Neurotransmitters are the chemical messengers of our nervous system that act as part of the endogenous molecular machinery that allow cells to communicate with one another.
This biochemical telegraph coordinates actions from basic metabolic processes to complex feelings and emotions. Genetics, environment, chemicals, and nutritional deficiencies represent several of the factors that impact neurotransmitter production; when these factors combine to realize a state of optimal neurotransmitter homeostasis, proper nervous system function and health are achieved. However, if something occurs that compromises or otherwise causes imbalance in this system, the mind or body may become under (or over) stimulated, leaving the individual susceptible to a wide variety of neurological or psychological symptoms.
A neurotransmitter test provides information that may identify imbalances before they manifest as a symptom or problem, such as depression, anxiety, ADHD, Bipolar Disorder, insomnia, memory impairment, weight issues, or a plethora of other potential maladies. There are over 200 endogenously produced neurotransmitters that have been identified that facilitate neurotransmission via an intracellular electrical wave known as the action potential. Neurotransmitters, synthesized by enzymes in the axon terminal of the cell body using amino acids and nutrients, are generally categorized into small biogenic amine molecules, amino acids, and neuropeptides. Biogenic amine neurotransmitter substances include serotonin, dopamine, epinephrine, norepinephrine and histamine, whereas amino acid neurotransmitters include GABA, glycine, and glutamate. Furthermore, neuropeptides modulate neuronal communication by acting on cell surface receptors in concert with other biogenic amines. For example, the biogenic amine norepinephrine is released with its corresponding neuropeptides Galanin, Enkephalin, and Neuropeptide Y.
Neurotransmission, or the movement of an electrical signal through a nerve cell and across the synapse, occurs when the synaptic vesicles located at the axon terminal are activated by an action potential and subsequently released into the synapse to interact at the post synaptic interface of another neuron, myocyte, or gland cell. A neurotransmitter that is released into the synapse faces one of four fates: 1) enzymatic degradation, 2) receptor mediated reuptake by the presynaptic neuron, 3) bind postsynaptic receptors of target cell to modulate signal transduction, or 4) remain in the local area for longer periods of time as neuromodulators.
Neurotransmitters are classified by their function and signal influence: excitatory, inhibitory, or modulatory. Excitatory neurotransmitters, such as glutamate, amplify the signal and promote depolarization of the neuron, and facilitates an action potential to transmit the signal to an adjacent cell. GABA is the classic inhibitory neurotransmitter that dims the signal and promotes hyperpolarization of the nerve cell which depresses or inhibits the propagation of neurotransmissions. Modulatory neurotransmitters, such as adenosine, are not limited to fast-acting signals on one particular neuron, but instead cause slower reactions that affect multiple local neurons simultaneously. The complex interplay between excitatory, inhibitory, and modulatory neuronal signalling is further entangled when the patient uses OTC and prescription drugs, for example caffeine and fluoxetine. These chemicals change the way our bodies regulate the various neurotransmitters, and ultimately, how we function.
Serotonin, also known as 5-hydroxytryptamine (5-HT), is an inhibitory neurotransmitter that is generally regarded as the “Master” neurotransmitter. It is a monoamine formed by the hydroxylation and decarboxylation of tryptophan. In the central nervous system, serotonin usually acts as an inhibitory neurotransmitter (like GABA) and balances excitatory activities involved in mood, pain modulation, body temperature regulation, sexuality, metabolism, and the sleep/wake cycle. In addition to its role as a brain neurotransmitter, it is an important regulatory factor in the gastrointestinal (GI) tract and other organ systems. In fact, greater than 90% of the body’s serotonin is synthesized in the gut, where it activates as many as 14 different receptor subtypes located on enterocytes, enteric neurons, and immune cells.
When serotonin is out of balance, symptoms such as depression, anxiety, obsessive-compulsive behavior, hypertension, carbohydrate cravings, migraines, emesis, PMS, and memory disturbances can occur. Occasionally, none of these symptoms will occur when serotonin is low; the patient may simply present as lethargic.
Dopamine, a catecholamine synthesized by the removal of a carboxyl group from its precursor L-DOPA, acts as both a neurotransmitter and neuromodulator in multiple biological processes. Primarily known for its role in cognitive behavior, memory, and the pleasure-reward pathways, this neurotransmitter also modulates endocrine, cardiovascular, renal, gastrointestinal, and immune function. Dopamine also plays an important role in muscular coordination, sexual function, focus, mood, addiction, where it may produce both inhibitory and excitatory functions based on the receptor subtype it activates. Low levels of dopamine are associated with lack of motivation, addictive disorders, and Parkinson’s disease, a neurodegenerative disorder with symptoms that include tremors and motor movement impairments. High levels of dopamine are associated with autism/spectrum disorders, ADD/ADHD and gastrointestinal disorders.
