
Normal function of the central and peripheral nervous systems depend on the transmission of electrical signals from one neuron to another across the synapse, or gap, between neurons. Neurotransmitters convert the electrical information into chemical information that can cross the synapse and stimulate or inhibit the next neuron (Hyman 2005). There are many types of neuroactive substances. "Classic" neurotransmitters are called small molecule neurotransmitters or biogenic amines (Eisenhofer 2004). Some amino acids obtained from the diet or synthesized in the body may act as neurotransmitters or neuromodulators (Berry 2007; Eisenhofer 2004; Paul 2002). A neuromodulator alters a nerve cells' response to a neurotransmitter signal. Other essential amino acids serve as precursors for neurotransmitter synthesis (Cansev 2007). Many neuroactive molecules are synthesized by gut bacteria, such as gamma-aminobutyric acid (GABA; Dhakal et al. 2012; Saulnier et al. 2013), and many hormones have neuroactive properties (Lyte 2013). Some nerve cell metabolites may also act as neurotransmitters or neuromodulators. Other metabolites have no known function and are simply excreted from the body by the liver and kidneys. Currently under investigation are several gases, such as nitric oxide, that may also modulate the action potentials of neurons (Kakizawa 2013).

Figure 1: Enzymes of Neurotransmission

Enzymes of Neurotransmission

Because enzymes are expressed differently in various body tissues, circulating levels of the neurotransmitters and their metabolites may have distinctive sources (Figure 1). In the periphery, the catecholamine epinephrine is synthesized in the medulla of the adrenal glands; the majority of norepinephrine is synthesized in the sympathetic nerves that surround blood vessels (Goldstein 2003). Serotonin synthesis occurs primarily in the enteric nervous system of the gastrointestinal (GI) tract (Hansen 2003) but may also de novo in blood vessels and renal proximal tubules (Watts et al 2012). Dopamine is released from the peripheral nervous system when sympathetic noradrenergic nerves are stimulated to release norepinephrine (Goldstein 2010). Up to 45% of peripheral dopamine may be synthesized in mesenchymal organs and the digestive tract; however the dopamine found in urine is primarily synthesized de novo in the kidneys (Eisenhofer 2004). Many biogenic amines are actively taken up and stored by platelets, which have no neurotransmitter synthesis capacity of their own (Audhya et al 2012). Evaluation of platelet levels may offer an excellent assessment of the cellular active transport mechanisms necessary for normal neurotransmission, but will offer little insight into the synthesis or metabolism of neurotransmitters (Jedlitschky 2012).

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 (Eisenhofer 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  (Cansev 2007). Urinary neurotransmitter analysis may be clinically useful to identify neurotransmitter imbalances, evaluate enzyme function, and in risk assessment.

Urinary Neurotransmitters May Identify Imbalances
Plasma epinephrine concentrations increase markedly in response to hypoglycemia, hemorrhagic hypotension, asphyxiation, circulatory collapse and importantly, due to emotional distress. Other catecholamine neurotransmitters do not elevate like epinephrine (Goldstein 2005). A 2004 epidemiologic study of posttraumatic stress disorder (PTSD) found significantly higher mean urinary levels of dopamine, epinephrine, and norepinephrine in those with lifetime PTSD, when compared with controls in the community without PTSD (Young 2004). Other research indicates that specific urinary neurotransmitter levels may correlate with neuropsychiatric conditions such as depression (Marc 2010) and attention deficit/hyperactivity disorder (ADHD; Dvorakova 2007).

Evaluate Function
Enzyme function. Catecholamines are metabolized by enzymes such as monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT; Goldstein 2005). Inherited or acquired factors may affect enzymatic activity. Mutations (Hyland 2007) or single nucleotide polymorphisms (SNPs) may alter enzyme function and affect the metabolism of neurobiogenic amines. Mutations and SNPs and have been associated with neurodegenerative (Dorszewska 2013) and neuropsychiatric disorders (Inoue 2003) in the scientific literature.

Defects in enzyme functions may be evident in neurotransmitter analysis as elevations or deficiencies. Neurotransmitter levels have been associated with symptom severity in some disorders. For example, patients with MAO-A deficiency have low plasma 3,4-dihydroxyphenylacetic acid (DOPAC) levels and may have an increased tendency to violent antisocial behaviors. Patients with MAO-B deficiency exhibit normal behavior and have normal DOPAC metabolite levels (Goldstein 2005). Addison's disease, secondary adrenocortical insufficiency, and severe 21-hydroxylase deficiency all have impaired adrenal secretion of epinephrine, and plasma levels are decreased (Goldstein 2005); it is possible that these findings might be reflected in urine.

MAO-A metabolic pathways work in conjunction with aldehyde/aldose dehydrogenase and aldehyde/aldose reductase enzymes; MAO-A is the first step in a two-step enzymatic process (Eisenhofer 2004). Some aldehyde metabolites of catecholamine metabolism, such as formaldehyde may cause neurotoxicity if the aldehyde dehydrogenase and reductase enzymes are deficient (Marchetti 2007). Analysis of neurotransmitter metabolites in urine may indicate which enzyme pathways are compromised. For example, the catabolism of the catecholamine neurotransmitters epinephrine and norepinephrine into metanephrine and normetanephrine (respectively) primarily occurs in the same cell where they are synthesized. The metabolites are then released from the cell for excretion in the urine (Eisenhofer 2004). Many of the enzymes in the neurotransmitter synthesis pathways require various nutrient cofactors and the presence of SNPs may further affect nutrient requirements (Stover 2006).

