After an extensive and careful review of test results over the past year, the scientists and clinical consultants at ZRT have concluded that the monoamine metabolites ZRT includes as part of its panel of 14 neurotransmitters are essential for the best and most comprehensive interpretation of test results.

We've determined that while looking at a more limited range of seven to nine neurotransmitters is helpful in assessing precursor availability, interpreting results based on those levels alone without their downstream metabolites can result in undertreatment, treatment of the wrong part of the system, or overtreatment with direct precursors.

It is only in looking at a complete set of parent neurotransmitters together with their metabolites that you glean the most precise information about systemic patterns – leading to a provider's ability to develop the most effective treatment plan. 

Following are several examples that have led us to these conclusions.

Serotonin Assessment Incomplete without 5-HIAA

When serotonin is low and its downstream metabolite 5-HIAA is normal or high, this usually indicates high activity of monoamine oxidase A (MAO-A), an enzyme that requires copper and vitamin B2. MAO-A, the gene of which resides on the X chromosome, is sensitive to estrogens. Higher estrogen inhibits MAO-A, allowing more serotonin in the synapse, and a happier you. When estrogen drops at menopause MAO-A activity is increased, resulting in a higher rate of serotonin conversion to its inert metabolite 5-HIAA, and an associated increase in low estrogen symptoms such as hot flashes, night sweats, and depression – an unhappy you. This is why drugs that treat serotonin deficiency, such as SSRIs, are often successfully used for treating symptoms of menopause like hot flashes and depression. Thus, knowledge of the levels of serotonin relative to 5-HIAA can be very valuable for postmenopausal women who suffer from symptoms of estrogen deficiency that are related to low serotonin.

The opposite (high serotonin and low 5-HIAA) can be observed in women who have higher estrogens; however, a high urinary serotonin may also be associated with just simply eating a handful of walnuts (high serotonin content [1]), or taking 5-hydroxytryptophan (5-HTP), which is readily available OTC. Combining 5-HIAA with serotonin provides a much clearer picture of what’s happening to serotonin and determines if, clinically, the problem is real (low estrogens) or an artefact of the patient’s diet or supplement regime.

Dopamine Results Only Actionable with DOPAC & HVA

The downstream metabolites of dopamine, DOPAC and HVA, provide better insight into interpretation of dopamine results. Many of you have probably heard about the “warrior gene” and its relationship to the reward/pleasure neurotransmitter dopamine [2]. When you have an abundance of dopamine you feel on top of the world; however, as we know with most things, too much of anything isn’t good for you – and too much dopamine makes for an aggressive personality and increased likelihood you’re going to end up in trouble [3].

The warrior gene results from a single nucleotide polymorphism in the MAOA gene, which sits on the X chromosome. Men are more susceptible than women to MAO-A deficiency because they only have one X chromosome. A single nucleotide change in the MAOA gene reduces the activity of the MAO-A enzyme, meaning that monoamines (serotonin, dopamine, norepinephrine) formed in the body are more likely to accumulate and overstimulate the brain because they are less likely to be converted to their inactive metabolites. The same thing happens with neurological dysfunctions such as schizophrenia, mania, and ADHD. This is easier to identify when you know the levels of dopamine, DOPAC (MAO-A metabolite), and HVA (methylation end-product of COMT).

However, just because you have high dopamine doesn’t make you a “warrior.” Dopamine might also be elevated with supplementation of OTC extracts of plants such as the velvet bean (e.g., Mucuna Pruriens) that contain very high levels of the dopamine precursor DOPA. These products, used widely in the supplement industry, have profound effects on levels not only of dopamine, but its downstream metabolites DOPAC and HVA. When all three are elevated, and we know the patient is supplementing with dopamine precursors, this has an entirely different clinical interpretation than when some, or all, of the monoamines (e.g., dopamine, serotonin and norepinephrine) and their metabolites are elevated. Mucuna only elevates dopamine and its metabolites. A genetic defect in MAOA (i.e., warrior gene) will have a different profile and generally show an increase only in the monoamines (serotonin, dopamine, norepinephrine), but not their metabolites. It is these subtleties that allow proper interpretation of the monoamine neurotransmitter results.

Dopamine and its metabolites might also be elevated in individuals with tumors [4][5]. While this is rare, we have seen a few cases, which is why the clinical history should include use of OTC herbal extracts that might raise dopamine and its metabolites [6][7]. ZRT is meticulous about collecting information on herbal products that we know profoundly affect urinary neurotransmitter levels. This information is recorded in our database and used in concert with symptoms to create individualized comments about the neurotransmitters. Without this information physicians may go searching for a tumor that doesn’t exist.

High Levels of Normetanephrine May Indicate a Tumor

We also felt compelled to include information on downstream metabolites of the two stress hormones/neurotransmitters, norepinephrine and epinephrine. The metabolites include normetanephrine (NMN) and vanillylmandelic acid (VMA), respectively. Very high levels of NMN are diagnostic of pheochromocytomas, tumors of the adrenal medulla [8][9]. We have seen two of these very rare tumors in the past year, both of which were confirmed by independent serum testing and imaging, and were successfully removed by surgery.