Norepinephrine (aka noradrenaline) is a catecholamine synthesized from the neurotransmitter dopamine in neurotransmitter storage vesicles. It functions as both a neurotransmitter and neuromodulator (hormone) aimed at preparing the body for action as part of the “fight or flight” pathway. By modulating neuron voltage potentials to favor glutamate activity and neurotransmitter firing, its turnover in the brain is increased during periods of stress. Norepinephrine is the excitatory neurotransmitter that deals with mood, attention, and focus, and is responsible for the stimulatory processes of the brain and body. It is rapidly converted to epinephrine, a neurotransmitter described in more detail later. Norepinephrine is highest during times of stress and lowest during periods of sleep in healthy individuals. During a stressful event, high levels of norepinephrine mobilize in the brain to increase alertness, enhance focus and memory retrieval, and prepare the body for a demanding situation. However, high levels of norepinephrine increases anxiety and blood pressure, causes mood dampening effects, and slows down gut motility. Ongoing high levels of norepinephrine can lead to fatigue, sleep cycle disturbances, and mood imbalances. Low levels of norepinephrine are associated with low energy, lack of motivation and decreased focus ability.
Epinephrine (aka adrenaline) is a catecholamine and hormone synthesized from norepinephrine. Produced mainly in the adrenal gland, epinephrine functions as an excitatory neurotransmitter and is involved in the body's fight-flight mechanism (pupil dilation, increased blood flow), regulation of brain function (depression, cognitive function) and metabolism (increase glucose levels, lipolysis). Elevated levels are associated with hyperactivity, anxiety, and low adrenal function. Elevations of epinephrine may manifest as anxiety, weight gain, focus issues, and ADHD. In some cases, long-term exposure to stressors or overstimulation of the adrenal gland may cause epinephrine levels to become depleted, a condition known as adrenal fatigue. Low epinephrine and adrenal fatigue are associated with decreased energy, depression, brain fog, and weight gain.
Gamma-aminobutyric acid (GABA) is an amino acid that serves as the predominant inhibitory neurotransmitter in the nervous system. Enhanced GABA activity translates into greater inhibitory control of neuronal membrane potential and a reduction in excess stimulation that may be caused, for instance, by glutamate. This occurs via a chloride ion influx that leads to hyperpolarization of the neuron which counteracts the depolarizing action of excitatory neurotransmitter processes. High excretion of GABA indicates excitatory overload due to the heightened demand for quenching surplus excitation. Higher levels of GABA in the nervous system may manifest as a “calm” state that may contribute to sedation, low energy and foggy cognition. Low GABA levels may indicate issues with the adrenal-stress response with symptoms that include impulsivity, anxiety, insomnia, and seizures.
Glutamate is derived from the amino acid glutamine, and serves not only as the primary excitatory neurotransmitter in the nervous system, but the most common neurotransmitter in the body. It’s neurotransmission is critical to proper brain development, with roles that range from learning and memory, to influencing behavior and motivation. Glutamate binds to ionotropic (NMDA, AMPA, KA) and metabotropic (mGlu) glutamate receptors to propagate excitatory signaling. When activated, NMDA receptors and AMPA receptors increase the influx of sodium or calcium, positive ions that potentiate the excitatory mechanism of neuronal depolarization. Normally, glutamate transporters are present in the neuronal membranes to help remove excess glutamate from the extracellular space. If this protective mechanism is compromised, whether through injury or disease, extracellular glutamate may accumulate. This causes calcium ions to enter the cell and activate calcium-sensitive enzymes and leads to excitotoxicity which if sustained, may lead to cellular death. Excitotoxicity due to glutamate occurs as part of the ischemic cascade and is associated with stroke, autism, spectrum disorders, neuro-developmental diseases, seizures and Alzheimer's disease. Elevated glutamate levels are associated with panic attacks, anxiety, excess adrenal function, and impulsivity. Low glutamate levels have been associated with agitation, memory loss, sleeplessness, low energy level, insufficient adrenal function, and depression.
Histamine is an excitatory monoamine neurotransmitter and neuromodulator that plays a vital role in the immune response, sleep-wake cycle, and gastrointestinal processes. Within the posterior region of the hypothalamus, there are a large number of neurons that synthesize and utilize histamine. These neurons not only promote the excretion of epinephrine and norepinephrine, but they also provide the stimulation that maintains or modulates activity in many other regions of the brain. Histamine-containing neurons have been found to have a pacemaker function within the brain; the firing rates of these neurons correlate positively with brain activity levels and exhibits distinct day-night rhythms. Elevated levels of histamine are associated with allergic symptoms, inflammation, and gastrointestinal concerns that may interfere with sleep. Low levels may affect learning, digestion and mood.