Figure 2:  Neurotransmitter Nutrient Cofactors

Neurotransmitter Nutrient Cofactors

Nutrition (Figure 2). The assimilation and absorption of nutrients requires a healthy digestive tract and a healthy microbiome (the presence of expected and beneficial microbes in the gastrointestinal tract). Bacteria in the microbiome synthesize neuroactive compounds as part of normal gut-brain-microbiome crosstalk. Imbalances in the gastrointestinal microbiome may affect mood and behavior (Lyte 2013). The addition of probiotics has been shown to be beneficial in some types of neuropsychiatric disorders. A 2009 double-blind placebo-controlled study of emotional symptoms in chronic fatigue patients reported that the addition of a Lactobacillus probiotics improved emotional symptoms (Rao 2009).

In addition, gastrointestinal disorders may
result from imbalances in neurotransmitter synthesis or metabolism (Hansen 2003) or may contribute to nutritional deficiencies that may then affect enzyme functions and neurotransmitter levels. Neurotransmitters arise from the precursor amino acids phenylalanine and tyrosine. The kidney is the primary source of circulating tyrosine; approximately 50% of phenylalanine-to-tyrosine conversion occurs in the kidneys. Renal disease may affect the levels of neurotransmitters in urine, and renal function should be evaluated prior to urinary neurotransmitter testing (Eisenhofer 2005).

Response to therapy. Normalizing urinary neurotransmitter levels based on test results has been shown to improve some mood and behavior symptoms (Marc 2010). Urinary neurotransmitter levels may be altered by nutrient or pharmaceutical supports. For example, urine serotonin levels may be increased by the addition of neurotransmitter precursors such as tryptophan or 5-hydroxytryptophan (5-HTP; Trachte 2009). The treatment of ADHD with Pycnogenol in a randomized, double-blind, placebo-controlled study resulted in a statistically significant decrease in urinary dopamine and a trend of decreasing norepinephrine and epinephrine levels (Dvorakova 2007).

Risk Assessment
The use of urinary neurotransmitters to diagnose carcinoid tumors and pheochromocytoma is well established (Goldstein 2005). The use of urinary neurotransmitters to evaluate the effects of other health conditions is more recent. Accumulating evidence indicates that insulin levels may be critical to normal CNS neuron function, and insulin dysregulation may contribute to the development of neurodegenerative disorders such as Alzheimer's disease (Kaidanovich-Beilin 2012). Altered levels of urinary neurotransmitters have been documented in health conditions such as sleep apnea (Kherahdish-Gozal 2013), gastrointestinal tumors (Eisenhofer 2004), and inherited disorders of neurotransmitter metabolism such as phenylketonuria (Hyland 2007). Urinary catecholamines and cortisol levels have been measured to evaluate the effects of socioeconomic and psychosocial factors on the risk for atherosclerosis (Castro-Diehl 2014). An epidemiologic study of PTSD found significantly higher mean urinary levels of dopamine, epinephrine, and norepinephrine in those with lifetime PTSD, when compared with controls (Young 2004). The study also described an increase in urinary catecholamines for study subjects with no PTSD but with major depressive disorder. Alterations in urinary neurotransmitters have been reported in studies of ADHD (Marc 2010), and decreased levels of urine amino acids important in neurotransmission, such as glutamate, phenylalanine, tyrosine, and tryptophan, have been reported (Ghanizadeh 2013). A 2015 study (Fryar-Williams 2015) reports elevations in urinary norepinephrine, epinephrine, dopamine, and histamine in schizophrenic patients compared with controls; the results also correlated with the subject's symptom intensity ratings.

Exposures to environmental toxicants may also alter urinary neurotransmitter levels and may be associated with neuropsychiatric symptoms. A statistically significant increase in 5-hydroxyindoleacetic acid (5-HIAA), compared with nonexposed controls, was found in Chinese welders exposed to manganese (Yuan 2006). In a study designed to monitor the health effects of industrial exposure to polychlorinated biphenyls (PCBs), urinary concentrations of the dopamine metabolite homovanillic acid (HVA) and the epinephrine/norepinephrine metabolite vanillylmandelic acid (VMA) were analyzed over a 3-year period (Putschögl 2015). The study documents alterations in HVA and VMA for different types of PCBs, with effects dependent upon the degree of chlorination within the chemical. Increasing levels of exposure to all PCBs reduced urinary HVA and VMA levels. The findings are consistent with many animal studies that document decreased levels of dopamine in the central nervous system after PCB exposure. Coke oven workers exposed to benzo[a]pyrene (B[a]P) had decreased urine levels of dopamine, norepinephrine, serotonin, and HVA with elevated levels of 5-hydroxyindoleacetic acid (5-HIAA; Niu 2009). According to the World Health Organization Neurobehavioral Core Test Battery (NCTB), memory and learning capacity were reduced in the exposed workers.

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