Science Shows Dried Urine has Better Accuracy

Another technical problem that is not well appreciated, but well documented in the scientific literature, is that some of the neurotransmitters and their downstream metabolites are unstable and degrade in the liquid form even when stabilized by acid. One example is serotonin and 5-HIAA, which can be unstable in liquid urine and result in false-low levels [10]. The collection vessel for liquid urine contains an acid as a preservative which helps prevent the neurotransmitters from degrading during shipment. The acid (e.g., hydrochloric acid) reduces the urine pH, which stabilizes some neurotransmitters that would otherwise degrade rapidly. However, if the acid is too strong, which can occur with low volume or very dilute urine, it will degrade some neurotransmitters if maintained in the liquid state. This degradation is accelerated by temperature, which makes shipment during the hot months of the summer much more problematic if the sample is sitting in the back of the transporting vehicle for hours.

What we confirmed is that serotonin and its metabolite 5-HIAA are very susceptible to acid degradation [10]. As reported by others, a very low pH of 2-3 is problematic, but in the range of 3-4 it is not. Drying urine on the filter cards affords much better stabilization of all neurotransmitters vs. keeping them in liquid state during transport and storage prior to testing. We have found that drying urine on the filter cards immediately after collection is superior to collecting liquid urine in acid and allowing it to be exposed for a prolonged time in this state. Drying urine, or other body fluids such as blood, shortly after collection has proved to be an excellent way to stabilize the analytes (neurotransmitters, steroids, peptide hormones, etc.) to be tested as we and others have shown and published [11][12][13]. 

If serotonin and 5-HIAA are allowed to degrade because the acid conditions and time from collection to testing are not optimal, the clinical interpretation would be low serotonin synthesis. Thus, if the levels of both serotonin and 5-HIAA are found to be low in liquid urine in the absence of any other neurotransmitter deficiencies and symptoms of low serotonin (e.g., depression, low energy, sleep disturbances, vasomotor symptoms) it is quite likely that the results are a urine collection problem and not a serotonin deficiency.

Only ZRT Offers the Added Insight of Monoamine Metabolites

Given the importance of these monoamine metabolite levels to correct interpretation of neurotransmitter results and development of subsequent treatment plans, ZRT Laboratory will begin including all 14 tests it offers in all neurotransmitter reports this month.

Going forward, too, ZRT will offer only its NeuroAdvanced Profile, which includes all 14 of these critical tests. This collection is only available from ZRT, and when combined with ZRT’s customized comments, delivers the most insightful report available from any lab.

Learn more about the scientific importance of these tests by joining us for webinar on Case Reviews on the Importance of Testing Neurotransmitters with their Metabolites.

To ask about kits and pricing, please contact customer service at 866.600.1636 or info@zrtlab.com.

Related Resources

• Blog: Clinical Pearls - Getting the Most Out of Your Neurotransmitter Test
• Blog: Pheochromocytoma - A Rare Condition Exposed by Neurotransmitter Testing

References

[1] Strasser, B, et al. Mood, food, and cognition: role of tryptophan and serotonin. Curr. Opin. Clin. Nutr. Metab Care. 2016;19(1): 55-61.

[2] Harro, J and Oreland, L. The role of MAO in personality and drug use. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016;69: 101-11.

[3] Godar, SC, et al. The role of monoamine oxidase A in aggression: Current translational developments and future challenges. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016;69: 90-100.

[4] Foo, SH, et al. Dopamine-secreting phaeochromocytomas and paragangliomas: clinical features and management. Singapore Med. J. 2010;51(5): e89-e93.

[5] Verly, IR, et al. Catecholamines profiles at diagnosis: Increased diagnostic sensitivity and correlation with biological and clinical features in neuroblastoma patients. Eur. J. Cancer 2017;72: 235-43.

[6] Pathak-Gandhi, N and Vaidya, AD. Management of Parkinson's disease in Ayurveda: Medicinal plants and adjuvant measures. J. Ethnopharmacol. 2017;197: 46-51.

[7] Weldin, J, et al. Quercetin, an over-the-counter supplement, causes neuroblastoma-like elevation of plasma homovanillic acid. Pediatr. Dev. Pathol. 2003;6(6): 547-51.

[8] Eisenhofer, G and Peitzsch, M. Laboratory evaluation of pheochromocytoma and paraganglioma. Clin. Chem. 2014;60(12): 1486-99.

[9] Crona, J, et al. New perspectives on pheochromocytoma and paraganglioma: towards a molecular classification. Endocr. Rev. 2017; Aug 4 [Epub ahead of print].

[10] Corcuff, JB, et al. Urinary sampling for 5HIAA and metanephrines determination: revisiting the recommendations. Endocr. Connect. 2017;6(6): R87-R98.

[11] Du JY, et al. Percutaneous progesterone delivery via cream or gel application in postmenopausal women: a randomized cross-over study of progesterone levels in serum, whole blood, saliva, and capillary blood. Menopause. 2013;20(11): 1169-75.

[12] Drolet J, et al. Integrated Metabolomics Assessment of Human Dried Blood Spots and Urine Strips. Metabolites. 2017;7(3).

[13] Zava TT, et al. Iodine and creatinine testing in urine dried on filter paper. Anal Chim Acta. 2013;764: 64-9.