Creatinine is a normalizing parameter used to calculate neurotransmitter levels. Creatinine is a by-product of muscle metabolism produced at a constant rate through the kidneys and excreted in urine. Therefore, by using creatinine as the constant factor, spot urinary measurements can be performed without having to factor in the patient’s hydration state, possible renal disorders or diuretic substances that may have been used.
Since specific clinical symptoms may arise relative to a particular neurotransmitter being out of balance, urinary neurotransmitter testing provides valuable insight for practitioners on a wide range of disease states for both male and female patients. Certainly, individuals presenting with gastrointestinal complaints should be considered a prime candidate for neurotransmitter testing, as sufficient neurotransmitter production is dependent on proper nutrient intake and absorption. It’s important to keep in mind that hormones and neurotransmitters are interrelated from a functional perspective; therefore, changes in hormone levels may have an effect on neurotransmitter levels, and vice versa. Common clinical indicators associated with neurotransmitter imbalances include:
- Adrenal dysfunction (high stress)
- Medications (chronic antibiotic use)
- Hormonal imbalances
- Depressed mood
- Cognitive fog and poor memory
- Sleep disorders and insomnia
- Food sensitivities/intolerances
- Heartburn/GERD symptoms
- Food sensitivities/intolerances
- Chronic pain syndromes
- Migraine headaches
- ADD and ADHD
- Irritable Bowel Syndrome (IBS)
- Chronic environmental allergies
- Auto-immune conditions
- Thyroid disorders
- Bipolar Disorder and mood swings
- Addiction or dependency
- Cravings and appetite control
- Impulsivity and gambling
- Blood pressure disturbances
- Blood sugar dysregulation
- Spectrum disorders
The current standard of care for evaluation and treatment of mental health disorders relies solely on patient reported symptoms and clinical observation, followed by trial-and-error dosing of pharmaceutical medications. Despite the absence of measured biomarkers, these subjective measures do lead to treatments that are effective for many patients. However, many of these treatments have detrimental side effects that contribute to treatment failures that may lead to relapse. Even though neurotransmitter testing has been in use for over sixty years, it by itself is not enough to diagnose any disease, as there are no tests that can measure neurotransmitter concentrations in the synapse. However, when combined with a complete patient history and other serum biomarkers, it provides objective, relevant insight into the patient’s biochemistry and aids in the development of truly personalized functional treatment protocol. Dried urine spot (DUS) testing is easier on the patient because it doesn’t require a puncture like the more expensive and invasive analysis using cerebrospinal fluid. It utilizes enzyme-linked immunosorbent assay (ELISA) methods to quantify the clinically relevant molecules in the sample. While there is some debate in the literature regarding the validity of urinary neurotransmitter testing, sufficient clinical evidence exists that correlates neurotransmitter levels to various clinical conditions. In conclusion, urine neurotransmitter testing provides a non-invasive method for the quantitative measurement of relevant neurotransmitters in the complex evaluation of neuro-biochemical imbalances. The results of this analysis, when combined with other clinical assessment tools, gives clinicians a biochemical edge in the struggle against a variety of diseases.
While urine neurotransmitter testing is not a diagnostic tool in and of itself, when coordinated with traditional biomarkers such as blood work, pharmacogenomic testing, patient history, and imaging studies, it provides valuable information to guide the practitioner in creating a comprehensive treatment protocol. The information gleaned from a urine neurotransmitter panel is especially helpful in the diagnosis and subsequent treatment of mental health disorders, and may reduce the trial-and-error approach traditionally utilized in the prescribing of psychotropic medications. For example, a patient presenting with dysthymia with generalized anxiety disorder whose urine neurotransmitter results reveal low serotonin and an elevated norepinephrine would likely experience negative side effects when initiating an NSRI (duloxetine, venlafaxine), but may experience more complete relief from an SSRI (fluoxetine, escitalopram). From a nutritional perspective, further consideration should be given to supplementing the diet with targeted amino acid precursors, either alongside or in lieu of pharmaceuticals. For instance, 5-hydroxytryptophan (5-HTP) is the precursor amino acid to serotonin, while tyrosine and phenylalanine serve as the building blocks for catecholamines. Utilizing naturally occurring molecules, rather than pharmaceuticals, may be a helpful alternative to those sensitive to medications or individuals that prefer a more natural approach to healing. Targeted amino acid therapy is an effective way to restore certain nutritional deficiencies that ultimately contribute to the initiation and progression of many neurological diseases.
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- Nieto-Alamilla, G; Márquez-Gómez, R; García-Gálvez, AM; Morales-Figueroa, GE; Arias-Montaño, JA (November 2016). "The Histamine H3 Receptor: Structure, Pharmacology, and Function". Molecular Pharmacology. 90 (5): 649–673.
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